REPORTS ON SEMINARS
(1) Seminar on "Radiation Therapy Research"
A seminar on Radiation Therapy Research was held in Chiba and Kyoto, Japan, on October 2-5, 1982.
Despite many advances in radiotherapy treatment methods, failure of local tumor control remains a significant problem. Local failure may be related to resistance of certain tumors to irradiation, possibly resulting from areas of cellular hypoxia. It also may be due to disproportionately radiosensitive critical organs adjacent to the tumor or target volume. Prom its inception, the Radiation Research portion of the U.S.-Japan Cooperative Cancer Research Program has been devoted to an exchange of information and techniques related to methods of increasing the relative radiosensitivity of the tumor tissue (e.g., high-LET radiations, hypoxic cell radiation sensitizers, and hyperthermia) and to techniques for delivering increased doses to the target volume while protecting nearby normal tissues and organs (e.g., intraoperative radiotherapy and proton beam radiotherapy). Attention has been directed toward (1) development of machinery for new radiation sources and tissue heating; (2) dosimetry; (3) tissue temperature measurement; (4) the complex radiobiology associated with the new techniques; and (5) the clinical application, including clinical trials, of these methods of therapy. While the initial Radiation Research seminar under the U.S.-Japan agreement dealt totally with high-LET radiation problems, subsequent seminars have included radiation sensitizers, radiation protectors, and hyperthermia and intraoperative radiation therapy.
The first day of the 1982 seminar was held in Chiba, Japan, on October 2, 1982. The first paper dealt with the design and construction of the high energy accelerator (in the order of 70-MeV) being built at the Institute of Physical and Chemical Research at Saitama. The facility, machine, and beam transport system should be completed in approximately 4 years; it will have multiple beam lines for bioresearch, isotope production, and medical application. The second paper detailed the design and estimated construction cost of a dedicated heavy ion accelerator for radiotherapy. The design has been under development at UC-LBL for several years and is virtually complete; construction depends on availability of financing. Maximum energy is 800-MeV/nucleon. It will use scanning with rapidly variable energy to provide three-dimensional beam shaping.
The next paper described the use of a 500-MeV beam for neutron production and a 250-MeV proton beam for therapy at the High Energy Physics Laboratory at the University of Tsubuda. The next paper was related to the double-sized microtron for pion production being designed at the Atomic Energy Research Institute, Nihon University, 'Tokyo. This is a smaller, less expensive machine than other proposed hospital-based pion generators; they propose use of an electron beam linac rather than one using a proton beam. Proton conformation therapy using a three-dimensional 90-MeV spot beam scanning system at NIRS was then described. Computerized interactive treatment planning at LBL was the subject of the next paper. The remainder of the first day was devoted to presentation and discussion of clinical results and complications of proton and neutron beam radiotherapy in the United States and Japan. Approximately 900 patients have been treated with neutrons and 16 with 70-MeV protons at NIRS. At LBL, Berkeley, 419 patients have been entered into the heavy charged particle clinical trial. Dose-response relationships both for local control of advanced head and neck tumors and for complications based on the neutron experience at the M.D. Anderson Hospital constituted the last paper of the first day.
The second and third days of the seminar were in Kyoto. Papers from the United States and Japan on the late complications of fast neutron therapy and on how to score such reactions so that results could be compared internationally were presented. Also, three papers on the radiobiology of neutrons, pions, and heavy particles in single and/or iractionated doses were given. Next, speakers presented a set of six talks on the biological bases for hyperthermia in cancer therapy and clinical trials with hyperthermia and irradiation. There was considerable discussion regarding how to heat tissues uniformly and reliably as well as how to measure in vivo temperature.
The next nine papers dealt with various aspects of radiation sensitizers and radiation protectors. The subject matter ranged from development of new and better compounds (there are several promising new sensitizers almost ready for clinical use in Japan and the United States), to biological studies and finally to clinical trials in the United States and Japan. The final three papers summarized the status of intraoperative radiotherapy in both countries.
