Ainaz Sourati · Ahmad Ameri

Mona Malekzadeh

Acute Side Effects of

Radiation Therapy

A Guide to Management

123
Acute Side Effects of Radiation Therapy
Ainaz Sourati • Ahmad Ameri
Mona Malekzadeh

Acute Side Effects of

Radiation Therapy
A Guide to Management
Ainaz Sourati Ahmad Ameri
Department of Clinical Oncology Department of Clinical Oncology
Imam Hossein Educational Hospital, Shahid Imam Hossein Educational Hospital, Shahid
Beheshti University of Medical Sciences Beheshti University of Medical Sciences
(SBMU), Shahid Madani Street (SBMU), Shahid Madani Street
Tehran Tehran
Iran Iran

Mona Malekzadeh
Department of Radiotherapy and Oncology
Shohadaye Tajrish Educational Hospital
Shahid Beheshti University of Medical
Sciences (SBMU)
Tehran
Iran

ISBN 978-3-319-55949-0    ISBN 978-3-319-55950-6 (eBook)

DOI 10.1007/978-3-319-55950-6

Library of Congress Control Number: 2017944188

© Springer International Publishing AG 2017

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To my dear mother who I will forever be
beholden to her.
To my loving husband, Arash, who I really
appreciate his support and endurance
through my most trying times.
Ainaz Sourati
To my love Zhila.
Ahmad Ameri
To my dear parents and my beloved son,
Hooman.
Mona Malekzadeh
Foreword

Dichotomies in medicine are common, but it is nowhere more clearly demonstrated

than in radiation exposure either used in diagnoses or in treatment as compared to
excessive or unwanted radiation exposure either locally or systematically. Other
dichotomies demonstrated in radiation injury include the separation between acute
and late radiation damage, locally applied as contrasted to systemic or total body
exposure, one or few radiation exposures vs. fractionated radiation exposures, and
use of preventive or ameliorating agents applied before exposure in contrast to post-­
exposure treatments. All of these are important to our understanding of the effective,
appropriate use of radiation as a treatment modality. This can only be ameliorated
by accurate information about the causes, frequency, severity, and prevention or
treatment of these radiation-associated conditions.
In the clinic, observed reactions to radiotherapy range from minor to serious and
from temporary to permanent. Physician concern for these potential debilitating
effects permeates the clinical practice of radiation and influences the selection of
treatments on a day-to-day basis. Optimal utilization of radiation as a cancer ther-
apy requires a clear understanding of the range of the major tissue sequela that can
occur, including the risk of occurrence, natural history, and their management. This
understanding leads to better clinical practice: greater confidence in recommending
aggressive radiation treatment programs when appropriate or selection of other
therapies when they are safer and equally effective.
Acute reactions of radiation therapy, the inflammatory reactions that occur as
part of normal tissue reaction to radiotherapy, are often considered as an expected
part of therapy, but they also may become debilitating to the patient during the treat-
ment course. Understanding of the mechanism, timing of occurrence, preventable
measures, and management of these side effects warrant discussion of their success-
ful management, including ways to facilitate more comfortable therapy course for
the patient.
In the era of multimodality therapy, it’s also important to understand the risk fac-
tors of radiation therapy when combined with other modalities, i.e., systemic che-
motherapy or biological agents. It is also important to realize the impact of other
modalities as sole cause of side effect or as a co-positive impact along with radia-
tion. Therefore, clinicians must be aware of these alternative possibilities and the
method diagonals and modify them.

vii
viii Foreword

In this volume, the clinician-scientists of Shahid Beheshti University and Dr.

Sourati and her associates have successfully provided to the readers the plethora of
these concerns in a comprehensive yet relatively straightforward and simple text for
day-to-day use of clinicians. Organ-specific effects are detailed as appropriate to
understanding, minimizing, and managing radiation injuries. I congratulate them in
their successful effort, and I am certain that many clinicians and their patients would
significantly benefit from the information provided by these authors.

Maywood, IL, USA Bahman Emami, MD, FACR, FASTRO, FACRO

Introduction

Cancer is one of the leading causes of death worldwide [1]. Currently, cancer
patients survive longer than they did more than two decades ago, and the population
living with cancer is increasing. Understanding more about cancer radiobiology and
major developments in radiation therapy technology play a critical role in increas-
ing the life expectancy of these patients. Radiation therapies are used with three
different concepts in cancer that are definitive, adjuvant, or palliative. It has been
estimated that more than 50% of all cancer patients receive radiation therapy
throughout the course of their disease [2]. With new technological advancements in
imaging and radiation delivery, radiation therapy has been possible for more com-
plicated cases, increasing the rate of radiation therapy in cancer treatments.
In addition to the tumor sterility and tumoricidal effects of radiation therapy,
radiation has the potential to affect normal tissues, which includes tissue damage in
radiation therapy fields or systemic side effects (e.g., hematologic side effects,
fatigue). Physicians try to lower radiation therapy side effects by defining smaller
targets and using more dedicated machines, but side effects continue to occur and
their spectrum and severity are changing. As these patients live longer, more atten-
tion is directed on their quality of life.
Radiation therapy side effects are divided into acute and late. Late side effects
occur 3 months after treatment completion, and acute side effects occur during
treatment or within 3 months after treatment.
Late side effects can develop without dose thresholds, which include stochastic
side effects, or with distinctive thresholds, which include deterministic side effects
(e.g., neurologic effects, cardiac effects). Deterministic late side effects are dose-­
limiting and can be the result of the healing process following severe acute side
effects. This kind of late side effects could be predictable, and efforts should be
made to protect normal tissues [3].
Acute side effects are a type of deterministic effects, which have distinctive
thresholds, and there is a direct relation with delivered dose and severity of resultant
damage. These effects usually cause no limit in treatment dose because they occur
in rapidly dividing cells, which have rapid cell repopulation; as a result, they are
reversible. The main point in acute side effects is necessary actions for prevention
and proper treatment in accordance with their severity to prevent radiation therapy
disruption because treatment disruption can affect treatment results, particularly in
tumors with rapid cell growth, which intensify cell growth inversely. Severe acute

ix
x Introduction

side effects can also result in consecutive late effects. Using new techniques in radi-
ation therapy (e.g., 3D-conformal radiation therapy, intensified modulated radiation
therapy, image-guided radiation therapy) reduces normal tissue dose and conse-
quently reduces treatment complications. However, the percentage of acute side
effects is still noticeable because the dose threshold in these side effects’ occurrence
is less than late side effects. Furthermore, in some treatments, it is necessary to
increase radiation dose to reach a definite complication (e.g., in locally advanced
breast cancer after radical mastectomy, enough radiation must be delivered to reach
dermatitis). We have to know the proper actions in approaching the complications
in order to inhibit unwanted treatment disruption. Acute side effects may increase
risk of late side effects, and prevention of these effects should be considered.
With respect to all points, acute side effects of radiation therapy are one of the
most important issues in the treatment of cancer patients. Approach and manage-
ment of these side effects are substantial to improve treatment results and increase
patient compliance with treatment. We attempt to assemble the most common of
these acute side effects in this book. In each part, we describe a summary of inci-
dence, mechanism, symptoms, grading, and management of distinct acute side
effects based on available evidence. Our main goal is gathering articles about each
acute side effect for convenient and practical use for all involved in the radiation
therapy process.

References

1. Stewart BW, Wild C (2014) World Cancer Report 2014. International Agency for Research on
Cancer. World Health Organization. 505
2. Slotman BJ, Cottier B, Bentzen SM, Heeren G, Lievens Y, Van den Bogaert W (2005) Overview
of national guidelines for infrastructure and staffing of radiotherapy. ESTRO-QUARTS: work
package 1. Radiother Oncol 75(3):349. E1–E6
3. ICRP (1977) Recommendations of the International Commission on Radiological Protection.
Ann ICRP. Sect. ICRP Publication 26
Contents

1 Radiation Dermatitis ���������������������������������������������������������������������������������� 1

1.1 Mechanism�������������������������������������������������������������������������������������������� 1
1.2 Timing�������������������������������������������������������������������������������������������������� 2
1.3 Sign and Symptoms������������������������������������������������������������������������������ 3
1.4 Scoring�������������������������������������������������������������������������������������������������� 4
1.5 Risk Factors������������������������������������������������������������������������������������������ 4
1.5.1 Treatment-Related Factors Including���������������������������������������� 4
1.5.2 Patient-Related Factors Include������������������������������������������������ 5
1.6 Diagnosis���������������������������������������������������������������������������������������������� 6
1.7 Prevention �������������������������������������������������������������������������������������������� 7
1.7.1 General Measures��������������������������������������������������������������������� 7
1.7.2 Intensity-Modulated Radiation Therapy (IMRT)���������������������� 8
1.7.3 Low-Level Laser Therapy�������������������������������������������������������� 8
1.7.4 Amifostine�������������������������������������������������������������������������������� 8
1.7.5 Ascorbic Acid��������������������������������������������������������������������������� 8
1.7.6 Oral Zinc ���������������������������������������������������������������������������������� 8
1.7.7 Silver Leaf Dressing ���������������������������������������������������������������� 9
1.7.8 MAS065D �������������������������������������������������������������������������������� 9
1.7.9 Soft Dressing or Barrier Film �������������������������������������������������� 9
1.7.10 Hyaluronic Acid������������������������������������������������������������������������ 9
1.7.11 Trolamine���������������������������������������������������������������������������������� 9
1.7.12 Topical Sucralfate ������������������������������������������������������������������ 10
1.7.13 Theta Cream���������������������������������������������������������������������������� 10
1.7.14 Dexpanthenol (Provitamin B5) ���������������������������������������������� 10
1.7.15 Calendula�������������������������������������������������������������������������������� 10
1.7.16 Pentoxifylline�������������������������������������������������������������������������� 10
1.7.17 Aloe Vera�������������������������������������������������������������������������������� 10
1.7.18 Deodorant�������������������������������������������������������������������������������� 11
1.7.19 Laughter Therapy�������������������������������������������������������������������� 11
1.8 Management���������������������������������������������������������������������������������������� 11
1.8.1 Grade 1 Dermatitis������������������������������������������������������������������ 11
1.8.2 Grade 2–3 Dermatitis�������������������������������������������������������������� 12
1.8.3 Grade 4 Dermatitis������������������������������������������������������������������ 13
References���������������������������������������������������������������������������������������������������� 13

xi
xii Contents

2 Hair Loss���������������������������������������������������������������������������������������������������� 21
2.1 Mechanism������������������������������������������������������������������������������������������ 22
2.2 Timing������������������������������������������������������������������������������������������������ 22
2.2.1 Risk Factors���������������������������������������������������������������������������� 22
2.2.2 Symptoms ������������������������������������������������������������������������������ 22
2.3 Scoring������������������������������������������������������������������������������������������������ 23
2.4 Prevention ������������������������������������������������������������������������������������������ 23
2.5 Management���������������������������������������������������������������������������������������� 24
References���������������������������������������������������������������������������������������������������� 24
3 Radiation Brain Injury������������������������������������������������������������������������������ 27
3.1 Mechanism������������������������������������������������������������������������������������������ 28
3.2 Timing������������������������������������������������������������������������������������������������ 28
3.3 Risk Factors���������������������������������������������������������������������������������������� 28
3.3.1 Treatment-Related Factors������������������������������������������������������ 28
3.3.2 Patient-Related Factor������������������������������������������������������������ 29
3.4 Symptoms ������������������������������������������������������������������������������������������ 29
3.5 Diagnosis�������������������������������������������������������������������������������������������� 30
3.6 Scoring������������������������������������������������������������������������������������������������ 31
3.7 Prevention and Management�������������������������������������������������������������� 31
3.7.1 Dexamethasone Prescription�������������������������������������������������� 32
References���������������������������������������������������������������������������������������������������� 33
4 Radiation Orbital Toxicity������������������������������������������������������������������������ 39
4.1 Blepharitis and Eyelid Dermatitis������������������������������������������������������ 40
4.2 Eyelash Loss �������������������������������������������������������������������������������������� 40
4.3 Conjunctivitis�������������������������������������������������������������������������������������� 40
4.4 Xerophthalmia������������������������������������������������������������������������������������ 41
4.5 Corneal Toxicity���������������������������������������������������������������������������������� 43
4.5.1 Treatment�������������������������������������������������������������������������������� 43
4.6 Iris Toxicity ���������������������������������������������������������������������������������������� 44
References���������������������������������������������������������������������������������������������������� 44
5 Ear Toxicity������������������������������������������������������������������������������������������������ 47
5.1 Mechanism������������������������������������������������������������������������������������������ 47
5.2 Timing������������������������������������������������������������������������������������������������ 48
5.3 Risk Factors���������������������������������������������������������������������������������������� 48
5.4 Symptoms and Diagnosis�������������������������������������������������������������������� 49
5.5 Scoring������������������������������������������������������������������������������������������������ 49
5.6 Management���������������������������������������������������������������������������������������� 50
References���������������������������������������������������������������������������������������������������� 51
6 Oral Mucositis�������������������������������������������������������������������������������������������� 53
6.1 Mechanism������������������������������������������������������������������������������������������ 53
6.2 Timing������������������������������������������������������������������������������������������������ 54
6.3 Risk Factors���������������������������������������������������������������������������������������� 55
6.3.1 Tumor Site������������������������������������������������������������������������������ 55
6.3.2 Concomitant Systemic Therapy���������������������������������������������� 55
Contents xiii

6.3.3 Radiation Dose������������������������������������������������������������������������ 55

6.3.4 Radiation Fractionation Schedule ������������������������������������������ 56
6.3.5 Patient-Related Factors ���������������������������������������������������������� 56
6.4 Symptoms ������������������������������������������������������������������������������������������ 57
6.5 Scoring������������������������������������������������������������������������������������������������ 58
6.6 Prevention ������������������������������������������������������������������������������������������ 59
6.6.1 Prophylactic Interventions������������������������������������������������������ 59
6.6.2 Prophylactic Intervention Under Evaluation�������������������������� 60
6.7 Management���������������������������������������������������������������������������������������� 63
6.7.1 Patient Assessment������������������������������������������������������������������ 63
6.7.2 Mouth Care ���������������������������������������������������������������������������� 64
6.7.3 Management of Oral Pain ������������������������������������������������������ 64
6.7.4 Antifungals������������������������������������������������������������������������������ 68
6.7.5 Antivirals�������������������������������������������������������������������������������� 68
6.7.6 Feeding Tube/Nutritional Support������������������������������������������ 69
References���������������������������������������������������������������������������������������������������� 69
7 Xerostomia�������������������������������������������������������������������������������������������������� 79
7.1 Mechanism������������������������������������������������������������������������������������������ 79
7.2 Timing������������������������������������������������������������������������������������������������ 81
7.3 Risk Factors���������������������������������������������������������������������������������������� 81
7.4 Symptoms ������������������������������������������������������������������������������������������ 82
7.5 Diagnosis�������������������������������������������������������������������������������������������� 83
7.6 Scoring������������������������������������������������������������������������������������������������ 83
7.7 Prevention ������������������������������������������������������������������������������������������ 84
7.7.1 Amifostin�������������������������������������������������������������������������������� 85
7.7.2  IMRT�������������������������������������������������������������������������������������� 86
7.7.3 Submandibular gland transfer ������������������������������������������������ 86
7.7.4 Pilocarpine ���������������������������������������������������������������������������� 87
7.7.5 Acupuncture���������������������������������������������������������������������������� 88
7.8 Management���������������������������������������������������������������������������������������� 89
7.8.1 Supportive Care���������������������������������������������������������������������� 89
7.8.2 Saliva Supplementation������������������������������������������������������������ 90
7.8.3 Acupuncture������������������������������������������������������������������������������ 89
7.8.4 Drugs���������������������������������������������������������������������������������������� 91
References���������������������������������������������������������������������������������������������������� 92
8 Loss of Taste����������������������������������������������������������������������������������������������� 97
8.1 Mechanism������������������������������������������������������������������������������������������ 97
8.2 Timing������������������������������������������������������������������������������������������������ 98
8.3 Risk Factors���������������������������������������������������������������������������������������� 99
8.4 Symptoms ������������������������������������������������������������������������������������������ 99
8.5 Diagnosis�������������������������������������������������������������������������������������������� 99
8.6 Scoring���������������������������������������������������������������������������������������������� 100
8.7 Prevention ���������������������������������������������������������������������������������������� 100
8.8 Management�������������������������������������������������������������������������������������� 100
References�������������������������������������������������������������������������������������������������� 102
xiv Contents

9 Laryngeal Edema ������������������������������������������������������������������������������������ 105

9.1 Mechanism���������������������������������������������������������������������������������������� 105
9.2 Timing���������������������������������������������������������������������������������������������� 105
9.3 Risk Factors�������������������������������������������������������������������������������������� 106
9.4 Symptoms ���������������������������������������������������������������������������������������� 106
9.5 Scoring���������������������������������������������������������������������������������������������� 106
9.6 Prevention ���������������������������������������������������������������������������������������� 107
9.7 Management�������������������������������������������������������������������������������������� 107
References ������������������������������������������������������������������������������������������������ 107
10 Radiation Pneumonitis���������������������������������������������������������������������������� 109
10.1 Mechanism�������������������������������������������������������������������������������������� 109
10.2 Timing�������������������������������������������������������������������������������������������� 110
10.3 Risk Factors������������������������������������������������������������������������������������ 110
10.3.1 Volume and Dose Parameters�������������������������������������������� 110
10.3.2 Fractionation Schedule������������������������������������������������������ 110
10.3.3 Chemotherapy/Hormone Therapy�������������������������������������� 111
10.3.4 Smoking ���������������������������������������������������������������������������� 111
10.3.5 Other Factors���������������������������������������������������������������������� 111
10.4 Symptoms �������������������������������������������������������������������������������������� 111
10.5 Diagnosis���������������������������������������������������������������������������������������� 112
10.6 Scoring�������������������������������������������������������������������������������������������� 112
10.7 Prevention �������������������������������������������������������������������������������������� 113
References�������������������������������������������������������������������������������������������������� 114
11 Pericarditis������������������������������������������������������������������������������������������������ 117
11.1 Mechanism�������������������������������������������������������������������������������������� 118
11.2 Timing�������������������������������������������������������������������������������������������� 118
11.3 Risk Factors������������������������������������������������������������������������������������ 118
11.4 Symptoms �������������������������������������������������������������������������������������� 119
11.5 Diagnosis���������������������������������������������������������������������������������������� 119
11.6 Scoring�������������������������������������������������������������������������������������������� 120
11.7 Prevention �������������������������������������������������������������������������������������� 121
11.8 Treatment���������������������������������������������������������������������������������������� 122
References�������������������������������������������������������������������������������������������������� 122
12 Esophagitis������������������������������������������������������������������������������������������������ 125
12.1 Mechanism�������������������������������������������������������������������������������������� 125
12.2 Timing�������������������������������������������������������������������������������������������� 125
12.3 Risk Factors������������������������������������������������������������������������������������ 126
12.4 Symptoms �������������������������������������������������������������������������������������� 127
12.5 Scoring�������������������������������������������������������������������������������������������� 127
12.6 Diagnosis���������������������������������������������������������������������������������������� 128
12.7 Prevention �������������������������������������������������������������������������������������� 128
12.8 Management������������������������������������������������������������������������������������ 128
References�������������������������������������������������������������������������������������������������� 129
Contents xv

13 Radiation Gastritis���������������������������������������������������������������������������������� 133

13.1 Mechanism�������������������������������������������������������������������������������������� 133
13.2 Risk Factors������������������������������������������������������������������������������������ 134
13.3 Timing�������������������������������������������������������������������������������������������� 134
13.4 Symptoms �������������������������������������������������������������������������������������� 135
13.5 Diagnosis���������������������������������������������������������������������������������������� 135
13.6 Prevention �������������������������������������������������������������������������������������� 135
13.7 Management������������������������������������������������������������������������������������ 135
References�������������������������������������������������������������������������������������������������� 136
14 Radiation-Induced Liver Disease ���������������������������������������������������������� 137
14.1 Mechanism�������������������������������������������������������������������������������������� 137
14.2 Risk Factors������������������������������������������������������������������������������������ 138
14.3 Timing�������������������������������������������������������������������������������������������� 138
14.4 Symptoms �������������������������������������������������������������������������������������� 139
14.5 Scoring�������������������������������������������������������������������������������������������� 139
14.6 Diagnosis���������������������������������������������������������������������������������������� 140
14.7 Prevention �������������������������������������������������������������������������������������� 140
14.8 Management������������������������������������������������������������������������������������ 141
References�������������������������������������������������������������������������������������������������� 142
15 Enteritis���������������������������������������������������������������������������������������������������� 145
15.1 Mechanism�������������������������������������������������������������������������������������� 145
15.2 Timing�������������������������������������������������������������������������������������������� 146
15.3 Risk Factors������������������������������������������������������������������������������������ 146
15.4 Symptoms and Diagnosis���������������������������������������������������������������� 147
15.5 Scoring�������������������������������������������������������������������������������������������� 147
15.6 Prevention �������������������������������������������������������������������������������������� 148
15.7 Management������������������������������������������������������������������������������������ 149
15.7.1 Dietary Modification�������������������������������������������������������� 150
15.7.2 Antidiarrheals�������������������������������������������������������������������� 150
15.8 Antispasmodics ������������������������������������������������������������������������������ 150
References�������������������������������������������������������������������������������������������������� 151
16 Radiation Cystitis������������������������������������������������������������������������������������ 155
16.1 Mechanism�������������������������������������������������������������������������������������� 155
16.2 Timing�������������������������������������������������������������������������������������������� 156
16.3 Risk Factors������������������������������������������������������������������������������������ 156
16.4 Symptoms and Diagnosis���������������������������������������������������������������� 157
16.5 Scoring�������������������������������������������������������������������������������������������� 157
16.6 Prevention �������������������������������������������������������������������������������������� 158
16.6.1 Bladder Sparing���������������������������������������������������������������� 158
16.6.2 Intravesical Instillation������������������������������������������������������ 158
16.7 Management������������������������������������������������������������������������������������ 158
16.7.1 Anticholinergics���������������������������������������������������������������� 159
16.7.2 Alpha-1 Blocker���������������������������������������������������������������� 159
16.7.3 Analgesics ������������������������������������������������������������������������ 160
16.7.4 Intravesical GAG�������������������������������������������������������������� 160
References�������������������������������������������������������������������������������������������������� 160
xvi Contents

17 Radiation Proctitis ���������������������������������������������������������������������������������� 165

17.1 Mechanism�������������������������������������������������������������������������������������� 165
17.2 Risk Factors������������������������������������������������������������������������������������ 165
17.3 Timing�������������������������������������������������������������������������������������������� 166
17.4 Symptoms �������������������������������������������������������������������������������������� 166
17.5 Scoring�������������������������������������������������������������������������������������������� 166
17.6 Prevention �������������������������������������������������������������������������������������� 167
17.7 Management������������������������������������������������������������������������������������ 168
References�������������������������������������������������������������������������������������������������� 169
18 Fatigue������������������������������������������������������������������������������������������������������ 173
18.1 Mechanism�������������������������������������������������������������������������������������� 173
18.2 Timing�������������������������������������������������������������������������������������������� 174
18.3 Risk Factors������������������������������������������������������������������������������������ 174
18.4 Symptoms �������������������������������������������������������������������������������������� 175
18.5 Diagnosis and Scoring�������������������������������������������������������������������� 176
18.6 Management������������������������������������������������������������������������������������ 178
18.6.1 Non-pharmacologic Interventions������������������������������������ 178
18.6.2 Exercise���������������������������������������������������������������������������� 179
18.6.3 Counseling and Education������������������������������������������������ 179
18.6.4 Optimize Sleep Quality���������������������������������������������������� 179
18.6.5 Complementary Therapies������������������������������������������������ 180
18.6.6 Other Psychosocial Interventions ������������������������������������ 180
18.6.7 Nutrition Counseling�������������������������������������������������������� 181
18.6.8 Pharmacologic Intervention���������������������������������������������� 181
References�������������������������������������������������������������������������������������������������� 182
19 Hematological Side Effects���������������������������������������������������������������������� 191
19.1 Mechanism�������������������������������������������������������������������������������������� 191
19.2 Timing�������������������������������������������������������������������������������������������� 192
19.3 Risk Factors������������������������������������������������������������������������������������ 193
19.4 Symptoms �������������������������������������������������������������������������������������� 193
19.5 Prevention �������������������������������������������������������������������������������������� 194
19.6 Treatment���������������������������������������������������������������������������������������� 195
19.6.1 Neutropenia���������������������������������������������������������������������� 195
19.6.2 Thrombocytopenia������������������������������������������������������������ 197
19.6.3 Anemia������������������������������������������������������������������������������ 198
References�������������������������������������������������������������������������������������������������� 199
20 Radiation-Induced Nausea and Vomiting (RINV)�������������������������������� 207
20.1 Mechanism�������������������������������������������������������������������������������������� 207
20.2 Timing�������������������������������������������������������������������������������������������� 208
20.3 Risk Factors������������������������������������������������������������������������������������ 208
20.4 Symptoms �������������������������������������������������������������������������������������� 208
20.5 Prevention and Management���������������������������������������������������������� 209
References�������������������������������������������������������������������������������������������������� 211
Index������������������������������������������������������������������������������������������������������������������ 213
Radiation Dermatitis
1

Anticancer properties of radiation were discovered by skin changes after exposure

to radiation; initially, radiation was used for the treatment of skin diseases such as
lupus erythematous. Skin cancer was the first cancer treated by radiation, and der-
matitis accompanies radiation therapy since its discovery.
Radiation dermatitis is one of the most common adverse effects of radiation
therapy. Approximately 90–95% [1, 2] of all patients treated with radiation ther-
apy will experience a skin reaction at the treated area. Radiation dermatitis is
especially seen in radiation therapy for breast cancer, head and neck cancer, lung
cancer, and sarcoma due to the superficial position of these cancers and higher
radiation doses to the skin. Various degrees of radiation dermatitis are experienced
by patients undergoing radiation therapy. In most patients, the radiation dermatitis
is mild to moderate (Grades 1 and 2); about 15–25% of patients experience severe
reactions [3–5].

1.1 Mechanism

Radiation to the skin results in direct cellular injury and inflammatory cell influx.
After the initial dose of radiation, cellular damage to epidermal basal cells, endothe-
lial cells, Langerhans cells, and vascular components occur, and an inflammatory
response in the epidermis and dermis develops following every subsequent fraction
of radiation [1].
Initial cellular injury results from short-lived free-radical production and irre-
versible double-stranded breaks in nuclear and mitochondrial DNA [6]. Clumping
of nuclear chromatin, swelling of the nucleus, nuclear disfiguration or loss of the
nuclear membrane, mitochondrial distortion, and degeneration of the endoplasmic

© Springer International Publishing AG 2017 1

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_1
2 1 Radiation Dermatitis

reticulum, as well as direct cellular necrosis and apoptosis, occur due to cellular
damage. Repetitive cellular damage caused from each fraction of treatment does not
allow time for cells to repair DNA damage [7–11].
Because of free-radical production, an inflammatory cytokine cascade is induced,
and several cytokines and chemokines are produced including interleukins 1 and 6,
tumor necrosis factor-α, and transforming growth factor-β [12]. These cytokines act
on the endothelial cells of local vessels, which express adhesion molecules consti-
tutively and induce migration of leukocytes and other immune cells from circulation
to irradiated skin [13].
Reduction and impairment of functional stem cells induced by radiation lead to
an alteration in the normal turnover of skin cells [6].
A prompt skin reaction may appear after exposure that is related to the inflamma-
tory response, release of histamine-like substances, permeability and dilation of capil-
laries, and subsequent dermal edema. It presents with early transient skin erythema
that can be seen within a few hours after radiation and subsides after 24–48 h [14].
After subsidence of initial erythema, the later phase includes additional edema,
an increased dilation in capillaries, and erythrocyte extravasation, which resulted in
an erythematous reaction. This phase is followed by thinning of the epidermis, dam-
age to epithelial cells, degeneration of glands, reduced secretion of sebum, and
sweat and clumps of exfoliated corneocytes (scales), which manifests as dry
desquamation.
If damage to the basal cells and glands is more severe, epidermal necrosis, fibrin-
ous exudates, and moist desquamation occur. The manifestation of moist desquama-
tion results from the formation of small blisters in and around the basal layer of the
epidermis that may also extend into the more superficial layers. The epidermis
sloughs when these blisters rupture and coalesce, denuding the dermis and causing
permanent epilation [15–17]. Finally, skin necrosis or ulceration of the full-­thickness
dermis may develop as the most severe damage of higher radiation doses [15, 16].

1.2 Timing

As noted above, a transient early erythema can be seen within a few hours of radia-
tion, even after a single fraction of radiation (2 Gy) and subsides after 24–48 h [14].
The main erythematous reaction appears at about the second to third week (within
1–4 weeks) of radiation. Earlier reaction can be seen in patients with particularly
sensitive skin. Effects typically continue to progress during treatment [18–20], and
subsequently dry desquamation can develop after the third week or after a cumula-
tive dose of 30 Gy, which is clinically characterized by dryness, scaling, and pruri-
tus. Following 4–5 weeks (45–60 Gy) of therapy, moist desquamation may occur,
which is characterized by serous oozing and exposure of the dermis [14]. Symptoms
persist for the duration of radiation therapy and peak 1–2 weeks after treatment
completion. At about 3–5 weeks after radiation, the skin begins to recover with
epidermal regeneration and within 1–3 months (depending on the severity of reac-
tion), complete healing occurs [1, 6, 18, 19, 21, 22]. Post-inflammatory
1.3 Sign and Symptoms 3

hyperpigmentation may persist for 5–7 weeks or even longer after radiation [20, 23].
Patient skin type may also influence timing and severity of radiation reactions,
reflected by interindividual variation in skin presentation of radiation damage.

1.3 Sign and Symptoms

Mild dermatitis (Grade I) presents with erythematous skin accompanied by mild

edema, pruritus, or pain. Dry, peeling skin (desquamation) and temporary epilation
due to involvement of adnexal structures may occur (Fig. 1.1).
Moderate dermatitis (Grades 2 and 3) consists of tender or edematous reactions
and moist desquamation (Fig. 1.2). The integrity of the dermis is impaired, and
secondary infection with Staphylococcus aureus may occur (Fig. 1.3).
Severe dermatitis (acute radionecrosis) is rarely seen and may occur in the set-
ting of very extensive superficial tumors treated with massive radiation doses over a
very short period. It manifests as a very painful inflammatory or hemorrhagic plaque
with deep necrosis, which can expose the muscles, tendons, and bones [19, 21, 22].

Fig. 1.1 Grade 1

dermatitis of neck after
radiation therapy for
laryngeal cancer

Fig. 1.2 Grade 2

dermatitis of neck after
radiotherapy for
nasopharyngeal cancer
with multiple node
involvement
4 1 Radiation Dermatitis

Fig. 1.3 Grade 3

dermatitis in
inframammary fold after
breast irradiation

Table 1.1 CTCAE v4.3 for dermatitis

Definition
Grade 1 Faint erythema or dry desquamation
Grade 2 Moderate to brisk erythema; patchy moist desquamation, mostly confined to skin
folds and creases; moderate edema
Grade 3 Moist desquamation in areas other than skin folds and creases; bleeding induced by
minor trauma or abrasion
Grade 4 Skin necrosis or ulceration of full-thickness dermis; spontaneous bleeding from
involved site

1.4 Scoring

The severity of radiation dermatitis is graded using several grading systems such as
Common Terminology Criteria for Adverse Event (NCI-CTCAE grading), Radiation
Therapy Oncology Group (RTOG) toxicity scoring system, and the Radiation-­
Induced Skin Reaction Assessment Scale (RISRAS).
Common Terminology Criteria for Adverse Event (NCI-CTCAE grading) is one of
the most commonly used, and NCI-CTCAE v4.3 has been shown in Table 1.1 [24].
RTOG scoring is quite similar to NCI-CTCAE grading.

1.5 Risk Factors

Treatment and patient-related factors may affect incidence and severity of

dermatitis.

1.5.1 Treatment-Related Factors Including

The higher total dose, higher dose per fraction, reduced overall treatment time,
beam energy (depend on type and quality of the beam), higher volume and surface
1.5 Risk Factors 5

area exposed, the junction between the electron and photon field, use of tissue
expander and bolus material [25–27], concurrent systemic therapy with radiation
(radiosensitizing drug such as paclitaxel, docetaxel, anthracyclines, dactinomycin,
methotrexate, 5-fluorouracil, hydroxyurea, bleomycin, and cetuximab) [6, 28] are
related to the development of radiation dermatitis.
Epidermal growth factor receptor (EGFR) is highly expressed in the epidermis,
particularly in the proliferative basal cell layers, and has a major role in the regula-
tion of multiple phases of epithelial biology, including cell cycle progression, dif-
ferentiation, cell movement, and cellular survival; it also has an essential impact on
the inflammatory reactions of the skin [29–31]. There is a reciprocal relationship
between radiation and epidermal growth factor receptor inhibitors’ (like cetuximab)
effects on skin.
More severe radiation dermatitis is seen in patients receiving cetuximab plus
radiation therapy than radiation therapy alone or even concurrent chemoradiother-
apy [5, 15]. There is a slightly longer duration of radiation dermatitis (11.1 versus
9.4 weeks) [32] and an earlier onset of radiation dermatitis (week 1 or 2 compared
with 3–5 weeks, respectively) [15], when cetuximab is added to radiation therapy.
Dermatitis usually reveals rapid recovery with no scarring following the end of
treatment of cetuximab plus radiation therapy [15]. A deferred cetuximab-induced
acne-like rash appears within irradiated fields in concurrent treatment of cetuximab
with radiation therapy (about 3–5 weeks after initiation of treatment versus
7–10 days, respectively). It seems that there is no significant relationship between
the severity of cetuximab-associated acne-like rash outside irradiated fields and the
severity of radiation dermatitis [32].

1.5.2 Patient-Related Factors Include

Demographic and behavioral factors, comorbid diseases, inherited disorders, and

site of radiation therapy can affect incidence and severity of radiation-induced der-
matitis [2, 33–41] (Table 1.2).

Table 1.2 Patient-related predisposing factors for radiation-induced dermatitis

Demographic and Site of radiation
behavioral factors Comorbid disease Inherited disorders therapy
Black race Actinic skin lesions Basal cell nevus Anterior neck
Obesity Seroma aspiration after disease Extremities
Female gender breast surgery Fanconi anemia Submammary
Advanced age Systemic lupus Bloom syndrome Skin folds
Breast implant erythematosus Xeroderma
Smoking Systemic sclerosis Pigmentosum
Poor nutrition Juvenile rheumatoid Ataxia-telangiectasia
arthritis
HIV infection
Diabetes mellitus
Hypertension
6 1 Radiation Dermatitis

Smoking seems to impair wound healing by cutaneous vasoconstriction [17].

The impact of increasing age on radiation dermatitis is related to decreased epi-
dermal turnover resulting in extended healing times. Coexisting diseases like hyper-
tension, diabetes, obesity, or malnutrition in older patients affect the severity and
resolution of radiation dermatitis [17].
It has been reported that aspiration of a seroma following breast surgery may
lead to damage to the lymphatic system, compromising wound healing and leading
to a severe skin reaction during radiation therapy [41].
Patients with systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis
(JRA), and systemic sclerosis have significantly greater radiosensitivity and are at
greater risk for developing radiation side effects. The presence of this connective tis-
sue disease is considered as a relative contraindication to radiation therapy [42, 43].
Wound healing is complicated in patients with uncontrolled diabetes mellitus
due to poor macrophage function including phagocytic activity, prolonged inflam-
matory phase, and greater risk of infection. Diabetes’ effect on normal tissue reac-
tion during radiation therapy needs further study [17].
There are a few rare genetic mutations that may predispose patients to severe
radiation dermatitis, including mutations in the ataxia-telangiectasia gene. It has
been suggested that unanticipated severe radiation dermatitis may indicate the pres-
ence of undetected genetic abnormalities in the ATM gene (ataxia-telangiectasia
mutated) that can predispose patients to cutaneous complications [44, 45].
No studies have specifically investigated the effect of hemoglobin level on nor-
mal skin exposed to radiation therapy.

1.6 Diagnosis

Acute radiation dermatitis is a clinical diagnosis based on the finding of skin changes
that shows a sharp demarcation of the skin changes and their limitation to the irradi-
ated areas and the history of radiation therapy and its duration. A skin biopsy is
usually not necessary for the diagnosis of radiation dermatitis [13].
Two important differential diagnoses of acute radiation dermatitis are radiation
recall and cellulitis. Radiation recall is an acute inflammatory skin reaction limited
to the area that was previously irradiated and occurs following cytotoxic agents or
other drug administration. It occurs at least 7 days after radiation therapy and may
occur weeks to years after radiation therapy [46–48]. Cytotoxic drugs such as
docetaxel, doxorubicin, and paclitaxel have been associated with radiation recall.
Radiation recall manifestations include a rash, dry desquamation, erythema, ulcer-
ation, hemorrhage, or even necrosis. Radiation recall generally resolves within
1–2 weeks after drug discontinuation. Patient’s history of skin reaction following
radiation treatment and medications will help to reach an accurate diagnosis [49].
Cellulitis is a bacterial infection of skin and subcutaneous tissues. It is character-
ized by localized erythema, warmth, swelling, pain, tenderness, fevers, and even
purulent drainage. These clues can differentiate cellulitis from radiation dermatitis.
However, radiation dermatitis is a predisposing factor of secondary cellulitis, and it
1.7 Prevention 7

may be possible for both conditions to exist together. In this condition a culture
from the wound may confirm the diagnosis of cellulitis. Empiric antibiotic treat-
ment may also be helpful in these patients [49].
Eczema is a chronic, relapsing, inflammatory skin condition that is diagnosed by
clinical presentation of symmetrical, pruritic, dry skin that persists for <6 months.
Chronic eczema may exacerbate radiation dermatitis as both conditions are inflam-
matory in nature. Eczema may be distinguished from radiation dermatitis by its
symmetrical distribution. In contrast, radiation dermatitis will only appear within
radiation fields [49].
Recurrent or secondary tumors should be considered if atypical plaques and nod-
ules develop within the radiation field. Although irradiated skin may present some
difficulty in healing, a biopsy is useful in this clinical situation.
Atopic dermatitis [49], lichen planus [50], pemphigus [51, 52], and dermato-
phyte infection [53] rarely occur in the site of radiation therapy that clinical course,
lesion distribution, and laboratory studies are helpful to distinguish from other
diagnoses.

1.7 Prevention

1.7.1 General Measures

General recommendations for skin care in patients that are treated with radiation
therapy include [13, 54]:

Washing the irradiated area daily with water and mild soap (pH-neutral agents) or
normal saline then dry it and use a water-based moisturizer.
Wearing loose-fitting clothes.
Avoiding skin irritants such as perfumes and alcohol-based lotions and wax or other
depilatory creams.
Avoiding extremes of heat and cold.
Avoiding sun exposure and use of sunscreen with a minimum SPF 30.

Currently, application of topical steroids is the only prophylactic intervention

for radiation dermatitis protection suggested with a high level of evidence [55,
56]. Prophylactic application of topical steroids can reduce the severity of radia-
tion skin reaction because of their anti-inflammatory effects (i.e., reducing the
production of IL-1, IL-2, IL6 IFN-γ, TNF, and histamine and inhibiting leukocyte
migration) [14, 57].
Low- to medium-potency topical corticosteroids (groups 4–6) such as mometa-
sone furoate 0.1% or hydrocortisone 1% cream or methylprednisolone aceponate
cream 0.1% or beclomethasone dipropionate spray are applied to the treatment field
once or twice daily after each radiotherapy treatment [13, 58–61].
Treatment should be stopped if there is any exudate from the affected area [54]
or if a skin infection is suspected.
8 1 Radiation Dermatitis

Other protective options with primarily positive results that warrant further
research on their efficacy in preventing and managing acute radiation dermatitis
include:

1.7.2 Intensity-Modulated Radiation Therapy (IMRT)

There is some evidence suggesting that IMRT significantly reduces the severity and
duration of radiation dermatitis compared with standard conventional technique
[62–64].

1.7.3 Low-Level Laser Therapy

Low-level laser therapy is a form of phototherapy that induces the wound-healing

process [65]. It has generated great interest in preventing radiation side effects such
as dermatitis, xerostomia, or oral mucositis. The primary promising results of these
trials warrant further research on its efficacy in preventing and managing acute radi-
ation dermatitis [66].

1.7.4 Amifostine

Amifostine is a thiol that selectively protects normal cells from radiation damage by
scavenging oxygen-derived free radicals. It has been shown that the severity of radi-
ation dermatitis is significantly lower among patients receiving amifostine [67–69].
Further studies are needed to determine the impact and safety of amifostine as a
cytoprotective agent against acute radiation dermatitis.

1.7.5 Ascorbic Acid

Ascorbic acid has antioxidant capacity and anti-free-radical action. No benefit of its
topical application has been found for radiation dermatitis protection. However, oral
ascorbic acid in breast cancer radiation therapy with a volume lower than 500 mL
and in those that received a radiation dose between 107% and 110% of the pre-
scribed dose showed positive results [70, 71].

1.7.6 Oral Zinc

Zinc (Zn) as an antioxidant has been evaluated in normal tissue protection studies
against radiation injuries. There are primarily positive results for dermatitis that
need further evaluation [72, 73].
1.7 Prevention 9

1.7.7 Silver Leaf Dressing

Silver leaf dressing has antimicrobial activity and is another option proposed for
radiation-induced dermatitis prevention. There are positive results about its efficacy
[74–76] that should be confirmed in further studies.

1.7.8 MAS065D

MAS065D (Xclair) is a nonsteroidal water-in-oil cream that contains hyaluronic

acid, shea butter (emollient), glycyrrhetinic acid (licorice extract with anti-­
inflammatory properties), Vitis vinifera (antioxidant activity), and telmesteine
(anti-­elastase and anti-collagen activity in vitro) [77]. MAS065D seems to be
effective in the management of radiation dermatitis, but further studies are neces-
sary [78, 79].
Oral proteolytic enzymes (e.g., products containing papain, bromelain, trypsin,
and chymotrypsin) seem to be effective in protection against radiation dermatitis,
and further evaluation is recommended [72, 80].

