Review

Radiotherapy toxicities: mechanisms, management, and

future directions
Ioannis I Verginadis, Deborah E Citrin, Bonnie Ky, Steven J Feigenberg, Alexandros G Georgakilas, Christine E Hill-Kayser, Constantinos Koumenis,
Amit Maity, Jeffrey D Bradley, Alexander Lin

Lancet 2025; 405: 338–52 For over a century, radiotherapy has revolutionised cancer treatment. Technological advancements aim to deliver high
Published Online doses to tumours with increased precision while minimising off-target effects to organs at risk. Despite advancements
January 16, 2025 such as image-guided, high-precision radiotherapy delivery, long-term toxic effects on healthy tissues remain a great
https://doi.org/10.1016/
clinical challenge. In this Review, we summarise common mechanisms driving acute and long-term side-effects and
S0140-6736(24)02319-5
discuss monitoring strategies for radiotherapy survivors. We explore ways to mitigate toxic effects through novel
Department of Radiation
Oncology (I I Verginadis PhD, technologies and proper patient selection and counselling. Additionally, we address policies and management
Prof S J Feigenberg MD, strategies to minimise the severity and impact of toxicity during and after treatment. Finally, we examine the potential
Prof C Koumenis PhD, advantages of emerging technologies and innovative approaches to improve conformity, accuracy, and minimise off-
Prof J D Bradley MD,
target effects.
Prof A Lin MD,
C E Hill-Kayser MD), and
Department of Cardiovascular Introduction organs at risk of off-target effects. This improvement has
Medicine (Prof B Ky MD), Radiotherapy has been an effective cancer treatment been accomplished through various advances imple­
Perelman School of Medicine,
for more than a century. The origins of radiotherapy mented at different points in the therapeutic process.
University of Pennsylvania,
Philadelphia, PA, USA; can be traced back to the late 19th century, when Before treatment begins, diagnostic imaging (such as CT,
Radiation Oncology Branch, Wilhelm Conrad Roentgen (later awarded the first PET, and MRI) can be used to identify and outline
National Cancer Institute, Nobel Prize in Physics in 1901) accidentally discovered tumours to target during radiotherapy treatment. In the
National Institutes of Health,
x-rays while using a tube invented by William Crookes.1 late 1980s to early 1990s, the incorporation of CT scans
Bethesda, MD, USA
(Prof D E Citrin MD); This finding provided the groundwork for the use of allowed for the reconstruction of tumours and healthy
Department of Physics, School ionising radiation in medicine, laying the foundation organs in three dimensions, and thereby led to the
of Applied Mathematical and for the development of radiotherapy as a therapeutic development of three dimensional (3D) spatial radiation
Physical Sciences, National
Technical University of Athens,
technique. planning (3D conformal radiotherapy). This advance
Athens, Greece Recent technical advancements in radiotherapy have allowed for multiple radiation beams to be used,
(Prof A G Georgakilas PhD); allowed for better delivery of therapeutic doses of conforming radiation as much as possible to the tumour
Cancer Center, Children’s radiation to areas of cancer involvement, while minimi­ and avoiding healthy organs. Subsequent advances, with
Hospital of Philadelphia,
Philadelphia, PA, USA
sing the dose delivered to the surrounding healthy further confinement of high-dose radiation by small
(C E Hill-Kayser MD); beamlets of varying intensity (intensity-modulated
Department of Radiation radiotherapy), have resulted in improved patient
Oncology, University of Utah Search strategy and selection criteria outcomes through toxicity reduction.2 Another means to
Health, Salt Lake City, UT, USA
(Prof A Maity MD) We searched PubMed, Scopus, and MEDLINE using the search reduce the dose of radiation to which healthy tissues are
Correspondence to: terms “radiation-induced adverse events”, “radiation exposed became available with the advent of particle
Dr Ioannis I Verginadis, toxicity”, “management of toxicities”, “monitoring of side therapy. The physical properties (eg, mass and charge) of
Department of Radiation
effects”, or “acute and late side effects” in titles or abstracts. the particles used in particle therapy, a form of external
Oncology, Perelman School of beam radiotherapy (using, for example, protons, carbon
Medicine, University of In addition, we searched for combinations of the terms
Pennsylvania, Philadelphia, “radiotherapy and immunotherapy”, “stereotactic body ions, or helium ions), have the benefit of inducing the
PA 19104-156, USA radiation therapy and immunotherapy”, “abscopal effect Bragg peak effect, whereby the majority of the radiation
vioannis@pennmedicine.
radiation”, “FLASH”, “proton therapy and toxicity”, “MRI and dose is deposited at a specific depth corresponding to the
upenn.edu tumour location. The Bragg peak effect results in a
radiation toxicity”, “adaptive radiation”, “temporal and
spatial fractionation”, “liquid biopsy and biomarkers”, and minimal dose delivery to healthy tissues around the
“artificial intelligence”. Searches were done on multiple dates tumour, which can help to reduce the risk of adverse
between Aug 10, 2023, and Sept 28, 2024, with a final events. During daily treatment, imaging can be done
update on Oct 8, 2024. Relevant articles published in English by the radiotherapy unit (image-guided radiotherapy)
between April 7, 1934, and Aug 30, 2024 were identified. to visualise anatomy, ensuring optimal accuracy
Abstracts and reports from meetings were included only if and precision throughout treatment. Image-guided
they were directly related to previously published work. radio­therapy thereby allows for any required adaptation
All authors had access to the full text of all selected of the radiotherapy plan (adaptive radiotherapy) based on
publications. Due to the large number of eligible publications, changes in patient anatomy during treatment (such as
the final selection of references for this Review was based on from tumour response).
the most recent and relevant studies that offered the highest Currently, radiotherapy is indicated for more than 50%
combined level of evidence. of all patients with cancer.3 Although the benefits of
radiotherapy are well established, even the most advanced