(2) Seminar on "Drug Development"
The Eighth Annual Treatment Area Review Meeting of the U.S.-Japan Cooperative Cancer Research Program was held in Bethesda, Maryland, on November 22-24, 1982. The first 2 days of the meeting were devoted to a series of scientific presentations in the areas of anticancer drug development, biological response modifiers, and clinical chemotherapy trials. During the first day of the session, there was a discussion of the application of the human tumor stem cell assay to anticancer drug development as well as several presentations concerning the important area of drug resistance. This was followed by several excellent presentations concerning new antitumor antibiotics and the extent to which these agents might be useful in the treatment of malignancy. The topic of biological response modifiers and how to screen for these agents in in vitro laboratory assay and animal tumor models also was discussed. Several new immunomodulatory compounds were described.
The second day of the scientific session was devoted to a discussion of clinical trials. After several papers describing the optimal way to design clinical trials with regard to various statistical considerations and data management, there was a presentation of Phase I data concerning new anticancer agents, including anthracycline and cis-platinum analogues, mitomycin, and interferon. The final portion of the scientific session was devoted to a discussion of clinical trials in the areas of breast cancer, small cell lung cancer, and gastric cancer. The session was concluded with a most informative discussion of strategies for drug development and future clinical trials.
SEMINAR AGENDA AND PARTICIPANTS
(1) HIGH-LET PARTICLE IRRADIATION AND OTHER APPROACHES TO INCREASING
EFFECTIVENESS OF RADIATION THERAPY FOR CANCER
Chiba and Kyoto, Japan, October 2, 4-5, 1982
AGENDA
| Saturday, October 2 | ||
| 10:00-10:10 | Opening remarks | G. Sheline M. Abe |
| 10:10-10:15 | Welcome address | T. Tsunemoto |
| Session I. High-LET Radiation Moderator: D. Hussey |
||
| 10:15-10:45 | Medical application project of light and heavy ion beam from IPCR separate sector cyclotron | H. Kamitsubo |
| 10:45-11:15 | Design of accelerator for particle beam radiotherapy | T. Elioff |
| 11:15-11:45 | Outline of PARMS and some preliminary dosimetry | T. Inada |
| 11:45-12:15 | Some remarks on the double-sided microtron for therapeutic use | K. Tsukada |
| 12:15-13:15 | LUNCHEON | |
| Moderator: T. Inada | ||
| 13:15-13:45 | Proton conformation therapy system by three-dimensional spot beam scanning method | K. Kawachi |
| 13:45-14:15 | Computerized treatment planning for heavy charged particle radiotherapy | G.T.Y. Chen |
| 14:15-14:45 | Proton radiotherapy in NIRS | A. Akanuma |
| 14:45-15:15 | Clinical results with particle radiotherapy | J.R. Castro |
| 15:15-16:30 | COFFEE BREAK and Visit to proton therapy facility at NIRS | |
| Moderator: T. Elioff | ||
| 16:30-17:00 | Results of clinical trials with fast neutron in Japan | H. Tsunemoto |
| 17:00-17:30 | Results of neutron radiation therapy with emphasis on U.S. clinical trials | D. Hussey |
| 17:30-19:00 | DINNER | |
| Monday, October 4 | ||
| 9:00-9:10 | Introduction | M. Abe |
| Moderator: J.R. Castro | ||
| 9:10-9:40 | Clinical evaluation of 252Cf banchytherapy | K. Kaneta |
| 9:40-10:10 | Complications of fast neutron therapy of NIRS and IMS: Scoring and incidence |
