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Principles of cancer treatment by radiotherapy
CANCER TREATMENT
Principles of cancer treatment by radiotherapy
Clinical indications for radiotherapy Radiotherapy plays a variety of roles of in both the radical and palliative treatment of cancer. Definitive radiotherapy Radiotherapy may be used as the definitive cancer treatment modality in certain tumour sites. This includes head and neck, anal, prostate, bladder, oesophagus and cervical cancers, where radiotherapy offers the significant advantage of organ preservation over surgical intervention. Radiotherapy may also be an alternative radical treatment for patients unsuitable for surgery because of significant co-morbidities, inoperable disease or proximity of the cancer to critical structures. One example includes early peripheral lung cancers, historically treated with surgery, which may be treated with stereotactic ablative radiotherapy (SABR) as curative alternative, particularly in those with co-morbidities unsuitable for surgery. Commonly, radiotherapy is given concurrently with a systemic agent to enhance tumour control. Examples include the use of cytotoxic chemotherapy such as cisplatin for cervical cancer and biological agents, including cetuximab, for head and neck cancers.3 Both agents act as radio sensitizers and enhance the tumourcidal effect of radiotherapy. Hormone therapy such as antiandrogens for prostate cancer is also given with radiotherapy in the definitive setting; it is usually started 3 months prior to radiotherapy to allow time for the prostate to reduce in volume, reducing side effects as well as improving tumour control.
Elin Evans John Staffurth
Abstract Radiotherapy plays an integral role in the management of more than 50% of cancer cases and 40% of patients cured of their cancer have radiotherapy as a part of their management. For some patients, it can be used definitively in place of surgery, offering the advantage of organ preservation. It is sometimes used before surgery to improve resection rates or after surgery to reduce recurrence rates. Outcomes may be improved if radiotherapy is combined with systemic therapies such as chemotherapy. The process of delivering radiotherapy is multi-level, involving clinical oncologists, medical physicists and therapeutic radiographers. Each step takes advantage of new technology that allows more accurate definition of the tumour and delivery of radiation, with the aim of improving treatment outcomes and reducing normal tissue toxicity. There have been significant advances in defining the target and delivering the radiation in the last few years, discussed further in this article.
Keywords Adjuvant; cancer; radiation; treatment
Neoadjuvant radiotherapy Radiotherapy given prior to definitive surgery is termed ‘neoadjuvant’ radiotherapy. This approach is used in selected rectal cancer cases to reduce the risk of local recurrence. Given concurrently with chemotherapy, complete pathological response rates (i.e. no residual tumour) of 15e27% have been demonstrated in histopathological specimens.4
Introduction Radiotherapy is an effective and commonly used treatment modality in cancer management. In England, 125,000 patients each year are treated with external beam radiotherapy (EBRT)1 and it is estimated that 52% of patients with cancer receive radiotherapy at some point during their illness.2 The primary intent can be radical (curative) or palliative (symptom control). Forty per cent of all patients cured of their cancer have radiotherapy as a part of their therapy, either on its own or in combination with surgery or chemotherapy.1 Radiation therapy can be delivered in three main ways e EBRT (photons/ electrons/protons), implanted radioisotopes (brachytherapy) and injected radioisotopes. These are detailed in Table 1. Radiotherapy is usually used as a local or locoregional therapy. Tumour types have inherently different radiation sensitivities that determine whether radiotherapy has a role in the treatment and also the dose required. Radiosensitive types include seminoma and lymphoma; moderately radiosensitive tumours are breast, lung and squamous cell carcinomas; poorly radiosensitive cancers include osteosarcoma and melanoma.
Adjuvant radiotherapy Radiotherapy may be given after definitive surgery (adjuvant radiotherapy). An example includes patients with early breast cancer, who may be offered adjuvant radiotherapy to the whole affected breast after breast-conserving surgery, as an alternative to mastectomy. Whole breast radiotherapy in this setting reduces the rate at which the disease recurs by half at 10 years and reduces the breast cancer death rate by approximately a sixth at 15 years.5 Salvage radiotherapy Radiotherapy may be given for local or locoregional relapse after radical surgery. Patients with prostate cancer following radical prostatectomy undergo prostate-specific antigen (PSA) monitoring to detect early relapse. Patients with rising PSA levels (biochemical relapse) often have very low volume disease localized to the surgical bed, that can be treated by radical radiotherapy, thus maximizing the chance of long term control or potential cure.
Elin Evans MRCP FRCR is a Clinical Oncology Research Fellow at Velindre Cancer Centre, Cardiff, UK. Conflict of interests: none declared.
Palliative radiotherapy Radiotherapy is effective in the palliative setting for symptom control. It relieves pain from bony metastases in at least 60% of
John Staffurth MD FRCP FRCR is a Professor in Clinical Oncology at Cardiff University and Consultant Clinical Oncologist, Velindre Cancer Centre, Cardiff, UK. Conflict of interests: none declared.