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 Review

technologies cannot completely prevent exposure of appears dependent on number of fractions and field size)
healthy tissues to clinically significant incidental doses of is also an important concern, especially in the era of
radiation, which can lead to considerable long-term immuno­ modulatory drugs and radiotherapy
morbidity and adversely affect patients’ quality of life. combinations.48 Much attention is now being given to the
Depending on the treatment site and the delivered dose effective dose to immune cells (amount of radiation dose
of radiotherapy, various radiotherapy-induced toxic received by immune cells as they circulate through the
effects across different organs have been identified body during radiotherapy treatments).49,50 A high effective
(figure 1, table),4,5 including a low but measurable risk of dose to immune cells is associated with severe
radiation-induced malignancy among long-term lymphopaenia, leading to worse clinical outcomes in
survivors42 (for example, in a single-site study in oesophageal and lung cancer, suggesting that the
the USA,43 8·3% of children who received radiotherapy immune system should also be considered to be an
for a primary tumour developed a secondary malignancy, organ at risk. A high effective dose also correlates with
mainly within the original site of radiotherapy). Among increased morbidity, often manifested through acute
adults, women who receive breast radiotherapy and men hospitalisations, which could be attributed to the lysis of
who receive prostate radiotherapy comprise patient circulating lymphocytes, which might lead to reduced
populations for whom radiotherapy is a commonly used anti-tumour activity.51
treatment with long-term follow-up. Among women The toxic effects on which this Review focuses are
receiving breast radiotherapy, 13·0% developed a mostly due to cell death, which can eventually lead to
secondary malignancy, of which 3·4% were attributable organ dysfunction. Historically, these were termed
to radiotherapy.44 In men treated for prostate cancer, deterministic effects, but are now sometimes referred to
those who received radiotherapy had a 1·2% greater as tissue reactions.52,53 Radiation is also associated with
incidence of a second primary cancer than those treated stochastic effects, which can result from DNA mutations
without radiotherapy.45 and lead to a second malignancy. These two broad
In this Review, we broadly discuss the mechanisms of categories—tissue reactions and stochastic effects—are
radiotherapy toxicity and explore key clinical considera­ characterised by very different features. The
tions related to radiotherapy, including monitoring of deterministic nature of acute and most late tissue
late side-effects, strategies for optimisation of patient reactions means that these are directly related to the
selection for radiotherapy, and methods for the manage­ dose received; higher doses lead to more severe and
ment of toxic effects without treatment interruption. immediate side-effects, such as skin redness or hair loss,
Finally, we explore the latest innovative technologies with a clear dose threshold below which these effects do
aiming to improve conformity and accuracy while not occur. By contrast, the relationship between dose
minimising healthy tissue toxicity. and some specific effects, such as secondary

Mechanisms CNS and head and neck All sites

Radiotherapy can cause both acute and late toxic effects
Cognitive impairment; Second malignancy and
(figure 2). The acute (early) reactions are thought to be vascular toxicity; growth asymmetry
due to damage of cells with a rapid turnover rate, such as xerostomia; and dysgeusia
those in the epithelium of the gastrointestinal tract, oral
Heart
mucosa, and skin (figure 2). This damage can lead to
side-effects such as diarrhoea, mucositis, oesophagitis, Heart valve disease;
and desquamation, but is often reversible, resulting in no cardiomyopathy; and
coronary artery disease
permanent sequelae. By contrast, late effects, which are
seen in tissues where cells divide slowly, are often more
consequential and not readily reversible. Abdominal Lung

Although early toxicity from radiotherapy is primarily Obstruction; fistula; Pulmonary fibrosis;
attributed to the death of rapidly dividing cells, cirrhosis; and end-stage airway stenosis;
renal disease and fistula formation
accumulated evidence suggests that the microbiome is
closely associated with the development and prevention
of various radiation-induced toxic effects. Specifically, the Genitourinary
oral and gut microbiome might modulate the effects of
Proctitis; cystitis; stricture;
radiation on oral mucositis in patients receiving and necrosis
treatment to the head and neck region, or on enteritis for
those receiving abdominal or pelvic radiation.46,47 These
findings suggest that microbiome-targeted therapies,
such as probiotics or prebiotics, could improve patient
Figure 1: Toxic effects of radiotherapy by site
outcomes by mitigating the adverse events of General overview of the most common long-term toxic effects of radiotherapy arising in different regions of the
radiotherapy. Radia­ tion-induced lymphopaenia, (which body. Figure created with BioRender.com.

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Long-term adverse events Expected incidence rates (%)* Potential management strategies
Abdomen
Bile ducts Biliary stenosis 4% (grade 1)8 Limit dose when treating hepatic region with SBRT to 40·0 Gy over 5 fractions8
Liver Radiation-induced liver disease <5% (dependent on pre-existing liver Conventionally fractionated radiotherapy: limit average dose to whole liver to
disease)9 ≤28·0 Gy (for primary liver cancer) or ≤30·0 Gy (for liver metastases).10 SBRT
(3–6 fractions): limit average dose to whole liver to <20·0 Gy (for primary liver
cancer) or <18·0 Gy (for liver metastases);10 symptomatic management,
diuretics, and paracentesis
Kidney Renal dysfunction <5%9 Limit mean radiotherapy dose to both kidneys to <15·0 Gy; limit volume
receiving 12·0 Gy to <55%, volume receiving 20·0 Gy to <32%, volume receiving
23·0 Gy to <30%, and volume receiving 28·0 Gy to <20%;9 medical management
of hypertension and electrolyte abnormalities; dialysis for end-stage renal disease
Small intestine Enteritis, obstruction, and fistula Obstruction: 0·8–13·0%; fistula: Limit volume of small intestine receiving 15·0 Gy to <120 cc;9 symptomatic
0·6–4·8%11,12 management: low-fibre diet, probiotics, hyperbaric oxygen, and surgery
Stomach Ulceration <7%9 Limit volume of stomach receiving 45·0 Gy to ≤2 cc13
Stomach Perforation <2%14 Limit maximum dose to <50·0 Gy14
Bone, skin, and soft tissue
Bone Fracture 0·6% (<50·0 Gy) and 7% (>60·0 Gy)15 Limit maximum dose to bone to ≤50·0 Gy; if treating with high-dose
radiotherapy, limit maximum dose to bone to <60·0 Gy15
Lymphatic system Lymphoedema In the neck (with high-dose direct Limit the extent and volume of lymphatic regions that require both surgical
irradiation): 75%;16 in the arm (after resection and radiotherapy; physical decongestive lymphoedema therapy
radiotherapy for breast cancer): 6–18%17
Soft tissue Fibrosis In the neck (with high-dose direct Limit the extent and volume of soft tissues that require both surgical resection
irradiation): 74%;18 in the breast: 5% and radiotherapy; physical therapy (eg, exercise, stretches)
(grade 2 or higher)19
CNS
Brain Symptomatic necrosis <20% (with high-dose direct irradiation)9 Limit maximum dose to <60·0 Gy;9 with stereotactic radiosurgery, limit volume
receiving 12·0 Gy to <10 cc9
Brainstem Permanent cranial neuropathy or <5%9 Limit brainstem dose to ≤59·0 Gy to 1–10 cc of brainstem or <64·0 Gy (point
necrosis dose <1 cc of brainstem);9 with stereotactic radiosurgery, limit maximum dose
to brainstem to <12·5 Gy9
Cochlea Sensorineural hearing loss <30% (with high-dose irradiation close to Limit mean dose to cochlea to ≤45·0 Gy (conventional fractionated
the organ)9 radiotherapy) or ≤14·0 Gy (stereotactic radiosurgery) 9
Cochlea Tinnitus 11·6%20 (grade ≥2) Limit mean dose to ≤32·0 Gy20
Eye (lens) Cataracts 5%21 Limit maximum dose to lens to <10·0 Gy21
Eye (retina) Retinopathy leading to vision loss 5%21 Limit maximum dose to retina to <45·0 Gy21
Optic nerve and chiasm Optic neuropathy leading to <3%9 Limit maximum dose to optic nerves or chiasm to <55·0 Gy;9 with stereotactic
vision loss radiosurgery, limit maximum dose to optic nerves or chiasm to <12·0 Gy9
Pituitary gland Hypopituitarism 37%22 (with high-dose irradiation to the Limit pituitary dose according with specific hormone or dysfunction:23
anterior cranial skull base) 18·0 Gy for growth hormone deficiency or central precocious puberty;
30·0 Gy for follicle-stimulating, luteinising, thyroid stimulating,
adrenocorticotropic hormone; 50·0 Gy for hyperprolactinaemia
Spinal cord Myelopathy <1%9 Limit maximum dose to spinal cord to <50·0 Gy;9 with stereotactic radiosurgery
or SBRT, limit maximum dose to spinal cord to <13·0 Gy (stereotactic
radiosurgery) or <20·0 Gy (3 fraction SBRT)9
Head and neck
Brachial plexus Plexopathy 1–2%24 Limit median dose to ≤69·0 Gy†;25 with stereotactic radiosurgery or SBRT, limit
max dose to† 17·5 Gy (stereotactic radiosurgery), 24·0 Gy (3 fraction SBRT),
27·2 Gy (4 fraction SBRT), or 32·0 Gy (5 fraction SBRT)25
Carotid artery Carotid stenosis and stroke Stenosis: 29%; stroke (with high-dose Screening carotid ultrasounds, screening for dysautonomia, and optimal
direct irradiation): 5% management of cardiovascular risk factors (blood pressure)
Lacrimal glands Xerophthalmia 0–19% (with average dose to lacrimal Limit average dose to lacrimal gland to <30·0 Gy
gland of <30·0 Gy vs 30·0–45·0 Gy)27
Larynx Voice changes, aspiration, and <20% (with high-dose direct irradiation)9 When radiating close to the larynx (but not directly), limit mean dose to larynx
oedema to <40·0 Gy
Mandible Osteoradionecrosis 3%28 For prevention, maintenance of dental health and hygiene; prescription fluoride
(for patients with xerostomia); surgical debridement or resection
Parotid gland Xerostomia 32% (grade 2–3, with high-dose Limit average dose to <25·0 Gy to the combined parotid glands or <20·0 Gy to a
irradiation close to the organ)29 single parotid gland;9 dietary modifications (avoidance of dry, starchy foods)
and pharmacological treatments (salivary stimulants or substitutes and
lubricants)
(Table continues on next page)

