Radiotherapy - What GPs need to Know

Radiotherapy is a key component of both radical (curative) and palliative treatment for cancer. Most patients are treated using a high energy beam of x-rays delivered to a precise area, using a linear accelerator. Radiotherapy can be given either as external radiotherapy from outside the body or from within the body as internal radiotherapy.

• Curative therapy:
  • When used in early stages of certain cancers, radiotherapy on its own can be curative. These include:
    • Hodgkin's disease
    • Non-Hodgkin's lymphoma
    • Carcinoma of the larynx, prostate, cervix
    • CNS tumours, e.g. medulloblastoma
    • Breast cancer following lumpectomy (equivalent survival outcome to modified radical mastectomy)
• Curative when combined with chemotherapy:
  • In limited stage small cell lung cancer, non-Hodgkin's lymphoma with aggressive histology and anal carcinoma, combination of radiotherapy with chemotherapy can be curative.
• Adjuvant and neoadjuvant therapy:
  • In rectal and gastric cancer combination with 5-FU can reduce risk of recurrence and improve survival.
  • Also in oesophageal carcinoma and stage III lung cancer, combination with cisplatin-based chemotherapy can improve survival.
• Palliative:
  • Useful in the management of severe acute complications of cancer including:
    • Bony metastases to reduce pain and reduce risk of pathological fractures
    • Spinal cord compression: reduce risk of permanent neurological damage
    • Brain metastases: primary therapy with multiple lesions or prophylaxis for those with a solitary brain metastasis
    • Lung cancer: relieve obstructive symptoms
    • Bleeding tumours: local control of haemorrhage

• The exact mechanisms of action of radiation's anti-mitotic properties are still being elucidated. It is largely thought to function through the generation of free radicals that break double-stranded DNA and cause irreversible loss of a cell's reproductive capacity leading to its death.
• Since cancer cells tend to have a reduced ability to repair this damage compared with normal cells, they are selectively harmed by the radiation. It is also thought that radiation influences the cell cycle, interfering with the normal processes of growth, senescence and 'programmed' cell death (apoptosis).
• Another factor in sparing normal tissues is the precision with which radiotherapy beams are 'aimed' to take account of any anatomical distinction between normal and cancerous tissues.
• The toxic effects of radiation require the presence of oxygen, so hypoxic tissues are less sensitive to radiotherapy. Resection of a large, poorly vascularised tumour can improve outcome from irradiation.

• Gamma rays are produced by decay of radioactive isotopes while X-rays and proton beams are produced by high-powered electrical machines.
• Common radioactive isotopes that are used include Ra₂₂₆, Co₆₀, Cs₁₃₇, Ir₁₉₂ and I₁₂₅.

• Dose is defined as irradiation absorbed by each kg of tissue expressed as Grays (Gy). 1 Gy=1 J/kg of tissue.
• Dose is usually given in a number of daily fractions with the total dose determined by tumour sensitivity and normal tissue tolerance.
• Treatment is planned by a multidisciplinary team on the basis of a combination of physical findings, diagnostic imaging information, anatomy, pathology and natural history of the tumour involved.
• Seminoma is exquisitely sensitive to radiation and only requires 30Gy while some solid tumours, e.g. lung cancer, require 60Gy.
• Other tumours, e.g. melanoma, are relatively resistant to radiotherapy.
• Spacing of fractions: cells start to recover within 6 hours of radiation; therefore if fractions are too close together then normal tissues would suffer excessive toxicity, but too far apart and sub-lethal damage to cancerous tissue could be repaired.
• Conventional therapy gives daily fraction of 1.8-3Gy over 15-35 treatments to a total dose of 40-65Gy.

• Radiation is usually delivered either by external beam irradiation or brachytherapy, where a radiation device is placed within or nearby the target tumour. This latter technique is used successfully in treatment of cancers affecting the head and neck, cervix and endometrium.
• Radioactive I₁₃₁ can be taken orally to treat thyrotoxicosis and thyroid cancers.
• The delivery of radiotherapy is carefully planned using CT or MRI scans to localise target tissues. Contemporary treatment-planning computers allow 3D anatomical data to be used to design the irradiation beams and fields. This maximises the dose to the required target but spares adjacent normal tissue as much as possible.
• Patients are very carefully immobilised and thermoplastic masks or other similar positioning devices are often used. Treatment technique and volume are tried on a radiation simulator which duplicates the treatment plan using only superficial radiation for imaging and accessing accurately the location of the radiation beam.
• Tattoos are placed on the patient to ensure that treatments are delivered to the same tumour volume each time. Blocks are often used to shield normal tissues such as heart and lungs.
• A common technique is to use maximum tolerated dose to the total treatment volume plus a boost delivered directly to the tumour.

