PROGRAM AREA REPORT

CANCER CHEMOTHERAPY

Coordinators: Dr. Stephen K. Carter
Dr. Yoshio Sakurai


Prior to the initiation of this U.S.-Japan Cooperative Cancer Research Program, there had been a long standing and successful collaboration and relationship between the Japanese and American scientists in the field of cancer chemotherapy, particularly since Japan and the U.S. have the two largest programs in cancer drug development. There have been four effective drugs developed in Japan which are now being tested in the U.S. This program has greatly enhanced and provided greater opportunities for cooperation among scientists in both countries. The cancer chemotherapy program area had a highly successful initial year building a firm foundation of cooperation which reflects in large part the previously coordinated efforts developed between the Division of Cancer Treatment, NCI and the Japanese Foundation for Cancer Research.
The joint seminar on “Comparative Study on Cytosine Arabinoside and Cyclocytidine” and a workshop on the Phase I Study was held in Tokyo in February 1975. The purpose was to collect the cyclocytidine-arabinoside cytosine presentation from the respective countries to learn how both countries approach analogue development and clinical testing. Experimental and clinical studies indicate that Cytosine Arabinoside (Ara-C) is more effective than cyclocytidine in acute myelocytic leukemia and showing lower toxicity. The use of combination chemotherapy and combined modalities, and the possibilities of cooperative phase I studies on new drugs were discussed.

As a result of the seminar, the following conclusions were drawn about cyclocytidine:

