Radiotherapy principles and side effects

• Radiotherapy treats cancer by aiming high-energy ionizing radiation at a tumour. That radiation damages the DNA inside cancer cells so they stop dividing or die, and the lethal dose comes from enough fractions to allow as much normal-tissue recovery as possible. ^[1]
• It is a local treatment: it controls disease in the region treated rather than treating the whole body, so it is usually combined with surgery, systemic anti-cancer therapy, or both to treat the whole disease.
• The intent of treatment is decided before the first fraction is planned: curative, neoadjuvant, adjuvant or palliative. That decision changes the dose, volume and safety budget.
• Fractionation (how the total dose is split over time) is chosen to exploit the different repair and proliferation of tumour and normal tissue; modifying the number of fractions is now evidence-based for several common cancers. ^[5]
• Side effects are predictable and dose-dependent: acute effects in tissues that turn over fast (skin, mucosa, gut, bone marrow) and late effects in organs that repair slowly (lung, heart, spinal cord, kidney, peripheral nerve).
• Expect fatigue, skin erythema and, depending on the site, mucositis, diarrhoea, dysuria or a dry mouth. Late problems can appear months to years after treatment and include fibrosis, necrosis, xerostomia, pneumonitis, myocardial fibrosis and rectal bleeding. ^[1]

By the end of this page you should be able to:

1. Explain how ionizing radiation kills cancer cells and why it is usually a regional rather than a systemic treatment.
2. State the four principal intents of radiotherapy and give a clinical example of each.
3. Describe the main indications for radiotherapy across common cancers, including organ-preserving and palliative roles.
4. Define fractionation and compare conventional, hypofractionated and ultra-hypofractionated schedules, with evidence from a guideline you can name.
5. List the typical acute and late effects of radiotherapy, linking each to the tissue involved, and name the red flags that need urgent attention.
6. Interpret the idea of tolerated dose (TD5/5, TD50/5) and explain why side-effect risk rises with dose, volume and concurrent treatment.
7. Outline the practical pathway from consent and simulation to delivery and follow-up.
8. Compare the burden of radiotherapy with surgery and explain when the two work best together.

Radiotherapy is one of the three pillars of cancer treatment (surgery, systemic anti-cancer therapy and radiotherapy). It uses high-energy ionizing radiation to damage cancer cell DNA, stopping division and ultimately causing cell death. It is administered externally as external beam radiotherapy, or from very close to the tumour as brachytherapy, where sealed sources are placed in a cavity, lumen or tissue. ^[1] Because radiation is a physical agent delivered to a defined volume, it is a local treatment: it eliminates or shrinks disease in the region treated rather than acting throughout the body. That is why it is planned together with surgery or systemic therapy in a multidisciplinary team.

The discipline matters because a course of radiotherapy looks simple from the outside (lie on a table, press a button) but the real decisions are made beforehand. They are the target volume, the total dose, the fraction size and number, the tolerance of the organs around the tumour, and the patient's other treatments. Modern radiotherapy (image-guided, intensity-modulated, volumetric modulated arc therapy and stereotactic body radiation therapy) exists to widen the gap between tumour kill and normal-tissue injury by improving targeting. ^[1]

Intent is not a label attached afterwards. It is the working hypothesis that shapes the dose, volume and tolerance budget for the whole course.

• Curative (radical) radiotherapy aims to eradicate the tumour with no residual disease. It is used when disease is localised and the patient can be treated to a radical dose with acceptable risk.
• Neoadjuvant radiotherapy is given before an operation to shrink the tumour and make complete resection more likely, or to eliminate microscopic disease at the margin.
• Adjuvant radiotherapy is given after surgery to destroy residual disease and reduce recurrence risk.
• Palliative radiotherapy is given to relieve or prevent symptoms (bleeding, pain, obstruction, compression) or to prolong useful survival when cure is not possible.

A useful distinction for students is that curative treatment is usually limited by the tolerance of the surrounding normal tissue, whereas palliative treatment is limited by the symptom being treated. Palliative radiotherapy can be delivered safely to bone, soft tissue or viscera for bleeding, pain and obstruction, such as bladder-directed radiotherapy for symptomatic or high-burden metastatic bladder disease. ^[6]

Radiotherapy spans a wide range of indications, from radical treatment to a single fraction for palliation. Common uses include the following.

