CHEMOTHERAPY
The seminar on "Development and Evaluation of Treatment of Cancer with Combined Modalities" (7th Annual Program Review of Treatment Area) held on November 4-6, 1981 , in Gettysburg, Pennsylvania, was an excellent meeting. It covered three different topics: 1) Treatment of oat cell carcinoma of lung in the United States and Japan as a disease oriented update problem; 2) New development of methodology in clinical and preclinical investigations. For instance, there were discussions on the progress of the human tumor cloning assay as a predictor for the sensitivity in situ of human tumors to the drugs administered; 3) Topics on the new antitumor agents, natural and synthetic, now in Phase I and II stages, and also those still in the preclinical phases of development.
The preclinical study of new synthetic compounds, such as4-carbamoyl-imidazolium-5-olate and M-83, were presented. All studies of preclinical toxicology have been completed and these drugs are about to be put in Phase I studies in Japan. Many useful informations on the compounds in Phase I and II studies were exchanged and discussed, since mitoxantrone and the derivatives of nitrosourea are now in clinical study concurrently in both countries.
Development of effective antitumor antibiotics is still an area of anticipated progress in cancer chemotherapy. Discovery of new antibiotics, CC-1065 and Pip 1B, was a topic of interest, and the recent advance of pentostatin and neothramycin into clinical evaluation attracted attention of the participants. Aclacinomycin is an unique anthracycline developed in Japan, and the results of clinical trials in both countries were presented. PEP-bleomycin has been under active investigation in Europe and the United States; it has low pulmonary toxicity, exhibiting promising effectiveness in the treatment of testicular cancer.
The exchange of materials and concurrent clinical trials with well planned cooperation are effective ways to accelerate the progress in this field. Recent advances in the techniques of biotransformations of antitumor agents of natural origins were topics of discussions. These advances might bring about the possibilities to prepare new antibiotics with improved efficacy. The seminar referred to some biologic response modifiers. Bestatin and forphenicinol were reported on for their biologic activities and as well as the recent results of Phase I and II studies. Informations of clinical trials with interferons in the United States and Japan were also presented.
On the other hand, the clinical studies with radiation combined with hyperthermia or with radiation potentiators exploited a new field of combined modality treatment. The experience of using misonidazole in Japan was presented to compare with that of the United States.
Before closing the seminar, a presentation was given summarizing the Cooperative Clinical Trial of Advanced Gastric Cancer Patients with common protocols, which has been carried out jointly by investigators in the United States and Japan since the end of 1977. The trial was of great success. According to the comparability study, it was found that there was no difference in the survival between the patients of both countries with the common arm, adriamycin and 5-FU. It is especially noteworthy that manifestation of toxicity during treatments was also perfectly comparable between the patients of both countries, although the effect on the cancer was not so promising with any of the treatment arms adopted.
One of the most urgent problems is to establish a common and mutually acceptable concepts and means of clinical trials between the two countries in order to facilitate joint studies, because the cooperation could save considerable time and labor for making conclusive evaluations of each new protocol with combined modality.
IMMUNOTHERAPY
The seminar on "Evaluation of Cancer Immunotherapy" was held on October 12 to 14, 1981 at the Maui Sheraton Hotel, Hawaii, U.S.A. This joint seminar was organized by Dr. Richard Hodes and Professors Yuichi Yamamura and Ichiro Azuma. A total of 7 scientists from the United States and 11 scientists from Japan participated in this seminar. The seminar covered following topics.
I. Experimental Study of Cancer Immunotherapy
1) Adoptive immunotherapy
Recently, it has been shown that T lymphocytes can be cultured for long term in vitro with T cell growth factor (TCGF, Interleukin II). Drs. Cheever and Rosenstein have reported the prolongation of the survival period of tumor-bearing mice by the adoptive immunotherapy of sensitized T lymphocytes, which were cultured in vitro with TCGF. Dr. Rosenstein has also reported on the preliminary results of adoptive transfer of in vitro cultured autochthonous lymphocytes into cancer patients.
2) Hybridoma technique
Dr. Kishimoto described the biological properties of two kinds of human T cell clones, clones 24A and 55A, established by hybridization technique. The 24A clone was shown to secrete TCGF in their culture supernatant. The 55A clone showed helper activity in the induction of cytotoxic T cells. Dr. Kishimoto also reported on the properties of cell line which secreted killer helper factor, TCGF, T cell replacing factor and!!
!-interferon. The possibility of these cell lines and their secreted factors for the application to the cancer treatment were discussed. 3) Monoclonal antibody
Dr. Levy reported on the efficacy of mouse monoclonal antibody (L17F/2 antibody) which reacted to human T cell antigens in the treatment of the patients with T cell leukemia and lymphoma. The clinical application of antiidiotype antibody on the treatment of cancer patients was also reported.
4) Cell-cell cooperation
Dr. Takatsu reported on the experimental model for the augmentation of tumor antigen-specific killer T cell by the immunization of PPD-conjugated tumor cells in mice which were presensitized with tubercle bacilli.
5) Biological response modifiers
Drs. Azuma and Yamamura presented the recent results on the antitumor activities of several bacterial cell walls and synthetic adjuvants, especially on the cell-wall skeletons of P. acnes and L. monocytogenes, quinonyl muramyl dipeptide derivatives, in experimental tumor systems. Dr. Ishizuka also reported on the immunological and antitumor activities of low molecular adjuvant, Bestatin. The antitumor activity of interferon is now being widely examined in the United States. Dr. Oldham summarized the recent results of phase I and phase II trial of!!
!and!!
