REPORTS ON SEMINARS

1. Seminar on "Combined Modality of Chemotherapy and Radiotherapy" (see Attachment 1 for Agenda and Participants)
A joint seminar was held in Tokyo, Japan on October 10-11, 1985 for the purpose of comprehensively discussing issues of combined modality treatment with chemotherapy and radiation therapy. Attention was focused on both disease-site oriented issued and new modality applications (radiation and hyperthermia techniques).
The first day was dedicated to discussions of selected tumor sites where radiation, and chemotherapy have historically had collaborative roles to play. Drs. Inuyama and Leibel discussed platinum-based chemotherapy combinations with radiation in head and neck cancer. Drs. Kaneda and Aisner discussed methods of local and systemic tumor control in breast cancer patients. Drs. Ohnoshi and Aisner discussed the many current challenges in small cell and Drs. Morita and Friedman in non-small cell lung cancer. Drs. Abe and Macdonald described new opportunities in gastrointestinal cancer and Drs. Kawai, Okawa and Leibel discussed clinical challenges in genitourinary and gynecologic tumors. Considerable data was exchanged concerning promising opportunities which exist for maximizing interrelationships between chemotherapy and radiation in order to minimize toxic side-effects, especially to normal tissues, and increase not only local control but also overall survival (systemic manifestations of malignancy). Basic science issues of potential relevance were also introduced including, for example, the preclinical techniques of Dr. William Looney of the University of Virginia to reduce inherent drug and radiation resistance. Models such as that of Goldie and Coldman are being applied to clinical settings with greater regularity and precision.
The second day of the seminar dealt with modality development issues and developing new areas. Drs. Ogawa and O'Dwyer discussed means in which new drugs could be screened not only for radiation sensitization but for maximizing combination chemotherapy effects as well. Drs. Mori and Phillips offered indepth discussion of radiation sensitizers (such as the family of nitroamidazoles) and the radioprotectors (including the sulfhydryl donors). Although none of these compounds have yet to demonstrate increased therapeutic efficacy, there is considerable interest in their investigation.
Drs. Hiraoka and Oleson discussed promising approaches with hyperthermia, chemotherapy and radiation explored both in the United States and Japan. Attempts to devise new and better equipment which provides more uniform and controllable heating are ongoing.
Issues related to high energy particles were next presented. Dr. Kitagawa described the Tsukuba University clinical experience with protons. Dr. Morita described the trials of fast neutron therapy for lung cancer in Japan, and Dr. Castro described the high LET particle experience in the United States. These new particle experience offer considerable opportunity for interesting physics in clinical experiments.
Finally, Dr. Theodore Phillips provided an overview of radiation and chemotherapy, synthesizing the previous two days' discussion as well as a comprehensive review of the recent experiments.
This meeting was a follow-up of that held in Seattle, Washington in May 1984 where the initial discussions of many of these topics first occurred. It was generally felt that this current meeting was a highly successful one where strong links between the radiation therapy communities of Japan and the United States were forged. It was possible for several of the attendees of both meetings to discuss topics of high interest. Both Dr. Abe and Dr. Phillips (the coordinators for the radiation therapy sections of this meeting and this treatment activity) will be consulted concerning a future meeting to be held in two years. Major topics were summarized by Dr. M. Ogawa in the Japanese Journal of Cancer Chemotherapy 13(1): 164-167, 1986.

2. Seminar on "Clinical Trials Methodology" (see Attachment 2 for Agenda and Participants)
A symposium on clinical trials methodology was held on Oahu, Hawaii on January 30-31, 1 986. This was the first such meeting in which issues relating to statistical and regulatory aspects of new therapy development were discussed in detail. Representatives from government agencies, cancer centers and private industry took part in a wide ranging evaluation of the means for increasing the reliability and efficiency of Phase I, II, and III therapeutic testing. The discussion was organized in the following logical ways. On the first day, discussions began with Phase I and early Phase II specific issues by Drs. Ogawa, Hoth and Tamura. Special attention was given to the new guidelines recently drawn up by Japanese investigators for testing new agents in Phase I and disease-oriented Phase II situations. Specific emphasis was given to those methodologic features which make formal studies of acute leukemias, lymphomas and solid tumors each somewhat different. Contrasts were drawn between methods used in Japan and those used in the United States for the evaluation of new products. Specific examples discussed included the conduct of Phase II trials in acute leukemia and in the screening of an analogue and the biologic response modifier in leukemias and adult T-cell lymphoma leukemia. Drs. Kataoka and Mihich described some of the intricacies of preclinical methodology to evaluate biologic response modifiers. This is a rapidly expanding new area where techniques for evaluation are being modified radically. Dr. Ohno and Dr. Sherwin described clinical investigations in Phase II and Phase III situations with biologicals in the two countries. Dr. Sherwinis perspective from private industry in the United States was especially helpful in this regard since his company is sponsoring studies in both nations.
The second day was dedicated to Phase III trial methodology with discussions by Drs. Yamada and Carter who critically analyzed those pivotal studies for new agents and analogues, which are necessary for product approval in the respective Federal drug agencies of each country. As specific disease-site examples, adjuvant therapy for breast cancer and for gastric cancer were discussed by Drs. Friedman and Nakajima, respectively.
The final portion of the day was dedicated to a discussion of statistical methodologies by Drs. Sakuma, Brown and Fleming. The clinical relevance of various statistical methodologies was examined. Specific attention was given to means for improving the efficiency of prospective randomized trials in advanced tumors, for better estimating sample size requirements for clinical trials, for more carefully monitoring the effects and outcomes of treatment and for a new computer method for interim analysis to permit a more effective opening and closing of Phase II and Phase III trials.
Overall, the conference was a success with lively discussion and a great deal of new information being exchanged. At a time of unprecedented access of new agents to the therapeutic arena, new and improved trial methodologies are required. It is hoped that such continuing discussion will permit better interaction between the two countries in this important area. Dr. Ogawa reported major topics and discussions in the Japanese Journal of Cancer Chemotherapy 13(5): 2011-2015, 1986.