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Long-term adverse events Expected incidence rates (%)* Potential management strategies
(Continued from previous page)
Pharynx (pharyngeal Symptomatic dysphagia or 4% (grade 3–4)29 Limit average dose to <50·0 Gy to the pharyngeal constrictors;9 evaluation and
constrictors) aspiration rehabilitation with speech and swallow therapists
Thyroid gland Hypothyroidism 36% (with high-dose irradiation close to Limit volume of thyroid gland receiving 50·0 Gy to <50%;31 limit average dose to
the organ)30 thyroid gland to <55·0 Gy31
Pelvis
Bladder Bladder dysfunction (frequent <6% (grade ≥2)9 For bladder cancer treatment, limit maximum dose to bladder to <65·0 Gy;9 for
urination, dysuria, haematuria, prostate cancer treatment (conventional fractionated radiotherapy), limit the
and reduction in capacity) percentage of the bladder receiving 65·0 Gy to ≤50%, 70·0 Gy to ≤35%, 75·0 Gy
to ≤25%, 80·0 Gy to ≤15%;9 for prostate cancer treatment (hypofractionated
radiotherapy), limit the percentage of the bladder receiving the percentage of
the total prescribed radiotherapy dose to <5% for 100% of the prescribed dose or
<50% for 68% of the prescribed dose32
Penile or urethral bulb Severe sexual dysfunction <35% (with high-dose irradiation close to For conventional fractionated radiotherapy, limit the percentage of the bulb
the organ)9 receiving 50·0 Gy to ≤50% or 60·0 Gy to ≤10%;32 for hypofractionated
radiotherapy, limit the percentage of the bulb receiving the percentage of the
total prescribed radiotherapy dose to <10% for 81% of the prescribed dose or
<50% for 68% of the prescribed dose32
Rectum Rectal dysfunction <15% (grade 2); <10% (grade 3, with With conventional fractionated radiotherapy, limit the percentage of the rectum
high-dose irradiation close to the organ)9 receiving 50·0 Gy to <50%, 60·0 Gy to <35%, 65·0 Gy to <25%, 70·0 Gy to <20%,
or 75·0 Gy to <15%;9 with hypofractionated radiotherapy, limit the percentage
of the rectum receiving 28·0 Gy to ≤45%, 32·0 Gy to ≤35%, or 38·4 Gy to ≤15%;33
medical management with stool softeners, fibre, sucralfate enemas, and
glucocorticoid suppositories for mild proctitis, and ablative approaches
(coagulation), formalin, hyperbaric oxygen, and surgery for moderate to severe
proctitis
Ovary or testes Infertility Variable due to possible multiple Fertility preservation before radiation and assisted reproduction (Survivorship
contributing factors (eg, chemotherapy), Guidelines)
but common even after low-dose
exposure of ovaries or testes to
radiotherapy
Vagina Stenosis, necrosis, and fistula 1–15% (depending on radiotherapy Vaginal dilation, vaginal oestrogen, and surgical repair for vaginal fistula34
technique and dose)34
Thorax
Oesophagus Fistula and stenosis Fistula (with chemoradiation for non- Limit max dose to oesophagus to <50·0 Gy
small-cell lung cancer): <1% (grade 5);35
stenosis: 2% (at 50·0 Gy or less) to 15%
(at >60·0 Gy)36
Heart Cardiovascular events (eg, 23–32% (with high-dose irradiation close Limit mean dose to heart to <20·0 Gy;38 limit volume of left anterior descending
coronary disease, valvular to the organ)37 artery receiving 15·0 Gy to <10%39 and volume of left ventricle receiving 15·0 Gy
dysfunction, heart failure, to <1%39
pericardial disease, and arrythmia)
Lung Pneumonitis 12% (grade 1–2); <1% (grade ≥3, with With conventional radiotherapy, limit volume of lung receiving 20·0 Gy to ≤40%
high-dose direct irradiation)40 and mean lung dose to ≤20·0 Gy†25
Lung Fibrosis 10% (grade 1–2, with high-dose direct Limit dose to <30 Gy41
irradiation)40
Expected incidence rates are for the setting of curative-intent radiotherapy (definitive or adjuvant), unless also inclusive of treatment with SBRT or stereotactic radiosurgery as a management strategy. Toxic
effects for which a specific grade is not listed are generally assessed by presence (yes vs no), do not have dedicated grading systems, or reliable data to estimate incidence are not available. For toxic effects with
listed grades, these generally reference rates from published randomised controlled trials. SBRT=stereotactic body radiotherapy. *Before 1985, the radiotherapy literature used inconsistent terminology to report
toxicity. From 1985 to 2000, toxicity was reported using the criteria as defined by the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer.6 Since 2000,
toxicity has been graded according to the Common Toxicity Criteria.7 †National Comprehensive Cancer Network Clinical Practice Guidelines.

