EXCHANGE SCIENTIST REPORTS

Lynn James Verhe Ph.D.,
Massachusetts General Hospital, Boston, Massachusetts

Dates of Visit: April 16 to April 25, 1980
Hosts:
Dr. Yoichiro Umegaki, National Institute of Radiological Sciences (NIRS), Chiba.

Summary of Activities.
The primary objectives of the study were to implement dosimetric intercomparisons in both cobalt-60 treatment beams and the proton beams of the INS and the NIRS. These intercomparisons were performed by myself and groups from both NIRS and the Institute of Medical Science in Tokyo. Each group made dosimetric determinations using ion chambers and electrometers from their home institutions, calibrated using techniques common to their institution. These types of intercomparisons along with biological intercomparisons also accomplished by the U.S.-Japan Cooperative Cancer Research Program, give one confidence to compare future clinical results achieved with proton beams in Japan and the United States. Although the entire analysis is not yet complete, the results of the intercomparison will be reported in November 1980 at the Hawaiian meeting of the U.S.-Japan Cooperative Cancer Research Group. At that time I will report on our own results as well as the summary of the results from the Japanese group and a calorimetric measurement made by Mr. Joseph C. McDonald of the Sloan-Kettering Institute in New York. No publication in the open literature is planned, but the proceedings of the November meeting in Hawaii will be printed and circulated to the participants.
My participation in this scientific exchange program has permitted me to improve my understanding of proton dosimetry measurements and techniques of intercomparison which will assist me in my contributions toward a charged particle dosimetry protocol which will be produced by the Charged Particle Physics Dosimetry Group, a task force of the AAPM, of which I am a member. In addition, previous work which I have done with other charged particle facilities in the United States and future planned intercomparisons in combination with this Japanese work will permit an indirect comparison of dosimetric techniques with groups in Japan and a number of charged particle groups in the United States.
It is my hope that this collaboration in which I have participated will continue as the Japanese and United States groups work in cooperative fashion toward the production of quality proton radiation therapy. I am grateful for the opportunity to have participated in the bilateral program and to have made many friends in the Japanese scientific and medical communities.


George T. Bryan M.D.,
University of Wisconsin, Madison, Wisconsin

Dates of Visit: July 17 to August 16, 1980
Hosts:
Various sponsors at several centers.

Summary of Activities.
This trip was taken (1) to visit certain centers conducting bladder cancer research in order to exchange views on recent progress in this area; (2) to stimulate further collaboration between scientists in the United States and Japan on this topic; and (3) to participate in the "International Study Group for Tryptophan Research" (ISTRY-80 KYOTO) meeting August 4 to August 7, 1980.
Eleven talks were presented to groups of six to fifty participants (an average of 25 per presentation). In addition, ward rounds were made with attending physicians and staff on seven occasions. About 350 patients with a variety of urologic malignancies were seen and discussed. Topics covered in formal and informal discussions included epidemiology, carcinogenesis and biology, diagnosis and detection, and therapy of bladder and other urologic malignancies. Specific comments concerning each of these areas are presented below. Additionally, I attended the ISTRY-80 meeting and presented a paper. This meeting provided a comprehensive review of L-tryptophan, especially as it relates to cancer. A copy of my schedule appears later in this report.
There is strong desire on the part of Japanese clinicians and scientists to continue to formally and informally participate in future U.S.-Japan program exchanges. Clinical aspects of this exchange will be led in Japan by Professor Tadao Niijima. Certain problems must be addressed before such exchanges will be of maximal utility; these are cited in the following comments.
Topics covered:

1. Epidemiology.
   Industrial-related bladder cancer occurs in high frequency (20~) in Tokyo, Nagoya, and Wakayama; in lower frequency (5%) in Osaka; and rarely (less than I~) in Yamaguchi prefecture. Excellent data have been collected by Professor T. Ohkawa and associates concerning the relationship of exposure to benzidine manufacture and the latent period of bladder cancer formation in workers. No other chemical exposures are known to occur in these individuals. Surprisingly, the latent period decreased with increasing age of entry into this industry. For example, those entering at age 20 to 25 exhibited a mean latent period of about 25 years; those entering after age 50 had a mean latent period of about 9 years. Intermediate aged groups were intermediate in latent periods. About 1,000 individuals have been registered as having exposures to benzidine between the 1930s and 1970 when manufacture was stopped by government action. About seven percent of these people have developed bladder cancer, and new patients are developing disease at the rate of 25 to 40 per year.
   There appears to be an increase in bladder cancer among individuals exposed to atomic radiation at Hiroshima and Nagasaki in 1945.
   Epidemiology (continued)
   This increase has not yet reached statistically significant levels. Dr. K. Clifton is interested in investigating this problem further, so I suggested several urologists and scientists in Japan that might help him.
   Studies at the Fukuoka Environmental Research Center (Drs. Saruta and Nakamura) include continuous monitoring of known environmental contaminants and relating these levels to human disease processes.
   
2. Carcinogenesis and Biology.
   Drs. Ito, Okajima, Otsuka, Sugimura, and Yoshida appear to be most active in continuing studies of bladder carcinogenesis and pathogenesis. Dr. Ito has recent evidence that saccharin promotes bladder carcinogenesis induced by N-butyl-N-hydroxybutylnitrosamine (BBN). On the other hand, the artificial sweetener, Aspartame, did not exhibit such effects. Drs. Yoshida and Otsuka continue studies of arylamine and azodye bladder carcinogenesis, and Dr. Sugimura is most involved in early molecular events related to carcinogenesis.
   