1.7.9 Soft Dressing or Barrier Film

It seems that prophylactic use of friction protections with soft dressing or barrier
film in areas at risk such as the axilla, head and neck region, perineum, and skin
folds could be an effective intervention for reducing skin reaction severity [81].
Other options without well-designed trial support include:

1.7.10 Hyaluronic Acid

Hyaluronic acid cream appears to reduce inflammatory response and oxidative free-­
radical damage and have been evaluated in radiation therapy studies as a preventive
method for radiation dermatitis. Additional studies are required to clarify hyaluronic
acid role as a preventive option in radiation dermatitis [82, 83].

1.7.11 Trolamine

A topically applied salicylates analgesic, this agent has been shown to promote
the wound-healing process by recruitment of macrophages and enhancement of
granulation tissue formation, which has therapeutic applications in dermatology.
Current evidence does not support the use of trolamine for radiation dermatitis
and requires more research to clarify its efficacy in prevention of radiation derma-
titis [84–87].
10 1 Radiation Dermatitis

1.7.12 Topical Sucralfate

Sucralfate is a topical drug that has been applied for the treatment of several types
of epithelial wounds such as ulcers, inflammatory dermatitis, mucositis, and burn
wounds. Some studies have evaluated the efficacy of sucralfate cream for preven-
tion of radiation dermatitis with differing results. Current data do not support it to
prevent radiation dermatitis [87–90].

1.7.13 Theta Cream

It contains glucan, Hydroxyprolisilane, and matrixyl with the immune system-­

modulating effects and tissue regeneration properties [91]. Evidence from a limited
number of randomized trials does not support theta cream in radiation dermatitis
prevention [92].

1.7.14 Dexpanthenol (Provitamin B5)

A stable alcohol form of pantothenic acid, dexpanthenol is converted in tissues to

pantothenic acid, which is essential to normal epithelial function and enhances skin
regeneration and wound healing [93–95]. Current evidence does not support the use
of dexpanthenol for radiation dermatitis [92].

1.7.15 Calendula

Fabricated from a plant of the marigold family Calendula officinalis, Calendula has
antioxidant and anti-inflammatory properties. Studies evaluating the efficacy of
calendula in management and prevention of radiation dermatitis have mixed results
that warrant further investigation [96, 97].

1.7.16 Pentoxifylline

A useful drug in a variety of vaso-occlusive disorders, pentoxifylline has ant-­

inflammatory properties. The pentoxifylline effects on acute skin reactions need to
be determined in well-designed studies [98, 99].

1.7.17 Aloe Vera

An ancient herbal remedy and natural product, there are mixed results of its efficacy
in radiation dermatitis protection that warrants more research before its extensive
usage is recommended [100, 101].
1.8 Management 11

1.7.18 Deodorant

Using deodorant did not demonstrate any effect on preventing radiation dermatitis
development [102, 103].

1.7.19 Laughter Therapy

Laughter therapy may have a beneficial role in preventing radiation dermatitis. To

confirm laughter therapy effect on radiation dermatitis, well-designed randomized
studies with large sample sizes are required [104].

1.8 Management

Patients should be visited at least weekly during their radiation therapy course with
regard of the skin reaction at each visit. The management of radiation dermatitis is
guided by the severity of skin damage.

1.8.1 Grade 1 Dermatitis

For most patients, general skin care measures seem to be sufficient for ameliorating
patient’s symptoms. Patients should be educated on washing their skin gently with
a mild soap (pH-neutral agents) or normal saline as a supportive care for erythema-
tous skin. Washing reduces bacterial load and risk for infection.
Dry desquamation is managed by moisturizing the area with a thin layer of non-­
scented, hydrophilic, lanolin-free ointment or cream (e.g., Eucerin, Lubriderm) 2–4
times daily [49]. Topical moisturizers can act as a skin bolus and increase the radia-
tion skin dose, so patients should be informed not to apply these products shortly
before radiation treatment.
Pruritus or irritation can be controlled with mid-potency topical corticosteroids.
Although there is insufficient information to support using topical corticosteroids
(corticosteroids Group IV and V) in radiation-induced dermatitis, most practitioner
is prescribing steroid for it. Topical steroid which is usually prescribed in radiation-­
induced dermatitis is listed in Table 1.3 [105].

Table 1.3 Topical corticosteroids used in radiation dermatitis

Group IV Group V
Fluocinolone acetonide 0.01–0.2% Fluticasone propionate 0.05%
Hydrocortisone valerate 0.2% Desonide 0.05%
Hydrocortisone butyrate 0.1% Fluocinolone acetonide 0.025%
Flurandrenolide 0.05%
Triamcinolone acetonide 0.1%
Mometasone furoate 0.1%
12 1 Radiation Dermatitis

Antihistamines do not seem to be effective in reducing pruritus related to radia-

tion dermatitis [13].
Normal saline compress is applied up to four times daily and may help patients
to clean their skin better and ameliorate symptoms related to inflammation. Patients
are instructed to moisten gauze with warm or room-temperature saline solution and
apply moist gauze to the affected area for 10–15 min. The gauze is removed and the
wound is gently irrigated with normal saline and dried [54].

1.8.2 Grade 2–3 Dermatitis

In Grades 2 and 3 radiation dermatitis, in addition to general skin care measures, a

number of topical applications can be helpful to reduce symptoms.
Patients with moist desquamation are at increased risk of infection and should be
monitored for purulent drainage and fevers.
Moist desquamation typically is managed by wound dressings that provide the
ideal moist wound-healing environment allowing for faster reepithelization,
phagocytosis of bacteria, extracellular debris, and necrotic material, absorbing
wound secretions, diminishing pain, and protecting the wound from contamination
[6, 7, 106].
Dressings should be comfortable to increase patient compliance for prolonged
use. They should also be able to absorb large amounts of serous leakage from the
wound to prevent maceration of the surrounding healthy skin and must be removed
without disturbing granulation and new tissue.
Various forms of dressings are available in clinical practice with no sufficient
evidence to support particular types in the management of moist desquamation
[13, 75, 107, 108]. Simple dressings alone are not recommended, due to the pain
and trauma caused at dressing changes [41]. Hydrocolloids or hydrogels dressings
have a traditional interest in the use of moist desquamation. However, a recent
study that compared hydrogel versus dry dressing on healing time of moist desqua-
mation found that healing time was significantly prolonged in the hydrogel group
dressings without any improvement in patient comfort [109]. A new range of sili-
cone foam skin dressings (e.g., Mepilex Lite) is currently available commercially
with promising primary results [110].
Patients should be instructed to place normal saline compresses several times a
day, applying a dressing after cleaning the wound and changing dressings frequently
depending upon the severity of weeping.
When infection occurs, treatment should be done with topical and/or systemic
antibiotics. Silver-based dressings are antibacterial and have proven to be effective for
this purpose. Beta glucan or silver sulfadiazine cream may also be useful (but should
only be applied after radiation therapy and after cleaning the irradiated area; caution
use in patients with severe renal and hepatic impairment and patients with G6PD
deficiency) [111]. In patients treated with concomitant chemotherapy or at increased
risk of developing neutropenia, complete blood count should be checked. In patients
with neutropenia or signs of sepsis, blood cultures should be obtained [15].
References 13

Nonsteroidal anti-inflammatory drugs can often be effective for pain manage-

ment and can also relieve the discomfort associated with itching and swelling
around the skin reaction.
Treatment interruption may be needed in Grade 3 radiation dermatitis depending
on patient performance status, presence of sepsis or severe neutropenia, and the
radiation oncologist’s judgment [13].
Biologic preparations are investigated in some types of radiation dermatitis
including the use of calcineurin inhibitors (e.g., pimecrolimus cream or tacrolimus
ointment) for radiation dermatitis in patients receiving cetuximab [15] or topical
granulocyte-macrophage colony stimulating for vulvar radiation dermatitis [112].
The effects of foam dressing with human recombinant human epidermal growth
factor (rhEGF) [68] and granulocyte-colony stimulating factor (G-CSF) subcutane-
ously administered at the periphery of the wound [113] has been proposed in radia-
tion dermatitis with moist desquamation. Further studies are required to evaluate
optimal dosage, treatment scheduling, and confirming the mechanism of action of
these agents.
Lianbai liquid is a Chinese remedy that has been reported to be effective in the
treatment of Grade III acute radiation dermatitis and needs further evaluation [114].

1.8.3 Grade 4 Dermatitis

Grade 4 radiodermatitis is a rare complication. Surgical interventions are the treat-

ment backbone. This grade should be treated with discontinuation of radiation ther-
apy and surgical debridement, full-thickness skin graft, or myocutaneous or pedicle
flaps [13].

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Hair Loss
2

Whenever the skin is irradiated, hair loss may occur as a side effect. Because hair
loss of scalp induced by radiation of brain or head and neck cancer has a significant
importance due to its effect on appearance (Fig. 2.1), we focus on scalp hair loss in
this chapter.
Hair loss may be a temporary or permanent radiation side effect depending
on radiation dose [1]. Temporary hair loss is typically observed in all patients
undergoing whole-brain radiation therapy [2, 3]. Temporary hair loss with some
areas of permanent alopecia is one of the common complications (more than 10
out of 100), in patients with primary brain tumors treated with cranial radiation
therapy [4]. Permanent hair loss occurs in 50% of patients with the follicle dose
of 43.0 Gy [5].

Fig. 2.1 Hair loss at

posterior scalp after
radiation therapy for
sinonasal tumor that
exposed to exit dose of
antro-posterior radiation
beam

© Springer International Publishing AG 2017 21

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_2
22 2 Hair Loss

2.1 Mechanism

Radiation-induced hair loss is due to high susceptibility of anagen follicles to

radiation.
Hair follicles are located approximately 3–5 mm below the scalp [6]. Hair growth
has a cyclical process [7]. The three phases during the hair life cycle are anagen
(active phase), catagen (transitional phase), and telogen (resting phase). Most hairs
are normally in the anagen phase. During this phase, the bulb matrix cells are rap-
idly proliferating with high mitotic activity [8–10]. Any acute damage to actively
dividing matrix cells of anagen follicles leads to abrupt loss of hairs called anagen
effluvium. Chemotherapy and radiation therapy are common causes of anagen
effluvium [8, 9, 11, 12].
Ionizing radiation primarily targets DNA and leads to double-strand DNA breaks
[13, 14]. Radiation-induced DNA damage of hair follicular matrix cells causes apop-
tosis with increase in tumor-suppressor protein p53 levels in the matrix cells [15, 16].

2.2 Timing

Hair shedding may start as soon as 1–3 weeks after the first dose of radiation [17].
The hair follicle resumes normal cycling within a few weeks of treatment cessation
[9] and usually resolves within 2–3 months after completion of radiation therapy [5].
Regrowth of hair may be sparser with different thickness or texture after treatment.

2.2.1 Risk Factors

Radiation dose is the most significant factor-related radiation-induced alopecia.

Temporary alopecia can be detected after doses of about 2 Gy [18]. Permanent alo-
pecia has been reported in a range of 0–80% (median risk 5%) of patients with dose
of 36 Gy (2 Gy/fraction, 5 d/wk) and of 5–100% (median 15%) of patients with a
dose of 45 Gy. Permanent alopecia occurs with a 7 Gy single-fraction dose [5].
Lower-beam energies, use of multiple overlapping beams, or use of fixation mate-
rials with high thicknesses can increase the risk of radiation-induced alopecia [5].
Previous or concomitant chemotherapy (alkylating agents most commonly
reported) increase the risk of radiation-induced alopecia [5, 19].
Patients with personal history of alopecia may have a trend of developing perma-
nent alopecia. Patient’s age, family history of baldness, gender, tobacco use, and
diabetes have not reported to correlate with alopecia [5].

2.2.2 Symptoms

Radiation therapy will generally cause alopecia limited to the treated area but may
also occur in the adjacent area due to beam penumbra or at existing areas of the
radiation beam.
2.4 Prevention 23

Table 2.1 CTCAE hair loss scoring

Definition
Score 1 Hair loss of <50% of normal for that individual that is not obvious from distance but
only on close inspection; a different hairstyle may be required to cover the hair loss,
but it does not require a wig or hairpiece to camouflage
Score 2 Hair loss of ≥50% normal for that individual that is readily apparent to others; a wig
or hairpiece is necessary if the patient desires to completely camouflage the hair loss;
associated with psychosocial impact

After hair loss, scalp is sensitive to radiation damage and radiation dermatitis
may occur (see Chap. 1).

2.3 Scoring

Common Terminology Criteria for Adverse Events (CTCAE) v4.0 has defined two
scores for hair loss of scalp (Table 2.1) [20].

2.4 Prevention

It has been shown that patients affected by hair loss have a poorer quality of life,
lower self-esteem, and heightened self-consciousness [21, 22]. Novel strategies to
decrease radiation-induced alopecia have been proposed. New radiation delivery
techniques such as intensity-modulated radiation therapy (IMRT) or volumetrically
modulated arc therapy (VMAT) for whole-brain radiation therapy (WBRT) are
being evaluated to reduce the dose to the hair follicles [3, 23–25]. Primary results of
these techniques are promising, which warrant further investigation.
Tempol, formally 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl, is a
membrane-­permeable radical scavenger. Both the preclinical and clinical studies
showed that topical application of tempol may be effective at preventing radiation-­
induced alopecia [26–28]. Larger studies are needed to evaluate its efficacy and
safety in clinical practice.
Antioxidant compounds such as glutathione, lipoic acid, and antioxidant vitamins
A, C, and E could act as natural radioprotectors and reduce the toxicity of radiation
therapy. But possible tumor-protective effects of these nonselective free-­radical scav-
engers are matters of great concern. Topical application of these antioxidants has been
tested to reduce systemic absorption and subsequent tumor protection, but this does
not seem to be able to eliminate the tumor-protective effect. Additional studies need
to determine the safety of using these agents during radiation therapy [29].
Base on preclinical studies, systemic and topical application of prostaglandin E2,
systemic administration of vitamin D3, topically applied vasoconstrictors, subcuta-
neously applied keratinocyte growth factor, Panax ginseng administration, and caf-
feine may protect hair follicles from radiation toxicity [30–34]. Further clinical
trials should be conducted to prove the preventive effect of these agents on radiation-­
induced alopecia.
24 2 Hair Loss

2.5 Management

General recommendations during treatment may be helpful for the patient to mini-
mize scalp reaction including avoiding excessively hair combing, hair color and hair
styling products, hair dryers, using baby shampoo or other mild shampoo and hair
conditioner without any perfumes, and cutting hair to medium to short lengths [35].
Reconstructive surgery options can be considered in selective patients with post-
radiation therapy and permanent alopecia based on alopecia area, size, patient’s age,
and prognosis [36].
Botulinum toxin type A (BTXA) is used successfully to treat radiation-induced
alopecia in a case report, which warrants more studies to identify the mechanisms
and efficacy of BTXA [37].
There are no reports about other hair loss treatments such as minoxidil or low-­
level laser therapy in the setting of radiation-induced hair loss.

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Radiation Brain Injury
3

Cranial irradiation has an important role in the treatment of brain tumors either
with curative intent or for palliation. Cranial irradiation has a unique application
in prevention of distant metastasis to brain parenchyma, and prophylactic cranial
irradiation may be carried out in selected patients at high risk of neoplastic cranial
involvement. Brain is also an organ at risk during radiotherapy of tumors which
are located in base of skull and in some head and neck cancers. Cranial irradiation
in any condition can cause brain injuries that are classified into three groups based
on the timing of their occurrence after radiation exposure: acute (during radiation
or up to 6 weeks after radiation), early delayed or subacute (up to 6 months after
radiation), and late delayed (6 months or more after the completion of radiation).
However in more trials, brain injury simply is defined as acute (within 90 days of
the commencement of therapy) and late reactions (after 90 days of the commence-
ment of therapy) [1]. Reports indicate that patients that undergo standard fraction-
ated cranial irradiation and stereotactic radiosurgery may have acute brain
reactions in the range of 2–40% [1–12]. However, up to 50% of patients with high
doses per fraction (more than 3 Gy) to a large part of the brain may develop acute
encephalopathy [3, 13].
Early-delayed reactions may present with worsening of primary symptoms or
radiation somnolence syndrome (SS), which has been observed mainly after pro-
phylactic radiation therapy for leukemia in children, with a mean incidence of 50%
(in the range of 10–79% of these patients) [14–20].
It is important to differentiate brain tumor progression from radiation-induced
acute injury. Pseudoprogression is defined as radiologic abnormality in postirradia-
tion imaging because of radiation-induced injury that mimics tumor recurrence.
Pseudoprogression occurs a few weeks up to 3–6 months after radiation therapy
that is coincidental with early-delayed radiation reaction. The majority of patients
with pseudoprogression are asymptomatic, but it can present with worsening of
primary symptoms, transient cognitive decline, or somnolence syndrome [21].
Pseudoprogression incidence varies from 9% in patients treated with radiation

© Springer International Publishing AG 2017 27

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_3
28 3 Radiation Brain Injury

therapy alone to 32% in patients undergoing chemoradiotherapy [22, 23].

Somnolence syndrome may develop in adults as a subacute reaction [24, 25] but
have not been uniformly investigated.

3.1 Mechanism

Cranial irradiation causes vascular and cellular injuries. Endothelial cell damage,
vasodilation, increased in blood-brain barrier permeability, cerebral edema, and
consequent rise in intracranial pressure occur in early phase [3]. Oligodendrocytes
are extremely sensitive to radiation. Subacute reactions are thought to be a result of
oligodendrocyte depletion and transient demyelination [26, 27].

3.2 Timing

Brain edema could begin a few hours after the first treatment with a single dose of
2 Gy to a portion of the brain [28]. Symptoms of increased intracranial pressure or
worsening of primary neurologic symptoms can occur and progress with additional
fractions. With doses up to approximately 60 Gy, symptoms are usually mild and
transient [29, 30].
Subacute reaction (somnolence syndrome, cognitive dysfunction, transient neu-
rologic deficit) usually begins 4–8 weeks after treatment completion. The symp-
toms last from a few days to 6 weeks [14, 24, 31] and spontaneously subside over
few weeks to months [20]; however, somnolence syndrome can cause long-term
neurologic dysfunction [32].

3.3 Risk Factors

3.3.1 Treatment-Related Factors

Radiation therapy: Type of fractionation and fraction size, total dose [33], and field
size [34] are important in the severity of acute brain toxicity. There are more acute
cranial complications in the rapid course of radiation therapy with higher doses per
fraction [5, 35] or multiple daily fractionated radiation therapy [1]. Risk of SS may
be associated with the total dose of radiation [14] and fraction size [14, 18], but
these results need further studies to be better defined [19, 36].
Combined treatment: Combination of surgery [7, 11] or radiosurgery [10] with
fractionated radiation therapy seems to not significantly increase the acute compli-
cation, although surgery type (biopsy versus partial/total resection) may be a signifi-
cant variable to predict the occurrence of acute brain toxicities [1]. Chemotherapy
or radiation sensitizers during cranial irradiation are well tolerated without signifi-
cantly increasing in acute brain toxicity [37–42]. No significant difference has been
reported in the incidence of SS between patients that received radiation alone and
3.4 Symptoms 29

those that received irradiation and intrathecal methotrexate [15]. An obvious

increase in pseudoprogression rate occurs in patients that are treated with chemo-
therapy and radiation therapy versus radiation therapy alone.

3.3.2 Patient-Related Factor

Age over 50, functional status, neurological function, and mental status have not
been reported to be important in the occurrence of acute brain reactions [1].
Somnolence syndrome has not been related to patient factors such as age, initial
white blood count [14], and anatomical site or histological type of brain tumor [43].
Glioblastoma patients with promoter methylation of the repair enzyme
06-­methylguanine-DNA methyltransferase (MGMT) are at a higher risk of tumor
pseudoprogression [23].

3.4 Symptoms

In the acute phase, all presenting symptoms are related to increased intracranial
pressure including headache, nausea, vomiting, and mental status changes or an
exacerbation of the symptoms or signs caused by the lesion being treated [44].
These symptoms can be controlled with medication and are transient with conven-
tional fractionation (1.8–2 Gy/day given five times per week) to a total dose of
60 Gy to the whole brain or even higher doses to limited volumes [44]. However, in
very few patients with higher doses per fraction (more than 3 Gy) to a large area of
brain and in patients with significant pretreatment elevated intracranial pressure,
cerebral herniation may occur.
Imaging including computed tomography (CT) scan or MRI in acute radiation
brain injury is usually unremarkable and could differ from no clear changes to dif-
fuse brain swelling (Fig. 3.1) [45].
Somnolence is referred to as excessive drowsiness or sleep [15, 46]. The
somnolence syndrome is a collection of symptoms that consists of drowsiness,
lethargy, fatigue, anorexia, headache, dysphagia, dysarthria, nausea, and vomit-
ing and is sometimes associated with low-grade fever [36, 47–50]. Brain MRI
may demonstrate nonspecific white matter hyperintensity [51]. The cerebral spi-
nal fluid (CSF) analysis of these patients shows increased levels of protein and
pleocytosis [17], and electroencephalogram (EEG) shows diffuse generalized
slowing in electrocortical activity more than expected for all children that
receive cranial radiation [52].
Somnolence syndrome in adults may manifest with some different symptoms
from pediatric patients due to much greater dosage of radiation therapy applied in
adults [47]. A transient worsening in primary symptoms (e.g., epileptic seizure,
increased paralysis, etc.) can develop in addition to other classic symptoms of som-
nolence syndrome [47]. These symptoms may be severe enough to need supportive
treatment and steroid administration [24]. A transient cognitive dysfunction may
30 3 Radiation Brain Injury

Fig. 3.1 Increased edema in a patient that treated with radiation therapy for glioblastoma multi-
form. (a) Before starting of radiation therapy, (b) 6 weeks after completion of radiation therapy

occur during 6–8 weeks after the end of radiation therapy [53]. MRI findings in the
postradiation phase can vary from non-enhancing white matter hyperintensities on
T2-weighted imaging, indicative of edema, to an increased size of contrast-­
enhancing lesions within or near the irradiated tumor volume due to radiation-­
induced endothelial damage and blood-brain barrier disruption [22, 45].

3.5 Diagnosis

The diagnosis of acute brain reactions is based on clinical picture and response
assessment to steroid treatment.
Somnolence syndrome is characterized by excessive drowsiness or sleep accom-
panied by signs of elevated intracranial pressure such as headache, anorexia or nau-
sea, and vomiting. It is diagnosed based on a group of symptoms that starts
4–8 weeks after radiation therapy, especially in children.
In patients with clinical deterioration after brain radiation therapy, distin-
guishing between tumor progression and radiation reaction is challenging.
Imaging cannot help in this regard unless in new lesions appear outside the
radiation field. Symptoms related to treatment injury usually respond to escalat-
ing or starting steroid treatment. Patients closely follow-up and reimaging at
approximately 4-week intervals are a logical approach in these patients [30, 54].
Biopsy is an invasive action with confounding results and is not recommended
in this setting. The value of metabolic imaging like positron emission tomogra-
phy (PET) scan in this situation is unclear [55]. New functional MRI techniques
such as magnetic resonance spectroscopy or diffusion-weighted and perfusion
seem to be promising [56]. Further investigations are needed before they are
incorporated into widespread use.
3.7 Prevention and Management 31

Table 3.1 RTOG/EROTC radiation-induced brain injury grading [57]

Definition
Grade 1 Fully functional status (i.e., able to work) with minor neurologic findings, no
medication needed
Grade 2 Neurologic findings present sufficient to require home case/nursing assistance may
be required/medications including steroids/antiseizure agents may be required
Grade 3 Neurologic findings requiring hospitalization for initial management
Grade 4 Serious neurologic impairment which includes paralysis, coma, or seizures >3 per
week despite medication/hospitalization required

Table 3.2 Somnolence syndrome scale of Littman

Definition
None No evidence of change in behavior
Minimal Disturbance with some tiredness but activity not curtailed
Mild Decreased activity and increased tiredness, may have a low-grade pyrexia
Moderate Sleeping much of the day, decreased appetite, low-grade fever, most activities
curtailed
Severe Inactive, sleeping 18–20 h per day, low-grade fever, markedly decreased appetite,
and only taking oral fluids

3.6 Scoring

Different scoring systems have been defined for radiation-induced injury. Two of
them (RTOG/EORTC and Littman SS scale) are given in Tables 3.1 and 3.2.
Somnolence symptoms may be assessed by a patient-completed daily diary in
which main symptoms like drowsiness, sleep, fatigue, lethargy, mental concentra-
tion, or appetite are scored by patients with visual analogue scales consisting of
100 mm long with opposing sensations [58]. Littman et al. [19] provided an
observer-based scale (Table 3.2).

3.7 Prevention and Management

It has been recommended that pre-radiation corticosteroid administration should be

considered in patients with significant peritumoral brain edema and who have
symptomatic brain edema. Asymptomatic patients with minimal brain edema could
be spared from pretreatment corticosteroids [59, 60].
A short course of corticosteroids may be helpful in patients with acute and sub-
acute brain reaction to the irradiation.
Corticosteroids usually resolve the symptoms of somnolence syndrome; how-
ever, optimal steroid schedule for its management is still unknown [61]. The preven-
tive effect of steroids [31, 36, 43] and antidepressants [62] to reduce the incidence
of SS has been proposed. These results are needed to be tested in further studies
before conclusion.
32 3 Radiation Brain Injury

Dexamethasone is the drug of choice between steroids due to its long half-life,
low mineralocorticoid activity, and a relatively low effect on cognition [63].
Dexamethasone causes general improvement in patient condition within 4–6 h [64,
65], and neurological improvement occurred within 24–72 h in majority of patients
[66]; however, the pressure may not be consistently reduced until 2–4 days after
initial dosing [67].

3.7.1 Dexamethasone Prescription

Prophylactic:
Dexamethasone (oral or parenteral): 4–16 mg daily for the first 2 weeks of radiation
therapy [51, 59].
Therapeutic:
10 mg IV stat then 4 mg IM/IV every 6 h [51]

Corticosteroids have rapid and complete gastrointestinal absorption, and oral and
parenteral dosing is equivalent. Parenteral therapy should be converted to oral ther-
apy at the earliest appropriate opportunity [68].
The dose can be divided over 4 doses, but owing to its biologic half-life (about
36–54 h), dosing once or twice a day would be a rational practice [69].
Based on UptoDate “if dexamethasone dose of 16 mg is insufficient, the dose can
be increased up to 100 mg per day.”
A proton pomp inhibitor like omeprazole should be coadministered for gastric
protection with concomitant use of NSAIDs or bisphosphonates in the immediate
postoperative period, in those patients receiving unusually high doses of corticoste-
roids or previous history of gastrointestinal bleeding [70].
Some guidelines recommend Pneumocystis carinii prophylaxis with trimethoprim-­
sulfamethoxazole in patients with dexamethasone treatment during concomitant
chemoradiation therapy [63, 71].
In patients with diabetic mellitus, additional medications during steroid therapy
need to be increased based on blood glucose levels.
Higher doses of dexamethasone may be needed to control brain edema in patients
with anticonvulsants (e.g., phenytoin, carbamazepine and phenobarbital), due to
their ability to induce hepatic microsomes [70, 72]. In addition, serum phenytoin
concentration may be interfered with by steroids [73].
After maximal clinical improvement, dexamethasone dose is reduced to the low-
est effective dose and after the completion of radiation therapy is tapered over
2–4 weeks and discontinued [59, 74]. A gradual tapering of dexamethasone should
be considered because dexamethasone doses used in brain tumor patients can sup-
press the hypothalamic-pituitary-adrenocortical axis when it is given for more than
2 weeks. More importantly, gradual discontinuation of dexamethasone can prevent
rebound edema and recurrence of symptoms that may occur even with less than
14 days of treatment [68]. With less than 5–7 days of steroid use, treatment can usu-
ally be abruptly discontinued [75].
References 33

There are various steroid tapering guidelines in cancer patients. Guidelines for
use of steroids in cancer patients recommend that steroids be discontinued abruptly
if less than 4 mg per day of dexamethasone has been used for less than 3 weeks;
otherwise, a gradual tapering is indicated [76]. BC Cancer Agency Cancer
Management Guidelines for dexamethasone tapering recommends reducing by
4 mg every 5 days [71]. With any symptoms returning or worsening during tapering,
the dexamethasone should be return to the previous dose [77].
Because of the corticosteroid complications, other agents that can reduce vaso-
genic brain edema without corticosteroid side effects are under investigation.
Corticorelin acetate (a synthetic peptide formulation of the normal endogenous
human corticotropin-releasing factor) [78–81], vascular endothelial growth factor
(VEGF) receptor, tyrosine kinase inhibitors such as cediranib or monoclonal anti-
bodies (e.g., Bevacizumab [82, 83], and selective COX-2 inhibitors [84] are some of
these medications.

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Radiation Orbital Toxicity
4

The orbit contains the globe and connective tissues including extraocular muscles,
orbital fat, eyelids, eyelashes, lacrimal gland, and lacrimal draining system. Different
parts of the globe (e.g., the lens, iris, conjunctiva, sclera, retina, ciliary body, cornea,
and optic nerve) have different sensitivities to irradiation. Some structures like the
optic nerve respond to radiation in a chronic manner (late-responding tissue), and
some like the conjunctiva and eyelids are acute-responding tissues. Some parts of
the mentioned structures are very sensitive, and some of them like the lens and
sclera are very resistant to radiation. The orbital area may be irradiated as the treat-
ment target or as an organ at risk in the vicinity of the target. Radiation-induced
acute side effects in this area require prompt attention to prevent long-term issues
like ophthalmitis, permanent dry eyes, and impaired visual acuity. In this chapter,
we will focus on more sensitive acute-responding tissues.
Most of the acute side effects of orbital radiation therapy have a mild severity,
and there is often no need for treatment break [1–10]. These acute side effects (e.g.,
dry eyes, excessive tearing, conjunctivitis, transient periorbital erythema, and
edema) have been reported in 30–50% of patients based on volume of the area
within the radiation field [2, 3, 10–13]. Based on animal studies, the acute side
effects of orbital radiation therapy in decreasing frequency include conjunctivitis,
blepharitis, keratoconjunctivitis sicca, keratitis, and ulcerative keratitis [14].
The orbit is a small area that compared with its size, consists of a collection of
many different structures as mentioned above. Each orbital structure has varying
sensitivity to radiation effects and different signs and symptoms will develop at dif-
ferent times during radiation therapy. Here, the acute radiation effects will be
reviewed for different orbital structures separately in each section.

© Springer International Publishing AG 2017 39

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_4
40 4 Radiation Orbital Toxicity

4.1 Blepharitis and Eyelid Dermatitis

The eyelid is a thin fold of skin and its response to radiation is more than skin at
other sites. It also contains hair follicles in its free edge that are sensitive to radia-
tion. Radiation blepharitis (eyelid edge inflammation), as a radiation dermatitis,
begins with erythema followed by dry and moist desquamation (and rarely necro-
sis). Erythema takes approximately 2–4 weeks to develop after radiation exposure;
it is usually transient and disappears rapidly. Moist desquamation of skin can
develop after 5–6 weeks of radiation therapy (50–60 Gy in 1.8–2.2 Gy daily frac-
tions). Healing is typically slow and may take up to 6–12 weeks [15, 16].
The following guidelines will provide comfort and healing of the periocular skin
radiation-induced dermatitis and blepharitis [17]:

• Washing the eyelids with lukewarm water and mild soap and gently drying at
least once daily.
• Applying an eyelid moisturizer, black tea soaks (soak tea bags in hot water, allow
them to cool, lie down, and put them over the eyes).
• Avoiding extremes of heat and cold, skin irritants, and any eyelid rubbing or
scratching friction.
• More severe dermatitis in eyelid skin may need a radiation break and should be
treated like a skin burn using silver sulfadiazine ointment or similar medications.

4.2 Eyelash Loss

Loss of the eyelashes may occur (Fig. 4.1) with doses more than 10–20 Gy (1.5–2 Gy
per fraction) [16, 18]. It may be temporary and regrowth after approximately
2 months [15] or may be permanent at radiation doses of more than 30 Gy [16].
Eyelash loss can result in irritation of the conjunctiva and cornea due to loss of
the protective blink reflex. These complications are discussed below.

4.3 Conjunctivitis

Signs and symptoms of radiation-induced conjunctivitis include conjunctival injec-

tion, watery discharge, and discomfort that occur 1–3 weeks after the start of radia-
tion treatment. Acute conjunctivitis is common with doses ≥30 Gy [11, 19].
Secondary infectious conjunctivitis (mostly bacterial or rarely viral) may also occur
[20] (Fig. 4.1). A thicker, purulent, yellow-green discharge should raise suspicion
for bacterial conjunctivitis [21].
Radiation conjunctivitis is a clinical diagnosis based on patient signs and symp-
toms including a red eye, discharge, and normal vision as well as exclusion of other
diagnoses in patients with a history of irradiation to or near the orbit [21].
4.4 Xerophthalmia 41

Fig. 4.1 Conjunctivitis

and eyelash loss at the end
of radiation therapy for
advanced maxillary sinus
undifferentiated carcinoma

The risk of conjunctival toxicity can be reduced by positioning the orbit out of
the radiation field or reducing dose buildup on the conjunctival surface by higher
beam energy or treating patients with the eye open during radiation exposure if eyes
are irradiated from the anterior aspect of the orbit [20].
It is recommended that artificial tears be used 4–8 times daily to relieve the irrita-
tion caused by conjunctivitis [20].
Secondary infectious conjunctivitis should be managed as a primary form. Viral
conjunctivitis is self-limited and topical antihistamine/decongestants may be needed
for symptom relief. The efficacy of antiviral agents is not clear [22, 23]. Bacterial
conjunctivitis is treated with a broad-spectrum topical antibiotic (trimethoprim with
polymyxin B eye drops or erythromycin ophthalmic ointment). Gram stain or cul-
tures generally are not carried out, and empiric antibiotics are usually prescribed
[17, 24, 25].

4.4 Xerophthalmia

Tears are produced by the lacrimal functional unit consisting of the lacrimal glands,
ocular surface (cornea and conjunctiva), eyelids, meibomian glands, and the inter-
connecting innervation [26, 27].
The tear film consists of three layers: mucous (inner layer), aqueous (middle
layer), and lipid (outer layer).
The mucous layer is produced by conjunctival goblet cells and epithelial
cells of the cornea and conjunctiva. The lacrimal glands consist of the main
lacrimal gland and the accessory Krause and Wolfring lacrimal glands, which
are located around the upper border of the tarsal plate and the conjunctival for-
nix, respectively. The aqueous component is secreted by these glands. The lipid
component is secreted by the meibomian glands (at the rim of the eyelids inside
the tarsal plate) and Zeis glands (anterior to the Meibomian gland, at distal eye-
lid margin) [28].
42 4 Radiation Orbital Toxicity

Radiation therapy leads to damage to the meibomian glands [29] and cause lac-
rimal gland acinar cell apoptosis and gland atrophy [30] or both [27]. Tear film
aqueous and lipid deficiency develop due to dysfunction of lacrimal glands and
Meibomian gland, respectively [20, 31].
With low-dose radiation therapy (about 24–25 Gy) of lymphoid lesions of the
orbit and ocular adnexa, early mild radiation-induced xerophthalmia and chemosis
have been noted in up to 50% of patients [12]. Irradiation of lacrimal glands to doses
more than 30–40 Gy can lead to dry eye syndrome; the incidence increases dramati-
cally with doses ≥50 Gy and doses greater than 60 Gy may cause permanent tear
loss [20, 32, 33].
Diagnosis is based on characteristic symptoms and clinical appearance. Early
effects are conjunctival inflammation, chemosis (swelling of the conjunctiva), and
tear film instability with a resultant dry eye sensation [34]. Patients develop a red,
painful, scratchy eye (foreign-body sensation), and photophobia. Severe problems
may produce corneal desiccation, ulceration with bacterial infection, neovascular-
ization, opacification, and ultimately perforation [35].
Xerophthalmia can be avoided by positioning lacrimal glands out of the radiation
field, shielding them, or modifying dose distributions by using intensity-modulated
radiation therapy (IMRT) [36, 37].
Supplemental lubrication or artificial tears are the mainstay of treatment for
xerophthalmia; however, they act only as a replacement therapy without any effect
on tear secretion. There are various artificial tear products with different formula-
tions with no evidence suggesting a specific single brand being superior [38].
Preservative-free eye drops contain fewer additives and are generally recommended
in the setting of extreme and long-term use of teardrop including severe dry eyes or
multiple teardrop application daily due to lower effects of these products on the
cornea and conjunctival epithelium [39].
In addition to artificial teardrops, there are other forms of supplemental lubrica-
tions like gels or ointments. Artificial tear ointments and gels offer longer-lasting
relief but may blur vision [38].
There is no proven difference in efficacy between different topical dry eye treat-
ments, including artificial tears, ointments, or gels [40].

Artificial Tear Prescription:

Solution: Instill 1–2 drops into eye(s) as necessary to relieve symptoms [39].
Ointment: Pull down lower lid of affected eye and apply 0.25 mL of ointment to the
inside of the eyelid [39].

Stimulation of tear production has been seen by using topical sodium hyaluronate,
cyclosporine, and tacrolimus, which increase the aqueous component of the tear layer
and goblet cell density while also decreasing the inflammation process [41, 42]. These
agents need to be studied in radiation-induced xerophthalmia. Oral pilocarpine could
palliate dry eye and dry mouth symptoms in Sjögren’s syndrome [43, 44] and has also
been used in the management and prevention of radiation-­induced xerostomia (see
Chap. 7). But currently, there is no evidence for its application in radiation-induced
xerophthalmia.
4.5 Corneal Toxicity 43

Topical anti-inflammatory agents (corticosteroids or nonsteroidal anti-­

inflammatory drugs (NSAIDs)) are beneficial for selective patients with severe dry
eyes [45], but there isn’t sufficient evidence for their efficacy in radiation-induced
xerophthalmia.
Autologous serum eye drops (with essential tear components for epithelial pro-
liferation, similar properties of tears, and no additive preservatives) [46], punctal
occlusion (mechanical blocking of the draining system) [47], and dry eye mois-
ture chamber goggles (a chamber for protecting the dry eyes from the environ-
ment) [20], all have been suggested for severe dry eye treatment with some
limitations in clinical use including need for frequent blood tests and potential
risk of infection transmission in autologous serum eye drops, insufficient evi-
dence of efficacy in punctal occlusion, and cosmetic concerns in wearing the
moisture chamber goggles.

4.5 Corneal Toxicity

Acute corneal toxicity of radiation therapy can be secondary to radiation xeroph-

thalmia or a primary effect of irradiation on the corneal surface epithelium, corneal
stroma, and endothelium [20].
Secondary keratopathy due to tear film dysfunction is the common form of acute
corneal toxicity and is presented by superficial punctate epithelial erosions or, in the
case of severe dry eyes, corneal scarring [34].
Direct radiation injury can induce punctuate corneal erosions and corneal edema
at doses of 40–50 Gy in 4–5 weeks and corneal ulceration at doses more than 60 Gy
(with conventional fractionated radiation) and with 20 Gy delivered in a single dose
[48].
Corneal damage is diagnosed clinically by signs and symptoms and eye exami-
nation including slit lamp exam. Patients usually present with photophobia, foreign-­
body sensation, tearing, pain, haloes, decreased vision, and red eye. In the penlight
examination, conjunctival injection may be present. In slit lamp microscope exami-
nation, a corneal opacity or infiltration with corneal ulcers could be seen. The cor-
nea may have a hazy appearance with corneal edema. Punctate epithelial erosions
and corneal ulcers stain positively with fluorescein.
A corneal shield, which is placed between the lids and globe, could minimize
corneal radiation dose and prevent toxicity if the treatment target is superficial to the
cornea. These internal eye shields are used in radiation treatment planning of skin
cancer near the eye and can give excellent protection from lower-energy X-rays and
electron beams with energies ≥6 MeV [49, 50].

4.5.1 Treatment

4.5.1.1 Topical Lubricants (e.g., Ophthalmic Ointment)

Patient should be instructed to pull down the lower lid of the affected eye and apply
a small amount of ointment once daily or more if needed [51, 52].
44 4 Radiation Orbital Toxicity

Some practitioners prescribe lubricant antibiotic ointment (e.g., erythromycin

0.5% ophthalmic ointment, polymyxin B/trimethoprim (Polytrim) ophthalmic solu-
tion, and sulfacetamide 10% ophthalmic ointment) [53].

4.5.1.2 Analgesics
Pain is common with corneal damage and is alleviated with oral nonsteroidal anti-­
inflammatory drugs (NSAIDs) and acetaminophen or narcotic analgesics (in severe
cases). Topical NSAIDs (e.g., diclofenac 0.1%, ketorolac 0.4%), are administered
by some practitioners in selective patients that request immediate pain relief or that
cannot tolerate oral analgesics, but these topical agent have not been approved for
this indication [54].
Patching and topical cycloplegics and topical anesthetics have not shown signifi-
cant benefit for uncomplicated corneal abrasions [53].

4.5.1.3 Ophthalmologist Consult

Early ophthalmologist consultation is recommended and in the setting of significant
vision loss, corneal infiltration or ulcer, vision worsening, or no improvement of
symptoms with initial management, referring a patient to an ophthalmologist is nec-
essary [53].

4.6 Iris Toxicity

Acute complications of radiation therapy in the anterior chamber are rarely reported,
but transient early iritis can develop after single doses ≥10 Gy [20]. Iritis presents
with pain, photophobia, red eye, and blurred vision and is distinguished from other
causes of red eye by slit lamp examination (presence of leukocytes in anterior cham-
ber) [55]. There is little published evidence about management of radiation iritis.
Ophthalmologic consultation should be considered early in these patients.

