Clinical response to normal tissue with radiation

Clinical Response of Normal
Tissues
Parag Roy
LOK NAYAK HOSPITAL

Cells and Tissues
• Majority of radiation effect on normal tissues attributed to cell killing,
• But some cannot
• Nausea or vomiting hours after irradiation of abdomen
• Fatigue of patients with large volume irradiation
• Acute edema or erythema from radiation-induced acute inflammation
and vascular leakage
• Somnolence after cranial irradiation
2

Cells of normal tissues
• Not independent structure
• Complete integrated structure
• Cell death and birth balanced to maintain tissue organization
• Response to damage governed by
• Inherent cellular radiosensitivity
• Kinetics of the tissue
• The way cells are organized in the tissue
3

Weaknesses in Single-Cell Study
 Individual cells
 Continuous monotonic relationship between dose and fraction of cells killed
(e.g., loss of reproductive integrity)
 Tissues
 No effect observed after small doses
 Effects observable increase after threshold reached
 Conclusion
 Killing a few cells in a tissue matters very little, requires more massive killing
 Also, time between irradiation and expression of damage varies greatly among
tissue types.
4

Cells and tissues, continued
➡ Cell death after irradiation mainly occurs as cells attempt to divide
➡ Tissues with rapid cell turnover consequently show damage more quickly (e.g.,
hours for intestinal epithelium, days for skin mucosa)
➡ Tissues where cells rarely divide may have long latency to express damage
➡ Radiation damage to cells and tissues already on the path to differentiation is
of little consequence
➡ Interestingly
➡ Cells that are differentiating may appear more radioresistant than stem cells
➡ In fact, the fraction of cells surviving a given dose may be identical (at the single-
cell level)
5

Early (Acute) and Late Effects
 Radiation effects commonly divided into early and late
 Shows different patterns of response to dose fractionation
 Dose-response relationships characterized by a/ß ratios
 Late effects more sensitive to changes in fractionation than early effects
 Early (acute) effects result from death of large number of cells and occur
within weeks to days of irradiation in tissues with rapid rate of turnover
6

Examples of early effected tissues
 Examples
 Epidermal layer of skin
 Gastrointestinal epithelium
 Hematopoietic system
 Response is determined by hierarchical cell lineage composed of stem
cells and differentiating offspring.
 Time of onset correlates with lifespan of mature functional cells
7

Example of late-effected tissues
 Late effects appear after delay of months or years
 Occur predominantly in slowly proliferating tissues
 Lung
 Kidney
 Heart
 Central nervous system
8

Distinction between early and late effects
 Progression distinguishes early and late effects
 Acute (early) damage
 Repaired rapidly because of rapid proliferation of stem cells
 May be completely reversible
 Late damage
 May improve
 But never completely repaired
9

Mechanism of late effect
 Reactive oxygen species from NADPH Oxidases Mitochondria Superoxide
anion
 Role of Inflammation
 Radiation-Induced Vascular Changes
 Possible Metabolic Changes by carbonic anhydrase 9
10

Functional Subunits (FSUs) in Normal
Tissues
 Fraction of cells surviving determines the success (or failure) of radiation
therapy
 If a single cells survives it may result in regrowth of the tumor
 Normal tissue tolerance for radiation depends on
 Ability of clonogenic cells to maintain sufficient number of mature cells suitably
structured to maintain organ function
 Survival of clonogenic cells and organ function (or failure) depends on the
structural organization of the tissue
 Many tissues are thought to consist of functional subunits (FSUs)
11

Functional Subunits (FSUs)
 Some tissues FSUs
 Are discrete, anatomically delineated structures whose relationship to the
tissue function is clear
 Example kidney nephron, lobule in liver, acinus in the lung
 In other tissues, no clear anatomic demarcation.
 Examples skin, mucosa, spinal cord
 Radiation response of two tissue types quite different
12

Structure of Skin
 The skin consists of two layers:
the epidermis and the dermis.
Beneath the dermis lies the
hypodermis or subcutaneous
fatty tissue.
14

