Medical Applications of Electron Linear Accelerators

The role of radiation therapy in cancer management is first defined: today among the cancer patients who are cured (≅ 45 %) about one half are cured by radiation therapy applied alone or in combination with surgery or chemotherapy. The experience accumulated in decades shows that, to be efficient, the radiation treatment must be delivered with a high physical selectivity. At present, electron linear accelerators are the primary equipment of a modern radiotherapy department, and a large proportion of the patients are treated with a linear accelerator for at least part of the treatment. Photon beams of about 6-20 MV have, in general, a sufficient penetration in the tissues to treat most of the tumours with an adequate physical selectivity. A single beam is never used alone, but a combination of several beams adequately oriented allow the radiation-oncologist to deliver the prescribed dose to the target volume without exceeding the tolerance of the surrounding normal tissues. Modern linear accelerators also allow us to apply electron beam therapy. Electron beam therapy is suitable for the treatment of superficial lesions (e.g., skin tumours) and is also the best available irradiation treatment for Intra-Operative-Radiation-Therapy (IORT). Finally, conformation therapy, which is developed in many wellequipped and well-staffed centres, will probably further improve, in the near future, the efficiency of linear accelerators at least for some tumour locations. 1 . INTRODUCTION — ROLE OF RADIATION THERAPY IN CANCER MANAGEMENT Electron linear accelerators today constitute the core of the equipment of a modern radiation therapy department. Nowadays, the majority of the patients referred to a radiation therapy department are treated with a linear accelerator for at least part of their treatment. It is likely that this will remain true for the foreseeable future. Linear accelerators thus play, and will keep playing, a significant role in cancer management in general and are responsible for the therapeutic success obtained in many tumour treatment. To illustrate the situation, Table 1 gives the number of linear accelerators at present used in France for radiotherapy applications (their type and energy). The numbers of the other radiotherapy units are also given for comparison [1]. Cancer has an increasing impact on the death rates in the Western world, as well as in the developing countries. For example, in 1980, 730 000 deaths were attributed to cancer in the countries of the European Union and there were 1 186 000 new cancer cases diagnosed in that year alone [2, 3]. These estimates exclude non-melanoma skin cancer, which, although a rare cause of death, nevertheless demands medical care. Even with the current prevention programs, the numbers will further increase within the next two decades. Similar figures have been published for North America. Table 1 Number of radiotherapy units in France, on 1 January 1994 1) A. LINEAR ACCELERATORS GECGR Mev Other companies Total 4-6 MV NEPTUNE 6 ORION 5 18 Philips (SL 75/5) Clinac 600 C 8 4 31 10 MV NEPTUNE 10 SATURNE 1M 27 3 30 15 MV SATURNE 15 SATURNE 1 SATURNE 41 5 9 16 Philips (SL 18) 4 34 20 MV SATURNE 20 SATURNE 11 SATURNE 42 9 9 4 Philips (SL 75/20) Siemens Mevatron Clinac 2100 C 3 19 4 48 25-40 MV SAGITTAIRE 32 MV SAGITTAIRE 40 MV SATURNE 25 MV 10 2 5 17 20-25 MV SATURNE 111 4 4 25 MV SATURNE 43 35 Philips (SL 75/25) 9 44 Total Linear Accelerators 157 51 208 (+ 19) B. OTHER TYPES OF RADIATION THERAPY UNITS RX 50-100 kV RX 150-305 kV Cobal Units (including 1 gamma knife) Betatrons Cyclotron neutron therapy Cyclotron neutron + protontherapy Synchrotron protontherapy 116 (-6) 34 (-8) 144 (-19) 1 (-2) 1 1 1 1) The differences since 01.01.1993 are given (+) or (-) Today, at the first consultation, approximately 65% of the patients have apparently localized tumours. About 2/3 of these are cured either by surgery, radiotherapy, or a combination of both treatments. In this group of patients with probable but unproved subclinical metastatic disease, chemotherapy used as an adjutant treatment may prolong life and maybe cure some additional patients. Among the other 35% of patients arriving at the first consultation with already inoperable or metastatic disease, only about 5% will be cured by combined treatment including chemotherapy and immunotherapy as well as radiotherapy and/or surgery (Table 2). Although there is promising progress in the field of medical oncology, this cure rate is largely limited to solid paediatric tumours, leukaemias, lymphomas, and testicular tumours. These tumours represent only about 5% of all cancers seen in a general population [4-6]. Although these percentages [5] are useful as an indication of the contribution of the different techniques to cancer cure, they will