  1. In the experimental predicting tumor (L1210) cyclocytidine does not have superiority to Ara-C when both optimal schedules are compared.
  2. Cyclocytidine is superior to Ara-C on daily administration in the early L1210 (10 cells i.p. therapy started day 1). This superiority disappears with a higher tumor inoculum or when treatment is delayed until day 5 when the tumor is advanced. It is worth noting that the classical schedule dependency for Ara-C in the L1210 (Q3H day 1, 5, 9) disappears when the tumor is advanced and this plus the lack of deaminase in the L1210 system explains the failure of the clinical data to correlate with the L1210 prediction.
  3. Cyclocytidine is not active against Ara-C resistant tumors (both naturally resistant and induced resistant).
  4. Cyclocytidine is ultimately broken down to Ara-CTP which is the active moiety of Ara-C.
  5. Pharmacologically, it has been shown that cyclo-cytidine is excreted predominantly as unchanged cyclocytidine with low levels of Ara-C and Ara-U (the inactivated metabolite of Ara-C). In the plasma one sees high levels of cyclocytidine which rapidly fall off and more sustained but lower levels of Ara-C and Ara-U. This compares to Ara-C which has a short half life and is excreted in the urine almost exclusively as Ara-U. Therefore, cyclocytidine would appear to be pharmacologically superior to Ara-C giving a higher C x T of Ara-C and presumably of Ara-CTP.
  6. Clinically, cyclocytidine is active in AML in the Japanese study. When given as a single agent to AML patients without previous exposure to Ara-C the complete remission rate is 25%, the dosage schedule is 10/mg/kg/day i.v. push. This is not superior in any way to the induction ability of Ara-C.
  7. American studies with cyclocytidine have been phase I studies mostly in solid tumors. Since Ara-C combinations are so effective for initial therapy of AML in the United States, American investigators would not consider using cyclocytidine in patients not exposed to Ara-C. This raises one of the critical aspects of the clinical trial strategy for an analogue which was brought up at the meeting.
  8. Cyclocytidine is toxicologically inferior to Ara-C in that it has all the toxicities of Ara-C plus two additional side effects which are troublesome. These are: a) jaw pain, and b) postural hypotension. Both of these make the drug less attractive than Ara-C.
  9. Cyclocytidine is possibly more convenient to use than Ara-C, since it can be effectively given s.c. or by i.v. push while Ara-C is best given by continuous infusion. The latest studies by Dr. Kimura and his group, however, indicate that cyclocytidine may be more active when given as continuous infusion. This may be because most of the administered cyclocytidine is rapidly excreted as unchanged cyclocytidine in the urine. The need for infusion, however, would vitiate the argument that cyclocytidine is a more “convenient” form of Ara-C.
From the workshop on Phase I study, the following conclusions were drawn:
  1. It is much easier to initiate a phase I study in Japan than it is in the U.S. since there is relatively less regulatory control over phase I studies in Japan.
  2. There is no overall phase I strategy as the input comes from the drug companies who provide the precilinical data and have total control of the drug.
  3. Better risk patients with less prior therapy are used in Japan for phase I studies than in the U.S. reflecting the greater importance placed by the clinical investigators in new drug testing.
  4. Phase I studies are done by cooperative groups. Cyclocytidine was worked up by a cyclocytidine team designed specifically for the purpose, and a large phase I cooperative group (22 institutions) has now been formed to do phase I studies. This group is now evaluating methyl CCNU and a new nitrosourea called ACNU. This kind of approach was utilized in the U.S. until a few years ago when it was abandoned because the large numbers of patient entered into the phase I studies of this kind exposes more patients than necessary to toxicity and the early suboptimal dosage levels.
Future plans for the exchange of scientists were discussed. Seven Japanese were sent to the U.S.A. for collaborative work in 1974 and 1975. The Japanese side will start sending younger scientists for longer periods of time and cut back the senior scientist trips to shorter periods. The emphasis for senior scientist travel ought to be for specific interactions and to stimulate specific cooperative ventures. The Japanese oncologists were encouraged to attend meetings in the United States. It was agreed at this seminar that stomach cancer was a good subject for an initial chemotherapy visit.
A team drawn from the NCI Division of Cancer Treatment Gastrointestinal Tumor Study Group, which had been heavily involved in the treatment of gastric cancer, consisting of 6 U.S. scientists, visited Japan in December 1975 for a cooperative study on gastrointestinal tumors.
A five day meeting was held in Tokyo during the U.S. team had the opportunity to make an in-depth study on the treatment of gastric cancer in Japan. The following important conclusions were drawn: as an adjuvant chemotherapy, combination of 5-FU and methyl CCNU is being applied widely in the U.S., while that of 5-FU and mytomycin C is extensively used in Japan. Because most of the Japanese patients do not tolerate CCNU well, it was, therefore, recommended by the respective sides that the existing protocol continue for future comparative studies. In the chemotherapy of GI tract malignancies a common fixed protocol will be expected.
The success of this visit of the U.S. scientists has resulted in the U.S. side inviting several Japanese specialists in gastroenterlogy to visit three major hospitals in the U.S. to develop intensive collaboration in the diagnosis and treatment of gastric cancer in late 1976.
A symposium on the status of clinical trials with bleomycin and nitrosoureas in Japan and the U.S. and surgical adjuvant approaches was proposed to for February 1976, in Hawaii.
In the area of information exchange through the NCI International Cancer Research Data Bank, 233 current research projects have been added from Japan to the Data Bank.
More collaborative efforts are needed for more effective testing and in-depth studies for the clinical evaluation of new drugs. The methodology of testing may be somewhat different between the two countries but there is a great need for exchange of ideas in evaluating clinical trials.
The atmosphere of clinical drug testing have become more difficult and restrictive in both countries, because of recent changes in regulations governing the testing and use of new drugs, and there are some difficulties in staging clinical trials, particularly in Phase I studies. It is felt that a change of attitude by the U.S. Food and Drug Administration is needed since the pending regulations could paralyze clinical studies. It is noted that currently the regulations in Japan are also changing.
The exchange of information, standardization of clinical trials, exchange of criteria and information on new treatments and protocols are of particular importance for future efforts and the methodology and strategy on drug testing must be continually modified to develop more effective cancer treatment.
In the joint symposium on the status of clinical trials of bleomycin and nitrosoureas, held in Hawaii in February 1976, the exchange of informations on the clinical and preclinical aspects of bleomycin and nitrosoureas was made. Some highlights of the symposium includes:
  1. Exchange of some nitrosourea compounds with sugar chains - GANU from Japan, and TCNU from the U.S. - was planned for the future collaboration in the accumulation of their clinical and preclinical data.
  2. The Japanese side presented the status of clinical trials of bleomycin, including its application as a radiation sensitizer.
  3. In response to the U.S. scientists questioning of the side effects of bleomycin, new delivatives of bleomycin were introduced by a Japanese participant.
  4. A U.S. scientist introduced a canine system in which bleomycin-induced pulmonary fibrosis has been investigated extensively, offering collaboration in testing the new bleomycin delivatives.
  5. Development of a new preclinical screening system was proposed to minimize the number of drugs selected for clinical screening.

In the successive executive session the following project areas have been confirmed for the intensive joint collaboration in the coming years:

  1. Gastric cancer - diagnosis and treatment.
  2. Nitrosourea compounds.
  3. Bleomycin and its delivatives.
  4. Antracyclic antibiotics.