MINUTES
3RD JOINT STEERING COMMITTEE MEETING
U.S.-JAPAN COOPERATIVE CANCER RESEARCH PROGRAM
June 1-2, 1981
Annapolis, Maryland

The meeting was convened by Dr. Gregory T. O'Conor at 9:00 a.m., June 1, 1981 in the Anne Arundel Room of the Maryland Inn, Annapolis, Maryland.
The delegation representing the Japan Society for the Promotion of Science (JSPS) included Dr. Haruo Sugano, Dr. Yoshio Sakurai, Dr. Takashi Sugimura, Dr. Yuichi Yamamura, Mr. Kichimasa Soda, and Mr. Iwao Abe. The members of the National Cancer Institute (NCI) Steering Committee were Dr. Stephen K. Carter, Dr. John D. Douros, Dr. Robert W. Miller, Dr. Gregory T. O'Conor, Dr. William Terry, Dr. I. Bernard Weinstein, and Dr. Robert R. Omata.
Dr. O'Conor welcomed the Joint Steering Committee members and expressed his delight in joining the meeting after two years absence while he was Director, Division of Cancer Cause and Prevention. He also stated that he had returned as Director, Office of International Affairs, and that he will he more intimately associated with the U.S.-Japan Cooperative Cancer Research Program. He stated that this was the third meeting of the NCI-JSPS Steering Committee and that he was greatly impressed with the progress and activities of the Program since it was restructured two years ago.
The Program is the most successful of the various bilateral programs in the wide coverage of cancer research and includes the participation of leading scientists from both countries. Dr. O'Conor expressed his hope that the program coordinators will continue to carry on the momentum gained through the past years. Although there may be tighter budgets on both sides, he encouraged the leaders to carry on their excellent work and to continue the interaction and communication among the scientists.
Dr. O'Conor introduced Dr. Douros, who has been appointed Program Coordinator for Cancer Treatment. Dr. Douros has had many years of association with Japanese investigators and the pharmaceutical industry. He has expertise in the exchange of information on the development of new anticancer drugs as well as information on preclinical and clinical drug studies. Dr. Carter will continue to provide his expertise in clinical research and treatment studies.
Dr. O'Conor reported that Dr. Weinstein wished to be relieved of his program responsibilities and that a new coordinator will be appointed. Dr. O'Conor asked Dr. Weinstein to continue to lend his knowledge and participation in the Program. Dr. O'Conor expressed appreciation on behalf of the Joint Steering Committee for Dr. Weinstein's contributions to the Program.
Dr. Sugano expressed his pleasure to be visiting in historic Annapolis, capital of the State of Maryland. He was delighted to be staying in such an historic hotel, which is over 200 years old. Dr. Sugano also expressed his pleasure at having Dr. O'Conor return to participate again on the Joint Steering Committee, and welcomed Dr. Douros to the Committee. He introduced the members of the Japanese Committee and thanked the JSPS and NCI for arranging the meeting and the support given. Dr. Sugano stated that this was the third meeting of the Joint Steering Committee and the mid-point of the second five years of the Program. He has been greatly impressed with the progress and described the Program like the blooming of a flower, with the petals slowly, but surely, unfolding into full bloom. He reported that this Program has stimulated cancer research in Japan and is well-accepted and highly regarded by Japanese investigators for the high scientific quality and its timely and realistic approaches to cancer research.
Dr. Miller welcomed current members of the Joint Steering Committee to the meeting, welcomed Dr. Douros as a new member, and thanked Dr. Weinstein for his contributions to the Program. Dr. Miller stated that this Program has been a most successful binational program, which has accrued a great deal of mutual benefit for both sides. He reiterated the remarks of Dr. Sugano, pointing to the Program's stimulation of cancer research in Japan. He attributed this progress to the Program's problem-oriented approach to the complexities of cancer problems. He has been impressed that Annual Reports submitted by the Program Coordinators are including more science and less administrative matters; details on the greater number of scientific exchanges; the interdisciplinary approach evident in all program areas; and the accomplishments and scientific content of each of the meetings reported.
Mr. Soda stated that he was very happy to visit Annapolis and its historic environs. He was glad to see Dr. O'Conor and others again. He reported that the Program is considered to be very successful by many Japanese, even by those who have not actively participated in it. The Ministry of Education, Science, and Culture and the hierarchy of the JSPS have been impressed with the Program and will continue to give strong support. He reported that, due to the budget restrictions of the Japanese Government, the funds for 1981-82 have not been increased. The government has an austere fiscal policy and has, therefore, cut back on all excess budget needs. He encouraged the Steering Committee to spend its valuable time discussing science and program contents and plans, keeping administrative matters to the minimum.
Dr. Omata made a few announcements, including the luncheon to be hosted by the JSPS and the dinner at the Maryland Inn honoring the JSPS delegation.