• Acute effects are defined as occurring during the treatment and within 2-3 weeks after its completion.
• Acute effects can be distressing but tend to resolve.
• Rapidly proliferating tissues, e.g. skin, mucosa and bone marrow are most sensitive to toxic affects of radiotherapy.
• Skin:
  • Erythema, dry and moist desquamation, skin tanning (starts in hair follicles), hair loss and sweat/sebaceous gland dysfunction.
  • The use of high-energy radiographs has vastly reduced the severity of skin reactions to radiotherapy.
  • When a need for skin irradiation exists, e.g. skin involvement by tumour or skin as the target for basal cell cancers, the technique is altered to produce a brisk skin reaction.
  • Where the skin is denuded (moist desquamation), it must be kept scrupulously clean to avoid superinfection.
  • Skin heals from the outer margins inwards by about 3 weeks.
  • Hair loss occurs in the treatment field but is usually temporary, re-growing within a few weeks of ceasing treatment.
  • Chemotherapeutic agents can enhance skin sensitivity.
  • Topical aloe vera gel has been claimed as a useful prophylactic agent for skin burns in radiotherapy, particularly at high doses,^1,2 but some randomised trials have not demonstrated a significant effect.³
  • Aqueous cream can be used to soothe the symptoms of dry desquamation.³
• Gastrointestinal tract:
  • Loss of taste, salivary dysfunction, oral mucositis, diarrhoea, nausea and vomiting.
  • Severe, painful mucositis may be complicated by yeast or bacterial superinfection and anti-microbials should be considered.
• Bone marrow:
  • Patients may develop cytopenias.
  • In whole body irradiation, white cell count falls with immune suppression.
  • When bone marrow reactions are severe enough, repeat treatments may need to be delayed to allow normal tissues to repair.
• Lungs:
  • Irradiation of the lung can cause pneumonitis with fevers, cough, dyspnoea and pulmonary infiltrates that may require steroids.⁴

Long-term complications are specific to tissues involved and usually occur if normal tissue tolerance is exceeded. Needs careful dosimetry and planning to avoid this, e.g. >45Gy to spinal cord causes myelitis and >20Gy to kidney can cause renal impairment.

• Neck: high dose can lead to fibrosis and decreased movement with a woody texture, especially after surgery.
• Jaw muscles: fibrosis impairing mastication. Post-operative jaw exercises may reduce this complication.⁵
• Lymphatic system: lymphoedema, intermittent erysipelas.
• Wounds: delayed healing.
• Skin:
  • Telangiectasis can occur as a late complication.
  • Ulceration over bone with exposure and possible osteoradionecrosis is fortunately rare and requires a long-term approach that may involve antibiotics, hyperbaric oxygen and surgery.
• Salivary function:
  • Loss of salivary flow with xerostomia is a common complication after head/neck irradiation and particularly likely if the parotids have been irradiated.
  • Pilocarpine may help to increase salivary flow, and artificial saliva or frequent sipping of water may be useful.⁵
  • Intravenous amifostine given during treatment has been shown to reduce the severity and duration of radiotherapy-related xerostomia without effects on survival.⁶ However it is expensive, needs to be injected daily, and can cause nausea and vomiting, so it may not be widely accepted.⁵
  • Close attention should be paid to oral hygiene during head and neck radiotherapy to reduce the risk of oral disease.
  • Oral and gingival tissue may undergo atrophy and telangiectasis as a late complication.
• Central nervous system:
  • Spinal cord irradiation may cause transverse myelitis and Lhermitte's symptom (electric-shock like sensation in upper limbs on neck flexion).
  • Full transverse myelitis with Brown-Sequard syndrome is fortunately rare and a complication that should be carefully avoided at all costs.
• Endocrine: hypothyroidism directly or through hypothalamo-pituitary axis.
• Eye: cataracts, dry-eye syndrome, retinitis.
• Ears: otitis or sensorineural hearing loss.
• Increased risk of subsequent malignancy:
  • Can cause development of secondary tumours.
  • Not a problem where radiotherapy is palliative but where used curatively, e.g. in Hodgkin's disease, tumours such as sarcomas and cancers of the lung, oesophagus and breast can prove fatal.