• Curative treatment of localised cancer. Non-small cell lung cancer treated with stereotactic body radiation therapy achieves roughly 90% one-year local control in early-stage resectable disease. ^[1] Prostate and bladder cancers are increasingly treated with radiotherapy alone or as part of trimodal therapy, and anal and laryngeal cancers are treated with organ-preserving radiotherapy and concurrent systemic therapy.
• Adjunct to surgery. Breast cancer is routinely treated with radiotherapy after lumpectomy or mastectomy to improve local control. Head and neck cancers at high risk benefit from postoperative radiotherapy, often combined with chemotherapy.
• Neoadjuvant and adjuvant chemoradiation. Preoperative radiotherapy or chemoradiotherapy improves regression and reduces recurrence in rectal and oesophageal cancers when tumours are locally advanced.
• Palliation. Radiotherapy is used for bone pain, haemorrhage, obstructed airways, and obstructed hollow viscera or bladder, and to prolong useful survival. ^[6]
• Re-irradiation or salvage. Selected sites can be re-irradiated when recurrence appears after a prior course; decisions here depend on cumulative normal-tissue dose and are taken case by case.

Whenever tumour volume or organ tolerance is the limiting factor, modern techniques (image-guided, intensity-modulated and volumetric modulated arc radiotherapy) are chosen to widen the therapeutic index. ^[1]

Radiotherapy is inappropriate or must be deferred in certain circumstances.

• Pregnancy is a contraindication to exposing a fetus to scatter, particularly in the first and second trimesters; treatment is deferred or alternative sites are shielded by a specialist team.
• Severe concurrent uncontrolled infection or poor healing at the treatment site can worsen acute mucosal or skin reactions; treatment is paused while the problem is corrected.
• Prior radiotherapy to the same region limits what can safely be delivered again.
• Impaired organ reserve (renal failure treated with drugs excreted by the kidney, severe cardiac or pulmonary disease) counts against regimens whose side effects are dose-limited by that organ.
• Poor performance status or short expected survival, compared with the time needed to complete a radical course, favours a short palliative schedule or no treatment.

The radiation oncologist must know both what is being treated and what must be spared. For any site the clinician identifies the gross tumour, the clinical margin (tissue likely to harbour microscopic disease), the organs at risk (spinal cord, brain, lung, heart, gut, bladder, rectum, skin, bone, peripheral nerve), and the vascular and lymphatic drainage. Common frailties are modest: the spatial geometry of a target relative to the cord or bowel, rather than any single anatomical landmark. Treatment margins are set from the imaging, tumour biology and the institutional protocol.

Radiotherapy may be delivered in two broad ways. ^[1]

• External beam radiotherapy directs radiation at the tumour from outside the body. Conventional linear accelerators deliver photon or electron beams; advanced systems include intensity-modulated radiotherapy, volumetric modulated arc therapy, image-guided radiotherapy, stereotactic radiotherapy and proton therapy.
• Brachytherapy places sealed radioactive sources very close to or inside the tumour or tumour bed, as in intracavitary or interstitial implants.

The choice is made on tumour site, stage, anatomy and what the service available allows.

Before the first fraction the pathway is standardised.

• Consent names the expected acute and late effects for the specific site and dose. Patients should be told that tiredness, skin redness, mouth dryness, changes in taste, swallowing difficulty, bowel or bladder upset, and mild blood-count suppression are common and usually settle over weeks to months; they should also be told that late changes are possible.
• Simulation and immobilisation. The patient is positioned and reproduction of that position is achieved with masks, moulds and supports. Imaging (often a planning CT, sometimes MRI) in the treatment position defines the target and organs at risk.
• Planning. A radiation treatment plan is produced, reviewed and verified. Consent, plan review and quality-assurance checks are repeated; the patient is given a treatment schedule and appointments to attend daily for several weeks. ^[1]
• Site-specific protective advice is given (for example oral and dental hygiene advice before head and neck or oral cavity treatment, skin-moisture and sun avoidance before skin, chest-wall or neck treatment).

A standard external beam course follows a predictable sequence.

