Radiation therapy is highly successful at killing cancer cells and shrinking tumors and its use is on the rise as newer and better technology like CyberKnife emerge, delivering exact, high doses of radiation to cancer sites without damaging surrounding vital organs or healthy tissues, and improving the quality of life while patients undergo treatment. Here are Clinical and practical applications of radiation therapy: Authors: Dr. Julia Skliarenko and Dr. Aisling Barry
Abstract: Radiation therapy uses high-energy radiation from X-rays, γ-rays, neutrons, electrons, protons and other sources to kill cancer cells and shrink tumours. External-beam radiation therapy (EBRT) is a form of radiation therapy delivered via a machine outside the body, while brachytherapy is a form of internal radiation therapy, which comes from radioactive material placed in the body near or within the tumour. EBRT is the most common method of delivering radiation treatment. Curative treatment regimens are usually given on an outpatient basis over a 1–8-week period. Palliative treatment regimens range from a single treatment to up to 2 weeks’ duration. Chemotherapy is sometimes given concurrently with radiation therapy and acts as a radiation sensitizer. Brachytherapy is most frequently used to treat prostate and gynaecological cancers. Although radiation therapy is usually described as a ‘local’ treatment, systemic radiation therapy uses a radioactive substance, such as a radiolabelled monoclonal antibody, that travels throughout the body via the bloodstream. This article describes the role of radiation therapy and its adverse effects in various clinical situations.
Key Points: Modern techniques such as intensity-modulated radiotherapy and image-guided radiotherapy allow an increase in the dose of radiation that can be administered safely to the tumour, while sparing neighbouring organs
Improved local control of cancer optimizes survival in many cancer patients
Improved normal tissue sparing has been shown to improve patients’ quality of life
Treatment of limited metastatic (oligometastatic) disease with high-dose stereotactic radiation therapy is increasingly used and can give prolonged palliation, occasionally long-term disease control and improved survival in select patients
High-dose-rate brachytherapy, using magnetic resonance imaging guidance for planning, allows focused high doses of radiation therapy to be delivered over a short period to the tumour, with acceptable morbidity to neighbouring bowel and bladder
Introduction: Radiotherapy is effective in controlling various malignant and benign tumours. Approximately 50% of cancer patients are currently given radiotherapy, whether to achieve cure for localized tumours or to palliate symptoms caused by the primary tumour or metastases. With recent technological advances (see Figure 1), it is expected that the role and use of radiotherapy will continue to increase.
Figure 1. Dose distribution of radiation therapy to treat nasopharyngeal cancer, showing the ability of IMRT to deliver 70 Gy (dark blue line) to the tumour (yellow volume) while keeping the brainstem (purple volume) dose to 45–50 Gy (purple line).
Pre-treatment Evaluation: Careful evaluation of past medical and surgical history, pathology, risk factors, contraindications to treatment and imaging is necessary before administering therapeutic radiotherapy. Tissue diagnosis must also be clearly established. Histological proof and identification of malignancy is a basic requirement, except in well-defined clinical situations such as tumour of the midbrain or optic tracts. Even in palliative settings, biopsy should be routine practice before administering radiation therapy.
The tumour’s site of origin must be established when possible and the extent of disease determined before delivery of radiotherapy. This can usually be achieved by clinical examination, endoscopy (when appropriate) and cross-sectional imaging (computed tomography (CT) and/or magnetic resonance imaging (MRI) and/or positron emission tomography-CT).
Aims of Treatment: After careful evaluation, individualized treatment plans are established for each patient. Radiotherapy is administered with curative or palliative intent. When treatment is given with curative intent, a relatively high incidence of adverse effects may be acceptable. Treatment is typically given over 1–8 weeks, usually daily Monday through Fridays. When treatment is delivered with palliative intent, a short course of radiotherapy (1–10 treatments) is usually indicated and adverse effects are minimized.