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47. Ervin AM, Wojciechowski R, Schein O (2010) Punctal occlusion for dry eye syndrome.
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ease. Cornea 24:909–914
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aluminum in high-energy electron beams. Int J Radiat Oncol Biol Phys 41:233–237
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shields in electron beam treatment. Int J Radiat Oncol Biol Phys 35:599–604
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55. Rosenbaum J. Uveitis: etiology, clinical manifestation, and diagnosis. Available from www.
uptodate.com
Ear Toxicity
5

The acute ear complications of radiation therapy include external, middle, and inner
ear injuries. The acute external ear complications include otitis externa or skin reac-
tions involving the preauricular region, the auricle, and the external auditory canal
that occur in about 28% of head and neck cancer patients treated with radiation
therapy [1]. The acute middle ear complications that include mastoiditis, Eustachian
tube dysfunction, consequential otitis media, and transient conductive hearing loss
occur in 40–45% of head and neck cancer patients during or after radiation therapy
[2, 3]. The acute inner ear complications include sensorineural hearing loss (SNHL)
and tinnitus [4]. SNHL may occur early after treatment in up to 50% of patients with
head and neck tumors treated with radiation therapy [5–7].

5.1 Mechanism

The external ear is a tube covered by skin that conducts sound waves to the middle
ear. Radiation effects on the external ear mimics the skin effects of radiation and for
mechanism, timing, and symptoms (see Chap. 1).
The mechanism of radiation-induced otitis media is due to swelling of the mucosa
following the radiation and subsequent obstruction of the Eustachian tube. The
Eustachian tube obstruction results in resorption of the air oxygen and nitrogen from the
middle ear, which results in negative pressure and tympanic retraction leading to con-
ductive hearing loss. With further reduction of the negative pressure in the middle ear
cavity, fluid transudation takes place resulting in serous otitis media [4, 8].
Stria vascularis in the inner ear is responsible for endolymph production and
absorption. Stria vascularis injury after radiation exposure leads to endolymphatic
hydrops and temporarily increased intralabyrinthine pressure, which could lead to
ear fullness, hearing loss, tinnitus, dizziness, and vertigo [9].
Hearing loss may be conductive, sensorineural, or mixed type. Early hearing loss
during radiation therapy is usually conductive due to Eustachian tube dysfunction
and radiation-induced otitis media. The incidence of SNHL increases with time, and

© Springer International Publishing AG 2017 47

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_5
48 5 Ear Toxicity

sensorineural or mixed-type hearing loss occurs either near the end of or shortly
after the completion of radiation therapy. The sensory component of early hearing
loss is usually related to stria vascularis degeneration and disturbances in normal
perilymph and endolymph physiology [9, 10].

5.2 Timing

Acute otitis media usually occurs within a few weeks of radiation therapy. It is usually
transient [1] and resolves within a few weeks after completion of the treatment [4].
SNHL may occur near the end of treatment or after the completion of radiation
therapy and increase with time. SNHL may be transient or permanent. Transient
SNHL could recover within 6–12 months; however, it may last over 12 months in a
few cases [5].
Patients with no severe SNHL (less than 30 dB drop from baseline) and no post-
irradiation serous otitis media have a good chance for recovery of sensorineural
hearing within 6 months to 1 year. On the other hand, if severe SNHL develops or
the SNHL persists beyond 1 year, it is likely permanent [5].

5.3 Risk Factors

No specific risk factor has been defined for radiation-induced ear toxicities. As with
other organs, the maximum dose and ear irradiated volume could affect the preva-
lence and severity of toxicities. Background skin disease such as lupus erythema-
tous and other autoimmune disease may cause more toxicity for the external ear.
Previous middle ear disease such as otitis media or mastoiditis may also increase
middle ear radiation-induced toxicities. Concomitant administration of chemother-
apy may also increase the risk and severity of otitis in external ear (Fig. 5.1).
Platinum-based regimens are used as induction or concurrent chemotherapy
in locally advanced head and neck cancers and can potentially affect inner ear toxic-
ity so the risk of SNHL may increase.

Fig. 5.1 External otitis in

a patient treated with
cisplatin-based
chemoradiation of head
and neck cancer
5.5 Scoring 49

Fig. 5.2 Otitis media after

chemoradiation for parotid
tumors

5.4 Symptoms and Diagnosis

Symptoms of otitis media are conductive hearing loss, ear pain, fullness, and tinnitus in
the affected ear [4]. As a result of radiation therapy, the tympanic membrane may become
dull, retracted, bulged, and congested or may remain normal (Fig. 5.2) [3]. An inner ear
injury can manifest with tinnitus, dizziness, vertigo, and high-­frequency SNHL [5].
Diagnosis of these complications is based on patient symptoms and ear examina-
tion including otoscopic assessment. Hearing loss may be diagnosed by simple tests
like general assessment of each ear with words spoken at various volumes or a tun-
ing fork or by more thorough audiometry testing. A pure tone audiometer test offers
an audiogram based on a person’s ability to hear sounds with different loudness and
pitches and characterizes the type and degree of hearing loss.

5.5 Scoring

No distinct grading system has been published for external, middle, and inner ear
radiation-induced toxicities separately. Radiation Therapy Oncology Group (RTOG)
and the European Organization for Research and Treatment of Cancer (EORTC)
have defined the ear toxicity grading system, which considers all three parts as an
organ (see Table 5.1) [11].

Table 5.1 RTOG/EORTC ear toxicity scoring

Definition
Grade 1 Mild external otitis with erythema, pruritus, secondary to dry desquamation not
requiring medication. Audiogram unchanged from baseline
Grade 2 Moderate external otitis requiring topical medication/serous otitis media/hypoacusis
on testing only
Grade 3 Severe external otitis with discharge or moist desquamation/symptomatic hypoacusis/
tinnitus not drug related
Grade 4 Deafness
50 5 Ear Toxicity

5.6 Management

All patients that are undergoing radiation therapy to a portion of the temporal bone
or any ear compartment should have pretreatment audiometric evaluation (pure tone
audiometry, otoacoustic emission audiometry, tympanometry) [12]. Patients should
be assessed again after the end of treatment or sooner, if the clinical situation war-
rants [13, 14], and then audiometric evaluation should be repeated based on patient
symptoms at each visit.
All patients should be informed to maintain aural hygiene. Any traumatic actions
to the ear canal like the use of a curette for cerumen removal should be avoided. The
routine use of agents such as mineral oil or carbamide peroxide supplemented, as
needed, with gentle irrigation is recommended to prevent cerumen impaction [13].
External otitis is a skin reaction to radiation exposure that commonly occurs dur-
ing radiation therapy and resolves after the completion of treatment [9]. External
otitis symptoms can be alleviated with over-the-counter analgesics and topical ear
drops in our experience; however, there is no study evaluating the use of different
topical medications in treatment of this complication during radiation therapy.
Corticosteroids (betamethasone or dexamethasone otic solutions) decrease
inflammation and relieve ear pain [15]. Corticosteroids could be used 2–4 drops in
the affected ear canal every 2 or 3 h. Patients should tilt the head to the affected ear,
instill the drops, and keep this position for about 5 min [15].
Acetic acid drop changes the pH of the ear canal [16] and has antibacterial and
antifungal properties [17]. The patient should be instructed to use acetic acid 4–6
drops every 2–3 h into the external auditory canal [17].
The combination of the hydrocortisone and acetic acid is available in the form of
otic solution that can be used in patients with external otitis [16].
Perforated tympanic membrane is a contraindication to the use of any medication
in the external ear canal.
Otitis media is generally treated symptomatically with analgesics and antipyretics.
Antipyrine and benzocaine otic solution is a combination solution containing
antipyrine, benzocaine, oxyquinoline sulfate, and anhydrous glycerin that is applied
as a local anesthetic for otitis media [18]. It can be used every 1–2 h as needed for
pain relief with a sufficient amount of solution to fill the affected ear canal [19].
Aqueous lidocaine 2% can provide rapid pain relief in acute otitis media.
Aqueous lidocaine is not available in a bottle with a dropper. Injectable lidocaine
2% can be used with a dropper [20].
Oral analgesics (e.g., NSAIDs, acetaminophen) can reduce acute otitis media
pain much slower than topical medication [21]. Oral analgesics may be used in
combination with topical agents such as lidocaine and benzocaine [18].
Middle ear ventilation tube insertion may be needed in the setting of long-lasting
radiation-induced secretory otitis media (3–6 months) [22].
References 51

References
1. Bhandare N, Antonelli PJ, Morris CG, Malayapa RS, Mendenhall WM (2007) Ototoxicity
after radiotherapy for head and neck tumors. Int J Radiat Oncol Biol Phys 67(2):469–479
2. Jereczek-Fossa BA, Zarowski A, Milani F, Orecchia R (2003) Radiotherapy-induced ear toxic-
ity. Cancer Treat Rev 29(5):417–430
3. Upadhya I, Jariwala N, Datar J (2011) Ototoxic effects of irradiation. Indian J Otolaryngol
Head Neck Surg 63(2):151–154
4. Borsanyi SJ, Blanchard CL (1962) Ionizing radiation and the ear. JAMA 181(11):958–961
5. Kwong DL, Wei WI, Sham JS, Ho W, Yuen P, Chua DT et al (1996) Sensorineural hearing loss
in patients treated for nasopharyngeal carcinoma: a prospective study of the effect of radiation
and cisplatin treatment. Int J Radiat Oncol Biol Phys 36(2):281–289
6. Malgonde MS, Nagpure P, Kumar M (2015) Audiometric patterns in ototoxicity after radio-
therapy and chemotherapy in patients of head and neck cancers. Indian J Palliat Care 21(2):164
7. Yilmaz YF, Aytas FI, Akdogan O, Sari K, Savas ZG, Titiz A et al (2008) Sensorineural hearing
loss after radiotherapy for head and neck tumors: a prospective study of the effect of radiation.
Otol Neurotol 29(4):461–463
8. Bhide S, Harrington K, Nutting C (2007) Otological toxicity after postoperative radiotherapy
for parotid tumours. Clin Oncol 19(1):77–82
9. Linskey ME, Johnstone PA (2003) Radiation tolerance of normal temporal bone structures:
implications for gamma knife stereotactic radiosurgery. Int J Radiat Oncol Biol Phys
57(1):196–200
10. Singh J, Jaiwardhan G, Yadav S, Gulia J, Bhisnoi S (2014) Effect of radiotherapy on hearing
thresholds in patients of head and neck malignancies. Int J Otorhinolaryngol 16(1)1–6. https://
print.ispub.com/api/0/ispub-article/14729
11. Cox JD, Stetz J, Pajak TF (1995) Toxicity criteria of the radiation therapy oncology group
(RTOG) and the European organization for research and treatment of cancer (EORTC). Int
J Radiat Oncol Biol Phys 31(5):1341–1346
12. Saluja M, Thakur J, Azad R, Sharma D, Mohindroo N, Seam R et al (2014) Radiotherapy
induced hearing loss in head neck cancers: screening with DPOAE. Head Neck Oncol 6(3):3
13. O’Neill JV, Katz AH, Skolnik EM (1979) Otologic complications of radiation therapy.
Otolaryngol Head Neck Surg 87(3):359–363
14. Raaijmakers E, Engelen AM (2002) Is sensorineural hearing loss a possible side effect of
nasopharyngeal and parotid irradiation? A systematic review of the literature. Radiother Oncol
65(1):1–7
15. Betamethasone otic [Internet]. Available from www.drugs.com
16. Otitis externa medication [Internet]. Available from emedicine.medscape.com
17. Acetic acid [Internet]. Available from www.drugs.com
18. 19-Antipyrine and benzocaine ear drops [Internet]. Available from www.drugs.com
19. Antipyrine and benzocaine otic medical facts from drugs [Internet]. Available from ­https://
www.drugs.com
20. Prasad S, Ewigman B (2008) Use anesthetic drops to relieve acute otitis media pain. J Family
Pract 57(6):370
21. Bertin L, Pons G, d’Athis P, Duhamel J, Maudelonde C, Lasfargues G et al (1996) A random-
ized, double-blind, multicentre controlled trial of ibuprofen versus acetaminophen and placebo
for symptoms of acute otitis media in children. Fundam Clin Pharmacol 10(4):387–392
22. Anteunis LJ, Wanders SL, Hendriks JJ, Langendijk JA, Manni JJ, de Jong JMA (1994)
Prospective longitudinal study on radiation-induced hearing loss. Am J Surg 168(5):408–411
Oral Mucositis
6

Almost no patients that are undergoing radiation therapy of head and neck cancers
can run away from radiation-induced oral mucositis, especially if the oral cavity is
included in the treatment target. Trotti et al. have confirmed the high incidence of
induced oral mucositis in a systematic review with rates of 97% during conventional
radiation therapy, 100% during altered fractionation radiation therapy, and 89%
during chemoradiation therapy [1]. In a retrospective study of 204 head and neck
cancer patients that received radiation therapy with or without chemotherapy, oral
mucositis occurred in 91% of patients; the rates of mucositis grades 1, 2, 3, and 4
were 4%, 21%, 60%, and 6%, respectively [2].
Another study of 450 head and neck cancer patients that received radiation ther-
apy with or without chemotherapy found that the majority of patients (83%) devel-
oped oral mucositis (mild in 19%, moderate in 35%, and severe in 28% of patients).
Oral mucositis has significant pain, dysgeusia, and odynophagia that can result
in dehydration, malnutrition, and reduced quality of life scores.
Oral mucositis also can reduce radiation therapy tolerance and consequently
affect treatment results. Unplanned breaks/delays in radiation therapy were reported
in 2.4%, 15.8%, and 46.8% of patients with mild, moderate, and severe oral muco-
sitis, respectively [3].

6.1 Mechanism

The oral mucosa is covered by stratified squamous epithelium. The basal layer of
mucosal epithelium has columnar cells with rapid division properties to maintain a
constant epithelial population as cells are shed from the surface [4]. The lamina
propria underlies the epithelium, which consists of fibroblasts and connective tis-
sue, capillaries, inflammatory cells (macrophages), and extracellular matrix [4, 5].
Radiation-induced oral mucositis is not a simple epithelial process and results from

© Springer International Publishing AG 2017 53

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_6
54 6 Oral Mucositis

complex pathways embracing all different cellular and tissue compartments of the
mucosa. It has been proposed that endothelial and connective tissue damage pre-
cedes epithelial changes in irradiated oral mucosa [5].
Radiation directly damages cellular DNA of rapidly dividing cells of the oral
basal epithelium and cells in the underlying tissue [6]. Radiation also generates oxi-
dative stress and reactive oxygen species (ROS) that lead to further tissue damage by
activating a number of transcription factors such as nuclear factor-κB (NF-­κB) in the
epithelium, endothelium, macrophages, and mesenchymal cells. Subsequently, the
upregulation of genes and the production of pro-inflammatory cytokines including
TNF-α, IL-1β, and IL-6 occur, leading to an injury to the connective tissue, endothe-
lium, and apoptosis of cells within the basal epithelium. Pro-­inflammatory cytokines
also activate molecular pathways that amplify production of TNF-α, IL-1, and IL-6
and resulted in further tissue damage (positive feedback loop).
Until this stage, the clinical appearance of mucosa seems to be normal, and only
the thinning of the mucosa and edema related to acute vascular response may
develop and cause early signs and symptoms of mucositis (mild erythema and burn-
ing sensation). But as radiation therapy continues, all events from the prior phase
result in further injuries and loss of the basal epithelial stem cells with continuing
cell loss from the mucosal surface, reducing the cellular population of the mucous
membrane. Atrophic changes and breakdown of mucosa occur and patients experi-
ence obvious symptoms of mucositis [6–12].
The ulcerative phase of mucositis is accompanied by significant inflammatory
cell infiltration. Beside the intrinsic factors, this phase may be affected by extrinsic
factors that have reciprocal relation together. Damaged epithelium of the ulcerative
mucositis is susceptible to bacterial colonization. Following the colonization with a
mixed microbial flora, including mostly gram-negative bacteria, bacterial cell wall
products penetrate the injured mucosa and increasingly stimulate pro-inflammatory
cytokine release, amplifying the severity of mucositis and tissue injury [6]. When
radiation therapy is completed, tissue repair begins with renewal of epithelial prolif-
eration and differentiation and reestablishment of the local microbial flora [13].

6.2 Timing

In conventional fractioned radiotherapy (2 Gy per fraction daily), mucosal erythema

with mild discomfort occurs within 1–2 weeks of treatment at doses of approxi-
mately 10–20 Gy [13]. Patchy pseudomembranous formation can develop after
2 weeks (20 Gy), and ulcerative radiation-induced mucositis often arises at doses of
more than 30 Gy and peaks during the fourth to fifth week of therapy. This timing
of symptom presentation is varied based on treatment schedule. In accelerated radi-
ation therapy, mucositis reaches its peak within 3 weeks [11, 14]. The symptoms
usually become more severe with treatment and remain for about 2–3 weeks after
the end of therapy at its peak [2, 15]. Healing then begins and may take weeks to
months (generally 3–6 weeks) to resolve [16]. However, chronic open wounds rec-
ognized as soft-tissue necrosis may occur in a few cases due to excessive depletion
of mucosal stem cells depending on their recovery [17].
6.3 Risk Factors 55

6.3 Risk Factors

Several factors have been identified for the development of more severe oral muco-
sitis during radiation therapy. These factors could be related to treatment, tumor,
and/or patient characteristics.

6.3.1 Tumor Site

Primary tumors of the oral cavity, oropharynx, or nasopharynx [16] increase the risk
of oral mucositis due to including higher volumes of the oral mucosa and salivary
gland in irradiation fields.
In the treatment planning of oral cavity, oropharyngeal, and nasopharyngeal can-
cer, a significant surface of oral mucosa includes in radiation field that increase the
rate of oral mucositis. In the oral cavity, some areas, including the lateral borders and
ventral surface of the tongue as well as the soft palate and floor of the mouth, have
increased susceptibility to developing oral mucositis due to higher cell turnover
rates. Instead, buccal mucosa has less sensitivity to radiation-induced mucositis [13].
Salivary gland radiation-induced injury leads to changes in quality (low production of
glycoproteins and an increased acidity of saliva) and quantity of saliva (see Chap. 7) that
inhibit the protective effects of saliva and increases the risk of developing mucositis [18].

6.3.2 Concomitant Systemic Therapy

When chemotherapy is combined with radiation therapy, both normal tissue and
tumor response alter due to their additive effects. Both radiation therapy and anti-
neoplastic agents disrupt normal cell division of the oral mucosa and result in
increased oral mucositis incidence [13, 19, 20]. Dose, type, and schedule of sys-
temic therapy all affect severity and frequency of mucositis in the setting of concur-
rent chemoradiotherapy (weekly versus every 3 weeks; cisplatin or paclitaxel are
associated with higher rates of oral mucositis) [21, 22].
There is a paucity of data about oral mucositis rates when cetuximab is used concur-
rently with radiation therapy. Some proposed no exacerbation of the common mucosi-
tis associated with radiation therapy [23, 24], and others found an increase of oral
mucositis compared to radiation alone or conventional cisplatin with radiation therapy
[25–27]. Future clinical trials are needed to more precisely evaluate the incidence and
severity of mucositis, the time of occurrence, and the impact on quality of life and
treatment interruption of patients treated with cetuximab and radiation therapy.

6.3.3 Radiation Dose

Higher total radiation dose to the oral cavity and higher dose per fraction are signifi-
cantly correlated to the grade of acute mucositis. It has been reported that patients
with cancer of the larynx, hypopharynx, oral cavity, nasopharynx, or oropharynx
56 6 Oral Mucositis

that are treated with radiation therapy with cumulative radiation dosage more than
50 Gy are at an increased risk for oral mucositis [3, 16].
With the introduction of high conformal radiation therapy, the correlation
between the dose to the oral cavity and the severity of acute mucositis has been
evaluated more precisely.
In a study of patients undergoing intensity modulated radiation therapy (IMRT)
for head and neck cancer, it was demonstrated that a cumulative point dose of 39 Gy
resulted in mucositis for 3 weeks or longer; mild severity and short duration of
mucositis were found at cumulative point doses less than 32 Gy [28]. Another study
found that the percentage of oral cavity volume receiving doses higher than 15, 30,
40, 45, and 50 Gy significantly correlated with acute mucositis grade [29].

6.3.4 Radiation Fractionation Schedule

Altered fractionation radiation schedules, such as concomitant boost or

hyperfractionation seem to be associated with higher incidence of severe muco-
sitis [15, 30–34].

6.3.5 Patient-Related Factors

The incidence of mucositis is related to various patient variables including younger

patients, smoking, alcohol consumption, metallic dental restorations, preexisting
periodontal disease, low body mass index, poor functional status, low leukocyte
count, advanced disease and stage, a prior history of severe mucositis, and various
comorbid conditions [3, 35–37].
It has been suggested that with increasing number of patient-related factors, the
risk, duration, and severity of mucositis increases (see below).
Some argue that younger cancer patients have a higher rate of mucosal turnover
that increases their susceptibility to mucositis [38].
The use of dental guards is proposed in the areas of metallic restoration because
it reduces back scatter exacerbated radiation doses to adjacent mucosa caused by
metallic restoration materials [13].
Genetic polymorphisms may be a susceptibility factor for radiation-induced
mucositis (XRCC1 polymorphisms, NBN polymorphisms) [39, 40]. It has been seen
that cytokine phenotype may be correlated to the risk of radiation-induced injury.
During radiation therapy, an elevation in serum levels of cytokines IL-6, TNF-α, and
IL-1β and low levels of IL-8 seem to correlate with mucositis severity [35, 41–43].
A weak correlation between high pretreatment epidermal growth factor (EGF) lev-
els and decreased severity of mucositis has been seen that is suggestive of the protective
EGF effect for oral mucosa damage [44]. Further study is needed to clarify cytokines
and growth factors role in predicting, preventing and treating oral mucositis.
Suresh et al. evaluated a collection of patient-related risk factors and proposed a
comprehensive tool to predict the probable incidence and severity of mucositis in
head and neck cancer patients receiving chemoradiotherapy. In this suggested
6.4 Symptoms 57

system, patients are scored based on age > 40, erythrocyte sedimentation rate (ESR)
>3-times the upper limit, albumin <3.0 g/dL, white blood count (WBC) less than
3000/μL, Eastern cooperative oncology group (ECOG) performance status (PS) of
more than 2, stage III or higher disease, use of tobacco, and presence of any comor-
bid conditions. One point is given to each of these parameters. Scores of 3 or less
and 6 or above predicted the differences in the incidence of mucositis [45].

6.4 Symptoms

The early signs of radiation mucositis are red appearance of the oral mucosa due to
dilation of capillaries in the endothelial layer and reduced epithelial thickness. A
whitish appearance may be seen due to transient hyperkeratinization prior to ery-
thema. Patients are mostly asymptomatic or complain of a mild burning sensation
or intolerance to spices or hot food in this early phase. Erythema (Fig. 6.1) is fol-
lowed by fibrinous pseudomembranous formation, followed by erosion and ulcer-
ation (Fig. 6.2). Under the pseudomembranes, the epithelial surfaces are denuded,
and hemorrhage occurs easily. Pseudomembranous ulcerative lesions are very

Fig. 6.1 Grade 1 of oral

mucositis at second week
(14 Gy) of radiation
therapy

Fig. 6.2 Grade 2–3 of oral

mucositis at fifth week
(48 Gy) of radiation
therapy
58 6 Oral Mucositis

painful, and patients complain of severe pain and difficulty in chewing that inter-
feres with their oral intake or speaking, eventually leading to weight loss.
Oral pain follows a similar pattern of objective clinical findings of oral mucositis
but it may begin sooner and reach its peak earlier (between weeks 2 and 4) [2].
Correlation between patient-reported and clinical manifestations of mucositis is low
in early parts of treatment [46].
Bacterial infection (usually gram-negative) or viral infections (such as herpes
simplex virus (HSV)) and fungal infections (usually candidiasis) can sometimes be
superimposed on oral mucositis [13, 37]. Infectious mucosal lesions often extend
beyond the field of radiation. An infected oral mucosa usually manifests with a deep
ulceration with a yellow-white necrotic center and raised borders. Fungal mucositis
presents with white removable fungal plaques [13]; however, erythematous forms
may occur and complicate the exact diagnosis [47].

6.5 Scoring

Patients undergoing radiation therapy to the oral cavity should be seen at least once
a week. At each visit, patient symptoms and their oral intake should be assessed;
their oral mucosa should also be examined.
A variety of assessment scales exist for measurement of oral mucositis. Three of
the most commonly utilized scales (Table 6.1) for radiation-induced mucositis are
toxicity criteria of the Radiation Therapy Oncology Group (RTOG), the European
Organization for Research and Treatment of Cancer (EORTC) [48], the National
Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) [49],
and the World Health Organization (WHO) oral toxicity scale [50].

Table 6.1 RTOG, WHO, and CTCAE mucositis grading

RTOG WHO CTCAE
Grade 1 Irritation/may experience mild Mild Asymptomatic or mild
pain not requiring analgesic Soreness ± erythema symptoms; intervention
not indicated
Grade 2 Patchy mucositis that may Moderate Moderate pain; not
produce an inflammatory Erythema, ulcers; interfering with oral
serosanguinous discharge/may patient can swallow intake; modified diet
experience moderate pain solid food indicated
requiring analgesia
Grade 3 Confluent fibrinous mucositis/ Severe Severe pain; interfering
may include severe pain requiring Ulcers with with oral intake
narcotic extensive erythema;
patient cannot
swallow food
Grade 4 Ulceration, hemorrhage, or Life-threatening
necrosis consequences; urgent
intervention indicate
Grade 5 Death
6.6 Prevention 59

6.6 Prevention

Maintenance of good oral hygiene is critical to preventing oral mucositis. All

patients should be informed of proper oral hygiene before starting treatment:

–– Cleaning teeth with toothpaste and a soft toothbrush after each meal and at bed-
time [51], using a mild-tasting toothpaste or a solution of 1 teaspoon of salt
added to 4 cups (1 quart) of water (if not tolerating any toothpaste) [19].
–– Dental flossing once daily.
–– Dental screening at least several weeks before the beginning of therapy extrac-
tions and major surgeries should be planned 10–21 days and 4–6 weeks before
beginning radiation therapy, respectively [52].
–– Rinsing the mouth two to four times a day (1 tablespoon (15 mL) of oral rinse,
swish in oral cavity for 30 s, then spit out).
Recommended oral rinses [51]:
• Water
• Sodium chloride 0.9% for irrigation
• Salt solution by adding a little salt (1/4 to 1/2 a teaspoon) to a cup of warm
water
–– Be aware that alcohol-based mouth rinses should be avoided.
–– Moisten lips with a moisturizing cream.
–– Adequate oral fluid intake (daily fluid intake of 8–12 cups, 2–3 L).
–– Avoiding alcohol, tobacco, caffeine, fluid or foods with high sugar, highly acidic
fluids and foods (e.g., lemon glycerin swabs, vitamin C lozenges), hot and spicy
foods, and crunchy foods.

6.6.1 Prophylactic Interventions

Benzydamine is a nonsteroidal anti-inflammatory drug with local analgesic, anes-

thetic, and antimicrobial properties that inhibits pro-inflammatory cytokines includ-
ing IL1 and TNF-α. It has been shown to reduce the severity and frequency of
mucositis in patients with head and neck cancer undergoing radiation therapy.
Benzydamine oral rinse appears to be effective in the prevention of radiation-­
induced oral mucositis in head and neck cancer patients [53–58]. Benzydamine
(15 mL of oral rinse 0.15%) is used as a mouth rinse. It should be held or rinse
within the mouth for at least 30 s, followed by expulsion from the mouth and try not
to swallow, 3–4 times per day. It is recommended to begin the day prior to radiation
therapy and continue during treatment.
Benzydamine is well tolerated. If patients complain of numbness or irritation or
a burning sensation as result of benzydamine usage, diluting the liquid with an equal
amount of warm water helps alleviate this issue. Other side effects are nausea and
60 6 Oral Mucositis

vomiting, xerostomia, headache, cough, and pharyngeal irritation. It can be absorbed

through the oral mucosa and should be used with caution in patients with renal
impairment.

6.6.2 Prophylactic Intervention Under Evaluation

Intensity-modulated radiation therapy (IMRT) allows sparing a greater area of the

oral mucosa from higher doses of radiation. However, an obvious superiority of
IMRT to conventional three-dimensional conformal radiotherapy (3D–CRT) and
conventional two-dimensional radiotherapy (2DRT) in the prevention of the acute
oral mucositis is not established [59, 60].
Low-level laser therapy seems to be effective in the prophylaxis of radiation-­
induced oral mucositis [61–66]. As a noninvasive measurement, it can decrease the
incidence and severity of oral mucositis [67]. Laser therapy modulates three main
biological effects: an analgesic effect with increase in endorphin release and pain
signal inhibition, an anti-inflammatory and wound healing properties with energy
production at the mitochondrial level, and an increase in vascularity and regenera-
tion of injured tissues [2, 63, 68]. It refers to local application of a high-density
monochromatic narrow-band light source with the output power range from 5 to
500 milliwatts and a wave-length between 600 and 1000 nanometers [69]. It is a
simple procedure that is administered immediately after radiation therapy and takes
only about 6–8 min to administer. All is done extraorally unless intraoral lesions
develop [47].
Glutamine is a nonessential amino acid in the body. Glutathione, a byproduct of
glutamine metabolism, protects normal tissues against oxidative injury [70, 71].
Glutamine depletion may develop in cancer patients due to cachexia and normal
tissue damage from radiation or chemotherapy [72].
It has been found that oral glutamine administered daily during radiation therapy
can reduce the severity and frequency of oral mucositis in head and neck cancer
patients. These results warrant further investigation in future trials [72–77].
Zinc renders multiple essential functions in the body such as cell proliferation,
wound healing, free radical protection, immunity, and anti-inflammatory effects. It
has been shown that oral zinc sulfate can prevent and cause delay in development of
oral mucositis [78].
Payayor (Clinacanthus nutans) is a traditional herbal medicine originating from
Thailand with anti-inflammatory and analgesic properties. There are some studies
that support payayor as a prophylactic intervention for radiation-induced oral muco-
sitis [79, 80]. However, no guideline for use exists currently due to insufficient
evidence.
Calendula officinalis, commonly known as Marigold, possesses some anti-­
inflammatory and antioxidant properties. It has been suggested that Calendula offi-
cinalis can be effective in decreasing oral mucositis severity [81, 82].
Natural honey has been recently shown to be effective in reducing radiation-­
induced mucositis. Honey has immunomodulatory properties and antibacterial
6.6 Prevention 61

activity and can accelerate wound healing. Honey is an easily available agent that
warrants further trials to validate its effect [83–85].
Royal jelly is a secretion of hypopharyngeal and mandibular glands of worker
bees with antioxidative, antibiotic, and anti-inflammatory action. Royal jelly could
improve the signs and symptoms of oral mucositis and shorten healing time [86].
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported
to regulate proliferation and maturation of leukocytes, macrophages, and dendritic
cells. GM-CSF can improve wound healing by enhancing fibroblasts and keratino-
cyte growth [87].
Subcutaneous GM-CSF has been shown to decrease pain and severity of oral
mucositis [88, 89]. However, topical administration of GM-CSF to treat radiation-­
induced oral mucositis has mixed results [87, 90, 91]. Saarilahti et al. studied topical
use of GM-CSF and reported promising effects in prophylaxis of radiation-induced
oral mucositis [92]. There are also conflicting data about effectiveness of subcutane-
ous GM-CSF in radiation-induced mucositis prophylaxis [93, 94].
Keratinocyte growth factor (KGF) is an epithelial cell growth factor expressed by
fibroblasts and endothelial cells and has an important role in wound healing by
increasing proliferation and maintaining integrity of epithelial cells and enhancing
neovascularization and collagen deposition [95].
Primary results show that recombinant human keratinocyte growth factor
Palifermin resulted in reduction of radiation mucositis with no stimulation of the
proliferation of tumor cell lines [96–98], which needs further evaluation.
Oral recombinant human epidermal growth factor (rhEGF) has been shown to
improve wound repair by stimulating epithelialization. rhEGF appears to be effec-
tive for the treatment of radiation-induced mucositis [99, 100]. Another growth fac-
tor with promising results in preclinical study is velafermin (recombinant human
fibroblast growth factor-20, rhFGF-20) [101]. Further studies are needed to deter-
mine these agents’ efficacy and safety for prevention and treatment of radiation-­
induced mucositis.
Amifostine is a thiol compound that selectively protects normal tissue from radia-
tion effects [102]. Amifostine decreases the frequency and severity of xerostomia. The
salivary preservation by amifostine may offer a protective effect against oral mucositis
[17]. However, the amifostine studies for the prevention of oral mucositis offer insuf-
ficient evidence to support its use for this purpose. Additional investigation is needed
to clarify the role of amifostine as an intervention for oral mucositis prevention [103].
Fluconazole (100 mg/daily) in head and neck cancer patients receiving radiation
therapy can lead to decreased candida carriage and incidence of severe mucositis
[5, 104–107]. Patients that are receiving head and neck radiation therapy are at
increased risk of developing oral candida infection (17–29%) and colonization
(93%) [108].
PTA is a multi-agent lozenge containing a mixture of polymyxin E, tobramycin,
and amphotericin B and has a broad spectrum of antibacterial and antifungal effects.
It has been used to prevent radiation-induced mucositis with inconclusive results.
Results of the topical antibiotic approach in prevention of oral mucositis are insuf-
ficient and need to be further studied [109–114].
62 6 Oral Mucositis

Chlorhexidine antimicrobial oral rinse is not recommended for the prevention of

radiation-induced oral mucositis. It has no clinical benefit for the reduction or pre-
vention of radiation-induced oral mucositis [18]. Chlorhexidine oral rinse is not
well tolerated and may cause a degree of discomfort (e.g., taste alteration, burning
sensation and teeth staining) without any clinical benefit [115].
Sucralfate is an oral ulcer coating complex of sucrose-sulfate-aluminum salt.
Clinical trials found no significant advantage for sucralfate in the prevention or
treatment of radiation-induced mucositis [116–120].
Prostaglandins are known to be cytoprotective. Misoprostol is a synthetic prosta-
glandin E1 analogue. Misoprostol mouthwash has been studied to prevent oral
mucositis in head and neck cancer patients, and the data does not demonstrate a
prevention benefit [121, 122]. There are limited studies for prostaglandin E2 appli-
cation in the radiation-induced mucositis prevention and treatment that do not draw
any conclusions.
Steroids have several effects on different systems of the human body and have
been studied for radiation-induced oral mucositis prevention. Currently, there is
insufficient evidence to support using systemic steroids for reducing the frequency
or severity of oral mucositis [47].
Early morning radiation delivery has been shown to marginally reduce the sever-
ity of mucositis because of circadian variations in cell cycle proteins. The most
radiosensitive phase of the cell cycle (G2-M) occurs in the late afternoon and eve-
ning in human oral mucosa [123, 124]. Currently, there is no recommendation for
this observation in clinical practice [125].
Pilocarpine has not shown any preventive effect on oral mucositis during radia-
tion therapy in head and neck cancer patients [125].
Supplemental antioxidants during radiation therapy have been proposed to pro-
tect the normal tissue and reduce side effects caused by radiation therapy. However,
these antioxidants may act unselectively and protect cancer cells against the damag-
ing effects of reactive oxygen species induced by radiation. Antioxidant supplement
safety during radiation therapy is particularly controversial. The American Cancer
Society and most other national nutrition guidelines recommend that patients with
active cancer treatments limit the usage of supplements to obvious deficiency of
essential agents [126].
RK-0202 (RxKinetix), an oral rinse, comprises the potent antioxidant
N-acetylcysteine in a polymer matrix. RK-0202 has demonstrated primarily posi-
tive results in reducing the incidence of severe mucositis in patients treated with
radiation therapy for head and neck cancer [127].
Vasoconstrictor agents such as phenylephrine with transient vasoconstriction,
tissue hypoxia, and suppression of mucosal cell death during irradiation would pre-
vent radiation-induced oral mucositis based on preclinical studies [128]. Further
clinical trials should be conducted to prove the preventive effect of these agents on
radiation-induced mucositis.
Caphosol (Cytogen Corp) is an electrolyte solution with high ionic content
(Ca2+ and PO43− ions) that help tissue repair by diffusing ions into the inter­cellular
6.7 Management 63

spaces in the epithelium, thus permeating the mucosal lesion and modulate the
inflammatory process. Recent studies did not find significant reduction in the inci-
dence or duration of severe oral mucositis in patients receiving head and neck radia-
tion therapy [129, 130].
Oxygen nebulization that uses high-flow oxygen could improve local mucosal
oxygen content leading to angiogenesis, anti-inflammatory effect, and improved
wound healing. It has been studied in patients with nasopharyngeal cancer to pre-
vent radiation-induced mucositis with promising results. Future studies are required
to better determine effectiveness [131].
Several herbal mouth rinses like Korean red ginseng [132], manuka (Leptospermum
scoparium) and kanuka (Kunzea ericoides) [133], or chamomile [134] have been
studied with a positive effect on the development of radiation-­induced mucositis.
Future investigation is needed to confirm the efficacy and safety of these products.
Persian traditional medicines have different compounds with various local and
systemic effects on the mucosal surface and can theoretically be used to reduce
mucositis [135]. One of the combinations (Malva sylvestris L and Alcea digitata
(Boiss) Alef), which is effective in reducing xerostomia [136], has also been evalu-
ated in a small randomized trial in our patients and primary results are promising
(not published yet).
The mammalian target of rapamycin (mTOR) inhibition plays a role in the pro-
tection of normal oral epithelial cells from radiation-induced epithelial stem cell
depletion. mTOR inhibition with rapamycin may have a potential effect on the pre-
vention of radiation-induced mucositis [137]. Clinical studies need to evaluate
rapamycin efficacy in this setting.
Mothers against decapentaplegic homolog 7 (SMAD7) is a protein encoded by the
SMAD7 gene and has an antagonistic effect on transforming growth factor beta (TGF-
β) and NF-κB signaling. Its prophylactic and therapeutic effects on radiation-­induced
oral mucositis as a well as its safety need to be determined in future studies [138].
Wobe-Mugos is a combination of proteolytic enzymes comprised of papain,
trypsin, and chymotrypsin that has an anti-inflammatory effect. It seems not to be
efficient in preventing radiation-induced oral mucositis [139].

6.7 Management

Principles of management consist of patient assessment, oral care, management of

oral pain, treatment of secondary infection, and consideration of nutritional
support.

6.7.1 Patient Assessment

All patients treated with radiation therapy should be seen as least once weekly,
and the oral mucosa should be examined at each visit. In the patients with oral
64 6 Oral Mucositis

mucositis, baseline grading of oral mucositis and the patient’s general status
should be determined. After initial assessment, decision-making about treatment
protocol can be provided. Most cases can be managed in an outpatient setting
except in the setting of grade 4 mucositis, fever (more than 38.3 °C), or severe
neutropenia. Patients with inadequate fluid intake may require oral supplementa-
tion or IV hydration. Complete blood count is proposed in patients that have
severe mucositis, fever, or at risk of developing neutropenia.

6.7.2 Mouth Care

Mouth care includes all measurements noted for maintaining good oral hygiene (see
above), with intensity and frequency modification based on mucositis grading [140].

6.7.3 Management of Oral Pain

Pain management is the most important aspect of symptom control. Systemic anal-
gesia may be prescribed in addition to topical agents in moderate to severe pain.
Pain control can encourage patients to eat and drink more and wash the mouth more
efficiently, resulting in improved medication effects.

6.7.3.1 Benzydamine Mouth Wash

Benzydamine can reduce the severity of oral mucositis and associated pain in
radiation-­induced oral mucositis [51, 141].
Benzydamine (15 mL of oral rinse 0. 15%) is used as a mouth rinse. It should be
held in the mouth for at least 30 s, followed by expulsion (should not be swallowed),
up to every 1–2 h.
Benzydamine is well tolerated. If patients complain of numbness or irritation or
a burning sensation, dilution with an equal amount of warm water may reduce these
symptoms. Other side effects are nausea and vomiting, xerostomia, headache,
cough, and pharyngeal irritation. It can be absorbed through the oral mucosa and
should be used with caution in patients with renal impairment.

6.7.3.2 Doxepin
Doxepin is a tricyclic antidepressant. Topical application is prescribed for pruritus
and neuropathic pain [142]. Topical doxepin rinse has been shown to be an adequate
analgesia for oral mucositis pain up to 4 h after application. Patients usually have
good compliance; however, mild burning or stinging, unpleasant taste, and drowsi-
ness could develop as common adverse effects [143].
Usage: oral rinse at a dosage of 25 mg (10 mg/mL × 2.5) diluted in 5 mL of water
for 1 min 3–6 times per day.
6.7 Management 65

6.7.3.3 Magic Mouthwash

Magic mouthwash usually contains at least three of these basic ingredients [144]:

–– An antibiotic
–– An antihistamine or local anesthetic
–– An antifungal
–– A corticosteroid
–– An antacid

Magic mouthwash is used every 4–6 h, maintained in the mouth for 1–2 min
before being either spit out or swallowed (in pharyngeal or esophageal involve-
ment). It’s recommended not to eat or drink for at least 30 min after using magic
mouthwash [144].
There are various formulations for magic mouthwash with no standard mixture.
Some of the more common formulations are defined here [145]:

• 80 mL viscous lidocaine 2%, 80 mL Mylanta, 80 mL diphenhydramine (12.5 mg

per 5 mL elixir), 80 mL nystatin 100,000 U suspension, 80 mL prednisolone
(15 mg per 5 mL solution), and 80 mL distilled water
• 1 part viscous lidocaine 2%, 1 part Maalox (do not substitute Kaopectate), and 1
part diphenhydramine (12.5 mg per 5 mL elixir)
• 30 mL viscous lidocaine 2%, 60 mL Maalox (do not substitute Kaopectate),
30 mL diphenhydramine (12.5 mg per 5 mL elixir), and 40 mL Carafate (1 gm
per 10 mL)
• 100 mL dexamethasone (0.5 mg per 5 mL elixir), 60 mL nystatin 100,000 U
suspension, 100 mL diphenhydramine (12.5 mg per 5 mL elixir), and 3 capsules
tetracycline 500 mg

Different contributors of magic mouthwash are added for different purposes:

Diphenhydramine provides local analgesia but can exacerbate xerostomia.

Lidocaine also provides local analgesia.
Corticosteroids reduce inflammatory responses.
Nystatin is added as an antifungal agent.
Tetracycline as an antibiotic (inhibits bacterial protein synthesis).
Antacid (magnesium hydroxide/aluminum hydroxide) component to adequately
coat the oral mucosa [54].

