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Impact of radiation research on clinical trials in radiation oncology
Clinical Radiology (1989) 40, 68-75
Impact of Radiation Research on Clinical Trials in Radiation Oncology P.
RUBIN and
J. D .
VAN ESS
Department of Radiation Oncology, University of Rochester Cancer Center, 601 Elmwood Avenue, Box 647, Rochester, New York 14642 The scientific basis for the practice of radiation oncology is derived from research in medical physics and radiation biology. Many of the radiation research accomplishments can be traced to, and were in part generated by, the identification of clinical needs. This interplay between science and the clinic led to the design of co-operative clinical trials. In July 1975, the Radiation Oncology Coordination Subcommittee (ROCS) of the Board of Scientific Counselors of the Division of Cancer Treatment at NCI, was appointed by the Director, Vincent De Vita. This subcommittee was reponsible for: reviewing and assessing the state of science in radiation oncology; developing a scientific plan and recommending future research activities; and co-ordinating research among scientific investigators in the fields of radiation oncology, biology and physics. A research plan was formulated (Radiation Oncology Cooperative Subcommittee Research Plan, 1979) and, initially, six interdependent research areas were selected and Working Groups formed as follows: - T h e Experimental Combined Modality Working Group developed scientific plans and recommendations for preclinical chemotherapy/radiation therapy studies, consisting of a core of investigations with biologically well-defined tumour systems (Experimental Combined Modalities Study Group, 1979). - The Radiosensitisers and Radioprotection Working Group, a special committee in the Division of Cancer Treatment Drug Development Network at the National Cancer Institute, worked on hypoxic cell radiosensitisers and radioprotectors (ROCS Radiosensitisers/Radioprotectors Working Group, 1979) - T h e Hyperthermia Working Group planned proposals for instrumentation, thermometry and pathophysiologic and biologic cellular studies (ROCS Hyperthermia Working Group, 1979). - The Radiation Immunology Working Group planned preclinical and clinical research using radiolabelled tumour-specific and/or tumour-associated antibodies (ROCS Radiation Immunology Working Group, 1979). - The Toxicity Working Group planned experimental small and large animal late effects studies, searched for predictive assays, and recommended studies related to combinations of modalities (ROCS Toxicology Working Group, 1979) - The High LET Particle Working Group made a series of proposals for developing a sufficient number of centres to study neutrons, charged particles, and pi mesons (The Radiation Oncology Research Program: High-LET, 1979). These Groups reported to a Council of Radiation Oncology Chairpersons who directed the protocol design and development in various national co-operative groups. They incorporated these research themes into clinical trials, developing a clinical database for future
directions in both clinical radiation therapy and multimodal research. This effort was actualised by 1980 with more than 50 million dollars awarded by NCI; this funding level has been largely maintained to date. In 1968, the Radiation Therapy Oncology Group (RTOG) was organised in response to the need for developing clinical trials in radiation oncology. The research strategies of the RTOG reflected the research planning in RCOS (Radiation Oncology Cooperative Subcommittee Research Plan, 1979) and the Committee for Radiation Oncology Studies (1976). In April of 1986, a new effort to foster international collaboration among investigators was organised. At a Spring meeting in Paris, investigators from major cooperative groups in the United States and Europe (mainly from RTOG, European Organisation for Research & Treatment of Cancer (EORTC) and the Medical Research Council (MRC)) formed a co-operative group called the 'International Clinical Trials in Radiation Oncology' (ICTRO). The ICTRO is developing an international radiation research plan in response to an NCI directive that radiation oncology clinical trials research will be the first named Core Subject in 'bilateral agreements' between the United States and other world governments. Much of the analyses and results presented are from the document resulting from this ICTRO conference (ICTRO Research Plan, 1988). Progress in a number of specific areas will now be reviewed together with some projections for the direction of clinical trials in radiation oncology into the 1990s.
Radiosensitisers
Phase I studies, using misonidazole, began in 1977 to determine its neurotoxicity and monitor serum drug levels to determine effective drug delivery schedules. Phase II studies were initiated shortly thereafter by the RTOG, in a variety of disease sites. The optimal misonidazole dose proved to be 12-15 g/m2; neurotoxicity proved to be the major risk factor. From 1981 to 1986, in 11 Phase II studies (Chemical Modifiers of Cancer Treatment, 1984) accumulating 591 patients, the tolerance dose schedules of misonidazole were established and a variety of fractionated dose regimen were designed in an attempt to find an effective programme. As these studies were completed, a series of randomised Phase II clinical trials evaluated high and low fractional misonidazole doses in a variety of fractionation schemes in seven sites. No advantage was shown after accumulating 2181 patients in the RTOG studies, which included head and neck cancers, brain metastases, lung cancer, gliomas, hepatic metastases, and cervix cancer (Chemical Modifiers of Cancer Treatment, 1984). In EORTC or MRC Phase III studies in head and neck cancer, cervix cancer, and gliomas, no survival or local
IMPACT OF RADIATION RESEARCH ON CLINICAL TRIALS"
control advantage could be shown (Chemical Modifiers of Cancer Treatment, 1984). In the near future (1987-1991), a new generation of compounds will be available, SR-2508 (Coleman et al., 1984) and RO-03-8799 (Roberts et al., 1984); they are three to five times more effective in cumulative sensitising efficacy than misonidazole, because of lower toxicity and higher penetration. These agents, unlike misonidazole, fill the criteria of a drug with a good therapeutic ratio, allowing for the administration of high fractional doses to yield enhancement ratios greater than 1.5, a sufficient drug dose to administer more than 15 individual doses during a course of radiotherapy, and effective combination with more conventional radiation fractionation regimens. Phase I/II studies, which began in 1983, are complete and Phase III clinical trials are being developed in head and neck cancers, cervix cancer, and lung cancer. Combining SR-2508 and RO-03-8799 seems promising if no increase in toxicity is found. In addition, buthionineSR-sufoximine is being evaluated as its action in depleting cellular glutathione might further increase sensitisation.
Radioprotectors Based upon the known scavenger capacity of sulphydryl radicals to reduce oxidative reactions, many sulphydryl-containing compounds were developed by the US Army to protect people in the event of nuclear war. The US Army developed over 300 000 such compounds; the highest degree of radioprotection was found with thiophosphates, among which WR-2721 was best. In 1969 it was reported that these agents, especially WR-2721, preferentially protected normal tissue versus tumours (Yuhas and Storer, 1969); this was attributed to deficient vascularity in tumours, the limitation of transfer inherent in the tumour cell membrane, which reduces drug absorption, and the relative inability of hypoxic cells to respond to protection, since this competes against oxygen sensitisation. Kligerman and Yuhas carried out Phase I studies during the early 1980s, which identified toxicity comprising hypotension, nausea, vomiting, and somnolence, these effects were reduced by rapid intravenous infusion (Kligerman et al., 1984). Multiple dose Phase I/II studies led to establishing 450 mg/m 2, repeated four times a week for 5 weeks, as a tolerable dose with acceptable toxicity. Experimental evidence suggested that maximal concentrations yield differential protection in the range of 2-3, especially for bone marrow. Because WR-2721 protects bone marrow but does not protect the central nervous system, and is only modest in its ability to protect lung and kidney, hemibody irradiation in patients with overt metastases seemed a suitable target population to launch Phase II trials. Currently, effective haematologic radioprotection is strongly suggested, in comparison to historical controls with less striking nadirs, more rapid recovery of leucocytes and platelets, and fewer life-threatening and sever toxicities (Rubin et al., 1982). It is suggested that the radiation dose could be increased by 20% with WR-2721. Between 1986 and 1991, Phase III clinical trials will be conducted. Single doses of WR-2721, ranging between 750 and 900 mg/m 2, will be used with a range of hemibody radiation doses of 700 900 cGy, to more firmly demonstrate bone marrow radioprotection. Similarly, Phase III fractionated studies will be explored with WR-2721 and accelerated fractionation to establish differential radio-
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protection. Such novel ideas as combining radiosensitisers and radioprotectors are under consideration.
Drug-Radiation Interactions Of all the ROCS programmes, none began with more enthusiasm for research planning than did the Experimental Combined Modalities Study Group for studying drug radiation interactions. Twelve laboratories were chosen to provide a battery of tumours whose biological characteristics were thoroughly studied for radiation responsiveness and cellular kinetics. These tumours were the EMT6, the mammary C3H carcinoma, the Lewis lung cancer, gliomas, sarcomas and human xenografts to which colon 26 carcinoma and B6 melanoma were added (Experimental Combined Modalities Study Group, 1979). The following clinically effective drugs were most actively studied: doxorubicin, cyclophosphamide, nitrosoureas (BCNU, CCNU), 5-fluorouracil, methotrexate, vincristine and, of the then newer agents, cis-platinum. In addition to tumours, a number of normal tissues were chosen to develop therapeutic ratios; they included: skin, gut, bone marrow, brain, spinal cord, heart, and lung. The first major scientific meeting was held at Hilton Head (Conference on Combined Modalities Chemotherapy/Radiotherapy, 1979). Optimal timing of drug administration seemed to be either hours before, simultaneous to, or hours after radiation therapy, but no clear guidance emerged from the laboratory for clinical study although several Phase I trials were attempted with little encouragement for a Phase III study. Simultaneously, the major national co-operative geographic chemotherapy groups became multidisciplinary and chose radiation oncology chairpersons to develop their Phase I-II drug and radiation combination studies. Phase III randomised studies were initiated, such as the R T O G use of methotrexate and irradiation in head and neck cancer. The Eastern Cooperative Oncology Group and Gastrointestinal Tumour Study Group favoured the combination of 5-fluorouracil and irradiation in gastrointestinal, rectal, and pancreatic cancers, whereas paediatric groups favoured cyclophosphamide, actinomycin, and vincristine and irradiation. Most of these initial studies began enthusiastically with the expectation of therapeutic gains and increased survival. This optimism faded as most major Phase III studies failed to show any gains. There was no concurrence as to the best sequence or combinations of drugs and radiation in many major disease sites, including lung (both small cell and non-small cell carcinomas), head and neck cancers, brain tumours, gastrointestinal cancers, and soft tissue sarcomas. As a result, numerous Phase I and II studies have been initiated, replacing the Phase III studies of 30-40 patients. What is disheartening is that the drugs are active and yet combining them with irradiation in a more effective combination is elusive. Currently, the most widely used combinations are simultaneously infused 5-fluorouracil sometimes combined with either cis-platinum or mitomycin C. Cis-platinum alone with irradiation is being explored as a radiosensitiser in head and neck and bladder cancer (Phillips et al., 1988). No true supra-additivity exists except from cis-plantinum, and most other combinations are negative. DMF's of 1.9 and 2.2 can be obtained with cis-platinum and irradiation. In vivo experiments in normal tissue indicate a
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D M F of 1.3 for many drugs, which suggests that cisplatinum should be a favourable combination agent clinically. Accordingly, the majority of R T O G , EORTC, M R C protocols currently use cis-platinum (Phillips et al., in press). For the future the trend will be to combine infusion chemotherapy with irradiation; the prominent agents are 5-fluorouracil, cis-platinum, and mitomycin-C singly or together. One success story emerging is the treatment of anal carcinomas where radical surgical management is being replaced by moderate dose irradiation with 5fluorouracil and mitomycin-C infusion, with anal sphincter preservation (Nigro et al., 1974). This strategy has emerged and is being applied to other squamous cell and adenocarcinomas of the digestive tract.