S. Morita |
| 10:10-10:40 | Complications of neutron radiation therapy: Scoring and incidence | D. Hussey |
| 10:40-10:55 | COFFEE BREAK | |
| Moderator: T. Sugahara | ||
| 10:55-11:25 | Comparison of the effects of pion and heavy ion beams in a mouse tumor system | K. Sakamoto |
| 11:25-11:55 | The radiobiology of particle beam radiation therapy | E. Hall |
| 11:55-12:25 | Effects of fast neutrons on experimental tumors in fractionated schemes | K. Ando |
| 12:25-13:30 | LUNCHEON | |
| Session II. Hyperthermia Moderator: P. Gibbs |
||
| 13:30-14:00 | Fundamental studies on hyperthermia in cancer treatment | E. Kano |
| 14:00-14:30 | Biological basis for hyperthermia in radiation therapy | E. Hall |
| 14:30-15:00 | Trials of clinical hyperthermia in cancer therapy | J. Egawa |
| 15:00-15:15 | COFFEE BREAK | |
| Moderator: E. Hall | ||
| 15:15-15:45 | Technical aspects of in vivo hyperthermia | P. Gibbs |
| 15:45-16:15 | Clinical results of hyperthermia combined with radiation in cancer therapy | M. Abe |
| 16:1 5-16:45 | Clinical trials with hyperthermia and irradiation | P. Gibbs |
| 16:45- | DINNER | |
| Tuesday, October 5 Session III. Radiation Sensitizing and Protecting Agents Moderator: T.H. Wasserman |
||
| 9:00-9:30 | Effects of misonidazole on tumor cell radiation sensitivity and potentially lethal damage repair in vivo and in vitro | K. Sakamoto |
| 9:30-10:00 | Radio-chemical mechanism of sensitizer | T. Kagiya |
| 10:00-10:30 | Radiation sensitizing and protecting agents, biologic basis, and development of new agents | E. Hall |
| 10:30-10:45 | COFFEE BREAK | |
| Moderator: K. Sakamoto | ||
| 10:45-11:15 | Recent research for hypoxic cell sensitizer in Japan | T. Mori |
| 11:15-11:45 | Repair in radio- and chemosensitization in cancer treatment | T. Sugahara |
| 11:45-12:15 | Clinical trials with hypoxic cell radiation sensitizing agents including results of the Radiation Therapy Oncology Group | T. H. Wasserman |
| 12:15-13:15 | LUNCHEON | |
| Moderator: J. Tepper | ||
| 13:15-13:45 | Clinical trials of hypoxic cell sensitizer misonidazole in Japan | Y. Onoyama |
| 13:45-14:15 | Clinical experiences of chemical radioprotector (WR-272D in tumor radiotherapy | Y. Tanaka |
| 14:15-14:45 | Clinical application of radiation protecting agents including preliminary results of Radiation Therapy Oncology Group Studies | T. H. Wasserman |
| 14:45-15:00 | COFFEE BREAK | |
| Session IV. Intraoperative Radiotherapy Moderator: J. Egawa |
||
| 15:00-15:30 | Intraoperative radiotherapy of pancreatic carcinoma | T. Matsuda |
| 15:30-16:00 | Intraoperative radiotherapy in the United States | J. Tepper |
| 16:00-16:30 | Intraoperative radiotherapy of refractory cancers | M. Abe |
| Closing remarks | G. Sheline M. Abe |
|
| 17:00-19:00 | BANQUET | |
PARTICIPANTS
UNITED STATES
Joseph R. Castro, M.D.
Professor of Radiation Oncology
University of California Medical Center
George T.Y. Chen, Ph.D.
Head, Radiotherapy Physics
LBL Heavy Ion Project
Radiotherapy Section
University of California
Tom Elioff, Ph.D.
Deputy Director
Accelerator & Fusion Research Division
Lawrence Berkeley Laboratory
University of California at Berkeley
Frederic Gibbs, M.D.
Assistant Professor
Division of Radiation Oncology
University of Utah Medical Center
Eric Hall, Ph.D.
Professor of Radiology
Columbia University
David Hussey, M.D.