Table: Brief summary of long-term adverse events associated with radiotherapy by affected organs or sites

malignancies or genetic mutations, is stochastic. risk is proportional to the dose received. With the For more on the Survivorship
Therefore, these effects occur randomly, with the increasing use of radiotherapy in the setting of Guidelines see http://www.
survivorshipguidelines.org/
probability increasing with the dose, but without a multimodal therapy (which includes immunotherapy,
specific threshold. Of note, late effects are generally drug-antibody conjugates, and biologically targeted
absent at low radiation doses and many confounding agents), some adverse events can occur even with low
factors, such as systemic therapy, can influence the doses of radiotherapy used in combination with other
occurrence of late toxic effects. Even low doses can therapies (compared with higher doses of radiotherapy
potentially cause secondary malignancies because a used alone). For example, stereotactic radiosurgery
mutation in a single gene could lead to cancer, but the followed by immunotherapy can increase the risk of late

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Malignant Second
transformation malignancy
Apoptosis; survival of resistant cells
of resistant cells

Inflammation and Unresolved

recruitment of chronic
immune cells inflammation

DNA damage
and repair Loss of blood
vessel integrity Development Tissue and organ
of fibrosis dysfunction or mortality

Loss of intestinal
epithelium integrity
Apoptosis, necrosis, or function
ROS or senescence
Chronic
inflammation
Loss of skin
epithelium integrity
or function

Loss of oral mucosa

integrity or function

Minutes to hours Days to weeks Months to years

Time

Figure 2: Timeline of acute and late adverse events after radiotherapy

Radiotherapy causes DNA damage and triggers an inflammatory response in which cells attempt to repair the damage. If the repair is insufficient, cells can undergo
senescence or death, leading to various acute and late adverse events. Residual DNA damage in tissue stem cells can lead to malignant transformation and second
cancers. Typically, long-term adverse events are irreversible, and limits to radiation doses are necessary to prevent these events. Figure created with BioRender.com.

brain necrosis. The cumulative effects of multiple growth factors, and the release of chemokines that recruit
treatments on healthy tissue response should therefore inflammatory cells. One key cytokine implicated in
be considered when patient treatment is planned. radiotherapy-related toxicity is transforming growth
Many early effects can be explained by the target cell factor-β (TGF-β), which plays a crucial role in various
hypothesis, in which specific cell types are destroyed by pathological conditions,55 including radiation-induced
radiation, but the pathophysiology of late injury is much fibrosis.56 Radiation exposure can trigger the cellular
more complicated. Late injury could involve both the loss release of TGF-β and its dissociation from latency
of parenchymal cells and vascular endothelial cells,54 associated peptide, which normally maintains TGF-β in
potentially explaining effects such as hypoxia and an inactive state. Activated TGF-β promotes the
necrosis. Although acute effects are not generally recruitment, proliferation, and activation of fibroblasts,
correlated with late effects, consequential late effects can leading to secretion of collagen into the extracellular
arise from a persistent early effect. Consequential late matrix.
effects are hypothesised to result from the depleted The wound healing response is often self-limiting, but
stem-cell population falling below the required amount in the case of pathological fibrosis in the post-radiation
needed for tissue regeneration. Because acute damage to setting, the process could be perpetuated over the course
tissues can lead to inflammation and cell death (which, if of years by activation of feed-forward loops that trigger
not adequately repaired, results in chronic inflammation further inflammation and fibrosis (figure 2). Proposed
and fibrosis), the ongoing damage and insufficient repair reasons for this activation include the generation of
mechanisms can cause a progressive decline in tissue hypoxia in irradiated tissues due to endothelial cell loss57
function, ultimately leading to long-term complications and a disruption in the homoeostatic control of reactive
such as fibrosis, organ dysfunction, or secondary oxygen species and reactive nitrogen species, which can
malignancies. However, neither the target cell hypothesis also lead to TGF-β activation.54 In radiation-induced
nor the loss of parenchymal and vascular cells directly fibrosis, particularly in the kidneys and possibly the
account for the fibrosis observed in organs such as the lungs, the renin-angiotensis system has been
heart, lungs, kidney, and liver after radiation exposure. implicated,58 in addition to the senescence of healthy
Interestingly, parallels can be drawn between radiation- stem cells as a result of oxidative stress and DNA damage.
induced fibrosis and wound healing: both involve the This process results in an inability to repopulate after the
induction of cytokine cascades, including tumour original cell deaths and in the advent of a senescence-
necrosis factor, interleukin-1, interleukin-6, and other associated secretory phenotype, which is characterised by

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the presence of a complex mixture of mitogenic and connective tissue disorders, such as scleroderma or
immuno­ modulatory cytokines, accounting for the systemic lupus erythematosus might be at high risk of
chronic and progressive nature of injury. developing complications,60,62–64 particularly with pelvic
Animal data have suggested that radiation-induced radiation.62 The decision of whether to offer radiotherapy,
apoptosis could be responsible for many of the late therefore, needs to consider these variables and factors
effects observed in humans, but a causative association on an individual, patient-specific basis.
in humans has been difficult to establish. Ultimately, the In order to assess how these variables affect the
pathophysiology of radiation late effects is likely therapeutic ratio for patients who might be particularly
multifactorial, tissue-dependent or organ-dependent, sensitive to radiotherapy, best practices to mitigate the
and needs to be further investigated and understood so risk of toxic effects, and factors for clinicians to consider
that approaches to mitigate the risk of toxic effects can be when evaluating a patient for radiotherapy are
developed. summarised in panel 1.

Optimisation of selection of patients for Management of toxic effects without treatment

