HIGH LET RADIOTHERAPY PROGRAM AREA REPORT
September 1977 to October 1978

Program Coordinators: Dr. Akira Tsuya
Dr. Glenn E. Sheline


Summary of Activities and Accomplishments
Activities during this reporting period included Meetings, Seminars, and Conferences: and the Exchange of Scientists.

MEETINGS, SEMINARS, AND CONFERENCES
A two-day symposium, the "High LET Radiation Therapy Workshop," was held on June 19 and 20, 1978, in Philadelphia, Pennsylvania. It was preceded by a business meeting on June 18. The symposium consisted of five sessions aimed at reviewing the present status of work in Japan and the United States with a total of 31 papers presented and discussed. The first session dealt with fast neutron radiobiology and radiotherapy with emphasis on clinical studies. The second session included three papers on radiobiology of charged particles, three on clinical trials with particulate radiations, and two on the status of high energy accelerator projects in Japan. The third session was on treatment planning with emphasis on the special problems of tissue inhomogeneity, compensating and field flattening filters, etc., related to treatment with charged particles. The fourth session concerned high dose rate brachytherapy and intraoperative therapy. It consisted of six papers in which clinical experiences in Japan and the U.S. with these forms of therapy were reviewed The last session contained seven papers on hypoxic cell sensitizers and hyperthermia. Both radiobiologic and clinical studies were included (a listing of the papers presented at this workshop follows this report). The program concluded with a lively discussion on problems of con-ducting randomized clinical studies in the U.S. and Japan. It was evident that many fundamental scientific, cultural, and ethical problems are involved. This area needs further discussion.
Ten Japanese, twelve Americans, and one Canadian presented papers and/or formally participated in the symposium. Approximately 30 other Americans also attended and participated in the discussions; they were mostly representatives from various high LET projects currently active in the U.S.
In keeping with precedent set at previous meetings, this was a hard working symposium with high quality papers and free and lively discussion.
Another workshop was held in the period under consideration (September 29 and 30, 1977. Tokyo). The Summary Report is contained in the second two-year Progress Report for 1976 and 1977.

EXCHANGE OF SCIENTISTS
During this reporting period, two Japanese and four U.S. scientists participated in the exchange program.
Mitsuyuki Abe, M.D., Professor, Department of Radiology, Kyoto University Medical School, Kyoto, Japan, visited particle radiotherapy facilities in the U.S., participated in the Philadelphia symposium, and gave several lectures on intraoperative radiotherapy. His visits included the University of California at Berkeley (Dr. Cornelius Tobias), University of California at San Francisco (Drs. Theodore Phillips and Glenn Sheline), Los Alamos (Dr. Morton Kligerman), Howard University (Dr. Ulrich Henschke), the National Cancer Institute (Dr. Eli Glatstein), and the Massachusetts General Hospital (Dr. Herman Suit).
The second Japanese exchange scientist was Koichi Kaneta, M.D., Assistant Chief of the Division of Radiotherapy, Cancer Institute Hospital, Tokyo, Japan. Dr. Kaneta was chiefly concerned with Californium-252 brachytherapy, including the U.S. Radiation Therapy Oncology Group clinical trials. Discussions were held at Jefferson Medical School (Dr. H. Gunter Seydel), Memorial Sloan-Kettering Cancer Center (Dr. Basil Hilaris), M.D. Anderson Hospital (Dr. L. Delclos), the University of California at San Francisco (Dr. Theodore Phillips); and Albert B. Chandler Medical Center, University of Kentucky (Dr. Y. Maruyama).
Peter R. Almond, Ph.D., Professor, Department of Physics, M.D. Anderson Hospital and Tumor Institute, Houston, lectured at four facilities in Japan. These included Tohoku University in Sendai; the Radiological Society in Kansai District at Osaka; Tokyo University; and the National Institute of Radiological Sciences (NIRS) in Chiba. He spoke on various aspects of fast neutron radiotherapy as experienced with the Texas A & M variable energy cyclotron. Dr. Almond also con-ducted physical dosimetry measurements at the Institute of Medical Sciences (IMS) in Tokyo (completing the physical dosimetry intercomparison studies).
Hermann A. Grunder. Ph.D., Professor of Physics, University of California, Berkeley, reviewed the status of medical accelerators in Japan and worked with the Neutron Study and Design Group at the Institute for Nuclear Science near Tokyo. He visited and gave lectures at KEK (Tsukuba City), the Institute for Nuclear Science (Tokyo), the Institute for Physical and Chemical Research (Tokyo), Tohoku University (Sendai), the Research Center for Nuclear Physics (Osaka University), the pion facility at Nihon University and NIRS at Chiba.
Theodore L. Phillips, M.D., Professor, Division of Radiation Oncology, University of California at San Francisco, visited and gave lectures at Tohoku University (Dr. Matsuzawa), Kyoto University (Dr. M. Abe), the regional Radiological Society meeting at Osaka, Tokyo University (Dr. Okada). and NIRS in Chiba (Dr. Umegaki). His primary interest was related to high LET radiobiology and radiotherapy but lectures and discussion included hypoxic cell sensitizers and intraoperative radiotherapy.
Herman D. Suit, M.D., Ph.D., Professor of Radiation Medicine, Massachusetts General Hospital, Boston, visited the Medical Center at Sapporo (Dr. Kikuchi), Kyoto University Medical Center (Dr. M. Abe). University of Tokyo Medical Center (Drs. Okada and Sakamoto), IMS in Tokyo (Dr. Ito), and NIRS in Chiba (Dr. Umegaki). Dr. Suit gave lectures on clinical studies with proton beams and participated in seminars on basic radiobiology.