Professor, Department of Radiotherapy
M.D. Anderson Hospital
G.E. Sheline, M.D.
Professor
Department of Radiation Oncology
University of California
Joel Tepper, M.D.
Massachusetts General Hospital
Department of Radiation Medicine
Todd H. Wasserman, M.D.
Associate Radiation Oncologist Washington University
Mallinckrodt Institute of Radiology
JAPAN
Mitsuyuki Abe, M.D.
Professor
Department of Radiology
Faculty of Medicine
Kyoto University
Atsuo Akanuma, M.D.
Lecturer
Department of Radiology
Faculty of Medicine
Tokyo University
Koichi Ando, M.D.
Researcher
Division of Clinical Research
National Institute of Radiological Sciences
Tadayoshi Matsuda, M.D.
Head, Department of Radiotherapy
Tokyo Metropolitan Komagome Hospital
Tomoyuki Mori, M.D.
Professor
Radiation Oncology
School of Medicine
Tokai University
Shinroku Morita, M.D.
Chief, Division of Hospital
National Institue of
Radiological Sciences
Jun Egawa, M.D.
Professor
Department of Radiology
Teikyo University
School of Medicine
Tetsuo Inada, Ph.D.
Professor
Institute of Basic Medical Sciences
The University of Tsukuba
Tsutomu Kagiya, Ph.D.
Professor
Department of Hydrocarbon
Chemistry, Faculty of Engineering
Kyoto University
Hiromichi Kamitsubo, Ph.D.
Chief Researcher
Institute of Physical and Chemical Research
Koichi Kaneta, M.D.
Head, Department of Radiation Therapy
Cancer Institute Hospital
Eichi Kano, M.D.
Professor
Department of Experimental Radiology and Health Physics
Fukui Medical University
School of Medicine
Kiyomitsu Kawachi, Ph.D.
Chief Researcher
Division of Physics
National Institute of Radiological Sciences
Yasuto Onoyama, M.D.
Professor
Department of Radiology
Osaka City University
Medical School
Kiyohiko Sakamoto, M.D.
Professor
Department of Radiation Research
School of Medicine
Tohoku University
Tsutomu Sugahara, M.D.
Director, Kyoto National Hospital
Yoshimasa Tanaka, M.D.
Professor
Department of Radiology
Kansai Medical University
Kineo Tsukada, Ph.D.
Professor
Atomic Energy Research Institute of Nihon University
Hiroshi Tsunemoto, M.D.
Director
Division of Clinical Research
National Institute of Radiological Sciences
(2) U.S.-JAPAN EIGHTH ANNUAL TREATMENT PROGRAM AREA REVIEW MEETING
Bethesda, Maryland, November 22-24, 1982
AGENDA
| Monday, November 22 | ||
| 8:30-9:00 | Welcome | G. O'Conor B. Chabner |
| Opening Remarks | V. DeVita H. Umezawa B. Chabner Y. Sakurai |
|
| Session I. New Concepts in Pharmacology | ||
| 9:00-9:20 | The human tumor stem cell assay | M. Wolpert R. Shoemaker |
| 9:20-9:35 | Comparative evaluation of drugs in the stem cell assay and in the nude mouse (with emphasis on gastric cancer) |
M. Ogawa |
| 9:35-10:10 | Genetic mechanisms of drug resistance | B. Chabner |
| 10:10-10:30 | Approaches to selective cytotoxicity based on DNA damage | K. Kohn |
| 10:30-10:50 | COFFEE BREAK | |
| 10:50-11:10 | Mechanism of vincristine resistance, and circumvention of vincristine and adriamycin resistance by calcium influx blockers and calmodulin inhibitors | T. Tsuruo |
| 11:10-11:40 | Cell kinetic and genetic R. Simon considerations in the delivery of treatment | |
| Session II. biology of Metastasis | ||
| 11:40-12:15 | Genetic mechanisms responsible for the development of heterogeneous metastases | I. Fidler |
| 12:15-12:30 | Models for the evaluation of drugs that inhibit the formation and growth of metastases | T. Tsuruo |