Curative radiotherapy can be classified as radical (given as the definitive treatment) or neoadjuvant (given before) or after (adjuvant) management of the primary tumour, usually surgery. Neoadjuvant radiotherapy aims to decrease tumour size and render the tumour surgically resectable, as well as minimize the extent of surgery, improve the chance of obtaining microscopically clear surgical margins and maximize preservation of normal tissue function. Postoperative radiation therapy is often undertaken after conservative surgery (e.g. lumpectomy in breast cancer) to eradicate residual microscopic tumour extension into normal tissues; this lessens the chance of local recurrence and improves the chance of local control.
Types of Radiotherapy: There are two main types of radiotherapy: external-beam radiation therapy (EBRT) and internal radiation therapy (brachytherapy). EBRT is discussed in detail in Radiotherapy: technical aspects on pages 11–16 of this issue. Stereotactic ablative body radiotherapy (SABR) is a type of EBRT that enables the delivery of extremely high doses of radiation to small volumes over a shorter treatment course while sparing normal surrounding tissue.
There are several different types of brachytherapy, during which single or multiple radioactive sources are placed inside the patient’s body under image guidance:
• Intracavitary – involves placing the radioactive source in a cavity or space adjacent to the tumour (e.g. vagina, trachea, oesophagus).
• Interstitial – involves implanting radioactive sources directly into the tumour:
– low dose rate: radioactive sources are implanted within the tumour (e.g. prostate) and the radiation is delivered as the radioactive isotope decays over time. Some sources can be left within the tumour indefinitely; others are removed after delivery of the intended dose.
– high dose rate: thin catheters are placed inside the tumour (e.g. cervix). High-dose rate sources travel through these catheters so that focused high-dose radiation is delivered to the tumour over a few minutes. The catheters are then removed.
Radical/adjuvant radiotherapy
The principal role of radiotherapy is in the radical curative treatment of localized cancer. The risks and benefits of radiotherapy must always be weighed against the risks and benefits of other local therapies such as surgery or interventional radiology procedures. In many cancers, the use of primary radical radiotherapy does not preclude ‘salvage’ surgery if radiotherapy fails. This is particularly the case in head and neck cancer, in which salvage surgery for radiotherapy failure is an integral part of the management of many tumours. The standard radiotherapy regimen is given daily, Monday through Friday, for 1–8 weeks, although other schedules are being evaluated for many tumour sites.
Head and neck cancer: loco-regional disease control is the major concern in head and neck cancer. About 60% of patients have lymph node metastases at the time of presentation. Treatment must be individualized, taking into account tumour stage, site, size and histology, and patient factors such as age and nutrition. For example, a small squamous cell tumour in the oral cavity is best treated by surgery (to avoid the morbidity caused by radiotherapy to the oral mucosa), whereas a similarly sized squamous cell tumour in the tonsil is optimally managed by radiotherapy (because surgery, which would be necessary to remove the tumour with an adequate margin of normal tissue, would cause considerable morbidity). Using intensity-modulated radiotherapy (IMRT), high-dose radiotherapy can be delivered to the primary tumour, grossly involved lymph nodes and nodal regions at risk of microscopic involvement in the neck. Excellent local control with good sparing of normal organs is typically achieved; however, salvage nodal dissection is considered if residual disease is identified 10–12 weeks after completion of radiation therapy. Adjuvant postoperative radiotherapy is used when residual microscopic disease is suspected after surgical resection (e.g. high-grade salivary tumours). Radiotherapy is often combined with systemic therapies such as cisplatin and cetuximab, having shown to improve patient outcomes.
