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BMJ. 2001 November 10; 323(7321): 1107–1110. | PMCID: PMC1121599 |
Radiotherapy R P Symonds, reader in clinical oncology University Department of Oncology, Leicester Royal Infirmary, Leicester LE1 5WW Radiotherapy is the art of using ionising radiation to destroy malignant tumours while minimising damage to normal tissue. This treatment can be highly effective. For instance, for early cancer of the larynx the cure rate is over 90%, 1 and palliative radiotherapy can reduce or eliminate pain from bone metastases in 80% of patients. 2 Although higher doses of radiation can produce better tumour control, the dosage that can be given is limited by the possibility of normal tissue damage. Ulceration, fistulas, severe fibrosis, and strictures may develop months or years after treatment, severely affecting the quality of life. The recent advances described in this paper focus on new techniques that produce the maximum ratio between tumour destruction and normal tissue damage and the increasing participation of patients in treatment planning. 3A comprehensive literature search looking for recent advances in radiotherapy was not straightforward. Between 1996 and 2001 Medline listed 22  937 articles published in English on human radiotherapy, of which 1878 were listed as reviews. The search was focused on the main topic subheadings (conformal radiotherapy, intensity modulated radiotherapy, combined radiotherapy and chemotherapy treatments, fractionation schedules, and radiosurgery), and this was supplemented by articles from six cancer and three general journals on radiotherapy. The vast improvement in diagnostic imaging has been immensely helpful in treatment planning. If a small portion of the cancer is excluded from the irradiated volume, the treatment is bound to fail. Reconstructed matched computed tomograms and magnetic resonance images can now be used during treatment planning, and this reduces the possibility of “geographic miss.” Moreover, the dose distribution to the target volume can be shaped to conform tightly to the shape of the tumour, reducing the volume of normal tissue irradiated by up to 50% and late damage (side effects developing months or years later). The dose to the tumour can be increased, with a greater probability of local control. The radiation beams used to treat the tumour can be shaped to the irregular volume required by using either customised shaped dense blocks or by multileaf collimators (part of the beam shaping apparatus in a modern linear accelerator). Up to 40 pairs of tungsten bars usually 1 cm in width, can be adjusted in length to define the x ray beam. Recent advances - The use of computed tomography and magnetic resonance imaging has led to more accurate treatment planning and the ability to define a target volume that tightly conforms to the tumour shape
- This irregular volume can be treated to higher doses with sparing of normal tissue, leading to increased local control
- Increased destruction of tumours without increased late toxicity has also been seen with new fractionation regimens and chemoradiotherapy treatments
- The internet has allowed patients to be more informed about the investigation and treatment of cancer, although as a result patients ask more questions
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The value of conformal techniques has been well shown in the treatment of prostate cancer, now the second most important cause of death from cancer in men in the developed world. 4 Prospective dose escalation studies have shown that higher doses can be given with a marked improvement in five year “cure” (as judged by prostate specific antigen values and lack of clinical or radiological evidence of disease) without any increase in late toxicity. 5Intensity modulated radiotherapy Intensity modulated radiotherapy is the most advanced form of conformal radiotherapy. Conventional radiation beams are of uniform intensity across the field. In intensity modulated radiotherapy, however, the dose distribution is non-uniform across several radiation beams, which summate to produce an optimum dose distribution conforming closely to the shape of the target volume. The intensity of the radiation beam can be modulated by specifically manufactured metallic compensators (an expensive and time consuming task) or by multileaf collimators. The multileaf collimator may be stationary, with treatment given to multiple segments of a field (the “step and shoot” technique) or by moving the collimator's leaves during treatment (the “sliding window” technique). 