Survival of Structurally defined FSUs to
Radiation Exposure
 Depends on survival of one or more clonogenic cells within the FSU
 Surviving clonogens cannot migrate from one FSU to another
 Each FSU is small and autonomous, low doses can deplete the clonogens in it.
 Example kidney composed of large number of small FSUs (e.g., nephrons) each
independent of the neighbor
 Survival of a nephron following irradiation depends on survival of at least one
clonogen within it therefore on the initial number of renal tubule cells per nephron
and their radiosensitivity
 Because it is small, it can be easily depleted of clonogens by low doses,
 Therefore the kidney has a low dose tolerance
15

Other structurally defined FSUs
 Other organs that resemble the kidney include
 Those with branching treelike structure of ducts and vasculature that
terminates in end structure or lobules of parenchymal cells
 Lung
 Liver
 Exocrine organs
 Many of these have low tolerance to radiation
16

Radiation response structurally undefined
FSUs
 Clonogenic cells in these systems not confined to one particular FSU
 Cells can migrate from one FSU to another
 Allows repopulation of a depleted FSU
 Example re-epithelialization of a denuded area of skin can occur either
from surviving clonogens within denuded area or by migration from
adjacent areas
17

Tissue Rescue Unit
 Concept proposed to link survival of clonogenic cells and functional
survival
 Defined as minimum number of FSUs required to maintain tissue function
 Assumes
 Number of TSUs is proportional to number of clonogenic cells
 FSUs contain constant number of clonogens
 FSUs can be repopulated from single clonogen
18

Issues with FSUs
 Some tissues defy classification
 Crypts of jejunum (structurally well
defined but surviving crypts can/do
migrate from one crypt to another
to repopulate depleted neighbors
19

Volume Effect in Radiotherapy
 Total dose that can be tolerated depends on volume irradiated
 Tolerance dose (TD) is defined as the dose that produces an acceptable
probability of a treatment complication.
 Includes objective criteria like radiobiology and subjective factors like
socioeconimic, medicolegal etc
 Serial and parallel structure
20

Dose vs Complications
 Spatial arrangement of FSUs in tissue is critical
 Serially arranged FSUs
 Example spinal cord integrity of each FSU is critical to organ function
 Elimination of any FSU in this system can result in measurable probability of
complication
 Radiation damage shows binary response threshold below which is normal
function, above which there is loss of function
21

Clinical tolerance
 For both kidney and lung, clinical tolerance depends on volume irradiated
 Both organs are sensitive to irradiation of their entire volume, but small
volumes can be treated to much higher doses
 Considerable functional reserve capacity (only 30% of organ required to maintain
function under normal physiologic conditions)
 Inactivation of small number of FSUs does not lead to loss of organ function
 Implication there is a threshold volume of irradiation below which functional
damage does not develop, even after high dose irradiation
 Above threshold, damage is exhibited as a graded response (increasing severity of
functional impairment) rather than binary-all or nothing response
23

Clinical tolerance- structurally undefined
FSUs
 Example - Skin and mucosa have no well defined FSUs
 Respond similarly to defined FSUs with parallel architecture
 Do not show volume effect at lower doses where healing can occur from
surviving clonogens
 The severity of skin reaction is relatively independent of the area irradiated
because healing occurs through regeneration from clonogens scattered
throughout the tissue
 Therefore there is a volume effect (in practice)
24

Radiation Pathology of Tissues
 Response of tissue to radiation depends on 3 factors
 Inherent sensitivity of the individual cells
 Kinetics of the tissue as a whole
 Way the cells are organized in the tissue
 These factors combine to account for the substantial variation in radiation
response characteristics of different tissues
25

Casaretts Classification
 Suggested classification of mammalian cell radiosensitivity based on
histologic observation of cell death
 Divide parenchymal (functioning) cells into 4 major categories, I-IV
 Supporting structures (e.g., connective tissue and endothelial cells of small
blood vessels) were regarded as intermediate in sensitivity between groups II
and III of parenchymal cells
 Most sensitive cells die mitotic death after irradiation
 Most cells that don't divide require very large doses to kill them
 Lymphocyte
 Does not usually divide
 Dies an interphase death
 One of the most radiation sensitive cells
26