Dose/Time/Fraetionation The search for optimum dose/time/fractionation schedules for each cancer, based on tumour biology and cellular kinetics, is synonymous with the history of radiation therapy. The classic radiobiologic observations in the ram's testes demonstrated that a fractionated dose would more efficiently result in sterility, with a lower total dose, than would a single high exposure dose (Regaud and Ferroux, 1929). Because fractionation also provided scrotal skin sparing and a better therapeutic ratio, this study is a cornerstone of radiation oncology. The concept of rapid renewal systems, where the tumour is selectively eradicated while the normal tissue is spared, is the impetus for exploring different fractionation schemes. Much mathematical modelling has been performed to determine a single number that can express the dose/time/ fractionation and the effect of different schedules in a relative, comparative scale. The formulations or coefficients most frequently used are those developed by Ellis (1969) and Orton (1972) whose calculated equivalent doses - NSD, and T D F respectively - are useful clinical guides for large fractions. Exploring multiple daily fractions and smaller fractionation doses is a logical derivative of radiation biology research into late effects. Withers has emphasised the difference in slopes for acute versus late effect tissues (Withers, 1970). Because the majority of malignant tumours require total doses near the tolerance of their surrounding normal tissues or organs, using hyperfractionation or accelerated fractionation to improve the therpeutic ratio for their control has appealed to radiation oncology investigators. The ability to deliver higher total doses in shorter time periods, while maintaining late effects complications at a low rate ( < 5 % ) , has been incorporated into the R T O G and E O R T C protocol designs. The current generation of protocols began in 1980, with R T O G defining and exploring hyperfractionation as dividing a conventionally daily dose into smaller individual fractions, and E O R T C defining and exploring accelerated fractionation as a conventional daily dose of 150-200 cGy given several times in I day at 4-6 h intervals (Cox and van der Schueren, 1988). Upon reviewing the R T O G trials in fractionation, the initial emphasis from 1975 to 1981 was split-course schedules (Marcial and Pajack, 1985). From 1981 to 1986 a major commitment was made to hyperfractionation in randomised Phase II studies, where doses have ranged from 68 to 86 Gy with escalations of 4-6 Gy so that in many sites, 80 Gy has been administered. A definition of
Table 1 Fractionation definitions Fractionation schedule
Dose/fraction (Gy)
No ofJ?actions each week
Treatment internal (h)
Common Hypo Hyper Rapid Accel
1.0-2.5 > 3.0 0.7-1.3 > 2.5 1.5-2.5
5-6 1 4 10-25 5 10-15
24 48-168 2 12 24 4-12
different fractionation schedules has been offered by (Cox and van der Schueren, 1988) (Table 1). This represents a 10 15 % increase in total dose with hyperfractionation for head and neck cancers, lung cancers, and gliomas; sufficient time for follow-up is required to ascertain late effects. One randomised head and neck cancer study has been completed, but total doses were conservative (70 Gy conventional compared with 60 Gy hyperfractionated) so that the issue is unsettled (Marcal et al., 1987). The E O R T C has followed accelerated schedules and have completed a glioma and a head and neck cancer clinical trial with hyperfractionation. The preliminary analysis favours the latter approach. The unpublished results indicate that 80 Gy hyperfractionated is superior to conventional therapy schedules (Horiot, personal communication). In the E O R T C accelerated schedules, 2 Gy were given three times daily (30 Gy weekly), with another 30 Gy after a 2-week rest. Although the overall time was reduced from 6 weeks to 4 weeks, no therapeutic gain was seen in head and neck cancers. In another version, a very rapid administration of 48 Gy was given in 2 weeks followed by a second series of 24 Gy to provide a total of 72 Gy in 7 weeks, similar to conventional schedules. Once more, no gain was seen (Cox & van der Schueren, in press) In the future, dose fractionation will be one of the most important research themes because of its potential widespread application, although the required extra machine time could be a major impediment. More difficult fractionation schedules are envisioned with more than dose schedules being evaluated. Careful analyses of tumour control and normal tissue late effect complications are essential to be certain that the therapeutic ratio is being improved. The impact on more megavoltage equipment needs, patient waiting-rooms, and technical staff could be demanding because this may significantly increase the number of patient visits for a curative course of irradiation. The priorities for future studies include further Phase III comparisons of different dose fractionation regimes and the definition of correction factors to adjust the fraction size in relation to the altered schedules.
Hyperthermia Hyperthermia has been used to treat thousands of patients with malignant disease; although it has been sporadically used since 1900s, it has recently become a major investigational modality. During the 1960s, interest shifted from total body heating to more localised and regionalised heating methods. With improvement in instrumentation, a variety of heating sources is now available for clinical use, including: radiofrequency antennae for interstitial heating, microwave for regional and superficial heating with radical arrays designed for deeper heating, and ultrasound for focused heating in depth to avoid air cavities and bone. The biological experiments in vivo and in vitro have indicated that
I M P A C T OF R A D I A T I O N RESEARCH ON C L I N I C A L T R I A L S
temperatures-above 41°C must be maintained because fluctuations of 1-2°C can dramatically alter the effectiveness of heat killing of tumour cells in culture, particularly in combination with irradiation. This has created a demand for accurate invasive and non-invasive isotherm mapping thermometry. The quality assurance is more demanding than for radiation therapy, because physiological factors, such as blood flow, can alter the temperatures in tumours and normal tissues despite a constant power deposition. In 1979, the ROCS research plan (ROCS Hyperthermia Working Group, 1979) encompassed the elements of modality development, the need for experimental in vivo systems in both small and large animals, and initiating both Phase I and Phase II clinical trials. Within 5 years, improvement in heat delivery systems occurred with some effort at standardisation, as individually constructed units were supplanted by commercially manufactured sources. The major effort in Phase I clinical trials was to determine and consequently avoid toxicity by controlling temperature and time of exposure through thermometry. Phase II established the sequence and time interval of heating and irradiating for differential therapeutic effect. Because fractionation of treatment was essential with irradiation, the phenomenon of thermal tolerance needed to be addressed (Arcangeli et al., 1985; Arcangeli, 1988). Prior heating could confer temporary heat resistance, therefore the interval between heat treatments has been lengthened to two applications a week, rather than daily. Protocols were of two basic designs: for recurrent and metastatic disease using large fractions of radiation and associated heating; and for advanced disease, using regular radiation fractionation schedules with heating twice a week, to determine if there was an additional benefit due to heating. From 1981 to 1986, clinical experience has rapidly accumulated which shows significant benefit from combining hyperthermia and irradiation. In studies where comparable lesions have been treated with radiation alone versus radiation and heat combined, the complete response rate has been consistently improved despite variations in the heating procedure (Overgaard, 1983). Where dose response analyses are possible from the clinical trials, specific histopathologic types and sites show a thermal enhancement of 1.4 for neck nodes, 1.5 for breast cancer and 2.0 for melanoma (Arcangeli et al., t988). General response durations can be derived from Arcangeli's experience with heating and irradiating neck nodes; that is at 2 years the local control rate was 58%, versus 14% for conventional treatment, clearly favouring the combined modality approach. Many possibilities exist for clinical trials in the next 5 years: regional deep hyperthermia, interstitial and endocavitary hyperthermia, whole body hyperthermia and hyperthermic perfusion in addition to irradiation. The major challenge will be in combining hyperthermia with other innovations that enhance tumor cell kill effect, such as radiosensitisers and selected chemotherapeutic agents (cis-plantinum, bleomycin, CCNU), when sensitivity to drugs is increased and resistance is decreased by heating as well as by irradiation.
Biologic Response Modifiers and Radiolabelled Antibodies The diagnostic and therapeutic potential of radiolabelled antibodies was established as the research
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approach with greatest potential in the field of biologic response modifiers. The antibody to tumour offers specificity and the radiolabelling with 1131allows sensitivity for detection and assay. Either I TM or 1125 provide a therapeutic approach for tumours on which radiolabelled antibodies concentrate. Tumour-associated antibodies, particularly ferritin, show a high affinity for hepatocellular carcinomas (Order et al., 1985), lung cancers, and Hodgkin's disease (Katz et al., 1973). The research plan which evolved in 1975 has been developed as a laboratory and clinical model (Order, 1976). Although used with other modalities, the response rates with radiolabelled antibodies in radioresistant and refractory cancer suggest that this remains an encouraging avenue to pursue for wider clinical application. The technology for producing labelled tumour antibodies is sufficiently advanced so that its application in clinical settings should not be an obstacle to wider introduction, once tumour specificity is established. In the past decade, considerable progress has been made using hepatocellular cancer as a model disease for radiolabelled antibodies (Order et al., 1985). Volumetric reconstruction is essential for dose determination depending upon radiolabel uptake and turnover in a specific tumour and host. Dose escalation between 30 and 50 mCi has been demonstrated, and bone marrow toxicity is a major limitation to repeated doses. Response rates of 48% are impressive in hepatocellular cancers (7% complete, 41% partial regression), in intrahepatic bile duct cancer a 26% partial response rate has occurred, and refractory Hodgkin's disease patients have experienced a 40% partial response rate (Order, 1988). Rescue with autologous bone marrow transplantation would increase the number of patients surviving aggressive therapy, but it would also intensify the cost of patient care. Studies worthy of further investigation would be in hepatocellular cancer because this disease is prevalent in the Far East and Third World Countries. More nations must participate to take labelled antibodies into a main research direction. Quality control for distribution of labelled antibodies is essential and could be established by a central production laboratory. Unexplained is the relative effectiveness of low dose irradiation; the maximal radiation dosage delivered by this approach is 1000-2000 cGy. Training for administration of large dose radioisotope therapeutics is also important because it combines both diagnostic and therapeutic aspects.