Dr. O'Conor thanked the others for their remarks and stated that NCI had cooperative agreements with eight other countries: Egypt, the Federal Republic of Germany, France, Hungary, Italy, Poland, the People's Republic of China, and the Union of Soviet Socialist Republic (USSR). He reported that the U.S.-Japan Cooperative Cancer Research Program was the second oldest bilateral program, beginning with preliminary discussions in September 1973 in Hakone, Japan, and the signing of the first agreement in Honolulu in May 1974. Since then the Program has steadily improved and can still be improved because of many common problems. The Program has made it possible to bring different scientific approaches to cancer research, mutually benefiting both countries. He stated that this Program was the largest and most active, due to the mutual respect and the high degree of interaction among the individual scientists from both sides. Although the NCI budget will not be increased in Fiscal Year 1982, the Program should continue to flourish and bring together the best scientists from both countries.
Dr. Miller reported that other NCI bilateral programs are more selective in the areas for cooperation and have a limited number of exchanges. The French and Italian bilateral Programs have considerable emphasis placed on cooperation in clinical trials and clinical research. He believes that the U.S.-Japan Program has greater scientific depth in its seminars and workshops, high levels of interest, excellent communication, and stimulation of research resulting from program contents, as well as collaboration between scientists. He stated that the excellent quality of the Program is due to the work and interest of the Program Coordinators and the fact that program transition did not change the essential character of the Steering Committee.
Dr. Sugimura stated that the success of the Program should also be credited to the excellence of scientist-to-scientist interactions and personal relationships, which have proven to be most effective and friendly.
Mr. Soda stated that this Program was the only bilateral program supported by the JSPS, which concentrates its efforts on cancer research.
Dr. Sugimura reported that there is an informal program with the German Cancer Research Center in Heidelberg, Germany, which will eventually become a formal bilateral program. He stated that the cooperation between JSPS and NCI has much greater flexibility.
Dr. Miller stated that there are three contributing factors for this program's success: (1) human-to-human interaction, (2) differences in scientific information and approach, and (3) excellent administrative procedure with the least amount of bureaucratic difficulty.
Dr. O'Conor reported that there are readily available opportunities for cooperation with European countries. He has been particularly impressed with the improved exchanges and open communication that have resulted from U.S.-Japan cooperation, as well as the involvement of large groups of people.
Mr. Soda stated that the primary mission of the JSPS has been the support of basic sciences. The Society is deeply concerned about whether basic science contributes to Japanese scientific advancement. In August 1981, the JSPS is sponsoring a seminar on "Science Policy." He stated that most of the basic science research is university based, receiving the greatest share of support from the Ministry of Education, Science, and Culture; while research and development support emanates from Japan's Science and Technology Agency. The Ministry of Education supports basic research, but it has become difficult to draw distinctions, particularly in technological research and discoveries. He is hoping that the seminar will provide some ideas on the coordination between basic and applied research.
Dr. O'Conor stated that he believes that the success of the U.S.-Japan Program is due to the separation of basic and applied research. The difference in scientific approach has been stimulating and has produced good science. He asked why we need this bilateral program. The reasons are that there are great differences in approach, (such as to disease manifestations and treatment), and there is flexibility built into the Program.
Dr. Weinstein believes that there has been an excellent blend of seminars, workshops, and scientist exchanges, which have contributed greatly to each of the program areas and has resulted in expression of ideas and differences in scientific opinion.
Dr. Sugimura stated that the Ministry of Education supports basic research, and the Ministry of Health and Welfare supports cancer centers and clinical research. However, the JSPS is able to cross over between basic and applied research to cover the entire spectrum of cancer research in Japan. Although Japanese-American relationships in trade and politics are currently strained, he believes that the friendly relationship is most important for the progress of science.
Mr. Soda stressed the important contributions and service that Dr. Sugimura has given to the JSPS. Dr. Sugimura has been very interested in the pros and cons of a flexible program and the benefits derived from a bilateral program versus a multilateral one. The United States Council of Social Sciences has a multinational approach to study comparative social problems, particularly postwar social problems. If the JSPS wishes to support multinational programs, there are many budgetary limitations; therefore, it is much easier to utilize the bilateral program mechanism for targeted areas.
Dr. O'Conor feels that a bilateral approach has been the best way for cooperation to date, but there are benefits to be derived from informal multinational arrangements with built-in flexibility. Dr. Omata mentioned that past experience has been to invite limited numbers of scientists from third countries (Great Britain, Canada, and the Netherlands) to participate in U.S.-Japan workshops and seminars.
Dr. Weinstein stated that forward and future planning of bilateral programs is very important. The success of the U.S.-Japan Program can be traced to the long and strong tradition of cancer research in Japan and the strong interest in cancer research in both countries. The areas of carcinogenesis research and cancer therapy have been particularly successful in their contributions. In the epidemiology area, the successful exchange of information has been in the contrasting epidemiologic data from each of the two countries. There has been a merging and blending of interests and intellect, which has benefited both sides.
Dr. Miller stated that there have been other binational cooperative efforts, such as that in the field of teratology, but this subject has not been easily blended into a cooperative activity.
Dr. O'Conor welcomed the interesting discussion and encouraged all to think about the relevance of basic and applied research and the possibilities of developing the strengths and weaknesses of science in Japan and the United States.
