SUMMARY REPORTS OF EXCHANGE SCIENTISTS
1. Dr. Robert Young, NCI
Dr. Daniel Ihde, NCI
Dr. Robert Golbey, Memorial Sloan-Kettering Cancer Center
Dates of Visits: December 5-9, 1983
Summary of Activities
Drs. Young, Ihde, and Golbey participated in a series of seminars and visits in Tokyo and Nagoya, the primary focus of which was on three curable cancers, small cell lung cancer, testicular cancer, and ovarian cancer. These visits provided an opportunity to exchange information on clinical studies being carried out in both countries with these cancers.
2. Dr. Makoto Ogawa,
Cancer Chemotherapy Center, Tokyo
Dates of Visits: January 17-23, 1984
Dr. Ogawa participated in the Phase I-II meeting at NCI to exchange information on clinical trials. In addition, he visited Drs. Glenn Sheline and Theodore Philips at University of California at San Francisco.
Summary Reports on Biochemical Modulators Meeting and Phase I Working Group Meeting
The meeting held during 18-19 January, 1984 in National Cancer Institute (NCI) in Bethesda, Washington, D.C. was divided into two parts; Biochemical Modulators Meeting and Phase I Working Group Meeting.
1. Biochemical Modulators Meeting
The experimental and clinical results of biochemical modifications including methotrexate (MTX) plus 5-fluorouracil (5FU), 5FU plus citovorum factore (CF) rescue, PALA plus 5FU, cytosine arabinoside plus MTX and activicin plus cytosine arabinoside were presented in this meeting. Among these methods, a sequential use of MTX and 5FU has been most extensively tested in head and neck tumors, gastrointestinal tumors and others. However, it appears that the optimal dose and timing to deliver both drugs has not yet established, while most investigators have used 1-3 hours intervals.
Concerning with timing to use MTX and 5FU, Cadman in University of San Francisco presented an experimental evidence suggesting that more than 24 hours will be necessary in order to achieve sufficient accumulation of PRPP, which is a key metabolite relating to binding of FdUMP to thymidylate, an active compound of synthesis which could contribute to the enhanced cell kill.
Bruckner in Mount Sainai Hospital presented their preliminary results of a simultaneous combination of 5FU and CF rescue which was designed in order to reduce toxicity and therefore to enhance clinical efficacy of 5FU.
This approach is a similar modality to the high dose MTX and CF rescue which showed a significantly enhanced activity over MTX alone for lymphomas, osteogenic sarcoma and others. However, his result suggested that CF did not conribute for reduction of gastrointestinal and central nervous toxicities of 5FU.
Overall, biochemical modification purposing enhancement of antitumor efficacy and/or reduction of toxicity is an attractive investigational direction, however none of these attempt appears to have established its clinical usefullness until now.
2. Phase I Working Group Meeting
The results of Phase I trials of various new antitumor agents were presented by investigators in USA and in Early Clinical Trial Group (ECTG) in EORTC. Thirty minutes were given for me to review current results of new drugs developing in Japan and, therefore, I summarized experimental and clinical results of an anthracycline: THP-adriamycin, antimetabolites: PL-AC, SM-l08, UFT and 5DFUR, a new cisplatin: 1-OHP and others.
Major drugs reported from USA and ECTG were 2nd generation compounds of cisplatin: CBDCA, CHIP, TNO-6 and JM-40; analogs of adriamycin: Epirubicin, Idarubicin and Esorubicin, a new bleomycin: tallysornycin, and others. Furthermore, methodology of Phase I trial in children was reviewed by Marsoni in the NCI.
Firstly, eighty percent of an optimal dose determined by adult's Phase I trial is safe to be selected as an initial dose in children. Secondly, the modified Fibonacc's method was used to escalate the doses, but the doses of each step can increase upto 100% until reaching a subtoxic dose. Thirdly the dose limiting toxicities is the same in both children and adults. Finally, the maximum tolerated doses decided in children were mostly higher doses than those in adults.
It is well recognized that incidences of pediatric solid tumors which are major target tumors relected for Phase I trial are much less than those in adults, so that an efficient methodology to conclude Phase I trial is essential.
Thus, in this respect, this presentation was educational and, in my opinion, the independent Phase I trial from adults is definitively necessary in order to determine the optimal dose and schedule in children. The chance given for me to attend this meeting was extremely precious, because informations of new drugs were obtained through presentations and by personal communications with participants including my friends.