High LET Of the one million patients diagnosed with cancer annually, approximately one-third (300,000) wilt die because of uncontrolled local or regional disease. The biological basis for using high LET irradiation is exemplified by neutron beam radiation. It can overcome all differences in various cell types that relate to radioresistance, such as hypoxia, repair of sublethal/potentially lethal injury, and non-cycling prolonged G1 or Go cell populations. Neutrons reduce variation in cell radiosensitivity through a variety of mechanisms; they kill cells independent of oxygenation level; they inhibit the repair capacity of cells; and they are lethal in all phases of the cell cycle, unlike photon beams. With their greater RBE for tumour cell kill, it is important to obtain a favourable physical dose distribution since their effectiveness exists for normal tissue as well and late effect complications are
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Table 2-Results of high-LET studies
Radiation
Site/histology
Neutrons
Salivary gland Prostate Bone sarcomas
No. of pts Results* 150 285 105
Soft tissue sarcoma 540 Head and neck 2000 Lung 367 Bladder 145 Cervix 260 Brain 600 Oesophagus 74 Protons and Occular melanoma 450 helium i o n s Chordomas,chondro100 sarcomas(spineand skull) Other sites 100 Carbon, neon and All sites 100 silicon ions
+ + + + + + + + +
++ Equivocal Equivocal Equivocal Equivocal Negative Negative ++++ +++ Equivocal Too early to evaluate
* Compared to photon or electron beam radiotherapy
common. Proton and charged particle beams have Bragg peaks which provide superior distributions, compared to fast neutrons, which are more comparable to photon beams. One of the important aspects of controlled clinical trials is to have hospital-based instruments or cyclotrons in the 30-50 MeV range, rather than 16 MeV. This is akin to having 5-10 MeV accelerators rather than 250 kV units. Accordingly, a recommendation by ROCS and CROS called for a sufficient number of high L E T facilities in 1975, of which eight were to be neutron facilities. Unfortunately, most of the clinical trials were conducted by laboratory facilities of lower energy such as those at Hammersmith, Edinburgh and T A M V A X , near M D Anderson Hospital; the same was true for neutron sources at the University of Washington and George Washington University. D-t generators were used in West G e r m a n y and Amsterdam (Batterman and Mijnheer, 1986). Clinical trials have been slowly conducted through the 1970s both in the United States and in Europe; the results in a number of disease sites and cancers are promising as shown in Table 2. Briefly, head and neck cancer randomised trials are in a state of controversy because the Hammersmith and R T O G trials report a significant difference in local regional control without a high increase in complication for neutrons versus photons. Catterall (1982) reported a local control rate of 76% for neutrons and 19% for photons; and the R T O G had a 52% complete response rate for neutrons versus 19% for photons and mixed beams. Duncan (Duncan et al., 1982, 1984) noted, however, a complete response rate and ultimate control of 70% versus 60%, and 44% versus 40% for neutrons and photons, respectively, which were not statistically significant. In salivary gland tumours (Carterall and Errington, 1987), the high RBE of 6-8 associated with neutrons may contribute to successful control. For unresectable advanced neoplasms, the fast neutron control rate is 71%, comparable to results achieved with local wide excision and post-operative irradiation with photons. An R T O G Phase III randomized clinical trial of prostrate cancer, Stage C and D, compared mixed beam to photons with resultant local regional rates of 93 % and 62%, respectively, at 5 years (Laramore et al., 1985). Similarly, the 5-year survival rates showed favourable results for neutrons (60% versus 40%) with a significance
of P < 0.01. Little difference in late effect complications was noted. Both soft tissuesarcomas and bone sarcomas are better controlled with neutrons. For unresectable soft tissue sarcomas, the overall results are 50% local control, in osteogenic sarcoma, 67%, and in chondrosarcomas, 56% (Griffin et al., 1988). With photons the most impressive result is the 95% cure rate for ocular melanomas with eye preservation (Munzenrider et al., 1986). Clinical trials with neutrons are just beginning in America, with new facilities at M D Anderson, the University of Washington and UCLA, as well as older facilities at Fermi Lab in Chicago and at the Cleveland Clinic. The list of third generation neutron protocols in order of priority are: carcinoma of the prostrate (Stages C and D), squamous cell carcinoma of the head and neck (Stages III and IV), advanced and recurrent rectal cancer, locally advanced soft tissue and bone sarcomas, carcin o m a of the cervix (stages III and IVa) and non-small cell lung cancer (Stage III).
Large field irradiation Total body irradiation is limited by the tolerance of different organs. Bone marrow is considered one of the most radiosensitive. With bone marrow transplantation it is possible to offer supralethal doses of irradiation, plus chemotherapy, to treat leukaemias successfully. Hemibody irradiation is more tolerable to bone marrow since it provides a large segment unexposed to irradiation to regenerate the irradiated half. By treating both upper and lower half body segments a form of whole body irradiation is possible to provide 'systemic irradiation' for occult (Mason et al., 1982) and overt (Urtasun et al., 1983) metastases as an out-patient without the need for costly bone grafting. The technique is clearly effective for overt metastases but its potential to be curative for occult metastases requires its use in combination with chemotherapy, radiosensitisers, radioprotectors or hyperthermia. Key questions to be answered by clinical trials are: 1 definition of the most effective, least toxic, single dose in a dose escalation from 600 cGy to 1000 cGy for upper, mid and lower half-body segments. 2 To determine if elective half-body irradiation can objectively delay the appearance of new metastases in a variety of known malignances, such as breast, prostate, lung and gastrointestinal cancers. 3 To assess the ability of systemic hemi-body irradiation (both halves) to eradicate occult metastases in lung cancer (non-small cell and small cell), prostate cancer, and gastrointestinal cancer. 4 To identify effective chemotherapy combinations, as in small cell cancer of the lung, multiple myeloma and Ewing's sarcoma, that can ablate occult metastases. 5 To evaluate radiosensitisers, such as misonidazole and SR-2508, in combination with hemibody irradiation to more effectively ablate overt metastases. 6 To determine if radioprotectors, such as WR-2721, can protect the bone marrow from the deleterious, suppressive effects o f irradiation.
lntra-operative Irradiation Currently, 45 institutions are regularly involved in use of intra-operative irradiation in Japan (Abe and Takahashi, 1981), and 35 centres in the United States and
I M P A C T OF R A D I A T I O N R E S E A R C H O N C L I N I C A L T R I A L S
perhaps another l0 in Europe. This increasing interest lead the R T O G in 1985 to activate six Phase II protocols (Calvo and Hanks, 1988) in a variety of disease sites to determine efficacy and toxicity. There is a need to follow a logical and deliberate process that progresses from Phase I/II (Gunderson et al., 1982) to randomised Phase III trials to conclusively demonstrate whether there is an advantage. The ability to combine intra-operative therapy with innovative approaches such as radiosensitisers, chemotherapy and hyperthermia makes this an exciting multimodal approach. Possible tumours for further evaluation of this approach include gliomas, advanced renal carcinomas, non-resectable lung cancer, oeso: phageal cancer and bladder cancer. Research on T u m o u r s at Specific Sites
For individual disease sites, the impact of research in clinical trials has varied, depending upon the effectiveness of standard treatment modalities, such as surgery, radiation and chemotherapy, as well as the patterns of failure and local recurrence, with and without metastases. The options available include: -Optimisation of radiation treatment regimens by researching dose/time/fraetionation or volume considerations such as extended fields, particularly where chemotherapy has not been effective. - Synchronisation or determining the best sequence or combination of surgery and/or chemotherapy with irradiation. -Innovations in radiation research, such as radiosensitisers, hyperthermia, radiolabelled antibodies, and high LET, for radioresistant tumours or advanced malignances, where tolerance would be exceeded with conventional doses of radiation. The major sites where the highest priority will be given to searching for the optimal dose/time/fractionation will be head and neck cancers, lung cancers of the squamous cell and adenocarcinoma variety and glioblastoma multiforme. The therapeutic ratio can be improved through hyperfraction and accelerated split dose schedules. Phase II investigations of these concepts are being completed. Since local regional control is a major problem in advanced cancers, the desire for the highest total dose in the shortest time consistent with improved tumour ablation at minimal complication rate will be actively pursued. Synchronisation of chemotherapy/surgery and radiation therapy where sequencing and timing are important to increase therapeutic efficacy will be investigated in advanced head and neck cancer, small cell lung cancers, prostate (including hormonal combinations with agents such as Zoladex and Flutamide) bladder cancer, rectal cancer, breast and cervix cancer. There are sufficient numbers of cancers at these sites to allow more than one research theme to be explored. When multi-agent chemotherapy is effective as in haematologic malignancies, paediatric cancer, breast cancer, and to a lesser degree, small cell cancer of the lung, it is desirable since it can also act against occult metastases. Concomitant infusional therapy with 5-fluorouracil, mitomycin-C or cis-platinum will be most actively studied where advanced cancers need control as in head and neck, prostate, rectal and oesophageal cancers and cervix cancer. The innovations of radiation research have an impact on most major sites where standard treatment, particu-
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larly chemotherapy, is ineffective. There are some disease sites that are more promising than others. The need to establish priorities depends upon the promise of Phase II trials and the toxicity encountered, but the commitment to Phase II is very costly in both money and patient resources, and better statistical models are needed. Combinations of multiple modalities and innovative approaches are also possible. All of these add to the complexity of protocol design. Conclusions
Radiation research has had a major impact on protocol design in clinical trials involving irradiation; in the past decade, 30 000 patients have entered R T O G controlled studies and comparable numbers have been entered into E O R T C and MRC trials. Through such co-operative group studies, the field of radiation oncology has changed from a specialty with individualistic: treatment approaches, and very few attempts at serious research, to a highly disciplined community of investigators that integrate basic science into larger clinical protocols. The promise of research masterplans and national co-operative clinical trials remains unfulfilled at present despite an exciting decade in which thousands of patients have been accrued. Critical analysis indicates that most of the innovations remain largely in Phase I/II studies. Despite this large research effort, the ability to demonstrate obvious gains and advantages so that newer modalities and agents can be adopted into a standard practise, remains elusive. High LET irradiation with neutrons requires more clinical trials to establish its value in soft tissue sarcomas, prostrate cancer, bone tumours, head and neck cancers, bladder cancer and brain tumours. For most disease sites, standard radiation treatment factors have emerged so that the parameter of dose/time/ fractionation and prescribed tumour and target volumes are appreciated and tolerance factors recognised. The promise of new combinations of radiation-chemotherapy remain to be established and, other than paediatric tumours and haematologic malignancies, only breast cancer treatment has changed dramatically. With early detection of breast cancer by screening mammography, conservative segmental quadrantectomies and irradiation have been effective in control and cure with good to excellent cosmesis. Adjuvant chemo-hormonal therapy, especially in pre-menopausal patients, is a widely accepted practice. Improved dose response rates have not been translated into improved survival in all sites. To fulfill the promise, international co-operation is essential. The hundreds of American and European clinical trials conducted thus far have not actualised the potential expressed in radiation research laboratories. The patient resources are limited but ideas are increasing. We must use our patient resources carefully, particularly curative patients, or, increase resources through the entry of Asian and developing countries into co-operative group trials. For EORTC and M R C clinical trials, it is important to exchange concepts with RTOG, ECOG, SWOG, and other multidisciplinary co-operative groups so that curative patient resources are not squandered. New research designs should be established to decrease control arm numbers. Quality assurance standards related to dose/ time/fractionation must be standardised so that results
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are comparable. N e w modes can be introduced by European colleagues. C o m m o n arms and joint protocols can be our goal. The Japanese radiation oncology investigators are adding more strengths in the protocol developing arena, particularly for new modalities. The use of Asian and developing countries clinical resources for curative oncology patients is important. Modern concepts for randomised studies and protocols through a new mechanism would permit standard analysis such as is available in RTOG. International Clinical Trials Radiation Oncology (ICTRO) is such a vehicle. The ICTRO seeks to extend the patient resources for clinical trials and share the state of the art advances in radiation technology. The challenge will be in the transfer o f concepts of radiation technology worldwide so that a single high standard exists. The introduction of more megavoltage equipment will improve the standards of care and in turn reduce the time to complete clinical trials. The ICTRO concept has been adopted by N C I as the first core subject in a series of bilateral and multilateral research agreements.