After the intermission, Dr. Weinstein and Dr. Sugimura were asked to present the report for the Etiology Program Area.
Dr. Weinstein began by saying that it was good to meet again with the Joint Steering Committee and that past meetings have been very rewarding experiences. The past years have nurtured very good interactions and intellectual experiences. He presented a brief resume of the Annual Report, which is included in the Progress Report for 1980 and 1981, representing an extensive coverage of cancer etiology.
Drs. Sugimura and Weinstein then led an informal discussion on what has happened in the area of carcionogenesis research, its future direction, and how the U.S.-Japan Program has fit in with recent advances. It was brought out that cancer epidemiologic information shows that a majority of cancers (60 to 80%) are related to environmental or exogenous factors. Some of the factors external to the body may involve the following:
1. Geographical Differences: There are needs for new experimental or investigative approaches such as migrant studies.
2. Identification of Factors: There are many difficulties in identifying the carcinogenic factors. There is a need for strong evidences for these factors, as in the case of gastric cancer.
What is missing in the present approach and research? These needs include: identification of specific factors, such as initiators and DNA material; the role of co-factors (i.e., promotors); dietary factors, such as vitamins, food fiber, fats, and other dietary factors; chemical and viral agents, such as aflatoxin and hepatitis virus; the relation between chemical and biological factors, including tumor promoters and EBV virus in nasopharyngeal cancer (NPC) or lymphomas (e.g., relation among phorbol esters, herbal medicines and herbal teas, and the activation of EBV virus in nasopharyngeal cancer leading to cell transformation). These are stimulating ideas, but involve very complex investigations.
Dr. Douros brought up the subject of phorbol esters. He reported that there are new drug studies on promotoers, particularly the relationship between herbal tea and the high incidence of esophageal cancer in Curacao in the Carribean Islands.
Dr. Miller stated that there is a genetic problem associated with the very high incidence of NPC among the Hakka people in Southern China.
Dr. Weinstein stated that host factors are very important, especially in cases of complex cancers such as gastric and lung cancers. There is a great need to know more about host factors. In the case of aflatoxin metabolism in humans, differences exist among individuals and family members. There appears to be active metabolism of aflatoxin in the patient with hepatoma. One questions if there is a family disposition in metabolizing aflatoxin. In recent years, there has been great emphasis placed on bioassay of carcinogens in animals. There is a tremendous problem in extrapolating data on the role of environmental carcinogens in animals to its application in humans. Short-term tests for mutagens and carcinogens have proven extremely valuable in screening many potential carcinogens. Dr. Sugimura has contributed much to the methodology and interpretation of short-term tests. There is a new crisis in extrapolating test data for use in studying human risk factors. Many scientists are now skeptical of recent test results, such as the data on saccharin and caffeine.
The recent conference on "Biochemical Epidemiology" was very fruitful and successful. Discussions at the conference showed the need for new approaches to investigate the cause and effect relationship.
There are many currently active studies on the mechanisms of carcinogenesis. A great deal of effort is being focused on DNA damage, and on initiators in which mutagenicity assay methods have been very useful. Dr. Sugimura reported that many potent mutagens have been found by using his method. Specific mutagens found in cooked foods include three amino acid pyrolysates and two new compounds found in charred sardines and fried beef. There are also several new heterocyclic amine compounds. The modified Ames test has been most useful in screening for new mutagenic and carcinogenic compounds. Dr. Sugimura and his associates have recently isolated several new pure materials.
Dr. Weinstein stated that Dr. Sugimura's research is a major contribution to the know-ledge of mutagens and carcinogens. He further stated that dietary factors, such as aromatic hydrocarbons, are highly mutagenic. There are several new classes of compounds in diet which are potent mutagens. There is a great need for mechanistic research since there have been a considerable number of good, fundamental studies on diet and nutrition and the role of carcinogens, as well as an excellent flow of information, and the exchange of compounds. Dr. Weinstein mentioned his appreciation for the exchange of research materials.
As for the future of carcinogenesis research, there is currently a tremendous influx in the number of investigations on the relationship of carcinogens and DNA damage. What are the next steps?
1. Relationship of complex genetic material damage and the carcinogenic process
2. The movement of genetic materials
3. Gene rearrangement studies
In the next few years, the following areas of research will be explored: gene cloning, cell and DNA damage, cell transformation, the conversion of normal to cancer cells, and new techniques in DNA cloning and sequencing.
From what is currently known, carcinogenesis is a multistage process. There are new studies on the multistep process, investigating multiple factors, the initiation to promotion stages, DNA damage caused by promoters, and the progression of transformed cells. Therefore, there are many opportunities for joint workshops to discuss the relationship between etiology and therapy of cancer, and the approach to therapy.
Most recently the new field of chemoprevention has come to the forefront, particularly with regard to Vitamin A and other retinoids, which inhibit action of tumor promotors, glucocorticoids, and other hormones.