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Evans E, Staffurth J, Principles of cancer treatment by radiotherapy, Surgery (2017), https://doi.org/10.1016/ j.mpsur.2017.12.006
CANCER TREATMENT
Types of radiation treatment used Type of radiation
Indication
Photons
Able to penetrate deep into the body while sparing the skin. Commonest modality used for most deep-seated tumour types e.g. rectal cancer. Provide a high dose to a few centimetres depth from the skin surface with little dose beyond. Therefore, used for superficial treatment e.g. skin cancers. Deposit energy with extreme precision, therefore limiting unwanted dose. Currently used for paediatric cancers, skull base cancers and some spinal tumours. Radioactive sealed sources temporarily or permanently inserted into the tumour e.g. cervical and prostate cancer. Radio-iodine for thyroid cancer and strontium-89 for bone metastases.
Electrons Protons Brachytherapy Injected radiotherapy Table 1
patients6 and may be used to palliate symptoms from spinal cord compression, brain metastases and uncontrolled bleeding.
vasculature and the immune system, with emerging evidence that radiation-induced cell death is ‘immunogenic’. These mechanisms of action may explain why certain systemic agents enhance the radiotherapy effect and there is huge interest in combining novel immune checkpoint inhibitors and DDR pathways inhibitors with radiotherapy. Normal tissue effects may be acute due to direct cell death (e.g. mucosal surface), or late due to indirect effects on vasculature or stem cell component, thereby impacting future repair mechanisms. Radiation itself may be carcinogenic, with the potential risk of inducing second malignancies, particularly in the young.
Types of radiotherapy Radiation therapy can be delivered in three main ways e external beam radiotherapy (EBRT) (photons/electrons/protons), implanted radioisotopes (brachytherapy) and injected radioisotopes. These are detailed in Table 1. The most common type of radiotherapy used is photons. These are high-energy X-rays (6e18 megavolts) targeted to a specific area of the body for treatment. Photons are produced by accelerating electrons colliding with a metal target. They are delivered via a linear accelerator (LINAC) housed in a thickwalled bunker for radiation protection. The dose of radiation is defined as the energy absorbed per unit mass and is expressed in Grays (Gy) (1 Gy ¼ 1 J/Kg). Radical radiotherapy is usually delivered in multiple treatments (fractions) on a daily basis over 3e7 weeks depending on the dose prescribed. Fractionating treatment optimizes the balance between the tumourcidal effect of radiation and the adverse effects on normal tissue. However, the benefit of long fractionation schedules may diminish as improved radiotherapy techniques reduce the volumes of normal tissues being irradiated. Longer schedules also give more opportunity for cancer growth during treatment and are more inconvenient and time-consuming for patients. The optimal fractionation schedule is likely to vary between cancer types but shorter schedules providing effective doses have become standard of care for breast and prostate following results of very large randomized clinical trials e.g. START and CHHiP.7,8
The radiotherapy process The process of radiotherapy is complex and involves an understanding of medical physics, radiobiology, radiation safety, dosimetry, radiation treatment planning, simulation and interaction of radiation with other treatment modalities. It consists of three distinct steps: immobilization, imaging and target volume definition treatment planning treatment delivery and set up verification. Immobilization, imaging and target volume definition The first step in the radiotherapy process is a ‘planning CT scan’, which is used to define the area to be treated. Patients are scanned in the treatment ‘set up’ position. Treatment positioning commands patient comfort and reproducibility for optimal delivery and is tailored to each tumour site, e.g. supine and arms up for thoracic cancers. To ensure accurate delivery of radiotherapy is maintained for each fraction delivered, patients require appropriate immobilization. This includes the use of thermoplastic shells for head and neck and brain tumours. Three volumes are usually delineated: the gross tumour volume (GTV) consists of the actual tumour that is then extended with a margin to encapsulate microscopic spread to create the clinical target volume (CTV).9 The CTV often also includes nodal areas at risk. A further margin is added to the CTV to allow for potential daily variation in tumour position, which can be from patient positioning or from internal organ motion. This is known as the planning target volume (PTV) and ensures that the CTV is always treated.