3. Diagnosis and Detection.
   Pathologists and urologists in Japan do not use common histopathologic criteria for the classification of urologic malignancies. Each school has its own scheme in which some criteria are commonly shared, and others are used only locally. This creates serious problems for interpreting reports from the various centers, especially in trying to evaluate treatment results. The Japanese Urological Association is attempting to correct this problem under the leadership of Dr. T. Niijima. Committees have been established to deal with standardization of criteria for bladder and prostatic malignancies. These committees have just begun their work, but it is expected that uniform standards will be agreed upon within two years.
   Dr. Watanabe is continuing his studies of the use of ultrasound in the detection and staging of prostatic cancer. Dr. Niijima and his associates are conducting similar studies with bladder cancer. These studies use an intraurethral ultrasonic probe with computer resolution of sonic waves. Preliminary results appear impressive.
   
4. Therapy.
   Recent investigations with chemotherapy have centered on continued studies of direct intravesical therapy with a variety of agents (Drs. T. Mishima, T. Niijima, and S. Hayashida), and gluteal or internal iliac arterial catheter infusion of chemo-therapeutic agents (Dr. O. Yoshida). Numbers of patients studied are small (generally less than fifteen per treatment) but some successful long-term effects have been seen. Some apparent failures have also been noted.
   With direct intravesical therapy for superficial low-stage bladder cancer, Mitomycin C and Adriamycin appear most useful. With human interferon, only one in fifteen patients exhibited a transient response (Dr. T. Mishima). With hyperthermia (43°C) plus bleomycin, none of eight patients responded. All developed contracted and fibrotic bladders, with severe dysuria requiring urinary bypass (Dr. S. Hayashida).
   Internal iliac or gluteal arterial catheter placement is accomplished surgically in patients with locally invasive bladder neck or prostatic neoplasms. Catheter placement and retention is checked serially by radiographic methods. Chemotherapeutic agents used include PEP-bleomycin, cyclo-phosphamide, Mitomycin C, Adriamycin, or 5-FU. These drugs are given in consecutive sequence at varying dosages. About fifteen patients each with bladder or prostatic cancer have been studied, and a few remissions lasting as long as two years have been seen. Systemic toxicity is minimal. Patients retain catheters for long periods, and can be ambulatory during therapy. No problems with infection have been encountered. Unfortunately, no standard treatment protocols have yet been developed, and no comparative studies have been conducted. Few medical oncologists are available or interested in working with urologists in Japan, and this is a serious problem that hampers progress. Nevertheless, responses that have been seen appear to be well documented and impressive. Pulmonary toxicity with PEP-bleomycin appears less than with bleomycin.
   

Exchange Visit Schedule:

Takeshi Horai M.D.,
The Center for Adult Diseases, Osaka

Dates of Visit: February 9 to March 30, 1981
Hosts:
Dr. Myron R. Melamed, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
Dr. Clifton F. Mountain, Thoracic Oncology, M.D. Anderson Hospital and Tumor Institute, Houston, Texas
Dr. John D. Minna, NCI-VA Medical Branch, Veterans Administration Hospital, Washington, D.C.

Summary of Activities.
The study objectives of this exchange visit were (1) intensive chemotherapy of lung cancer in the United States; (2) subtypes of small cell carcinoma, and the relation between prognosis of patients and cytologic findings; and (3) cell kinetics and its application to the treatment of lung cancer.
High-dose combination chemotherapy is being used for the treatment of small cell carcinoma in the United States. At M.D. Anderson Hospital, intravenous hyperalimentation and protected environment-prophylactic antibiotics programs make it possible to intensify chemotherapy. They currently have a high response rate with no prolongation of survival time as a result of this intensive chemotherapy. The remaining challenge is to improve the response rate and to prolong the survival time.
In the area of subtypes of small cell carcinoma, the NCI-VA Medical Oncology Group stressed that there was no difference in tumor regression or survival time between the lymphocytic type and the intermediate type. At the time of diagnosis, it is difficult to identify the histologic subtype by cytology. Thus it may not be wise to judge treatment results by the subtypes. My studies on the cytologic characteristics of small cell carcinoma in relation to the effect of chemotherapy were evaluated as a means for predicting the effect of chemotherapy.
In the Sloan-Kettering laboratory, Dr. Melamed and his associates showed me the technique of cell kinetics using flow cytometry. It was valuable for me to study the influence of chemotherapeutic agents on cell cycle. Future studies on the changes of DNA patterns before and after chemotherapy, and on the relationship between DNA patterns and response to chemotherapy, will be applied to the clinical field.
I learned clonogenic assay using double agar layers. This shows the sensitivity of the cancer cell to anticancer drugs in a short time. This work should be applied to the treatment of patients.
Recommendations:
Studies of cell kinetics and clonogenic assay will be of much help in the treatment of patients with lung cancer.
Since the purpose of treatment of small cell carcinoma is to obtain a higher response and a longer survival, the most effective protocol should be discussed. For non-small cell carcinoma, we should try revised combination chemotherapy using new anticancer drugs to improve the response rate and to prolong the survival time. It is worthwhile to exchange our clinical results with United States scientists and to continue our collaboration.
For choosing effective treatment for small cell carcinoma, my studies on cytologic characteristics in relation to the effect of chemotherapy were evaluated.