The mechanism of action of promoters is an intriguing area of study. There are some 15 or 20 compounds (such as phorbol esters, TPA, croton oil, and Chinese herbal medicines), which are extremely potent in the formation of mouse skin tumors. There is a whole new group of compounds. The phorbol esters act on the cell surface membranes of fibroblasts and other cells, but are not mutagenic. The compounds bind to the cell membrane receptors. There is also a new class of compounds which are weak or less potent than TPA on mouse skin. Recently, teleocidins (which have an indole nucleus) and other indole alkaloids have been found to be tumor promoters. A cell culture system is now available for the testing of promoters, fully mimicking TPA action on mouse skin cells. Potent promoters act on mouse skin and on the cell membrane receptors. It has been found that all promoters may not act on the same receptors and that promoters act on similar types of receptors.
The structure of promoters is very interesting. These compounds have both hydrophilic and hydropholic parts in the molecule. The question arises as to whether there is a polypeptide in the host cell which attracts promoters to the cell membrane receptor. .
Dr. Sugimura reported that the teleocidin research has been a direct outgrowth of the cooperation between Japanese and American scientists sponsored by the binational program. Recent cooperative studies on seaweed resulted in the discovery of lyngbyatoxin.
It has been suggested that a promoter-occupied cell membrane receptor may change cell functioning, particularly the effect on the various cell growth factors, resulting from the complex signaling from the membrane. Dr. Sakurai reported that the Japanese are testing a number of new compounds and drugs for anti-tumor activity. He questioned whether these compounds and drugs should be checked as potential tumor promoters. It has been reported that Valium has been found to act on cell surface receptors. It is possible that many drugs now in use have specific or groups of cell surface receptors. Dr. Terry asked about the animal assay for receptors and promoters. There is a good system using mouse fibroblast cultures for testing promoter action on receptors.
In the field of viral carcinogenesis, there are many studies on the complex relationship between chemical and viral carcinogenesis (i.e., oncogenic studies). It is known that some RNA tumor viruses can transform cells by altering the Src genes. It has also been found that certain animal leukemia viruses have picked up Src genes, thus causing cell transformation. There are interesting ideas on the relationship between chemical and viral carcinogenesis. As a result of this bilateral program, Japanese and' American scientists are collaborating on research on Src genes.
Another area of interest is the studies on protein kinases and their role in cell surface action.
This past year a total of eight scientists were exchanged under the Etiology Program Area. Among these were two biostatisticians and three scientists involved in tumor virology and molecular genetics.
Two seminars were sponsored under the Etiology Program Area: "Biochemical Epidemiology" and "Interspecies Correlation of Chemical Carcinogenesis."
Future plans were discussed by Drs. Weinstein and Sugimura. Seminars on "Carcinogenesis and Gene Expression in Liver Cancer Cells" and "Intestinal Metaplasia and Stomach Cancer" were approved, while eleven proposed exchange scientists (five from Japan and six from the United States) were tentatively approved.
Thus far, there have been seven proposals submitted for consideration in 1982-83. Some of the topics which are of particular interest are: (1) biological dose versus total dose of carcinogens, including the possibility of using DNA binding as an index of exposure to mutagens and carcinogens; (2) use of urine analysis; (3) assay of metabolites; (4) sister chromatoid studies; and (5) the effect of nitro-pyrenes, which are found in the exhaust of diesel engines and material used in xerography reproduction.
Dr. Sugimura reported that an interesting new strain of rats, which lack blood albumin, has been developed at the National Cancer Center in Japan. This strain is extremely sensitive to bladder carcinogens. There is another strain which lacks gluconyl transferase and is subject to jaundice. These are most interesting strains and may be very useful experimental animals in the future.
Another area which should be explored in the future is the differences between Japan and the United States on the methodology and use of biostatistics. A previous workshop was held, but it would be most interesting to do an in-depth study.
The first session was recessed for the luncheon hosted by Mr. Soda and Dr. Sugano.
The meeting was reconvened by Dr. Sugano. He requested that Drs. Yamamura and Terry give their report on the Cancer Biology Diagnosis Program Area. Dr. Terry stated that he would be unable to be in attendance on the second day because of previously scheduled Senate hearings.
Drs. Yamamura and Terry agreed that the morning discussions had been most interesting and very stimulating. During the past five years, there has been an explosion in the field of immunology with the development of new immunological tools for cancer research, such as the monoclonal antibodies and radioimmunoassay systems.
The recent development of a viral vaccine against hepatitis has led to in-depth immunological studies to investigate the relationship between hepatitis and liver cancer. Studies are now focusing on immunological stimulation to decrease the incidence of cancer.
In the diagnosis area, investigations are being conducted on immunodiagnosis and serological diagnostic methods using fetal antigen and chorioembryonic antigen (CEA) for various types of cancer. There are no reliable assay methods, but there are continuing investigations on the progress of treatment, using some of the more recently developed methodologies.
New studies using radiolabelled antibodies (e.g., anti-CEA antibody), for detecting sub-clinical metastases, have recently been initiated. These studies may provide a highly promising approach to the study of cancer treatment. Radio-antibodies made from monoclonal anti-bodies might be used for diagnostic purposes. At present, the number of false positives is very high for general acceptance, and the qualitative control can be improved in the future.