| 12:30-13:30 | LUNCH | |
| Session III. Screening of Drugs and BRMS | ||
| 13:30-13:50 | NCI Drug Screening Program- New developments | J. Venditti |
| 13:50-14:00 | BRM screening in the NCI | R. Oldham |
| Session IV. New Chemotherapeutic Agents and Analogues: Structures; In Vitro and In Vivo Studies | ||
| 14:00-14:30 | A review of the most promising new agents in the U.S. | J. Driscoll |
| 14:30-14:45 | New antitumor synthetic compounds and their mode of action | Y. Sakurai |
| 14:45-15:00 | New antitumor antibiotics and their mode of action | N. Tanaka |
| 15:00-15:30 | Antitumor antibiotics and low molecular weight immunomodifiers | H. Umezawa |
| 15:30-15:45 | Chemical modification of mitomycins and their biological activity | K. Shirahata |
| 15:45-16:00 | COFFEE BREAK | |
| Session V. New Developments in Biological Response Modification | ||
| 16:00-16:30 | Phase I trials of BRMS including interferon and monoclonal antibodies | R. Oldham |
| 16:30-16:45 | Liposome-encapsulated immunomodulators | I. Fidler |
| 16:45-17:00 | Effect of a low molecular weight immunomodifier, forphenicinol, in combination with cyclophosphamide, on growth and immunity of experimental animal tumors | K. Nitta |
| 17:00-17:15 | Role of BRM-activated macrophages in inhibiting the pulmonary metastases of Lewis lung carcinoma | E. Tsubura |
| 17:15-17:30 | Tumor growth-inhibiting factor induced in the host by antitumor polysaccharides | K. Nitta |
| 17:30-17:45 | Effect of combined use of BRM with cyclophosphamide against Lewis lung carcinoma in C57BL/N7 mice | E. Tsubura |
| 18:30- | RECEPTION | |
| Tuesday, November 23 Session VI. The Design and Analysis of Clinical Trials |
||
| 8:30-8:50 | Design considerations | R. Simon |
| 8:50-9:10 | Statistical analysis | R. Makuch |
| 9:10-9:30 | Data management | R. Wesley |
| Session VII. Phase I Drug Trials (Most Important New Agents): Clinical Results and Pharmacology Studies | ||
| 9:30-10:00 | In U.S. | D. Hoth |
| 10:00-10:15 | Phase I/II study of THP-adrlamycin | H. Majima |
| 10:15-10:30 | Phase I/II study of neothramycin | M. Ogawa |
| 10:30-10:45 | COFFEE BREAK | |
| Session VIII. Important New Phase II Trial Results | ||
| 10:45-11:00 | In Japan: New Mitomycins (M83, KD0122) and fluorinated pyrimidines | H. Majima |
| 11:00-11:15 | Interferon trials in Japan | M. Ogawa |
| 11:15-11:45 | In U.S. | S. Marsoni |
| 11:45-12:00 | Phase II interferon trials | R. Smalley |
| 12:00-12:15 | The current status of Phase II trials of anthracycline and cis-platinum analogues | S. Carter |
| 12:15-13:00 | LUNCH | |
| 13:00-14:00 | Tour of the ACRF and Radiation Therapy Facility | R. Young E. Glatstein |
| Session IX. Major New Phase III/IV Trial Results in Japan and U.S. | ||
| 14:00-14:30 | Current therapeutic issues in small cell lung cancer | D. Ihde |
| 14:30-15:00 | Current therapeutic issues and major U.S. trials in breast cancer | M. Lippman |
| 15:00-15:30 | U.S.-Japan gastric cancer study: Ideas for the next gastric study; joint protocols for laboratory and clinical studies of hepatoma patients | M. Friedman |
| 15:30-15:45 | COFFEE BREAK | |
| 15:45-16:15 | Summary of recent results of Phase III and IV trials in Japan with special reference to gastric cancer, breast cancer, and small cell carcinoma of the lung | M. Ogawa |