become progressively less relevant to the extent that combination of these different techniques is more and more successfully applied. It is axiomatic that one must control the local disease if one aims ultimately at curing any cancer patient. In fact, it has been shown that 1/3 of the patients who die of cancer had uncontrolled local disease. If local failure could be reduced by 50%, one could expect a 10-15% improvement in cure rate [7]. Surgical techniques have already reached a very high level. Further improvement will be seen in a reduction of mutilating procedures (limb-sparing operation, breast-conserving therapy, reduction of colostomies, and urinary diversions). On the other hand, wider excisions are still foreseeable as a result of safer anaesthesiology, intensive care support, and improvement in reconstructive surgery. Table 2 Summary of the present situation concerning cancer cure rate Patients Cure rate % With localised tumour: cured by surgery cured by radiotherapy cured by combination of surgery and radiotherapy 65 22 12 6 With inoperable or metastatic disease: cured by combined treatment including chemoand immunotherapy 35 5 Total 100 45 Furthermore, the combination, on a wider scale, of surgery with irradiation will help to increase the local control rate. In that respect, Fletcher (M.D. Anderson Hospital, Houston) has shown that, after radical surgery, doses of 50 Gy given over 5 weeks are able to eradicate expected occult infestation ("subclinical disease") in the lymphatic nodes for cancer of the breast, upper respiratory and digestive track and some pelvic tumours, in more than 90% of the cases. Doses of 50 Gy do not exceed the tolerance limit of many normal tissues. Today, about 70% of the cancer patients are referred to a radiation therapy department, either for a radical treatment (aiming at a local control) or after surgery (also aiming at a local control) or for a palliative treatment often in combination with chemotherapy (e.g., a painful bone metastasis) [8]. 2 . RATIONALE FOR RADIATION THERAPY Soon after the discovery of x-rays by Röntgen in 1895 and of radium by Marie Curie in 1898, it became evident that ionizing radiations could sterilise malignant tumours and thus cure cancer patients. It also became rapidly evident that, above a certain dose level, x-rays induce damage to the normal tissues they traverse. The effects produced by radiation are not instantaneous. In particular, tumour shrinkage after irradiation is a process extending over weeks or even months. This is due to the fact that cells, doomed to die, do not disappear immediately: they remain present for hours or days; sometimes they are able to undergo a few divisions before disintegration and elimination. This progressive tumour shrinkage reduces the risk of acute complications, such as haemorrhage after electro-coagulation. It is a major advantage of irradiation for cancer management [9]. Since local control probability increases with dose, radiation must reach the whole volume(s) of tissues invaded by malignant cells at a sufficiently high dose level to be effective. This goal must be reached without inducing severe and irreversible sequelae in the surrounding normal tissues. A first approach to reach this goal is the improvement of the physical selectivity. 2 . 1 Physical selectivity of a therapeutic irradiation The physical selectivity of irradiation is defined as the ratio of the dose to the "tumour" relative to the dose to the surrounding "normal tissues". It can be improved by varying the nature and energy of the radiation or the beam arrangement (number and orientation of the beams, and their size and shape as in conformation therapy). The best historical illustration of the importance of the physical selectivity in radiation therapy is the impressive improvement in the clinical results achieved in the 1950's–60's when 200 kV x-rays (orthovoltage) were replaced by cobalt-60 gamma rays and high-energy x-rays, as shown in Table 3. The high-energy x-rays mentioned in this table are x-rays (≥ 2–3 MV) produced by Van de Graaff machines, betatrons or electron linear accelerators. Linear accelerators have played an important role in the improvement of the physical selectivity in radiation therapy in the last decades, as will be discussed in detail in the following sections. Table 3 Improved survival of patients with several types of cancer treated with megavoltage radiotherapy Survival (%) after Type of cancer 200 kV x-rays High-energy x-rays Hodgkin's disease Cancer of the cervix Cancer of the ovary 30–35 35–45 15–20 70–75 55–65 50–60 Cancer of the bladder Cancer of the prostate Seminoma of the testis Embryonal cancer of the testis 0–5 5–15 65–70 20–25 25–35 55–60 90–95 55–70 Cancer of the nasopharynx Cancer of the tonsil Retinoblastoma 20–25 25–30 30–40 45–50 40–50 80–85 From the