In the preclinical treatment area, nontransplantable ultraviolet (UV) induced tumors in mice have recently been studied. By suppressing immunity in mice, the UV induced tumors can be transplanted. This may be due to the involvement of UV damaged DNA.
In the area of applied aspects of immunology, there has been no major breakthrough, but numerous clinical trials have been started. In the fields of cellular and molecular biology, there is a natural overlap with carcinogenesis. During the past year, a seminar was sponsored in Honolulu on the "Genetic and Epigenetic Aspects of Cancer" (see Annual Report for Biology and Diagnosis).
A conference on "Analysis of Mechanisms for Inducing Tumor-Specific Immunity and Experimental Approaches for Immunotherapy" was held in Osaka, Japan (see Annual Report). As a result of this discussion, future studies are focusing on fundamental immunology, differences in skills and techniques in immunology research, and (in the area of applied studies) on isolation and purification of bacterial and other microbial cell wall materials. The Japanese investigators have made considerable advances in their studies on cell wall materials.
In the field of cancer diagnosis, collaborative work is continuing on automated cytology comparing flow cytometry and imaging methods. Interest is continuing in ultrasonic diagnostic screening, particularly in the diagnosis of breast cancer. Recently, laser endoscopy has been receiving consideration. In immunodiagnosis, anti-CEA antibody is being used for localizing metastatic lesions. There was some discussion on the prospects of research on the metastatic process.
The conference on "Oncodevelopmental Proteins: Basic Biological and Clinical Aspects" was held in San Diego, California, in December 1980. For details, please see the Annual Report on Cancer Biology and Diagnosis.
Three exchange scientists were sponsored during the past year to collaborate in molecular biology and immunology.
Future program plans were discussed and three proposed seminars on automated cytology, tumor immunology, and cell adhesion and interaction were approved. Two proposals for the exchange of scientists (both from Japan) were tentatively approved.
After intermission, Dr. Sugimura chaired the next session and asked Drs. Sugano and Miller to present the report of the Interdisciplinary Program and Coordination Area.
Dr. Miller reported on the workshop on "The Differences in Lymphocytic Diseases between the U.S. and Japan" which was held in Honolulu. The differences in the incidence and pattern of lymphocytic diseases between Japan and the United States are quite pronounced, according to many observations. It has been shown that among U.S. whites lymphoma is more frequent in males and autoimmune diseases in females with a ratio M:F=1:9 and Hashimoto's thyroiditis, M:F=1:20. In Japan, the incidence of autoimmune disease is four times greater than in the United States, but certain lymphoid neoplasia are rare in Japan. It was learned that the incidence of chronic lymphocytic leukemia (CLL) is near zero among the Japanese and the Chinese population, while CLL comprised about 30 percent of all leukemias in U.S. adults. It was also reported that follicular (or non-Hodgkin's) lymphoma is almost absent in Japan. There were other very interesting data presented at the meeting, which strikingly illustrated the differences in the incidence patterns between Japan and the United States.
One of the most interesting diseases reported at the meeting was the Adult T Cell Leukemia clusters, which occurred in eastern Kyushu and Okinawa and was mapped in recent years. This disease is rarely seen in western countries. Extensive discussions were held on the possibilities of future collaboration to make an in-depth study of the incidence pattern and pathology of this interesting T cell leukemia. There appears to be an ethnic difference in the lymphocytic functions. In general, lymphomas in Japan are found to be B cell type in 50 percent of the cases and 50 percent of T cell lymphomas. In the United States the picture is quite different with 90 percent in the B cell type and 10 percent in the T cell type.
Dr. Sugano reported that Adult T Cell Leukemia shows peculiar morphology of cells, poor prognosis for the patient, and no response to currently used treatments. The incidence in Kyushu and Okinawa is high in the spring months, and the average age of the patients is between 52 and 53. Several Japanese investigators have suggested that the Adult T Cell Leukemia may be the latent result after filariasis or a virus infection. Recently, a few rare cases have been found in the U.S. Pacific Northwest.
Collaborative studies are being planned for the future. As for 1981-82 plans, a seminar entitled "Neural Crest Tumor" and two exchange scientists from Japan were approved. With regard to another proposed seminar on "Liver Cancer: Multidisciplinary Approach for Etiology and Carcinogenesis," it was rather strongly suggested that it be merged with the "Carcinogenesis and Gene Expression in Liver Cancer Cell" seminar which is to be organized by the Etiology Area. For detailed information, please refer to the Annual Report of the Interdisciplinary Program and Coordination Area.
Dr. Sugano reported that the breast cancer collaborative study on atomic bomb survivors in Hiroshima and Nagasaki is being prepared for publication in an international journal. Preliminary reports of the findings were presented in the Progress Report for 1979-80.
Dr. Sugano stated that pancreatic cancer was increasing rather rapidly in Japan. Consequently, Dr. Fujio Kasumi was appointed as an exchange scientist to spend six months with Dr. Joseph G. Fortner at the Memorial Sloan-Kettering Cancer Center in New York to observe and learn about recent advances in the diagnosis and treatment of pancreatic cancer.