Casaretts Classification of Mammalian Cell
Radiosensitivity
27

Classification
 Vegetative Intermitotic Cells.(VIM)
 Undifferentiated rapidly dividing cells which generally have a quite short life
cycle. Examples are erythroblasts, intestinal crypt cells and basal cells of the
skin.
 Essentially continuously repopulated throughout life
 Differentiating Intermitotic Cells (DIM)
 Actively mitotic cells with some level of differentiation. Spermatogonia are a
prime example as well as midlevel cells in differentiating cell lines.
 Have substantial reproductive capability but will eventually stop dividing or
mature into a differentiate cell line
28

Classification..cont
 Reverting Postmitotic Cells (RPM)
 Does not normally undergo division but can do so if called upon by the body to
replace a lost cell population.
 These are generally long lived cells.
 Mature liver cells, pulmonary cells and kidney cells make are examples of this type
of cell.
 Fixed Postmitotic Cells (FPM)
 Most resistant to radiation
 Highly differentiated and lost ability to devide
 May have long (neurone) and short life span (granulocyte)
29

Michalowski Classification
 Tissues follow either a hierarchical (H) or flexible (F) model
 Within tissues 3 distinct categories of cells
 Stem cells continuously divide and reproduce to give rise to both new stem cells
and cells that eventually give rise to mature functional cells.
 Functional cells, which are fully differentiated; they are usually incapable of further
division and die after a finite life span, though the life span varies enormously
among different cell types. Example- circulatory granulocytes
 Between these two extremes are maturing partially differentiated cells ; these are
descendants of the stem cells, still multiplying as they complete the process of
differentiation. In the bone marrow, for example, the erythroblasts and
granuloblasts represent intermediate compartments
30

H-type & F-type populations
 Hierarchical (H-type) populations- The cell types that progress from the stem
cell through the mature cell with nonreversible steps along the way.
 They include bone marrow, intestinal epithelium, epidermis and many others.
 Flexible tissue(F-type) populations- The cell lines in which the adult cells can
under certain circumstance be induced to undergo division and reproduce
another adult cell.
 Examples include liver parenchymal cells, thyroid cells and pneumocytes as
well as others.
31

Growth Factors
 Radiation causes injury of normal tissue through cell killing,
 But in addition to mitotic and apoptotic cell death, radiation can induce
changes in cellular function secondary to tissue injury
 Altered cell-to-cell communication
 Inflammatory responses
 Compensatory tissue hypertrophy of remaining normal tissue, and
 Tissue repair processes
 Recognition of these "non-cytocidal" radiation effects has enhanced
understanding of normal tissue radiation toxicity
 IL-1,6- rdioprotector of hematopoetic cells, Fibroblastic growth factor inhibits
radiation induced apoptosis, TGF- induce pneumonitis
32

General Organ System Responses
 Individual Organ/Tissue sensitivity to radiation injury
 Discussion-
 Skin
 Hematopoietic system
 Digestive system
 Lung
 Kidneys
 Bladder
 Nervous system
 Genitalia
33

Hemopoietic (blood and lymph)
 Refers to the parenchymal cells of the bone marrow and the circulating
blood.
 Does not refer to the vessels themselves
 Critical cells are the marrow blast cells and circulating small lymphocytes.
 Non-circulating lymphocytes and other circulating white cells fairly
radioresistant
 Red Blood Cells are the radioresistant cell
 Irradiation of a small region of the body generally has no effect on
circulating levels
 An exception is lymphocyte counts following therapy level doses to the
chest.
34

 Irradiation of a majority of the
bone marrow will cause
marked decreases in
circulating cell levels post
irradiation.
 Platelets at 2-4 days
 White cells at 5-10 days
 Red cells at 3-4 weeks
 Due to irradiation of stem cells
of these cell lines.
35