How does radiotherapy work? Radiotherapy can be considered simply as ‘targeted DNA damage’. Radiation absorption in tissues can cause ionization and excitation of atoms through electron displacement. These damaged atoms and molecules react with cellular components, consequently breaking chemical bonds to form highly reactive ‘free radicals’, which in turn may cause cellular insult, particularly DNA damage. This leads to activation of the sophisticated DNA damage recognition and repair (DDR) pathways and most DNA damage is repaired if these pathways are functional; if not, cell death inevitably occurs, usually when the cells try to pass through mitosis. Radiation also has an effect on tumour
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Please cite this article in press as: Evans E, Staffurth J, Principles of cancer treatment by radiotherapy, Surgery (2017), https://doi.org/10.1016/ j.mpsur.2017.12.006
CANCER TREATMENT
Diagnostic imaging modalities such as PET scanning (e.g. for lung or head and neck cancers) and MRI (e.g. for prostate and brain cancers) aid target volume delineation by accurately identifying the tumour and improve the clinician’s ability to delineate the tumour more accurately. Functional imaging e.g. PET or multi-parametric MRI may allow identification of biologically aggressive disease and facilitate targeted radiotherapy ‘boosts’. In some cases, co-fusion of diagnostic imaging with the planning CT scan aids tumour delineation.10,11
targeted region(s). This aims to spare normal tissue as much as possible. This technique however, is increasingly being superseded by more advanced radiotherapy techniques as outlined below. Intensity modulated radiotherapy (IMRT)12: uses variable intensity profiles from multiple radiotherapy beams or with a beam rotating 360 around the patient to achieve a more complex dose distribution than is achievable using 3D conformal radiotherapy. Continuously rotating IMRT is known as volumetric arc therapy (VMAT) and can be delivered by modern LINACs very quickly. The main advantages of IMRT are improved target volume coverage and sparing of normal tissues as it can achieve complex concave shaped treatments with steep dose gradients (Figure 2). It also allows simultaneous delivery of different doses to different target volumes. IMRT is commonly used in the treatment of head and neck cancers and in pelvic nodal irradiation for prostate and anal cancers. IMRT results in reduced toxicity through optimally sparing normal tissues e.g. reduced xerostomia with the use of parotid-sparing IMRT in head and neck cancers.13
Treatment planning The next part of the process is to define the optimal radiotherapy beam arrangement that will deliver the required dose to the PTV (Figure 1). At this stage, critical normal structures surrounding the target volume are outlined, known as ‘organs at risk’ (OARs). These are structures that limit the dose that can be delivered to the target volume (e.g. the rectum is an OAR in prostate cancer radiotherapy). Planning is done by the physicists using a combination of three or more beams entering from different directions. Physicists optimize the plan to maximize PTV dose deliverance and minimize dose to OARs, using constraints defined from previous cohorts of patients. Once an optimal plan is created, it is reviewed and approved by the treating clinician and the data are transferred to the treatment machine.
Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT)14: deliver high-precision radiotherapy to stereotactically defined cranial lesions (benign or malignant). This allows delivery of very high radiation doses to small targets with rapid dose fall-off, sparing the rest of the brain. In SRS, a one-off high radiotherapy dose is delivered, whereas SRT entails fractionated treatment. Treatment can be LINAC-based (i.e. X-rays) or via gamma knife, which uses g-rays as a single fraction where approximately 200 cobalt-60 sources in a
Treatment delivery: recent advances in radiotherapy means there are a number of ways external beam radiotherapy may be delivered. Three-dimensional conformal radiotherapy: is a common technique used to treat tumours and entails shaping the radiation beams, usually with ‘multi-leaf collimators’ to the shape of the
Figure 1 Three-dimensional conformal radiotherapy plan of an oesophagus showing four beams entering from the front and back and one from left and one from the right. The red outline (labelled PTV) is the volume to be treated and the coloured lines are the dose lines (isodoses) indicating the dose the structures contained within that line receive. The ideal plan would have all the PTV contained within the 95% isodose with no areas of high dose outside of this volume. SURGERY --:-
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Please cite this article in press as: Evans E, Staffurth J, Principles of cancer treatment by radiotherapy, Surgery (2017), https://doi.org/10.1016/ j.mpsur.2017.12.006
CANCER TREATMENT
hemispheric array are focused onto the target. Previously, external fixation devices were used to immobilize the skull and virtually eliminate movement but a move towards frameless systems can match the positional accuracy of external fixation devices and are less invasive. Stereotactic body radiotherapy (SBRT): also known as stereotactic ablative body radiotherapy (SABR), allows radiotherapy delivery to extracranial areas using repeated imaging before and during treatment. Accurate delivery enables curative doses to be delivered in 3e10 fractions as the volume of normal tissue irradiated is greatly reduced (Figure 3). This technique is used as standard of care for selected early lung cancer cases and is increasingly being used as primary treatment for oligometastatic disease.15 Protons: are a form of EBRT that allow delivery of radiotherapy with greater sparing of OARs in selected clinical sites. The required dose builds up to a ‘Bragg’ peak and then falls off steeply, sparing critical structures and lowering the total delivered dose, which is expected to reduce the risk of radiationinduced malignancies. Currently, protons are not routinely available in the UK and require patients to travel overseas for treatment. As such, strict criteria and patient selection, via the NHS Proton Overseas Programme, enables a limited number of patients to receive proton therapy. Eligible cases include certain childhood cancers and adults with malignancies close to critical structures (e.g. skull base sarcomas). Two NHS Proton centres under development in the UK are due to open in 2018 and 2020, respectively. Treatment verification Prior to each treatment, the patient must be set up in the same position as they were for the planning scan to ensure the radiation is delivered to the targeted region accurately for each fraction. Various forms of imaging techniques have been developed to verify the set up and to visualize the internal position of the tumour itself.9,16 Image-guided radiotherapy (IGRT) ensures accurate delivery of radiotherapy by using imaging before or during treatment delivery. Tumour movement or shape change can be identified allowing for smaller safety margins to be used therefore minimizing toxicity. This approach is particularly important for IMRT because of steep dose gradients. IGRT may be achieved by: Integrated imaging modalities on the LINAC including cone beam CT. Insertion of markers to localize the target, e.g. gold seeds for prostate and titanium clips for breast.9,16 IGRT is commonly adopted for tumours in areas prone to movement e.g. lung tumours in respiration or prostate position affected by bowel function.9,16 Figure 2 IMRT plan for a right tonsillar tumour. The red outline (labelled PTV60) is the volume to be treated and is surrounded by the 95% isodose (orange line on 2a and orange colour wash on 2b). IMRT allows concave shaped treatments which are more conformal to the target volume and allow sparing of organs at risk. In this case, there is sparing of the spinal cord and the contralateral parotid.