Dr. Weinstein stated that there is a need for a multidisciplinary approach for systematic investigation of lymphatic diseases. Dr. Sugimura reported that a new group has been formed for multidisciplinary investigation. In Japan, since the Ministry of Education supports basic research of cancer (including etiology), and the Ministry of Health and Welfare supports research on the diagnosis and treatment of cancer, there have been some problems in the past. The recent outbreak of Adult T Cell Leukemia has stimulated new studies combining clinical and epidemiological research.
After a brief recess, Dr. O'Conor chaired the business session. He stated that he was impressed with the newly structured program, which shows a great improvement over the former format. Much has been gained from the scientific themes which have been targeted to specific topics of current mutual interest. He stated that the NCI Steering Committee was pleased to have Dr. Douros as Program Coordinator for Treatment. Dr. Carter will continue to advise on clinical research and studies. Since heavy commitments have been pressing, Dr. Weinstein asked to be relieved of his duties as Program Coordinator for Etiology. The Joint Steering Committee expressed its deep appreciation to Dr. Weinstein for his devotion and many contributions toward the advancement of this Program. Dr. O'Conor asked that he lend his expertise and advice in the future as time permits.
The Committee discussed dates for the 1982 meeting. It was unanimously agreed to hold a two-day meeting near Tokyo, Japan, on an agreeable date during the week of June 7, 1982.
The subject of the next biennial conference was also discussed. The need for sponsoring the biennial conference was discussed with regard to tighter budgets for 1981 -82 and possibly for 1982-83. The Committee finally decided that, although the biennial conference held in Osaka last year was a success, such conferences on broader topics will not be organized every two years but may be organized under the Interdisciplinary Program and Coordination Area whenever deemed necessary. It was also suggested that a Joint Steering Committee meeting be held in conjunction with the "International Conference on Genetic Engineering," and that several experts be invited to speak on genetics and cancer. Another suggested subject was new data on the biochemical (enzyme) and molecular aspects of gastrointestinal cancers.
The Joint Steering Committee discussed and approved proposals for the following meetings for 1981-1982:

The meeting was adjourned at 5:45 p.m. The NCI Steering Committee hosted a dinner at the Maryland Inn in honor of the JSPS Steering Committee.
The meeting was reconvened at 9:00 a.m., June 2, 1981, by Dr. Miller as Chairman. He asked Drs. Sakurai, Carter, and Douros to report on the Cancer Treatment Program Area.
Dr. Carter expressed his regrets for being unable to attend the first day of this meeting. He recently took on the added responsibility of serving as Chairman of the Board of Scientific Counselors for the newly reorganized Division of Resources, Centers, and Community Activities (DRCCA) of the National Cancer Institute. He reported that the Chemoprevention Group recently held its first workshop on "Chemoprevention" to discuss design and plans for a study using accessible compounds, which include beta-carotene, Vitamin C, Vitamin E (or alphatocopherol), and selenium. There is a body of knowledge concerning the role of retinoids in cancer prevention; however, present retinoids are rather toxic. The group suggested an epidemiologic observation of subjects on beta-carotene with high intake of green leafy vegetables. It is known that Vitamin C affects nitrosofication, but there is some question about the role of nitrosamines causing cancer in humans. Vitamin C appears to be a candidate for nutritional study in the area of chemoprevention. Questions have been raised about Vitamin E as an anticancer agent. Selenium is being considered for the chemoprevention of colon cancer. Other materials with potential for development were discussed, including retinoids and proteases. The Chemoprevention Group is considering recommending that NCI sponsor chemoprevention trials. The next meeting will be held at the National Institutes of Health, June 26 to 27, 1981.
Dr. Sugimura stated that Dr. Takeshi Hirayama and Dr. Richard Peto have discussed the role of beta-carotene in chemoprevention. There are some epidemiologic data which are quite controversial; therefore, a great deal of planning should be done before starting a large scale trial.
Dr. Carter stated that there are two philosophies on initiating a clinical trial: the "grand leap" approach, where there is some experimental data, but a high potential for trials; and initiation of a trial after there is rational understanding of the involved mechanism (i.e., beginning trials after some good scientific evidence is obtained). The latter approach has been tagged as "obstructionist." In the area of chemotherapy, the "small leap" approach has been used when trials were started after some of little scientific evidence was available. Dr. Weinstein believes that any trials should be started after there is some good evidence. Dr. Sugimura said that intervention studies will deal with the general public and that there is a problem of preliminary public education. He is skeptical about any large scale study. He believes that retinoids show some possibilities and should be tested on a larger scale than previously tested.
Dr. Yamamura reported that an immunoprevention or prophylaxsis study on lung and stomach cancer in high-risk groups has been started in Japan. A five-year study using Nocardia cell wall skeleton material is being tested for preventing the development of squamous carcinoma. Each group will involve 300 persons. He believes that prevention studies using high-risk groups would be more productive.
Dr. Sugimura stated that recent data show that individuals with low blood cholesterol levels have high risk for colorectal cancer.