radiotherapy cessation
As for any other cancer treatment option, the decision to Radiotherapy can cause clinically significant acute side-
offer and recommend radiotherapy can only be made effects, which can lead to treatment delay or cessation. In
after a thorough patient evaluation and discussion of the this section, we review specific situations for which
potential benefits and risks associated with therapy. In radiotherapy cannot or should not be interrupted, discuss
this section, we will review specific situations in which the importance of symptom management and supportive
the use of radiotherapy might be contraindicated (such care to minimise treatment breaks, and outline best
as with specific genetic syndromes and medical clinical practices to either avoid or minimise treatment
conditions) and propose best practices for selection of interruptions due to radiotherapy-induced toxic effects.
patients to receive radiotherapy. From initiation to completion of treatment, a course of
Certain genetic disorders can predispose patients to an radiotherapy can be challenging from a medico­
excessive risk of complications from radiotherapy. social perspective. Patients often require between
Although rare, conditions such as ataxia–telangiectasia, five and ten radiation treatments per week, for up to
Fanconi anaemia, and Nijmegen breakage syndrome 7 weeks. During this time, due to the multidisciplinary
share a common pathophysiology of defective DNA nature of cancer care, the incorporation of other
damage repair and can cause hypersensitivity to treatments (such as surgery or chemotherapy) add to the
radiotherapy of a factor of two to four times that of the burden of treatment—not only medical (ie, due to
general population.59 Collagen vascular diseases are a toxicity), but also financial, logistical, and social.
heterogeneous classification of systemic autoimmune Treatment delays and interruptions, therefore, are not
connective tissue disorders and include rheumatoid uncommon. Even in well resourced environments such
arthritis, systemic lupus erythematosus, and scleroderma. as academic, comprehensive cancer centres,72 or as part
They share a similar pathophysiology marked by vascular of randomised clinical trials,73 treatment can be
inflammation, obliteration, and fibrosis, with systemic suboptimal, with as many as 20–25% of all patients
and visceral effects. Therefore, the risk of radiotherapy to missing radiotherapy sessions and deviating from the
augment adverse events in these tissues has led to originally intended time course. These delays highlight
consideration of a concomitant diagnosis of collagen the scope and severity of the challenges that patients
vascular disease to potentially be a relative face when undergoing cancer therapy. Treatment
contraindication to radiotherapy. The evidence and interruptions are deleterious. Even when missed
literature supporting such a practice, however, is variable. treatments are ultimately rescheduled and accounted for,
Reviews of studies have documented higher occurrences midcourse interruptions and delays in radiotherapy can
of acute and late toxic effects in patients with systemic allow for accelerated tumour cell repopulation, which
autoimmune connective tissue disorders,60 whereas may result in poor disease outcomes such as
others have reported negligible (<2%) rates of grade 4 or 5 compromised locoregional control and reduced
toxic effects,61 and no difference between patients with recurrence-free and overall survival.72 Patients with
collagen vascular diseases and controls.62 These data are specific cancers, such as head and neck tumours74 or
challenging to interpret and apply to clinical practice cervical cancer,75 for whom treatment prolongation has
because of variables such as the heterogeneity in collagen been associated with a decrease in local control and
vascular diseases subtype and severity, details of overall survival of 1% per day of missed treatment, could
radiotherapy (dose, anatomic site, and volume of be at particularly high risk of worse outcomes from
radiation), and concurrent medical therapies treatment interruptions.
(medications for collagen vascular diseases and Proactive and reactive strategies to avoid or make up
chemotherapy), all of which can affect the risk of toxic for treatment interruptions are of crucial importance for
effects. For example, patients with specific autoimmune these patients. Such strategies are multidisciplinary in

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Panel 1: Factors to consider when evaluating a patient for radiotherapy

Are viable alternatives to radiotherapy available? clinical studies.68 However, changes in radiation dose and
Can other treatment options (eg, surgery) provide similar fractionation could be of benefit. If a specific organ at risk is of
disease outcomes as those attainable with radiotherapy? particular concern, baseline organ function should be assessed
Examples include surgical resection or active surveillance for before radiotherapy and integrated into the customisation of
patients with low-risk prostate cancer, or surgery alone for the radiotherapy plan. For example, if a patient with chronic
appropriately selected patients with low-risk breast cancer, who graft-versus-host disease has lung disease, a ventilation–
might have such a small absolute benefit in the reduction of perfusion scan can be used to determine the areas of functional
local recurrence with the addition of radiotherapy that lung to avoid irradiating; however, ventilation–perfusion scans
avoidance of radiotherapy might be a reasonable option. are not reconstructed in 3D space, so incorporation of its
If so, and if an alternative treatment would eliminate the need information into radiotherapy treatment planning is difficult.
for radiotherapy, the alternative should be discussed and Similarly, a split renal function scan can help ascertain whether
considered. When several potential treatment options are one kidney functions better than the other and should thus be
under consideration, evaluation in a multidisciplinary clinic selectively avoided. Finally, new functional data can emerge
setting (whereby an expert in each therapeutic approach sees and become important as in the case of the effective dose to
and assesses the patient before multidisciplinary discussion) is immune cells, which is now becoming an important predictor
recommended. Patients should be actively involved in the of injuries to the immune system by radiotherapy. Thus,
subsequent conversations and in the decision-making process assessing organ function before treatment can help to identify
with their care providers (shared decision making). Patients areas to be preferentially spared during irradiation to preserve
engaged in shared decisions more often report satisfaction with organ function after treatment.
their physicians’ communication and better quality of care.65 During treatment
If radiotherapy is necessary, what can be done before or Important factors to consider are dose of radiation (dose
during treatment to minimise its toxicity? per fraction and total dose) and the healthy tissue and organs at
Before treatment risk of toxic effects. Although stereotactic body radiotherapy or
Priority should be given to reducing the severity of comorbid hypofractionated radiotherapy of some sites (eg, breast) have
conditions. Such prioritisation means that the treating been shown to be effective and well tolerated, caution is
radiation oncologist needs to communicate and work closely in needed when irradiating large volumes of sensitive healthy
collaboration with the physicians who treat, for example, tissues (eg, the brachial plexus and mucosal structures in the
a patient’s concomitant diagnosis of a collagen vascular disease. head and neck area), especially in combination with systemic
Although the severity of collagen vascular diseases at the time therapies, given that hypofractionation can lead to increased
of radiotherapy might influence a patient’s risk of radiotherapy- toxicity in those cases.69 In patients who are at particularly high
induced toxic effects,66,67 this risk is counterbalanced by the risk (eg, due to collagen vascular disease subtype and
medications used to treat these conditions, which often act as radiotherapy site) or who have early and unusual signs of acute
radiosensitisers. For patients who would usually be toxic effects, careful monitoring and symptom management is
recommended to receive chemotherapy in conjunction with essential. Consistent and close monitoring and early
radiotherapy, consultation and collaboration with a medical implementation of aggressive symptom management can
oncologist is paramount in the determination of the necessity improve tolerance, reduce risk of toxic effects, and improve
for and role of chemotherapy for each specific patient. outcomes.70,71 In particularly severe cases, modifications in the
Additionally, modifications in the chemotherapy regimen or planned radiotherapy course, such as planned treatment
dosing can be considered on the basis of cancer type, treatment breaks, reduction of daily radiation fraction size, volume,
location, and toxic effect risk. The use of pharmacological or total dose might need to be considered on a case-by-case
agents for radioprotection, while appealing in concept, has basis and discussed and reviewed with the patient at time of
mostly yielded no substantial improvements in outcome from consultation and during treatment.

nature, with approaches focusing on both medical and Technological advances in radiotherapy delivery
social barriers to compliance. Medical interventions techniques and technologies can also play a part in
range from better preventive care, such as symptom and mitigating treatment interruptions. Conformal radio­
pain management, to technological advances in therapy, such as intensity-modulated radiotherapy,
radiotherapy delivery. Consistent and careful evaluations which better spares healthy tissues and organs, has
for symptom management can reduce treatment been shown to substantially decrease toxicity and
deviations, decrease rates of hospitalisation, and improve patient quality of life.2 Advances in radiation
improve outcomes.70 Early implementation of symptom- dosing and delivery, such as with hypofractionation and
focused care in conjunction with standard-of-care stereotactic body radiotherapy, have helped to minimise
therapy not only improves quality of life but also survival.71 the logistical, social, and financial burden to a patient,