Genitourinary cancer: radical radiotherapy is used with curative intent in many patients with prostate cancer, bladder cancer or stage II testicular seminoma. Treatment of localized prostate cancer is similar to that of many other cancers. If disease is confined to the prostate (T1/T2), the prostate can be removed by surgery (radical prostatectomy) or treated with radiotherapy (brachytherapy alone, EBRT + brachytherapy, definitive EBRT including SABR). These two approaches are similar in terms of outcome, but their adverse effects differ considerably. With the development of IMRT and three-dimensional conformal therapy, the dose of radiation that can safely be administered has increased by 15–25% over the last decade. In modern EBRT series, the 5-year freedom from relapse in patients with T1/T2 disease is 80–85%. Despite the greater dose of radiation delivered by these methods, the toxicity of therapy has decreased considerably because a high dose is delivered to a smaller volume of normal rectum. Adjuvant hormonal therapy improves survival in locally advanced disease and is being investigated in earlier stage disease. Interstitial brachytherapy should be reserved for patients with low-risk disease, such as T1/T2a disease with well-differentiated tumours (cT1–T2, Gleason score ≤6 and serum prostate-specific antigen (PSA) concentration <20 ng/ml; or cT1–T2, Gleason score 7 (3 + 4), PSA <15 ng/ml and <50% cores involved) (see Prostate cancer on pages 48–52 of this issue). The main benefit of radical radiotherapy in bladder cancer is bladder preservation. Local tumour control is achieved in about 50% of patients. The results of radical radiotherapy, with salvage surgery if radiotherapy fails, are similar to those of radical cystectomy. Individuals with severe pre-treatment irritative bladder symptoms are not good candidates for radiotherapy and are usually best treated by surgery. Outcomes are improved with concurrent chemo-radiotherapy. Adjuvant radiotherapy is sometimes used in stage I seminoma but surveillance or single dose carboplatin is now more frequently recommended as there is increasing evidence of induction of second non-testicular cancers by radiotherapy in these young patients. After radical prostatectomy, adjuvant radiotherapy should be considered in individuals with disease extending outside the prostate and positive margins. Salvage radiotherapy can be curative in a proportion of patients with biochemical relapse after radical prostatectomy.
Gynaecological cancer: radical radiotherapy is the primary treatment modality in patients with locally advanced carcinoma of the cervix. Adjuvant postoperative radiotherapy is given to selected patients with cervical, endometrial or vulvar tumours with high-risk pathological features and can also be used in ovarian cancer.
Cervix – in cervical cancer, the choice of treatment depends on the extent of disease at the time of presentation. In early-stage disease, the cure rate with radiotherapy is similar to that with surgery, so surgical management is often preferable to avoid morbidity from radiotherapy (vaginal scarring, bowel damage, ovarian dysfunction). Unfortunately, a significant number of patients present with either locally advanced disease or nodal involvement, making concurrent chemo-radiotherapy (a combination of EBRT and intracavitary or interstitial brachytherapy) the treatment of choice.1
Brachytherapy facilitates delivery of a high dose of radiation directly to the cervix and surrounding tissues (which are often involved) while sparing normal tissue. Implementation of MRI guidance to help delineate target volumes for brachytherapy has significantly improved local control and overall survival rates, and decreased grade 3 and 4 toxicity. With image guidance, treatment outcomes have improved significantly, even for extensive local disease, with 3-year overall survival rates of 85% reported.2 There is conclusive evidence that concurrent cisplatin-containing chemo-radiotherapy improves local control and survival.
Breast cancer: adjuvant breast irradiation after lumpectomy is now the standard approach for early breast cancer; local control and survival results are similar to those achieved with mastectomy. Adjuvant breast radiotherapy can be omitted in select patients with a luminal A breast cancer subtype based on recent reported local recurrence rates of 2.3% at 5 years. Mastectomy can be necessary for large primary tumours, although neoadjuvant chemotherapy is increasingly used, enabling breast-conserving surgery and adjuvant radiotherapy in these patients. Adjuvant radiotherapy (chest wall with or without nodal radiotherapy) after mastectomy is used in those at high risk of local relapse after surgery, with a view to improving loco-regional control and survival. There are now convincing data that improved local control, for both lumpectomy and mastectomy, leads to better survival – around 5% at 15 years.