Dr. Carter stated that chemoprevention may appropriately be a new subject for interdisciplinary study.
The Cancer Treatment Program Area held a meeting in Tokyo in June 1980 at which clinical research and drug development were reviewed. The exchange of new drugs for preclinical trials has been actively continuing. Dr. Carter reported that Aclacinomycin was now in clinical trials in the United States and that PEP-bleomycin is under active investigation in Europe and will subsequently be in the United States. This new analogue of bleomycin has low pulmonary toxicity and has shown very good results in treating testicular cancer.
The June meeting also included a program review of activities in Japan and the United States. Subjects included: (1) new analogue development, such as anthracyclines, bleomycin, pyrimidines, and the nitrosoureas, which have been rather disappointing and highly toxic drugs; (2) progress in Biological Response Modifiers, with special emphasis on interferons and thymosin; (3) radiation oncology, with emphasis on high LET radiation therapy; and (4) the progress of the U.S.-Japan Cooperative Trials in Gastric Cancer. Dr. Carter reported that presentations at this meeting will be published. The publication of the San Francisco meeting in May 1979 was just released.
The Radiation Oncology Seminar was held in Hawaii in November 1980. This meeting was highly successful, particularly the cooperative studies on high LET radiation therapy and the exciting new area of the use of radiosensitizers. There were good experimental data on Phase I studies presented at the meeting. The radiation therapists are now using the third and fourth generation of newly developed radiosensitizers, which are hypoxic agents with low toxicity. There was considerable discussion on chemo-radiation therapy with the use of radiation protective compounds, such as WR 2721 , cis-platinum, and compounds with SH radicals to mediate toxicity. Radiosensitizers enhance cytotoxicity to radiated cells which are hypoxic. Data suggest that these compounds increase the blood supply to tumor cells. Several alkylating agents are being used as bases for development of new compounds. Hyperthermia is another area which has attracted considerable interest. This is a new and exciting treatment possibility, but there are many technological problems. Hyperthermia may provide a new treatment modality in the future.
The meeting on Treatment of Breast Cancer was very successful. The use of hormone therapy and chemotherapy in treating breast cancer shows a completely different toxicity picture, possibly a synergistic effect. The sequence of treatment is complex, but results are encouraging.
There is very good collaboration between Japanese and American oncologists. Dr. Carter reported that the first trials on treatment of gastric cancer between the Japanese oncology group and the Northern California Oncology Group (NCOG) have been completed. It has been shown that none of the treatment regimens was superior over the others. A second study is under discussion and being planned for combined modality. Hepatoma is being considered since it occurs with high frequency in Japan and among the Asian population in California. Treatment will use high dosage of drugs and low dose plus radiation. It is estimated that 60 to 70 percent of the patients will show liver shrinkage. About 170 patients will be studied in these trials.
Future plans are to sponsor the annual program review meeting on drug development and treatment in November 1981, a seminar on clinical immunotherapy, and a meeting on the diagnosis and treatment of bladder cancer. These three seminars, as well as proposals for three exchange scientists (two from Japan and one from the United States), were tentatively approved.
Dr. Sakurai presented many cogent observations and comments as follows:
"A remarkable advancement in tools and methods of investigation in cancer chemotherapy has been established by the U.S.-Japan Cooperative Cancer Research Program since its start in 1974.
It is, of course, important to make each original effort in each country respectively, to carry out fundamental studies to find out new effective agents. It is true to some extent that the basic studies should be endeavored by each scientist with his own creativity and that it does not necessarily need international cooperation at this stage.
The most successful results of cooperation would, however, be expected when a compound in question comes to the stage of evaluation (especially evaluation of pre-clinical pharmacology and toxicology; and further, clinical effect and side effects). In this respect, we have taken the policy for Treatment Area to organize each year at least one seminar exclusively devoted to the discussions and information exchange about new anti-tumor drugs just coming up for Phase I and II studies in each country. In fact, we have experienced the excellent fruits of having them presented in symposia at this stage in developing several new drugs prepared in the United States and Japan. I believe the policy has been very adequate and a great success.
Though the experiences of the past several symposia focused on drugs in Phase I and II trials in each country, the topics are tending to move to joint clinical study. When we think of this as a project in the U.S.-Japan program, it is necessary to find and fix some common understanding in both countries. I have gotten a personal impression that it may be worthy or necessary to figure out such a seminar some time in the following few years that is focused mainly on general methodologies and criteria of preclinical toxicology and pharmacology, and also on the clinical evaluation of anticancer drugs or immunomodulators with controlled comparative trials.
Thinking of organizing such a symposium, I cannot deny that the situation in Japan is far behind the United States about the sense of randomized controlled clinical trial and judging its result, except in a few organizations. In addition, it is a trend in Japan recently to limit practicing Phase II trial mainly from an ethical standpoint, because today the combined use of drugs has been demonstrating fairly good response rates on a certain number of tumors. Consequently, we need to evaluate more effectively a new drug in Phase III in combination with other known drugs to find the tumor's responsiveness to the drug. In this process, an adequate and concrete method of controlled comparative clinical trial is strongly required. I think it is very important in Japan to build up at this moment a general and authorized system of controlled clinical trial and criteria of evaluation, which is commonly understandable for (scientists) both in the United States and Japan. Only after having a general consensus in each country, and then between both countries, can we go further into joint clinical studies, which are becoming more and more important.
