REPORTS ON SEMINARS


(1) Seminar on “Research Direction of New BRM and Cytotoxic Combination Treatments”
San Francisco, California, November 13-14, 1989
This meeting was planned to explore new directions in the research of biologicals and chemotherapy.
Dr. Saijo presented information on rhG-CSF in lung cancer patients. The scheduled for therapy was chemotherapy followed by G-CSF 72 hours later (continued for 7 to 14 days). The chemotherapy utilized was MMC + VDS + CDDP or VDS + CDDP or VP-16 + CDDP. There was a dose related increase of WBC based on CSF dosage. The side effects of CSF was fever (21 %) chest pain (13%) etc. A second study with SCLC, the combination of PACE + CSF was evolved (CSF given on day 7-21). Also a combination of VM26 (escalating) and CDDP + GCSF is being evaluated. This work of the Kanto Lung Cancer Group and the National Cancer Center is ongoing.
Dr. Peters reviewed his data on CSF use in BMT. Usually CSF merely shortens the period of absolute neutropenia but does not abort it. The Duke experience was with 275 breast and a lesser number melanoma and ovarlan cancerpatients. All received Cytoxan + BCNU + CDDP and BMT. In refractory breast cancer patients 27% responded but only briefly. These same patients, at first relapse had a 54% complete response rate and 10%, are in continuous CR. Toxicity remains a major problem. Combinations of all 3 CSF’s have been studied (GM-498, G-CSF-45, M-CSF-13). GM seems to be more active in stimutating marrow and G to transport cells to periphery. Clinical benefits were seen with both GM and G - as demonstrated by less hepatic and renal toxicity and possibly less systemic infection. Two additional possible strategies are the use of Peripheral Blood Stem Cells or to give IL-3 or IL-1 to improve hematopoetic recovery.
Dr. Ogawa described the use of G-CSF with chemotherapy for lymphoma patients. Bone pain was noted in 10% at 400 g/M2 but was only notable toxicity. A total of 64 patients received SQ G-CMF, and received CHOP-like regimen. A second, double-blind study was performed in NHL patients. Approximately 60 patients were evaluated. He concluded that neutropenia was shortened with the CSF and an optimal dose was 75 mg/m2 sq and 100-200 g/M2 IV.
Dr. Appelbaum described the Seattle experience with ABMT utilizing Cytoxan + TBI and GM-CSF. Above 60 g/m2/d x 14 days, benefits were noted (500 PMN). There was no evidence of late graft failure or unexpected late toxicity. A double blind, randomized study of ABMT in lymphoid malignancies was performed. Definite benefits were noted for days of fever, time in hospital, bilirubin and creatinine levels. He postulated that GCSF might increase GVH and rejection (but this was not demonstrated in the canine model). With allogeneic transplants very rapid recovery was noted. Graft failure or rejection is a serious problem (10% survival) and can be affected by CSF. Patients received GMCSF if fewer than 100 cells were noted by day 28. More than 100 patients were treated and about 50% of allogeneic or autologous patients are surviving.
Dr. Masaoka then presented a similar body of data from Japan. In a Phase 11 study of AloBMT and ABMT in 74 patients, rapid leucocyte recovery was noted. The late relapse rate and survival rate was similar for both Alo and ABMT to historical controls for ANLL, lymphoma, and CML. A RDBPC trial with several hematologic diseases was performed with GCSF. Very few side effects were noted and no change in the incidence of GVH. Further research into the potential for stimulating leukemias, cell growth, means of harvesting PBSC, etc. is ongoing.
Dr. Mizoguchi described CSF studies in Aplastic Anemia, MDS, and refractory leukemia. Aplastic patients with less than 100 PMN usually responded poorly to GCSF. MDS patients (25) were evaluated and most patients had increased neutrophils. Leukemia transformation occurred in 5/10 RAEB patients but no conclusion could be drawn as to possible stimulation.
Dr. Izaki presented the preliminary data on combinations of chemotherapy and IFN. Single agent IFN-Beta caused a 17% response rate in 42 glioblastoma multiforme, and IV therapy was as good as IT therapy. A clinical study of previously untreated, biopsy proven brain tumor patients was carried out. IFN-Beta 2x106/day x 5 qwk x 5 with 5000-6000r and ACNU was used. A total of 102 patients were randomized. Major toxicities in IFN group were fever, chills, and leukopenia. Overall, responses in both groups were noted, but were significantly better for the IFN group. Survival and TTR were not however, significantly different. A second Study of Adult T cell leukemia-lymphoma was also presented. Patients received IFN (6x106 qd) and combination of estrogen-chlorambucil and prednisolone (30-60 g/d). Thirteen patients had active ATLL and 9/12 evaluable patients had PR but only of short duration (MDS = 2 Mo). For MDS IFN-Beta has been evaluated. Doses of 1x106 daily was given for 4 or more weeks. A total of 29 patients were entered (RAEB-6, RAEB- + -11, CMMOL-6, etc.). Overall 11/25 benefited with decreased blasts and increased PMN and platelets. Fever, chills and fatigue were the toxicities most commonly observed. No chromosomal clonal changes were noted and he postulated that IFN-Beta could be a differentiator.
