PROGRAM AREA REPORTS

CANCER THERAPY PROGRAM

The Cancer Therapy Program Area has conducted an organized exchange of information on the development and testing of antitumor drugs in both experimental animal systems and clinical trials. This program is an expansion and formalization of a collaborative relationship which predated the U.S.-Japan Cooperative Cancer Research Program. In addition to the information exchange, a joint U.S.-Japan clinical trial for the therapy of gastric cancer has been initiated.
To date, the program has been implemented primarily via a series of seminars, alternating in locale between the two countries. The initial seminar, “Comparative Study on Cytosine Arabinoside and Cyclocytidine” held in Tokyo in February 1975, was described in the First Report 1974-1975 of the U.S.-Japan Cooperative Cancer Research Program. In December 1975, six U.S. scientists visited Japan and participated in a “Symposium on the Treatment of Gastric Cancer.” That meeting, although occurring within the time span of the current report, was also described in the First Report 1974-1975. Briefly summarized, it was determined that the surgeon is the dominant individual in gastric cancer therapy and needs to be included in future collaborative efforts. The Japanese use a complicated surgical staging system based on a detailed lymph node analysis not feasible in the U.S.
Due to the effectiveness of the highly successful gastric cancer screening program in Japan, gastric cancer frequently has been diagnosed at a relatively early stage of the disease, resulting in a comparatively high overall cure rate. Advanced gastric cancer in Japan, as in the U.S., is a virulent disease which usually leads to death in a relatively short period of time. There have been a number of adjuvant chemotherapy studies in Japan. In contrast to the practice in the U.S., the Japanese have generally used a single peri-operative course of chemotherapy and, while control groups are always used, random allocation is not consistently applied. In both countries, the results with chemotherapy for advanced disease are similar. With the agents tested to date, even the responders to chemotherapy have shown no increase in survival rate.
In February 1976 a “Joint Symposium on Clinical Trials with Bleomycin and Nitrosourea Compounds” was held in Hawaii. A number of interesting facts were brought out. The Japanese pharmaceutical industry is active in the development of analogues of the nitrosourea compounds. ACNU, a pyrimidine derivative of CCNU, has been produced and studied in Phase I trials. Based on demonstrated activity in the L1210 test system, ACNU was chosen for clinical evaluation and found to have an activity similar to that of CCNU. It has delayed marrow toxicity, minor hepatotoxicity with activity in upper gastrointestinal cancer, or Hodgkin's disease. GANU is an analogue of Streptozotocin and is closely related to Chlorozotocin. Both GANU and Chlorozotocin are highly active in the L1210 system and their bone marrow toxicity is relatively low. GANU and Chlorozotocin will undergo clinical trials in Japan and the U.S., respectively. A controlled clinical trial using Bleomycin and radiotherapy for the treatment of head and neck and esophageal cancer has been instituted in Japan. This trial differs from those in the U.S. in that the radiotherapy dose is relatively low, stratification is not used, and there is a heterogeneity in follow-up therapy. Thus, comparison of data from the two countries will be difficult. In the February 1976 meeting, it was agreed that promising analogues of Bleomycin will be sent to the U.S. for evaluation in experimental tumor systems such as P388 leukemia, B-16 melanoma, and Lewis lung carcinoma.
In May 1977, a “Symposium on Antitumor Antibiotics” was held in San Francisco with eleven Japanese and twenty American scientists participating. In Japan, antitumor drug development has been pursued vigorously by the pharmaceutical industry. The major thrust is to produce analogues of known active drugs. New drug testing in Japan does not require the same regulatory approval as occurs in the U.S. This simplifies the initiation of testing but as a result there is no common source of information on the state of development and trial of such drugs. The extensive roles played by Actinomycin D, Mitomycin C, Bleomycin, and Adriamycin were reviewed. These drugs have been employed with curative intent in a variety of clinical research protocols. Preclinical studies on antitumor antibiotics were discussed with emphasis on fermentation techniques, selection criteria, and bioassay methods of identification. One of the agents described was Macromomycin, a new compound with considerable antitumor activity demonstrated in preclinical studies.
The second portion of the San Francisco symposium was devoted to clinical investigation. Although chemotherapy studies in both countries are roughly equivalent, differences do exist. Japanese chemotherapy does not cause myelosuppression to the degree that occurs in the U.S. where chemotherapy tends to be more aggressive. Continuous low-dose drug schedules are popular in Japan, whereas high-dose intermittant schedules are generally used in the U.S. In Japan, Mitomycin C is the drug of choice for advanced gastric cancer; it has been utilized in several surgical adjuvant studies but has not been shown to be of value. In the U.S., Mitomycin C plus Fluorouracil and either Adriamycin or Streptozotocin have been shown to have activity in combination against both gastric and pancreatic cancer. American chemotherapists have used Bleomycin against a wide range of lymphomas and tumors of the head, neck, and testicle. In Japan, Bleomycin is being studied in combination with radiation therapy for head and neck cancer. Recently, Bleomycin plus Mitomycin C has been shown effective against advanced cancer of the uterine cervix; in one Japanese study this combination produced complete regression in 13 of 21 patients. Bleomycin plus Mitomycin C and Vincristine have been studied in the U.S. and have shown good tumor response rates. PEP Bleomycin, a Bleomycin analogue produced by Nippon Kayaku, has shown promise of reduced pulmonary toxicity.
Another session at San Francisco was devoted to the anthracyclines. Rubidazone is effective in adult acute leukemia but is cardiotoxic. The Adriamycin-DNA complex appears to have no advantage over free Adriamycin and is also cardiotoxic. A new Japanese analogue called Aclacinomycin is of interest. The newly developed endomycardial biopsy technique permits evaluation of cardiac injury prior to its clinical appearance. With this technique it has been shown that virtually all patients have cardiac damage when the total dose of Adriamycin is in excess of 200 mg/m² and that concommitant mediastinal radiation enhances the injury.
In addition to the symposia described above, the cancer chemotherapy group has been working on establishment of a U.S.-Japan protocol for the treatment of gastric cancer. A joint study has been agreed upon and participation in the U.S. will be via the Northern California Oncology Group (part of the NCI-sponsored Northern California Cancer Program). The study will include one arm common to both countries, namely, Adriamycin plus 5-FU. In addition, there will be independent study arms in each country. The common arm will provide a basis for comparison of results.
Future plans for the Cancer Therapy Program Area include participation in the Princess Takamatsu Symposium (November 1977) and the Fourth Annual Symposium and Program Review (spring of 1978).