For this purpose, it may be one of the best and shortest ways, at present, to hold a seminar on design of controlled clinical trial, its practice, clinical judgment, and criteria for the final evaluation of the result. It will have an educational meaning to the Japanese side. The participants may include clinical physicians, scientists, mathematicians, or statisticians. Topics may include method of data processing and also how to train the personnel in charge of data processing.
When we had a statistician from the United States visit Japan as a member of a mission on Diagnosis and Treatment of Gastric Cancer in December 1975, the Japanese side was not ready to correspond to him in clinical cancer research, and I feel this is the time to hold such a seminar and include such experts as mentioned.
I believe this kind of symposium will contribute greatly to the further collaborative efforts in clinical investigation in this U.S.-Japan program."
Dr. Sakurai was thanked for his excellent presentation.
Dr. Sugano stated that Dr. Curtis Harris, NCI, informally proposed and discussed the possibilities of organizing a seminar on drug-induced tumors or tumors related to drug treatment. There have been many reports of post-treatment leukemia resulting from chemotherapy of breast cancer. The iatrogenic tumors after treatment include retinoblastoma. This meeting could be a multidisciplinary workshop including etiology, chemotherapy, radiation oncology, cancer biology, and cancer diagnosis.
Dr. Yamamura reported that Japanese patients with systemic lupus erythematosus (SLE), treated with steroids and cyclophosphamide have high incidence of leukemia and sacromas.
Dr. Sugimura stated that the problem of secondary cancer after radiation therapy and chemotherapy had been discussed during the recent visit of Dr. Harris to Japan.
Dr. Carter reported that secodary cancers have become a major problem, increasing with adjuvant therapy, particularly with the increasing number of cases developing acute myelocytic leukemias after treatment with anthracyclines and alkylating agents.
Dr. Weinstein believes that dosimetry, both in chemotherapy and radiation therapy, is most important. There is a considerable lag period between new secondary neoplasias and after therapy.
Dr. Sugimura believes that the broad subject of the occurrence of secondary tumors after treatment is a good area for further exploration and that the topic should not be focused too sharply or narrowly.
Dr. Miller expressed his thanks to Dr. Weinstein for his contributions to the Program, particularly for his expertise which blends basic research and clinical medicines. He also expressed his hope that Dr. Weinstein will continue to act as advisor to the Program in the future. Dr. Sugano joined Dr. Miller in expressing his appreciation to Dr. Weinstein.
Dr. Weinstein responded by stating his deep appreciation for the many personal contacts he has made. He also appreciated the minimum amount of bureaucratic procedure and administrative "red-tape" in the Program. He said that it has been a privilege and a rewarding experience for him, in spite of his busy schedule. He thanked everyone for the support and assistance he has received during the past years.
Dr. Douros mentioned that there is an excellent relationship between the NCI Drug Development Program and Japanese pharmaceutical laboratories and investigators. Some 150 natural and fermentation products are now available in Japan, and a number of new drugs are being processed for screening and preclinical testing. Some of the products are undergoing clinical studies in the United States. Five compounds which are biological response modifiers, are now under review. Japan is a very fertile location for obtaining new and interesting natural products with pharmaceutical potential.
He reported that plans for the future meeting on program review will include discussions on oat cell carcinoma, hyperthermia, biological response modifiers, and preclinical review.
Dr. Miller asked about the toxicity of interferon in patients under treatment.
Drs. Carter and Douros stated that the use of interferon is based on the "cell-kill" hypothesis. The material has intrinsic toxicity, therefore, dose must be titrated in individual patients with a white blood cell (WBC) count in the three to four thousand range as the base. There is also a problem of idiosyncratic toxicity when WBC counts can go down to two thousand cells. Therefore, it is most important to adjust the dosage for each individual patient. In general, drug toxicity varies with each patient and each drug, depending on the pharmacologic handling of the given drug by the patient.
Dr. Miller said that there are reports in the peculiarities among various patients in their response to therapy. A case in point is that children with Wilm's tumor respond fairly well to chemotherapy. There is a group of kidney tumors, which are questioned as being Wilm's tumor, that do not respond to treatment.
Dr. Carter stated that there is a trend for in-depth study of those tumors and cancers which do not respond to therapy. In order to understand this, a natural history of a particular tumor must be studied. He believes that some time in the future an interdisciplinary workshop should be organized on iatrogenic tumors, including kidney tumors, Wilm's tumor, and several others. He also stated that secondary tumors may result from a drug resistant subline of the original (or primary) tumor cell.
Dr. Miller thanked the participants for their time and contributions. This meeting was extremely informative and gave everyone many things to think about for future planning within the Program as well as in their own research.
Dr. Sugano also expressed his appreciation to the participants for the impressive discussions and thanked them for their hospitality.
The meeting was adjourned at 12:30 p.m.