REFERENCES Abe, M & Takahashi, M (1981). Intraoperative radiotherapy: The Japanese experience. International Journal of Radiation Oncology, Biology, Physics, 7, 863-868. Arcangcli, G, Arcangeli, G.C, Guerra, A, Lovisolo, G, Cividalli, A, Marino, C et al. (1985) Tumor response to heat and radiation: Prognostic variables in the treatment of neck node metastases from head and neck. International Journal of Hyperthermia, 1,207 217. Arcangeli, G, Overgaard, J & Gonzalcs, GD (1988). ICTRO Research Plan-Hyperthermia. Phys. International Journal of Radiation Oncology, Biology, Physics, 14, $93-S109. Batterman, JJ & Mijnhecr, BJ (1986). The Amsterdam fast neutron therapy project: A final report. International Journal of Radiation Oncology, Biology, Physics, 12, 2093 2099. Calvo, F & Hanks G (1988). International clinical trials in radiation oncology-intra-operative radiotherapy. International Journal of Radiation Oncology , Biology, Physics, 14, $111 S117. CatteralI, M (1982). Results of neutron therapy: Differences, correlations and improvements. International Journal of Radiation Oncology, Biology, Physics, 8, 2141 2144. Catterall, M & Errington, RD (1987). The implications of improved treatment of malignant salivary gland tumors by fast neutron radiotherapy. International Journal of Radiation Oncology, Biology, Physics, 13, 1313 1318. Chemical Modifiers of Cancer Treatment. (1984). International Journal of Radiation Oncology, Biology, Physics, 10, 1161- 1813. Coleman, CN, Urtasun, RC, Wasserman, TH, Hancock, S, Harris, JW, Halsey, Jet al. (1984). Initial report of the Phase I trial of the hypoxic cell radiosensitizer SR-2508. International Journal of Radiation Oncology, Biology, Physics, 10, 1749-1753. Committee for Radiation Oncology Studies: Research Plan for Radiation Oncology - - Manpower Goals in Radiation Oncology. (1976). Cancer, 37, 2140 2148. Conference on Combined Modalities Chemotherapy/Radiotherapy (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 1139-1721. Cox, J & van der Schueren, E (1988) Clinical research on dose/time/ fractionation factors. International Journal of Radiation Oncology, Biology, Physics, 14, $51 $56. Duncan, W, Arnott, SJ, Battermann, J J, Orr, JA, Schmitt, G & Kerr, GK (1984). Fast neutrons in the treatment of head and neck cancers: The results of a multi-centre randomly controlled trial. Radiotherapy and Oncology, 2, 293 300. Duncan, W, Arnott, SJ, Orr, JA & Kerr, GR (1982). The Edinburgh experience of fast neutron therapy. International Journal of Radiotherapy On cology, Biology, Physics, 8, 2155 2157. Ellis, F (1969). Dose time and fractionation: A clinical hypothesis. Chemical Radiology, 20, 1 7. Experimental Combined Modalities Study Group. (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 633-649. Griffin, T, Wambersie, A, Laramore, G & Castro, J (198?). ICTRO
ResearchPlan-Heavy Particles Therapy. International Journal of Radiation Oncology, Biology, Physics, 14, $83 $92. Gunderson, LL, Shipley, WU, Suit, HD, Epp, ER, Nardi, G, Wood, W et al. (1982). Intraoperative irradiation: A pilot study combining external beam photon with 'boost' dose intraperative electrons. Cancer, 49, 2.259-2.266. 1CTRO Research Plan. (1988) International Journal of Radiation Oncology, Biology, Physics, 14. Katz, DH, Order, SE, Graves, M, Benacerraf, B e t al. (1973). Purification of Hodgkin's disease tumor-associated antigens. Proceedings of the National Academy for Science USA, 70, 396-400. Kligermann, MM, Glover, D J, Turrisi, AT, Norfleet, AL, Yuhas, JM, Coia LR et al. (1984). Toxicity of WR-2721 administered in single and multiple doses. International Journal of Radiation Oncology, Biology, Physics 10, 1773 1775. Laramore, G.E, Krall, J.M, Thomas, F.J, Griffin, T.W, Maor, M.H, Hendrickson, F.R. (1985). Fast neutron radiotherapy for locally advanced prostate cancer. Results of an RTOG randomized trial. International Journal of Radiation Oncology, Biology, Physics, 11, 1621 1628. Marcial, VA, Pajack, TF, Chang, C, Tupchong, L & Stetz, J (1987). Hypeffractionated photon radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx, and sinuses, using radiation therapy as the only planned modality: Preliminary Report by the Radiation Therapy Oncology Group (RTOG). International Journal of Radiation Oncology, Biology, Physics, 13, 41 49. Mason, BA, Richter, MP, Catalano, RB & Creech, RB (1982). Upper hemibody and local chest irradiation as consolidation following response to high-dose induction chemtherapy for small bronchogenic carcinoma - - a pilot study. Cancer Treatment Reports 66, 1609 1612. Munzenrider, JE, Gragoudas, E, Seddon, JM, McNulty, P, Sisterson, J, Johnson, K et al. (1986). Survival in photon irradiated uveal melanoma patients: Implications for prospective randomized trials. International Journal of Radiation, Oncology, Biology, Physics, 12 (Supplement 1), 121. Nigro, ND, Vaitkevicius, VK & Considine, B, Jr (1974). Combined therapy for cancer of the anal canal: a preliminary report. Diseases of the Colon and Rectum, 17, 354-356. Order, SE (1976). The history and progress of serologic immunotherapy and radiodiagnosis. Radiology, 118, 219-223. Order, SE (1988). ICTRO Research Plan Radiolabelled Antibody. International Journal Radiation Oncology, Biology, Physics, 14, $77 $8l. Order, SE, Stillwagon, GB, Klein, JL, Leichner, PK, Siegelman, SS, Fishman, EK et al. (1985). Iodine 131 antiferritin, a new treatment modality in hepatoma: A Radiation Therapy Oncology Group Study. Journal of Clinical Oncology, 3, 1573 1582. Orton, CG, Ellis, F (1973) A simplification in the use of the NSD concept in practical radiotherapy. British Journal of Radiology, 46, 529-537. Overgaard J (1983) Hyperthermic modification of the radiation response in solid tumours. In: Fletcher GH (ed). Biological basis and clinical implications of tumor radioresistance. Masson, New York, 337-352. Phillips, TL, Bartelink, H & Bleehen, N (198?). ICTRO research plan: chemical modifiers. International Journal Radiation Oncology, Biology, Physics, 14, $39 $49. Radiation Oncology Cooperative Subcommittee Research Plan (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 593-632. Radiation Oncology Research Program: High-LET (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 757 766. Regaud CL, Ferroux, R (1929) Influence de 'facteur temps' sur la sterilisation des ignees cellulaires normales et neoplasiques par la radiotherapie. Acta Radiologica, Supplement III, 107 123. ROCS Hyperthermia Working Group (1979). International Journal of Radiation, 5, 699-707. ROCS Radiation Immunology Working Group (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 727 734. ROCS Radiosensitizers/Radioprotectors Working Group (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 651 658. Roberts JT et al. (1984) A phase I study of the hypoxic cell sensitiser R003-8799. International Journal of Radiation Oncology, Biology, Physics, 10, 1755-1759. Rubin, P, Costine, LS & Phillips, L (1982). WR-2721 and half-body or mid-body irradiation for the palliation of widespread symptomacti metastases. Radiation Therapy Oncology Group Study 82-03. Urtasun, RC, Belch, A & Bodnar, D (1983). Hemibody radiation, an active therapeutic modality for the management of patients with
IMPACT OF RADIATION RESEARCH ON CLINICAL TRIALS small cell lun~g cancer. International Journal of Radiation Oncology, Biology, Physics, 9, 1575-1578. Withers, H R (1979). Capacity for repair in cells of normal and malignant tissues. In: Proceedings of the Carmel Conference on Time and Dose Relationships in Radiation Biology as Applied to
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Radiotherapy. B N L Report 50203 (C-57). pp. 54-65. Brookhaven National Laboratory, Upton, New York. Yuhas, JM & Storer, JB (1969). Differential ehemoprotection of normal and malignant tissues. Journal of the National Cancer Institute, 42, 331 335.
Book Reviews Orthopaedics - Self Assessment in Radiology and Imaging 4. By D. J. Stoker and E. A. Tilley, Wolfe Medical Publication, London, 1988, 219 pp., £19.50. This soft-back book is the fourth in a series of self assessment texts in radiology and imaging. Ninety-seven independent cases are ordered at random, ranging in difficulty from the simple torus fracture of the forearm to M R of osseous leukaemic deposits. Each exercise consists of an image, short clinical history and relevant questions on the facing page, and overleaf a short discussion including the diagnosis, differential diagnosis, odd reference and derivation of any applicable eponym. The authors attention to detail is indicated by the clarity o f the radiographs which have the added benefit of being expanded to exclude any unnecessary information and in the vast majority of exercises the abnormalities are readily detectable. Exceptions include the periarticular osteoporosis of early rheumatoid which can be notoriously difficult to reproduce. The emphasis of the book is correctly on plain films although other imaging modalities have been included where relevant. The book is not aimed exclusively at radiologists and, as stated in the preface, cannot cover the whole range of bone and joint disorders. Orthopaedic surgeons m a y find the title a little misleading in that although there is a moderate a m o u n t of trauma included, the remainder is principally 'skeletal radiology' as apposed to "orthopaedic radiology'. This may appear to be semantics but experience would suggest that the specific interests of radiologists and orthopaedic surgeons in X-rays can be somewhat different. The result is a relatively inexpensive book, with a neat and consise format, particularly suitable for radiologists early in their training. Also, for those preparing for the part II Fellowship examination it should prove a welcome diversion from the tedium of the standard radiological tomes. M. Davies
An Atlas of Radiological Interpretation - The Bones. By J. Calder and G. Chessell, Wolfe Medical Publications, London, 1988, 279 pp., £19.50. This atlas is based on teaching material from courses given to undergraduates and post-graduates to D M R D level. It includes m o s t of the c o m m o n bone conditions and a few rarer lesions. Each illustration is combined with a line drawing and a short text. The specific features of each example are identified by letters on the line drawings thus avoiding any obliteration of the X-rays. The atlas provides a simple m e t h o d of assimilating information from illustrations as compared to reading extensive descriptions in text. It is therefore, particularly suitable for introductory or basic information. It is, however, fundamental that the illustrations are of top quality. In the book the transition from slide to paper has not succeeded. There are some very poor quality radiographs which are so under-penetrated that one cannot make out the basic features. Particular examples are the fractures of the facial bones but there are too many to mention them all.
The line drawings are also imprecise in many cases which reduces their value. An example is the lateral view of a compression fracture of the dorsal spine which is difficult to see on the radiograph and is drawn as a block vertebra. M a n y of the line drawings seem superfluous as the lesions are so obvious on the X-rays. The text is brief in m a n y cases and is insufficient to do justice to the subject. This is particularly the case in some bone tumours and in the joint diseases. One is amazed that there is no mention of calcium pyrophosphate deposition or of diffuse idiopathic skeletal hyperostosis. The text is generally accurate although the stated 10% incidence of bone changes in sarcoidosis is well above recognised levels. There is a complete absence of any examples of the newer imaging techniques, in particular C T and nuclear medicine. The authors do not indicate to w h o m this book is directed, although one m a y assume from the brief introduction, that it is undergraduates and trainees for D M R D . It is unlikely that this book will provide sufficient information for the latter group and the former may have difficulty recognising the features on a number of the radiographs. I. W. McCall
Nuclear Medicine - Applications to Surgery. Edited by E. Rhys Davies and W. E. G. Thomas, Castle House Publications, Tunbridge Wells, 1988, 311 pp., £60. This book is aimed at surgeons, both consultant surgeons and those in training. There are 19 chapters with 20 contributors, all of w h o m are well-known in the field of nuclear medicine. The book has a conventional layout with two chapters on basic principles and equipment used, and the rest on clinical topics. As one would expect with a large number of contributors there is some variability in the type of presentation. Some of the chapters give detailed information on how to perform the scans whereas others concentrate on the role of the tests in a clinical context. The images are of good quality although there is an occasional mistake in labelling. One other negative comment is that many of the chapters omit recent advances or potential advances such as these of H M P A O for white cell scanning and M A G 3 for renal imaging. Having said all this, I showed the book to a junior surgical colleague who thought it was very good and found it very useful. I think one of the problems with a book like this is that the editors need to decide precisely for w h o m it is intended. In the introduction it states that whilst the main target for the book is surgeons, it should also appeal to physicians and to radiologists in training. I think surgeons and physicians could well be served by a single book which concentrates on the clinical uses of nuclear medicine. Radiologists, however, need something different since they also need to know how to do the tests. Trying to satisfy both groups of people with one book has not been entirely successful. At £60, the book is too expensive for a trainee to consider buying but I think it is a very useful reference point for surgeons and physicians in training who wish to know more about what nuclear medicine has to offer. T. O. N u n a n
Impact of Radiation Research on Clinical Trials in Radiation Oncology P.