Side effects of magic mouthwash may include problems with taste, a burning or
tingling sensation in the mouth, drowsiness, constipation, diarrhea, and nausea.
Lidocaine can cause a gag reflex impairment and increase the risk of aspiration,
mouth numbness, and tongue biting.
66 6 Oral Mucositis

6.7.3.4 Gelclair
As an oral gel, Gelclair consists mainly of polyvinylpyrrolidone and sodium hyal-
uronate. It is indicated for the management of oral mucositis-related pain due to
establishing a barrier over the oral mucosa [142].
Usage: Oral gel, available in 15 mL single-use packet, is poured into a glass.
Then add up to two tablespoons or 40 mL of water, stir the mixture well and use
immediately. Rinse for at least 1 min and spit 3 times a day or as needed. Do not eat
or drink for at least 1 h following treatment; this may provide relief for up to 7 h.

6.7.3.5 CAM2028
CAM2028 is a bioadhesive barrier-forming lipid solution that can also act as a lipid-­
based drug carrier system for local and extended delivery of benzydamine. After
application, lipid components spread in the oral cavity and form a barrier that pro-
tects the sore and inflamed mucosa. Recently, it has been shown that CAM2028,
with benzydamine or without benzydamine, provides significant pain reduction for
patients suffering from oral mucositis. Its effect begins within 5 min of application
and is maintained for up to 8 h [146, 147].
Usage: Patients are instructed to spray a 0.15 mL-metered dose of the liquid into
the oral cavity 1–3 times and to allow 5 min for the bioadhesive barrier to form
before eating or drinking [146].

6.7.3.6 MF 5232

MF 5232 (Mucotrol) is a concentrated oral polyherbal gel wafer formulation with
local analgesic, antioxidant and immunomodulatory activity, and wound-healing
properties [148]. It has received FDA approval for pain relief associated with oral
lesions [149]. The efficacy of MF 5232 therapy in radiation-induced mucositis man-
agement has been reported [148]. Further studies are required to confirm these posi-
tive results.

6.7.3.7 Acetylcysteine
Acetylcysteine oral rinse, as a mucolytic agent to reduce the viscosity of mucous
secretions, is being studied to improve saliva thickness and painful mouth sores in
patients with head and neck cancer undergoing radiation therapy [150].

6.7.3.8 Opiates
Low-dose opiates may be used in patients with inadequate pain relief with nonnar-
cotic topical agents. Oral, transdermal, or parenteral opiates may be used. Elixir
should not be used because it contains alcohol, which exacerbates mucositis.
Constipation prophylactic laxatives should be considered in patients taking opi-
ates [47].
Fentanyl has various forms that all can be used in patients with oral mucositis
depending on patient preference. Transdermal fentanyl patch can deliver a steady-­
state dose through the skin and provide pain relief to cancer patients with less con-
stipation and sedation than morphine [151]. The level of drug increase over 12–24 h
and reach steady state in about 72 h. Oral transmucosal fentanyl is a sweetened
6.7 Management 67

matrix of fentanyl that is dissolved in the mouth. It is effective for breakthrough

pain and could be particularly useful in patients with mucositis. It has been demon-
strated that oral transmucosal fentanyl citrate may provide more efficacious treat-
ment options than morphine sulfate in treating breakthrough cancer pain [152, 153].
Fentanyl buccal tablet allows rapid absorption through the oral mucosa and pro-
duces a greater early systemic level than oral transmucosal fentanyl citrate. Fentanyl
buccal tablet can be absorbed with a similar profile in patients with or without mild
oral mucositis [154].
Mouthwashes with a morphine-containing solution can effectively decrease pain
in oral mucositis associated with radiation therapy compared to magic mouthwash.
More studies are required in this regard [155, 156].
Sublingual methadone has been proposed as an alternative of standard treat-
ment for mucositis-related pain. Additional studies need to better illuminate the
potential benefits of this formulation of methadone in radiation-induced mucosi-
tis [153].
Usage:
Morphine (opioid-naive patients): SC/IM; 5–10 mg q4hr PRN/IV; 2.5–5 mg
q3-4 hr. PRN/oral; 15–30 mg PO q4hr PRN; 10–20 mg PR q4hr.
Fentanyl transdermal patch (12.5 mcg/hr., 25 mcg/hr., 50 mcg/hr., 75 mcg/hr.,
100 mcg/hr): 25–100 mcg/hr., reapplied q72hr (or every 48 hr. administration may
be needed in a few cases).
Initial patch is selected based on patient need for daily PO morphine dose, then
decrease by 25–50%.
Oxycodone: 10 mg PO q12hr initially; increase by 25–50% gradually every
1–2 days, q12hr dosing interval should be maintained.
Methadone: 2.5 mg PO q8-12 hr.; increase slowly, then every 3–5 days.

6.7.3.9 Corticosteroids
Corticosteroids are useful [51] and are usually administered as a component of a
magic solution. Hydrocortisone tablet (2.5 mg buccal tablets) can be used orally.
Patients are instructed to dissolve the tablet slowly in mouth in contact with the
ulcer three times daily.

6.7.3.10 Gabapentin
Gabapentin is an antiepileptic drug. It is an effective agent in the treatment of neu-
ropathic pain. It also has an application for pain relief that is related to radiation-­
induced mucositis that seems to be successful [157].
Gabapentin begins at a dose of 600 mg and can gradually increase to 1800–
3600 mg/day.

6.7.3.11 Other Analgesic Agents

Carmellose sodium paste [52]
Lidocaine 1% gel [52]
Choline salicylate dental gel [52]
Kaolin-pectin [158]
68 6 Oral Mucositis

Codeine/acetaminophen (1–2 tablets dissolved in a little water) as a mouthwash

up to four times daily [52]
Aspirin 300 mg (1–2 tablets dissolved in a little water) as a mouthwash up to four
times daily [52].

6.7.3.12 Sucralfate
Sucralfate mouthwash is not recommended to be used to treat oral mucositis in
patients receiving radiation therapy for head and neck cancer.

6.7.3.13 Phenytoin Mouthwash

Phenytoin mouthwash was compared with normal saline in patients with radiation-­
induced mucositis in a pilot study. Phenytoin mouthwash (1% solution) was more
effective for pain control without significant efficacy on mucositis severity [159].

6.7.3.14 Low-Level Laser Therapy

Low-level laser therapy is a promising treatment therapy of oral mucositis that has
been shown to reduce mucositis pain significantly [47, 160].

6.7.4 Antifungals

As was previously mentioned in Sect. 7.4, patients undergoing head and neck radia-
tion therapy are at risk of developing candidiasis [108]. Fungal mucositis presents
with white removable fungal plaques [13]; however, erythematous form may occur
and complicate exact diagnosis [47]. The diagnosis is usually based on clinical sus-
picious and can be readily confirmed through identification of yeast forms on gram
stain or KOH preparation of the scrapings [161].
Patients with early, mild presentation are treated with topical agents including nystatin
or clotrimazole. Patients with moderate to severe candidiasis or recurrent disease are
treated with more potent systemic agents including fluconazole and itraconazole [161].
Clotrimazole troches (10 mg oral troches): Dissolve 1 troche in the oral cavity 5
times a day for 14 days [161] (not tolerated in patients with xerostomia).
Nystatin oral suspension (100,000 U/mL): rinse mouth with 5 mL (400,000–
6,000,000 units) four times a day. Swish in mouth and retain for 2 min, and then
swallow or expectorate [161]. Continue treatment for at least 48 h after perioral
symptoms have disappeared.
Fluconazole: 200 mg PO loading dose then 100–200 mg daily for 1–2 weeks [162]
Itraconazole oral solution: 200 mg daily for 1–2 weeks [162]

6.7.5 Antivirals

The incidence of herpes simplex virus-1 (HSV-1) infection has been estimated to be
29% in patients with mucositis during head and neck cancer radiation therapy,
which is isolated from smears taken from patients with ulcerative mucositis [162].
The lesions present primarily as mucosal vesicles, which rupture spontaneously and
References 69

form ulcerative lesions. The early vesicular stage may be so rapid that it is not seen
in immunocompromised patients [163].
Patients with oral mucositis that experience a prolonged course of mucositis with
extreme pain or vesicular lesions, secondary HSV infection should be considered.
The gold standard diagnostic test for HSV-related oral mucositis is isolation of HSV
tissue culture (results usually take 2–7 days). A more rapid diagnostic test for muco-
cutaneous lesions uses staining of skin scrapings.
Treatment with oral or intravenous acyclovir or oral valacyclovir decreases the
duration of viral shedding and improves the severity of oral mucositis.

Oral acyclovir: 400 mg three times a day for 7–10 days (five times a day in immu-
nocompromised patients) [163]
Intravenous acyclovir (If oral intolerance develops): 5 mg/kg three times a day
[163, 164]
Oral valacyclovir: 1 g three times a day for 7–10 days [164]

6.7.6 Feeding Tube/Nutritional Support

In patients with severe symptoms of radiation mucositis, oral nutritional is compro-

mised and can lead to weight loss and nutritional depletion. Nutritional support and
feeding tubes should be considered in these patients [3, 165].
For short-term access, nasogastric and nasojejunal tubes may be used; for longer-­
term access, gastrostomy, gastrojejunostomy, and jejunostomy can be placed.
Percutaneous endoscopic gastrostomy is the method of choice unless in the setting
of esophagitis, gastroparesis, aspiration pneumonia, or limited gastric volume that
jejunostomy tube may be placed instead [166].
In patients without a functioning gastrointestinal tract due to obstruction, intrac-
table vomiting, diarrhea, poor GI motility, short bowel syndrome or severe pancre-
atitis, and total parenteral nutrition may be appropriate [166].

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Wilkins, Section V, Chapter 97
Xerostomia
7

Dry mouth (xerostomia) is one of the most common complications of radiation

therapy in head and neck cancers due to the high radiosensitivity of the salivary
glands.
Xerostomia is a common debilitating side effect of radiation therapy for head
and neck cancers that affects chewing, eating, tasting, swallowing, tooth decay, and
speaking. Xerostomia has a negative impact on quality of life in cancer patients.
It has been estimated that the incidence of acute xerostomia induced by radiation
therapy of head and neck cancers is 60–90% depending on tumor site, irradiation
technique, and time of evaluation; it is observed in 30% of patients with advanced
cancer in need of starting a palliative care program [1, 2].
In regard to timing of radiation therapy, the incidence of xerostomia is 6%, 93%,
and 83% before, during, and 1–3 months after treatment, respectively [3]. In regard
to type of radiation therapy, xerostomia occurs in 81%, and 71% of patients under-
went conventional head and neck radiation therapy during and 1–3 months after
treatment, respectively. New radiation techniques such as intensity-modulated radi-
ation therapy (IMRT) may spare salivary glands more than conventional therapies
and decrease xerostomia rate and severity [3].
Moderate to severe xerostomia occurs in 60.2% of patients with nasopharyngeal
carcinoma and in 32.9% of patients with other sites of head and neck cancer
3 months after treatment with intensity-modulated radiation therapy [4].

7.1 Mechanism

In order to understand the mechanism of xerostomia induction in radiation therapy,

salivary gland physiology needs to be understood.
The terms of major and minor salivary glands refer to their anatomic size. There
is a difference in the quality of content and quantity of production during different
time points through the day, which may affect the clinical symptoms related to each
salivary gland dysfunction.

© Springer International Publishing AG 2017 79

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_7
80 7 Xerostomia

Normal salivary flow is highly variable and is usually 0.25 mL/min (1–1.5 L per
day). A salivary flow of less than 0.12–0.16 mL/min is considered to be abnormal [5].
The parotid glands have only serous-secreting acinar cells and exclusively pro-
duce serous watery secretion. Up to 50% of stimulated saliva and approximately
20% of unstimulated saliva secretion volume comes from parotid glands
secretion.
The submandibular glands have both serous and mucous acinar cell types
(10% mucous cells and 90% serous cells) and produce a mixed serous and mucous
saliva. They contribute 65% of unstimulated saliva secretion and 35% of stimulated
saliva secretion.
The sublingual glands mainly have mucous acinar cells and produce predomi-
nantly thick, viscous saliva. They contribute less than 10% of unstimulated saliva
volume.
The minor glands, which are distributed throughout the upper aerodigestive
mucosa (e.g., labial, buccal, lingual, and palatinal mucosa), are mixed glands largely
comprised of mucous acinar cells. The minor glands produce less than 10% of the
total volume of saliva [6].
During the day, major saliva production in stimulated and unstimulated condi-
tions is related to parotid and submandibular glands, respectively [7].These major
salivary gland dysfunctions are major causes of xerostomia induced by radiation
therapy.
Salivary glands are highly radiosensitive. Serous acinar cells of the salivary
glands are well differentiated and have a slow mitotic rate and turnover, but they
behave like acutely responding tissues to radiation and undergo interphase cell
death by apoptosis [8, 9]. Mucous acinar cells of salivary glands have a lower
radiosensitivity than serous acinar cells, and they have a trend to retain their
function for some time later [10]. The parotid glands seem to lose more function
than do the other salivary glands, resulting in a decrease in watery saliva and
accumulation of sticky mucus. However, the difference in radiosensitivity
between the parotid and submandibular/sublingual salivary glands is still contro-
versial [11–13].
It has been found that saliva production reduces during the first days of radiation
therapy. Membrane damage of saliva-producing cells confounding with receptor-­
mediated signaling pathways of water excretion and functional loss is responsible
for the early hyposalivation. Cell death does not occur in the acute phase but is a late
event [14].
Saliva is a complex fluid, mostly composed of water (99%) and a minority of
various nonorganic and organic substances such as enzymes, hormones, antibodies,
antimicrobial constituents, and growth factors. Saliva quality changes during radia-
tion therapy, including increased viscosity, decreased transparency, yellow/brown
discoloration, declined production of glycoproteins (e.g., immunoglobulin A),
decreased salivary pH (from 6.8 and 7.0 to 5.5), altered salivary electrolyte levels
(increases in the concentrations of sodium, chloride, calcium, and magnesium with
slight potassium level change), and shift in certain intraoral microbial populations
7.3 Risk Factors 81

(increase in Streptococcus mutans and species of Lactobacillus, Candida (primarily

Candida albicans), and Staphylococcus, with parallel decreases in Streptococcus
sanguinis and species of Neisseria and Fusobacterium) [13, 15–18].

7.2 Timing

Radiation-induced xerostomia usually initiates early during radiation therapy for

head and neck cancers containing salivary glands within the radiation fields. When
the radiation dose reaches 10–20 Gy with 2 Gy per day, which corresponds to the
first to second week of treatment, a 50–60% decrease in salivary flow occurs, and
the patient may begin to experience mild to moderate dryness of the mouth, which
may progressively worsen over the course of treatment. After 7 weeks of radiation
therapy, salivary flow decreases to approximately 20% and continues to further drop
for more than 6 months after completion of treatment [11, 19, 20]. Some recovery
is possible until 12–18 months after radiation therapy depending on the dose
received by the salivary glands and the volume of the gland tissue included in the
irradiation volume; there is also a compensatory hypertrophy of the non-irradiated
salivary gland tissue. Xerostomia may rarely recover a few years after radiation
therapy [19, 20].
Radiation-induced salivary gland damage may be reversible or permanent based
on the radiation dose. With a dose less than 60 Gy, changes in the salivary glands,
including edema and inflammation, are reversible. Although, for acceptable func-
tion, the radiation doses to salivary glands should be more lower than 60 Gy. When
the dose exceeds 60 Gy, changes may be permanent, with fibrosis and glandular
degeneration [13].

7.3 Risk Factors

The occurrence and severity of radiation therapy-induced xerostomia are dependent on

radiation-related factors, mostly salivary gland radiation dose and volume within the
radiation field [21]. Altered fractionation schedules’ impact on the incidence of xero-
stomia is not clearly defined. It seems that accelerated and hyperfractionated radiation
therapy both increase acute side effects of treatment including xerostomia [22].
Concurrent chemotherapy is associated with a significant risk of developing
acute and late xerostomia [21]. However it has been shown in some studies that
concomitant chemotherapy and intensity-modulated radiation therapy do not
increase the incidence of acute or late xerostomia relative to intensity-modulated
radiation therapy alone [23]. Concomitant cetuximab (a monoclonal antibody
against EGFR) doesn’t increase the xerostomia rate when it’s prescribed concur-
rently with radiation therapy [24].
Patient age is also a contributing factor. With increasing age, the vulnerability of
salivary glands to radiation injury and development of xerostomia increases [7]. It
82 7 Xerostomia

should be noted that increasing age does not cause hyposalivation by itself [25]. The
higher incidence of xerostomia in elderly patients is mainly due to their comorbidi-
ties and use of medications with the potential to develop xerostomia.
No significant association between the risk of developing xerostomia and ethnic-
ity, marital, or socioeconomic status has been observed [21].
It has been proposed that the progression of xerostomia can be improved by mix-
ing clinical and dose-volume factors. The mean dose given to the contralateral and
ipsilateral parotid glands is the most significant predictors in multivariable normal
tissue complication probability models for xerostomia. Age, financial status,
T stage, and educational level are proposed clinical predictive factors for radiation-­
induced xerostomia. However some of these clinical datasets such as financial status
and education may affect the patient-reported xerostomia, many of which need to be
investigated before they are incorporated into the models [4].
The volumes of parotid and submandibular glands are decreased due to radiation
therapy. The parotid gland volume reduces about 30% during radiotherapy. The
lateral regions of the irradiated parotid glands move inward. The irradiated subman-
dibular glands also shrink and move upward. Parotid shrinkage during treatment is
accompanied by a decrease in tissue density consistent with a relative increase in fat
over glandular tissue [26, 27].
Parotid gland density and volume variations during radiation therapy may pos-
sibly predict acute xerostomia. It has been found that a higher score of acute xero-
stomia is predicted by higher density and volume variations in the first 2 weeks of
treatment. Further studies are necessary to definitively assess the potential of early
density/volume changes in identifying more sensitive patients at higher risk of
developing xerostomia [28].

7.4 Symptoms

Dryness is one of the most unpleasant oral symptoms that adversely affects all oral
functions and compromises oral health. Patients may experience dry oral mucosa
and thick, sticky saliva requiring them to adjust their diet and keep the mouth moist
with water [1, 29].
Both acute and chronic xerostomia induce functional alterations such as chew-
ing, swallowing, speaking, burning, and pain, with a propensity to bacterial and
fungal infection, demineralization of teeth, and increase in caries, dysgeusia, gag-
ging sensations, a fear of choking, and odynophagia. The patient may have bad
breath secondary to food stagnation in the oral mucosa, gingiva, teeth, or tongue
[30, 31].
Cheilitis, a fissuring or ulceration in the angles of the mouth and erythematous
tongue due to damage to the dorsal epithelium, can also be seen in patients with
xerostomia [29, 30].
Quality of life significantly worsens along with the severity of xerostomia. With
each milliliter decrease in saliva secretion, the quality of life score decreases by
2.25% [32].
7.6 Scoring 83

Fig. 7.1 Grade 2

xerostomia in tongue
cancer 1 month after
radiotherapy

7.5 Diagnosis

Xerostomia is a clinical diagnosis based on patient signs and symptoms (Fig. 7.1).
The objective tests of salivary flow are not usually used for diagnosis because there
is little correlation between patient symptoms and these tests. Therefore, clinical
management should be based on patient symptoms [33].
There are some differential diagnoses including oral infections, bad oral condi-
tions, and mucositis, which may be ruled out with a detailed history and clinical
exam. However, they can all occur in association with each other.

7.6 Scoring

For measuring the severity of xerostomia, there are assessment tools based on
patient- and observer-reported data.
Observer-based toxicity scoring is generally based on the Radiation Therapy
Oncology Group (RTOG)/European Organization for Research and Treatment of
84 7 Xerostomia

Table 7.1 RTOG/EORTC xerostomia scoring

Definition
Score 0 No change over baseline
Score 1 Mild mouth dryness/slightly thickened saliva/ may have slightly altered taste such as
metallic taste/these changes not reflected in alteration in baseline feeding behavior,
such as increased use of liquids with meal
Score 2 Moderate to complete dryness/thick, sticky saliva/markedly altered taste
Score 3 –
Score 4 Acute salivary gland necrosis

Table 7.2 Michigan University xerostomia questionnaire

0 1 2 3 4 5 6 7 8 9 10
Rate your difficulty in talking due to dryness
Rate your difficulty in chewing due to dryness
Rate your difficulty in swallowing solid food due to dryness
Rate the frequency of your sleeping problems due to dryness
Rate your mouth or throat dryness when eating food
Rate your mouth or throat dryness while not eating
Rate the frequency of sipping liquids to aid swallowing food
Rate the frequency of sipping liquids for oral comfort when
not eating

Cancer (EORTC) grading scale (Table 7.1). Because of the low correlation between
the measured salivary output and observer-reported xerostomia [34] and underesti-
mation of the severity of xerostomia with these scoring systems [35], several xero-
stomia questionnaires have been developed to permit patient self-reporting.
One of the most validated patient self-reported questionnaires is xerostomia
questionnaire (XQ), which was developed by the University of Michigan (Table 7.2).
It consists of eight questions; patients rate each item on a scale from 0 to 10. Higher
scores are related to more severe xerostomia [35].

7.7 Prevention

There are some preventive approaches for radiation-induced xerostomia, including

more conformal radiation delivery technology, radioprotective agents, and even pre-
irradiation surgical techniques [36, 37].

7.7.1 Amifostin

Available data show that amifostine significantly reduces the incidence of acute and
long-term xerostomia. Amifostine, an organic thiophosphate agent, is a prodrug that is
dephosphorylated by alkaline phosphatase in tissues after administration, converting it
into its active form. This active form enters the cells and acts as a scavenger against free
radicals. Amifostine concentrations in tumor cells are lower than normal tissue due to
7.7 Prevention 85

lower alkaline phosphatase levels and the pH of tumors, and therefore normal tissue
protection is provided [20]. However, amifostine’s effect on tumor cell protection is
still a concern that precludes it from extensive administration as a radioprotective agent.
Brizel et al. in a phase III trial randomized 303 patients that received conventional
radiation therapy for head and neck cancers (both postoperative and as primary treat-
ment) to receive amifostine daily before each fraction (200 mg/m2 intravenously). They
found that amifostine significantly reduced the incidence of grade 2 acute xerostomia
from 78% to 51% and reduced the incidence of grade 2 chronic xerostomia from 57%
to 34% without a difference in disease control or survival [38]. Amifostine was conse-
quently approved by the US Food and Drug Administration (FDA).
Amifostine can be administered only with standard fractionated radiation ther-
apy without chemotherapy and only when ≥75% of both parotid glands are exposed
to radiation in the postoperative setting. Amifostine should not be administered in
patients receiving definitive radiation therapy, except in the context of a clinical
trial, because of insufficient data to exclude a tumor-protective effect in this setting
[39]. Amifostine administration in the setting of concurrent chemotherapy with
radiation therapy and in the setting of accelerated and hyperfractionated therapy has
not been systematically studied [40–43].

7.7.1.1 Prescription
Each vial contains 500 mg of amifostine on the anhydrous basis, requiring reconsti-
tution for intravenous infusion [44]. Prior to intravenous injection, amifostine is
reconstituted with 9.7 mL of sterile 0.9% sodium chloride. The reconstituted solu-
tion (500 mg Amifostine/10 mL) is chemically stable for up to 5 h at room tempera-
ture (approximately 25 °C) or up to 24 h under refrigeration (2 °C–8°C). Amifostine
is prepared in polyvinylchloride (PVC) bags and is available at concentrations rang-
ing from 5 mg/mL to 40 mg/mL [45].
Standard amifostine intravenous administration: 200 mg/m2 over 3 min once
daily 15–30 min prior to radiation therapy [46, 47].
Amifostine can also be administered subcutaneously (unlabeled route): 500 mg
once daily prior to radiation therapy [46, 48, 49].
Note: Because of rapid clearance from the blood and tissue, the drug needs to be
delivered shortly before radiation therapy.

7.7.1.2 Contraindications
Hypersensitivity to aminothiol compounds or any component of the formulation.

7.7.1.3 Advers effects

Several adverse effects have been reported for amifostine including hypotension,
nausea and vomiting, hypocalcemia, and cutaneous reactions.
Blood pressure should be monitored every 5 min during the infusion and there-
after as clinically indicated. The infusion of amifostine should be interrupted if the
systolic blood pressure decreases significantly from baseline [45, 48].
Amifostine is a moderately to highly emetogenic agent, and antiemetic medica-
tions (including dexamethasone 20 mg I.V. and a serotonin 5-HT3 receptor antago-
nist) should be administered prior to and in conjunction with amifostine [50].
86 7 Xerostomia

Serum calcium levels at baseline should be checked and monitored in patients at

risk for hypocalcemia, such as those with nephrotic syndrome or patients receiving
multiple doses of amifostine for injection [45, 48].
Cutaneous evaluation of the patient prior to each administration and permanent dis-
continuation for serious or severe cutaneous reactions should be performed [44, 45].

7.7.2 IMRT

The volume of salivary tissue irradiated is related to the occurrence of xerostomia.

With introduction of novel radiation therapy delivery techniques including inten-
sity-modulated radiation therapy (IMRT), partial sparing of salivary glands may
become possible, and thus acute and late xerostomia are significantly reduced [51,
52]. Mean dose to the parotid glands should be reduced as much as clinically pos-
sible. A mean dose of less than 20 Gy for at least one parotid gland or a mean dose
of less than 25 Gy for both glands may prevent severe long-term xerostomia [53]. It
has been suggested that the mean parotid dose for both sides together has a higher
predictive value over considering each side separately [27].
The effect of amifostine combined with IMRT is not clear. It seems that the protective
effect of IMRT in sparing saliva is much greater than the effect of amifostine [54, 55].
In patients that need bilateral radiation therapy of the head and neck including
bilateral parotids within the radiation fields, the effect of IMRT in prevention of
xerostomia is limited.
IMRT provides a way to spare all salivary glands and improves xerostomia-­
related quality of life during meals and at rest; however, the largest effect is still on
xerostomia during meals [56]. As noted previously, the parotid glands are largely
responsible for the stimulated saliva output, whereas the minor salivary glands and
submandibular glands are mainly responsible for unstimulated saliva (lubrication in
rest). The risk of xerostomia decreases or is even eliminated with sparing of at least
one parotid gland and reduces with sparing of at least one submandibular gland
[53]. It has been reported that a lower mean dose to the oral cavity (<40 Gy) and
contralateral submandibular gland (<50 Gy) is each associated with lower patient-­
reported and observer-rated xerostomia [51].

7.7.3 Submandibular gland transfer

Another preventive approach is submandibular gland transfer. The submandibular

gland is responsible for most of the unstimulated salivary volume, which is impor-
tant in the subjective symptoms of xerostomia and oral homeostasis. Some argue
that sparing the submandibular gland is preferable to sparing the parotid gland [29].
In this approach, a single submandibular gland is transferred into the submental
space during a surgical procedure referred to as the Seikaly-Jha procedure (SJP).
The borders of the transferred gland are marked with wire to help identify it during
7.7 Prevention 87

radiation therapy and can be shielded from the radiation [57, 58]. The surgical
method of transfer is a quick, easy, and simple procedure that can be done during
surgical treatment of the primary tumor [20, 59–61].
The submandibular gland may be damaged during the transfer, and complete
prevention cannot be achieved, although it is still superior to some other preventive
options including pilocarpine in regard to median salivary flow and saliva consis-
tency. It has been estimated that the submandibular gland transfer could reduce
69% of the risk of acute xerostomia. However, after radiation therapy, the salivary
gland repaired itself and the rate of late xerostomia can reach 19% [62]. Local/
regional recurrence and survival outcome after submandibular gland transfer seem
not to be compromised; however there is some controversy and need for more
evaluation [41, 63].
Submandibular gland transfer should be conducted on the gland of the contralat-
eral side of the primary cancer. The procedure should not be performed for patients
with cancer of the oral cavity, bilateral neck lymph node involvement, submandibu-
lar or submental neck lymph node involvement, or advanced neck disease (N3). For
accurate selection of patients that are candidates for submandibular gland transfer,
suspicious nodes and all level I lymph nodes (submental and submandibular) are dis-
sected and sent for frozen section evaluation before transfer. If any of the nodes are
involved with cancer, the transfer procedure should be abandoned [62].
Collectively, quality of life in head and neck cancer patients that are at risk of
radiation-induced xerostomia may improve with submandibular gland transfer [58,
59, 63]. However, further studies are still needed to confirm the safety of this
surgery.

7.7.4 Pilocarpine

Pilocarpine has been approved for postradiation xerostomia. The administration of

pilocarpine during radiation therapy has been studied to prevent the subsequent
development of xerostomia.
Pilocarpine hydrochloride is a muscarinic-cholinergic agent that can stimulate
salivary glands [64–66].
Several studies have shown positive results of pilocarpine in the prevention of
radiation-induced xerostomia, especially when the doses of whole parotid glands
are more than 45 Gy. However, others have concluded that oral pilocarpine could
not be recommended to prevent xerostomia in patients receiving radiation therapy
for head and neck cancers [67].
It has been found that pilocarpine administration during radiation therapy can
result in a significant improvement in unstimulated salivary flow at the end of treat-
ment but not in stimulated flow. This observation can be explained with the mecha-
nism of pilocarpine’s protective effects [68]. Pilocarpine stimulates the residual
function of salivary tissues outside the radiation fields, including non-irradiated
parts of parotid and other major salivary glands/minor salivary glands, and it has no
88 7 Xerostomia

protective effect in the glands that are completely irradiated [69–72]. Prominently
unstimulated salivary flow is preserved.
The other hypothesis proposed for the mechanism of pilocarpine’s protective effect is
related to indirect inhibition of radiation-induced oxidative damage. Pilocarpine reduces
heavy metals such as zinc, manganese, and iron, which are found in secretary granules,
leading to reduction in intracellular leakage of proteolytic enzymes in secretary granules
after radiation damage and reduction in subsequent serous cell autolysis [67, 70].
Data based on in vitro studies indicate that pretreatment pilocarpine administration
does not protect tumor cells and has no effect on radiosensitivity of cell lines [73].

7.7.4.1 Prescription
Start pilocarpine 5 mg three times daily with irradiation, and continue until 3 months
after the end of radiotherapy [74].
Available tablets: 5 mg, 7.5 mg
Taking with a high-fat meal reduces pilocarpine absorption. Give the medication
with food if GI distress occurs.)

7.7.4.2 Contraindications
Hypersensitivity to pilocarpine or any component of the formulation, uncontrolled
asthma, acute iritis or glaucoma, and severe hepatic impairment (adjust dose with
moderate hepatic impairment) [75]
Pilocarpine should be used with extreme caution in patients that have chronic
obstructive pulmonary disease and cardiovascular disease.

7.7.5 Acupuncture

Acupuncture has been investigated in the management of patients with xerostomia

and demonstrated some benefits for improving salivary flow rates and reducing
xerostomia-related symptoms. Based on these observations, the preventive approach
of acupuncture has been recently addressed with promising results [76].
Low-level laser therapy refers to local application of a high-density monochromatic
narrowband light source with the output power range from 5 to 500 mW and a wave-
length between 600 and 1000 nanometers (like helium/neon with wavelength 632.8 nm
or diode laser with various wavelengths 630–680, 700–830, and 900 nm) [77].
Low-level laser therapy may result in improvement of the salivary flow by stimu-
lating salivary glands and the regenerative effect with an increase in the number of
mitosis [78]. Although the use of a low-power laser may prevent xerostomia, it
needs further study to be better implemented [78, 79].
Patients with Sjögren syndrome have been studied and shown that low-level laser
therapy can be safely and effectively used in these patients to reduce xerostomia
[80, 81]. However for detection of low-level laser therapy efficacy on radiation-­
induced xerostomia, long-term follow-up is necessary.
7.8 Management 89

7.8 Management

Therapeutic interventions include supportive care, saliva supplementation, and the

use of procholinergic salivary secretagogues.

7.8.1 Supportive Care

7.8.1.1 Oral Rinses

Oral rinses are recommended to keep the mouth moist and clean by removing
debris.
Patients are informed to use 1 tablespoon (15 mL) of oral rinse such as normal
saline (NS) or 1/2 teaspoon (2.5 mL) of salt in 240 mL of water to swish in the
oral cavity for 30 s and then spit out [82]. Commercially available alcohol-con-
taining oral rinses should be avoided due to their drying effect. Limited data have
proposed that all Biotène products, which include a range of toothpastes, mouth-
washes, mouth sprays, chewing gum, and gels, can improve many of the symp-
toms of radiation-­induced xerostomia, but larger studies are needed to evaluate
efficacy [83].

7.8.1.2 Chewing to Stimulate Secretion of Residual Glandular Tissue

Chewing is a stimulus for inducing salivary glands to secret more saliva, and chew-
ing several times a day can be helpful in reducing symptoms [40].

7.8.1.3 Maintaining Adequate Nutrition

Patients may benefit from a nutritional consult and should be encouraged to moisten
their foods by adding butter, mayonnaise, vegetable oil, yogurt ,or sauces and have
a sip of a liquid after each bite, which helps chewing and swallowing. Patients
should avoid foods high in sugar due to their susceptibility to dental caries, dry or
spicy food, and excessively hot or cold beverages [40].
Xylitol is a natural sweetener product that differs chemically from other sweet-
eners like sorbitol, fructose, or glucose. It actually interferes with the growth of
bacteria associated with tooth decay, and it is approved as a therapeutic sweetener
by the Food and Drug Administration [40].
These patients should avoid irritating foods that are astringents or that may stick
to the teeth [40].
Alcohol, tobacco, and large amounts of caffeine should be avoided due to their
drying effect [82].

7.8.1.4 Drink Adequate Fluids

Patients should be instructed to always carry water with them and keep themselves
well hydrated [82].
90 7 Xerostomia

7.8.1.5 Protection from Dry Lips

Using topically applied water- or aloe-based lubricant after oral care, at bedtime,
and as often as required is helpful [82].

7.8.1.6 Alleviating Nocturnal Symptoms

A mouth guard, a cold air humidifier in the form of a bedside vaporizer or household
humidifier, or applying a small amount of dentifrice on smooth dental surfaces
(especially using anti-xerostomia dentifrices) can alleviate the nocturnal oral dry-
ness [15].

7.8.1.7 Keeping Appropriate Oral Hygiene and Dental Care

Patients should be instructed on tooth brushing, dental flossing, tongue brushing,
and oral mouth rinsing with an appropriate antibacterial mouth rinse such as
chlorhexidine and hexitidine several times a day.

7.8.2 Saliva Supplementation

Replacement therapy with artificial saliva or saliva substitutes can be used to lubri-
cate the mouth. Various substitutes are available commercially that are formulated
to mimic natural saliva [41]. They have short-term activity with no stimulating
effect on salivary glands.
A variety of forms of products including solutions, sprays, gels, and lozenges are
available. In general, they contain an agent to increase viscosity, such as carboxy-
methylcellulose or hydroxyethylcellulose, minerals such as calcium and phosphate
ions and fluoride, preservatives such as methylparaben or propylparaben, and fla-
voring and related agents [41].
Artificial substitutes do not replace the antibacterial and immunologic protection
of saliva and do not exclude the need for regular dental care and appropriate oral
hygiene [11].

7.8.3 Acupuncture

Acupuncture may have a stimulating effect on saliva production and may be a useful
treatment for some patients. The possible mechanism of acupuncture is related to
parasympathetic central nervous system processes, which increase the concentra-
tion of salivary neuropeptides and modulate the complex process of salivary secre-
tion. Another possible mechanism of acupuncture is stimulation of minor salivary
glands present in non-irradiated buccal mucosa [15, 84, 85].
There are some studies that provide encouraging results for using acupuncture in
xerostomia [84, 86–90], while others do not provide a statistically significant effect
on the increase of salivary flow [91, 92]. Further research on acupuncture is neces-
sary prior to the recommendation for widespread clinical implementation in xero-
stomia treatment.
7.8 Management 91

7.8.4 Drugs

Patients with radiation-induced xerostomia may have a minimal response (mainly with
an increase in resting saliva) to systemic sialagogues, but small increases in saliva may
translate into subjective patient willingness [93]. Several therapeutic drugs have been
used to treat xerostomia. Pilocarpine and cevimeline are two systemic FDA-approved
sialagogues for the treatment of xerostomia [94]. In respect to radiation-induced xero-
stomia, pilocarpine is the sole sialagogue agent approved by the FDA [20].
Administration: 5 mg 3 times/day, titration up to 10 mg 3 times/day may be con-
sidered for patients that have not responded adequately (not to exceed 30 mg/day).
After the administration of pilocarpine, salivary output increases rapidly, usually
reaching a maximum within 1 h and returning to baseline at 3 h [31, 95–99].
Systemic administration of pilocarpine is associated with an increased risk of
side effects (e.g., mild-to-moderate sweating, flushing, headache, nausea, urinary
frequency, lacrimation, and rhinitis). Local administration of pilocarpine (topical
pilocarpine) may be an appropriate alternative with a potential decrease in systemic
side effects. Local stimulation of saliva more rapidly increases salivary production
rather than systemic pilocarpine. Overall improvement of xerostomia seems to not
be significantly different between oral and systemic pilocarpine. Further investiga-
tion is required to provide more definitive conclusions [72].
Cevimeline is a newer muscarinic agonist that has been studied in patients with
xerostomia after radiation therapy for head and neck cancers with positive results
[100]. Cevimeline (45 mg three times daily) studied in patients with radiation-­
induced xerostomia showed that 69% experienced an adverse effect, mostly mild to
moderate in severity. The most frequent side effects were sweating, dyspepsia, nau-
sea, and diarrhea [101]. There is no significant difference in overall increase of
production of saliva with cevimeline or pilocarpine [102]. Based on animal studies,
the central nervous system effects are more common with cevimeline than pilocar-
pine, but no clear difference was observed in respiratory and cardiovascular effects.
Clinical trials are ongoing to determine the efficacy and side effects of both cevime-
line and pilocarpine in the secretion of saliva for patients with xerostomia.
Bromhexine, a mucolytic agent, has been used by patients with radiation-induced
xerostomia. However, pilocarpine has demonstrated superiority to bromhexine in
improving xerostomia symptoms [103].
Bethanechol, with prolonged muscarinic and nicotinic-cholinergic activity, has
also been used in patients with radiation-induced xerostomia with no significant
difference in efficacy and side effects rather than pilocarpine [93, 104].
Malva sylvestris L and Alcea digitata (Boiss) Alef have been used as herbal reme-
dies in traditional Persian medicine for their antitussive, antioxidant, expectorant, anti-
inflammatory, antimicrobial, and laxative therapeutic effects [105]. They are useful for
lubrication of the throat and lungs and in respiratory disorders. Studies have shown
these plants to be immune stimulants that are useful in mucositis. This compound was
compared with artificial saliva in a randomized trial [106].The herbal group showed a
significant difference between the grade of dry mouth before and after intervention,
but no change was observed for the grade of dry mouth in the artificial saliva group.
92 7 Xerostomia

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Loss of Taste
8

A reduction in taste sensitivity (hypogeusia), an absence of taste sensation (ageu-

sia), or a distortion of normal taste (dysgeusia) are well-known side effects in cancer
patients that receive radiation therapy to the head and neck areas, and it has been
reported in up to 100% of these patients [1–4]. The generic term of dysgeusia more
commonly refers to any alteration in taste perception [5].

8.1 Mechanism

There are four basic taste intensities: salt, sour, bitter, and sweet. In addition to these
basic tastes, a novel taste that is referred to by the Japanese word umami, which
means delicious, has come to be recognized as a “fifth taste.” Umami is found in a
diversity of foods (e.g., fish, meat, milk, tomato, and some vegetables), which is
created by the combination of glutamate with 5′-ribonucleotides [6–8].
The sense of taste is mediated by the taste buds. They are found in the oral cavity,
primarily on the dorsum of the tongue in the circumvallate, fungiform, and foliate
papillae and on the palate, lips, cheeks, pharynx, epiglottis, larynx, and upper part
of the esophagus [9, 10].
The taste bud is an onion-shaped epithelial structure with 50–100 tightly packed
cells, including taste receptor cells, supporting cells, and basal cells [11]. Each taste
bud opens to the epithelial surface via a small opening called the taste pore [12].
Taste receptor cells have short microvilli, which emerge from the apical region
(outer end) of the taste cells to a taste pit below the inner taste pore. Taste receptor
sites are located on membranes of microvilli. The microvilli are the portion of the
cell that is exposed to the oral cavity [13]. The pore enables molecules and ions
taken into the mouth to reach the receptor cells inside [12].
The taste receptor cells contact with afferent sensory neurons at their inner ends.

© Springer International Publishing AG 2017 97

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_8
98 8 Loss of Taste

A nutritional, or trophic, interaction (i.e., one cell emits a substance that a second
cell needs to grow) between the nerve fibers and taste buds exists. The interruption
of the nerve fibers results in the disappearance of the taste buds [12].
Each of the different tastes is perceived in an individual taste bud with spe-
cific receptor cells that respond to distinct chemical stimuli. Furthermore, the
diverse sites of the tongue surface are sensitive to a distinctive taste. For exam-
ple, the anterior (tip) tongue is most sensitive to sweet or salty stimuli, while the
lateral edges and posterior aspects of the tongue respond predominantly to sour
and bitter substances, respectively. However, there is a concept that each taste
cell and each site of the tongue surface may be sensitive to more than one taste
[14], and all four different tastes can be perceived in all areas where taste buds
are located [15].
The mechanisms involved in taste loss during radiation therapy are complex.
Functional loss of taste buds occurs following radiation therapy due to the taste-cell
microvilli or their membrane injuries. Membrane damage causes interruption of the
synaptic contacts, impairment of taste bud trophic function of the nerve, and taste
bud atrophy [12, 16, 17]. Functional loss of taste buds precedes cell loss, which
occurs later following radiation therapy [12, 18].
Direct mucosal and epithelial cell damage of radiation results in desquamation of
the surface epithelium. The epithelial thickness is increased, the taste pores are cov-
ered, and the total area of the taste pores is also decreased [14, 19].