!interferons in cancer patients.II. Clinical Trials of Cancer Immunotherapy
In this session, the efficacy of living BCG and Nocardia rubra-CWS examined by randomized control clinical trials was reported. Dr. Hodes reported that the administration of living BCG to malignant melanoma patients with clinical stages I and II could not statistically prolong the survival period of the patients in comparison with the control group treated with surgery and chemotherapy. Drs. Ogura and Yamamura stressed that N. rubra-CWS was effective for the prolongation of survival period of the patients with small cell carcinoma (clinical stages I, II and III) and squamous cell carcinoma (stages II and III). Dr. Yasumoto also reported that N. rubra-CWS was effective in the patients with malignant pleurisy and resectable lung cancer patients.
Dr. Yamada presented data that the immunotherapy with N. rubra-CWS was effective in the prolongation of survival periods of patients with acute myelogenous leukemia after the induction of remission with chemotherapy. Dr. Ochiai examined the efficacy of N. rubra-CWS on the patients with gastric cancer. The survival rate was statistically significant with N. rubra-CWS immunotherapy in patients in clinical stage IV and surgically treated non-curable patients.
Dr. Sullivan reported on the clinical effectiveness of bone-marrow transplantation in acute leukemia patients. Dr. Ramming summarized the recent advance in the immunotherapy of lung cancer patients in the United States.
In the last fifteen years, regional and nonspecific immunotherapy with immuno-adjuvants were widely applied for the cancer treatment and various kinds of immuno-adjuvants were used for the cancer immunotherapy. At this seminar, the clinical efficacy in human cancer of living BCG and N. rubra-cell-wall skeleton was evaluated. The background factors affecting the clinical effectiveness of cancer immunotherapy were also discussed.
New approaches and their possibility for the cancer treatment were discussed. Cell-engineering techniques, such as in vitro culture of T cell, hybridoma, and monoclonal antibody, were suggested to be effective for the treatment of cancer in the future. The results presented in this seminar indicate clearly that the immunotherapy will become important modality for the cancer treatments in combination with other conventional modalities.
BLADDER CANCER
One of the most important clinical tasks in the treatment of bladder cancer is to establish the preventive method for the recurrent superficial bladder tumors and to achieve improved survivability in deeply infiltrating bladder cancer, which shows no potential for surgical intervention alone. Along these lines studies and investigations have been done by both basic researchers and clinicians on a world-wide scale. However, there have been many problems to be solved in this field of urologic oncology.
To overcome these difficulties a sequent of the U.S.-Japan Co-operative Cancer Research Program was established to foster the interchange of progress in bladder cancer research through seminar programs involving scientists between the two countries.
Preliminary meeting to discuss these problems, including bladder cancer pathology, was held on the 30th of January in 1981 at Hawaii, U.S.A. Participants included Dr. G.H. Friedell, and Dr. G. Farrow from U.S.A., and Professor N. Ito, Professor T. Enjoji, and Professor T. Niijima from Japan. Dr. Stemmermann was present as an observer. Dr. Friedell and Professor Niijima reviewed the purpose of this co-operative study and a seminar was scheduled for autumn in 1981. After discussion it was agreed that the seminar would be held at Tokyo for Nov. 16-18, 1981 and the intent would be to have around 10 official participants from U.S., and a like number from Japan with several observers. Final program agenda was developed in June, 1981, by Professor Niijima and Dr. Friedell, focusing to "Treatment of Bladder Cancer."
Upon this decision the seminar, supported by U.S. National Cancer Institute and Japan Society for Promotion of Science, was held during 16-18, November 1981 at Tokyo Prince Hotel. Participants were 8 from U.S., and 10 from Japan with 15 observers. Before this seminar Dr. Soloway (Urologist), Dr. Hafermann (Oncologic Radiologist) and Professor Niijima held a preliminary meeting on the treatment of bladder cancer including surgery, irradiation, chemotherapy and immunotherapy. They reached to the conclusion that multi-disciplinary treatment should be employed in some extent for treating deeply invasive cancer with the aid of cisplatin and radiation.
The seminar included the following items of the treatment of bladder cancer obtained from basic and clinical studies;
1) superficial bladder cancer
2) deeply invasive cancer
3) metastatic disease
4) prevention of the recurrence of bladder cancer
During this seminar fundamental problems on the treatment of bladder cancer were presented and discussed. These included the treatment of carcinoma in-situ, the precise mechanism of carcinogenesis and the recurrence of the superficial lesion with its prevention. For the diagnosis of carcinoma in-situ, karyotype analysis with nucleic acids staining by fluorescence dye was reported to be beneficial. Though the superficial bladder cancer treated trans-urethrally showed excellent survival rates, the recurrence rates were high. For the prevention, intravesical chemotherapy was found to be effective according to the results from randomized control trials.
Treatment of deeply invasive cancer should be multi-disciplinary. Selection of the chemotherapeutic agents for this purpose had to depend upon the sensitivity tests, using nude mice, tissue culture technique (stem cell culture), and biochemical parameters. Monoclonal antibody combined with a chemotherapeutic agent was used in experimental animals bearing bladder cancer. This therapeutic method could be promising for the future progress if it could be used clinically in humans.
The results from this seminar were fruitful and served to establish a foundation for further co-operative studies of the treatment of bladder cancer as well as basic and clinical investigations of this malignancy. This will make it possible to treat bladder cancer patients using the same criteria and protocols between the two countries. The development of such a link between U.S. and Japan will surely facilitate the mutual understanding and utilization of diagnostic, therapeutic and clinical technology as well as results obtained by basic studies.
These collaborative trials between the two countries would be so promising that results of the treatment could be criticized and evaluated at the next seminar, which all participants would like to have in the nearest future.
SEMINAR AGENDA AND PARTICIPANTS
(1) U.S.-Japan Cancer Agreement Meeting
November 4-6, 1981
Gettysburg, Pennsylvania
AGENDA