Five-Year Summary Report
The initial High LET Radiotherapy Program goals were to review the status of high LET radiation physics, radiobiology, and clinical trials and then to promote use of high LET particle therapy in the two countries. The intent was to develop a common body of knowledge and mutually accepted dosimetry (both radiobiological and physical), and to extend this activity to controlled clinical trials. It was also intended that related subject areas would be added as interest dictated. The program began with a study of fast neutron beams (neutron studies were more advanced in both countries) and was then extended to other particle beams. Since the initial contact in the Spring of 1975, the program has developed precisely along these lines and has been imminently successful from the viewpoints of both countries.
Intercomparative physical and biological dosimetry studies have been completed for all fast neutron beams in clinical use in the U.S. and Japan. These have included detailed physical and radiobiological measurements on the various neutron beams. Common dosimetry and similar dose units form the basis for any exchange of information and for international confidence in work reported.
While the radiobiological and physical dosimetry studies were in progress, discussions on controlled clinical trials were carried out. Even though no bilaterally acceptable randomized trial has as yet been formulated, the discussions influenced and aided development of protocols in each country. With respect to possible common protocols, the first effort concerned carcinoma of the uterine cervix. However, due to differences in the manner in which brachytherapy is used in the two countries (low dose rate and long exposure time in the United States versus high dose rate and short application times in Japan), carcinoma of the cervix may not prove to be a good choice for a common protocol. Other disease sites for common studies are being investigated.
Simultaneous with discussions on neutrons, consideration has been given to other particles. This has provided a valuable exchange of information and promoted basic research in both countries. Particles under consideration include protons, negative pi-mesons, carbon, and neon. Questions of design and construction of appropriate dedicated medical sources for particle beams have been dealt with in detail. Electron linacs currently are favored at Stanford University (California) and in Japan. At Los Alamos, a proton linac is under development and may, in the near future, become the machine of choice. The program has aided and stimulated the design and construction of such equipment in both countries. Since the costs involved are high, mutual assistance is of great value.
During the last few years there has been great interest in hypoxic cell sensitizers. There is a possibility that these may be of value in conjunction with particle therapy, or even in obviating the need for particle therapy. For this reason, the last "high LET" workshop (Philadelphia, 1978) included a session on hypoxic cell radiosensitizers. This session reviewed the present status of work in Japan and in the U.S. and explored possible areas for cooperation. It was evident that much interest exists in both countries. Radiobiological studies with cell cultures and animal tumor systems and clinical Phase I and Phase 11 trials are underway. Evident areas for cooperation include exchange of information, exchange of sensitizer compounds, and, later, clinical trials.
The 1978 symposium also included a discussion of intraoperative radiotherapy, an area under active investigation in Japan and in one site in the U.S. (Howard University). Other U.S. institutions (e.g., Massachusetts General Hospital, Boston) are developing the necessary facilities. In addition to the many technical difficulties, a substantial outlay of resources is required for delivery of radiation therapy in a sterile operating room type environment. Thus, much may be gained from exchange of technical information. Ultimately, the efficacy of the method must be tested through clinical trials. Since the method is time-consuming and the number of patients with suitable lesions limited, meaningful clinical trials will require cooperation between multiple institutions.
Future activities include continuation of studies on the physics and biology of neutrons, development of clinical trials, design and development of medically dedicated sources for particle beams, biological and physical dosimetry intercomparison studies for particles other than neutrons as they become available for biological and clinical use, and cooperative studies with hypoxic cell radiosensitizers and intraoperative therapy. Given time and resources, there are no inherent difficulties foreseeable in the design and development of particle radiation sources or in the conduct of the biological and physical studies outlined. Differences in attitude may impose philosophical constraints on randomized clinical trials. This most important area requires careful attention. Either suitable areas for randomized trials should be found, or methodology should be developed to circumvent the need for randomization.