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for whom a course of radiotherapy becomes feasible in a current efforts for monitoring late effects and propose
shorter number of treatments over a span of 1–3 weeks. best practices for practising oncologists and primary care
Equally important are ancillary services, which range providers to monitor and ameliorate radiotherapy-
from patient navigation,76 assistance with induced late effects.
transportation,77 and management of comorbid Many late toxic effects differ from acute toxic effects in
conditions such as mood disorders.78 Use of a signs, symptoms, and healthy tissue affected. Therefore,
multifaceted and multidisciplinary, holistic, patient- to best monitor for, and manage, late toxic effects,
centred approach to address all possible barriers to patients should be followed up regularly and consistently
treatment tolerance and compliance will allow optimal after treatment completion. The Institute of Medicine, in
management of radiation-induced toxic effects and its report From Cancer Patient to Cancer Survivor: Lost in
ensure the best possible outcomes (panel 2). Transition79 specifies four key aspects of survivorship
care: first, prevention of recurrent and new cancers and
Monitoring of late toxic effects in long-term of other late effects; second, surveillance for cancer
radiotherapy survivors spread, recurrence, second cancers, and medical and
In some patients, radiotherapy can cause late morbidity psychosocial late effects; third, intervention for
that is sometimes not observed for months, years, or consequences of cancer and its treatment (eg, medical
even decades after completion of radiotherapy, and which problems, symptoms, psychological distress of cancer
greatly impair quality of life for long-term cancer survivors and their caregivers, and concerns related to
survivors. In this section, we review and summarise employment, insurance, and disability); and fourth,

Panel 2: Measures to minimise the burden of radiotherapy toxic effects

Before treatment and continuation or modification of symptom management
• Assessment of potential social or logistical challenges: as clinically indicated throughout the course of treatment.
clinicians should facilitate a meeting between the patient Patient needs should be assessed on the basis of physical,
and a navigator or social worker who can assess needs such social, logistical, or financial burdens, with corresponding
as transportation, lodging, and leave of absence from work. referrals to appropriate services (social work and counselling).
Assistance can be provided by means of provision of reliable • Treatment adaptation: disease response and patient
daily transportation, convenient long-term lodging, and tolerance and compliance should be monitored during the
completion of required paperwork for medical leave. course of treatment. Interventions such as adaptation of the
• Management of comorbidities: clinicians should radiotherapy plan on the basis of anatomic change from
communicate with a patient’s other providers to ensure that disease response, or modification of the dose, scheduling,
all potential comorbid conditions are being optimally and fractionation of radiotherapy as clinically indicated
managed throughout treatment so as to not adversely based on patient tolerance can be implemented as needed.
affect the patient. • Communication: regular communication between the
• Ancillary services: other services should be consulted treating radiation oncologist and medical oncologist is
depending on the specific needs of a patient or the planned recommended throughout the treatment course to
treatment. Examples include smoking cessation facilitate decisions on the radiotherapy or chemotherapy
(for patients receiving treatment for lung cancer or head regimen on the basis of patient-specific factors, such as
and neck cancer), alcohol cessation (head and neck cancer), tolerance and sensitivity to toxicity. Towards the latter
nutritional support or feeding tube placement (for patients stages of a course of chemoradiation, radiation oncologists
entering treatment in a malnourished state), and fertility and medical oncologists should discuss the appropriateness
services (for patients who desire to have children and will of continuing radiotherapy even when further systemic
receive fertility-affecting treatments, such as pelvic therapy cannot be safely given.
radiotherapy or chemotherapy).
After treatment
• Symptom management and optimisation: symptom
• Regular inspection visits: providers should see patients at a
management should be assessed and implemented before
regular interval following completion of radiotherapy to
treatment initiation, with an optimised regimen in place to
assess late toxic effects and recovery progress. Interventions
promote patient comfort and compliance before, during,
and medications should be adjusted as clinically indicated
and after treatment.
on the basis of persistence or resolution of symptoms
During treatment secondary to disease or treatment.
• Regular (at least weekly) visits with the treating radiation • Survivorship and support groups: patients and their
oncology team: regular assessment by the treating radiation caregivers should be offered and connected to cancer
oncologist (or an advanced practice provider, such as a survivorship and support groups. These groups provide
physician’s assistant or a nurse practitioner) to assess resources and support to patients and families at various
symptoms (as related to disease or treatment) points during a patient’s treatment for cancer.

