PROGRAM AREA REPORTS

HIGH LET RADIATION THERAPY PROGRAM

The High LET (linear energy transfer) Radiation Therapy Program Area was initiated at a meeting in Tokyo in July 1975. Plans for the ensuing two to three years were developed at that time. Although the high LET component was the last of the eleven program areas of the U.S.-Japan Cooperative Cancer Research Program to be activated, progress has been substantial.
Interest in high LET radiation therapy is based on the fact that, in contrast to conventional photon irradiation, with high LET particles there is little protection afforded to the tumor cells by hypoxia. Neutrons, pions, and heavy stripped nuclei, such as carbon, argon, zeon, and neon, have the requisite biological properties of high LET irradiation. The heavy nuclei, and to a lesser extent pions, also have physical advantages over neutrons and photons in that with these particles a more precise delivery of a uniform dose to a specified tissue volume is possible. Protons, which are not high LET particles, possess the physical but lack the biological advantages of pions and heavy ions.
When the U.S.-Japan High LET Radiation Therapy Program was initiated, the radiobiology of neutrons already had been investigated extensively, and neutron sources were available for clinical use in both countries. Therefore, the initial emphasis was on neutron radiotherapy. It was planned that joint studies for pion and heavy particle radiotherapy would be developed at a rate commensurate with the accumulation of knowledge regarding their radiobiological and physical properties and the availability of suitable sources for clinical research.
The first goal of the joint neutron program was to compare the physical properties and physical dosimetry of fast neutron radiotherapy beams which were to be used for clinical investigation in the U.S. and Japan. This was necessary in order to place biological and clinical studies on a reliable physical base. During 1976 and 1977, Drs. Takeshi Hiraoka and Akira Ito, Japanese physicists, made visits of approximately three months each to various U.S. facilities to observe neutron dosimetry techniques. In the spring of 1976, three U.S. physicists, Drs. Peter Almond, James Smathers, and Hans Bichsel, visited Japan to compare physical properties and the calibration of the National Institutes of Radiological Sciences (NIRS) and the Institute of Medical Science (IMS) neutron beams with those in the U.S. Previously they had conducted similar studies of all U.S. neutron beams being used in clinical studies. Because of an equipment failure, measurements at IMS were not completed until the summer of 1977. The results of the intercomparison are very satisfactory. Although the Japanese radiation absorbed dose (rad) appears to be about 5 percent larger than the U.S. rad, the difference is known and is systematic, thus allowing for a simple conversion factor. To explain the 5 percent discrepancy, more basic data, particularly on the lower energy portion of the neutron spectra, are needed; this will require the development of better methods for measuring low energy neutrons. Formal reports on the physical intercalibration measurements have been prepared by Drs. Smathers and Almond and distributed to interested groups in each country. A manuscript is being prepared for publication.
Between December 1976 and March 1977, six American radiobiologists visited Japan to compare the biological properties of the IMS and NIRS neutron beams with those in use in the U.S. Similar studies had been made on the United States fast neutron beams. Because the energy spectra of the neutron beams differ (the relative biological effectiveness [RBE] of neutrons changes with energy and various biological systems react differently), it was necessary to study multiple biological test systems. Therefore, six different systems were selected for the comparison studies. Three of the systems used in vitro cultures of V79, CHO, or T1 cells. The three in vivo systems included measurements of DNA content and weight of mouse testes, skin reaction of mice feet, and surviving fraction of mouse jejunum crypt cells. Analyses of the data have been completed. The results were presented at the “Third High LET Workshop” held in Tokyo, September 1977, and manuscripts for publication are in preparation. Although in general the biological potency of the various neutron beams was inversely proportional to the energy of the deuterons or protons used in their production, minor discrepancies were found (e.g., the Chiba beam which is of slightly lower energy than that at NRL was 2 percent less effective). RBE estimates from the V79 and T1 in vitro cell systems were similar to those obtained with the skin and jejunal crypt cell in vivo systems. Of interest for future intercomparison studies, it was concluded that: (1) few biological systems yield sufficiently repeatable data for precise comparisons to be derived from separate experiments; and (2) intercomparison studies should be made on the same days, using cells from the same culture or animals from the same pool. Although there were minor discrepancies between the six biological test systems, the results permit progression to clinical studies. Nevertheless, additional biological data are desirable: for example, studies are needed for (1) experimental solid tumor systems in which hypoxic cells are present; (2) comparing neutron and photon irradiation with and without electron affinic radiosensitizer compounds; and (3) determining the combined effect of hyperthermia and high LET irradiation (with photon irradiation hyperthermia reduces the shoulder of the cell survival curve).
Japanese investigators have compared the neutron beams at NIRS and IMS. RBE as a function of neutron dose was determined for human glial cells, human kidney cells, and rat glioma cells in culture. Cells in plateau phase were found to be more resistant than cells in exponential phase. In contrast to photon irradiation, split-dose experiments confirmed that there is no repair of sublethal damage between individual exposure to neutrons.