RUBIN and
J. D .
VAN ESS
Department of Radiation Oncology, University of Rochester Cancer Center, 601 Elmwood Avenue, Box 647, Rochester, New York 14642 The scientific basis for the practice of radiation oncology is derived from research in medical physics and radiation biology. Many of the radiation research accomplishments can be traced to, and were in part generated by, the identification of clinical needs. This interplay between science and the clinic led to the design of co-operative clinical trials. In July 1975, the Radiation Oncology Coordination Subcommittee (ROCS) of the Board of Scientific Counselors of the Division of Cancer Treatment at NCI, was appointed by the Director, Vincent De Vita. This subcommittee was reponsible for: reviewing and assessing the state of science in radiation oncology; developing a scientific plan and recommending future research activities; and co-ordinating research among scientific investigators in the fields of radiation oncology, biology and physics. A research plan was formulated (Radiation Oncology Cooperative Subcommittee Research Plan, 1979) and, initially, six interdependent research areas were selected and Working Groups formed as follows: - T h e Experimental Combined Modality Working Group developed scientific plans and recommendations for preclinical chemotherapy/radiation therapy studies, consisting of a core of investigations with biologically well-defined tumour systems (Experimental Combined Modalities Study Group, 1979). - The Radiosensitisers and Radioprotection Working Group, a special committee in the Division of Cancer Treatment Drug Development Network at the National Cancer Institute, worked on hypoxic cell radiosensitisers and radioprotectors (ROCS Radiosensitisers/Radioprotectors Working Group, 1979) - T h e Hyperthermia Working Group planned proposals for instrumentation, thermometry and pathophysiologic and biologic cellular studies (ROCS Hyperthermia Working Group, 1979). - The Radiation Immunology Working Group planned preclinical and clinical research using radiolabelled tumour-specific and/or tumour-associated antibodies (ROCS Radiation Immunology Working Group, 1979). - The Toxicity Working Group planned experimental small and large animal late effects studies, searched for predictive assays, and recommended studies related to combinations of modalities (ROCS Toxicology Working Group, 1979) - The High LET Particle Working Group made a series of proposals for developing a sufficient number of centres to study neutrons, charged particles, and pi mesons (The Radiation Oncology Research Program: High-LET, 1979). These Groups reported to a Council of Radiation Oncology Chairpersons who directed the protocol design and development in various national co-operative groups. They incorporated these research themes into clinical trials, developing a clinical database for future
directions in both clinical radiation therapy and multimodal research. This effort was actualised by 1980 with more than 50 million dollars awarded by NCI; this funding level has been largely maintained to date. In 1968, the Radiation Therapy Oncology Group (RTOG) was organised in response to the need for developing clinical trials in radiation oncology. The research strategies of the RTOG reflected the research planning in RCOS (Radiation Oncology Cooperative Subcommittee Research Plan, 1979) and the Committee for Radiation Oncology Studies (1976). In April of 1986, a new effort to foster international collaboration among investigators was organised. At a Spring meeting in Paris, investigators from major cooperative groups in the United States and Europe (mainly from RTOG, European Organisation for Research & Treatment of Cancer (EORTC) and the Medical Research Council (MRC)) formed a co-operative group called the 'International Clinical Trials in Radiation Oncology' (ICTRO). The ICTRO is developing an international radiation research plan in response to an NCI directive that radiation oncology clinical trials research will be the first named Core Subject in 'bilateral agreements' between the United States and other world governments. Much of the analyses and results presented are from the document resulting from this ICTRO conference (ICTRO Research Plan, 1988). Progress in a number of specific areas will now be reviewed together with some projections for the direction of clinical trials in radiation oncology into the 1990s.
Radiosensitisers
Phase I studies, using misonidazole, began in 1977 to determine its neurotoxicity and monitor serum drug levels to determine effective drug delivery schedules. Phase II studies were initiated shortly thereafter by the RTOG, in a variety of disease sites. The optimal misonidazole dose proved to be 12-15 g/m2; neurotoxicity proved to be the major risk factor. From 1981 to 1986, in 11 Phase II studies (Chemical Modifiers of Cancer Treatment, 1984) accumulating 591 patients, the tolerance dose schedules of misonidazole were established and a variety of fractionated dose regimen were designed in an attempt to find an effective programme. As these studies were completed, a series of randomised Phase II clinical trials evaluated high and low fractional misonidazole doses in a variety of fractionation schemes in seven sites. No advantage was shown after accumulating 2181 patients in the RTOG studies, which included head and neck cancers, brain metastases, lung cancer, gliomas, hepatic metastases, and cervix cancer (Chemical Modifiers of Cancer Treatment, 1984). In EORTC or MRC Phase III studies in head and neck cancer, cervix cancer, and gliomas, no survival or local
IMPACT OF RADIATION RESEARCH ON CLINICAL TRIALS"
control advantage could be shown (Chemical Modifiers of Cancer Treatment, 1984). In the near future (1987-1991), a new generation of compounds will be available, SR-2508 (Coleman et al., 1984) and RO-03-8799 (Roberts et al., 1984); they are three to five times more effective in cumulative sensitising efficacy than misonidazole, because of lower toxicity and higher penetration. These agents, unlike misonidazole, fill the criteria of a drug with a good therapeutic ratio, allowing for the administration of high fractional doses to yield enhancement ratios greater than 1.5, a sufficient drug dose to administer more than 15 individual doses during a course of radiotherapy, and effective combination with more conventional radiation fractionation regimens. Phase I/II studies, which began in 1983, are complete and Phase III clinical trials are being developed in head and neck cancers, cervix cancer, and lung cancer. Combining SR-2508 and RO-03-8799 seems promising if no increase in toxicity is found. In addition, buthionineSR-sufoximine is being evaluated as its action in depleting cellular glutathione might further increase sensitisation.
Radioprotectors Based upon the known scavenger capacity of sulphydryl radicals to reduce oxidative reactions, many sulphydryl-containing compounds were developed by the US Army to protect people in the event of nuclear war. The US Army developed over 300 000 such compounds; the highest degree of radioprotection was found with thiophosphates, among which WR-2721 was best. In 1969 it was reported that these agents, especially WR-2721, preferentially protected normal tissue versus tumours (Yuhas and Storer, 1969); this was attributed to deficient vascularity in tumours, the limitation of transfer inherent in the tumour cell membrane, which reduces drug absorption, and the relative inability of hypoxic cells to respond to protection, since this competes against oxygen sensitisation. Kligerman and Yuhas carried out Phase I studies during the early 1980s, which identified toxicity comprising hypotension, nausea, vomiting, and somnolence, these effects were reduced by rapid intravenous infusion (Kligerman et al., 1984). Multiple dose Phase I/II studies led to establishing 450 mg/m 2, repeated four times a week for 5 weeks, as a tolerable dose with acceptable toxicity. Experimental evidence suggested that maximal concentrations yield differential protection in the range of 2-3, especially for bone marrow. Because WR-2721 protects bone marrow but does not protect the central nervous system, and is only modest in its ability to protect lung and kidney, hemibody irradiation in patients with overt metastases seemed a suitable target population to launch Phase II trials. Currently, effective haematologic radioprotection is strongly suggested, in comparison to historical controls with less striking nadirs, more rapid recovery of leucocytes and platelets, and fewer life-threatening and sever toxicities (Rubin et al., 1982). It is suggested that the radiation dose could be increased by 20% with WR-2721. Between 1986 and 1991, Phase III clinical trials will be conducted. Single doses of WR-2721, ranging between 750 and 900 mg/m 2, will be used with a range of hemibody radiation doses of 700 900 cGy, to more firmly demonstrate bone marrow radioprotection. Similarly, Phase III fractionated studies will be explored with WR-2721 and accelerated fractionation to establish differential radio-
69
protection. Such novel ideas as combining radiosensitisers and radioprotectors are under consideration.
Drug-Radiation Interactions Of all the ROCS programmes, none began with more enthusiasm for research planning than did the Experimental Combined Modalities Study Group for studying drug radiation interactions. Twelve laboratories were chosen to provide a battery of tumours whose biological characteristics were thoroughly studied for radiation responsiveness and cellular kinetics. These tumours were the EMT6, the mammary C3H carcinoma, the Lewis lung cancer, gliomas, sarcomas and human xenografts to which colon 26 carcinoma and B6 melanoma were added (Experimental Combined Modalities Study Group, 1979). The following clinically effective drugs were most actively studied: doxorubicin, cyclophosphamide, nitrosoureas (BCNU, CCNU), 5-fluorouracil, methotrexate, vincristine and, of the then newer agents, cis-platinum. In addition to tumours, a number of normal tissues were chosen to develop therapeutic ratios; they included: skin, gut, bone marrow, brain, spinal cord, heart, and lung. The first major scientific meeting was held at Hilton Head (Conference on Combined Modalities Chemotherapy/Radiotherapy, 1979). Optimal timing of drug administration seemed to be either hours before, simultaneous to, or hours after radiation therapy, but no clear guidance emerged from the laboratory for clinical study although several Phase I trials were attempted with little encouragement for a Phase III study. Simultaneously, the major national co-operative geographic chemotherapy groups became multidisciplinary and chose radiation oncology chairpersons to develop their Phase I-II drug and radiation combination studies. Phase III randomised studies were initiated, such as the R T O G use of methotrexate and irradiation in head and neck cancer. The Eastern Cooperative Oncology Group and Gastrointestinal Tumour Study Group favoured the combination of 5-fluorouracil and irradiation in gastrointestinal, rectal, and pancreatic cancers, whereas paediatric groups favoured cyclophosphamide, actinomycin, and vincristine and irradiation. Most of these initial studies began enthusiastically with the expectation of therapeutic gains and increased survival. This optimism faded as most major Phase III studies failed to show any gains. There was no concurrence as to the best sequence or combinations of drugs and radiation in many major disease sites, including lung (both small cell and non-small cell carcinomas), head and neck cancers, brain tumours, gastrointestinal cancers, and soft tissue sarcomas. As a result, numerous Phase I and II studies have been initiated, replacing the Phase III studies of 30-40 patients. What is disheartening is that the drugs are active and yet combining them with irradiation in a more effective combination is elusive. Currently, the most widely used combinations are simultaneously infused 5-fluorouracil sometimes combined with either cis-platinum or mitomycin C. Cis-platinum alone with irradiation is being explored as a radiosensitiser in head and neck and bladder cancer (Phillips et al., 1988). No true supra-additivity exists except from cis-plantinum, and most other combinations are negative. DMF's of 1.9 and 2.2 can be obtained with cis-platinum and irradiation. In vivo experiments in normal tissue indicate a
70
CLINICAL RADIOLOGY
D M F of 1.3 for many drugs, which suggests that cisplatinum should be a favourable combination agent clinically. Accordingly, the majority of R T O G , EORTC, M R C protocols currently use cis-platinum (Phillips et al., in press). For the future the trend will be to combine infusion chemotherapy with irradiation; the prominent agents are 5-fluorouracil, cis-platinum, and mitomycin-C singly or together. One success story emerging is the treatment of anal carcinomas where radical surgical management is being replaced by moderate dose irradiation with 5fluorouracil and mitomycin-C infusion, with anal sphincter preservation (Nigro et al., 1974). This strategy has emerged and is being applied to other squamous cell and adenocarcinomas of the digestive tract.