1. Clinical consultation and decision. Stage, fitness and patient goals are weighed by a multidisciplinary team; intent, dose and fractionation are chosen. ^[1]
2. Simulation and planning. The patient is imaged in the treatment position and a plan is produced that covers the tumour to the required dose while keeping organs at risk below tolerance.
3. Approval and verification. Plan and dosimetry are reviewed, and the first-fraction position is verified on the treatment unit before treatment starts.
4. Delivery. Each fraction takes a small part of the total dose. Treatment is usually daily, Monday to Friday, with breaks at weekends, lasting from a single fraction (palliative) to several weeks.
5. On-treatment assessment. Acute reactions are graded and managed (skin care, analgesia, anti-emetics, hydration, anti-diarrhoeal or urological measures) and the plan is adjusted if necessary.
6. End of treatment and records. The dose actually delivered is recorded, with organs at risk, so any future re-irradiation can be assessed.

The pathway below is a teaching outline only; local protocols and a multidisciplinary team guide each patient's plan.

Fractionation is the division of the total radiation dose into multiple smaller doses (fractions), usually one per day. It exists because tumours and normal tissues recover from radiation at different rates, and planning a course exploits that difference. Three everyday words are used.

• Conventional fractionation uses one modest fraction per day, five days a week, to a total dose tailored to the tumour and site.
• Hypofractionation uses larger fractions and fewer of them. An ASTRO clinical practice guideline on hypofractionated external beam radiotherapy for localized prostate cancer recommends moderate hypofractionation over conventional fractionation across risk groups, based on high-quality randomized data showing equivalent oncologic outcomes, toxicity and quality of life with a shorter treatment duration. ^[5]
• Ultra-hypofractionation gives a still larger dose in very few fractions; the same ASTRO guideline supports this as standard in low- and intermediate-risk prostate cancer and as an option in selected high-risk cases. ^[5]

Hypofractionation needs contemporary image-guided conformal techniques because the safety margin is smaller when each fraction is bigger. ^[5]

A hypofractionated alternative and a conventional schedule can be equally effective locally, but the normal tissue response depends on which tissue is irradiated and how much is treated. Randomized trials in skin cancer compared a range of dose-fractionation regimens without showing meaningful differences in local recurrence in basal cell carcinoma across schedules (29.61 Gy in 3 fractions, 35.91 Gy in 7 fractions, 38.70 Gy in 10 fractions) or between 48 Gy in 12 fractions and 60 Gy in 20 fractions. ^[2] Long overall schedules of smaller fractions (48 Gy in 12 fractions versus 60 Gy in 20 fractions) gave slightly more local control for squamous cell carcinoma with the larger dose, and compressed single-or-few-fraction schedules produced more necrosis and worse cosmetic tolerance than 48 Gy in 8 fractions. ^[2] That illustrates the classic teaching point: shortening the overall time while keeping dose per fraction high tends to increase late damage even when tumour control is similar.

Irradiated tissues also show a repopulation behaviour. Early or fast-turnover tissues (skin, mucosa, bone marrow) repopulate quickly between fractions, which is why acute reactions peak mid-treatment and settle; slowly turning-over tissues (lung, spinal cord, nerve, kidney) do not. Late effects therefore lag the course and reflect total dose and fraction size more than the speed of treatment.

Acute reactions are the price of irradiating rapidly dividing normal tissue. Timing is predictable: they usually begin during the course, may worsen to the end of treatment and the early aftermath, and then settle over the following weeks for most tissues. ^[1]

• Skin (radiation dermatitis). Erythema, dry or moist desquamation, pruritus, tenderness and pigmentation changes. Skin reactions range from simple erythema to moist desquamation and, in a randomized trial of basal cell carcinoma and squamous cell carcinoma, one fraction of 21 to 22.5 Gy or four fractions of 40 Gy produced much higher necrosis rates and worse cosmetic tolerance than eight fractions of 48 Gy. ^[2] Dry desquamation is expected; moist desquamation in skin folds is common.
• Head, neck and thoracic mucosa. Mucositis, glossitis, dysphagia, hoarseness, sore throat, oesophagitis, odynophagia, and dryness or reduction in saliva production in head and neck and upper thoracic treatments. Avasopasem manganese has shortened acute oral mucositis and acute oesophagitis in patients having conventional radiotherapy for head and neck and lung cancers respectively, illustrating that mucosal damage is a dose-limited targetable toxicity. ^[4]
• Gastro-intestinal tract. Nausea, vomiting, anorexia, taste change, diarrhoea, cramping and rectal discomfort for abdominal or pelvic fields; these usually resolve after treatment. ^[1]
• Genito-urinary tract. Dysuria, frequency, urgency and a sensation of bladder irritation for pelvic fields.
• Bone marrow. Herpes zoster and neutropenia, anaemia or thrombocytopenia when marrow-bearing bone is in the field, depending on site and dose.
• Systemic. Fatigue is the most common and most under-rated symptom, and it can outlast the course by weeks. ^[1]
• Lung. Acute radiation pneumonitis may appear during or just after treatment of the chest. Fractionation, concurrent systemic treatments and infection modify the risk.