Evolution of neutron clinical dose schedules, daily increments, and total accumulated dose followed the same pathway in the U.S. and Japan. First, physical and biological dosimetry were determined. The radiobiological studies included an evaluation of the variation of RBE according to the neutron energy spectrum, the size of each individual exposure dose, and the total number of dose fractions. Interestingly, there was good agreement between the RBE values found for the beams of similar energy at NIRS in Japan and the National Research Laboratory (NRL) in the United States (RBE = 3.3). Once the RBE values were derived, they were applied cautiously to the treatment of human tumors. Initially only very advanced carcinomas were treated. With the accumulation of human experience, the dose fractionation schemes were adjusted. Because a good radiobiological base had been established, the adjustments needed were relatively small.
At the initial meeting of the U.S.-Japan High LET Radiation Therapy Workshop held in Tokyo in July 1975, it was agreed that the ultimate objective of the neutron program was clinical trials in which the value of neutron radiotherapy could finally be determined. Clinical trials were discussed again at the 1976 Berkeley Workshop and were a major topic of the 1977 Workshop in Tokyo. During the last two years, several protocols for fast neutron clinical trials have been developed both in Japan and in the U.S. These protocols have begun to be accessible to patients, particularly in those protocols relating to tumors of the head and neck and carcinoma of the cervix. An effort has been made to include randomization between treatment options as an integral part of each protocol. There are, however, significant obstacles to the conduct of randomized clinical trials. Therefore, the Workshops have included the consideration of other approaches, such as: (1) the use of historical controls with matched pairs, (2) sequential assignment to different treatment arms, and (3) a scheme in which patient consent is obtained only from those randomized to the experimental or nonstandard treatment. Exploration of avenues other than classical randomized trials continues as an area of interest. For the present purposes, it was concluded that it would be best for the cooperating groups to develop protocols with one common treatment arm but in which the other arms could differ. This would provide a basis for comparison, yet allow maximum flexibility for differing restrictions imposed by individual preference and cultural variances. The consensus was for the U.S.-Japan cooperative clinical fast neutron trials to begin with a study of advanced carcinoma of the cervix, stages III and IV-A. This decision was influenced by the fact that the control arms of the existing U.S. and Japanese protocols for advanced cervical carcinoma are fairly similar, hence, a minimum of adjustment would be required in order to bring them into conformity with each other. The groups in Japan and the United States responsible for developing treatment protocols for cervical carcinoma are attempting to eliminate or to develop a means of compensating for minor differences which currently exist.
The non-neutron high LET program, i.e., that related to particles other than neutrons, has gradually gained momentum. Studies on means of production of other particles, their physical and radiobiological characteristics and possible clinical applications, have constituted areas of increasing interest. These were major topics of the Workshops of 1976 (Berkeley) and 1977 (Tokyo). A summary of the interchange follows: Equipment to produce pions or heavy stripped nuclei is expensive but the current state of the art makes construction entirely feasible. For heavy ion beams, the machine of choice is thought to be a variable energy synchrotron designed to produce beams of different particles. At present, an electron linac is probably best for pion production, but current studies of proton linac design may within the next few years tilt the balance toward the proton machine. If the pion system makes use of the Stanford Medical Pion Generator, a modification of its beam transport system will probably be needed; to clarify this problem a study of pion optics is being conducted at Nihon University. To provide the optimal dose distribution available with charged particles, a system of three-dimensional scanning with a pencil beam appears superior to the use of scattering foils or ridge filters. The best estimate (1977) of cost for hardware of a machine to deliver charged particles is in the order of five to ten million dollars. Taking into consideration the physical and biological properties of charged particle beams (e.g., relationship between physical dose of the entrance versus the peak portion of the beam, RBE factors, oxygen enhancement ratios, beam fragmentation, and exit dose), neon may be the superior particle for clinical radiotherapy. At the present time, such a conclusion is tentative and more research on both the physical and the radiobiological properties of these is necessary. This research is in progress and results can be expected during the next two or three years. To utilize the inherent advantages which accrue from the physical characteristics of charged particle or proton beams, it is necessary to perform exceedingly precise treatment planning with careful localization of both tumor and critical normal tissues. It is also necessary to compensate for inhomogeneities within tissue systems (fat, gas, bone). These problems were discussed in depth during the 1977 workshop. It was concluded that without precise tumor and tissue localization and inhomogeneity compensation, the theoretical advantages of pions, heavy charged particles, or protons over neutron or photon radiotherapy would in all probability be lost. To satisfy requirements for localization and compensation, computerized tomography (CT) and proton radiography are being developed. At least for the present, some form of CT scanning will play the major role; proton radiography is less well developed and its applicability less certain.
How vigorously to pursue heavy ion/pion radiotherapy is under discussion in both Japan and the U.S. At present, in the U.S. there is only one facility involved in clinical investigation with heavy ions and one with pions.
Future plans for the High LET Radiation Therapy Program Area include a continuation of activities related to fast neutron radiotherapy with special emphasis on randomized clinical protocol studies. Other high LET particle (e.g., pions) therapy, hypoxic cell radiosensitizers (e.g., electron affinic compounds), and hyperthermia will also be included. Although the program is directed primarily toward therapy, radiobiology and radiation physics will be integrated parts. The activities will be carried out via workshops and exchanges of scientists, materials (e.g., radiosensitizers), and methods (e.g., Iinear accelerator designs or techniques for producing controlled hyperthermia).