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Side effects of radiotherapy Radiotherapy side effects tend to be localized to the area that is being treated, but fatigue is a common side effect for all sites. Radiotherapy side effects are usually divided into early and late.
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CANCER TREATMENT
Figure 3 SBRT plan for an isolated pelvic node recurrence. The green line denotes the volume receiving the prescribed dose of 30 Gy. The dose falls off rapidly which enables dose sparing of the OARS, including the bowel. Outlining the OAR enables the dose it receives to be determined and therefore kept to a minimum.
Acute side effects include erythema, desquamation, hair loss, mucositis, diarrhoea, pneumonitis, marrow ablation, nausea and vomiting. Late side effects include fibrosis, necrosis, nerve damage, myelitis, telangiectasia, stricture (e.g. bowel, xerostomia, cataracts and secondary cancers). Some chronic symptoms may have a major impact on quality of life and require specialist management.17
2 Delaney G, Jacob S, Featherstone C, et al. The role of radiotherapy in cancer treatment: estimating optimal utilisation from a review of evidence-based clinical guidelines. Cancer 2005; 104: 1129e37. 3 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567e78. 4 Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11: 835e44. 5 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Darby S, McGale P, Correa C, et al. Lancet 2011 Nov; 378: 1707e16. 6 Chow E, Zeng L, Salvo N, et al. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol 2012; 24: 112e24. 7 The START Trialists Group. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008 Apr; 9: 331e41. 8 Dearnely D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5 year outcomes of the randomized, non-inferiority phase 3 CHHiP trial. Lancet Oncol 2016 Aug; 17: 1047e60. 9 Button MR, Staffurth J. Clinical application of image-guided radiotherapy in bladder and prostate cancer. Clin Oncol 2010; 22: 698e706. 10 Khoo VS, Joon DL. New developments in MRI for target volume delineation in radiotherapy. Br J Radiol 2006; 79(Spec No 1): S2e15. 11 MacManus M, Nestle U, Rosenzweig KE, et al. Use of PET and PET/CT for radiation therapy planning: IAEA expert report 20062007. Radiother Oncol 2009; 91: 85e94.
Future of radiotherapy Radiotherapy is a rapidly evolving field within medicine and a number of innovations are likely to be introduced over the next few years. Improvements in radiotherapy are driven by changes in imaging, computing and engineering. There is also considerable research in the field of radiobiology. Individualizing radiotherapy based on a number of variables including genomics, combining novel drugs with radiotherapy and assessing patient response on treatment is the vision for the future. Stratification of patients likely to benefit from radiotherapy is currently being evaluated. The use of functional imaging (PET, MRI) during treatment to assess the response of the tumour and surrounding normal tissue to radiation will facilitate personalization of treatment, as will the use of novel biomarkers, to allow better targeting and characterization of radiosensitive cancer cells. Real time imaging and tracking of tumours such as integrating an MRI and LINAC into one device, therefore enhancing the ability to revise plans during treatment (adaptive radiotherapy) is another area being evaluated.18 A REFERENCES 1 National Radiotherapy Implementation Group (NRIG). Radiotherapy services in England, 2012.
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CANCER TREATMENT
12 Staffurth JA. Review of the clinical evidence for intensitymodulated radiotherapy. Clin Oncol 2010; 22: 643e57. 13 Nutting CM, Morden JP, Harrington K, et al. Parotidsparing intensity modulated versus conventional radiotherapy in head and neck (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011; 12: 127e36. 14 Kirkbride P, Cooper T. Stereotactic body radiotherapy. Guidelines for commissioners, providers and clinicians: a national report. Clin Oncol 2001; 23: 163e4.
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15 Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastatic disease. Lancet Oncol 2013 Jan; 14: e28e37. 16 Gwynne S, Webster R, Adams R, et al. Image-guided radiotherapy for rectal cancer e a systematic review. Clin Oncol 2012; 24: 250e60. 17 Andreyev J. Gastrointestinal symptoms after pelvic radiotherapy: a new understanding to improve management of symptomatic patients. Lancet Oncol 2007; 8: 1007e17. 18 Vision for Radiotherapy 2014-2024: Cancer research UK and NHS England.