 Radiation doses to the entire marrow of greater than 8 gray are quite likely
to result in marrow death and patient death unless a successful marrow
transplant can be performed.
 Used in pre transplant marrow sterilization
 B lymphocytes has life span of 7 weeks and Plasmacyte has 2-3 days
 T lymphocyte has 5 months of life span
 Total body irradiation leads to a rapid fall in the number of circulating B and
T lymphocytes
 Total lymphoid irradiation to a dose of 30 to 40 Gy is used for the treatment
of lymphomas and leads to a long-lasting T-cell lymphopenia (used in organ
transplant).
36

Skin
 Composed of epidermis, dermis,
hypodermis
 Takes about 14 days from the
time a newly formed cell leaves
the basal layer to the time it is
desquamated from the surface
37

Skin
 A few hours after doses > 5 Gy, there is early erythema similar to sunburn, is
caused by vasodilation, edema loss of plasma constituents from capillaries.
 Erythema develops in 2nd to 3rd week of a fractionated, followed by dry or
moist desquamation resulting from depletion of the basal cell population
 higher doses, at which there are no surviving stem cells, moist desquamation
is complete, healing must occur by migration of cells from outside the treated
area.
 Skin & oral mucosa, the total dose tolerated depends more on overall time
than on fraction size.
 Telangiectasia developing more than a year after irradiation reflects late
developing vascular injury.
38

Skin
 Little or no reaction below 6-
8 gray
 Erythema w/a early and late
effects at 10 gray and above.
 Early effects
 Erythema
 Dry desquamation
 Moist desquamation
 Necrosis
39
 Late effects occur and increase
with dose
 Recovers well from fairly high
doses but late effects seen
 Thinning of skin
 Pigmentation or
depigmentation
 Loss or thinning of hair.
 Loss or thinning of
subcuntaneous fat
 Cancer induction years
later.

 Sources of radiation injury
 Solar UV
Probably major threat for most people
 Diagnostic x-ray
Fluoroscopy Especially cardiac
CT High speed spiral in juveniles
 Radiation therapy
Modern techniques keep dose low below 5 gray
Exception is when skin is primary target.
40

Digestive System
 Extends from mouth through rectum
 Sensitivity of individual parts rests with the number and reproductive
activity of the stem cells in the basal mucosal layer
 Mouth and esophagus relatively resistant
 Stomach more sensitive and has more secretory cells
 Small bowel very sensitive
 Colon and Rectum similar to esophagus
41

Order of events in HNC
Week Consequences
1st week Asymptomatic to slight focal hyperemia due to dilatation of capillaries,
Increased sensitivity with alcohol or tobacco, chemotherapy, infection
(oral candidiasis, herpes simplex virus),
or immunosuppression (HIV).
2nd week Increasing pain and loss of desire to eat. Sense of taste is altered; bitter
and acid flavors are most changed, with less change with salty and sweet
tastes. Basal cells are denuded and patchy mucositis
3rd week Mucositis and swelling with depletion of gland secretions leading to
difficulty in swallowing. Mucositis plaques are confluent.
4th week Confluent mucositis sloughs, resulting in denuded lamina propria.
Mucosa becomes covered by fibrin and polymorphonuclear leukocytes.
5th week Maximum radiation damage apparent by this time. Extreme sensitivity to
touch, temperature, and grainy food. Xerostomia and poor oral hygine
42

 Early effects are mucosal depopulation
 Clinical soreness and possible ulceration
 With very high doses bleeding and necrosis
 Loss of secretory cells
 Stomach and Intestine decreased mucus
 Decreased digestive enzyme production
 Decreased hormone production
 Late effects
 Repopulation functional recovery partial
 Epithelial metaplasia loss of function
 Scarring severe loss of function
 Chronic clinical signs
 Stricture - obstruction of GI tract
 Surgical mediation required.
43

Digestive Track
 Esophagus- Esophagitis and increased thickness of squamous layer
 Substernal burning with pain on swallowing at about 10 to 12 days after
the start of therapy
 Stomach- nausea and vomiting, delayed gastric emptying and epithelial
denudement are the two main early radiation effects.
 Dyspepsia may be evident in 6 months to 4 years and gastritis in 1 to 12
months
 Intestine- Acute mucositis frequently occurs, with symptoms such as
diarrhea or gastritis,
44