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coordination between specialists and primary care the release of Common Terminology Criteria for Adverse
providers to ensure that all of the survivor’s health needs Events version 2.0 in 1999.7 However, patient-reported
are met. outcomes are also important and should not be neglected,
The report recommended that a survivorship care plan, because providers’ and patients’ perspectives on toxicity
comprising a summary of the patient’s cancer diagnosis, might differ82,83 and because patient-reported outcomes
treatment summary, and follow-up care plan, be provide valuable direct insight on the long-term negative
developed for each patient to communicate and effect that treatment-related toxic effects has on patients.84
coordinate survivorship care. The barriers to such an To assist with this effort, The National Cancer Institute
undertaking are multiple, including the additional time Clinical Trials Planning Meeting was convened in 2011 to
required by the primary oncologic provider, inexperience help establish a standard set of patient-reported outcomes
in survivorship care, and little coordination in sharing domains to be routinely collected in clinical trials.85,86
survivorship with other involved care providers. Although These recommendations are customisable, for example
a majority of radiation oncologists discuss plans for for patients with ovarian,87 head and neck,88 and prostate
future care with their patients, few provide a written cancer.89
survivorship care plan to their patients or their primary
care physicians,80 despite evidence that patients are more Novel technologies for toxicity mitigation
likely to receive recommended care when follow-up is Various radiotherapy techniques and technologies could
shared by their oncologists and primary care physician.81 be chosen to deliver the intended dose to the target and
Radiation oncologists should therefore maintain minimise the dose to the organs at risk, with particular
communication with a patient’s primary care physician consideration given to functional changes rather than
from the time of diagnosis and throughout treatment relying solely on anatomical volume. The main risk
and post-treatment care, sharing follow-up and prevention strategy for organs at risk is to minimise the
survivorship. radiation dose and exposed volume (integral dose).
In follow-up care, attention to specific symptoms Tumour location is also a major determinant of toxic
(based on cancer type and treatment) by the provider and effect risk. Clinics should have available various
via patient-reported outcomes is recommended. radiotherapy technologies and equipment to best address
Two common toxic effects reporting scales used by patient-specific scenarios. The need for craniospinal
For more on Common providers are the Radiation Therapy Oncology Group6 irradiation in paediatric patients is perhaps the clearest
Terminology Criteria for and the Common Terminology Criteria for Adverse example of such challenges faced clinically. The
Adverse Events see https://ctep.
cancer.gov/protocol
Events. Radiation toxicity reporting transitioned from the craniospinal axis is a very large target volume, which
development/electronic_ Radiation Therapy Oncology Group toxicity scale to the should be treated with relative homogeneity in children
applications/ctc.htm Common Terminology Criteria for Adverse Events with with medulloblastoma and other brain tumours. The
target is geometrically close to many organs at risk,
including the heart, lungs, breasts, bowel, pancreas, and
Dose
2181·3 cGy
A B ovaries. In addition, most patients who require
2000·0 cGy Brain craniospinal irradiation are young; as such, their tissues
are particularly vulnerable to radiotherapy damage, and
1500·0 cGy young patients might have many years of life in which to
face late toxic effects. When 3D conformal radiotherapy
1000·0 cGy is used to deliver craniospinal irradiation, the visceral
organs at risk are exposed to unintentional radiotherapy;
proton therapy allows elimination of this dose and
500·0 cGy
Thorax reduces the expected resultant toxic effects (figure 3).90,91
In the concurrent delivery of radiotherapy and
Spine chemotherapy, which is the standard-of-care curative
treatment for various types of cancer, the selection of the
radiotherapy technique can potentially affect clinical
Abdomen outcomes. While results of completed phase 3
randomised trials comparing proton versus photon
therapy for intensity-modulated proton therapy are
Pelvis
awaited (eg, NCT01993810), proton therapy could prove
to be most useful in situations where dose–volume
metrics for organs at risk are exceeded in intensity-
Figure 3: Craniospinal irradiation plans for a prepubertal paediatric patient modulated radiotherapy plans. This benefit is suggested
Patient with a paediatric brain tumour, for whom radiotherapy to the brain and spinal column was required at a
dose of 2000 cGy, with (A) a typical photon-based radiotherapy plan compared to a (B) proton plan. The patient
by a retrospective, non-randomised comparative
received proton therapy, with no dose to critical healthy tissues and organs in the thorax, abdomen, and pelvis effectiveness study, which showed that the use of proton
(compared with 1500 cGy incidental dose that would have been delivered with photon-based radiotherapy). therapy concurrently with chemotherapy was linked to

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statistically significant fewer acute adverse events, with radiotherapy at an unprecedented rate, typically
similar disease-free and overall survival as compared exceeding 40 Gy/s. Unlike conventional radiotherapy,
with concurrent photon therapy.92 Additionally, a which administers radiation over several minutes
randomised phase 2b trial for locally advanced (0·01–0·03 Gy/s), FLASH radio­ therapy delivers the
oesophageal cancer showed a reduced risk and severity of same dose within a fraction of a second. This rapid
toxic effects with proton therapy compared with intensity- delivery of the same total dose has been shown in
modulated radiotherapy, while maintaining similar preclinical models to improve the therapeutic index of
progression-free survival.93 The use of image-guided radiotherapy by decreasing healthy tissue damage while
radiotherapy with onboard imaging (either CT or MRI) maintaining tumour response compared with standard
improves accuracy by reducing day-to-day variation and radiotherapy.95,96 Several preclinical studies have shown
allowing for reduction in planning target volume significant sparing of healthy tissues with FLASH
margins. The use of daily image-guided radiotherapy to radiotherapy, particularly in organs at risk such as the
make image-based adaptations on the radiotherapy plan brain, heart, head and neck, skin, and intestine, leading
is the basis of adaptive radiotherapy (adapting the to reduced acute and late toxic effects.97–100 The first-in-
radiotherapy plan throughout the course of treatment to human randomised trial of FLASH proton radiotherapy,
ensure maximum conformality of radiotherapy dose to focusing on patients with non-spine bone metastases,
tumour while minimising dose to healthy organs), which established the feasibility of this technique and showed
has been prospectively shown to clinically reduce that treatment efficacy and safety profiles were similar
radiotherapy toxic effects94 by reducing unintended to those seen with conventional dose rate photon
irradiation of healthy tissues. For mobile tumours, such radiotherapy.101 Future insights into the treatment
as those close to the diaphragm, tumour motion effectiveness and toxicity profiles of FLASH radiotherapy
mitigation is another technological challenge. Examples are expected from several clinical trials, such as the
of tumours often benefiting from motion management ongoing phase 2 trial with patients with localised
techniques include lower lobe lung and liver cancers. cutaneous squamous cell carcinoma or basal cell
The entire path of the tumour can be treated during carcinoma at the Centre Hospitalier Universitaire
ventilatory motion (defined using four-dimensional CT); Vaudois (Lausanne, Switzerland; NCT05724875). These
alternatively, tumour motion (eg, by abdominal findings provide support for further exploration of
compression or deep inspiration breath–hold) can be FLASH radiotherapy in the treatment of patients with
decreased to reduce the amount of healthy tissue in the cancer. However, challenges remain, including the
treatment volume. Gating mechanisms use either optimisation of treatment planning and delivery
surface anatomy (eg, camera-based systems) or internal systems to ensure safe and effective implemen­tation in
anatomy (eg, implanted fiducial markers, transponders, clinical settings. Concurrently, the pluridirectional
or MRI-based onboard imaging) to turn the beam off and high-energy agile scanning electronic radiotherapy
on when the visualised tumour (or surrogate marker) is (PHASER)102 has emerged as another potential
within the treatment volume. For patients receiving innovative approach to radiotherapy that can produce
radiotherapy for prostate cancer, metallic fiducials can be very high-energy electrons (100–200 MeV). Unlike
placed in the prostate gland to aid in visualisation for conventional linear accelerators, PHASER encompasses
daily image guidance, and a gel spacer can be placed several fundamental innovations aimed at achieving
between the anterior rectal wall and the prostate gland. nearly instantaneous delivery of highly precise image-
Fiducials allow more certainty in daily set up and a guided radiotherapy. This approach aims to provide
reduction in planning target volume margins, whereas superior dose conformity, reduce the effects of tumour
the gel space increases the distance between the radiated motion, and potentially leverage an enhanced FLASH
target (prostate) and a nearby healthy organ (rectal), radiobiological therapeutic index.
thereby reducing the risk of off-site toxic effects. The combination of stereotactic body radiotherapy and
immunotherapy has been hypothesised to improve
The future of radiotherapy survival by means of what is called the abscopal effect
In recent years, the field of radiotherapy has witnessed (whereby irradiation of a tumour site induces an
substantial technological innovation, leading to a new increased immune response in unirradiated tumours
era of precision and efficacy in cancer treatment. In this elsewhere in the body). However, the abscopal effect is
section, we aim to explore cutting-edge advancements rarely observed in clinical practice, and robust evidence
and innovative approaches to improving conformity and that the combination of radiotherapy and immuno­
accuracy, minimising side-effects, and increasing cost therapy increases the probability of this effect is yet to
effectiveness. observed. Multiple studies have yielded negative
The advent of ultra-high dose rate, also known as results,103–105 which should temper enthusiasm for this
FLASH radiotherapy, was an important advance in approach. Nevertheless, stereotactic body radiotherapy
radiotherapy delivery. FLASH radiotherapy is can still provide durable control of oligometastatic or
characterised by the administration of doses of oligoprogressive deposits in patients receiving systemic