Lung cancer: in most developed countries, lung cancer is the principal cause of cancer-related death in both men and women. In limited-stage small cell lung cancer, systemic chemotherapy with radiotherapy to the primary tumour in the chest and prophylactic cranial irradiation is the standard treatment but is curative in only a small proportion. Surgery is the mainstay of treatment in non-small cell lung cancer (NSCLC), particularly in early disease. There is no role for the routine use of postoperative radiation therapy in patients with early-stage NSCLC unless the surgical resection margins are positive or close and re-resection is not feasible. SABR is becoming the treatment modality of choice for those with early-stage NSCLC who cannot undergo surgery because of medical, technical or personal reasons. Studies have shown that SABR can be as effective as surgery for individuals with early-stage disease.
In patients with unresectable stage III disease, there is strong evidence that concurrent chemo-radiotherapy followed by immunotherapy improves survival compared with radiotherapy alone in patients with a good performance status and minimal weight loss.3,4 Select patients with unresectable disease at time of presentation can be eligible for a trimodality approach consisting of neoadjuvant chemo-radiation followed by surgical resection. However, overall 5-year cure rates in NSCLC are disappointing and potential benefits must be weighed against toxicity for individual patients.
Gastrointestinal cancer: radical radiotherapy is useful in the management of oesophageal cancer, anal canal cancer and primary liver cancers. Preoperative combination chemo-radiotherapy is also considered in certain stages of oesophageal cancer, rectal cancer and pancreatic cancer.
Oesophagus – oesophageal cancer is the sixth leading cause of cancer death worldwide. Its incidence increases with age, peaking at 50–60 years. In patients with stage I–III oesophageal cancer who are felt to be fit for surgery, preoperative radiation therapy and chemotherapy (a combination of paclitaxel and carboplatin) are frequently used. Radiotherapy and chemotherapy can also be used together as definitive treatment in patients who may not be surgical candidates.
Rectum – colorectal cancer is the third most common cancer after breast/prostate and lung. Radiation therapy is frequently used as one of the treatment modalities. Studies have shown that, in stage II–III locally resectable rectal cancers, preoperative concurrent chemo-radiotherapy (with 5-fluorouracil/capecitabine) results in improved local recurrence rates compared with surgery alone.
Anal canal – combination radiotherapy and chemotherapy (fluorouracil and mitomycin C) achieves up to 90% remission for anal canal tumours; most patients can be cured by this approach, avoiding abdominoperineal resection.
Primary liver cancer – advancing radiotherapy techniques and image-guided radiotherapy have increased the use of radiotherapy for patients with hepatocellular carcinoma (HCC). Transplant, surgery and thermal ablation is the main curative therapy for HCC. Radiotherapy can be used to bridge patients to liver transplant, as a downstaging or bridging treatment for unresectable disease, in the setting of local recurrence after other local therapies (such as trans-arterial chemo-embolization, radiofrequency ablation or in the palliation of local symptoms such as pain.
Pancreatic cancer – it is estimated that primary liver and pancreatic cancers will be the second and third most common causes of cancer death by 2040. Most patients with pancreatic cancer present at a later stage. Surgery is the standard of care in resectable cases, and the use of radiotherapy has demonstrated conflicting outcome results in the literature. For tumours that are borderline resectable (because the disease is located close to major vessels/organs or tissues), neoadjuvant combination chemoradiotherapy is often considered.
Palliative radiotherapy and metastases-directed radiotherapy
Palliative care combines active and compassionate therapies intended to comfort and support both patient and family (see Medicine 2022; 50 (12)). Palliative radiotherapy is an integral part of this approach, aiming to relieve symptoms, prevent impending problems, improve quality of life and possibly extend survival. It is essential that the morbidity from the treatment is not more severe than the symptoms for which the individual is being treated.
Symptomatic complications of progressive cancer that can be successfully treated by palliative radiotherapy include pain, spinal cord compression, nerve root compression, superior vena cava syndrome, haemoptysis, dysphagia and bleeding. A detailed list of symptoms that can be significantly improved and/or alleviated is shown in Table 1.