Acute effects in a randomized trial of early oropharyngeal cancer appeared as grade 3 mucositis, dermatitis, xerostomia or dysphagia in 34% of patients treated with primary radiotherapy. ^[1] Grade 3 to 4 treatment-related adverse effects occurred in 62.5% of patients treated with radiotherapy for resectable non-small cell lung cancer (versus 55% with surgical resection), and treatment-related pneumonitis or pneumonia was significantly more common in the radiotherapy group (7.5% versus 2.5%). ^[1]

Late effects are those that appear after the acute reaction has resolved; many only show themselves months later and can continue to worsen over years. They reflect slow-turnover tissues, so they take a long time to express.

• Skin and soft tissue. Permanent fibrosis, atrophy, telangiectasia, hyperpigmentation, desquamation, hair loss, cosmetic change and, for head and neck fields, osteoradionecrosis of the jaw.
• Salivary glands and taste. Xerostomia after head and neck radiation, which may be permanent and causes dental decay and dysphagia.
• Lung. Radiation pneumonitis acutely and pulmonary fibrosis late, with dyspnoea and reduced exercise tolerance.
• Heart. Myocardial fibrosis and a raised risk of cardiac events after thoracic radiotherapy.
• Gastro-intestinal tract. Rectal bleeding, stricture, fistula, malabsorption and bowel obstruction months to years later.
• Bones. Osteoradionecrosis of the mandible, pelvic or rib insufficiency, depending on site.
• Nervous system. Brachial or lumbosacral plexopathy, peripheral neuropathy and cognitive changes; treatment of the breast and axilla can produce brachial plexus injury.
• Sexual function and fertility. Ovarian and testicular injury following pelvic irradiation; endocrine deficiency after central nervous system fields.
• Secondary malignancy. Two peaks exist: early haematological cancers and later solid tumours, both dose and field dependent. ^[1]

A natural late effect is chest wall pain after breast radiotherapy: a systematic review found a pooled prevalence of 34.0%, with mild pain in 26.1% and moderate-to-severe pain in 5.7%. It is under-recognised and often treated as routine postoperative discomfort rather than a distinct late effect. ^[3] Lung fibrosis is another classic delayed effect and has been mitigated experimentally by radioprotectors given around a single 54 Gy exposure. ^[4]

The randomized comparison above also showed that late-tissue injury worsened with shorter schedules: necrosis after one high-dose fraction was far worse than after eight fractions, and cosmetic tolerance fell with compressed regimens. ^[2] (The published source gives the raw counts 12 events out of 120, 6 out of 125 and 1 out of 123 across the three arms; the comparison above quotes them as reported without re-analysis.)

Late effects are the price of cure or control; acute emergencies need to be recognised early.

• Neutropenic sepsis. Any patient with fever during radiotherapy involving marrow, or on concurrent chemotherapy, needs the same urgent pathway as oncology patients on chemotherapy: blood cultures, broad-spectrum antibiotics and close monitoring.
• Osteoradionecrosis. Pain, exposed bone, inability to open the mouth or non-healing ulceration after head and neck or mandibular exposure needs oral and maxillofacial referral.
• Pulmonary fibrosis with symptomatic dyspnoea after chest radiotherapy. Distinguish from infection or tumour recurrence before attributing to radiation.
• Radiation-induced myelopathy or plexopathy. New motor or sensory loss at the level of a previous spinal field is an emergency referral.
• Second cancer. Any new malignancy inside or near a previous radiation field should be managed as potentially radiotherapy-related.

The broad source reported that the minimum tolerated dose (TD5/5) and maximum tolerated dose (TD50/5) describe the doses at which life-altering complications occur in 5 and 50% of patients respectively, and that age, anaemia, immunity, body mass index, infection and comorbidity worsen late toxicity. ^[1] Late effects may be permanent because the tissue that repairs here is slow-turning (lung, brain, spinal cord, heart, kidney, peripheral nerve) while acute effects are fast-turning and usually recover.