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Principles of cancer treatment by radiotherapy
Clinical indications for radiotherapy Radiotherapy plays a variety of roles of in both the radical and palliative treatment of cancer. Definitive radiotherapy Radiotherapy may be used as the definitive cancer treatment modality in certain tumour sites. This includes head and neck, anal, prostate, bladder, oesophagus and cervical cancers, where radiotherapy offers the significant advantage of organ preservation over surgical intervention. Radiotherapy may also be an alternative radical treatment for patients unsuitable for surgery because of significant co-morbidities, inoperable disease or proximity of the cancer to critical structures. One example includes early peripheral lung cancers, historically treated with surgery, which may be treated with stereotactic ablative radiotherapy (SABR) as curative alternative, particularly in those with co-morbidities unsuitable for surgery. Commonly, radiotherapy is given concurrently with a systemic agent to enhance tumour control. Examples include the use of cytotoxic chemotherapy such as cisplatin for cervical cancer and biological agents, including cetuximab, for head and neck cancers.3 Both agents act as radio sensitizers and enhance the tumourcidal effect of radiotherapy. Hormone therapy such as antiandrogens for prostate cancer is also given with radiotherapy in the definitive setting; it is usually started 3 months prior to radiotherapy to allow time for the prostate to reduce in volume, reducing side effects as well as improving tumour control.
Elin Evans John Staffurth
Abstract Radiotherapy plays an integral role in the management of more than 50% of cancer cases and 40% of patients cured of their cancer have radiotherapy as a part of their management. For some patients, it can be used definitively in place of surgery, offering the advantage of organ preservation. It is sometimes used before surgery to improve resection rates or after surgery to reduce recurrence rates. Outcomes may be improved if radiotherapy is combined with systemic therapies such as chemotherapy. The process of delivering radiotherapy is multi-level, involving clinical oncologists, medical physicists and therapeutic radiographers. Each step takes advantage of new technology that allows more accurate definition of the tumour and delivery of radiation, with the aim of improving treatment outcomes and reducing normal tissue toxicity. There have been significant advances in defining the target and delivering the radiation in the last few years, discussed further in this article.
Keywords Adjuvant; cancer; radiation; treatment
Neoadjuvant radiotherapy Radiotherapy given prior to definitive surgery is termed ‘neoadjuvant’ radiotherapy. This approach is used in selected rectal cancer cases to reduce the risk of local recurrence. Given concurrently with chemotherapy, complete pathological response rates (i.e. no residual tumour) of 15e27% have been demonstrated in histopathological specimens.4
Introduction Radiotherapy is an effective and commonly used treatment modality in cancer management. In England, 125,000 patients each year are treated with external beam radiotherapy (EBRT)1 and it is estimated that 52% of patients with cancer receive radiotherapy at some point during their illness.2 The primary intent can be radical (curative) or palliative (symptom control). Forty per cent of all patients cured of their cancer have radiotherapy as a part of their therapy, either on its own or in combination with surgery or chemotherapy.1 Radiation therapy can be delivered in three main ways e EBRT (photons/ electrons/protons), implanted radioisotopes (brachytherapy) and injected radioisotopes. These are detailed in Table 1. Radiotherapy is usually used as a local or locoregional therapy. Tumour types have inherently different radiation sensitivities that determine whether radiotherapy has a role in the treatment and also the dose required. Radiosensitive types include seminoma and lymphoma; moderately radiosensitive tumours are breast, lung and squamous cell carcinomas; poorly radiosensitive cancers include osteosarcoma and melanoma.
Adjuvant radiotherapy Radiotherapy may be given after definitive surgery (adjuvant radiotherapy). An example includes patients with early breast cancer, who may be offered adjuvant radiotherapy to the whole affected breast after breast-conserving surgery, as an alternative to mastectomy. Whole breast radiotherapy in this setting reduces the rate at which the disease recurs by half at 10 years and reduces the breast cancer death rate by approximately a sixth at 15 years.5 Salvage radiotherapy Radiotherapy may be given for local or locoregional relapse after radical surgery. Patients with prostate cancer following radical prostatectomy undergo prostate-specific antigen (PSA) monitoring to detect early relapse. Patients with rising PSA levels (biochemical relapse) often have very low volume disease localized to the surgical bed, that can be treated by radical radiotherapy, thus maximizing the chance of long term control or potential cure.
Elin Evans MRCP FRCR is a Clinical Oncology Research Fellow at Velindre Cancer Centre, Cardiff, UK. Conflict of interests: none declared.
Palliative radiotherapy Radiotherapy is effective in the palliative setting for symptom control. It relieves pain from bony metastases in at least 60% of
John Staffurth MD FRCP FRCR is a Professor in Clinical Oncology at Cardiff University and Consultant Clinical Oncologist, Velindre Cancer Centre, Cardiff, UK. Conflict of interests: none declared.