Table 1. Some symptomatic complications of cancer
| Local disease |
|
Haemoptysis |
| •
Dysphagia |
| •
Haematuria |
| •
Pelvic pain from pelvic cancer |
| •
Vaginal bleeding |
| Regional disease |
| •
Superior vena cava syndrome |
| •
Brachial plexus involvement |
| •
Pelvic pain from nodal spread |
| •
Deep vein thrombosis from nodal spread |
| Distant metastases |
| •
Painful bony metastases |
| •
Spinal cord compression |
| •
Nerve root compression |
| •
Proptosis |
| •
Brain metastases |
Pain from osseous metastasis is the most common indication for treatment. The response varies according to primary tumour site but substantial pain relief is achieved in >80% of patients within 4 weeks of treatment delivery. Most patients with bone metastases are treated with a single fraction of radiotherapy, which can produce excellent outcomes.
Superior vena cava syndrome and troublesome haemoptysis caused by locally extensive lung or mediastinal malignancies respond equally well to palliative radiotherapy.
Spinal cord compression is a devastating complication of metastatic cancer, requiring prompt emergency treatment with surgical decompression or radiotherapy. Dexamethasone should be initiated when spinal cord compression is diagnosed, and tapered down after completion of radiation therapy. Radiotherapy rather than surgery is indicated when there are multiple levels of vertebral involvement or life expectancy is <3–6 months. Surgical decompression can be used in individuals who progress after palliative radiotherapy. In newly diagnosed malignancies where pathological diagnosis is pending, or for patients with multiple primaries and/or an unknown primary, tissue diagnosis of the lesion causing the spinal cord compression is usually required before radiotherapy. Symptoms such as pain and neurological function are often significantly improved after radiation treatment.
Brain metastases are the most common cause of an intracranial mass and are found in up to 45% of cancer patients. If the person presents with symptomatic brain metastases, dexamethasone should be initiated. Brain metastases can be treated with surgical resection, stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT) or a combination of these. Resection of a single brain metastasis followed by WBRT gives a survival advantage over WBRT alone. SRS to 1–3 brain metastases after WBRT has been associated with increased local intracranial control compared with WBRT alone. Furthermore, giving WBRT after SRS has been associated with increased local control and decreased distal brain treatment failure over SRS alone. Treatment recommendations are based on the number and size of brain metastases, patient’s age, performance status, state of extracranial disease and state of the primary tumour.
Oligometastatic cancers (a small number, usually <5, of metastases outside the primary disease) and potentially oligo-progressive cancers (widespread metastatic disease that is stable except for a small number of growing metastases, usually <3) can also show a role for radiotherapy in local treatment. Recent studies have suggested improved survival without a change in quality of life in individuals treated with SABR for oligometastatic disease compared with those not given SABR.5 However, we are continuing to learn which patients with oligometastatic/oligoprogressive disease are best suited to SABR because of the biology and location of the disease. Every person should be discussed in a multidisciplinary setting.
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Acknowledgement: The authors would like to acknowledge Padraig Warde who previously contributed to this article.
About the authors: Julia Skliarenko MD PhD FRCPC is a Lecturer and a Radiation Oncologist at the University of Toronto and the Credit Valley Hospital and Princess Margaret Cancer Centre, Toronto, Canada. Her research interests include gynaecological and breast malignancies. Competing interests: none declared
Aisling Barry MB BCh BAO MRCPI FFR RCSI FRCPC MSc is Professor and Chair of Radiation Oncology at University College Cork and Cork University Hospital, Ireland. Her research interests are in breast and gastrointestinal malignancies and, the use of metastatic directed radiotherapy. Competing interests: none declared
Here’s the direct link to the article in the medical journal Science Direct
https://www.sciencedirect.com/science/article/abs/pii/S1357303922002572