Recovery is a phase, not a single visit.

• Patients are generally followed every few weeks for the first three months, then at increasing intervals. Symptom questionnaires, dental checks after head and neck treatment, pulmonary function tests after chest or mediastinal treatment and cardiac monitoring after thoracic treatment are arranged according to institutional protocol.
• Symptomatic treatments are started early: saliva substitutes, dental care and nutritional support after head and neck radiotherapy; physiotherapy for fibrosis and lymphoedema; and analgesia for pain.
• Long-term cosmetic and functional surveillance matters. In breast radiotherapy, some pain never settles after treatment, which argues for treating chest wall pain as a distinct survivorship issue rather than an inevitable after-effect. ^[3]
• Keep a record of the dose and volume actually delivered (including the organs at risk), because it limits any future re-irradiation.

Radiotherapy is cheap relative to surgery or modern drugs but still depends on equipment that is unavailable in many countries.

• Linear accelerator shortages, maintenance and power cuts dominate local practice; journeys of many hours to the nearest centre are a real part of treatment. Shorter hypofractionated palliative schedules are pragmatically preferred where visits are hard.
• Common side effects can be managed cheaply: good skin protection during and after treatment, mouth care, nutritional support, pain control and early infection management.
• Chest wall pain after breast radiotherapy is probably under-recorded rather than rare. ^[3]
• Distinguishing radiation fibrosis from recurrent tumour needs biopsy rather than imaging alone where possible.
• Referral pathways should be clear: any suspicion of osteoradionecrosis, myelopathy or a new primary in an old field needs timely specialist review.
• Safety and quality assurance are the most common reasons for poor outcomes in settings with limited equipment.

• Children. Radiotherapy doses and volumes are reduced as far as possible, with risks of growth retardation, endocrine failure and second malignancies dominant over short-term toxicity.
• Pregnancy. Radiation is not given to the fetus; treatment of a pregnant patient needs careful shielding, deferral or change of plan.
• Older adults and frail patients. Hypofractionated and palliative schedules respect limited reserve and travel burdens; concurrent systemic treatments add to mucosal and marrow toxicity and are adjusted by fitness.
• Immunocompromised patients. Skin, mucosal and pulmonary reactions can be worse; infection thresholds are earlier.

• Radiotherapy is a local treatment: it damages DNA to stop cancer cells dividing or kill them. It is combined with surgery and systemic therapy for whole-body control. ^[1]
• It is delivered by external beam or brachytherapy and aims either to eradicate disease (curative) or to relieve symptoms and prolong useful survival (palliative). ^[1][6]
• Intent is decided before planning: curative resection-equivalent doses, neoadjuvant shrinking, adjuvant cleaning, or palliative symptom control.
• Common indications include curative treatment of localised lung, prostate and bladder cancer; organ-preserving definitive treatment of anal and laryngeal cancer; adjuncts to surgery in breast and head and neck cancer; neoadjuvant and adjuvant chemoradiotherapy in rectal and oesophageal cancer; and palliative treatment of bone, soft tissue and visceral complications. ^[1][6]
• Fractionation exploits tumour-versus-normal-tissue differences in repair and growth. Moderate and ultra-hypofractionation now have high-quality evidence in prostate cancer. ^[5]
• Acute and late effects follow the speed of turnover of the irradiated tissue; fast-turnover tissues recover in weeks and slow ones never, or only partially. ^[1]
• Acute effects: skin erythema and desquamation, mucositis, xerostomia, nausea and vomiting, diarrhoea, dysuria and fatigue. Late effects: fibrosis, atrophy, necrosis, xerostomia, pneumonitis, pulmonary fibrosis, myocardial fibrosis, rectal bleeding, endocrine deficiency and secondary malignancy. ^[1]
• Chest wall pain affects roughly one in three women after breast radiotherapy (34% pooled, 26.1% mild, 5.7% moderate to severe). ^[3]
• The tolerated dose (TD5/5, TD50/5) increases life-altering complication rates in 5% and 50% of patients and yields with patient and site factors. ^[1]
• Side effects are dose- and site-dependent, and modern conformal techniques widen the therapeutic index by reducing normal-tissue doses. ^[1]

chemotherapy classes and toxicities; surgical oncology principles; radiation dermatitis, xerostomia and mucositis; oncological emergencies; palliative care principles; oral cavity and salivary gland disorders; lung fibrosis and dyspnoea.