Dose/Time/Fraetionation The search for optimum dose/time/fractionation schedules for each cancer, based on tumour biology and cellular kinetics, is synonymous with the history of radiation therapy. The classic radiobiologic observations in the ram's testes demonstrated that a fractionated dose would more efficiently result in sterility, with a lower total dose, than would a single high exposure dose (Regaud and Ferroux, 1929). Because fractionation also provided scrotal skin sparing and a better therapeutic ratio, this study is a cornerstone of radiation oncology. The concept of rapid renewal systems, where the tumour is selectively eradicated while the normal tissue is spared, is the impetus for exploring different fractionation schemes. Much mathematical modelling has been performed to determine a single number that can express the dose/time/ fractionation and the effect of different schedules in a relative, comparative scale. The formulations or coefficients most frequently used are those developed by Ellis (1969) and Orton (1972) whose calculated equivalent doses - NSD, and T D F respectively - are useful clinical guides for large fractions. Exploring multiple daily fractions and smaller fractionation doses is a logical derivative of radiation biology research into late effects. Withers has emphasised the difference in slopes for acute versus late effect tissues (Withers, 1970). Because the majority of malignant tumours require total doses near the tolerance of their surrounding normal tissues or organs, using hyperfractionation or accelerated fractionation to improve the therpeutic ratio for their control has appealed to radiation oncology investigators. The ability to deliver higher total doses in shorter time periods, while maintaining late effects complications at a low rate ( < 5 % ) , has been incorporated into the R T O G and E O R T C protocol designs. The current generation of protocols began in 1980, with R T O G defining and exploring hyperfractionation as dividing a conventionally daily dose into smaller individual fractions, and E O R T C defining and exploring accelerated fractionation as a conventional daily dose of 150-200 cGy given several times in I day at 4-6 h intervals (Cox and van der Schueren, 1988). Upon reviewing the R T O G trials in fractionation, the initial emphasis from 1975 to 1981 was split-course schedules (Marcial and Pajack, 1985). From 1981 to 1986 a major commitment was made to hyperfractionation in randomised Phase II studies, where doses have ranged from 68 to 86 Gy with escalations of 4-6 Gy so that in many sites, 80 Gy has been administered. A definition of
Table 1 Fractionation definitions Fractionation schedule
Dose/fraction (Gy)
No ofJ?actions each week
Treatment internal (h)
Common Hypo Hyper Rapid Accel
1.0-2.5 > 3.0 0.7-1.3 > 2.5 1.5-2.5
5-6 1 4 10-25 5 10-15
24 48-168 2 12 24 4-12
different fractionation schedules has been offered by (Cox and van der Schueren, 1988) (Table 1). This represents a 10 15 % increase in total dose with hyperfractionation for head and neck cancers, lung cancers, and gliomas; sufficient time for follow-up is required to ascertain late effects. One randomised head and neck cancer study has been completed, but total doses were conservative (70 Gy conventional compared with 60 Gy hyperfractionated) so that the issue is unsettled (Marcal et al., 1987). The E O R T C has followed accelerated schedules and have completed a glioma and a head and neck cancer clinical trial with hyperfractionation. The preliminary analysis favours the latter approach. The unpublished results indicate that 80 Gy hyperfractionated is superior to conventional therapy schedules (Horiot, personal communication). In the E O R T C accelerated schedules, 2 Gy were given three times daily (30 Gy weekly), with another 30 Gy after a 2-week rest. Although the overall time was reduced from 6 weeks to 4 weeks, no therapeutic gain was seen in head and neck cancers. In another version, a very rapid administration of 48 Gy was given in 2 weeks followed by a second series of 24 Gy to provide a total of 72 Gy in 7 weeks, similar to conventional schedules. Once more, no gain was seen (Cox & van der Schueren, in press) In the future, dose fractionation will be one of the most important research themes because of its potential widespread application, although the required extra machine time could be a major impediment. More difficult fractionation schedules are envisioned with more than dose schedules being evaluated. Careful analyses of tumour control and normal tissue late effect complications are essential to be certain that the therapeutic ratio is being improved. The impact on more megavoltage equipment needs, patient waiting-rooms, and technical staff could be demanding because this may significantly increase the number of patient visits for a curative course of irradiation. The priorities for future studies include further Phase III comparisons of different dose fractionation regimes and the definition of correction factors to adjust the fraction size in relation to the altered schedules.
Hyperthermia Hyperthermia has been used to treat thousands of patients with malignant disease; although it has been sporadically used since 1900s, it has recently become a major investigational modality. During the 1960s, interest shifted from total body heating to more localised and regionalised heating methods. With improvement in instrumentation, a variety of heating sources is now available for clinical use, including: radiofrequency antennae for interstitial heating, microwave for regional and superficial heating with radical arrays designed for deeper heating, and ultrasound for focused heating in depth to avoid air cavities and bone. The biological experiments in vivo and in vitro have indicated that
I M P A C T OF R A D I A T I O N RESEARCH ON C L I N I C A L T R I A L S
temperatures-above 41°C must be maintained because fluctuations of 1-2°C can dramatically alter the effectiveness of heat killing of tumour cells in culture, particularly in combination with irradiation. This has created a demand for accurate invasive and non-invasive isotherm mapping thermometry. The quality assurance is more demanding than for radiation therapy, because physiological factors, such as blood flow, can alter the temperatures in tumours and normal tissues despite a constant power deposition. In 1979, the ROCS research plan (ROCS Hyperthermia Working Group, 1979) encompassed the elements of modality development, the need for experimental in vivo systems in both small and large animals, and initiating both Phase I and Phase II clinical trials. Within 5 years, improvement in heat delivery systems occurred with some effort at standardisation, as individually constructed units were supplanted by commercially manufactured sources. The major effort in Phase I clinical trials was to determine and consequently avoid toxicity by controlling temperature and time of exposure through thermometry. Phase II established the sequence and time interval of heating and irradiating for differential therapeutic effect. Because fractionation of treatment was essential with irradiation, the phenomenon of thermal tolerance needed to be addressed (Arcangeli et al., 1985; Arcangeli, 1988). Prior heating could confer temporary heat resistance, therefore the interval between heat treatments has been lengthened to two applications a week, rather than daily. Protocols were of two basic designs: for recurrent and metastatic disease using large fractions of radiation and associated heating; and for advanced disease, using regular radiation fractionation schedules with heating twice a week, to determine if there was an additional benefit due to heating. From 1981 to 1986, clinical experience has rapidly accumulated which shows significant benefit from combining hyperthermia and irradiation. In studies where comparable lesions have been treated with radiation alone versus radiation and heat combined, the complete response rate has been consistently improved despite variations in the heating procedure (Overgaard, 1983). Where dose response analyses are possible from the clinical trials, specific histopathologic types and sites show a thermal enhancement of 1.4 for neck nodes, 1.5 for breast cancer and 2.0 for melanoma (Arcangeli et al., t988). General response durations can be derived from Arcangeli's experience with heating and irradiating neck nodes; that is at 2 years the local control rate was 58%, versus 14% for conventional treatment, clearly favouring the combined modality approach. Many possibilities exist for clinical trials in the next 5 years: regional deep hyperthermia, interstitial and endocavitary hyperthermia, whole body hyperthermia and hyperthermic perfusion in addition to irradiation. The major challenge will be in combining hyperthermia with other innovations that enhance tumor cell kill effect, such as radiosensitisers and selected chemotherapeutic agents (cis-plantinum, bleomycin, CCNU), when sensitivity to drugs is increased and resistance is decreased by heating as well as by irradiation.
Biologic Response Modifiers and Radiolabelled Antibodies The diagnostic and therapeutic potential of radiolabelled antibodies was established as the research
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approach with greatest potential in the field of biologic response modifiers. The antibody to tumour offers specificity and the radiolabelling with 1131allows sensitivity for detection and assay. Either I TM or 1125 provide a therapeutic approach for tumours on which radiolabelled antibodies concentrate. Tumour-associated antibodies, particularly ferritin, show a high affinity for hepatocellular carcinomas (Order et al., 1985), lung cancers, and Hodgkin's disease (Katz et al., 1973). The research plan which evolved in 1975 has been developed as a laboratory and clinical model (Order, 1976). Although used with other modalities, the response rates with radiolabelled antibodies in radioresistant and refractory cancer suggest that this remains an encouraging avenue to pursue for wider clinical application. The technology for producing labelled tumour antibodies is sufficiently advanced so that its application in clinical settings should not be an obstacle to wider introduction, once tumour specificity is established. In the past decade, considerable progress has been made using hepatocellular cancer as a model disease for radiolabelled antibodies (Order et al., 1985). Volumetric reconstruction is essential for dose determination depending upon radiolabel uptake and turnover in a specific tumour and host. Dose escalation between 30 and 50 mCi has been demonstrated, and bone marrow toxicity is a major limitation to repeated doses. Response rates of 48% are impressive in hepatocellular cancers (7% complete, 41% partial regression), in intrahepatic bile duct cancer a 26% partial response rate has occurred, and refractory Hodgkin's disease patients have experienced a 40% partial response rate (Order, 1988). Rescue with autologous bone marrow transplantation would increase the number of patients surviving aggressive therapy, but it would also intensify the cost of patient care. Studies worthy of further investigation would be in hepatocellular cancer because this disease is prevalent in the Far East and Third World Countries. More nations must participate to take labelled antibodies into a main research direction. Quality control for distribution of labelled antibodies is essential and could be established by a central production laboratory. Unexplained is the relative effectiveness of low dose irradiation; the maximal radiation dosage delivered by this approach is 1000-2000 cGy. Training for administration of large dose radioisotope therapeutics is also important because it combines both diagnostic and therapeutic aspects.
High LET Of the one million patients diagnosed with cancer annually, approximately one-third (300,000) wilt die because of uncontrolled local or regional disease. The biological basis for using high LET irradiation is exemplified by neutron beam radiation. It can overcome all differences in various cell types that relate to radioresistance, such as hypoxia, repair of sublethal/potentially lethal injury, and non-cycling prolonged G1 or Go cell populations. Neutrons reduce variation in cell radiosensitivity through a variety of mechanisms; they kill cells independent of oxygenation level; they inhibit the repair capacity of cells; and they are lethal in all phases of the cell cycle, unlike photon beams. With their greater RBE for tumour cell kill, it is important to obtain a favourable physical dose distribution since their effectiveness exists for normal tissue as well and late effect complications are
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Table 2-Results of high-LET studies
Radiation
Site/histology
Neutrons
Salivary gland Prostate Bone sarcomas
No. of pts Results* 150 285 105
Soft tissue sarcoma 540 Head and neck 2000 Lung 367 Bladder 145 Cervix 260 Brain 600 Oesophagus 74 Protons and Occular melanoma 450 helium i o n s Chordomas,chondro100 sarcomas(spineand skull) Other sites 100 Carbon, neon and All sites 100 silicon ions
+ + + + + + + + +
++ Equivocal Equivocal Equivocal Equivocal Negative Negative ++++ +++ Equivocal Too early to evaluate
* Compared to photon or electron beam radiotherapy
common. Proton and charged particle beams have Bragg peaks which provide superior distributions, compared to fast neutrons, which are more comparable to photon beams. One of the important aspects of controlled clinical trials is to have hospital-based instruments or cyclotrons in the 30-50 MeV range, rather than 16 MeV. This is akin to having 5-10 MeV accelerators rather than 250 kV units. Accordingly, a recommendation by ROCS and CROS called for a sufficient number of high L E T facilities in 1975, of which eight were to be neutron facilities. Unfortunately, most of the clinical trials were conducted by laboratory facilities of lower energy such as those at Hammersmith, Edinburgh and T A M V A X , near M D Anderson Hospital; the same was true for neutron sources at the University of Washington and George Washington University. D-t generators were used in West G e r m a n y and Amsterdam (Batterman and Mijnheer, 1986). Clinical trials have been slowly conducted through the 1970s both in the United States and in Europe; the results in a number of disease sites and cancers are promising as shown in Table 2. Briefly, head and neck cancer randomised trials are in a state of controversy because the Hammersmith and R T O G trials report a significant difference in local regional control without a high increase in complication for neutrons versus photons. Catterall (1982) reported a local control rate of 76% for neutrons and 19% for photons; and the R T O G had a 52% complete response rate for neutrons versus 19% for photons and mixed beams. Duncan (Duncan et al., 1982, 1984) noted, however, a complete response rate and ultimate control of 70% versus 60%, and 44% versus 40% for neutrons and photons, respectively, which were not statistically significant. In salivary gland tumours (Carterall and Errington, 1987), the high RBE of 6-8 associated with neutrons may contribute to successful control. For unresectable advanced neoplasms, the fast neutron control rate is 71%, comparable to results achieved with local wide excision and post-operative irradiation with photons. An R T O G Phase III randomized clinical trial of prostrate cancer, Stage C and D, compared mixed beam to photons with resultant local regional rates of 93 % and 62%, respectively, at 5 years (Laramore et al., 1985). Similarly, the 5-year survival rates showed favourable results for neutrons (60% versus 40%) with a significance
of P < 0.01. Little difference in late effect complications was noted. Both soft tissuesarcomas and bone sarcomas are better controlled with neutrons. For unresectable soft tissue sarcomas, the overall results are 50% local control, in osteogenic sarcoma, 67%, and in chondrosarcomas, 56% (Griffin et al., 1988). With photons the most impressive result is the 95% cure rate for ocular melanomas with eye preservation (Munzenrider et al., 1986). Clinical trials with neutrons are just beginning in America, with new facilities at M D Anderson, the University of Washington and UCLA, as well as older facilities at Fermi Lab in Chicago and at the Cleveland Clinic. The list of third generation neutron protocols in order of priority are: carcinoma of the prostrate (Stages C and D), squamous cell carcinoma of the head and neck (Stages III and IV), advanced and recurrent rectal cancer, locally advanced soft tissue and bone sarcomas, carcin o m a of the cervix (stages III and IVa) and non-small cell lung cancer (Stage III).