Lungs
 One of the most radiosensitive of late responding organs
 Intermediate to late responding tissue
 Reverting Post mitotic populations of epithelium
 10 gray single dose or 30 gray fractionated to the whole lung cause
progressive fibrosis
 Type II pneumocyte is critical cell for edema
 Edema is acute toxicity (radiation pneumonitis- 2-6 months)
 Fibrosis is the late effect- several months to years
 The lung has large functional reserve
 Dose to less than ½ lung has minimal clinical effect
 Increased toxicity with bleomycin, cyclophosphamide
45

Kidneys
 Radiosensitive late-responding critical organ
 Radiation to both kidneys to a modest dose of about 30 Gy in 2-Gy fractions
results in nephropathy with arterial hypertension and anemia.
 FSUs are arranged in parallel, with each containing only about 1,000 stem cells
 Five distinct clinical syndromes occur
 acute radiation nephropathy,
 chronic radiation nephropathy,
 benign hypertension,
 malignant hypertension, and
 hyperreninemic hypertension secondary to a scarred encapsulated kidney
47

Liver
 Large organs which are fairly radiation sensitive
 Major radiation threat is from radiation therapy fields which include these
organs
 Vascular injury may play an important role.
 Whole organ doses of 30 gray are lethal
 FSU are arranged in parallel
 Greater tolerance if partially irradiated
 Fatal hepatitis if 35 Gy in whole liver is given
 Life span of hepatocyte is about 1 year
49

 The structure of the livers
functional units, or lobules.
 Blood enters the lobules
through branches of the
portal vein and hepatic artery,
then flows through small
channels called sinusoids that
are lined with primary liver
cells (i.e., hepatocytes).
 The hepatocytes remove toxic
substances, including alcohol,
from the blood, which then
exits the lobule through the
central vein (i.e., the hepatic
venule).
50

Male Reproductive System
 Adult sperm are Fixed Post Mitotic cells
 But, chromosomal damage may be passed on to a fetus. Mutations can result.
 Germinal cells very sensitive though
0.1 gray temporary reduction of no of spermatozoa
0.15 gray to testis causes temporary sterility
2 gray leads aazospermia lasting several year
6-8 gray to testis causes permanent sterility in 2gy/fr
 Diagnostic x-ray and nuclear medicine studies not a threat to function
 Radiation therapy near testis probably cause temporary sterility
 Radiation therapy including testis causes sterility and possibly loss of function.
 Functional sperm present 1-2 weeks after 1st dose
51

Female Reproductive System
 Radiation therapy is major sterility threat
 6.25 Gray to both ovaries expect sterility
 Oocytes do not divide thus no repopulation
 Radiation therapy is hormonal function threat.
 Hormonal function decreased/lost above 25 gray
 May require hormonal supplementation
 Oocytes do not divide and Themselves relatively resistant
 Chromosomal damage carried on and may become evident after fertilization.
 Ovarian sensitivity more tied to follicular cells which support oocytes during
 During follicle development there is great cellular growth activity in these cells.
 Inactive follicular cells are less sensitive
52

Eyes
 Eyes are a major dose limiting structure
 The lens is vary sensitive to radiation
 Cataract formation is major effect
Seen with doses as low as 2 gray
Very likely 6.5 to 11.5 Gy
 Occupational dose from diagnostic x-ray is a threat for cataract formation.
 Wear eye shields, esp. during fluoroscopy
 Major side effect of RT to head and neck
53

Cardiovascular System
 Vessels
 Endothelium is target cell type
 Endothelial injury causes thrombosis , hemorrhage and necrosis
 Endothelium can repopulate to limited degree normally
 Veins are more resistant to RT
 In vessels after radiation muscle layer are replaced by collagen, and
elasticy is lost, blood flow decreased
 Arterial damage at 70Gy and capillary are at 40Gy
54

Heart
 Considered resistant
 Late effects maybe seen years later.
 Acute or Fibrosing pericarditis most common
 At higher doses myocardial fibrosis seen
 Late effects seen are slowly progressive
 Revealed or exacerbated by chemotherapy
 Diagnostic radiation not usually a threat
 >50% of heart vol is irrediated then pericarditis occur at 20Gy
 Chemotherapy like doxorubicin, dacarbazine, dactinomycin increases risk
55