8.2 Timing

Alteration in taste is an early and rapid response to radiation and often precedes
mucositis [20]. Increase in taste thresholds begins from treatment with as little as
2–4 Gy and rises exponentially with a cumulative dose of about 30 Gy (3 weeks),
2 Gy per fraction. Rate of loss then slows down as the patients’ acuity approaches
nil at >30 Gy [18]. Subjective complaints of taste also are started early after the
beginning of the treatment, approximately 1–2 weeks after the initiation of treat-
ment [3, 21, 22]. Perception of bitter and acid flavors is more susceptible to impair-
ment than perception of salty and sweet flavors [23].
The clinical impairment pattern of umami taste has been investigated. Umami
taste declines during the third week after the start of radiation therapy and improves
after treatment conclusion [6, 24].
Loss of taste is usually transient. Patients often experience normal or near-­normal
levels of taste within 1 year after radiation therapy, although it can sometimes take
a few years, or even a residual reduction in taste acuity may permanently remain
[20, 23, 25–32].
A permanent loss of taste can occur at the dose of about 60 Gy [28, 33]. However,
due to the adaptation of the patient to the sensory loss, a minority of patients com-
plain of taste loss [11].
8.5 Diagnosis 99

8.3 Risk Factors

The proportion of the tongue that is contained within the radiation fields and the irra-
diation dose delivered has a significant correlation with the taste loss [12, 15, 34, 35].
A correlation between the tongue area that irradiated and the taste sensation mostly
lost has been observed [18].
The presence of saliva plays a significant role in the normal taste acuity by trans-
port and solubility of gustatory stimulants and protection of the taste receptors.
Saliva production may be reduced by radiation therapy and affects taste sensitivity
[11, 13, 20, 26, 34, 36].
Other factors that have some influence on the incidence or severity of loss of
taste caused by irradiation are malnutrition or specific vitamin or mineral defi-
ciencies like zinc deficiency [37] and destruction of the taste buds by the tumor
[9]. Head and neck surgery by a reduction of the total number of taste buds or
around the chorda tympani or glossopharyngeal nerve [2, 38] can also affect
acuity of taste. Chemotherapy drugs [12, 39], oral mucositis [40], and infection
[5] can exacerbate radiation-induced dysgeusia. Systemic disease like liver and
kidney disorders, endocrine disorders, diabetes mellitus, psychological disor-
ders, and central nervous system disorders, smoking, and alcoholism can also
decrease taste [2, 41].

8.4 Symptoms

Irradiation of the taste buds typically leads to partial (hypogeusia) or complete

(ageusia) inability to taste or an abnormal taste (dysgeusia) [18]. These taste abnor-
malities lead to the decreased hedonic aspect of food intake, decreased appetite, and
reduced nutrient intake, leading to anorexia and weight loss [2, 18, 21, 37, 42].
The nature of the taste sensation modifies the volume and character of saliva.
Loss of taste and failure of adequate salivation may explain difficulty in swallowing
reported by some affected patients [37].

8.5 Diagnosis

Loss of taste may be a subjective response, which patients may indicate a presence
of any subjective awareness of it.
Subjective awareness of taste loss and the presence of any distress caused by taste
impairment (e.g., decreased enjoyment of food and appetite) can be assessed by
using taste questionnaires [2], and objective detection of taste loss and recognition of
the thresholds for each taste quality can be determined in each patient by the increase
in threshold above the upper limit of normal and the lowest concentration of a solute
that the patient distinguishes as different from water, respectively [9, 21, 43–45].
100 8 Loss of Taste

Table 8.1 CTCAE. V4.03 for taste

Definition
Grade 1 Altered taste but no change in diet
Grade 2 Altered taste with change in diet (e.g., oral supplements); noxious or unpleasant
taste; loss of taste

8.6 Scoring

Common Toxicity Criteria for Adverse Effect (CTCAE), version 4.03, scoring sys-
tem has just defined two grades for taste abnormalities [46] (Table 8.1).

8.7 Prevention

Prevention of taste loss can be obtained by the modification of radiation therapy

including normal tissue shielding or placement of these tissues outside the radiation
field by means of field arrangements or repositioning prostheses (e.g., tongue
depressor) [47] or advanced radiation therapy technique (e.g., intensity-modulated
radiotherapy) [48, 49].
The effect of amifostine on taste loss is inconclusive. The administration of ami-
fostine may produce reductions in the severity of taste loss. However, the total fre-
quency of dysgeusia can be more frequent among patients given amifostine than
among controls [50, 51]. Further studies are needed in this regard.
All actions for prevention of xerostomia may be effective in reducing radiation-­
induced taste loss [48] (see Chap. 7).
There are a lack of data and controversial results on the effects of zinc supplemen-
tation in prevention/treatment of taste alterations in cancer patients (see Sect. 8.8).

8.8 Management

In most instances, taste gradually returns to normal or near-normal levels within 1

year after radiation therapy. Because of this transitory aspect, there is usually no
need for special treatment [25], but clinicians can help their patients by offering
counseling to improve their distressing symptoms. Dietary counseling and patient
education can result in improved nutrition status and prevent weight loss.
Patients should be instructed about methods to increase taste, including prepar-
ing foods with strong taste and creating an attractive presentation of foods. Patients
should be encouraged to avoid the use of tobacco and/or alcohol and management
of hyposalivation and poor oral hygiene.
The assessment for taste alterations includes a thorough dietary history, eating
habits, current appetite and desire for food, and weight measuring for compari-
son to baseline [52]. Nutritional counseling estimates each patient’s current
nutritional status, calculates increase in energy and protein requirements to
8.8 Management 101

overcome deficits, and provides the therapeutic diet based on personal eating pat-
terns and preferences, which are adjusted to the individual’s needs. Dietary coun-
seling corrects patient diets with appropriate manipulation and consideration of
foods with appealing taste, color, and smell; oral nutritional supplements may be
added to the diet only in patients with inadequate food intake for more than
5 days or BMI < 18.5 [53, 54].
In the setting of significant weight loss (>2% loss in 1 week), patients should be
evaluated by a registered dietician [52]. A dietician provides an individualized and
intensive dietary counseling based on standard nutrition protocol, the Medical
Nutrition Therapy (Cancer/Radiation Oncology) protocol of the American Dietetic
Association (ADA), to maintain and/or improve a patient’s energy and protein
intake [55–57].
In general, 25–30 kilocalories per kilogram body weight per day and 1–1.5 g of
protein per kilogram per day are appropriate for those of normal weight. For those
that are hypermetabolic or need to gain weight, 30–35 kilocalories per kilogram or
greater and 1.5–2.5 g of protein per kilogram may be necessary [58].
Energy requirements can be calculated using various formulas, which give more
precise estimates of resting energy expenditure. The Harris-Benedict equation is
practical and reliable for measuring metabolic rate. The equation is used to estimate
the basal energy expenditure (BEE) based on weight, height, and age [59]. To esti-
mate daily energy requirements, basal requirements were multiplied by a 1.5 activ-
ity factor [60].

In men :
BEE = 66.5 + (13.75 ´ kg ) + ( 5.003 ´ cm ) - ( 6.775 ´ age ) .
In women :
BEE = 655.1 + ( 9.563 ´ kg ) + (1.850 ´ cm ) - ( 4.676 ´ age )

Zinc plays an important role in taste perception [61]. Zinc deficiency results in
structural changes in taste buds cells, changes in the number and size profile of taste
buds, and decrease in related nerve sensitivity [62, 63]. The effects of zinc supple-
mentation in prevention/treatment of taste alterations in cancer patients are contro-
versial. Some have found that the administration of zinc sulfate (45–50 mg orally
three times daily) in cancer patients that had received radiation therapy to the head
and neck region is an effective approach both in the prevention and correction of
taste abnormalities [2, 3, 21, 64]. However, some found no statistically significant
effect of zinc sulfate therapy on radiation-induced taste alterations [65]. Further
studies with longer follow-ups and with different doses of zinc supplementation are
needed in this regard.
The use of megestrol acetate (480 mg/day) during radiation therapy may be
effective in the improvement of loss of taste, appetite, and reversing malnutrition.
Further evaluation of its effect on radiation-related complications and patient out-
comes is needed [66].
102 8 Loss of Taste

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Laryngeal Edema
9

Laryngeal edema occurs when the larynx is included in the treatment field and may
impact the voice. Laryngeal edema accompanied by hoarseness is a common acute
side effect in radiation therapy of laryngeal and hypopharyngeal carcinoma and
whenever the neck is irradiated [1]; however, no studies have reported its incidence
as an acute side effect. It has been estimated that 15–59% of patients with head and
neck cancers develop grade 2 or higher laryngeal edema within 2 years after radia-
tion therapy [2].

9.1 Mechanism

Ionizing radiation generates free radicals and produces various reactive oxygen
species (ROS) that result in DNA damage and changes in the local microenviron-
ment through the activation of cytokine cascades and influx of inflammatory cells
[3, 4]. These processes cause inflammation, hyperemia, and erythema of the
laryngeal mucosa.
The larynx has many mixed serous-mucinous-type glands that lubricate the lar-
ynx with thin mucus secretion and is essential to phonation. Radiation induces atro-
phic changes in laryngeal glands leading to changes in the quantity and quality of
secretions, poor lubrication of the vocal folds, and subsequent voice problems [5, 6].

9.2 Timing

Laryngeal edema may occur during the first 2–3 weeks of radiation therapy and
continue to increase to the end of treatment. Recovery begins 3 weeks after treat-
ment completion and may require 6–12 months to subside.

© Springer International Publishing AG 2017 105

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_9
106 9 Laryngeal Edema

9.3 Risk Factors

The incidence of acute laryngeal edema increases with total dose, field size, tumor
stage, smoking, supraglottic laryngectomy, and chemotherapy administration [2,
7–10].

9.4 Symptoms

In the acute phase, laryngeal edema related to radiation causes phonation dysfunc-
tion (Fig. 9.1) that rarely is severe enough to cause serious dysphagia or compro-
mise the airway [11]. Dryness of the laryngeal mucosa makes it sensitive to develop
referral ear or throat pain.

9.5 Scoring

RTOG Common Toxicity Criteria for acute laryngeal side effects is based on clini-
cal criteria and has been shown in Table 9.1 [12].

Fig. 9.1 Laryngeal edema 7 days after full dose 3DCRT for recurrent true vocal cord SCC

Table 9.1 RTOG common toxicity criteria for laryngeal toxicity criteria
Definition
Grade 0 No change over baseline
Grade 1 Mild or intermittent hoarseness/cough not requiring antitussive/erythema of mucosa
Grade 2 Persistent hoarseness but able to vocalize/referred ear pain, sore throat, patchy
fibrinous exudate, or mild arytenoid edema not requiring narcotic/cough requiring
antitussive
Grade 3 Whispered speech, throat pain, or referred ear pain requiring narcotic/confluent
fibrinous exudate, marked arytenoid edema
Grade 4 Marked dyspnea, stridor, or hemoptysis with tracheostomy or intubation necessary
References 107

9.6 Prevention

The volume of larynx in radiation field receiving high dose of radiation should be
kept as low as possible to minimize the edema. The investigators suggested that the
percentage of laryngeal volume receiving more than 50 Gy and the mean laryngeal
dose should be ideally constrained to less than 27% and 43.5 Gy, respectively [13].
Smoking and alcohol consumption will increase the risk of severe laryngeal edema,
and patients should be encouraged to cease smoking and alcohol consumption.

9.7 Management

Exacerbating behavior such as smoking and alcohol consumption should be discon-

tinued. Voice rest is recommended to all patients.
In patients with moderate to severe or persistent laryngeal edema unresponsive
to conservative treatment methods, treatment with steroids and occasionally antibi-
otics may be necessary [2].
In patients with severe laryngeal edema leading to compromise airway, tempo-
rary tracheostomy should be considered [10].

References
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2. Bae JS, Roh JL, Lee SW, Kim SB, Kim JS, Lee JH, Choi SH, Nam SY, Kim SY (2012)
Laryngeal edema after radiotherapy in patients with squamous cell carcinomas of the larynx
and hypopharynx. Oral Oncol 48(9):853–858
3. Barnett G, West C, Dunning A, Elliott R, Coles C, Pharoah P, Burnet N (2009) Normal tissue reac-
tions to radiotherapy towards tailoring treatment dose by genotype. Nat Rev Cancer 9(2):134–142
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Radiation Pneumonitis
10

Radiation pneumonitis (RP), the acute manifestation of radiation-induced lung

injury, is one of the main dose-limiting toxicities among patients receiving thoracic
radiation therapy. It has been reported to occur in 13–37% of patients receiving
definitive external beam radiation therapy for lung cancer [1]. Radiation pneumoni-
tis development following radiation therapy for other cancers actually depends on
lung volume, which is included in various irradiated volumes and dose parameters.
Some other factors such as smoking, background lung disease, or combined modal-
ity treatments are also important risk factors for radiation-induced pneumonitis. The
incidence of radiation pneumonitis is lower in Hodgkin disease (3%) [2] and breast
cancer patients (1%) [3] compared with lung cancer patients. Diagnosis and indica-
tions for therapeutic intervention are in a major controversy that will be discussed
in the next few paragraphs.

10.1 Mechanism

The first changes that are induced by radiation are increased vascular permeability
and exudation of proteinaceous material in the alveolar space [4]. Capillary endo-
thelial cells are very sensitive to ionizing radiation, and their damages are mani-
fested by detachment of cells from their basement membrane, which is followed by
blood flow turbulence and thrombosis formation. Following endothelial cell injury,
capillary permeation increases, fibrin-rich exudate leaks into the alveoli, and a hya-
line membrane is formed, which impairs gas exchange. Ionizing radiation can also
damage alveolar cells, which are manifested by depletion of type I pneumocytes
and hyperplasia of type II pneumocytes, in the context of the alveolar epithelium
regeneration process [5]. On the other hand, type II pneumocytes are also known to
be damaged by radiation therapy, resulting in release of surfactant into the alveolar
space and detachment of the pneumocytes from their basement membrane [6].
Later, the alveolar exudate clears, fibroblasts migrate into the alveolar walls, and the
alveolar septa are thickened.

© Springer International Publishing AG 2017 109

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_10
110 10 Radiation Pneumonitis

Fig. 10.1 Radiation-­

induced pneumonitis in a
patient with bulky Hodgkin
disease at 2 months after
mediastinal radiation
therapy

10.2 Timing

Although pathologic changes in lung tissue occur in the initial 24–48 h after radia-
tion, those changes are undetectable both clinically and radiologically. Radiation
pneumonitis occurs typically within 6 months after a course of radiation with a peak
onset at 1–3 months but may be seen as early as 1 week, especially in patients
receiving high total dose [7]. In some cases, no symptoms are present, and the diag-
nosis is made by imaging alone (Fig. 10.1).

10.3 Risk Factors

10.3.1 Volume and Dose Parameters

Nontarget lung dose and irradiated volume should be lowered as much as possible.
Different dose and volume parameters (mean lung dose, V5, V10, D15, V20, etc.)
have been evaluated to predict probabilities of radiation pneumonitis, but no defini-
tive dose and volume limits have been accepted as an optimal limit or parameter.
The percentage of lung volume exceeding 20 Gy (V20), percentage of lung volume
exceeding 30 Gy (V30), and mean lung dose (MLD) are the most predictive param-
eters evaluated in several studies. It has been shown that the risk of radiation pneu-
monitis is less than 20% when MLD is less than 20 Gy [8], less than 8% when V20
is 31% or lower [9], and less than 6% when V30 is 18% or lower [10]. These param-
eters are in respect of both lung volumes; however, a significant correlation was
recently found between these parameters when ipsilateral lung volume is consid-
ered and radiation pneumonitis rates have been reported [11].

10.3.2 Fractionation Schedule

The use of twice-daily fractionation has been shown to reduce the risk of radiation
pneumonitis compared with administration of the same total daily dose as a single
fraction [12].
10.4 Symptoms 111

Most dose volume parameters have been studied in areas of conventional frac-
tionated radiotherapy of lung cancer, and with increasing use of stereotactic body
radiation therapy with a large fraction size for lung cancer, well-designed studies
are needed to define new parameters for radiation-induced pneumonitis.

10.3.3 Chemotherapy/Hormone Therapy

The administration of chemotherapy concurrently or before radiation therapy

appears to increase the risk of radiation pneumonitis compared to radiation
therapy alone [13, 14]. It has been shown that concurrent taxane-based chemo-
radiation therapy increases the radiation pneumonitis risk more than cisplatin-
based chemotherapy regimens [15]. Additionally, chemotherapy administration
with certain agents (e.g., taxanes, anthracyclines, gemcitabine, etoposide, or
vinorelbine), following radiation therapy, can cause radiation-induced pneu-
monitis that is an inflammatory reaction within the previously treated radiation
field [16].
There is conflicting data about correlation of hormonal therapy including tamox-
ifen and aromatase inhibitors and radiation pneumonitis risk. Some found no posi-
tive effect of these agents on radiation pneumonitis risk; however, some reported a
significant correlation [14, 17, 18].

10.3.4 Smoking

There are also different results reported about smoking effects on radiation pneumo-
nitis risks [10, 19]. Surprisingly, some have shown that active smokers had a lower
frequency of radiation-induced pneumonitis.

10.3.5 Other Factors

Adequate data are not available for some variables including age, sex, tumor site,
Karnofsky performance status, comorbid lung disease, pulmonary function test, and
biological markers such as plasma cytokine levels and transforming growth factor
beta 1 (TGF-β1).

10.4 Symptoms

Dyspnea is the most common symptom, occurring in as many as 90% of cases.

Dyspnea is frequently accompanied by a dry cough, which occurs in about 50–60%
of cases. A low-grade fever is occasionally reported, which can be more pronounced
in severe cases. Some patients complain of chest pain with breathing, malaise, and
weight loss. Sensation of chest fullness usually develops 1–3 months after comple-
tion of radiation therapy.
112 10 Radiation Pneumonitis

10.5 Diagnosis

Radiation pneumonitis is a diagnosis of exclusion. Physical findings are usually not

prominent, but occasionally moist crackles, a pleural friction rub, or evidence of
consolidation may be present. There is no specific lab test to predict the develop-
ment of RP. Some patients might have a mild polymorphonuclear leukocytosis,
elevated ESR, serum LDH, and CRP, but these findings are nonspecific.
Chest X-ray and computed tomography are the most commonly used modalities
for assessing RP. The most common finding on CXR in early phases is perivascular
haziness, which often progresses to patchy alveolar-filling densities [20]. Pleural
effusions or atelectases are also sometimes seen. These changes occur shortly after
completion of radiation therapy, peak at 6 months, and become stable by 12 months.
One of the most characteristic features of radiation pneumonitis and fibrosis is that
these radiologic changes are confined to the outlines of the field of radiation
(Fig. 10.1). However, the use of oblique beam angles and the development of newer
irradiation techniques such as three-dimensional conformal radiation therapy and
intensity-modulated radiation therapy can result in an unusual distribution of these
findings [21].
Computed tomography (CT) is more sensitive than chest radiograph in detecting
subtle lung injury following radiation treatment but is not required to make the
diagnosis of RP. The most common findings on CT are ground-glass opacities in the
acute phase and traction bronchiectasis, volume loss, and consolidation in the late
phase [22].
Pulmonary function test (PFT) in patients with radiation pneumonitis usually
reveals a reduction in lung volumes and diffusing capacity of the lungs for carbon
monoxide (DLCO), but these changes are nonspecific [23].
Bronchoalveolar lavage and transbronchial biopsy are not useful in the diagnosis
of radiation pneumonitis but can be used to exclude other causes of pulmonary
infiltrates.

10.6 Scoring

Common Toxicity Criteria for Adverse Effect (CTCAE) (Table 10.1) [24] and
Radiation Therapy Oncology Group (RTOG) (Table 10.2) [25] have defined five
grades for radiation-induced pneumonitis with some differences.

Table 10.1 CTCAE v4.03 for pneumonitis

Grade 1 Asymptomatic; clinical or diagnostic observations only; intervention not indicated
Grade 2 Symptomatic; medical intervention indicated; limiting instrumental activity of daily
life (ADL)
Grade 3 Severe symptoms; limiting self-care ADL; oxygen indicated
Grade 4 Life-threatening respiratory compromise; urgent intervention indicated (e.g.,
tracheotomy or intubation)
Grade 5 Death
10.7 Prevention 113

Table 10.2 RTOG grading for radiation-induced pneumonitis

Grade 1 Asymptomatic or mild symptoms (dry cough); slight radiographic changes
Grade 2 Moderate symptomatic fibrosis or pneumonitis (severe cough); low-grade fever;
patchy radiographic changes
Grade 3 Severe symptomatic fibrosis or pneumonitis; dense radiographic changes
Grade 4 Severe respiratory insufficiency; continuous oxygen therapy/assisted ventilation
Grade 5 Death

10.7 Prevention

There are several agents reported to have preventive effects on radiation pneumonitis.
Amifostine is a thio-organic prodrug that is believed to scavenge harmful free
radicals and shield normal tissues from the toxic effects of chemotherapy and radio-
therapy. It is approved for use as a cytoprotectant, relieving problems of dry mouth
(xerostomia) in patients with head and neck cancers undergoing radiotherapy.
Multiple randomized trials have assessed the role of amifostine in preventing RP,
with contradicting results [26–28]. The largest study was performed by the Radiation
Therapy Oncology Group; the incidence of grade ≥3 pulmonary toxicity was not
statistically different between patients receiving amifostine and those that did not
[29]. Current guidelines do not advise amifostine for prevention of radiation-­
induced pneumonitis.
Pentoxifylline is an immunomodulator that is used primarily for patients with
intermittent claudication. In one small randomized study, the use of pentoxifylline
(400 mg three times daily) resulted in a noticeable reduction in grade 2 or 3 pulmo-
nary toxicity (20% vs. 50%), as well as the measured diffusing capacity after
6 months of follow-up [30].
Captopril is an angiotensin-converting enzyme inhibitor that has been shown to
reduce the development of radiation-induced fibrosis in rats [31], although no such
protective effect has been demonstrated in humans.
There is lack of high-quality evidence on the management of radiation pneumo-
nitis, and no prospective controlled studies have evaluated the efficacy of current
therapies for radiation pneumonitis in humans.
Treatment for acute radiation pneumonitis is mainly supportive. Patients that are
asymptomatic with radiographic abnormalities do not require treatment, and patients
with mild symptoms are generally treated with cough suppressants including
codeine and benzonatate.
Despite the lack of solid evidence, oral corticosteroids have been the mainstay of
therapy for radiation pneumonitis, often with dramatic results. Although the starting
dose and tapering schedule are undefined, based upon clinical experience, dose of
approximately 60 mg or 1 mg/kg of prednisone is given for 1–2 weeks, followed by
a slow taper over 4–8 weeks. The dose is tapered slowly because some patients
experience a rebound pneumonitis with a faster tapering schedule. In some cases,
symptoms and radiographic abnormalities tend to recur with discontinuation of
therapy, and patients might need to maintain a low-dose prednisone schedule for
more extended periods of time [32].
114 10 Radiation Pneumonitis

When prednisone dose exceeds 20 mg a day for greater than a month, prophy-
laxis for Pneumocystis pneumonia is recommended. It is worthy to mention that
established fibrosis is irreversible and will not improve with glucocorticoid
therapy.
Azathioprine and cyclosporine may be considered in patients that do not tolerate
glucocorticoids or that have disease refractory to glucocorticoid therapy based on
small case series [33].

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Pericarditis
11

Pericarditis is the most common acute presentation of radiation-induced heart dis-

ease. The incidence of pericarditis in patients with irradiation for different targets
within and around the thorax is estimated around 5% on average and even less;
indeed, with improvement in radiation treatment techniques, its incidence has
decreased from 25% to 2% [1–3]. Clinically significant pericarditis is observed just
in a limited percentage of patients after mediastinal radiation therapy [4].
Radiation-induced pericarditis most commonly occurs in Hodgkin and non-­
Hodgkin lymphoma and breast cancer patients [2]. It’s probably related to the
incidence and survival of these malignancies. The risk of pericarditis is higher
when the target volume for radiation therapy is in the mediastinum, and it will
decrease with increasing distance between the target volume and the mediastinum
and heart. Site and size of mediastinal lymphadenopathies are important factors in
the incidence of pericarditis for lymphoma patients. With effective chemothera-
pies, target volumes and pericarditis rate have decreased in patients with lym-
phoma after mediastinal radiation. Besides these, pericardial manifestations have
also decreased in lymphoma as well as breast cancer by radiation technique
improvements [5, 6].
Pericardial effusion has been reported in one third of esophageal cancer patients
following definitive chemoradiotherapy [7]. Wei et al. showed that pericardial effu-
sion will develop in 73% of patients if more than 40% of the heart volume receives
more than 30 Gy of radiation [8].
Although acute pericarditis is usually self-limited, the crucial point is the pro-
gression into chronic pericarditis and/or constrictive pericarditis in 10–20% of
patients. However, chronic pericarditis may occur in some patients without any his-
tory of acute pericarditis [9, 10].

© Springer International Publishing AG 2017 117

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_11
118 11 Pericarditis

11.1 Mechanism

After mediastinal radiation therapy, there are some acute and chronic effects on the
heart. Pericarditis is a dominant side effect among acute radiation-induced cardiac
complications, and the essential factors in the acute phase are tumor necrosis factor
(TNF) and interleukins (IL) (i.e., IL-1, IL-6, and IL-8) that cause neutrophil infiltra-
tion within the tissues [11]. Delayed radiation-induced pericarditis is generally the
consequence of an acute inflammatory process followed by fibrin deposition. Injury
is primarily initiated by microvascular damage, which causes episodic ischemia.
The next stage is neovascularization with abnormal and permeable vessels, which
lead to worsening of ischemia and fibrosis progression [12].
Fibrous thickening, pericardial adhesion, and effusion are pathological findings
after radiation to the heart and pericardium. These findings are secondary to micro-
vascular and mesothelial cell injuries. On the other hand, plasminogen activator
decreases, and considering its usual role in fibrinolysis, high levels of fibrin are
expected [13]. Pericardial effusions have high amounts of protein and fibrous adhe-
sions and are also accompanied by high levels of serum inflammatory markers dur-
ing the acute phase [10]. Mononuclear cells infiltrate the pericardium 2 days after
radiation exposure in optic microscopy. Other histologic findings are bizarre fibro-
blasts (with abnormalities in the nucleus and cytoplasm), sclerosis of small vessels,
and fat necrosis of the pericardium [14].

11.2 Timing

Acute pericarditis is uncommon, and it can present during or after radiation. It is

usually detected by subclinical pericardial effusion [11, 15]. The presentation of
pericarditis during the first year after radiation therapy, known as acute pericarditis,
is usually a self-limited and benign disease [16], although it has been named
radiation-­induced late pericardial disease by others [15].

11.3 Risk Factors

Several factors increase the risk of radiation-induced pericarditis, but the per-
centage of irradiated pericardial volume and mean pericardial dose are the most
important [3]. The percentage of cardiac silhouette irradiated could be as an
index of pericardial volume. Other risk factors are the nature of radiation source
and duration and fractionation of radiotherapy. There are some studies that deter-
mine the predictive parameters for radiation-induced pericarditis and pericardial
effusion. Daily dose per fraction more than 3 Gy has been shown to correlate
with pericardial complications [17, 18]. Mean dose to pericardium is a predictive
factor for pericardium injury, and 27 Gy is a proper cutoff point in most studies
[6, 8, 17].
11.5 Diagnosis 119

11.4 Symptoms

As a common manifestation of acute pericarditis, patients present with chest pain,

which usually includes characteristic pleuritic chest pain. This is accompanied by
low-grade fever, dyspnea, and tachycardia [10]. Pericardial friction rub can be found
on physical examination [13].
Patient signs and symptoms could be categorized into six groups depending on
time elapsed from radiation exposure [19]:

1. Acute pericarditis during radiation therapy, which presents with nonspecific

symptoms including chest pain, fever, and EKG abnormalities.
2. Late pericardial disease, which occurs during the first year of radiation therapy
[15].
3. Delayed pericarditis, which presents from months to years after radiation treat-
ment (most references include the second half of late pericarditis timing). In this
group of patients, the most common presentation is dyspnea; some others
develop pericardial pain. Tamponade may also rarely occur in these patients [2].
Pulsus paradoxus (decreasing peripheral arterial pulse paradoxically during
inspiration) is characteristic of tamponade [4].
4. Pancarditis, which manifests as heart failure, is difficult to control. It is a rare
compilation of heart radiation during the acute phase because of the delayed
effect of radiation on the myocardium.
5. Constrictive pericarditis usually develops several years after radiation [15].
Kussmaul’s sign (jugular venous distention on inspiration) is seen in constrictive
pericarditis and less frequently in cardiac tamponade [4].
6. Asymptomatic pericardial effusion, which is an incidental finding by
echocardiography.

11.5 Diagnosis

Considering positional pleuritic chest pain as a hallmark feature of acute pericardi-

tis, an EKG is usually the first diagnostic study obtained. Diffuse ST elevation with
or without PR interval depression could be seen, but sinus tachycardia may also be
seen [15].
Chest radiography in patients with pericardial effusion may show
cardiomegaly.
It is easy to detect loculated or generalized pericardial effusion by echocardiog-
raphy by measurement of echo-free pericardial space. There are other signs on
echocardiography (e.g., collapsing right atrium and ventricle in end-diastolic and
diastolic phase, respectively) [4].
By using computed tomography (CT), pericardial effusion and thickening are
showed and, in comparison to MRI, is more sensitive to detect constrictive pericar-
ditis [4]. Normal thickness of the pericardium is less than 2 mm on CT scan and
120 11 Pericarditis

MRI. Thickened pericardium could be enhanced after IV contrast injection, which

is a sign of inflammation and is used to differentiate between constrictive pericardi-
tis and restrictive cardiomyopathy [20].
Serum inflammation markers, such as white blood cell count, erythrocyte sedi-
mentation rate (ESR), and serum C-reactive protein (CRP), are usually elevated;
serum cardiac troponin I levels may be minimally elevated. CRP as an acute phase
protein can help in treatment monitoring in most patients that have elevated levels
of this marker [21].
In patients with malignant tumors and pericardial effusion, at least three dif-
ferential diagnoses should be considered. One of them is heart failure with peri-
cardial effusion, which is secondary to low cardiac output. Another is malignant
pericardial effusion, which could be accompanied by other metastases and is
confirmed by positive cytological examination for malignant cells. A third dif-
ferential diagnosis is hypothyroidism, which may be due to radiation to the
thyroid [2].

11.6 Scoring

Pericardial effusions and pericarditis have been scored in Common Toxicity Criteria
for Adverse Effect (CTCAE v4.03) as shown in Tables 11.1 and 11.2 [22]. In this
scoring system, no grade 1 has been described for pericardial effusion, and pericar-
dial tamponade is grade 4 at least.
RTOG scoring also classifies acute radiation heart effect into four grades
(Table 11.3) [23].

Table 11.1 CTCAE, version 4.03, scoring system for pericardial effusion
Definition
Grade 1
Grade 2 Asymptomatic effusion size, small to moderate
Grade 3 Effusion with physiologic consequences
Grade 4 Life-threatening consequences with urgent intervention indicated
Grade 5 Death

Table 11.2 CTCAE, version 4.03, scoring system for pericarditis

Definition
Grade 1 Asymptomatic, EKG, or physical findings (e.g., friction rub) consistent with
pericarditis
Grade 2 Symptomatic pericarditis (e.g., chest pain)
Grade 3 Pericarditis with physiologic consequences (e.g., pericardial constriction)
Grade 4 Life-threatening consequences with urgent intervention indicated
Grade 5 Death
11.7 Prevention 121

Table 11.3 RTOG/EORTC radiation toxicity grading for cardiac toxicity

Definition
Grade 1 Asymptomatic but objective evidence of EKG changes or pericardial abnormalities
without evidence of other heart disease
Grade 2 Symptomatic with EKG changes and radiological findings of congestive heart failure
or pericardial disease/no specific treatment required
Grade 3 Congestive heart failure, angina pectoris, and pericardial disease responding to
therapy
Grade 4 Congestive heart failure, angina pectoris, pericardial disease, and arrhythmias not
responsive to nonsurgical measures

11.7 Prevention

Multidisciplinary approach should be considered in the management of patients

with cancer. In some centers, cancer patients are evaluated by cardiologists with
respect to cardio-oncology history taking, physical exam, chest X-ray, and electro-
cardiography with strain and are routine, and based on these patients, risk is deter-
mined [1].
Lowering the pericardium-irradiated volume and dose without any defect in
treatment is an essential step in reducing the probability of pericardial side effect
development. Emami et al. published data on normal tissue tolerance by using TD
5/5 and TD 50/5 parameters. TD 5/5 is the dose associated with a 5% risk of com-
plications within 5 years, and TD 50/5 is the same but in 50% of patients. Considering
pericarditis as the end point, TD 5/5 in conventional radiation therapy is about
60 Gy for one third of the heart, 45 Gy for two third, and 40 Gy for the whole vol-
ume of the heart. For TD 50/5, these doses, respectively, change to 70, 55, and
50 Gy. In patients with predicted long survival, TD 5/5 is determined much lower
(25 Gy), corresponding to other cardiac complications [15].
If we consider two-dimensional planning of radiation therapy, by radiation to
more than 50% of the heart, we will observe an increase in the risk of pericarditis.
In three-dimensional planning, the volume of pericardium that receives ≥30 Gy
(V30) is a main determinant. In order to prevent pericardial injury, it is recom-
mended to keep mean pericardial dose less than 26 Gy or pericardial V30 less than
46% [24] although there are some challenges in defining heart volume [9].
Radiation-induced pericarditis occurs in less than 15% of patients by keeping the
mean dose to the pericardium less than 26 Gy [11].
Using modern techniques in radiation therapy, cardiac exposure has changed. In
breast cancer, irradiation on deep inspiration (unassisted or by using some devices
for active breathing control) and even breast board significantly reduces dose and
volume of irradiated heart. Another factor for decreasing heart dose is using elec-
tron beam irradiation, especially for internal mammary nodes if indicated [13].
Breast radiation therapy in prone position is also helpful to reduce irradiated peri-
cardium volume [5].
By using IMRT, more heart volume is irradiated by lower dose, but high-dose
volume decreases [1].
122 11 Pericarditis

11.8 Treatment

Acute pericarditis is usually self-limited, and half of the patients do not require any
intervention.
Patients are usually treated in the outpatient setting unless they have high-risk
features such as fever (temperature >38°C), leukocytosis, a large pericardial effu-
sion (echo-free space >20 mm), cardiac tamponade, acute trauma, immunosup-
pressed state, concurrent oral anticoagulation, failure of nonsteroidal
anti-inflammatory drug (NSAID) therapy, elevated troponin levels, and recurrent or
incessant pericarditis, all of which mandate hospitalization [21].
Forty percent of symptomatic patients are good responders to the rest and
NSAIDs.
Colchicine is suggested for patients with acute pericarditis as an adjunct to
NSAID therapy and sometimes is sufficient in relieving pain in patients with acute
pericarditis and preventing recurrences [11, 16, 21].
The important practical point is that this presentation is not a reason for radiation
therapy discontinuation, although a reduction in dose should be considered [11, 19].
Different NSAIDs with various dosages are recommended:

Aspirin: 500–1000 mg every 6–8 h (range 1.5–4 g/day).

Ibuprofen: 600 mg every 8 h (range 1200–2400 mg/day).
Indomethacin: 25–50 mg every 8 h; start at the lower end of dosing range and titrate
upward to avoid headaches and dizziness.
Naproxen: 500–1000 mg every 12 h may be used if tolerated and clinically indi-
cated and may increase to 1500 mg daily for a limited time (<6 months).

For geriatric patients, the lowest dose and frequency are recommended.
In patients with renal impairment and a creatinine clearance (CrCl) ≤30 mL/min,
NSAIDs are not recommended. Aspirin is slightly safer than others in these patients,
but it’s not recommended if CrCl is less than 10 mL/min.
NSAIDs should be also used with caution in hepatic impairment. Prophylaxis
with proton pump inhibitors is also an important treatment to implement.
Uncomplicated treatment continues for 1–2 weeks. However, symptom and CRP
normalization should be considered [25].
Pericardiocentesis may be performed for patients with persistent symptomatic
pericardial effusions. The approach to recurrent pericardial effusions would be sur-
gical by either a pericardial window or pericardiectomy [2].

References
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Esophagitis
12

Radiation esophagitis is an acute dose-limiting toxicity associated with radiation

treatment that decreases the patient’s compliance for treatment completion.
Incidence of acute esophagitis has been reported in about 29% of patients with
thoracic radiation therapy [1] and in 93% of patients undergoing thoracic chemora-
diation therapy [2]. Severe esophagitis requiring nutritional support or radiation
therapy breaks has been reported in 1–4% and 22–45% of patients that are treated
with radiation therapy alone or chemoradiation therapy, respectively [3, 4].

12.1 Mechanism

The luminal side of the normal esophagus is lined by mucosa. The mucosal layer
contains epithelium, lamina propria, and muscularis mucosae. The esophageal epi-
thelium is a nonkeratinizing, stratified, squamous epithelium and contains rapidly
dividing cells situated in the basal layer [5].
Radiation therapy affects the basal epithelial cell layer and limits the prolifera-
tion rate of the basal epithelium, causing mucosal thinning, ulceration, and initia-
tion of the inflammatory response resulting in congestion, edema, or erosion [6].

12.2 Timing

Acute radiation esophagitis begins on the second to third week after initiation of
irradiation (20–30 Gy). Generally, with single daily fractions of 2.0 Gy radiation
therapy, grade 1 esophagitis first appears in the second week, and grade 2 and higher

© Springer International Publishing AG 2017 125

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_12
126 12 Esophagitis

esophagitis begins during the third week of the treatment. As treatment continues,
the rate of symptomatic esophagitis increases. Patients experience grade 3 esopha-
gitis during the fifth week of treatment [7].
Esophagitis often recovers within 4–6 weeks of treatment completion. The dura-
tion of symptomatic esophagitis is longer for intensive treatment (hyperfractionated
radiation therapy or concurrent chemotherapy) [8].

12.3 Risk Factors

The most significant predictors of acute esophagitis are concurrent chemotherapy

[9–13] and hyperfractionated radiation therapy, especially in the setting of concur-
rent chemotherapy with hyperfractionated radiation therapy [12, 14–17].
It has been reported that the use of chemotherapy concurrent with irradiation is
associated with a nearly 12-fold greater risk of developing severe esophagitis [18].
Sequential chemotherapy seems not to significantly increase the risk of esophageal
radiation injury [3, 4, 14, 19]. The incidence of esophagitis in chemoradiotherapy is
also dependent on chemotherapeutic agents used. Cisplatin-based regimens are gen-
erally associated with a lower rate of significant esophagitis compared with proto-
cols using paclitaxel [7, 20, 21].
Radiation regimen schedule is an important factor in the rate of esophagitis.
Higher radiotherapy dose per fraction [22] and increasing the number of daily frac-
tions induce more severe esophagitis.
A number of studies evaluating dosimetric factors have shown that percentage
of esophagus volume receiving 10–60 Gy [7, 9, 23–30], mean esophageal dose
[24, 25, 31], the maximal esophageal dose [11, 13, 32], esophageal surface area
receiving 55 Gy [9], and higher length of the esophagus in the radiation treatment
field (with some contradictory results) [6, 15, 33] are all associated with acute
esophagitis.
A recent systematic literature review concluded that the valuable dosimetric
parameters predicting the occurrence of acute radiation esophagitis in patients
receiving concurrent chemoradiotherapy include maximum esophageal dose,
mean esophageal dose, and esophageal volume receiving 20, 30, 50, and 55 Gy
[34].
It is well known that with the similar dosimetric parameter consideration, only a
small proportion of patients develop esophageal toxicity. Individual variability in
radiosensitivity should be further investigated to identify genetic variations modu-
lating the development of radiation esophagitis. In this regard, it has been observed
that patients with the transforming growth factor-beta1 (TGFβ1)509 CC genotype
[35], heat shock protein beta-1 (HSPB1) CC genotype [36], and single nucleotide
polymorphisms (SNPs) in inflammation-related genes including three PTGS2
12.5 Scoring 127

(COX2) variants rs20417, rs5275, and rs689470 [37] are at greater risk for develop-
ing radiation esophagitis.
It has been shown that one of the most significant risk factors for dysphagia dur-
ing chemoradiation is the maximal grade of neutropenia. Indeed, the nadir of the
neutrophil granulocytes during treatment is strongly associated with developing and
severity of esophagitis [17, 38]. Patients with higher pretreatment platelet counts
and lower hemoglobin levels as a preexisting systemic inflammatory state have
greater rates of radiation esophagitis [39].
There are individual case reports demonstrated that patients with human immu-
nodeficiency virus (HIV) may experience unusually severe radiation-induced
esophagitis [40, 41].
Other factors proposed to be associated with acute esophagitis include the
­pretreatment body mass index [30].
Patient’s gender, age, performance status, and histology are not significantly
­correlated with esophageal toxicity [6, 42].

12.4 Symptoms

Radiation-induced esophagitis presents with retrosternal or substernal burning sen-

sation, pain, odynophagia, dysphagia, and anorexia. Weight loss could occur and
nutritional support may be needed. Rarely, with severe esophagitis, patients may
develop obstruction, perforation, or fistulas.

12.5 Scoring

The Radiation Therapy Oncology Group (RTOG) and European Organization for
Research and Treatment of Cancer (EORTC) have defined four grades for radiation-­
induced esophagitis (Table 12.1) [43].

Table 12.1 RTOG/EORTC esophagitis grading

Definition
Grade 1 Mild dysphagia or odynophagia (may require topical anesthetic or nonnarcotic
analgesics and a soft diet)
Grade 2 Moderate dysphagia or odynophagia (may require narcotic analgesics and puree or
liquid diet)
Grade 3 Severe dysphagia or odynophagia with dehydration or weight loss >15% from
pretreatment baseline requiring NG feeding tube, IV fluids, or hyperalimentation
Grade 4 Complete obstruction, ulceration, perforation, and fistulization
128 12 Esophagitis

12.6 Diagnosis

Radiation esophagitis is a clinical diagnosis in patients with dysphagia or odyno-

phagia, that is, receiving thoracic irradiation. In patients with symptoms progress-
ing after completion of radiation therapy despite the optimal treatment, endoscopy
should be considered to establish the diagnosis and rule out other etiologies like
infectious or fungal esophagitis.