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Evans E, Staffurth J, Principles of cancer treatment by radiotherapy, Surgery (2017), https://doi.org/10.1016/ j.mpsur.2017.12.006
CANCER TREATMENT
Types of radiation treatment used Type of radiation
Indication
Photons
Able to penetrate deep into the body while sparing the skin. Commonest modality used for most deep-seated tumour types e.g. rectal cancer. Provide a high dose to a few centimetres depth from the skin surface with little dose beyond. Therefore, used for superficial treatment e.g. skin cancers. Deposit energy with extreme precision, therefore limiting unwanted dose. Currently used for paediatric cancers, skull base cancers and some spinal tumours. Radioactive sealed sources temporarily or permanently inserted into the tumour e.g. cervical and prostate cancer. Radio-iodine for thyroid cancer and strontium-89 for bone metastases.
Electrons Protons Brachytherapy Injected radiotherapy Table 1
patients6 and may be used to palliate symptoms from spinal cord compression, brain metastases and uncontrolled bleeding.
vasculature and the immune system, with emerging evidence that radiation-induced cell death is ‘immunogenic’. These mechanisms of action may explain why certain systemic agents enhance the radiotherapy effect and there is huge interest in combining novel immune checkpoint inhibitors and DDR pathways inhibitors with radiotherapy. Normal tissue effects may be acute due to direct cell death (e.g. mucosal surface), or late due to indirect effects on vasculature or stem cell component, thereby impacting future repair mechanisms. Radiation itself may be carcinogenic, with the potential risk of inducing second malignancies, particularly in the young.
Types of radiotherapy Radiation therapy can be delivered in three main ways e external beam radiotherapy (EBRT) (photons/electrons/protons), implanted radioisotopes (brachytherapy) and injected radioisotopes. These are detailed in Table 1. The most common type of radiotherapy used is photons. These are high-energy X-rays (6e18 megavolts) targeted to a specific area of the body for treatment. Photons are produced by accelerating electrons colliding with a metal target. They are delivered via a linear accelerator (LINAC) housed in a thickwalled bunker for radiation protection. The dose of radiation is defined as the energy absorbed per unit mass and is expressed in Grays (Gy) (1 Gy ¼ 1 J/Kg). Radical radiotherapy is usually delivered in multiple treatments (fractions) on a daily basis over 3e7 weeks depending on the dose prescribed. Fractionating treatment optimizes the balance between the tumourcidal effect of radiation and the adverse effects on normal tissue. However, the benefit of long fractionation schedules may diminish as improved radiotherapy techniques reduce the volumes of normal tissues being irradiated. Longer schedules also give more opportunity for cancer growth during treatment and are more inconvenient and time-consuming for patients. The optimal fractionation schedule is likely to vary between cancer types but shorter schedules providing effective doses have become standard of care for breast and prostate following results of very large randomized clinical trials e.g. START and CHHiP.7,8
The radiotherapy process The process of radiotherapy is complex and involves an understanding of medical physics, radiobiology, radiation safety, dosimetry, radiation treatment planning, simulation and interaction of radiation with other treatment modalities. It consists of three distinct steps: immobilization, imaging and target volume definition treatment planning treatment delivery and set up verification. Immobilization, imaging and target volume definition The first step in the radiotherapy process is a ‘planning CT scan’, which is used to define the area to be treated. Patients are scanned in the treatment ‘set up’ position. Treatment positioning commands patient comfort and reproducibility for optimal delivery and is tailored to each tumour site, e.g. supine and arms up for thoracic cancers. To ensure accurate delivery of radiotherapy is maintained for each fraction delivered, patients require appropriate immobilization. This includes the use of thermoplastic shells for head and neck and brain tumours. Three volumes are usually delineated: the gross tumour volume (GTV) consists of the actual tumour that is then extended with a margin to encapsulate microscopic spread to create the clinical target volume (CTV).9 The CTV often also includes nodal areas at risk. A further margin is added to the CTV to allow for potential daily variation in tumour position, which can be from patient positioning or from internal organ motion. This is known as the planning target volume (PTV) and ensures that the CTV is always treated.