6 Intensity modulated radiotherapy can generate concave dose distributions, which can be advantageous in the treatment of pharynx or larynx cancer and the draining of lymph nodes in the neck. The target volume can be shaped to include all potentially tumour bearing areas with sparing of the vulnerable spinal cord. Intensity modulated radiotherapy is in its infancy in the United Kingdom, but techniques are better developed in the United States. The major value of this radiotherapy to date is the reduction of late side effects. Xerostomia is an unpleasant consequence of including the salivary glands in the treatment area when lymph nodes are irradiated on both sides of the neck. Treatment with intensity modulated radiotherapy has been shown to preserve substantial salivary function without compromising the target volume. 7 Cure rates may be increased in the treatment of brain tumours as higher doses can be given to the tumour with sparing of the vulnerable surrounding brain. Combined radiotherapy and chemotherapy treatments Chemotherapy for cervical cancer has been described as the most important improvement in the treatment of this disease in the past 40 years. 8 A Cochrane meta-analysis of all known randomised controlled trials has shown a reduction in the risk of death by 29%. Not only was there a significant increase in local control (odds ratio 0.61, P<0.0001) but there was also a marked decrease in distant metastases (0.57, P<0.0001). Acute toxicity, particularly haematological and gastrointestinal, was increased by combined treatment. No increase in late toxicity has been reported, although this was poorly described in many studies. 9More modest gains from combined treatment have been seen at other sites. A recent meta-analysis of randomised head and neck cancer trials showed that concomitant chemoradiotherapy led to an overall increase in five year survival of 8% compared with conventional treatment. 10 The best radiotherapy or chemotherapy regimen is not known, but cisplatin and 5-fluorouracil are the most commonly used drugs. One trial has shown improved survival if cisplatin and 5-fluorouracil are added to hyperfractionated radiotherapy, 11 but further randomised controlled trials are needed in this area. Chemoradiation schedules are being used in the treatment of anal 12 and oesophageal cancer. Almost on the strength of one study, 13 chemoradiotherapy is now the standard non-surgical treatment for oesophageal cancer in the United States. One randomised trial showed that chemoradiotherapy given before surgery improved survival, 14 but in view of trials with negative results further research is needed. More frequent fractionation schedules Radiotherapy given two or three times daily is more effective than daily treatment for patients with rapidly proliferating tumours—such as some squamous carcinomas, particularly those in the head and neck or bronchus. Repopulation during protracted treatment is one reason for tumour persistence after radiotherapy. A recent trial of 1113 patients with head and neck cancer show a significant improvement in local control and a trend for better long term survival for hyperfractionation (1.2 Gy twice daily) or the concomitant boost technique when compared with a standard schedule of 70 Gy given over seven weeks. Acute side effects were greater in the experimental arms, but there was no increase in late effects. 15 A Danish trial showed that by reducing treatment time from six and a half to five and a half weeks, five year survival in head and neck cancer was increased from 65% to 72% (P=0.04). 16 This intriguing result was achieved by giving an extra fraction either on Saturday or two fractions six hours apart on a Friday. Both arms of this study received the same dose (66-68 Gy). Patients with well or moderately well differentiated tumours seem to have the greatest capacity for repopulation during radiotherapy and seem to be the group most likely to benefit from accelerated fractionation. 17Radiosurgery is now the treatment of choice for arteriovenous malformations. 18 The volume of normal tissue irradiated is reduced to a minimum using the gamma knife, in which 201 Cobalt 60 sources in a fixed hemispheric array are focused on a small stereotactically defined target volume (figure). Normal tissue sparing is increased when treatment is given in multiple fractions using a specially adapted linear accelerator rather than in a single treatment using the gamma knife. In the treatment of acoustic neuromas, treatments with a gamma knife and linear accelerator produce similar impressive tumour destruction rates, but improved hearing has only been reported after fractionated treatment. 