3. Seminar on "New Drug Development and Regional Chemotherapy" (see Attachment 3 for Agenda and Participants)
On March 24-25, 1986 at the National Cancer Institute in Bethesda. Maryland, a meeting was held to discuss selected topics in drug development and regional approaches to chemotherapy. This is a regular feature of the US-Japan Cooperative Agreement and forms the comer-stone of the exchange in the treatment area. The first day's discussion dealt with drug development issues of mutual concern to Japanese and US investigators. Dr. Ogawa and Dr. Sarosy compared national experiences with two new anthracycline analogues (THP-Adriamycin and Menogoril) undergoing broad Phase II testing in solid and hematologic malignancies. Evidence of diminished cardiac toxicity have been noted with both agents but no definite increase in therapeutic index (i.e. better antitumor effect). To date, there is no particular tumor identified for which an analogue would be better than the parent compound, Adriamycin.
A second session dealt with studies of the family of platinum analogues. Drs. Ogawa and Foster described compounds undergoing broad clinical development including 254-S, CBDCA and CHIP. Similar to the anthracycline discussion, diminished (or different) toxicities have been noted with these new compounds but no increased efficacy demonstrable to date. A third session dealt with an area of great historic interest to Japanese and U.S. investigators — the antimetabolites, Drs. Taguchi, Tsukagoshi and O'Dwyer described a new fluorouracil derivative, an oral form of cytosine arabinoside, and a novel anti-fol, trimetrexate. Single agent and combination studies are ongoing in both nations.
The rest of the first day was given over to an examination of an assortment of miscellaneous agents. Drs. Taguchi, Tsukagoshi, Tsuruo, Chun, Grever, and O'Dwyer discussed a variety of new agents. of greatest immediate, potential interest is Deoxycoformycin, which is a presumed adenosine deaminase inhibitor. The drug is of real value in treating patients with both B and T cell lymphomatous diseases (including hairy cell leukemia). Discussions are ongoing concerning the collaborative use of this agent in acute T-cell leukemia/lymphoma in southern Japan.
The second day of the meeting was dedicated to a review of topics related to regional therapy and biologics. The first part of the morning dealt with fundamental approaches to pharmacologic modeling and the pharmacokinetics and pharmacodynamics of intraarterial therapy. Drs. Collins and Dedrick described fundamental preclinical in vitro and in vivo work they have performed at the NCI. Drs. Ensminger and Taguchi described experimental rationale for intraarterial therapy. In the discussion which followed, Dra. Miura, Taguchi, Hirabayashi, Ishikawa and Ogawa described clinical experience in Japan with regional therapy for a variety of gastrointestinal tumors including pancreatic and liver cancers.
Finally, the afternoon dealt with biologic response modifier issues. Dr. Tsuruo described mechanisms for new approaches in the circumvention of drug resistance. Drs. Longo, Hawkins and Roper presented several aspects of the clinical development of the biologic response modifiers including TNF, interferon, and monoclonal antibodies.
A good deal of unpublished and still ongoing work was described at this meeting. This sort of communication is exceptionally valuable since some of these data are industrial owned (and publication is not permitted), and some of the data is in a preliminary form and will not be published for one or more years. The opportunity for interacting with recently updated information is immense. This session is an especially valuable one for the Treatment Program.


SEMlNAR AGENDA AND PARTICIPANTS

U.S.-JAPAN JOINT SEMINAR ON COMBINED MODALITY OF CHEMOTHERAPY AND RADIOTHERAPY
October 10-11, 1985, Holiday Inn, Tokyo, Japan

AGENDA