How does radiotherapy work? Radiotherapy can be considered simply as ‘targeted DNA damage’. Radiation absorption in tissues can cause ionization and excitation of atoms through electron displacement. These damaged atoms and molecules react with cellular components, consequently breaking chemical bonds to form highly reactive ‘free radicals’, which in turn may cause cellular insult, particularly DNA damage. This leads to activation of the sophisticated DNA damage recognition and repair (DDR) pathways and most DNA damage is repaired if these pathways are functional; if not, cell death inevitably occurs, usually when the cells try to pass through mitosis. Radiation also has an effect on tumour
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Evans E, Staffurth J, Principles of cancer treatment by radiotherapy, Surgery (2017), https://doi.org/10.1016/ j.mpsur.2017.12.006
CANCER TREATMENT
Diagnostic imaging modalities such as PET scanning (e.g. for lung or head and neck cancers) and MRI (e.g. for prostate and brain cancers) aid target volume delineation by accurately identifying the tumour and improve the clinician’s ability to delineate the tumour more accurately. Functional imaging e.g. PET or multi-parametric MRI may allow identification of biologically aggressive disease and facilitate targeted radiotherapy ‘boosts’. In some cases, co-fusion of diagnostic imaging with the planning CT scan aids tumour delineation.10,11
targeted region(s). This aims to spare normal tissue as much as possible. This technique however, is increasingly being superseded by more advanced radiotherapy techniques as outlined below. Intensity modulated radiotherapy (IMRT)12: uses variable intensity profiles from multiple radiotherapy beams or with a beam rotating 360 around the patient to achieve a more complex dose distribution than is achievable using 3D conformal radiotherapy. Continuously rotating IMRT is known as volumetric arc therapy (VMAT) and can be delivered by modern LINACs very quickly. The main advantages of IMRT are improved target volume coverage and sparing of normal tissues as it can achieve complex concave shaped treatments with steep dose gradients (Figure 2). It also allows simultaneous delivery of different doses to different target volumes. IMRT is commonly used in the treatment of head and neck cancers and in pelvic nodal irradiation for prostate and anal cancers. IMRT results in reduced toxicity through optimally sparing normal tissues e.g. reduced xerostomia with the use of parotid-sparing IMRT in head and neck cancers.13
Treatment planning The next part of the process is to define the optimal radiotherapy beam arrangement that will deliver the required dose to the PTV (Figure 1). At this stage, critical normal structures surrounding the target volume are outlined, known as ‘organs at risk’ (OARs). These are structures that limit the dose that can be delivered to the target volume (e.g. the rectum is an OAR in prostate cancer radiotherapy). Planning is done by the physicists using a combination of three or more beams entering from different directions. Physicists optimize the plan to maximize PTV dose deliverance and minimize dose to OARs, using constraints defined from previous cohorts of patients. Once an optimal plan is created, it is reviewed and approved by the treating clinician and the data are transferred to the treatment machine.
Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT)14: deliver high-precision radiotherapy to stereotactically defined cranial lesions (benign or malignant). This allows delivery of very high radiation doses to small targets with rapid dose fall-off, sparing the rest of the brain. In SRS, a one-off high radiotherapy dose is delivered, whereas SRT entails fractionated treatment. Treatment can be LINAC-based (i.e. X-rays) or via gamma knife, which uses g-rays as a single fraction where approximately 200 cobalt-60 sources in a
Treatment delivery: recent advances in radiotherapy means there are a number of ways external beam radiotherapy may be delivered. Three-dimensional conformal radiotherapy: is a common technique used to treat tumours and entails shaping the radiation beams, usually with ‘multi-leaf collimators’ to the shape of the
Figure 1 Three-dimensional conformal radiotherapy plan of an oesophagus showing four beams entering from the front and back and one from left and one from the right. The red outline (labelled PTV) is the volume to be treated and the coloured lines are the dose lines (isodoses) indicating the dose the structures contained within that line receive. The ideal plan would have all the PTV contained within the 95% isodose with no areas of high dose outside of this volume. SURGERY --:-
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hemispheric array are focused onto the target. Previously, external fixation devices were used to immobilize the skull and virtually eliminate movement but a move towards frameless systems can match the positional accuracy of external fixation devices and are less invasive. Stereotactic body radiotherapy (SBRT): also known as stereotactic ablative body radiotherapy (SABR), allows radiotherapy delivery to extracranial areas using repeated imaging before and during treatment. Accurate delivery enables curative doses to be delivered in 3e10 fractions as the volume of normal tissue irradiated is greatly reduced (Figure 3). This technique is used as standard of care for selected early lung cancer cases and is increasingly being used as primary treatment for oligometastatic disease.15 Protons: are a form of EBRT that allow delivery of radiotherapy with greater sparing of OARs in selected clinical sites. The required dose builds up to a ‘Bragg’ peak and then falls off steeply, sparing critical structures and lowering the total delivered dose, which is expected to reduce the risk of radiationinduced malignancies. Currently, protons are not routinely available in the UK and require patients to travel overseas for treatment. As such, strict criteria and patient selection, via the NHS Proton Overseas Programme, enables a limited number of patients to receive proton therapy. Eligible cases include certain childhood cancers and adults with malignancies close to critical structures (e.g. skull base sarcomas). Two NHS Proton centres under development in the UK are due to open in 2018 and 2020, respectively. Treatment verification Prior to each treatment, the patient must be set up in the same position as they were for the planning scan to ensure the radiation is delivered to the targeted region accurately for each fraction. Various forms of imaging techniques have been developed to verify the set up and to visualize the internal position of the tumour itself.9,16 Image-guided radiotherapy (IGRT) ensures accurate delivery of radiotherapy by using imaging before or during treatment delivery. Tumour movement or shape change can be identified allowing for smaller safety margins to be used therefore minimizing toxicity. This approach is particularly important for IMRT because of steep dose gradients. IGRT may be achieved by: Integrated imaging modalities on the LINAC including cone beam CT. Insertion of markers to localize the target, e.g. gold seeds for prostate and titanium clips for breast.9,16 IGRT is commonly adopted for tumours in areas prone to movement e.g. lung tumours in respiration or prostate position affected by bowel function.9,16 Figure 2 IMRT plan for a right tonsillar tumour. The red outline (labelled PTV60) is the volume to be treated and is surrounded by the 95% isodose (orange line on 2a and orange colour wash on 2b). IMRT allows concave shaped treatments which are more conformal to the target volume and allow sparing of organs at risk. In this case, there is sparing of the spinal cord and the contralateral parotid.