19Clinical experience suggests that radiosurgery in the treatment of brain metastasis is as good as surgical removal followed by external beam radiotherapy, and clinical trials are in progress. 20 Radiosurgery techniques have been extended to the treatment of gliomas, which have a dismal prognosis. A randomised trial by a radiation therapy oncology group has shown that stereotactic boost treatments can produce a median survival four to 20 months longer (depending on prognostic category) compared with standard radiotherapy. 21 The value of these techniques in treating cerebral metastasis and gliomas needs to be explored further as stereotactic radiosurgery is labour intensive and time consuming. Patients' participation in care Access to information on the internet means that many patients are now well informed about treatment options. Some ask for treatments that may not be available in their regional cancer centre, and because of the variable quality of the information they access, patients may gain an exaggerated or distorted view of the value of new developments. Following the introduction of cancer units and regional cancer centres in the United Kingdom, more patients are referred to an oncologist. As a consequence more patients now receive radiotherapy. 22 The management of most patients is now discussed and decided in multidisciplinary meetings. 23 Such a meeting usually consists of at least an oncologist, a surgeon, a radiologist, a pathologist, and often nurse specialists; other specialists may also attend—such as paediatricians to discuss the management of brain tumours; the patient does not attend the meeting. Increased participation by patients in decision making is illustrated by a cross sectional survey in the west of Scotland showing that most wanted to know the diagnosis, treatment options, likely side effects of treatment, and chance of cure. 24 Additional educational resources Key review articles Hanks GE. Conformed radiotherapy for prostate cancer. Ann Med 2000;32:57-63. Nutting C et al. Intensity modulated radiation therapy: a clinical review Br J Radiol 2000;3:459-69. De Vita VT et al, eds. Cancer: principles and practice of oncology. Philadelphia: Lippincott, Williams, and Williams, 2001. BMJ archive Tobias JS et al. Synchronous chemoradiation for squamous carcinomas. BMJ 2001;322:876-8. Kunkler I. Adjuvant irradiation for breast cancer. BMJ 2000;320:1485-6. Burnett NG et al. Improving cancer outcomes through radiotherapy. BMJ 2000;320:198-9. Useful websites For doctors CancerNet gives information about cancer from the National Cancer Institute, the US federal government's principal agency for cancer research CancerWeb gives information on many different aspects of the investigation and treatment of cancer; suitable website for patients too OncoLink gives introductory and in-depth information (updated daily) about specific types of cancer, updates on treatments, and news about research advances For patients Macmillan Cancer Relief is a UK charity supporting people with cancer and their families with specialist information, treatment and care CancerBACUP provides a free cancer information service; publications on all aspects of cancer; and local centres in hospitals |
To some extent the need for more information can be partially met by pointing patients to reliable websites and by booklets (those produced by CancerBACUP and Macmillan Cancer Relief are particularly good). The major role of pamphlets and online information, however, should be to reinforce adequate oral communication. Most patients want more time to talk to their consultant. This can be difficult to schedule in busy units with large workloads. The average British oncologist sees two to three times as many new patients a year as his or her European or North American counterpart. In the past 10 years the technological advances in radiotherapy have been immense, but some of the technology has not been rigorously evaluated. For instance, although conformal radiotherapy has been shown in randomised trials to reduce late effects in prostate cancer, 25 randomised trials (such as the ongoing Medical Research Council's RTO1 trial) are needed to substantiate that this results in increased survival. Similarly, the potential of intensity modulated radiotherapy is great and should permit higher doses targeted at the tumour, with sparing of vulnerable normal tissue. But it is because of this promise, rather than because of established results, that linear accelerators capable of delivering this type of radiotherapy are being installed across the United States. I thank Mrs J Symonds and Mrs J McNair for constructive criticism and typing the manuscript. I am grateful for the helpful comments of Professor W Steward and Mr Steve Bolton, who also produced the illustrations. 