Bone and Cartilage
 Mature bone is composed of FPM cells from hierarchical cell lines –
 At high RT doses osteonecrosis and fractures seen
D/t loss of mature osteocytes
 Growing cartilage cells at growth plate are a target at risk. Especially at < 2 yrs old.
 Causes stunted growth and possibly deformity due to death of chondroblasts
 High dose to joint can cause ‘dry’ joint
 Diagnostic exposure in children from Multi-slice spiral CT can be enough to at least
cause some growth arrest.
 Radiation Therapy exposure will cause permanent growth arrest in open growth plate
of a young person
56

Central Nervous System
 CNS is considered quite radioresistant in adults.
 Development continues to 12 years of age therefore whole brain dose can reduce
development
 Glial cells and endothelial cells are the critical cells of interest as slow rate of
turnover.
 RT usually avoided in children.
 Increasing volume or dose the effects
 Large volumes irradiated above 40 Gray lead to decreased function.
 Spinal cord is serial structure
 Early injury- Lhermittes sign (reversable)
 Late injury- demyelination and necrosis of white matter and vasculopathy
57

Spinal Cord Structure
 Two major tissues
 Gray matter - nerve cell bodies and
thousands of connections between
nerves.
 White matter (composed of nerve axon
fibers) travels from the spine to the
brain.
 Ventral root carries motor axon fibers
from cells in gray matter out to muscles.
 Incoming sensory signals pass through
dorsal root into the grey matter
58

LENT AND SOMA
 European Organization for Research and Treatment of Cancer (EORTC)
and the Radiation Therapy Oncology Group (RTOG), formed working
groups to update their system for assessing late injury to normal tissues
 This led to the Late Effects of Normal Tissue (LENT) conference in 1992
 This conference led to the introduction of the SOMA classification for late
toxicity
 SOMA is an acronym for subjective, objective, management criteria with
analytic laboratory and imaging procedures
59

The SOMA Scoring System
 Subjective- injury, if any, will be recorded from the subject’s point of view
that is, as perceived by the patient
 Objective—in which the morbidity is assessed as objectively as possible by
the clinician during a clinical examination
 Management—which indicates the active steps that may be taken in an
attempt to ameliorate the symptoms
 Analytic—involving tools by which tissue function can be assessed even
more objectively or with more biologic insight than by simple clinical
examination
 There is no grade 0, because that would indicate no effect, and no grade 5,
because that would indicate totality, or loss of an organ or function.
60

Anatomic Sites for Which There Are LENT
and SOMA Scales
61

LENT and SOMA Scoring System and
Grading Categories
Grade I Grade II Grade III Grade IV
Subjective
(pain)
Occasional and
minimal
Intermittent
and tolerable
Persistent and
intense
Refractory and
excruciating
Objective
(neurological
defect)
Barely
Detectable
Easily
Detectable
Focal Motor
sign, vision and
disturbances
Hemiplegia,
Hemisensory
defect
Management
(pain)
Occasional
nonnarcotic
Regular
nonnarcotic
Regular
narcotic
Surgical
intervenrion
Analytic (CT,
MRI, Lab Tests)
63

QUANTEC
 Quantitative Analysis of Normal Tissue Effects in the Clinic
 Published in the International Journal of Radiation Oncology, Biology, and
Physics in 2010 (IJROBP)
64

Character/Content of Emami and
QUANTEC
65

Implications of QUANTEC
 Different mechanisms for radiation-induced injury in different organs
 Serially arranger organ have steep dose–response curves at doses beyond
an apparent critical threshold
 Several neural structures exhibit a similar threshold dose for injury, so
there is common mechanism of injury
 Organs that are classically considered structured in parallel (e.g., lung,
liver, parotid, and kidney, analogous to electrical circuits) experience injury
at far lower doses and have more gradual dose–response curves
compared to series organs
 QUANTAC is better quantify the relationship between dose– volume
parameters and clinical outcomes.
66

Clinical response to normal tissue with radiation

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