12.7 Prevention

Prediction of esophagitis severity allows prevention of esophagitis with treatment

deintensification and other measurements. Various dose constraints are proposed to
predict radiation-induced esophageal toxicity that should be considered in treatment
planning.
It has been shown that esophagitis as an inflammatory process results in elevated
18
F-fluordeoxyglucose (FDG) positron emission tomography (PET) uptake in the
postradiation period, which correlates to the treatment planning dose distribution.
Using posttreatment 18F-FDG-PET scans allows for developing a quantitative bio-
logical model to improve the accuracy of esophagitis prediction based on planned
dose [44]. Also an increase in FDG uptake during radiation therapy from pre-radia-
tion may predict radiation esophagitis and provides the opportunity for treatment
planning modification [45].
Advances in the radiation delivery with intensity-modulated radiation therapy
(IMRT) may allow radiation oncologists to prescribe higher doses to tumors with
normal structures being spared such and keep the incidence of radiation-induced
esophagitis quite low when the esophagus is not the treatment target [11, 46].
Amifostine is an organic thiophosphate compound that offers selectively normal
cell protection from radiation-induced damage and also chemotherapeutic agents by
scavenging oxygen-derived free radicals [47]. It seems that amifostine administra-
tion can protect the normal esophageal mucosa from radiation-induced injury and
delay the onset of esophagitis and reduce its severity and incidence.
In a multicenter trial of 146 patients with advanced lung cancer treated with a
daily fractionated radiation therapy to a total of 55–60 Gy with or without daily
amifostine administration reported that the incidence of esophagitis grade 2 or
higher was 42% in the radiation therapy alone group versus 4% in the group with
amifostine administration during 4 weeks of treatment [48].
Amifostine administration seems to reduce severe esophagitis and analgesic
intake in patients undergoing chemoradiation therapy without compromising treat-
ment outcomes [20, 49–51]. Further studies are required to determine the optimal
amifostine combination with therapeutic strategy.
Glutamine supplement administration during thoracic irradiation appears to
postpone onset and reduce the severity of radiation esophagitis [52]. Further inves-
tigation of this agent may therefore be warranted.
References 129

Oral sucralfate solution has been compared with placebo as prophylaxis in a

prospective trial and didn’t prevent esophagitis development, although it had signifi-
cant gastrointestinal side effects [53].

12.8 Management

Acute esophagitis is managed symptomatically.

Dietary modification that should be recommended to all patients are:

Eat frequent meals with small pieces throughout the day instead of three large
meals.
Eat soft foods that are warm or at room temperature.
Drink enough liquids.
Avoid hot or spicy foods, acidic foods, and hard and crunchy foods.
Avoid alcohol and tobacco.

Pain is managed with topical analgesics (e.g., viscous lidocaine), NSAIDs, or

narcotics.
If patients complain of reflux symptoms, antacids, proton-pump inhibitors, or H2
receptor blockers could be effective.
In the setting of severe dysphagia or odynophagia with significant weight loss,
short breaks from radiation therapy have been proposed. Feeding tube or parenteral
nutrition may be needed for these patients (see Sect. 6.7.5).

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inflammation-related genes are associated with radiation-induced toxicity following treatment
for non-small cell lung cancer. PLoS One 5(8):e12402
38. Everitt S, Duffy M, Bressel M, McInnes B, Russell C, Sevitt T et al (2016) Association of
oesophageal radiation dose volume metrics, neutropenia and acute radiation oesophagitis in
patients receiving chemoradiotherapy for non-small cell lung cancer. Radiat Oncol 11(1):20
39. Tang C, Liao Z, Zhuang Y, Levy LB, Hung C, Li X et al (2014) Acute phase response
before treatment predicts radiation esophagitis in non-small cell lung cancer. Radiother
Oncol 110(3):493–498
40. Leigh BR, Lau DH (1998) Severe esophageal toxicity after thoracic radiation therapy for lung
cancer associated with the human immunodeficiency virus: a case report and review of the
literature. Am J Clin Oncol 21(5):479–481
41. Costleigh BJ, Miyamoto CT, Micaily B, Brady LW (1995) Heightened sensitivity of the esoph-
agus to radiation in a patient with AIDS. Am J Gastroenterol 90(5):812–814
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42. Chapet O, Kong F-M, Lee JS, Hayman JA, Ten Haken RK (2005) Normal tissue complication
probability modeling for acute esophagitis in patients treated with conformal radiation therapy
for non-small cell lung cancer. Radiother Oncol 77(2):176–181
43. Cox JD, Stetz J, Pajak TF (1995) Toxicity criteria of the radiation therapy oncology group
(RTOG) and the European organization for research and treatment of cancer (EORTC). Int
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44. Nijkamp J, Rossi M, Lebesque J, Belderbos J, van den Heuvel M, Kwint M et al (2013) Relating
acute esophagitis to radiotherapy dose using FDG-PET in concurrent chemo-­radiotherapy for
locally advanced non-small cell lung cancer. Radiother Oncol 106(1):118–123
45. Yuan ST, Brown RK, Zhao L, Ten Haken RK, Gross M, Cease KB et al (2014) Timing and
intensity of changes in FDG uptake with symptomatic esophagitis during radiotherapy or
chemo-radiotherapy. Radiat Oncol 9(1):37
46. Kwint M, Uyterlinde W, Nijkamp J, Chen C, de Bois J, Sonke J-J et al (2012) Acute esophagus
toxicity in lung cancer patients after intensity modulated radiation therapy and concurrent
chemotherapy. Int J Radiat Oncol Biol Phys 84(2):e223–e228
47. Kouvaris JR, Kouloulias VE, Vlahos LJ (2007) Amifostine: the first selective-target and broad-­
spectrum radioprotector. Oncologist 12(6):738–747
48. Antonadou D, Coliarakis N, Synodinou M, Athanassiou H, Kouveli A, Verigos C et al (2001)
Randomized phase III trial of radiation treatment±amifostine in patients with advanced-stage
lung cancer. Int J Radiat Oncol Biol Phys 51(4):915–922
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(2013) The addition of amifostine to carboplatin and paclitaxel based chemoradiation in locally
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treated with chemoradiotherapy. Semin Radiat Oncol 12:34–39
52. Topkan E, Yavuz MN, Onal C, Yavuz AA (2009) Prevention of acute radiation-induced esoph-
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Placebo-controlled trial of sucralfate for inhibiting radiation-induced esophagitis. J Clin Oncol
15(3):1239–1243
Radiation Gastritis
13

Radiation-induced gastritis occurs in about 30–50% of patients undergoing radia-

tion therapy whenever the stomach is included in radiation fields as the main target
or an organ at risk (e.g., during radiation treatment of lymphoma, neoplasm of lower
esophagus, stomach, biliary tract, pancreas, testis, or including of thoracic stomach
in radiation field after gastric pull-up procedure) [1–4].

13.1 Mechanism

The gastric walls consist of mucosa, submucosa, muscularis, and serosal layers. The
gastric mucosa is the mucous membrane layer of the stomach, which contains the
glands and gastric pits. The epithelium of the mucosa has gastric pits (mucous mem-
brane invaginations), and lamina propria contains gastric glands. There are three
types of gastric glands including cardiac glands, which produce lysozyme and
mucus, fundic and body glands, which produce hydrochloric acid, pepsin, and intrin-
sic factor, and lipase and pyloric glands, which produce lysozyme and mucin [3].
Each fundic gland is divided into three segments: the isthmus, neck, and the
gland proper. The main epithelial cell types of the gland are the precursor mucous
neck cells, the parietal or oxyntic cell (secrete hydrochloric acid), and the chief or
zymogen cell (produce pepsinogen). The surface of the mucous membrane is cov-
ered by a single layer of mucous cells. These cells secrete mucous and develop the
gastric mucosal barrier [5].
Several types of endocrine cells are found throughout the gastric mucosa and
produce histamine, gastrin, and somatostatin.
Irradiation produces marked mucosal and submucosal edema, ulcerative or ero-
sive lesions, and changes in the quality and quantity of gastric secretion [2, 6].
The early changes in gastric mucosa include mucosal and submucosal edema
and inflammation, endothelial cell swelling, and capillary dilation, which could be
demonstrated after 20–25 Gy of radiation dose [3].

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DOI 10.1007/978-3-319-55950-6_13
134 13 Radiation Gastritis

With higher doses, more severe injuries could occur including gastric erosion or
ulcer. The gastric ulcer developing rate increases with doses above 45 Gy (25–30%
of patients) [6]. The degree of gastric acidity in radiation ulcers is variable. In some
cases, the acidity is somewhat increased; in the majority, it is normal or even sub-
normal [1].
Radiation initially reduces surface mucous cells due to their relatively short life-­
span. So breakdown of the mucosal barrier, net flux of electrolytes into the gastric
lumen, and back diffusion of the luminal hydrogen ion occur. Mucosal histamine is
released and stimulates secretion directly from the glandular cells, and a transient
increase in acid secretion during the radiation therapy exhibits [5, 7].
After the initial gastric hypersecretion, secondary mucosal damage occurs and
induces coagulation necrosis of glandular cells, denudation of glandular epithelium,
cystic dilatation of the glands and a reduction of the gastric glands, and the volume
of gastric secretion and its content change [7]. A significant reduction in the secre-
tion of hydrochloric acid and pepsin develops. The degree and duration of the radia-
tion effect on gastric secretion depends on radiation dose and biologic differences
[8]. It has been reported that gastric acidity may suppress or significantly decrease
with doses of less than 20 Gy [9]. Some have suggested that chief cells are more
radiosensitive than are parietal cells, and gastric acidity suppression occurs first due
to damage to the pepsinogen-secreting chief cells; parietal cells are more resistant
and are depressed later [10]. Another reason for gastric acidity suppression is reduc-
tion in gastric histamine content [11]. A decrease in gastric acidity occurs within
4–6 weeks after completion of radiation therapy [12].

13.2 Risk Factors

The severity and frequency of the acute gastric lesions depends upon the total dose
received by the stomach. The radiosensitivity of stomach seems to be higher than
the small and large intestine [13]. The gastric ulcer never occurs following less than
45 Gy. When the radiation dose exceeds 45 Gy, the incidence of gastric ulcer is
25–30%. With higher radiation dose, the more serious the gastric damage may
occur, leading to penetration hemorrhage and perforation [6]. The risk of perforated
ulcers increases with doses greater than 60 Gy [14].
Chemotherapy may also increase the gastric injuries induced by radiation.
With the exception of unknown factors of individual sensitivity, there is no report
of patient factor effects on frequency of the acute gastric lesions [9, 11, 14].

13.3 Timing

Gastritis will develop in the second and third week of irradiation (20–30 Gy) [15].
Patients may experience nausea, epigastric distress, and uncommon vomiting, and
these symptoms last for only a few hours after each fraction of radiation. Later with
higher radiation doses, more severe symptoms including epigastric pain may occur.
13.7 Management 135

Symptoms usually resolve 1–2 weeks after completion of the radiation therapy.
Occasionally the mild epigastric distress or dyspepsia persists for months or even
years [3].
Ulceration occurs from 1 month to 6 years with an average of 5 months after
radiation therapy [6].

13.4 Symptoms

Epigastric distress, anorexia, nausea, vomiting, and pain are more common symp-
toms of radiation gastritis [10, 16].
Acute ulceration may be seen shortly after radiation therapy. The usual symp-
toms of ulcer are present, but food and antacids usually afford no relief [6]. The
most severe symptoms appear when ulcers are accompanied by perforation or
obstruction, usually 1–2 months after irradiation [14].

13.5 Diagnosis

The diagnosis of radiation-induced gastritis is based on clinical suspicions in

patients that received radiation therapy with stomach at least partially within the
treatment portal. Barium meal examination and gastroscopy may be needed in some
patients with severe symptoms or no response to initial treatment.
Radiation therapy in patients that have a tumor in the stomach like lymphoma may
lead to destruction of deeply infiltrating tumor and result in gastric perforation. These
conditions should be considered in distinction of radiation-induced injuries [17].

13.6 Prevention

There is no prophylactic agent available to mitigate the acute gastric injury. Reducing
the irradiated volume specially for higher doses (when the stomach is not the treat-
ment target) is the best way to minimize gastritis probability, and new techniques
could help radiation oncologists in this way, although there are no definitive data
about dose-volume constraints for partial volume irradiation of stomach. Doses of
45 Gy to the whole stomach are associated with ulceration in 5–7% of patients [18].

13.7 Management

Medical management with antacids (H2 blockers and proton pump inhibitors) is
usually used in patients with gastritis symptoms.
Nausea and vomiting are treated with antiemetics. The management of radiation-­
induced nausea and vomiting is discussed separately (see Chap. 20).
136 13 Radiation Gastritis

Radiation-induced gastric ulceration less often responds to the medical manage-

ment than the usual peptic ulcer disease, and due to higher frequency of complica-
tions in these ulcers, early surgical intervention is indicated in patients who do not
respond to medical management [17].

References
1. Hamilton FE (1948) Gastric ulcer following radiation. Trans West Surg Assoc 54(54 Annual
Meet. (1946 Memphis)):51–56
2. Ohtsubo K, Watanabe H, Mouri H, Yamashita K, Yasumoto K, Yano S (2012) Endoscopic
findings of upper gastrointestinal lesions in patients with pancreatic cancer. JOP
13(4):420–426
3. Fajardo L-G, Berthrong M, Anderson R (2001) Radiation pathology. Oxford University Press,
New York
4. Matsumoto S, Kiyosue H, Komatsu E, Wakisaka M, Tomonari K, Hori Y, Matsumoto A, Mori
H (2004) Radiotherapy combined with transarterial infusion chemotherapy and concurrent
infusion of a vasoconstrictor agent for nonresectable advanced hepatic hilar duct carcinoma.
Cancer 100(11):2422–2429
5. Michalowski A, Hornsey S (1986) Assays of damage to the alimentary canal. Br J Cancer
Suppl 7:1–6
6. Sell A, Jensen TS (1966) Acute gastric ulcers induced by radiation. Acta Radiol Ther Phys
Biol 4(4):289–297
7. Ragins H, Fried M, Dombro R, Dittbrenner M, Liu SM, Johnson L, Sanfilippo L (1967) A
comparison of the radiosensitivity of the gastric mucosa at rest and during stimulation.
Secretory, histochemical, and histologic studies. Am J Dig Dis 12(12):1256–1271
8. Snell AM, Ballman JL (1934) Gastric secretion following irradiation of the exposed stomach
and the upper abdominal viscera by roentgen rays. Am J Dig Dis 1(2):164–168
9. Feiring W, Jampol ML (1950) Perforation of a gastric ulcer following intensive radiation ther-
apy. N Engl J Med 242(19):751–753
10. Novak JM, Collins JT, Donowitz M, Farman J, Sheahan DG, Spiro HM (1979) Effects of
radiation on the human gastrointestinal tract. J Clin Gastroenterol 1(1):9–39
11. Man WK, Gompertz RH, Li SK, Michalowski A, Baron JH, Spencer J (1988) Effect of gastric
irradiation on gastric secretion and histamine in mice. Agents Actions 23(3–4):297–299
12. Rider J, Moeller H, Althausen T, Sheline G (1957) The effect of x-ray therapy on gastric acid-
ity and on 17-hydroxycorticoid and uropepsin excretion. Ann Intern Med 47(4):651–665
13. Elliott AR, Jenkinson EL (1934) Ulcerations of the stomach and small intestine following
roentgen therapy. Radiology. doi:10.1148/23.2.149
14. Goldstein HM, Rogers LF, Fletcher GH, Dodd GD (1975) Radiological manifestations of
radiation-induced injury to the normal upper gastrointestinal tract. Radiology
117(1):135–140
15. Breiter N, Sassy T, Trott KR (1993) The effect of dose fractionation on radiation injury in the
rat stomach. Radiother Oncol 27(3):223–228
16. Nam T, Ahn J, Choi Y, Jeong J, Kim Y, Yoon M, Song J, Ahn S, Chung W (2014) The role of
radiotherapy in the treatment of gastric mucosa-associated lymphoid tissue lymphoma. Cancer
Res Treat 46(1):33–40
17. Keltum JM, Jaffe BM, Calhoun TR, Ballinger WF (1977) Gastric complications after radio-
therapy for Hodgkin’s disease and other lymphomas. Am J Surg 134(3):314–317
18. Kavanagh BD, Pan CC, Dawson LA, Das SK, Li XA, Ten Haken RK, Miften M (2010)
Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys
76(3 Suppl):S101–S107
Radiation-Induced Liver Disease
14

Radiation-induced liver disease (RILD), historically called radiation hepatitis, has

been reported in 6–66% of patients whose livers are irradiated based on radiation
dose, exposed liver volume, and baseline liver function [1, 2]. Abnormalities in
laboratory liver function tests may be found on routine evaluation of patients when
RILD is mild, but in severe cases, liver dysfunction may affect the treatment course
and eventually threaten patient’s lives.

14.1 Mechanism

The histologic hallmark associated with RILD is veno-occlusive disease (VOD). It

is characterized by severe congestion of the sinusoids in the central portion of the
lobules with sparing of the larger veins [3].
The pathogenesis of RILD is unknown. Some possible mechanisms have been
proposed. It has been postulated that radiation damages the sinusoidal and vascular
endothelial cells, which initiates the coagulation cascade leading to fibrin accumu-
lation and clot formation. The fibrin network is replaced by collagen deposition and
resulted in progressive fibrous obliteration of small hepatic veins [3, 4]. Irradiation
induces the dysregulated activation of myofibroblastic hepatic stellate cells, increas-
ing some cytokine expression like TGF-β1 (transforming growth factor) and hedge-
hog (Hh) pathway activation (an essential pathway for tissue remodeling), [5] which
are important in the development of fibrosis following exposure to radiation. GDC-­
0449 targets the Hh signaling pathway, and this suppressed Hh signaling may lead
to reduced proliferation of progenitor cells and fibrosis in irradiated livers [5].
Finally, hepatic vessels occlude, resulting in vascular leakage, distorted dilated
sinusoids, and congestion with erythrocyte trapping, causing central zone hypoxia
and hepatocyte death [6].

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138 14 Radiation-Induced Liver Disease

A cluster of NF-κB-regulated cytokines, including TNF-α, are induced by radia-

tion and increase the sensitivity of hepatocytes to radiation and induce cell apopto-
sis [7].
After 4 months, an effective circulatory system within the liver has apparently
developed leading to the disappearance of congestion and restoration of hepatic
cells [8].

14.2 Risk Factors

Radiation treatment factors have a strong correlation with RILD. Mean radiation
dose to the liver and volume of liver exposed to more than 30–35 Gy of radiation are
directly related to RILD occurrence [9, 10]. Emami et al. found a <5% rate of RILD
when the mean whole liver dose is ≤30 Gy in patients without preexisting liver
disease or primary liver cancer. The mean liver dose should be ≤28 Gy in those
patients with preexisting liver disease [11]. However, part of the liver could be
safely treated with higher doses with acceptable complications. Dose per fraction is
an important factor in the development of RILD. Altered fractionated radiation ther-
apy with large fraction sizes decreases liver tolerance [12].
The combination of chemotherapy agents with whole liver radiation seems to
decrease liver tolerance [13, 14], although studies with use of fluoropyrimidines
[15–18] or partial liver radiation have not been reported to significantly increase
hepatic complications of combination therapy.
Baseline liver function is an important factor in predicting the occurrence of
RILD. Cirrhotic livers have a lower tolerance for radiation. It has been reported that
patients with worse Child-Pugh Class (B vs. A) and chronic hepatitis B carriers are
at higher risk for developing RILD [9].
Patients with elevated liver enzymes during radiation therapy are at risk for
developing RILD [12]. Such liver abnormalities are presumably related to self-­
limited liver inflammation [19].
Primary hepatobiliary carcinoma is associated with a significantly increased risk
of RILD compared with a diagnosis of liver metastases; this could be related to
preexisting cirrhosis or hepatitis in patients with hepatobiliary carcinoma [20].
Other factors associated with elevated risk of RILD include prior transcatheter
arterial chemoembolization (TACE) [12], portal vein tumor thrombosis [21], tumor
stage [12], and male gender [22].

14.3 Timing

RILD typically occurs 4–8 weeks after the completion of treatment, although it has
been described as early as 2 weeks and as late as 7 months afterward [3].
14.5 Scoring 139

14.4 Symptoms

In severe cases, patients develop rapid weight gain, increase in abdominal girth,
liver enlargement, right upper quadrant discomfort, ascites, and jaundice [3].
Physical examination reveals ascites and hepatomegaly in moderate to severe cases,
although in mild cases these signs are detectable only by ultrasound or abdominal
CT scan [3]. Serum alkaline phosphatase is predominantly elevated (more than
twice the upper limit of normal or baseline value), with minimal increase or rela-
tively normal levels of aspartate transaminase (AST) and alanine (ALT) (in the
range of twofold above normal) and bilirubin [3, 19].
In patients with intrahepatic cancer, decreases in alkaline phosphatase because of
tumor response may mask alkaline phosphatase elevation resulting from RILD [23].
In patients with hepatitis and cirrhosis, nonclassic-type RILD with markedly
elevated serum transaminases (>5 times the upper limit of normal) rather than ele-
vated alkaline phosphatase or a decline in liver function (measured by a worsening
of Child-Pugh score by 2 or more) and jaundice can occur, indicating severe
radiation-­induced injury to hepatocytes [19].
Reactivation of viral hepatitis has been reported in patient who underwent radia-
tion therapy; however, its role in RILD pathogenesis is unclear. Elevation of trans-
aminases rather than commonly reported increase in alkaline phosphatase is seen in
hepatitis B carrier patients and implies radiation injury of hepatocytes rather than
bile ducts [9]. It has been suggested that the risk of hepatitis B reactivation is
decreased with prophylactic antiretroviral therapy [19].
Thrombocytopenia has been reported in children studies related to congestion of
the portal bed and spleen and secondary hypersplenism [24].

14.5 Scoring

Most research uses the Cancer Therapy Evaluation Program and Common
Terminology Criteria for Adverse Events (CTCAE) to evaluate liver toxicity after
radiation therapy [25]. The Cancer Therapy Evaluation Program, Common
Terminology Criteria for Adverse Events (CTCAE), Version 3.0, defines grades 2,
3, 4, and 5 liver dysfunction as jaundice, asterixis, encephalopathy or coma, and
death, respectively. No grade 1 has been defined (Table 14.1) [19].

Table 14.1 CTCAE.V3 Definition

liver dysfunction criteria
Grade 1 –
Grade 2 Jaundice
Grade 3 Asterixis
Grade 4 Encephalopathy
Grade 5 Death
140 14 Radiation-Induced Liver Disease

14.6 Diagnosis

Patients with typical clinical picture and history of recent radiation therapy to the
liver included in treatment field have a high likelihood of having RILD.
In patients with intrahepatic cancer, progression of cancer should be ruled out
before making the diagnosis of RILD. An abdominal CT scan and paracentesis of
the ascites are typically performed as part of the differential diagnosis [3].
Ascitic fluid obtained by paracentesis is consistent with a transudate feature (the
serum to ascites albumin gradient > 1.1) with cytological negativity for malignant
cells [26].
Irradiated liver in RILD appears hypodense on non-contrast CT scans. This CT
finding is limited to radiation fields with well-defined linear margins in partial liver
irradiation with more than 45 Gy [27, 28]. The sharp margins of demarcation are not
seen in patients that received radiation through several non-axial and non-coplanar
portals. The hypodensity of the irradiated area most likely correlates with changes
of increased water content resulting from either edema or vascular congestion [29].
On contrast CT scans, irradiated areas are hypodense on the portal venous phase due
to hypoperfusion and decreased contrast inflow and become hyperdense on the
delayed phase obtained 4 min after contrast injection due to decreased venous drain-
age and stasis [30]. Maximal effect of radiation on liver appearance in CT images is
seen 2–3 months after completion of therapy and is reversible with return to normal
appearance [29].
The area of low density on CT has high signal intensity on the T2-weighted and
low intensity signal on the T1-weighted sequence of MR images [27, 31]. Contrast
enhancement of the irradiated area could be seen in MRI imaging after administra-
tion of gadopentetate dimeglumine (Gd-DTPA) due to the increased capillary per-
meability and chondroitin sulfate iron colloid (CSIC) due to hypofunction of the
reticuloendothelial system [32].
The irradiation area has diminished function that could be detected with radio-
isotope scan as the area with decreased radioisotope uptake. These functional scans
have the potential to quantify hepatocyte function to distinguish functional regions
of hepatocytes from nonfunctional zones. Technetium (99mTc) sulfur colloid (SC)
single-photon emission computed tomography is used as the imaging modality to
image liver function, and there is a correlation between differential SC uptake and
varying doses of radiation delivered [33].

14.7 Prevention

Prevention of RILD is paramount due to its fatal potential.

Three-dimensional treatment planning offers the potential to determine the liver
radiation dose and volume, RILD risk could be estimated using dose-volume histo-
gram (DVH) parameters, and modification of treatment planning should be consid-
ered if the RILD risk is high enough.
14.8 Management 141

With the availability of intensity-modulated radiotherapy (IMRT), stereotactic

body radiotherapy (SBRT), and image guidance in radiation treatment planning,
radiation can be delivered with better liver sparing.
Coa et al. recently have proposed a risk assessment strategy for radiation treat-
ment planning and re-optimization of the plan during therapy for intrahepatic radia-
tion treatment. The assessment of the patient’s individual portal vein perfusion
dose-response function during therapy and prediction of residual liver function after
radiation could allow for detection of patients at high risk for RILD and adjusting
the treatment plan [34, 35].
Amifostine is an organic thiophosphate that was developed to selectively protect
normal tissues against the toxicities of chemotherapy and radiation. Systemically or
regionally, administration of amifostine effectively protects hepatocytes from ion-
izing radiation damage without compromising the antitumor effect of radiation.
Feng et al. observed that the use of amifostine allows for a higher dose of whole
liver radiation to be safely administered and suggested the possibility of using ami-
fostine in combination with radiation for patients with focal liver disease undergo-
ing intensity-modulated radiotherapy or stereotactic body radiotherapy for focal
liver tumors [36, 37].
Theoretically, anticoagulation may exert a protective effect against acute radia-
tion injury by precluding fibrin clot formation and decrease the hepatic congestion.
Lightdale et al. observed a possible protective effect for warfarin in a small group of
Hodgkin’s disease patients [23]. Further evaluation of anticoagulation effect on
radiation hepatic injury appears warranted.
Exposure to ionizing radiation enhances production of reactive oxygen species
and decreases the levels of antioxidant in liver, whereas selenium and vitamin E
supplementation can modulate the changes in liver. Gençel et al. observed signifi-
cant decrease in oxidative stress in rat liver with selenium and vitamin E administra-
tion prior to a 7 Gy exposure relative to control animals [38].

14.8 Management

Treatment of RILD is primarily supportive and involves the use of diuretics for fluid
retention, analgesics for pain, paracentesis for tense ascites, correction of coagu-
lopathy, and steroids to prevent hepatic congestion [39].
Most patients respond to this therapy and symptoms resolve over the subsequent
l–2 months. A minority of patients develop jaundice, progressive ascites refractory
to paracentesis and diuretics, and coagulopathy. Although some of these patients
may recover, a substantial fraction will die due to liver failure [3].
Thrombolysis using tissue plasminogen activator (rh-tPA) and heparin remains
unproven for the treatment of hepatic veno-occlusive disease due to the risk of
bleeding in VOD and suboptimal response rate [40]. tPA/heparin should not be used
in patients with severe VOD with multi-organ failure (MOF) and should be given
early in VOD [39].
142 14 Radiation-Induced Liver Disease

Defibrotide is a deoxyribonucleic acid derivative extracted from mammalian

organs that has fibrinolytic and antithrombotic properties. It has been successfully
used to treat severe hepatic VOD with MOF in patients that have received cytotoxic
chemotherapy in preparation for bone marrow transplantation. Investigations of
defibrotide appear warranted in the setting of radiation-induced liver injury [39, 41,
42].
Radiation will cause hepatocyte injury and suppress liver regeneration.
Hematopoietic stem cells or hepatocytes with normal regenerative potential would
proliferate and repopulate the liver; it has been suggested that G-CSF-mobilized
CD34+ hematopoietic stem cells (HSCs) [43] and transplanted hepatocytes [44]
may ameliorate radiation-induced damage to liver by the ability to engraft into liver
tissue and generate hepatocytes.

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Enteritis
15

Acute gastrointestinal complications occur in 80% of patients in pelvic radiation

therapy [1]. The small intestine appears to be more sensitive to radiation than the
colon and rectum [2] and is also more frequently exposed incidentally to radiation
during treatment of adjacent organs because of its situation within the peritoneal
cavity.
Different intestinal side effects were reported in the Postoperative Radiation
Therapy in Endometrial Cancer (PORTEC-2) Trial, which found that among 214
women with endometrial cancer treated with external beam radiation therapy after
total abdominal hysterectomy and oophorectomy, the rates of diarrhea, fecal leak-
age, rectal blood loss, and bloating were all increased from the baseline at a rate
of 22%, 5.3%, 1.8%, and 0.7% at 1–4 weeks after the end of treatment, respec-
tively [3].
In a study of 107 patients with gynecologic, urologic, or gastrointestinal cancer
within the pelvis that underwent radiation therapy, acute gastrointestinal toxicities
were assessed during the treatment. It was found that 94% of patients developed
altered bowel habits, 80% loose stool, 74% frequency, 65% difficult gas, 60%
pain, more than 48% distress, 44% tenesmus, more than 40% restrictions in daily
activity, 39% urgency, 37% fecal incontinence, and 40% required antidiarrheal
medication [4].

15.1 Mechanism

The intestinal epithelium is a single layer of columnar cells containing crypt-villous

units. Villous protrusions increase the absorptive surface of the small intestine.
Undifferentiated rapidly proliferating stem cells are in crypts that are dividing and
converted to other differentiated cells including enterocytes that migrate to the vil-
lous epithelium. The crypt-villous units are substantially degenerated in organiza-
tion after radiation injury.

© Springer International Publishing AG 2017 145

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_15
146 15 Enteritis

Radiation initially induces mitotic arrest in stem cells. Cryptal surface cell lay-
ers become swollen with nuclear shrinkage and degenerative cytoplasmic changes
and necrosis occur. Villi become shortened with a decrease in enterocyte cell num-
ber and microvilli length and number, leading to absorptive capacity reduction.
Acute inflammatory reaction, leukocyte migration (mostly polymorphonuclear leu-
kocytes and eosinophils), increased microvascular permeability, hyperemia, and
edema all occur causing tissue damage and mucosal breakdown, and, ultimately,
ulceration will develop [2]. Small bowel bacterial overgrowth also may occur dur-
ing pelvic radiation therapy in some patients and is likely related to gastrointestinal
symptoms [5].
Damaged epithelium results in impaired absorption of bile salts, fats, carbohy-
drates, proteins, and vitamin B12 during radiation therapy [6].
The small bowel motility pattern also changes during radiation therapy. The
exact mechanism of this change remains unclear. Some proposed mechanisms are
related to alteration in neurotransmitters release, activity and sensitivity, mucosal
injury, and change in water and electrolyte absorption or alterations in the function
of the smooth muscle cells [7, 8].

15.2 Timing

Symptoms such as cramping and diarrhea usually develop about 1–2 weeks after the
start of radiation therapy (5–12 Gy in fractionated radiation therapy) [9, 10], and its
peak is reached by the fourth to fifth week [10]. Symptoms gradually decrease in
severity within 2–6 weeks after treatment [11, 12], but it could last longer [13].

15.3 Risk Factors

Radiation dose and the volume of small bowel exposed to radiation correlate with
incidence and severity of acute enteritis [14, 15]. Small bowel loops are freely mov-
ing within the peritoneal cavity, and defining exact dose-volume parameters that are
consistent during the entire course of radiation therapy is not possible. Kavanagh
et al. found that severe acute small bowel toxicity could be prevented if the volume
of small bowel receiving radiation doses more than 15 Gy is kept under 120 mL
(D15 < 120 mL) when bowel loops are contoured as normal tissue volume; how-
ever, if the entire peritoneal cavity is considered as small bowel volume, the volume
receiving more than 45 Gy should be kept under 195 mL (D45 < 195 mL) [9].
Chemotherapy concomitant with radiation therapy increases the risk of all grades
of acute enteritis, especially higher grades [16–18]. A systematic review of acute
and late toxicity of concomitant chemoradiation for cervical cancer has reported a
twofold increase in acute grade 3 and 4 gastrointestinal toxicities in patients treated
with chemoradiation therapy rather than radiation alone [18].
Inflammatory bowel disease (IBD) is a known risk factor for small bowel
radiation-­induced toxicity, though very scant data are available. Irradiation can
15.5 Scoring 147

exacerbate IBD symptoms; IBD also increases the acute and late side effects of
radiation therapy significantly. Acute gastrointestinal toxicity that results in radia-
tion cessation was more than 20% in a retrospective study of 28 patients with IBD
that underwent external beam abdominal or pelvic irradiation, and there was no
difference in acute toxicities between patients with Crohn’s disease and ulcerative
colitis. It is recommended that radiation should be used with caution in these
patients [19]. If the radiation therapy is mandatory, efforts should be made to spare
the normal gastrointestinal tissue. Selecting appropriate patient position, computed
tomography (CT) simulator with contrast agent, and using more conformal treat-
ment techniques are effective to determine gastrointestinal tract irradiated volume
and doses.
Previous abdominal surgery is related to risk of acute enteritis due to a larger
volume and fixed loop of small bowel within the radiation field [20, 21]. Type of
surgery may be important in this view. In a retrospective study of 120 patients with
rectal cancer that received chemoradiation, severe radiation-induced diarrhea was
more common in patients with sphincter-preserving procedures versus abdomino-
perineal resection [22].
Low body mass index [14] and female gender [22] have been reported to be
associated with radiation-induced enteritis.
Diabetes, hypertension, age, field design, and number (two-, three-, or four-field
technique) have not been reported to significantly increase acute toxicity of pelvic
radiation [11].

15.4 Symptoms and Diagnosis

Acute injury to small bowel manifests mainly with diarrhea with or without abdom-
inal cramping during or shortly after radiation therapy. The diarrhea secondary to
acute radiation enteritis may be associated with decreased absorption of bile salts,
vitamin B12, lactose, fat, and more rapid small intestinal transit [13]. Nausea and
vomiting, bloating, and loss of appetite may occur [10, 13]. Weight loss can be a
secondary finding. Rarely, obstructive symptoms or bowel perforation due to pro-
found acute enteritis may occur and require surgical intervention, especially in
patients with underlying inflammatory disease [23].

15.5 Scoring

Radiation Therapy Oncology Group (RTOG) and European Organization for

Research and Treatment of Cancer (EORTC) have classified all symptoms
related to lower gastrointestinal and pelvic tissue in the single scoring category
(Table 15.1) [24].
Diarrhea is the main symptom of radiation-induced enteritis, and Table 15.2
shows the Common Terminology Criteria for Adverse Events (CTCAE) v4, which
classifies diarrhea into five grades [25].
148 15 Enteritis

Table 15.1 RTOG/EORTC lower gastrointestinal toxicity

Definition
Grade 1 Increased frequency or change in quality of bowel habits not requiring medication/
rectal discomfort not requiring analgesics
Grade 2 Diarrhea requiring parasympatheticolytic drugs (e.g., Lomotil)/mucous discharge not
necessitating sanitary pads/rectal or abdominal pain requiring analgesics
Grade 3 Diarrhea requiring parenteral support/severe mucous or bloody discharge
necessitating sanitary pads/abdominal distention (flat plate radiograph demonstrates
distended bowel loops)
Grade 4 Acute or subacute obstruction, fistula, or perforation; GI bleeding requiring
transfusion; abdominal pain or tenesmus requiring tube decompression or bowel
diversion

Table 15.2 CTCAE v4, diarrhea scoring

Definition
Grade 1 <4 stools per day over baseline; mild increase in ostomy output compared to baseline
Grade 2 Four to six stools per day over baseline; moderate increase in ostomy output
compared to baseline
Grade 3 ≥7 stools per day over baseline; incontinence; hospitalization indicated; severe
increase in ostomy output compared to baseline; limiting self-care ADL (activities of
daily living)
Grade 4 Life-threatening consequences; urgent intervention indicated
Grade 5 Death

15.6 Prevention

Frequently, different volumes of small bowel have to be included in irradiation por-

tals when abdominal or pelvic tumors are treated with radiation therapy. It should be
attempted to reduce the bowel volume in radiation portals or at least exclude from
high-dose exposure by various techniques such as patient positioning, use of a belly
board, treatment with a full bladder, or using multiple-field techniques [26–28].
Prone positioning on belly-board devices is an appropriate way to spare the small
bowel in both 3D-CRT (conformal radiation therapy) and IMRT (intensity modu-
lated radiotherapy) treatment plans [29, 30], although it may increase large bowel
volume in the treatment field when the limited arc technique is used [29].
With the introduction of new techniques for radiation delivery like IMRT, small
bowel volume with high radiation doses and resultant radiation toxicity have
decreased [31–34].
A number of surgical techniques have been applied for bowel exclusion from the
radiation field in patients with postoperative pelvic radiation therapy that have used
prosthetic materials (e.g., absorbable mesh or saline-filled tissue expanders) or
omentum [35–37]. These interventions are not routinely used in many centers [10].
European Society for Medical Oncology (ESMO) clinical practice guideline rec-
ommends using systemic sulfasalazine at a dose of 500 mg administered orally
twice a day to prevent radiation-induced enteropathy in patients receiving radiation
therapy to the pelvis.
15.7 Management 149

There are many preventive options that have been discussed in the literature but
cannot be recommended due to insufficient evidence [38–46].
Elemental nutritional formulas, low-lactose, low-fat, and low-fiber diets, and
probiotic preparations currently cannot be considered in clinical practice as pro-
phylactic interventions until better determination of their safety and efficacy is
made [42].
Amifostine [39] and vitamin E [40] before radiation therapy as well as angioten-
sin I-converting enzyme inhibitors (ACEi) and 3-hydroxy-methylglutaryl coenzyme
A reductase inhibitors (statins) [41] during radiation therapy appear to provide pro-
tection against lower gastrointestinal toxicity. These primary promising results need
to be established in future studies.
Glutamine is a major source of energy for intestinal epithelial cells and is neces-
sary for cellular proliferation, mucosal cell integrity, and immunological protection
of the small bowel [46, 47]. A protective effect of oral glutamine on the small bowel
mucosa has been suggested in several studies with contradictory results [43–46].
There is insufficient data to draw a definitive conclusion.
Different cytokines and peptides have been evaluated for protecting the gastrointes-
tinal tract from radiation side effects. The protection effects of insulin-like growth
factor-I (IGF-I) on small intestinal mucosal radiation damage have been proposed in
animal studies that need further evaluation [48–51]. Several other agents including
immunomodulators (e.g., orazipone, interleukin-11) [37, 52], trophic agents like gluca-
gon-like peptide-2 and its dipeptidyl peptidase-4 (DPP-IV) resistant analog teduglutide
[53], and other growth factors [54, 55] are proposed to modulate small intestine injury.
A circadian diurnal variation in the number of apoptotic cells in the intestinal
crypt has been shown in animal studies to affect radiation-induced enteritis fre-
quency [56, 57]. In a randomized study of 229 patients with cervical carcinoma that
were treated with radiation therapy in the morning (8:00–10:00 AM) or evening
(6:00–8:00 PM), the overall incidence and severity of diarrhea in patients increased
with the morning treatment as compared with the evening [38]. Currently there is no
recommendation for this observation in clinical practice.

15.7 Management

The key point in the approach to patients with radiation-induced diarrhea is deter-
mining the severity of diarrhea and patient’s general condition. Mild to moderate
diarrhea without any other significant symptoms and signs can be treated in the
outpatient setting with dietary modification, antidiarrheals, and antispasmodics (see
below). All of these patients should be examined every 24 h [58].
Patients with severe diarrhea or persistent mild to moderate diarrhea or presence
of some cautionary factors such as fever, dehydration, severe abdominal cramping,
nausea and vomiting, sepsis, neutropenia, or blood in the stool should be hospitalized
to be immediately worked up with complete blood count, stool exam and culture,
serum electrolyte and renal function test and aggressive treatment with octreotide,
antibiotic therapy, and fluid and electrolyte replacement, as indicated [58].
150 15 Enteritis

15.7.1 Dietary Modification

Patients should be encouraged for maintenance of adequate hydration (35 ml/kg/

day) and eating small, frequent high-protein food. Chocolate, alcohol, caffeine,
sorbitol-containing substances, beans, high osmolar beverage, foods with insoluble
fiber including skins of fruits and raw vegetables, whole-grain and multigrain foods,
strong spices, and extreme hot/cold food should be avoided. A transient lactose
intolerance may occur in up to 45% of patients that respond to the avoidance of milk
and milk products (a lactose-restricted diet) [5, 13, 59]. Fat malabsorption also
occurs in many cases that provides a rationale for the use of low-fat diet [10].
Soluble fiber may help build stool consistency (e.g., fruits without skins, oat, bran,
and barley) [59].

15.7.2 Antidiarrheals

Loperamide is often used as a first-line antidiarrheal agent. If diarrhea does not

respond to the use of loperamide after 48 h, octreotide has been shown to be
effective [10]. It has been reported that octreotide seems to be more
effective than diphenoxylate and atropine in the treatment of radiation-induced
diarrhea [60].
Loperamide should be started with an initial dose of 4 mg, then 2 mg after each
loose stool or every 4 h; treatment should be continued throughout the duration of
radiation therapy with standard dose. If diarrhea does not resolve after 24 h,
increasing the dose 2 mg every 2 h should be considered, not to exceed 16 mg/day
(8 mg/day for self-medication). These patients should be further assessed with
stool analysis and blood work-up. Oral supplementation or intravenous hydration
may be indicated in patients based on their general condition, lab test results, and
dehydration status. Treatment delay may be required based on physician judgment.
If no improvement has been seen within 48 h, loperamide is discontinued and
second-line treatment with octereotide 100 μg subcutaneously (SC) three times
daily will start [10, 59, 61].
Cholestyramine is a nonabsorbable high molecular resin that binds bile salts irre-
versibly. Some studies have supported cholestyramine efficacy in the treatment of
acute and chronic diarrhea in patients treated with radiation therapy [62, 63].
It has been observed that the inhibition of prostaglandin biosynthesis by sul-
phasalazine agents may relieve diarrhea caused by other reasons than radiation, and
this led to assessing aspirin in radiation-induced diarrhea. There is limited evidence
in this regard and no guideline recommended for its use [62, 64, 65].