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Side effects of radiotherapy Radiotherapy side effects tend to be localized to the area that is being treated, but fatigue is a common side effect for all sites. Radiotherapy side effects are usually divided into early and late.
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Figure 3 SBRT plan for an isolated pelvic node recurrence. The green line denotes the volume receiving the prescribed dose of 30 Gy. The dose falls off rapidly which enables dose sparing of the OARS, including the bowel. Outlining the OAR enables the dose it receives to be determined and therefore kept to a minimum.
Acute side effects include erythema, desquamation, hair loss, mucositis, diarrhoea, pneumonitis, marrow ablation, nausea and vomiting. Late side effects include fibrosis, necrosis, nerve damage, myelitis, telangiectasia, stricture (e.g. bowel, xerostomia, cataracts and secondary cancers). Some chronic symptoms may have a major impact on quality of life and require specialist management.17
2 Delaney G, Jacob S, Featherstone C, et al. The role of radiotherapy in cancer treatment: estimating optimal utilisation from a review of evidence-based clinical guidelines. Cancer 2005; 104: 1129e37. 3 Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006; 354: 567e78. 4 Maas M, Nelemans PJ, Valentini V, et al. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11: 835e44. 5 Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Darby S, McGale P, Correa C, et al. Lancet 2011 Nov; 378: 1707e16. 6 Chow E, Zeng L, Salvo N, et al. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol 2012; 24: 112e24. 7 The START Trialists Group. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008 Apr; 9: 331e41. 8 Dearnely D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5 year outcomes of the randomized, non-inferiority phase 3 CHHiP trial. Lancet Oncol 2016 Aug; 17: 1047e60. 9 Button MR, Staffurth J. Clinical application of image-guided radiotherapy in bladder and prostate cancer. Clin Oncol 2010; 22: 698e706. 10 Khoo VS, Joon DL. New developments in MRI for target volume delineation in radiotherapy. Br J Radiol 2006; 79(Spec No 1): S2e15. 11 MacManus M, Nestle U, Rosenzweig KE, et al. Use of PET and PET/CT for radiation therapy planning: IAEA expert report 20062007. Radiother Oncol 2009; 91: 85e94.
Future of radiotherapy Radiotherapy is a rapidly evolving field within medicine and a number of innovations are likely to be introduced over the next few years. Improvements in radiotherapy are driven by changes in imaging, computing and engineering. There is also considerable research in the field of radiobiology. Individualizing radiotherapy based on a number of variables including genomics, combining novel drugs with radiotherapy and assessing patient response on treatment is the vision for the future. Stratification of patients likely to benefit from radiotherapy is currently being evaluated. The use of functional imaging (PET, MRI) during treatment to assess the response of the tumour and surrounding normal tissue to radiation will facilitate personalization of treatment, as will the use of novel biomarkers, to allow better targeting and characterization of radiosensitive cancer cells. Real time imaging and tracking of tumours such as integrating an MRI and LINAC into one device, therefore enhancing the ability to revise plans during treatment (adaptive radiotherapy) is another area being evaluated.18 A REFERENCES 1 National Radiotherapy Implementation Group (NRIG). Radiotherapy services in England, 2012.
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12 Staffurth JA. Review of the clinical evidence for intensitymodulated radiotherapy. Clin Oncol 2010; 22: 643e57. 13 Nutting CM, Morden JP, Harrington K, et al. Parotidsparing intensity modulated versus conventional radiotherapy in head and neck (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011; 12: 127e36. 14 Kirkbride P, Cooper T. Stereotactic body radiotherapy. Guidelines for commissioners, providers and clinicians: a national report. Clin Oncol 2001; 23: 163e4.
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15 Tree AC, Khoo VS, Eeles RA, et al. Stereotactic body radiotherapy for oligometastatic disease. Lancet Oncol 2013 Jan; 14: e28e37. 16 Gwynne S, Webster R, Adams R, et al. Image-guided radiotherapy for rectal cancer e a systematic review. Clin Oncol 2012; 24: 250e60. 17 Andreyev J. Gastrointestinal symptoms after pelvic radiotherapy: a new understanding to improve management of symptomatic patients. Lancet Oncol 2007; 8: 1007e17. 18 Vision for Radiotherapy 2014-2024: Cancer research UK and NHS England.
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