Conquest of Cancer, Report of the National Panel of Consultants of the Committee on Labor and Public Welfare United States Senate, November 1970, p. 51 [9]. Today, with modern techniques, most critical normal tissues such as brain, eyes, spinal cord, kidneys, liver, etc. may be completely avoided or at least irradiated at levels well below tolerance (except, of course, in special cases depending on the tumour location: e.g. the normal brain is the normal tissue at risk when a brain tumour is treated, similarly the spinal cord is the normal tissue at risk when some cervical or mediastinal tumours are treated, etc.). Physical selectivity is a second specific advantage of radiation therapy compared to chemotherapy in which all the tissues in the body are exposed to the toxic drug. The real situation is however more complex. Outside the limits of the detectable tumour (i.e. the "gross tumour volume" as defined below), there is in general some "subclinical" involvement. A larger tissue volume must then be irradiated: not only the gross tumour volume itself but also a surrounding safety margin and, in some cases, the regional lymph node areas. Several types of volumes thus have to be defined and identified. 2 . 2 Concepts and definitions of volumes used in radiation therapy Gross Tumour Volume (GTV) Radiation oncologists first identify the gross tumour volume (GTV), which is the gross palpable or visible extent and location of the cancer disease (ICRU Report 50, [10]). The shape, size and location of the GTV is determined by means of different diagnostic methods such as clinical examination (e.g., inspection, palpation, endoscopy) and various imaging techniques (e.g., x-ray, CT, ultrasound, MRI, etc.). The gross tumour volume consists mainly of malignant cells, connective tissue and blood vessels, and necrotic areas. Clinical Target Volume (CTV) Clinical experience has shown that around the GTV there is in general "subclinical involvement", i.e., individual malignant cells, small cell clusters, or microextensions which cannot be detected by the clinical or imaging procedures. Thus a safety margin surrounding the GTV must be irradiated to ensure local control of the disease. The size of the safety margin depends on the type of tumour, its location, and its tendency to invade the surrounding normal tissues (histology, grading, etc.). The GTV together with this safety margin consisting of tissues with presumed or proven subclinical involvement is defined as a Clinical Target Volume (CTV). In addition to the safety margin around the tumour, other volumes with presumed or proven subclinical spread (such as regional lymph nodes) may also require irradiation. The Clinical Target Volume is thus the tissue volume that contains a demonstrable GTV and/or presumed/proven subclinical microscopic malignant disease. This volume must be treated at an adequate dose level (and time-dose pattern) to achieve the aim of therapy, cure, or palliation. Planning Target Volume (PTV) To ensure that all tissues included in the CTV receive the prescribed dose, one has, in principle, to plan to irradiate a volume geometrically larger than the CTV. It is the Planning Target Volume or PTV. The additional safety margin, included in the PTV, results from a number of factors: movements of the tissues which contain the CTV (e.g., with respiration), as well as movements of the patient. variations in size and shape of the tissues that contain the CTV (e.g., different fillings of the bladder, rectum, stomach). all variations and uncertainties in beam geometry and patient-beam geometry. There are some uncertainties in the beam sizes, shapes and directions, as well as in the relative position of the beam with respect to the patient, the CTV and the normal tissues. all uncertainties in dose distribution, especially in or close to the penumbra region, or where inhomogeneities have to be taken into account (e.g., beam penetration for electron beams). Delineation of the PTV is a matter of compromise and depends upon the judgement of the radiation-oncologist, who ultimately bears the responsibility for this decision. In particular, toolarge safety margins will result in unnecessary side effects and complications. 2 . 