15.8 Antispasmodics

An anticholinergic antispasmodic agent could alleviate bowel cramping.

References 151

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Radiation Cystitis
16

Radiation cystitis is a complication of pelvic radiation therapy that patients encoun-

ter when treated for bladder cancer or other pelvic cancers.
There is a wide range of radiation cystitis incidence because of variation in radia-
tion technique, time-dose-volume parameters, the subjective nature of the symp-
toms, and diversity in collecting and reporting patient data between studies that
evaluated radiation cystitis [1].
Up to 70–90% of patients with bladder cancer experience acute genitourinary
symptoms during radiation therapy [2–19]. Prostate cancer is the second most com-
mon reason for radiation-induced cystitis (41–100%) [20–30], followed by cervical
cancer (20–25%) [31–35] and rectal cancer (35–53%) [36, 37].

16.1 Mechanism

The bladder wall has three well-defined layers including the mucosa (urothelium,
basement membrane, and lamina propria), the muscularis propria, and the adventi-
tia/serosa.
Human urothelium is considered a transitional epithelial tissue that its cellular
differentiation increased from basal cells at basement membrane to surface cells of
superficial or apical layer [38]. Surface cells known as umbrella cells are joined to
each other with tight cell membrane junctions. The apical surface of umbrella cells
is almost entirely covered by rigid plaques (known as the asymmetric unit mem-
brane or AUM) consisting of a group of transmembrane proteins called uroplakins
(UP), i.e., UPIa, UPIb, UPII, and UPIII [39–42].
Between these particles, UPIII is a main subunit of urothelial plaques that play a
key role in urothelial structure [43].
The urothelium also contains a luminal negatively charged glycosaminoglycan
(GAG) called a mucous layer that covers the umbrella cells on top of the apical
membrane [44].

© Springer International Publishing AG 2017 155

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_16
156 16 Radiation Cystitis

GAGs can be in a non-sulfated form like hyaluronic acid (HA) or a sulfated form
like heparan sulfate and heparin, chondroitin sulfate (CS), dermatan sulfate, and
keratan sulfate [45].
Tight junctions between umbrella cells, the urothelial plaques, and the glycos-
aminoglycan (GAG) layer make an efficient barrier against electrolyte and nonelec-
trolyte urine concentrations in bladder mucosa [46, 47].
Data on underlying mechanisms of acute radiation effects in the urinary bladder
are limited. The urothelium barrier of the bladder is affected by radiation. Decrease
in the number of umbrella cells [48], loss of the superficial UPIII layer [48], and
GAG layer damage [49, 50] have been reported in patients with radiation cystitis.
However, due to slow cell turnover rate of bladder epithelium (in the range of
42–350 days) [46, 51], gross tissue breakdown does not occur in early radiation
cystitis [48].
Following the urothelium barrier impairment, urine substances infiltrate the
bladder wall and produce more injuries by induction of the inflammatory response,
mast cell proliferation, activation, degranulation and histamine release, vasodilata-
tion, and also erythematous swelling [48]. Urine ion content, histamine, and other
inflammatory substances irritate nerve terminals within the bladder wall [52]. This
damaged barrier is also susceptible to secondary infection that could produce more
injury [53].
Molecular responses including increased synthesis of intercellular adhesion mol-
ecules (ICAM1) [54] and prostaglandin [55] resulted in increased inflammatory
reactions and detrusor muscle edema and decreased the bladder capacity. All these
events finally produce overactive bladder symptoms.

16.2 Timing

The first symptoms of early radiation effects on the urinary bladder usually occur
4–6 weeks after treatment begins. They are usually mild and transient. It has been
found that grade 2 or higher acute bladder toxicity may take an average of 6 weeks
(range 2–21 weeks) after the completion of treatment to improve [55, 56], but
5–20% of patients may develop persistent late bladder damage from 6 months to
10 years after treatment [57]. The risk of late bladder damage depends on pre-­
radiation therapy genitourinary morbidity [4], smoking history (≥1 pack per day)
[58], body mass index(>30 kg/m2) [58], any kind of procedure before radiation
therapy [59], and a high dose per fraction [60] that go beyond the scope of this book.

16.3 Risk Factors

The risk of acute bladder damage increases with pre-radiation therapy genitourinary
morbidity score [4, 61].
Chemotherapy administered concurrently with radiation therapy has not been
shown to significantly increase the risk of acute bladder complications [12, 34, 62],
16.5 Scoring 157

whereas use of hormonal therapy in prostate cancer has been associated with more
acute genitourinary complications [4, 61].
Radiation total dose, maximum bladder dose, and higher volume of bladder
exposed to radiation are associated with a higher risk of acute toxicity [29, 63, 64].
The treatment time and dose per fraction have not been reported to be related with
acute bladder injury [56, 65].
Other clinical factors such as age, transurethral resection of the prostate before
radiation therapy, diabetes mellitus, and smoking have not been reported to be asso-
ciated with acute bladder toxicity [4, 56], although some of them as previously
mentioned are related to late toxicity.

16.4 Symptoms and Diagnosis

Radiation cystitis symptoms during the early reaction phase include frequency, noc-
turia, urgency, dysuria, and hematuria [66].

Urgency: Sudden and compelling desire to pass urine, which is difficult to defer
Incontinence: Involuntary leakage of urine with the feeling of urgency
Frequency: Voiding more than eight times during the day
Nocturia: Need to wake up more than once at night to void

Bacterial infection may complicate the clinical picture.

Direct examination of the urothelium demonstrates mucosal edema, hyperemia,
and inflammation.

16.5 Scoring

Radiation Therapy Oncology Group (RTOG) radiation induced bladder morbidity

scoring criteria presented in Table 16.1 [67].

Table 16.1 RTOG bladder morbidity scoring

Grade 1 Frequency of urination or nocturia twice pretreatment habit/dysuria, urgency not
requiring medication
Grade 2 Frequency of urination or nocturia that is less frequent than every hour. Dysuria,
urgency, and bladder spasm requiring local anesthetic (e.g., Pyridium)
Grade 3 Frequency with urgency and nocturia hourly or more frequency/dysuria, pelvis pain
or bladder spasm requiring regular, frequent narcotic/gross hematuria with/without
clot passage
Grade 4 Hematuria requiring transfusion/acute bladder obstruction not secondary to clot
passage, ulceration, or necrosis
158 16 Radiation Cystitis

16.6 Prevention

Acute symptoms of radiation injury to the bladder are usually self-limited and man-
ageable [68], but prevention of these symptoms is important because they are asso-
ciated with a marked impact on quality of life and increased occurrence of late
toxicities [56].

16.6.1 Bladder Sparing

With the introduction of novel radiation therapy techniques like intensity-­modulated

radiation therapy (IMRT) or image-guided radiotherapy (IGRT), treatment confor-
mity and normal tissue sparing improve, which minimize the risk of treatment-­
related toxicity. A significant reduction in acute bladder toxicity in prostate, cervical,
and rectal cancer patients treated with this highly conformal treatment versus 3D
conformal radiotherapy (3DCRT) has been found [69–73].
Different dose-volume parameters have been proposed to predict acute genito-
urinary toxicities. For example, maximum dose (Dmax) of bladder in prostate can-
cer study [29] and volume of bladder receiving 35 Gy or more in rectal cancer [36]
have been reported to have significant correlations with the risk of acute bladder
toxicity.

16.6.2 Intravesical Instillation

Intravesical GAG instillations including hyaluronic acid [73] and chondroitin sul-
fate [74] in patients undergoing radiation therapy may reduce overactive bladder
symptoms due to covering of the bladder urothelium and preventing of cellular
damage by urinary irritants.
The proposed treatment scheme of chondroitin sulfate is weekly instillations of
40 mL of 0.2% solution of chondroitin sulfate during radiation therapy in outpatient
clinic after a course of radiation therapy (at least 2 days after chemotherapy). A
single-use catheter is usually used to empty the bladder and then fill it with the
40 mL solution. Patients are asked not to void at least 2 h after the instillation [74].
The proposed treatment scheme of intravesical hyaluronic acid prescription is
instillations of 40 mg/50 mL intravesical hyaluronic acid. Instillations should begin
1 week before starting radiation therapy and then weekly instillations until 4 weeks
after completion of radiation therapy [73].

16.7 Management

Generally, all patients with acute radiation cystitis symptoms should be encouraged
to increase fluid intake. It can result in urine irritant dilution and prevent urinary
tract infections [75].
16.7 Management 159

Acute radiation cystitis often responds to symptomatic therapy. Anticholinergics

have been the mainstay of management for storage symptoms such as frequency.
Other treatment options include analgesics like phenazopyridine and alpha-1
blocker [66].

16.7.1 Anticholinergics

Anticholinergic agents block acetylcholine effects at muscarinic receptors and sup-

press bladder muscle contractions [76]. These agents improve bladder storage and
alleviate symptoms.
Oxybutynin and tolterodine are widely used for overactive bladder symptoms. They
are nonspecific muscarinic receptor blocker and can cause side effects by acting on
other parts of the body (e.g., dry mouth or eyes, constipation, or nausea). Oxybutynin
and tolterodine appear to have similar effects on patients’ symptom improvement but
have a lower risk of withdrawals and dry mouth [76, 77]. Extended release preparations
of these drugs are available and are associated with similar efficacy and less risk of dry
mouth [76, 77]. Hyoscyamine is another anticholinergic agent that is used to treat cys-
titis. Data for comparing hyoscyamine to other anticholinergic drugs are lacking.

Oxybutynin chloride:
Immediate release: 5 mg PO two to three times daily; not to exceed 5 mg PO four
times daily [78]
Extended release: 5–10 mg PO daily; may be increased by 5 mg/day at weekly
intervals, not to exceed 30 mg/day [78]

Tolterodine:
Immediate release: 2 mg PO q12h [79]
Extended release: 2–4 mg PO once daily [79]

Oxybutynin chloride and tolterodine are contraindicated in patients with gastric

or urinary obstruction or retention, paralytic ileus, severe ulcerative colitis, and
uncontrolled narrow-angle glaucoma [78, 79].

16.7.2 Alpha-1 Blocker

Tamsulosin is an α-1A-specific blocker that induces selective relaxation of the

detrusor muscle and improved bladder compliance [80]. Tamsulosin may be the
preferred drug to prescribe over other apha-1 blockers like prazosin because of its
more acceptable side effect profile and greater patient satisfaction [81].

Usage: 0.4 mg PO once daily, 30 min after same meal each day [82];

it should be used with caution in patients with coronary artery disease [82].
160 16 Radiation Cystitis

16.7.3 Analgesics

Phenazopyridine is a urinary analgesic that is excreted into the urine and induces a
local analgesic effect.
Usage: 100–200 mg PO after meals three times daily [83].
Phenazopyridine is contraindicated in hypersensitivity to drug, severe hepatitis,
and renal impairment (CrCl <50 mL/min) [83].

16.7.4 Intravesical GAG

Damage to the GAG layer has been found in radiation cystitis mechanism.
Intravesical GAG could be bound to the damaged bladder surface and reduce radia-
tion cystitis symptoms. The glycosaminoglycan molecule is not absorbed into the
body and doesn’t penetrate the bladder and remain on the mucosal surface [84].
Extensive clinical experience has been gained with formulations containing
either chondroitin sulfate, hyaluronic acid, or a combination of chondroitin sulfate
and hyaluronic acid in late radiation cystitis [50]. More trials are needed to deter-
mine the benefit of these agents in acute radiation cystitis.

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Radiation Proctitis
17

The rectum is the most affected organ during pelvic radiation therapy because of its
fixed position in the central part of pelvic cavity [1]. Acute radiation proctitis occurs
in more than 75% of the patients during pelvic radiation therapy [2]. Treatment
interruption due to severe acute radiation proctitis has been reported in 10–20% of
patients undergoing pelvic radiation therapy [3, 4].

17.1 Mechanism

Radiation-induced acute colorectal injury involves all mucosal compartments

including the epithelium, goblet cells, and lamina propria.
Mitotic arrest occurs in rapidly proliferating epithelial stem cells in mucosal
crypts and leads to cell depletion; shortening, narrowing, and loss of crypts; eroded
surface of epithelium; and mucosal break down. Inflammatory cell infiltration of the
epithelium by neutrophilic and eosinophilic cells occurs. Cryptitis due to neutrophil
infiltration through the crypt wall and crypt abscesses by eosinophil accumulation
develop. The number of goblet cells is reduced, and glandular atrophy occurs.
Significant inflammation of the lamina propria with vessel congestion occurs and
leads to hyperemia, edema, and ulceration [5–7].
Inflammatory mediators including eicosanoids are induced in the rectum as an
early response to direct radiation injury or secondary to mucosal damage and lead
to an increase in inflammatory cell infiltration and activation, capillary permeability,
and proctitis severity [8].

17.2 Risk Factors

Several patient-related factors have been reported to be associated with acute radia-
tion proctitis like patients with younger age (less than 60 years) [9], presence of
hemorrhoids, diabetes [10], and inflammatory bowel diseases [11] (see Chap. 15).

© Springer International Publishing AG 2017 165

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_17
166 17 Radiation Proctitis

Treatment-related factors including multiple radiation dosimetric factors (like

the percent volume of rectum receiving more than 30, 35, and 60 Gy, mean rectal
dose, the percent volume of anal canal receiving 15 Gy, the rectal length irradiated
to doses of 5 Gy, and more) [9, 10, 12] and concurrent chemotherapy are proposed
as factors related to probability of acute radiation proctitis [13].

17.3 Timing

Early symptoms can develop during the first or second week of radiation therapy
[14] and increase in frequency and severity throughout the radiation therapy course
[5]. Symptoms including anorectal dysfunction usually resolve within 2–3 months
after treatment completion [4].

17.4 Symptoms

Acute radiation proctitis manifests by increased frequency and urgency of defeca-

tion, rectal pain, tenesmus, mucous discharge, and less commonly bleeding and
fecal incontinence [3, 15]. Fecal urgency and incontinence are associated with alter-
ations in sphincter function and reduction in the minimum basal and mean squeeze
pressures in anorectal manometry [3]. Preexisting patient symptoms or medical
conditions may be worsened during radiation therapy. Preexisting hemorrhoids may
be inflamed and exacerbate patient symptoms.
Perianal skin reactions occur in patients with this area present in radiation portals
that presents with the skin changes that are discussed in Chap. 1.
Edematous mucosa with visible and friable vascular pattern is the most common
morphologic change that is seen endoscopically in its maximal score in the acute
phase of radiation proctitis [5]. Infrequently, spontaneous hemorrhage or visible
ulcers may be seen [14].

17.5 Scoring

Radiation Therapy Oncology Group (RTOG) and European Organization for

Research and Treatment of Cancer (EORTC) radiation toxicity grading classify all
symptoms related to the lower gastrointestinal tract in a single scoring category
(Table 17.1) [16].
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 classi-
fies proctitis (either acute or chronic) into five grades (Table 17.2) [17]:
17.6 Prevention 167

Table 17.1 RTOG/EORTC radiation toxicity grading for lower gastrointestinal tract
Definition
Grade 1 Increased frequency or change in quality of bowel habits not requiring medication/
rectal discomfort not requiring analgesics
Grade 2 Diarrhea requiring parasympatholytic drugs (e.g., Lomotil)/mucous discharge not
necessitating sanitary pads/rectal or abdominal pain requiring analgesics
Grade 3 Diarrhea requiring parenteral support/severe mucous or bloody discharge
necessitating sanitary pads/abdominal distention (flat plate radiograph demonstrates
distended bowel loops)
Grade 4 Acute or subacute obstruction, fistula, or perforation; GI bleeding requiring
transfusion; abdominal pain or tenesmus requiring tube decompression or bowel
diversion

Table 17.2 CTCAE v4 proctitis grading

Definition
Grade 1 Rectal discomfort, intervention not indicated
Grade 2 Symptoms (e.g., rectal discomfort, passing blood or mucus); medical intervention
indicated; limiting instrumental ADL
Grade 3 Severe symptoms; fecal urgency or stool incontinence; limiting self-care and ADLs
Grade 4 Life-threatening consequences; urgent intervention indicated
Grade 5 Death

17.6 Prevention

Intensity-modulated radiation therapy (IMRT) can reduce the irradiated volume of

the rectum and improve acute radiation-induced proctitis compared to 3D confor-
mal radiation therapy (3DCRT). However, dose-volume parameters do not signifi-
cantly change in rectal cancer treated with IMRT because of large volume of rectum
included in target volume of treatment fields [18–25].
Amifostine can reduce acute radiation-induced proctitis in patients receiving pel-
vic radiation therapy and is recommended at a dose of ≥340 mg/m2 intravenously to
prevent radiation proctitis [26, 27]. Intrarectal and subcutaneous application of ami-
fostine also have been reported to be effective alternative routes to the intravenous
amifostine in protection against acute radiation-induced rectal damage [28–30].
Investigational methods including injecting hyaluronic acid [31, 32] and human
collagen [33] in the perirectal fat as well as insertion of an inflatable balloon appli-
cator into the rectum [33, 34] have been proposed in prostate cancer radiation ther-
apy to increase the distance between rectum and prostate and consequently decrease
the radiation dose of the anterior rectal wall and proctitis.
Sucralfate is a nonabsorbable basic aluminum salt of sucrose sulfate that has
been proposed in prevention of radiation-induced proctitis due to its cytoprotective
168 17 Radiation Proctitis

properties, angiogenesis and epithelial proliferation improvement, protection of

denuded mucosa, and binding bile acids; however, several studies did not find sub-
stantial benefit of oral or rectal sucralfate in the reduction of acute radiation proctitis
symptoms [35, 36].
Rectal misoprostol, a prostaglandin E1 analog, is another agent that is evaluated
as a radioprotection of acute proctitis and provides mixed results in related studies
[37, 38]. It has been shown that rectal hyaluronic acid (HA), a major mucopolysac-
charide, can reduce epithelial cell death and provide a positive effect on radiation
proctitis [39].
Aminosalicylate compounds including prodrugs (sulfasalazine and balsalazide)
or active (mesalazine) agents have anti-inflammatory properties due to their ability
in inhibition of inflammatory mediators and cells. Balsalazide converts to active
form by colonic bacteria after oral administration with minimal systemic absorption
and has more efficacy in patients with more distal colon disease due to a high con-
centration of active drug to the distal compared to other oral agents like mesalazine
[40]. It has been suggested that oral balsalazide is able to prevent or reduce symp-
toms of radiation proctitis in patients undergoing irradiation for prostate cancer
[41]. Rectal mesalazine did not show any prophylactic effect on radiation-induced
proctitis during radiation therapy for prostatic carcinoma [42].
Nonsystemic glucocorticosteroids, such as beclomethasone dipropionate (BDP),
have been suggested as efficient agents for the prevention of radiation-induced
proctitis due to their anti-inflammatory properties and safer pharmacokinetic profile
compared with systemic agents. Further studies are needed to confirm these primary
promising results [43].
Clinical use of prophylactic sucralfate, misoprostol, HA, balsalazide, mesala-
mine, or BDP for radiation proctitis protection cannot be recommended based on
current results.
Butyrate enemas have not shown any benefit given for the prevention of acute
radiation proctitis [44].
Fecal calprotectin and lactoferrin are two indicative markers of intestinal inflam-
mation that are released by migrated intestinal neutrophils [45, 46]. It has been
shown that the fecal levels of calprotectin and lactoferrin increase during pelvic
radiation therapy and are associated with acute radiation proctitis in non-colorectal
cancers [47–49]. Increased fecal calprotectin and lactoferrin levels in colorectal
cancer limit their use as a diagnostic marker in this setting [50, 51]. Another marker
proposed in this regard is human DNA concentration that is excreted in feces due to
epithelial cell damage [51]. These factors are promising tools that allow monitoring
mucosal damage and treatment modification with the aim of acute injury
prevention.

17.7 Management

Acute proctitis can be treated with dietary modification, topical agents, and/or ces-
sation of treatment in severe cases.
References 169

Fecal urgency or incontinence can be improved by dietary modification. Patients

should be encouraged to have adequate soluble fiber (e.g., fruits without skins, oat,
bran, barley) in their regulatory diet. Dietary fiber increases stool bulk and enhances
stool consistency and viscosity [52]. Treatment of concomitant diarrhea may help to
control fecal urgency or incontinence. All dietary modification and medications that
are discussed for treatment of diarrhea in radiation-induced enteritis (Chap. 15)
could be effective in improvement of these patients’ symptoms. Loperamide is par-
ticularly useful in this setting due its positive effect on anal sphincter pressure that
helps in stool continence [3, 53, 54].
Current data support using of butyrate as an effective medical treatment of acute
radiation proctitis. Butyrate enema (80 mL once per day or enemas of 40 mL twice
daily) can improve patient symptoms. Butyrate, a distinct form of short-chain fatty
acid, is the major energy source for colonocytes and provides a trophic effect on
colonic mucosa by enhancing epithelial cell proliferation and differentiation
[55–57].
Other medical agents such as rectal sucralfate and rectal steroid enema plus oral
sulfasalazine may be effective [58], but there is no recommendation for using of
them in treatment of radiation proctitis. Due to high incidence of radiation proctitis,
there is substantial need for further studies to evaluate several topical agents alone
or in combination with oral medications as well as in combination with different
topical agents with different actions in treatment of radiation proctitis.
Patients with perianal skin reaction should be informed to have good hygiene and
use a sitz bath several times daily. Topical agents could be used based on severity of
reaction (see Chap. 1).

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Fatigue
18

Radiotherapy-induced fatigue is a common early and long-lasting side effect of

radiation therapy, which, despite its negative effect on patient quality of life, is often
underestimated and undertreated in daily practice. Patients usually do not consider
fatigue as a treatment side effect. Indeed only in one-fourth of cases are any inter-
vention proposed to the patient, and only about 50% of patients discuss it with a
physician [1].
Hickok et al. reported on the radiation-induced fatigue incidence in 372 patients
with various types of cancer who had received radiation therapy without concurrent
chemotherapy. They found that of the 160 patients who did not have any fatigue at
the start of irradiation, 70% (112 patients) developed the symptoms during radiation
therapy, and approximately 84% of patients that reported fatigue at the initiation of
therapy also reported fatigue over the course of treatment [2].

18.1 Mechanism

Several conditions can induce fatigue in cancer patients including anemia, mood,
and sleep disorders; patient’s symptoms such as pain, nausea and vomiting, diarrhea
and electrolyte disturbances, cardiopulmonary, hepatic renal or endocrine dysfunc-
tion, infection, and poor nutritional status; and the side effects of drugs such as
opioid analgesics or anticonvulsants [3].
Some of these variables may be produced by the tumor itself or treatment with
radiation or chemotherapy.
It has been proposed that anemia induced by radiation can cause fatigue due to
decreased oxygen delivery to tissue and a negative energy balance [3–5]. Irradiation
of different parts of the body may induce fatigue by different mechanisms. Severe
diarrhea during pelvic radiation therapy [6], hypothyroidism as a consequence of
neck radiation therapy [7], psychological effect in women receiving radiation ther-
apy for early breast cancer [8], direct effects on normal brain parenchyma related to
cranial radiation therapy [9], or a decline in neuromuscular efficiency in prostate

© Springer International Publishing AG 2017 173

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_18
174 18 Fatigue

cancer radiation therapy [10] may be related to fatigue etiology in patients treated
with radiation therapy.
Available data suggest that activation of the pro-inflammatory cytokine network
and inflammatory response may be responsible for radiation-induced fatigue. In
particular, increased levels of the interleukin-6 (IL-6), IL-1 receptor antagonist
(IL-1ra), and C-reactive protein (CRP) are associated with a higher frequency and
severity of fatigue [11–15]. Excessive nuclear factor (NF)-κB pathway activation
has been seen in fatigued patients who have a key role in controlling expression of
pro-inflammatory genes [16, 17].
Pro-inflammatory cytokines can also be produced in the central nervous system
in response to radiation and generate fatigue [11, 12, 18].
Persistent posttreatment fatigue is associated with elevated markers of pro-­
inflammatory cytokine activity and alterations in the cellular immune system along
with subtle dysregulation in hypothalamic-pituitary-adrenal axis function [11,
19–21].
Some investigators have not validated these relationships, so further evaluation is
needed [22].
Other mechanism proposed for radiation-induced fatigue is mitochondrial dys-
function. A defect in mitochondrial oxidative phosphorylation is induced by radia-
tion and causes genetic instability and cellular damage. Mitochondrial synthesis of
ATP is disrupted and fatigue develops [23].

18.2 Timing

Fatigue may be developed or increased from baseline levels during radiation ther-
apy. Fatigue usually begins during the second or third week of radiation therapy.
Symptoms of fatigue become more severe over the course of treatment (cumulative
fatigue) [24]. More than three-fourths of fatigue occurs by the third to fifth weeks of
treatment. Fatigue is usually reduced gradually after treatment completion to the
pretreatment levels within 4–8 weeks following the completion of treatment [25]
but in some patients is protracted over many weeks (may last from 3–4 weeks to
2–3 months after treatment stops) [20, 26–31].
It has been observed that the radiation therapy-free weekends are associated with
a lesser fatigue [32].

18.3 Risk Factors

There are inconsistent data across studies evaluating fatigue-related factors, and
additional research is warranted to determinate the predictor factors of radiation-­
induced fatigue. We discuss some of these factors here.
One of the uniformly reported predictive factors for fatigue during radiation
therapy is higher than the baseline fatigue level. The presence of fatigue at the
18.4 Symptoms 175

initiation of irradiation is associated with more fatigue experienced by patients dur-

ing radiation therapy [33, 34].
Both fatigue and psychological disorders (like anxiety and mood disorders) are
prevalent in cancer patients and have overlapping symptoms that produce some
ambiguity for conclusion. There are conflicting data regarding to relationship
between fatigue severity and psychological distress [7, 22, 35, 36]. Some have
reported no significant relationship [37], and others have shown predictability of
mood disorders for fatigue [36].
Some researchers have found differences in fatigue levels by radiation therapy
sites. High frequency of radiation-induced fatigue was seen in breast cancer patients
receiving radiation therapy rather than other common cancers including lung or
prostate cancer [38–44], although some reported that patients with lung, gastroin-
testinal, and head and neck cancers experience more severe fatigue and that their
fatigue increases more intensely over the course of radiation than does that of
patients with breast cancer [45].
There are sparse data about the treatment parameter for radiation-induced fatigue.
Radiation field sizes seem to be positively associated with maximum radiation-­
induced fatigue [46, 47]. Total dose might also be expected to influence the severity
of fatigue although linear increase in fatigue with cumulative radiation dose over
time is not seen [48].
Correlation between immune serum markers and fatigued patients has been pro-
posed [49]. An analysis of different variables showed that higher baseline neutrophil
counts have more consistent relation with fatigue than circulating cytokines, coagu-
lation factors, peripheral blood indices, and biochemical factors [33]; however,
more studies are needed to assess the relation of different immune markers and
fatigue level.
Data about the role of chemotherapy as a predictor of radiation therapy-induced
fatigue is also inconclusive. Some studies have shown that pretreatment with che-
motherapy may increase fatigue severity, although others have reported that fatigue
severity scores are not associated with chemotherapy [50, 51].
Other clinical variables including disease stage, previous surgery, weight [51,
52], and demographic variables such as race, gender, age, marital status, personality
characteristics, and employment status [2, 3, 48, 53, 54] have not been consistently
reported to be related with fatigue induced during radiation therapy.

18.4 Symptoms

Cancer-related fatigue is defined as a sensation of tiredness or lack of energy that is

associated with functional limitations and impaired quality of life [34, 53, 55–60].
Unlike simple tiredness, it is more debilitating and not relieved by sleep or rest. It
interferes with activities of daily living like preparing food or cleaning the house
and leads to withdrawal from enjoyable activities like social activities with friends
and family and even discontinuation of cancer treatment [26, 61]. Objective
176 18 Fatigue

physical function (performance status) [62–64] and psychological status (mental/

emotional aspects) [65–67] are also affected by fatigue.
There is a diurnal variation in radiation-induced fatigue, with increasing levels in the
evening, which is consistent with the diurnal pattern of fatigue in the general population
[68–71]. The severity of both evening and morning fatigue increases during radiation
therapy and then decreases following the completion of radiation therapy [72].

18.5 Diagnosis and Scoring

Fatigue is a sensation with multidimensional components including sensory, cogni-

tive, affective, behavioral, and physiologic aspects.
Based on NCCN guidelines “Cancer-related fatigue is defined as a persistent,
subjective sense of physical, emotional and/or cognitive tiredness or exhaustion
related to cancer or cancer treatment that is not proportional to recent activity and
that significantly interferes with usual functioning” [73].
Numerous assessment measures (including unidimensional and multidimen-
sional scales) have been developed for screening and diagnosis of cancer-related
fatigue. Most of them are based on patient self-report; however, there is no consen-
sus about the best method for assessment.
Multidimensional measures examine several domains of sensory, cognitive,
affective, behavioral, and physiologic function that is affected by cancer-related
fatigue. Therefore, a multidimensional measurement may seem to be a more spe-
cific and refined diagnostic tool but may be too long to complete and not be suitable
for screening or scoring in practice [9, 74].
Unidimensional measures (single-item or multi-item) are often single-question
scales that are rapid and sensitive and can be applied efficiently for screening of the
occurrence and measuring the severity of cancer-related fatigue but may lose the
multiple dimensions of fatigue [3, 75]. Moreover, some argue that the extent of
overlap between fatigue and depression is reduced with using a single item than a
multi-item measure for fatigue [76].
Consideration of the measurement properties, strengths, and limitations of these
instruments, including reliability, validity, specificity, sensitivity, recall period,
respondent burden, translation in multiple languages, and the availability of normed
values to aid interpretation, should be used to guide decisions about the utility of a
measure for specific clinical or research purposes [3].
Specific diagnostic criteria have been proposed for defining cancer-related
fatigue as an independent entity in the International Classification of Diseases, 10th
revision (ICD-10) [77–79].
Some of the other multidimensional scales for cancer-related fatigue have been
proposed including the Multidimensional Fatigue Inventory [80, 81], the Functional
Assessment of Cancer Therapy-Fatigue Scale [82], the Piper Fatigue Scale [83], the
Fatigue Symptom Inventory [84, 85], the Lee Fatigue Scale [86, 87], the revised
Schwartz Cancer Fatigue Scale [88], and the Cancer Fatigue Scale [89].
The Lee Fatigue Scale has established internal consistency reliability in a variety
of populations including cancer patients [86, 87, 90, 91]. In this scale, fatigue
18.5 Diagnosis and Scoring 177

severity is measured using 13 items. Each item has a 0–10 numeric rating scale with
higher scores indicating higher levels of fatigue severity. Respondents are asked to
rate each item based on how they felt “right now,” within 30 min of awakening (i.e.,
morning fatigue), and before going to bed (i.e., evening fatigue) for two consecutive
days and nights. The fatigue scale score is calculated as the mean of the 13 fatigue
items. It has established that cutoff scores for clinically significant levels of fatigue
(i.e., ≥3.2 for morning fatigue, ≥5.6 for evening fatigue) [86, 91].
There are several unidimensional single-item scales such as the Symptom
Distress Scale [92], the Rotterdam Symptoms Checklist [93], the European
Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 quality-­
of-­life measure [94], the Medical Outcomes Study 36-Item Short-Form Health
Survey (SF-36) [95], the MD Anderson Symptoms Inventory [96], the Zung Self-­
Rating Depression Scale [97], the Visual Analog Fatigue Scale [98], or multi-item
scales such as the Brief Fatigue Inventory [99].
Based on National Comprehensive Cancer Network (NCCN) guidelines, fatigue
should be assessed quantitatively on a 0–l0 scale (where 0 means no fatigue and 10
means the worst fatigue imaginable, how would you rate your fatigue at its worst
over the past 7 days?); A score of 0 indicates an absence of fatigue, a score of 1–3
indicates the presence of mild fatigue that does not require clinical intervention, and
scores of 4–6 and 7–10 indicate moderate and severe fatigue, respectively, which
require further evaluation and clinical intervention [73].
Proposed (1998 draft) ICD-10 criteria for cancer-related fatigue is shown in
Table 18.1.

Table 18.1 Proposed (1998 draft) ICD-10 criteria for cancer-related fatigue
Six (or more) of the following symptoms have been present every day or nearly every day
during the same 2-week period in the past month, and at least one of the symptoms is (A1)
significant fatigue (A1)
A1. Significant fatigue, diminished energy, or increased need to rest, disproportionate to any
recent change in activity level
A2. Complaints of generalized weakness or limb heaviness
A3. Diminished concentration or attention
A4. Decreased motivation or interest to engage in usual activities
A5. Insomnia or hypersomnia
A6. Experience of sleep as unrefreshing or nonrestorative
A7. Perceived need to struggle to overcome inactivity
A8. Marked emotional reactivity (e.g., sadness, frustration, or irritability) to feeling fatigued
A9. Difficulty completing daily tasks attributed to feeling fatigued
A10. Perceived problems with short-term memory
A11. Post-exertional malaise lasting several hours
B. The symptoms cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning
C. There is evidence from the history, physical examination, or laboratory findings that the
symptoms are a consequence of cancer or cancer therapy
D. The symptoms are not primarily a consequence of comorbid psychiatric disorders such as
major depression, somatization disorder, somatoform disorder, or delirium
178 18 Fatigue

18.6 Management

All cancer patients should be screened by a certain fatigue scale at their initial and
follow-up visits.
Patients with significant fatigue scale should be further evaluated by history and
physical examination. Cutoff for significant fatigue varies based on different fatigue
scale tools (see Sect. 18.5).
Based on NCCN guidelines, primary patient evaluation includes:

History and physical examination (disease status and treatment, review of systems,
social support status/availability of caregivers, economic status, onset, pattern,
duration change over time) [73]
Assessment of: Treatable contributing factors (pain, anemia, nutritional deficits/
imbalance, sleep disturbance/poor sleep hygiene, decreased functional status,
emotional distress, drug induced sedation comorbidities (alcohol/substance
abuse, cardiac dysfunction, hot flashes, hypothyroidism, hypogonadism, adrenal
insufficiency, gastrointestinal dysfunction, hepatic dysfunction, infection, neuro-
logic dysfunction, pulmonary dysfunction, renal dysfunction) [73]

In context with medical assessment of treatable factors, laboratory tests may be

ordered as clinically indicated including complete blood count (CBC), electrolyte
profile (sodium, potassium, chloride, bicarbonate), chemistry panel (creatinine,
blood urea nitrogen, glucose, magnesium, calcium, phosphorus, bilirubin, serum
transaminases, alkaline phosphatase, lactate dehydrogenase, albumin, total protein),
transferrin, total iron-binding capacity, ferritin, iron levels, folic acid, B12 level, and
thyroid function tests [100].
After primary patient evaluation, if there are any treatable contributing factors, it
should be managed, and if fatigue persists with clinical management of these condi-
tions, additional therapeutic modalities may be required [101].
There are both pharmacologic interventions and integrative non-pharmacologic
behavioral interventions to alleviate fatigue symptoms that physicians can consider
in the setting of no specific causal factors. Patients should be managed by multidis-
ciplinary teams (oncologist, psychologist, physical therapist, exercise specialist,
oncologist nurse, and nutritionist) for the best treatment approach.

18.6.1 Non-pharmacologic Interventions

There are various non-pharmacologic interventions including exercises (e.g., home-­

based exercise, supervised exercise), education and counseling, sleep therapy, and
complementary therapy. These non-pharmacologic interventions alone or in combi-
nation with pharmacologic approaches may be implemented for the effective man-
agement of cancer-related fatigue [102].
18.6 Management 179

18.6.2 Exercise

Exercise can be helpful for individuals with cancer-related fatigue during and post-­
cancer therapy [103–108]. Exercise improves patient function during radiation ther-
apy, which is attributed to reduce radiation fatigue and the improvement of quality
of life [109–111]. The proposed mechanism of exercise in reducing cancer-related
fatigue is balancing in energy resources, attenuation of the progressive muscle wast-
ing, and disruptions in muscle metabolism that occur with cancer and prescribed
treatments [112].
Both home-based exercise and supervised exercise can improve fatigue. Home-­
based exercise program is a potentially effective, low-cost, and safe intervention
[108], and supervised exercise allows individualizing the exercise regimen to the
specific condition of the patient and type of cancer by professional therapists and
offers greater motivation. Therefore, supervised exercise might be more effective
than home-based exercise in improvement in physical and psychological function-
ing especially in patients that have cancer or treatment-related morbidity [110,
113–116].
Exercise contraindications (such as extensive lytic bone metastases, extreme
thrombocytopenia) should be regarded. Neutropenic patients must avoid environ-
ments where the risk of exposure to infectious agents is high (e.g., public swimming
pools) [117]).
Home-based physical activity interventions usually consist of at least 10–30 min
per day for at least 2–5 days per week [102].
Supervised exercise interventions consist of combined aerobic, resistance, and
stretching exercises [118].

18.6.3 Counseling and Education

Education and counseling about cancer-related fatigue, its adverse effects, and strat-
egies to deal with it by telephone or online support programs, comprehensive cop-
ing strategy programs or other programs, or organizations have been reported to
greatly benefit cancer-related fatigue management [119, 120].
Efforts to educate should be directed at patient’s educational level. Open com-
munication between patient, family, and caregiving team can facilitate discussions
about the experience of fatigue and its effects on daily life.

18.6.4 Optimize Sleep Quality

One approach of non-pharmacologic supportive interventions to optimize sleep

quality and also decrease cancer-related fatigue is cognitive behavioral therapy,
which is a form of psychotherapy that treats problems and boosts happiness by
modifying dysfunctional emotions, behaviors, and thoughts.
180 18 Fatigue

Cognitive behavioral therapy for insomnia (stimulus control instructions, sleep

restriction therapy, and sleep hygiene counseling) seems to improve cancer-related
fatigue [120–122].
Due to some inconsistent results, additional research is needed to explore the
impact of this intervention on patients with different degrees of insomnia and
fatigue.
The aim of stimulus control is to limit the amount of time that patients spend
awake in bed. The recommendations consist of going to bed at the same time each
night or when sleepy, waking up at the same time every morning, and leaving the
bed after 20 min if unable to fall sleep [102].
The aim of sleep restriction is to limit the amount of time that patients spend in
bed to the amount of actual total sleep time to increase sleep consolidation. The
protocol includes avoiding afternoon naps and limiting total time in bed [102].
The sleep hygiene principle consists of a variety of behaviors and environmental
factors; it can be implemented by educating patients to avoid heavy meal closest to
bed time, avoiding caffeine in the afternoon, and establishing an environment that
can promote sleep, such as preparing a dark, quiet, and comfortable bedroom [102].

18.6.5 Complementary Therapies

Energy conservation such as tai chi (energy arts from China) [122, 123], polarity
therapy (energy therapy) [124], pranayama (control of breath) [125], and yoga [126,
127] may be effective interventions for managing cancer-related fatigue. Further
confirmatory studies are warranted.
The general consideration of energy conservation should be provided to patients
like balancing activities with rest, pacing slowly and steadily, selecting the tasks
based on priority and eliminating unnecessary tasks, and avoiding poor body pos-
ture [128].
There are some positive results about use of back massage [100] and acupuncture
[129] in cancer-related fatigue. Further research is required to investigate their
mechanism and efficacy in this era.

18.6.6 Other Psychosocial Interventions

Cognitive behavior therapy has a clinically relevant effect in reducing fatigue and
functional impairments in cancer survivors [130]. Although a variety of cognitive
behavioral and psychosocial interventions can be beneficial, discovering what patients
benefit from what type of psychosocial intervention is an unresolved issue [131].
Whether all patients require formal cognitive behavioral therapy by a psycholo-
gist or psychiatrist in addition of general counseling is unclear [131].
18.6 Management 181

Group therapy (approximately six patients per group) may be effective in both
emotional and physical symptoms and enhance quality of life for cancer patients
undergoing radiation therapy [117].
The results suggest that relaxation training [132] and hypnosis [133] may
improve several psychological parameters such as fatigue in ambulatory patients
who are undergoing radiation therapy [132].
Mindfulness-based stress reduction may be a useful therapeutic intervention for
improving cancer-related fatigue, although the evidence is preliminary [134].

18.6.7 Nutrition Counseling

Patients should be encouraged to have adequate intake of fluid* (e.g., 8–12 cups of
fluid throughout the day) and adequate nutrition (e.g., high-protein diet) [128].
Caution should be taken in patients with comorbidities that affect fluid balance
(e.g., congestive heart failure).