Large field irradiation Total body irradiation is limited by the tolerance of different organs. Bone marrow is considered one of the most radiosensitive. With bone marrow transplantation it is possible to offer supralethal doses of irradiation, plus chemotherapy, to treat leukaemias successfully. Hemibody irradiation is more tolerable to bone marrow since it provides a large segment unexposed to irradiation to regenerate the irradiated half. By treating both upper and lower half body segments a form of whole body irradiation is possible to provide 'systemic irradiation' for occult (Mason et al., 1982) and overt (Urtasun et al., 1983) metastases as an out-patient without the need for costly bone grafting. The technique is clearly effective for overt metastases but its potential to be curative for occult metastases requires its use in combination with chemotherapy, radiosensitisers, radioprotectors or hyperthermia. Key questions to be answered by clinical trials are: 1 definition of the most effective, least toxic, single dose in a dose escalation from 600 cGy to 1000 cGy for upper, mid and lower half-body segments. 2 To determine if elective half-body irradiation can objectively delay the appearance of new metastases in a variety of known malignances, such as breast, prostate, lung and gastrointestinal cancers. 3 To assess the ability of systemic hemi-body irradiation (both halves) to eradicate occult metastases in lung cancer (non-small cell and small cell), prostate cancer, and gastrointestinal cancer. 4 To identify effective chemotherapy combinations, as in small cell cancer of the lung, multiple myeloma and Ewing's sarcoma, that can ablate occult metastases. 5 To evaluate radiosensitisers, such as misonidazole and SR-2508, in combination with hemibody irradiation to more effectively ablate overt metastases. 6 To determine if radioprotectors, such as WR-2721, can protect the bone marrow from the deleterious, suppressive effects o f irradiation.
lntra-operative Irradiation Currently, 45 institutions are regularly involved in use of intra-operative irradiation in Japan (Abe and Takahashi, 1981), and 35 centres in the United States and
I M P A C T OF R A D I A T I O N R E S E A R C H O N C L I N I C A L T R I A L S
perhaps another l0 in Europe. This increasing interest lead the R T O G in 1985 to activate six Phase II protocols (Calvo and Hanks, 1988) in a variety of disease sites to determine efficacy and toxicity. There is a need to follow a logical and deliberate process that progresses from Phase I/II (Gunderson et al., 1982) to randomised Phase III trials to conclusively demonstrate whether there is an advantage. The ability to combine intra-operative therapy with innovative approaches such as radiosensitisers, chemotherapy and hyperthermia makes this an exciting multimodal approach. Possible tumours for further evaluation of this approach include gliomas, advanced renal carcinomas, non-resectable lung cancer, oeso: phageal cancer and bladder cancer. Research on T u m o u r s at Specific Sites
For individual disease sites, the impact of research in clinical trials has varied, depending upon the effectiveness of standard treatment modalities, such as surgery, radiation and chemotherapy, as well as the patterns of failure and local recurrence, with and without metastases. The options available include: -Optimisation of radiation treatment regimens by researching dose/time/fraetionation or volume considerations such as extended fields, particularly where chemotherapy has not been effective. - Synchronisation or determining the best sequence or combination of surgery and/or chemotherapy with irradiation. -Innovations in radiation research, such as radiosensitisers, hyperthermia, radiolabelled antibodies, and high LET, for radioresistant tumours or advanced malignances, where tolerance would be exceeded with conventional doses of radiation. The major sites where the highest priority will be given to searching for the optimal dose/time/fractionation will be head and neck cancers, lung cancers of the squamous cell and adenocarcinoma variety and glioblastoma multiforme. The therapeutic ratio can be improved through hyperfraction and accelerated split dose schedules. Phase II investigations of these concepts are being completed. Since local regional control is a major problem in advanced cancers, the desire for the highest total dose in the shortest time consistent with improved tumour ablation at minimal complication rate will be actively pursued. Synchronisation of chemotherapy/surgery and radiation therapy where sequencing and timing are important to increase therapeutic efficacy will be investigated in advanced head and neck cancer, small cell lung cancers, prostate (including hormonal combinations with agents such as Zoladex and Flutamide) bladder cancer, rectal cancer, breast and cervix cancer. There are sufficient numbers of cancers at these sites to allow more than one research theme to be explored. When multi-agent chemotherapy is effective as in haematologic malignancies, paediatric cancer, breast cancer, and to a lesser degree, small cell cancer of the lung, it is desirable since it can also act against occult metastases. Concomitant infusional therapy with 5-fluorouracil, mitomycin-C or cis-platinum will be most actively studied where advanced cancers need control as in head and neck, prostate, rectal and oesophageal cancers and cervix cancer. The innovations of radiation research have an impact on most major sites where standard treatment, particu-
73
larly chemotherapy, is ineffective. There are some disease sites that are more promising than others. The need to establish priorities depends upon the promise of Phase II trials and the toxicity encountered, but the commitment to Phase II is very costly in both money and patient resources, and better statistical models are needed. Combinations of multiple modalities and innovative approaches are also possible. All of these add to the complexity of protocol design. Conclusions
Radiation research has had a major impact on protocol design in clinical trials involving irradiation; in the past decade, 30 000 patients have entered R T O G controlled studies and comparable numbers have been entered into E O R T C and MRC trials. Through such co-operative group studies, the field of radiation oncology has changed from a specialty with individualistic: treatment approaches, and very few attempts at serious research, to a highly disciplined community of investigators that integrate basic science into larger clinical protocols. The promise of research masterplans and national co-operative clinical trials remains unfulfilled at present despite an exciting decade in which thousands of patients have been accrued. Critical analysis indicates that most of the innovations remain largely in Phase I/II studies. Despite this large research effort, the ability to demonstrate obvious gains and advantages so that newer modalities and agents can be adopted into a standard practise, remains elusive. High LET irradiation with neutrons requires more clinical trials to establish its value in soft tissue sarcomas, prostrate cancer, bone tumours, head and neck cancers, bladder cancer and brain tumours. For most disease sites, standard radiation treatment factors have emerged so that the parameter of dose/time/ fractionation and prescribed tumour and target volumes are appreciated and tolerance factors recognised. The promise of new combinations of radiation-chemotherapy remain to be established and, other than paediatric tumours and haematologic malignancies, only breast cancer treatment has changed dramatically. With early detection of breast cancer by screening mammography, conservative segmental quadrantectomies and irradiation have been effective in control and cure with good to excellent cosmesis. Adjuvant chemo-hormonal therapy, especially in pre-menopausal patients, is a widely accepted practice. Improved dose response rates have not been translated into improved survival in all sites. To fulfill the promise, international co-operation is essential. The hundreds of American and European clinical trials conducted thus far have not actualised the potential expressed in radiation research laboratories. The patient resources are limited but ideas are increasing. We must use our patient resources carefully, particularly curative patients, or, increase resources through the entry of Asian and developing countries into co-operative group trials. For EORTC and M R C clinical trials, it is important to exchange concepts with RTOG, ECOG, SWOG, and other multidisciplinary co-operative groups so that curative patient resources are not squandered. New research designs should be established to decrease control arm numbers. Quality assurance standards related to dose/ time/fractionation must be standardised so that results
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are comparable. N e w modes can be introduced by European colleagues. C o m m o n arms and joint protocols can be our goal. The Japanese radiation oncology investigators are adding more strengths in the protocol developing arena, particularly for new modalities. The use of Asian and developing countries clinical resources for curative oncology patients is important. Modern concepts for randomised studies and protocols through a new mechanism would permit standard analysis such as is available in RTOG. International Clinical Trials Radiation Oncology (ICTRO) is such a vehicle. The ICTRO seeks to extend the patient resources for clinical trials and share the state of the art advances in radiation technology. The challenge will be in the transfer o f concepts of radiation technology worldwide so that a single high standard exists. The introduction of more megavoltage equipment will improve the standards of care and in turn reduce the time to complete clinical trials. The ICTRO concept has been adopted by N C I as the first core subject in a series of bilateral and multilateral research agreements.