3 IMPROVEMENT OF THE DIFFERENTIAL EFFECT. A PROBLEM FOR THE RADIOBIOLOGIST As defined above, the safety margins contained in the CTV and in the PTV consist primarily of normal tissues and, only for a small proportion, of invading cancer cells. Because of the presence of these cells, the safety margin should be irradiated in principle to the highest possible dose to prevent a local recurrence, but the tolerance of the normal tissues included in the safety margin limits the dose which can be prescribed. The difficulty cannot be solved by improving the physical selectivity of the irradiation; it requires an improvement of the differential effect, and this brings us from the field of physics to the field of radiobiology. Improvement of the differential effect implies, for a given (physical) dose, increasing the effect of the cancer cell population and/or reducing the effects on the normal tissues [11, 12]. The possibility of improving the differential effect by adequately selecting the irradiation parameters is the third advantage of radiation therapy for cancer management. Historically the first, and presently the most efficient, method for improving the differential effect was the fractionation of the dose, as initiated in 1919 by Regaud, Ferroux and Coutard at the Fondation Curie in Paris. Today, five fractions of 2 Gy each per week are used as the conventional fractionation for most treatments. As a further refinement, the fractionation could be adapted to the growth characteristics of the individual tumour (such as, the tumour doubling time, or better the potential doubling time, TPOT). In that respect, an EORTC study has shown that a shorter overall time brings a benefit for some head and neck tumours with short TPOT. This implies the administration of several small (≤ 1.5 Gy) fractions per day, since large fraction sizes are known to be harmful. Combination of radiation with radiosensitizers is another method to improve the differential effect. Drugs such as misonidazole are used to sensitize selectively hypoxic cancer cells. Other drugs, such as actinomycin D, bleomycin, adriamycin, 5-fluorouracil, and, more recently, cis-platinum have been used as radiosensitizers in the treatment of oesophagus, lung, or intestinal tumours. Besides any synergistic effects, radiation and drugs have several complementary actions which further justify their therapeutic association. A third possibility for improving the differential effect is to replace x-rays (and other lowLET radiations) by high-LET radiations (ICRU Report 45 [10]). High-LET radiations bring a benefit for well-differentiated, slowly growing tumours and/or for tumours containing a large proportion of hypoxic cancer cells [13-15]. 2 . 4 ACCURACY REQUIRED IN RADIATION THERAPY Whatever the improvement in the radiobiological differential effect, the doses which are needed to control a malignant tumour are often of the same order of magnitude as the tolerance doses for the normal tissues. In addition, radiobiological and clinical evidence indicates that the dose-effect relations for tumour control are steep (Table 4) [16–18]. For some tumours, a dose variation of a few percent can modify significantly the observed local control rate. The doseeffect relations are even steeper for normal tissue complications (Table 5) [17]. For these two reasons, accurate dosimetry is needed, and, in 1976, the ICRU made the following recommendations: "the available evidence for certain types of tumours points to the need for an accuracy of ± 5% in the delivery of an absorbed dose to a target volume if the eradication of the primary tumour is sought" (ICRU Report 24 [10]). More recently (1987), Mijnheer et al. [17] recommended an accuracy in absorbed dose delivery of 3.5% (one standard deviation, for the dose at the specification point, for radical treatment). Over the years, the ICRU has played an important role in the world-wide improvement of dosimetry in radiation therapy. An important step in that direction was the definition of quantities and of a system of units (ICRU Report 33 [10]). Besides quantities and units, the ICRU has focused a great part of its efforts on the selection of procedures suitable for the measurement and application of these quantities. This implies a critical review of the existing procedures, value judgement, and finally the recommendation of selected procedures. These should be well described and codified, and widely accepted in the different countries. Several ICRU Reports have dealt with dosimetry protocols for photon therapy: Reports 14, 17, 23, 24 and 42 [10]. For electron beam therapy, Report 35 remains a world-wide reference. Other ICRU Reports have contributed to a better accuracy and uniformity of dosimetry procedures in radiation therapy: Reports 44, 46 and 48. Table 4 Relative steepness of the dose-effect curve for local tumour control. The steepness is expressed as the relative increase in absorbed dose (in %) producing a change in tumour control probability from 50 to 75%. Site of tumour Steepness (%) Supraglottic larynx T2 and T3 (Shukovsky) Larynx T3 (Stewart and Jackson) Supraglottic larynx all stages (Hjelm-Hansen et al.) 5 6 11 Larynx all stages (Hjelm-Hansen et al.) Bladder T4B (Battermann et al.) Epidermoid carcinoma head and neck (Cohen) 12 13 13 Supraglottic larynx T1 and T2 (Ghossein et al.) Skin and lip (Strandqvist) Supraglottic larynx T2 and T3, revised analysis of the Shukovsky date (Thames et al.) 13 17