HIGH LET RADIATION THERAPY WORKSHOP
Philadelphia, Pennsylvania
June 19 and 20, 1978

AGENDA
Co-Chairmen:
Akira Tsuya, M.D.
Glenn E. Sheline, Ph.D., M.D.

Session I: Fast Neutron Radiobiology and Radiotherapy
(Convener: Dr. T. L. Phillips)
1.
The Effect of Fast Neutrons on Chinese Hamster V79 Cultured Cells in Murine Epithelioma K. Sakamoto, University of Tokyo
2.
The Status of U.S, Clinical Neutron Studies L. Davis
3.
Results of Fast Neutron Therapy at NIRS S. Morita
4.
Fast Neutron Clinical Trial on Uterine Cervix Cancer at NIRS S. Morita
5.
U.S. Fast Neutron Clinical Trial for Cancer of the Cervix D. Hussey
6.
A Comparison of U.S. and Japanese Clinical Trials with Fast Neutrons for Carcinoma of the Cervix D. Hussey and T. Phillips
Session II : Proton and Charged Particle Radiobiology and Radiotherapy
(Convener: Dr. L. Davis)
1.
Radiobiology of 160-MeV Protons M. Urano
2.
Proton Therapy of Choroidal Melanoma with Discussion Y. Umegaki and H. Suit
3.
Update of Radiobiology of Charged Particles T. Phillips
4.
Clinical Trials with Charged Particles J. Castro
5.
The Effect of Negative Pi-meson on Murine Epithelioma K. Sakamoto
6.
Clinical Trials with Pions M. Kligerman
7.
High Energy Accelerator Projects with Medical Program in Japan S. Fukumoto
8.
Project Plan of Pi-meson Therapy Facility at Nihon University O. Hara
Session III: Treatment Planning
(Convener: Dr. J. Castro)
1.
Improved Physical Dose Distribution from Fast Neutron Beams (Build-up, Depth Dose, Inhomogeneities, Modification of Dose Distribution, etc.) V. Otte
2.
Treatment Planning for Charged Particle Radiotherapy G. Chen
3.
Planning of Proton Therapy at NIRS Y. Umegaki
Session IV: High Dose Rate Brachytherapy and Intraoperative Therapy
(Convener: Dr. H. Suit)
1.
High Dose Rate Brachytherapy for Gynecologic Cancer, Methods and Results S. Morita
2.
Experiences in U.S. with High Dose Rate Brachyiherapy J. Utley
3.
Experiences with Intraoperative Radiotherapy at the Kyoto University Hospital M. Abe
4.
Clinical Experiences of the Intraoperative Radiotherapy of Cancer of the Bladder and Digestive Tract Y. Umegaki
5.
Intraoperative Radiotherapy A. Goldson
6.
Is There a Place for Hypoxic Cell Sensitizers with Intraoperative or High Dose Rate Brachytherapy? T. Phillips
Session V: Hypoxic Cell Sensitizers and Radioprotectors
(Convener: Dr. E. J. Hall)
1.
Present State of Studies on Anoxic Sensitizers and Hyperthermia in Japan Y. Onoyama
2.
Experimental Animal Tumor Irradiation Using Hypoxic Sensitizer M. Abe
3.
Sensitizing Effect of Misonidazole on Spontaneous Mammary Carcinoma of C3H Mice Y. Onoyama
4.
C. PARVUM Enhanced Thermal Response of Murine Tumors M. Urano
5.
Hypoxic Cell Radiosensitizers E. Hall
6.
Clinical Studies with Radiosensitizers R. Urtasun
7.
Clinical Studies with Radiosensitizers T. Phillips
8.
Discussion of Areas for Joint Studies H. Suit