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therapy and might delay progression and enhance artificial intelligence (AI) and machine learning
survival. Ongoing clinical investigations are needed to algorithms can make adaptive radiotherapy more
clarify the potential benefits and limitations of combining efficient, enabling faster and more accurate adjustments
radiotherapy with systemic treatments. based on patient data.
Temporal and spatial fractionation in radiotherapy are Modern radiotherapy approaches have enhanced
innovative strategies designed to improve the therapeutic precision and personalisation, but adaptation to tumour
ratio by optimising the distribution of radiation doses biology remains a challenge. Biomarkers to predict
across time and space. In temporal fractionation, the tumour and healthy tissue radiosensitivity (eg, gene
timing and schedule of radiation doses are adjusted to signatures, protein concentrations, and radiogenomics)
exploit the differential repair capacities of healthy are needed to enable more personalised decision making,
and tumour tissues, potentially enabling higher doses dosing, and treatment planning. Although proteins
to tumours while sparing healthy tissue. Spatially remain the most common cancer biomarkers, other
fractionated radiotherapy delivers non-uniform radiation molecules, such as circulating cell-free tumour DNA,
doses to the tumour by creating alternating high-dose have emerged as promising alternatives for the
and low-dose regions within the target area, which is identification of cancer biomarkers. Liquid biopsy
especially beneficial for heterogeneous tumour micro- involves analysing cell-free DNA and other cellular
environments with severe hypoxic areas requiring components released by dying or damaged cells into the
higher, ablative radiation doses.106 An example is 3D bloodstream, which carry the genetic and epigenetic
lattice radiotherapy, which delivers a spatially fractionated features of the original tumour, including somatic
radiotherapy in 3D, essentially creating a network of mutations and DNA methylation.114,115 To date, analysis of
high-dose vertices within the tumour while minimising cell-free DNA has not been routinely used in radiotherapy
radiation exposure to surrounding healthy tissue.107 One dosing or scheduling. In virus-associated cancers such as
retrospective study showed that stereotactic body Epstein–Barr virus-related nasopharyngeal and human
radiotherapy for partial tumour irradiation, targeting papillomavirus-related oro­pha­ryn­geal cancers,
hypoxic segments of unresectable bulky tumours, measuring circulating tumour-derived DNA or viral load
effectively induced local bystander effects without during treatment has shown promise in guiding therapy
causing acute or late toxic effects of any grade.108 Working intensification or deintensi­fication.116,117 Although promis­
groups in NRG Oncology and in the American ing, validation and further research are required before
Association of Physicists in Medicine recommended such approaches become routine standard of care in
improving spatially fractionated radio­therapy in cancer radiotherapy.
treatment by developing clinical guidelines, enhancing The integration of AI in radiotherapy offers great
treatment planning systems, standardising reporting potential to enhance precision and personalisation in
templates, and advancing radiobiological models through cancer treatment. AI-driven tools are being used to
preclinical studies and clinical trials.109 improve tumour contouring, dose optimisation, and
Adaptive radiotherapy is an emerging approach in treatment planning, reducing variability and increasing
cancer treatment and is becoming more widely available accuracy in radiation delivery.118–120 By analysing large
in clinical practice. It uses real-time data and advanced datasets from previous treatments, machine learning
imaging to adjust radiotherapy plans during the course algorithms can predict optimal radiation doses and
of therapy. Adaptive radiotherapy can be applied to anticipate toxic effects, resulting in more efficient and
manage patient-specific treatment variations, such as effective therapies. Machine learning can also automate
systematic changes in weight, tumour and organ complex processes and enable real-time adjustments
geometry, biological responses, and stochastic factors during treatment, leading to improved patient outcomes.
such as organ deformation and movements due to Moreover, AI has substantially shortened treatment
respiration and peristalsis. Adaptive radiotherapy has planning time, using knowledge-based planning and
been reported to offer a dosimetric benefit of up to a deep learning to produce plans equivalent to those
10 Gy reduction in the mean parotid gland dose compared produced manually by medical dosimetrists, physicists,
with non-adaptive radiotherapy, and retrospective studies and radiation oncologists.121 Its role in prediction and
suggest potential clinical benefits, including improved prognosis, particularly through radiogenomics,
quality of life and local disease control.110–112 However, in a continues to grow and advance. Despite ongoing legal,
phase 3 randomised clinical trial, adaptive radiotherapy ethical, and regulatory challenges, such as data
did not improve salivary flow, patient-reported outcome ownership, informed consent, and reproducibility, AI
scores, or rates of toxic effects compared with standard continues to have a growing effect and shows potential
intensity-modulated radiotherapy.113 Several ongoing for future advancements in radiation oncology.
clinical trials (eg, NCT02031250, NCT03416153, By capitalising on such groundbreaking advancements,
NCT03224000, and NCT01504815) are investigating clinicians can introduce a new era of personalised and
functional subvolume boosting and adjustments to dose precise radiotherapy, offering improved outcomes and
schemes based on functional imaging. The integration of quality of life for patients with cancer worldwide.

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and AL prepared the figures. All authors contributed to the completion 9 Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue
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Cancer Society, the Thomas B and Jeannette E Laws McCabe Fund, and 11 Birgisson H, Påhlman L, Gunnarsson U, Glimelius B. Late adverse
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support to attend the American Society of Clinical Oncology and radiotherapy and limb-salvage surgery for lower extremity soft-
American Association for Cancer Research meetings; is Editor-in-Chief of tissue sarcomas. A comparison of high-dose and low-dose
JACC CardioOncology; and is part of the Board of Trustees of the radiotherapy. J Bone Joint Surg Am 2005; 87: 315–19.
American College of Cardiology. CK reports research funding from 16 Deng J, Ridner SH, Dietrich MS, et al. Prevalence of secondary
the US National Institutes of Health, The Mark Foundation for Cancer lymphedema in patients with head and neck cancer.
Research, and Ion Beam Applications group through a sponsored J Pain Symptom Manage 2012; 43: 244–52.
research agreement to his institution; honoraria from MD Anderson 17 Shaitelman SF, Chiang YJ, Griffin KD, et al. Radiation therapy
Cancer Center, Dartmouth University (Hanover, NH, USA), and Duke targets and the risk of breast cancer-related lymphedema:
University (Durham, NC, USA); support from the American Association a systematic review and network meta-analysis.
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Centered Outcomes Research Institute, honoraria from Galera
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Janssen Pharmaceuticals for participation in their steering committee. All
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other authors declare no competing interests.
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Acknowledgments tinnitus after head-and-neck intensity-modulated radiation therapy.
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