| 16:15-16:45 | Other important Phase III/IV trials in the U.S.- Emphasis on gastric and colorectal cancer | T. Jacobs |
| 16:45-17:15 | Drug development strategies and clinical trials | S. Carter |
PARTICIPANTS
UNITED STATES
Dr. Stephen K. Carter
Vice President
Anti-Cancer Research
Bristol-Myers Company
Dr. Bruce A. Chabner
Director
Division of Cancer Treatment
National Cancer Institute
Dr. Vincent T. DeVita
Director
National Cancer Institute
Dr. John Driscoll
Acting Associate Director
Developmental Therapeutics Program
National Cancer Institute
Dr. Isiah Fidler
Director
Cancer Metastasis and Treatment Laboratory
Frederick Cancer Research Facility
National Cancer Institute
Dr. Michael Friedman
Cancer Research Institute
University of California at San Francisco
Dr. Daniel Hoth
Acting Associate Director
Cancer Therapy Evaluation Program
National Cancer Institute
Dr. Daniel Ihde
Head, Clinical Investigations Section
National Cancer Institute
Navy Medical Oncology
National Naval Medical Center
Dr. Edwin Jacobs
Acting Chief
Clinical Investigations Branch
Cancer Therapy Evaluation Program
National Cancer Institute
Dr. Sylvia Marsoni
Acting Branch Chief
Investigational Drug Branch
Cancer Therapy Evaluation Program
National Cancer Institute
Dr. Gregory O'Conor
Director, Office of International Affairs
National Cancer Institute
Dr. Robert Oldham
Associate Director
Biological Response Modifiers Program
Frederick Cancer Research Facility
National Cancer Institute
Dr. Stephen A. Sherwin
Special Assistant to the Director
Division of Cancer Treatment
National Cancer Institute
Dr. Robert Shoemaker
Acting Chief
Cell Culture Section
National Cancer Institute
Dr. Richard Simon
Chief, Biometric Research Branch
Division of Cancer Treatment
National Cancer Institute
Dr. Richard Smalley
Chief, Biological Resources Branch
Frederick Cancer Research Facility
National Cancer Institute
Dr. John Venditti
Chief, Drug Evaluation Branch
National Cancer Institute
Dr. Kurt Kohn
Chief, Laboratory of Tumor Cell biology
Division of Cancer Treatment
National Cancer Institute
Dr. Marc Lippman
Chief, Medical Breast Cancer Sect ion
Clinical Oncology Program
National Cancer Institute
Dr. Robert Makuch
Senior Investigator
Biometric Research Branch
Division of Cancer Treatment
National Cancer Institute
Dr. Robert Wesley
Investigator
Biometric Research Branch
Division of Cancer Treatment
National Cancer Institute
Dr. Mary Wolpert
Deputy Chief
Drug Evaluation branch
Developmental Therapeutics Program
National Cancer Institute
JAPAN
Dr. Hisashi Majima
Head, Department of Internal Medicine
Chiba Cancer Center
Dr. Kazuo Nitta
Division of Cancer Chemotherapy
National Cancer Center Research Institute
Dr. Makoto Ogawa
Chief, Division of Clinical Chemotherapy
Cancer Chemotherapy Center
Acting Head, Department of Clinical Oncology
Cancer Institute Hospital
Japanese Foundation for Cancer Research
Dr. Yoshio Sakurai
Director
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Dr. Nobuo Tanaka
Professor
Institute of Applied Microbiology
The University of Tokyo
Dr. Eiro Tsubura
Professor of Internal Medicine
Tokushima University
School of Medicine
Dr. Takashi Tsuruo
Research Member
Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
Dr. Hamao Umezawa
Director, Institute of Microbial Chemistry