18.6.8 Pharmacologic Intervention

Methylphenidate (Ritalin®) is a central nervous system (CNS) stimulant that is

structurally related to amphetamines with a short half-life and a rapid onset of
action.
The results suggest that methylphenidate could be considered in patients with
severe cancer-related fatigue [135–138].
Prescribing strategy: start methylphenidate at 5 mg in the morning and 5 mg at
noon, titrating as necessary. The maximal dose with the potential for benefit in
cancer-­related fatigue is 40 mg daily [117].
Contraindications: hypersensitivity, glaucoma, family history of Tourette’s syn-
drome or motor tics, marked anxiety, tension, agitation, taking MAOIs within
2 weeks, and risk of severe hypertensive reaction.
Modafinil, a non-amphetamine wake-promoting agent, is used for the treatment
of narcolepsy. As compared with other psychostimulants such as methylphenidate,
it has a relatively selective site of action in the brain, with resultant fewer adverse
effects and lower potential for abuse.
There is insufficient evidence to prescribe modafinil for patients with cancer-­
related fatigue outside of a clinical trial context [139, 140].
Steroids (e.g., dexamethasone [141], methylprednisolone [142], megestrol ace-
tate [143]) may be effective in cancer-related fatigue in patients with advanced can-
cer [144, 145]. The possibility of steroid-induced secondary fatigue in terminally ill
cancer patients should be taken into consideration [146].
Antidepressants (e.g., paroxetine) have failed to demonstrate any improvements
in fatigue [145, 147]. There are some positive results about bupropion sustained-­
release efficacy in cancer-related fatigue. Further studies would be necessary to
establish the efficacy of this intervention [147, 148].
182 18 Fatigue

Guarana (Paullinia cupana) is a plant native to the Amazon basin. Guarana was
shown to be effective for fatigue in breast cancer patients receiving systemic chemo-
therapy. Further studies are needed to confirm its efficacy and its use in radiation
therapy-related fatigue [149].
High doses of American ginseng (Panax quinquefolius) have been shown to be
an effective and safe natural supplement for helping manage the fatigue associated
with cancer treatment. While data seem promising, additional studies are needed to
confirm these findings before ginseng can be recommended as a treatment for
cancer-­related fatigue [150].
Multivitamins do not improve radiation-related fatigue [151].
IV vitamin C administration appears to reduce cancer-related fatigue. Additional
well-designed placebo-controlled studies investigating the effects of IV vitamin C
on cancer-related fatigue appear warranted [152].
Donepezil is an inhibitor of acetylcholinesterase used for Alzheimer’s, and
dementia was not significantly superior to placebo in the treatment of cancer-related
fatigue [153].

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Hematological Side Effects
19

Profound hematologic toxicity, prominently leukopenia, frequently develops fol-

lowing radiation therapy that includes a large volume of bone marrow in the radia-
tion field [1–8]. The percentage of patients with radiation-induced leukopenia has
been reported in up to 50% and 90% of patients treated with pelvic field irradiation
alone and with concurrent chemotherapy, respectively [1, 6]. These values are lower
for thrombocytopenia (1% and 30% of patients treated with pelvic field irradiation
alone and with concurrent chemotherapy, respectively) and anemia (30% and 50%
of patients treated with pelvic field irradiation alone and with concurrent chemo-
therapy, respectively) [1, 10].

19.1 Mechanism

The bone marrow is a cellular stroma consisting of the vascular system with nutri-
tive vessels and a very complex sinusoidal system [11]. At birth, virtually all mar-
row is hematopoietic. Conversion of red marrow to yellow marrow with advancing
age begins in the distal bones, and the distribution of active red marrow in the adult
is in the skull (13.1%), clavicle (1.5%), scapula (4.8%), sternum (2.3%), ribs (7.9%),
vertebrae (28.4%), pelvis (36.2%), and proximal extremities (5.7%). There is a
gradual reduction in the percentage of cellularity of red marrow with age and its
replacement by fatty yellow marrow [12].
The cellular stroma of bone marrow houses active blood-cell-forming stem cells
[13]. The peripheral blood also contains hematopoietic stem and progenitor cells.
Due to the dynamic equilibrium between the hemopoietic cell populations in the
bone marrow and peripheral blood, the peripheral blood cell populations could be
sensitive indicators of radiation-induced damage to hematopoietic tissues [14].
The hematopoietic stem and progenitor cells are highly sensitive to radiation
[15]; however, nondividing mature cells (e.g., granulocytes, red cells, or platelets)
tolerate higher radiation doses. After exposures at doses as low as 4 Gy, the cellular-
ity of the irradiated bone marrow progressively declines [16–18]. It has been found

© Springer International Publishing AG 2017 191

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_19
192 19 Hematological Side Effects

that an exposure dose of 30–47 Gy delivered in a period of 3–4 weeks to the sternal
area results in severe depression of the sternal marrow [19].
Breakdown of the sinusoidal system results in erythrocytes spreading throughout
the parenchyma, and a hemorrhagic bone marrow develops with radiation [16].
The most sensitive indication of acute radiation effect on peripheral blood counts
is a reduction in number of circulating lymphocytes, together with the appearance
of abnormal lymphocyte figures [17]. If the limited volume of marrow receives
radiation (less than 3% of the total active adult marrow), the peripheral blood counts
may be within normal limits despite marrow hypoplasia [17].
It has been demonstrated that irradiated bone marrow sites can be recovered
early by the stem cell migration of the protected bone marrow sites or peripheral
blood [13, 20, 21]. Proliferation and release of stem cells increase in non-irradiated
bone marrow after radiation therapy. The depletion of stem cells in the protected
bone marrow at the beginning of radiotherapy seems to be due to such migration
[16, 22]. Another reason for this diminution could be the result of an increased rate
of differentiation.
After stem cell transplantation, the times to “rebuild” for the granulocytic, erythro-
poietic, and megakaryocytic cell lines are 10–12, 5–7, and 10 days, respectively [11].
Although blood count recovery occurs a few months after completion of therapy
in 90% of patients, bone marrow regeneration and recovery require a much longer
time. The potential of regeneration appears to depend on the dose received. It has
been shown that a dosage of 30 Gy or more of bone marrow radiation needs an
extended time to recover and may permanently depress the marrow [19, 23]. This
could be due to permanent damage to the precursor cells of the marrow elements or
to a physiological alteration of the blood vessels and supporting syncytium. These
factors could be responsible for the prevention of growth of the regenerating cells
and/or the repopulation of cells from marrow in other parts of the body [17].
Permanent loss of hematopoietic activity in the irradiated areas is compensated by
increased activity in the non-irradiated areas [24, 25].

19.2 Timing

In patients undergoing conventional fractionated radiation therapy, occurrence,

degree, and timing of blood count suppression are dependent on the proportion of
active marrow volume in the radiation fields. The field size is the most important
determining factor for the adverse hematologic effects on severity and timing. For
example, it is estimated that the proportion of active marrow included in the periaor-
tic, mantle, and pelvic fields is about 10%, 25%, and 40%, respectively, and nadir
levels of the cell counts occur at different times for these fields [26].
The number of peripheral blood cells decreases according to their radiation sen-
sitivity and life expectancy. The total white cell count declines during radiation
therapy. Lymphocytes are the most sensitive, and monocytes are the most refractory
leukocytes to change. The lymphocyte count drops first and by the greatest amount,
19.4 Symptoms 193

the neutrophils less, and the monocytes only exhibit a transient, early, modest dip.
After the nadir, counts for white cells levels maintain a plateau [27].
The platelet count declines gradually with radiation therapy to a nadir and there-
after is maintained its level [27].
The hemoglobin very gradually decreases during radiation therapy and reaches
its lowest value at the end of radiation therapy, which could be related to the long
red blood cell life expectancy compared to leukocytes and platelets [27].
Complete peripheral blood count recovery is observed at 1–3 months following
therapy, although it may still be below the pre-therapy levels, and lymphocyte count
recovers fastest [27]. Peripheral blood counts are an unreliable indicator for assess-
ing the true status of bone marrow reserve, and bone marrow suppression may sus-
tain for months to years despite normalized peripheral blood counts [28, 29].
Patients may have normal peripheral blood counts with a marked suppression of
bone marrow secondary to increasing proliferation of unexposed bone marrow [28].

19.3 Risk Factors

Radiation-related factors such as larger radiation field and higher radiation dose are
the most important factors affecting bone marrow injury and degree of depression
in the peripheral blood counts [19, 30].
Chemotherapy is another factor affecting hematologic toxicity of radiation ther-
apy. Patients with previous and concomitant chemotherapy have increased risk for
radiation-induced neutropenia [31].

19.4 Symptoms

Depression of each hematopoietic cell lineage translates into potential problems for
the patient. The Radiation Therapy Oncology Group has defined a scoring system
for acute hematologic toxicity of radiotherapy (Table 19.1) [9].

Table 19.1 RTOG acute radiation hematologic effects scoring

Grade 1 Grade 2 Grade 3 Grade 4
White blood cells/ml 3000 to <4000 2000 to 1000 to <2000 <1000
<3000
Platelet/ml 75,000 to 50,000 to 25,000 to <50,000 <25,000 or
<100,000 <75,000 spontaneous
bleeding
Neutrophils/ml 1500 to <1900 1000 to 500 to <1000 <500 or sepsis
<1500
Hgb (g/dl)/Hct(%) 9.5 to <11/28 7.5 to <9.5/ 5 to <7.5 (pack cell –
to <32 <28 transfusion
required)
194 19 Hematological Side Effects

Patients with isolated neutropenia may not have any specific symptoms.
Neutropenia may place the patient at substantial risk for infection, and a fever may
be the first sign.
Thrombocytopenia is generally not associated with any symptoms and is self-­
limited, but manifestations of bruising, petechiae, and mucosal bleeding infre-
quently occur. Intracranial hemorrhage is the most dangerous manifestation of
thrombocytopenia, though it is particularly rare, and most episodes occur at platelet
counts less than 5000/mL.
Symptoms related to significant anemia are easy fatigue, low compliance for
activity, rapid heart rate, and shortness of breath.

19.5 Prevention

There is correlation between radiation technique parameters regarding bone marrow

and hematologic toxicity. These parameters could be modifiable with intensity-­
modulated radiation therapy (IMRT) and more advanced techniques. New tech-
niques can reduce radiation dose to bone marrow and decrease acute hematologic
toxicity [32–35].
One problem with standard IMRT planning is the large volume of bone marrow
that needs to be avoided. By considering only red (active) marrow in marrow con-
touring, the planning process could be improved [36]. The distribution of marrow
containing red (active) and yellow (inactive) marrow is different among individuals
[37]. Active red marrow can be visualized poorly in computed tomography (CT)
scanning. Functional bone marrow imaging like 2-deoxy-2-[F-18]fluoro-D-glucose
(FDG)-positron emission tomography (FDG-PET) [38] or single-photon emission
computed tomography (SPECT) [18] can provide information about functional nor-
mal bone marrow and its physiologic distribution. Incorporation of these modalities
into the IMRT planning process avoids the unnecessary contouring of inactive yel-
low marrow for calculation of dose constraints. Structural imaging techniques such
as magnetic resonance imaging (MRI) in place of functional imaging may be useful
in this regard [18, 37, 38].
The potential for cytokines in prevention of the hematopoietic system radiation
injury has been studied in lethally irradiated animals, and observations suggest that
some cytokines such as G-CSF [39, 40], interleukin-1 (IL-1) [41, 42], tumor necro-
sis factor (TNF)-alpha [43], and Fms-related tyrosine kinase 3 ligand (FLT3LG)
[44–46] may mediate radioprotective effects to the hematopoietic progenitor cell
and stem cell compartments. It has also been shown that meloxicam, a selective
inhibitor of cyclooxygenase 2, can modulate hematopoiesis and elevate numbers of
granulocytic precursor cells in bone marrow and granulocyte counts in peripheral
blood by increasing endogenous G-CSF production [47]. Currently, there is no rec-
ommendation for the prophylactic use of these factors.
19.6 Treatment 195

19.6 Treatment

19.6.1 Neutropenia

The proliferation and differentiation of hematopoietic cells are regulated by a fam-

ily of cytokines including colony-stimulating factors (CSFs) and interleukins, which
are specific to each cell lineage [48]. Granulocyte colony-stimulating factor (G-CSF)
controls the production, differentiation, and function of neutrophilic granulocytes.
Single classes of high-affinity receptor for G-CSF are present on the precursor and
mature cells of neutrophilic granulocytes [48].
The mature human G-CSF is a 19.6 kDa glycoprotein containing 174 amino
acids [49], and its molecular cloning has been well described [50].
It is well known that E. coli is a useful host for the production of recombinant
human G-CSF [51], but there are also various products that are derived from differ-
ent tissues (e.g., yeast, transgenic plants, and mammalian cells) [52].
There are lots of controversies about using of colony-stimulating factors during
radiation therapy regarding acute and late side effects.
G-CSF treatment is well tolerated during continuous fractionated radiation ther-
apy and can be used clinically to alleviate severe and threatening neutropenia caused
by radiation therapy or by combined radio-chemotherapy [53, 54].
The number of G-CSF receptors on bone marrow cells increases with radiation
[55], and administration of recombinant human G-CSF can accelerate the recovery
of radiation-induced neutropenia [56–58] and reduce its severity and duration
[59–62].
After administration of recombinant human G-CSF, the level of circulating neu-
trophils increases by accelerating production, inhibition of neutrophil apoptosis,
reduction of transit time from stem cell to mature neutrophil, and accelerating neu-
trophil entry into the blood, and neutrophil function is enhanced. An increase in
neutrophil progenitors in the marrow and hematopoietic stem cell mobilization can
be seen in G-CSF administration [63–65].
Clinical application of recombinant human G-CSF is hampered in some situa-
tions by various side effects. G-CSFs should not be included in patients receiving
concomitant chemotherapy and radiation therapy, particularly involving the medias-
tinum based on the results of GM-CSF or G-CSF morbidity in mediastinal chemo-
radiotherapy. More severe thrombocytopenia was seen in patients with CSF
administration [66–68]. Further studies will be required to determine if chemora-
diotherapy for other sites of disease will provoke similar problems.
Possible reason for thrombocytopenia observed in this site of irradiation is that
the CSF mobilizes progenitor cells into the peripheral blood and new precursor cells
are destroyed during migration into the irradiation volume because large numbers of
these cells may be irradiated as they pass through the heart [67].
Outside of clinical trials, in patients receiving concomitant chemotherapy and
radiation therapy, treatment is suspended for severe neutropenia and is resumed
when the toxicity decreases to lower grade.
196 19 Hematological Side Effects

There is a concern about the reduction in the capacity of bone marrow recovery
with simultaneous treatment of G-CSF during radiation therapy in the postradiation
phase. Mechanisms like enhanced production of inhibitory cytokines, a decrease in
endogenous production of the growth factors due to the exogenously induced phar-
macological levels, downregulation of growth factor receptors on target cells [69],
and decreased sensitivity of bone marrow to radiation during G-CSF application are
proposed for this phenomenon [70]. Further investigations are needed to determine
the late bone marrow effect of G-CSF administration during radiation therapy and
the timing, duration, and dosage of G-CSF application for successful treatment and
a favorable outcome.
The American Society of Clinical Oncology (ASCO) guidelines recommend that
“CSFs should be avoided in patients receiving concomitant chemotherapy and radi-
ation therapy, particularly involving the mediastinum. In the absence of chemo-
therapy, therapeutic use of CSFs may be considered in patients receiving radiation
therapy alone if prolonged delays secondary to neutropenia are expected.”
European Society of Clinical Oncology (ESMO) guidelines also recommend that
“primary prophylaxis with G-CSF is not indicated during chemoradiotherapy to the
chest due to increased rate of bone marrow suppression associated with an increased
risk of complications and death” [71].
Three clinically available forms of G-CSF are [72]:

*A glycosylated form (lenograstim), which is produced by using the expression in

mammalian cells, and a *non-glycosylated form (filgrastim), which is produced
by using expression in E. coli [73]
*A pegylated form of non-glycosylated Hu G-CSF (pegfilgrastim)

Pegfilgrastim is developed to produce a long-acting filgrastim requiring less fre-

quent dosing than its parent drug [74]. A single dose of PEG-rhG-CSF has a similar
clinical safety to rhG-CSF and significant advantageous effects [75].
The recommended dose for G-CSF is 5 g/kg/day and for Pegfilgrastim is as a
single dose of either 100 mcg/kg (individualized) or of a total dose of 6 mg (general
approach) [71, 76]. Both are injected subcutaneously. A single subcutaneous injec-
tion of rhG-CSF results in an increase in circulating granulocytes within 2 h; the
granulocyte concentration peaks by 12 h and remains elevated for the next 36 h
before decreasing slowly back to baseline [77]. The median time to reach the peak
concentration is 2.5–5 days for pegfilgrastim, and neutrophilic level remains above
baseline for around 9–10 days [74].
Patients should be monitored with serial CBCs. Administration should be contin-
ued until the absolute neutrophil count reaches to upper level or normal [78].
The G-CSF receptors are expressed not only on myeloid cells but also on other
hematopoietic cells including monocytes, platelets, and possibly certain lympho-
cyte subsets [79]. No significant changes in lymphocyte or monocyte counts have
been observed during the course of rhG-CSF treatment.
Data on the effects of G-CSF on platelet function are limited. It seems that
G-CSF enhances platelet aggregation and activation in humans [80].
19.6 Treatment 197

Radiation-induced thrombocytopenia may be worsened by G-CSF administra-

tion, possibly due to a decrease in the number of megakaryocytes in the bone mar-
row and an increase in the trapping of megakaryocytes in the spleen [72, 81].
G-CSF-induced thrombocytopenia seems to be a transient event and may improve
spontaneously despite continual G-CSF treatment [82].
Common side effects observed during G-CSF treatment consist of mild muscu-
loskeletal pain, papular skin rash, and some laboratory abnormalities like elevated
alkaline phosphates [54, 61, 82].
The exact effects of G-CSF administration on cancer cells remain controversial.
G-CSF administration increases the production of neutrophils, and cytotoxic media-
tors produced by neutrophils could kill the cancer cells [83, 84]. On the other hand,
G-CSF has been shown to promote tumor angiogenesis by upregulating VEGF [85],
which is released by neutrophils and reduces radiation-induced vascular damage [86].
It has been shown that prophylactic G-CSF administration for treatment of
advanced unresectable head and neck cancers resulted in an unexpected reduced
local control [87, 88]. The effects of G-CSF on tumor growth, especially during
radiation therapy, are controversial and require further investigation [84].
Furthermore G-CSF can stimulate the clonal growth of some non-hematopoietic
tumor cells like bladder [89] or colon [90] cancers, and the remote effect of G-CSF
on the growth of tumor cells lying outside radiation treatment portals is proposed by
some [91].
It has been suggested that the simultaneous or sequential administration of two
or more complementary cytokines has resulted in better patterns of hematologic
recovery. The capacity of multiple cytokine combinations (like GM-CSF and IL-3
[92–94], TPO with IL-4 or IL-11 [95], IL-3 receptor agonist and rhG-CSF [96], and
rhG-CSF and pegylated megakaryocyte growth and development factor [97]) to
accelerate hematologic recovery and ensure multi-lineage protection following
severe radiation-induced myelosuppression has been assessed in animal studies
with promising results [92–98]. Further investigations in this field will clearly be
necessary before drawing any conclusions.

19.6.2 Thrombocytopenia

There is no threshold for platelet counts that for counts below which prophylactic
transfusion should be prescribed to all patients with radiation-induced thrombocy-
topenia. Several studies support a threshold of 10,000 platelets/mL or less for initi-
ating transfusions to patients with solid tumors and a higher threshold; perhaps
20,000/mL has been proposed for patients with tumor with the presence of necrotic
sites (e.g., gynecologic, colorectal, melanoma, or bladder tumors) [23, 99].
Thrombopoietin, a lineage-specific growth factor specific for platelets, regulates
platelet production via the stimulation of its receptor on megakaryocytes and plate-
lets leading to proliferation and differentiation. Two variant forms of human throm-
bopoietin have been developed including first-generation agents, recombinant
198 19 Hematological Side Effects

human thrombopoietin (rHuTPO) and pegylated recombinant human megakaryo-

cyte growth and development factor (PEG rHuMGDF), and second-generation
agents—the TPO peptide mimetics, TPO non-peptide mimetics, and TPO agonist
antibodies [100–102].
Clinical trials with recombinant TPO [100] and recently romiplostim (a TPO
peptide mimetic) [103] have shown that these agents can improve platelet counts in
patients receiving chemotherapy. Further studies need to be performed for use of
these agents in radiation-induced thrombocytopenia.
Platelet factor 4 (PF4) is released from radiation-damaged megakaryocytes and
inversely affects platelet count recovery after radiation. Anti-PF4 strategy can improve
outcomes of radiation-induced thrombocytopenia and needs to be explored [104].
Interleukin 11 (IL-11) is a stromal cell-derived cytokine that enhances the growth
of early progenitors and promotes megakaryocytopoiesis and erythropoiesis [105].
Given recombinant human interleukin-11 (rHuIL-11) activity in chemotherapy-­
induced thrombocytopenia, it needs to be studied as one possible therapeutic option
in radiation-induced thrombocytopenia [106–108].

19.6.3 Anemia

Radiation is more effective on tumor cells with higher oxygenation. Anemia is asso-
ciated with poor tumor oxygenation, relative tumor radioresistance, and decreases
the effectiveness of radiation therapy, with subsequent reductions in treatment out-
comes including locoregional control and overall survival of cancer patients [10,
109]. Correcting the radiation-induced anemia and maintaining normal hemoglobin
levels in patients undergoing radiation therapy have a significant importance due to
decrease in tumor hypoxia, improve treatment outcomes, and have a determinant
impact on quality of life [109–112]. Both blood transfusion and use of erythropoiesis-­
stimulating agents (e.g., darbepoetin, erythropoietin) can increase the hemoglobin
levels during radiation therapy, but the effects of medications used for correction of
radiation-induced anemia on locoregional control and overall survival are question-
able [113–117].
Many radiation oncologists have not given ample attention to treating mild to
moderate anemia during radiation therapy unless symptoms of severe anemia are
present or the hemoglobin falls below a threshold of 9–10 g/dL. However, managing
mild to moderate anemia is important for radiation therapy outcome improvement
and quality of life preservation [109, 118].
Radiation-induced anemia is usually mild and readily correctable. It has been
reported that for most patients with uterine and cervical cancer, the severity of ane-
mia during radiation therapy was modest (59% of anemic patients with hemoglobin
levels between 10 g/dL and 11.9 g/dL and 11% with hemoglobin levels between
9 g/dL and 9.9 g/dL). Only a few patients had levels below 8.9 g/dL. Data on
colorectal, prostate, lung, and breast cancers yielded similar results [109].
References 199

Blood transfusion and recombinant human erythropoietin (rHuEPO) administra-

tion can significantly improve radiation-induced anemia [111, 113, 119–122]. There
are no randomized studies comparing blood transfusion and rHuEPO efficacy and
safety in patients undergoing radiation therapy.
A number of studies have shown an effect of perioperative transfusion on cancer
recurrence rates [123–128]. The mechanism of how blood transfusion affects tumor
viability is related to some types of immunosuppression [129]. Therefore, some
have proposed that rHuEPO administration in patients undergoing radiation therapy
may have some benefits over transfusion due to its potential to correct anemia with-
out the risks associated with transfusion [130].
Several studies using transfusion to correct radiation-induced anemia have shown
improvement in local control, but there is no study comparing transfusion with
rHuEPO, and no definitive conclusion can be drawn about transfusion or rHuEPO
safety during radiation therapy.
It has been demonstrated that erythropoietin receptors are expressed in several
human cancer cells and may modulate the cellular effects of recombinant human
erythropoietin on cancer cells, leading to increased cell survival and growth [131,
132]. Belenkov et al. reported that the addition of exogenous recombinant human
erythropoietin induces cancer cells to become more resistant to ionizing radiation
and to cisplatin [133]. These data indicate that the administration of rHuEPO to
cancer patients undergoing radiation therapy should proceed with caution, espe-
cially when the cancer type has been shown to be positive for erythropoietin
receptor.
There is no guideline for erythropoietin use during radiation therapy. Based on
these findings, we recommend that erythropoietin should not be administered dur-
ing radiation therapy outside of the experimental setting.

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Radiation-Induced Nausea and Vomiting
(RINV) 20

Radiation-induced nausea and vomiting (RINV) is generally less frequent and less
severe than the nausea and vomiting encountered in patients receiving chemother-
apy. This problem is often underestimated and undertreated by radiation oncologists
in clinical practice; however, it can be very distressing and may cause delay or even
interruption of radiotherapy [1–3]. The incidence of RINV was studied in two pro-
spective observational studies. The Italian Group for Antiemetic Research in
Radiotherapy (IGARR) analyzed the incidence of RINV in 1020 patients receiving
various kinds of radiation therapy without concurrent chemotherapy. Vomiting and
nausea occurred in 11% and 27.1% of patients, respectively, and 27.9% of patients
had both vomiting and nausea [1]. Nausea was twice as frequent as vomiting (27.1%
vs. 11%) and lasted longer (median duration 10 vs. 3 days). The RINV incidence
rates based on anatomical sites were 28% for breast, 39% for pelvis, 40.4% for head
and neck, 48.8% for thorax, 40.4% for brain, and 71.4% for upper abdominal sites.
In a second study of 368 patients receiving radiation therapy again without con-
current chemotherapy, the overall incidence rates for nausea and vomiting were
39% and 7%, respectively, with 63% in abdominal or pelvic fields and by 48% in
head/neck/brain fields [4].

20.1 Mechanism

The mechanism of RINV differs depending on radiation site. RINV is primarily due
to a serotonin (5-hydroxytryptamine)-mediated pathway [5]. Damage to the entero-
chromaffin cells of the gastrointestinal mucosa by radiation leads to release of sero-
tonin, which may initiate the emetogenic response through activation of serotonin
receptors, visceral afferent fibers, and the chemoreceptor trigger zone (CTZ) in the
brain stem [6].
If the gastrointestinal tract is included in the field of radiation, direct effects are
likely with stimulation of afferent pathways in the upper gastrointestinal tract.

© Springer International Publishing AG 2017 207

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6_20
208 20 Radiation-Induced Nausea and Vomiting (RINV)

RINV also can be mediated by activation of CTZ through release of humoral factors
from tissue injury [7].
Increased intracranial pressure due to radiation-induced edema and inflamma-
tory processes associated with radiation injury may also play a role in RINV [7].

20.2 Timing

Acute RINV is seen most frequently with radiation therapy. The latent period ranges
from 30 min to 4 h in single-fraction study [6], and it generally begins 3–4 days after
fractionated radiation therapy [1, 4, 8]. Delayed emesis is not observed with radia-
tion therapy, unlike with chemotherapy, and anticipatory emesis is extremely rare
with radiation therapy [6].

20.3 Risk Factors

The risk of developing RINV depends on several patient and treatment-related risk
factors.
The most significant radiotherapy-related risk factors include the site (upper
abdomen) and radiation field size (>400 cm) [1, 9]. Other factors like single and total
dose, fractionation schedule, and treatment techniques are also important [6]. A sin-
gle high dose and larger dose per fraction have a greater risk of inducing RINV [10].
Gagnon and Kuettel demonstrated diurnal variation in the gastrointestinal tract
with more sensitivity to radiation-induced damage in the late morning than in the
afternoon. This study was limited to prostate cancer patients [11].
Patient-related risk factors include age, gender, general health status, alcohol
consumption, concurrent or previous chemotherapy, and previous experience of
emesis [6]. The risk of RINV is higher in female patients, those younger than
50 years, and patients with a previous history of poorly controlled emesis.
Conversely, the risk is decreased in those with a high alcohol intake [6].
It has been reported that the incidence of RINV may have some correlation with
ABO blood group and it seems that patients with type A blood groups are the most
vulnerable individuals to these side effects [12].

20.4 Symptoms

Patients with RINV experience lower well-being and quality of life, lower satisfac-
tion with aspects of daily living, and more frequent fatigue, anxiety, and depression
[4]. Prolonged vomiting can cause dehydration, electrolyte imbalances, and
malnutrition.
20.5 Prevention and Management 209

20.5 Prevention and Management

Radiation therapy sites are classified base on their potential risk for developing
RINV in ASCO and MASCC/ESMO guidelines (Table 20.1) [13, 14]. The National
Comprehensive Cancer Network (NCCN) [15], Multinational Association for
Supportive Care in Cancer (MASCC)/European Society for Medical Oncology
(ESMO) [14], and American Society of Clinical Oncology (ASCO) [13] have
released guidelines for the management of RINV based on risk category (Table 20.2).
The NCCN guidelines stratify patients into two categories of total-body irradia-
tion and upper abdomen/localized sites [15]. Localized sites have not been deter-
mined, but recommendations for both are nearly the same (Table 20.2).
In the setting of concurrent chemoradiotherapy, antiemetic strategies consistent
with chemotherapy agents being used should be offered based on each of the three
guidelines.
Neurokinin-1 (NK-1) receptor inhibitors in combination with a 5-HT3 receptor
antagonist and dexamethasone improve control of acute and delayed chemotherapy-­
induced nausea and vomiting after highly and moderately emetogenic chemother-
apy. The role of these agents in the management of RINV is not well studied. Dennis
et al. have suggested that the combination of aprepitant and granisetron may have a
protective effect against RINV after both single- and multiple-fraction moderately
emetogenic radiation therapy for thoracolumbar irradiation, which is more than his-
torical control data from patients receiving prophylaxis with a 5-HT3 receptor
antagonists alone [16]. Further evaluation of this combination in patients receiving
concurrent chemoradiotherapy is ongoing.
The optimal duration of antiemetic therapies for the prevention of RINV is not
clear. The MASCC/ESMO guidelines have no recommendation for the duration of
5-HT3 antagonist treatment, and the ASCO and NCCN guidelines recommend
5-HT3 antagonist administration prior to each radiation fraction for high- and
moderate-­risk radiation therapies. Some argued that RINV episodes occur signifi-
cantly during the first and second week of treatment, and prophylactic antiemetics
may not be necessary for a full course of radiation therapy. This issue needs to be
further evaluated in future studies to demonstrate the optimal duration of adminis-
tration [8, 17].

Table 20.1 Risk classification for RINV

Definition
High risk Total body irradiation and total nodal irradiation
Moderate risk Upper abdomen, half-body irradiation, upper-body
irradiation
Low risk Cranium, craniospinal, head and neck, lower thorax
region, pelvis
Minimal risk Breast, extremity
210 20 Radiation-Induced Nausea and Vomiting (RINV)

Table 20.2 Recommendations for RINV

MASCC/ESMO ASCO NCCN
High risk A 5-HT3 receptor A 5-HT3 receptor Total-body irradiation:
antagonist + dexamethasone antagonist before Granisetron 2 mg PO daily
each fraction and or ondansetron 8 mg PO
for at least 24 h twice daily ± dexamethasone
after completion 4 mg PO daily prior to each
or radiotherapy + a day of radiotherapy
5-day course of
dexamethasone
during fraction
1–5
Moderate A 5-HT3 receptor antagonist; a A 5-HT3 receptor
risk short course of dexamethasone is antagonist before
optional each fraction and
for at least 24 h
after completion
or radiotherapy + a
short course of
dexamethasone
during fraction
1–5 may be
offered
Low risk A 5-HT3 receptor antagonist as A 5-HT3 receptor
either prophylaxis or rescue antagonist alone
as either
prophylaxis or
rescue. For
patients suffering
from RINV while
receiving rescue
therapy only,
prophylactic
treatment should
continue until
radiotherapy is
completed
Minimal A dopamine receptor antagonist or A dopamine
risk a 5-HT3 receptor antagonist rescue receptor
antagonist or a
5-HT3 receptor
antagonist rescue.
Antiemetic
prophylaxis
should continue
throughout
radiation
treatment if a
patient
experiences RINV
while receiving
rescue therapy
References 211

There are five different 5-HT3 receptor antagonist agents. Granisetron and
ondansetron are commonly employed for the treatment of RINV. In general, these
agents are considered to be equally effective; however, pharmacologic differences
do exist between these two agents [17–19].
Granisetron binds irreversibly to 5-HT3 receptors with antiemetic activity up to
48 h following administration, and ondansetron binds reversibly to the receptor, losing
antagonist activity by 24 h following administration of commonly employed doses.
Higher doses or multiple-daily dosing of ondansetron may be required to maintain
antiemetic efficacy; however, granisetron is effective as a once-daily dose [19]:

Granisetron: 2 mg orally, 1 mg or 0.01 mg/kg IV

Ondansetron: 8 mg orally 2–3 times daily, 8 mg or 0.15 mg/kg IV

Side effects include headache, constipation, diarrhea, asthenia, and dizziness.

5-HT3 receptor antagonists have been reported to produce some dose-dependent,
nonclinically asymptomatic changes in electrocardiographic parameters like
increased PR interval, QT interval, or QRS complex duration. Intravenous granise-
tron has been shown to be associated with fewer effects on the electrocardiogram
than intravenous ondansetron [20]. In patients at risk for QT prolongation, 5-HT3
receptor antagonists should be used with caution (e.g., patients with electrolyte
abnormalities, congestive heart failure, brady-arrhythmias, in combination with
other medications that cause QT prolongation) [21].
Two dopamine agonist receptors are more commonly used [18]:

Metoclopramide: 20 mg orally
Prochlorperazine: 10 mg orally or IV

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Index

A Doxepin, 64
Acetylcysteine, 66 Dry mouth. See Xerostomia
Acute radiation dermatitis, 6
Amifostine, 8, 61, 84, 85–88, 113, 128, 141,
149, 167 E
Antifungals, 68 Ear toxicity
Ascorbic acid, 8 diagnosis, 49
management, 50
mechanism, 47–48
B risk factors, 48–49
Barrier film, 9 scoring, 49
Benzydamine mouth wash, 64 symptoms, 49
Brain injury. See Radiation brain injury timing, 48
Breast irradiation, 4 Eczema, 7
Enteritis
diagnosis, 147
C management
CAM2028, 66 antidiarrheals, 150
Caphosol (Cytogen Corp), 62–63 antispasmodics, 150
Carmellose sodium paste, 67 dietary modification, 150
Cellulitis, 6 mechanism, 145–146
Chlorhexidine, 62, 89 prevention, 148–149
Common Terminology Criteria for Adverse risk factors, 146–147
Events (CTCAE) v3, 139 scoring, 147–148
Common Terminology Criteria for Adverse symptoms, 147
Events (CTCAE) v4, 23, 147, timing, 146
167, 168 EORTC. See European Organization for
Common Toxicity Criteria for Adverse Effect Research and Treatment of Cancer
(CTCAE) v4.03, 100, 112, 120, 139 (EORTC)
Corticosteroids, 67 Epidermal growth factor receptor (EGFR), 5
Cystitis. See Radiation cystitis Esophagitis
diagnosis, 127
management, 128–129
D mechanism, 125
Deodorant, 11 prevention, 127–128
Dermatitis. See Radiation dermatitis risk factors, 126–127
Dexpanthenol, 10 scoring, 127
Dimensional conformal radiotherapy symptoms, 127
(3D–CRT), 60, 148 timing, 126

© Springer International Publishing AG 2017 213

A. Sourati et al., Acute Side Effects of Radiation Therapy,
DOI 10.1007/978-3-319-55950-6
214 Index

European Organization for Research and I

Treatment of Cancer (EORTC), 31, Intensity-modulated radiation therapy (IMRT),
49, 58, 72, 83–84, 121, 127, 8, 23, 42, 56, 60, 79, 86, 121, 128,
147–148, 166–167 141, 147, 158, 167, 194

F J
Fatigue Juvenile rheumatoid arthritis (JRA), 6
diagnosis, 176–177
management
complementary therapies, 180 K
counseling and education, 179 Keratinocyte growth factor (KGF), 61
exercise, 179
non-pharmacologic interventions, 178
nutrition counseling, 181 L
optimize sleep quality, 179–180 Laryngeal cancer, 3
pharmacologic intervention, 181–182 Laryngeal edema
psychosocial interventions, 180–181 management, 107
mechanism, 173–174 mechanism, 105
risk factors, 174–175 prevention, 107
scoring, 176–177 risk factors, 106
symptoms, 175–176 scoring, 106
timing, 174 symptoms, 106
Free-radical production, 1–2 timing, 105
Laughter therapy, 11
Loss of taste
G diagnosis, 99
Gabapentin, 67 management, 100–101
Gastritis. See Radiation gastritis mechanism, 97–98
Gelclair, 66 prevention, 100
Glutamine, 60, 128, 149 risk factors, 99
Granulocyte-macrophage colony-stimulating scoring, 100
factor (GM-CSF), 61 symptoms, 99
timing, 98
Low-level laser therapy, 8
H
Hair loss
management, 24 M
mechanism, 22 Magic mouthwash, 65
prevention, 23 Mammalian target of rapamycin (mTOR), 63
scoring, 23 Marigold, 60
timing MAS065D, 9
risk factors, 22 Mothers against decapentaplegic homolog 7
symptoms, 22–23 (SMAD7), 63
Hematological side effects
mechanism, 191–192
prevention, 194 N
risk factors, 193 Nasopharyngeal cancer, 3
symptoms, 193–194 National Cancer Institute Common
timing, 192–193 Terminology Criteria for
treatment Adverse Events (NCI-CTCAE
anemia, 198–199 grading), 4, 58
neutropenia, 195–197 Natural honey, 60–61
thrombocytopenia, 197–198 Nonsteroidal anti-inflammatory drugs
Hyaluronic acid, 9 (NSAIDs), 44
Index 215

O timing, 118
Opiates, 66–67 treatment, 122
Oral mucositis Phenytoin mouthwash, 68
management Pilocarpine, 62, 87, 88, 90, 91
antivirals, 68–69 Proctitis. See Radiation proctitis
feeding tube/nutritional support, 69 Prostaglandins, 62
mouth care, 64 Provitamin B5, 10
oral pain, 64–68
patient assessment, 63–64
mechanism, 53–54 R
prevention Radiation brain injury
prophylactic interventions, 59–60 dexamethasone prescription, 32–33
prophylactic intervention under diagnosis, 30–31
evaluation, 60–63 mechanism, 28
risk factors prevention and management, 32–33
concomitant systemic therapy, 55–56 risk factors
patient-related factors, 56–57 patient-related factor, 29
radiation fractionation schedule, 56 treatment-related factors, 28–29
tumor site, 55 scoring, 31
scoring, 58–59 symptoms, 29–30
symptoms, 57–58 timing, 28
timing, 54 Radiation cystitis
Oral pain management diagnosis, 157
acetylcysteine, 66 mechanism, 155–156
antifungals, 68 prevention
benzydamine mouth wash, 64 alpha-1 blocker, 159
CAM2028, 66 analgesics, 160
carmellose sodium paste, 67 anticholinergics, 159
corticosteroids, 67 bladder sparing, 158
doxepin, 64 intravesical GAG, 160
gabapentin, 67 intravesical instillation, 158–159
gelclair, 66 phenazopyridine, 160
low-level laser therapy, 68 risk factors, 156–157
magic mouthwash, 65 scoring, 157
MF 5232, 66 symptoms, 157
opiates, 66–67 timing, 156
phenytoin mouthwash, 68 Radiation dermatitis
sucralfate, 68 diagnosis, 6–7
Oral zinc, 8 management
Orbital radiation therapy, 39. See also grade 1 dermatitis, 11–12
Radiation orbital toxicity grade 2-3 dermatitis, 12–13
Orbital toxicity. See Radiation orbital toxicity grade 4 dermatitis, 13
Oxygen nebulization, 63 mechanism, 1–2
prevention
Aloe vera, 10
P amifostine, 8
Payayor, 60 ascorbic acid, 8
Pentoxifylline, 10 barrier film, 9
Pericarditis Calendula, 10
diagnosis, 119–120 deodorant, 11
mechanism, 118 dexpanthenol (provitamin B5), 10
prevention, 121 general measures, 7–8
risk factors, 118 hyaluronic acid, 9
scoring, 120–121 intensity-modulated radiation therapy
symptoms, 119 (IMRT), 8
216 Index

Radiation dermatitis (cont.) Radiation pneumonitis (RP)

laughter therapy, 11 diagnosis, 112
low-level laser therapy, 8 mechanism, 109
MAS065D, 9 prevention, 113–114
oral zinc, 8 risk factors
pentoxifylline, 10 chemotherapy/hormone therapy, 111
silver leaf dressing, 9 fractionation schedule, 110–111
soft dressing, 9 smoking, 111
theta cream, 10 volume and dose parameters, 110
topical sucralfate, 10 scoring, 112–113
trolamine, 9 symptoms, 111
risk factors timing, 110
patient-related factors, 5–6 Radiation proctitis
treatment-related factors, 4–5 management, 168–169
scoring, 4–5 mechanism, 165
sign and symptoms, 3–4 prevention, 167–168
timing, 2–3 scoring, 166–167
Radiation gastritis symptoms, 166
diagnosis, 135 timing, 166
management, 135–136 Radiation Therapy Oncology Group (RTOG),
mechanism, 133–134 4, 31, 49, 58, 83, 106, 112, 113,
prevention, 135 120, 121, 125, 127, 147, 148, 157,
risk factors, 134 166–167
symptoms, 135 Radiotherapy-induced fatigue. See Fatigue
timing, 134–135 Rectum. See Radiation proctitis
Radiation-induced liver disease (RILD) RILD. See Radiation-induced liver disease
diagnosis, 140 (RILD)
management, 141–142 RINV. See Radiation-induced nausea and
mechanism, 137–138 vomiting (RINV)
prevention, 140–141 RK-0202 (RxKinetix), 62
risk factors, 138 Royal jelly, 61
scoring, 139 RP. See Radiation pneumonitis (RP)
symptoms, 139 RTOG. See Radiation Therapy Oncology
timing, 138 Group (RTOG)
Radiation-induced nausea and vomiting
(RINV)
management, 209–211 S
mechanism, 207–208 Sensorineural hearing loss (SNHL), 47–48.
prevention, 209–211 See also Ear toxicity
risk factors, 208 Silver leaf dressing, 9
symptoms, 208 Soft dressing, 9
timing, 208 Steroids, 62
Radiation orbital toxicity Sucralfate, 68
blepharitis, 40 Systemic lupus erythematosus (SLE), 6
conjunctivitis, 40–41 Systemic sclerosis, 6
corneal toxicity
analgesics, 44
ophthalmologist consult, 44 T
topical lubricants, 43–44 Taste buds, 97. See also Loss of taste
treatment, 43–44 Taste sensitivity, 97, 99
eyelash loss, 40 Theta cream, 10
eyelid dermatitis, 40 Topical sucralfate, 10
iris toxicity, 44 Trolamine, 9
xerophthalmia, 41–43 Two-dimensional radiotherapy (2DRT), 60
Index 217

V dental care, 89
Vasoconstrictor, 62 drink adequate fluids, 89
drugs, 90–91
dry lips, protection
W from, 89
Wobe-Mugos, 63 nocturnal symptoms, 89
oral hygiene, 89
saliva supplementation, 90
X supportive care, 88–89
Xerostomia mechanism, 79–81
amifostine, 85 prevention, 84–85
contraindications risk factors, 81–82
amifostine, adverse effects of, 85–88 scoring, 82–83
pilocarpine, 88 symptoms, 82
diagnosis, 82 timing, 81
management
acupuncture, 90
adequate nutrition, 89 Z
chewing, 89 Zinc, 60