1. Wang CC. Radiation therapy for head and neck neoplasms. New York: Wiley-Liss; 1997. 2. Hoskins PJ, Price P, Easton D, Regan J, Austin D, Palmer S, et al. A prospective randomised trial of 4Gy or 8Gy single doses in the treatment of metastatic bone pain. Radiother Oncol. 1992;23:74–78. [PubMed] 3. Steel GG, editor. Basic clinical radiobiology. London: Arnold; 1993. 4. Wingo PA, Ries LA, Rosenberg HM, Miller DS, Edwards BK. Cancer incidence and mortality, 1973-1995: a report card for the US. Cancer. 1998;98:1197–1207. [PubMed] 5. Hanks GE. Conformed radiotherapy for prostate cancer. Ann Med. 2000;32:57–63. [PubMed] 6. Nutting C, Dearnaley DF, Webb S. Intensity modulated radiation therapy: a clinical review. Br J Radiol. 2000;73:459–469. [PubMed] 7. Eisbruch A, Marsh LH, Martel MK, Ship JA, Haken PT, Pu AT, et al. Comprehensive irradiation of head and neck cancer using conformed multisegmental fields: assessment of target coverage and non involved tissue sparing. Int J Radiat Oncol Biol Phys. 1998;41:559–568. [PubMed] 8. Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to loco-regional treatment for head and neck squamous cell carcinoma: three meta-analyses of updated individual data. Lancet. 2000;355:949–955. [PubMed] 9. Eifel PJ. Chemoradiation for carcinoma of cervix: advances and opportunities. Radiat Res. 2000;154:229–236. [PubMed] 10. Green JA, Kirwan JJ, Tierney J, Symonds P, Fresco L, Collingwood M, et al. Systematic review and meta-analysis of randomised trials of concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: better survival and improved distant recurrence rates. Lancet. 2001;358:781–786. [PubMed] 11. Brizel DM, Albers ME, Fisher SR, Scher RL, Richtsmeier WJ, Hars V, et al. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med. 1998;338:1798–1804. [PubMed] 12. Ryan DP, Compton CC, Mayer RJ. Carcinoma of the anal canal. N Engl J Med. 2000;342:792–800. [PubMed] 13. Herskovia A, Martz K, Al-Sarraf M, Leichman L, Brindle J, Vaitbevicius L, et al. Combined chemotherapy and radiotherapy compared to radiotherapy alone in patients with cancer of the oesophagus. N Engl J Med. 1992;326:1593–1597. [PubMed] 14. Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TPJ. A comparison of multi-modal therapy and surgery for oesophageal adenocarcinoma. N Engl J Med. 1996;335:462–467. [PubMed] 15. Fu KK, Pajak TF, Trotti A, Jones CU, Spencer SA, Philips TL, et al. A radiation therapy oncology group (RTOG) Phase III randomised study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionated radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. Int J Radiat Oncol Biol Phys. 2000;48:7–16. [PubMed] 16. Overgaard J, Sandhansen H, Overgaard M, Bastholt L, Specht L, Evenson J, et al. Conventional radiotherapy as primary treatment of squamous cell carcinoma of the head and neck. A randomised multicentre study of 5 versus 6 fractions per week—report from the DAHANCA 7 trial. Int J Radiat Oncol Biol Phys. 1997;39(suppl 2):188. 17. Slevin NJ, West CML, Wilson GD, Hendry JH. The potential benefit from individualised radiotherapy scheduling for head and neck tumours on the basis of both histological grade and kinetics. Radiother Oncol. 1999;51:109–111. [PubMed] 18. Steiner L, Linquist C, Adler JR, Tomer JC, Alves W, Steiner M, et al. Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg. 1992;77:1–8. [PubMed] 19. Sims E, Doughty D, Macauley E, Royle N, Wraith C, Darlison R, et al. Stereotactically delivered cranial radiation therapy: a ten year experience of linac-based radiosurgery in the UK. Clin Oncol. 1999;11:303–320. 20. Eban A, Loeffler JS. Intracranial metastatic tumour management. The case for radiosurgery. Clin Neurosurg. 1999;45:32–40. [PubMed] 21. Sarkaria JN, Mehta MP, Loeffler JS, Buatti JM, Chappell RJ, Levin AB, et al. Radiosurgery in the initial management of malignant gliomas. Survival comparison with the RTOG recursive partitioning analysis. Int J Radiat Oncol Biol Phys. 1995;32:931–941. [PubMed] 22. Expert Advisory Group on Cancer. A policy framework for commissioning cancer services. London: Department of Health; 1995. 23. Department of Health. Manual of cancer services standards. London: NHS Executive; 2000. 24. Meredith C, Symonds P, Webster L, Lamont D, Pyper E, Gillis CR, et al. Information needs of cancer patients in West Scotland: cross sectional survey of patients' views. BMJ. 1996;313:724–726. [PubMed] 25. Dearnaley DP, Khoo VS, Norman AR, Meyer L, Nahun A, Tait D, et al. Comparison of radiation side effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet. 1999;353:267–272. [PubMed]
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