REFERENCES Abe, M & Takahashi, M (1981). Intraoperative radiotherapy: The Japanese experience. International Journal of Radiation Oncology, Biology, Physics, 7, 863-868. Arcangcli, G, Arcangeli, G.C, Guerra, A, Lovisolo, G, Cividalli, A, Marino, C et al. (1985) Tumor response to heat and radiation: Prognostic variables in the treatment of neck node metastases from head and neck. International Journal of Hyperthermia, 1,207 217. Arcangeli, G, Overgaard, J & Gonzalcs, GD (1988). ICTRO Research Plan-Hyperthermia. Phys. International Journal of Radiation Oncology, Biology, Physics, 14, $93-S109. Batterman, JJ & Mijnhecr, BJ (1986). The Amsterdam fast neutron therapy project: A final report. International Journal of Radiation Oncology, Biology, Physics, 12, 2093 2099. Calvo, F & Hanks G (1988). International clinical trials in radiation oncology-intra-operative radiotherapy. International Journal of Radiation Oncology , Biology, Physics, 14, $111 S117. CatteralI, M (1982). Results of neutron therapy: Differences, correlations and improvements. International Journal of Radiation Oncology, Biology, Physics, 8, 2141 2144. Catterall, M & Errington, RD (1987). The implications of improved treatment of malignant salivary gland tumors by fast neutron radiotherapy. International Journal of Radiation Oncology, Biology, Physics, 13, 1313 1318. Chemical Modifiers of Cancer Treatment. (1984). International Journal of Radiation Oncology, Biology, Physics, 10, 1161- 1813. Coleman, CN, Urtasun, RC, Wasserman, TH, Hancock, S, Harris, JW, Halsey, Jet al. (1984). Initial report of the Phase I trial of the hypoxic cell radiosensitizer SR-2508. International Journal of Radiation Oncology, Biology, Physics, 10, 1749-1753. Committee for Radiation Oncology Studies: Research Plan for Radiation Oncology - - Manpower Goals in Radiation Oncology. (1976). Cancer, 37, 2140 2148. Conference on Combined Modalities Chemotherapy/Radiotherapy (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 1139-1721. Cox, J & van der Schueren, E (1988) Clinical research on dose/time/ fractionation factors. International Journal of Radiation Oncology, Biology, Physics, 14, $51 $56. Duncan, W, Arnott, SJ, Battermann, J J, Orr, JA, Schmitt, G & Kerr, GK (1984). Fast neutrons in the treatment of head and neck cancers: The results of a multi-centre randomly controlled trial. Radiotherapy and Oncology, 2, 293 300. Duncan, W, Arnott, SJ, Orr, JA & Kerr, GR (1982). The Edinburgh experience of fast neutron therapy. International Journal of Radiotherapy On cology, Biology, Physics, 8, 2155 2157. Ellis, F (1969). Dose time and fractionation: A clinical hypothesis. Chemical Radiology, 20, 1 7. Experimental Combined Modalities Study Group. (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 633-649. Griffin, T, Wambersie, A, Laramore, G & Castro, J (198?). ICTRO
ResearchPlan-Heavy Particles Therapy. International Journal of Radiation Oncology, Biology, Physics, 14, $83 $92. Gunderson, LL, Shipley, WU, Suit, HD, Epp, ER, Nardi, G, Wood, W et al. (1982). Intraoperative irradiation: A pilot study combining external beam photon with 'boost' dose intraperative electrons. Cancer, 49, 2.259-2.266. 1CTRO Research Plan. (1988) International Journal of Radiation Oncology, Biology, Physics, 14. Katz, DH, Order, SE, Graves, M, Benacerraf, B e t al. (1973). Purification of Hodgkin's disease tumor-associated antigens. Proceedings of the National Academy for Science USA, 70, 396-400. Kligermann, MM, Glover, D J, Turrisi, AT, Norfleet, AL, Yuhas, JM, Coia LR et al. (1984). Toxicity of WR-2721 administered in single and multiple doses. International Journal of Radiation Oncology, Biology, Physics 10, 1773 1775. Laramore, G.E, Krall, J.M, Thomas, F.J, Griffin, T.W, Maor, M.H, Hendrickson, F.R. (1985). Fast neutron radiotherapy for locally advanced prostate cancer. Results of an RTOG randomized trial. International Journal of Radiation Oncology, Biology, Physics, 11, 1621 1628. Marcial, VA, Pajack, TF, Chang, C, Tupchong, L & Stetz, J (1987). Hypeffractionated photon radiation therapy in the treatment of advanced squamous cell carcinoma of the oral cavity, pharynx, larynx, and sinuses, using radiation therapy as the only planned modality: Preliminary Report by the Radiation Therapy Oncology Group (RTOG). International Journal of Radiation Oncology, Biology, Physics, 13, 41 49. Mason, BA, Richter, MP, Catalano, RB & Creech, RB (1982). Upper hemibody and local chest irradiation as consolidation following response to high-dose induction chemtherapy for small bronchogenic carcinoma - - a pilot study. Cancer Treatment Reports 66, 1609 1612. Munzenrider, JE, Gragoudas, E, Seddon, JM, McNulty, P, Sisterson, J, Johnson, K et al. (1986). Survival in photon irradiated uveal melanoma patients: Implications for prospective randomized trials. International Journal of Radiation, Oncology, Biology, Physics, 12 (Supplement 1), 121. Nigro, ND, Vaitkevicius, VK & Considine, B, Jr (1974). Combined therapy for cancer of the anal canal: a preliminary report. Diseases of the Colon and Rectum, 17, 354-356. Order, SE (1976). The history and progress of serologic immunotherapy and radiodiagnosis. Radiology, 118, 219-223. Order, SE (1988). ICTRO Research Plan Radiolabelled Antibody. International Journal Radiation Oncology, Biology, Physics, 14, $77 $8l. Order, SE, Stillwagon, GB, Klein, JL, Leichner, PK, Siegelman, SS, Fishman, EK et al. (1985). Iodine 131 antiferritin, a new treatment modality in hepatoma: A Radiation Therapy Oncology Group Study. Journal of Clinical Oncology, 3, 1573 1582. Orton, CG, Ellis, F (1973) A simplification in the use of the NSD concept in practical radiotherapy. British Journal of Radiology, 46, 529-537. Overgaard J (1983) Hyperthermic modification of the radiation response in solid tumours. In: Fletcher GH (ed). Biological basis and clinical implications of tumor radioresistance. Masson, New York, 337-352. Phillips, TL, Bartelink, H & Bleehen, N (198?). ICTRO research plan: chemical modifiers. International Journal Radiation Oncology, Biology, Physics, 14, $39 $49. Radiation Oncology Cooperative Subcommittee Research Plan (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 593-632. Radiation Oncology Research Program: High-LET (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 757 766. Regaud CL, Ferroux, R (1929) Influence de 'facteur temps' sur la sterilisation des ignees cellulaires normales et neoplasiques par la radiotherapie. Acta Radiologica, Supplement III, 107 123. ROCS Hyperthermia Working Group (1979). International Journal of Radiation, 5, 699-707. ROCS Radiation Immunology Working Group (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 727 734. ROCS Radiosensitizers/Radioprotectors Working Group (1979). International Journal of Radiation Oncology, Biology, Physics, 5, 651 658. Roberts JT et al. (1984) A phase I study of the hypoxic cell sensitiser R003-8799. International Journal of Radiation Oncology, Biology, Physics, 10, 1755-1759. Rubin, P, Costine, LS & Phillips, L (1982). WR-2721 and half-body or mid-body irradiation for the palliation of widespread symptomacti metastases. Radiation Therapy Oncology Group Study 82-03. Urtasun, RC, Belch, A & Bodnar, D (1983). Hemibody radiation, an active therapeutic modality for the management of patients with
IMPACT OF RADIATION RESEARCH ON CLINICAL TRIALS small cell lun~g cancer. International Journal of Radiation Oncology, Biology, Physics, 9, 1575-1578. Withers, H R (1979). Capacity for repair in cells of normal and malignant tissues. In: Proceedings of the Carmel Conference on Time and Dose Relationships in Radiation Biology as Applied to
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Radiotherapy. B N L Report 50203 (C-57). pp. 54-65. Brookhaven National Laboratory, Upton, New York. Yuhas, JM & Storer, JB (1969). Differential ehemoprotection of normal and malignant tissues. Journal of the National Cancer Institute, 42, 331 335.
Book Reviews Orthopaedics - Self Assessment in Radiology and Imaging 4. By D. J. Stoker and E. A. Tilley, Wolfe Medical Publication, London, 1988, 219 pp., £19.50. This soft-back book is the fourth in a series of self assessment texts in radiology and imaging. Ninety-seven independent cases are ordered at random, ranging in difficulty from the simple torus fracture of the forearm to M R of osseous leukaemic deposits. Each exercise consists of an image, short clinical history and relevant questions on the facing page, and overleaf a short discussion including the diagnosis, differential diagnosis, odd reference and derivation of any applicable eponym. The authors attention to detail is indicated by the clarity o f the radiographs which have the added benefit of being expanded to exclude any unnecessary information and in the vast majority of exercises the abnormalities are readily detectable. Exceptions include the periarticular osteoporosis of early rheumatoid which can be notoriously difficult to reproduce. The emphasis of the book is correctly on plain films although other imaging modalities have been included where relevant. The book is not aimed exclusively at radiologists and, as stated in the preface, cannot cover the whole range of bone and joint disorders. Orthopaedic surgeons m a y find the title a little misleading in that although there is a moderate a m o u n t of trauma included, the remainder is principally 'skeletal radiology' as apposed to "orthopaedic radiology'. This may appear to be semantics but experience would suggest that the specific interests of radiologists and orthopaedic surgeons in X-rays can be somewhat different. The result is a relatively inexpensive book, with a neat and consise format, particularly suitable for radiologists early in their training. Also, for those preparing for the part II Fellowship examination it should prove a welcome diversion from the tedium of the standard radiological tomes. M. Davies
An Atlas of Radiological Interpretation - The Bones. By J. Calder and G. Chessell, Wolfe Medical Publications, London, 1988, 279 pp., £19.50. This atlas is based on teaching material from courses given to undergraduates and post-graduates to D M R D level. It includes m o s t of the c o m m o n bone conditions and a few rarer lesions. Each illustration is combined with a line drawing and a short text. The specific features of each example are identified by letters on the line drawings thus avoiding any obliteration of the X-rays. The atlas provides a simple m e t h o d of assimilating information from illustrations as compared to reading extensive descriptions in text. It is therefore, particularly suitable for introductory or basic information. It is, however, fundamental that the illustrations are of top quality. In the book the transition from slide to paper has not succeeded. There are some very poor quality radiographs which are so under-penetrated that one cannot make out the basic features. Particular examples are the fractures of the facial bones but there are too many to mention them all.
The line drawings are also imprecise in many cases which reduces their value. An example is the lateral view of a compression fracture of the dorsal spine which is difficult to see on the radiograph and is drawn as a block vertebra. M a n y of the line drawings seem superfluous as the lesions are so obvious on the X-rays. The text is brief in m a n y cases and is insufficient to do justice to the subject. This is particularly the case in some bone tumours and in the joint diseases. One is amazed that there is no mention of calcium pyrophosphate deposition or of diffuse idiopathic skeletal hyperostosis. The text is generally accurate although the stated 10% incidence of bone changes in sarcoidosis is well above recognised levels. There is a complete absence of any examples of the newer imaging techniques, in particular C T and nuclear medicine. The authors do not indicate to w h o m this book is directed, although one m a y assume from the brief introduction, that it is undergraduates and trainees for D M R D . It is unlikely that this book will provide sufficient information for the latter group and the former may have difficulty recognising the features on a number of the radiographs. I. W. McCall
Nuclear Medicine - Applications to Surgery. Edited by E. Rhys Davies and W. E. G. Thomas, Castle House Publications, Tunbridge Wells, 1988, 311 pp., £60. This book is aimed at surgeons, both consultant surgeons and those in training. There are 19 chapters with 20 contributors, all of w h o m are well-known in the field of nuclear medicine. The book has a conventional layout with two chapters on basic principles and equipment used, and the rest on clinical topics. As one would expect with a large number of contributors there is some variability in the type of presentation. Some of the chapters give detailed information on how to perform the scans whereas others concentrate on the role of the tests in a clinical context. The images are of good quality although there is an occasional mistake in labelling. One other negative comment is that many of the chapters omit recent advances or potential advances such as these of H M P A O for white cell scanning and M A G 3 for renal imaging. Having said all this, I showed the book to a junior surgical colleague who thought it was very good and found it very useful. I think one of the problems with a book like this is that the editors need to decide precisely for w h o m it is intended. In the introduction it states that whilst the main target for the book is surgeons, it should also appeal to physicians and to radiologists in training. I think surgeons and physicians could well be served by a single book which concentrates on the clinical uses of nuclear medicine. Radiologists, however, need something different since they also need to know how to do the tests. Trying to satisfy both groups of people with one book has not been entirely successful. At £60, the book is too expensive for a trainee to consider buying but I think it is a very useful reference point for surgeons and physicians in training who wish to know more about what nuclear medicine has to offer. T. O. N u n a n