Dr. Wadler described the clinical and preclinical studies of 5FU + IFN-Alpha. There is a synergistic effect in vitro and little impact on cell cycle time. A group of 27 Phase I patients with large bowel cancer were treated and most had fever, chills, malaise. In previously untreated patients 5/18 responded. In a Phase 11 study of 32 patients (no prior 5FU) there were 3 toxic deaths associated with diarrhea and sepsis. Of 32 patients, 20 had a PR and 23/32 alive at 1 year. Two ACUP patients responded, 1/10 patients responded, and 2 esophageal patients responded.
Dr. Kimoto described the Japanese experience with LAK+IL2, utilizing a mixture of type compatible PBL from normal donors. In 16 patients with various tumors an initial Phase I experience was obtained. Overall, 25 CNS, 8 lung, 20 HCC and 4 H&N patients were treated in Japan. This allogenic experience is unique.
Dr. Urba described the BRMP experience with IL2 + LAK or other combinations. IL-2 alone was effective in 11/52 renal and 9137 melanoma patients. LAK cells may be necessary for renal cell cancer (especially for obtaining CR rate). In attempting to increase endogenous LAK activity other agents like Cytoxan, FAA, MoAbs, etc. with a specific regimen (largely outpatient) Leu-19 cells could be successfully recruited. Little benefits were noted for the addition of Cytoxan, Poly ICLC or FAA + IL2.
Dr. Saijo presented data on IL2 + IFN-Beta which in a murine model is a potent therapy. It is superior to IL2 + IFN-Gamma and was roughly equivalent to IL2 + IFN-Alpha Three different schedules were evaluated and toxicities were noted with all 3 and LAk generation were likewise evident. Patients received 5 CI IL2 q wk and IFN /dx5 q wk on a Phase I schedule. So far 26 patients have been treated and 19 had NSCLC. The MTD 1 x 106/M2/dx5 for IL-2 (C.1.) and 6x106/d for IFN-Beta. A Phase II trial was initiated and so far 21 patients are entered; it is too early to confidently predict efficacy.
Dr. Takaku described both preclinical and Phase I studies of IL-1 (OCT43). Derived from E. Coli, it has both antitumor activity (in vitro) and hematopoietic activity. Given to normal mice, increases in PMN and platelets were noted. Benefits were noted after radiation or 5FU in murine studies. IL-1B stimulates hematopoietic factors and directly stimulates stem cells. G and GM-CSF are produced from fibroblasts, endothelium etc after IL-1 (or TNF) stimulation. Using MethA or S180, sq IL-1B injections inhibited tumor growth. Probably an intact immune system is necessary for IL-1B to work (since there was no prolonged survival in nude mice). It is not active in most hematologic human cell lines (not active in HL60). Preclinical tox demonstrated decrease weight, appetite, albumin etc. in 16 patients, treatment was given day 1 or 1 +2 weekly subcutaneous. Systems in 8/16 included fever, chills, malaise, N + V, headache at highest dose 7.2 x 104 units/body. 3/16 had LFT abnormalities in Phase II studies 1x106 u/body were employed and only 5/70 had any response whatsoever. There were increases in PMN and platelets.
Dr. Ogawa described the use of Bestatin in MDS patients. Using 30 g/d 4CR and 2GR in RAEB ± T and some stimulation of precursors was postulated. These data are not yet Jear. In a second series, IL-2 of 1-3x106 u/div continuous. In 5/12 hemangiosarcoma also held good objective response.

(2) Seminar on “Frontiers of Radiotherapy and the Combined Modalities”
Park Hotel, Kyoto, Japan
Organizers: Mitsuyuki Abe, M.D. and Theodore L. Phillips, M.D.
This conference was held to review the latest developments in the major areas of research in radiation oncology by the U.S. and Japanese participants and to plan f . or possible future collaborative research. There were seven speaking participants from the U.S. side and twenty-four speaking participants from the Japanese side.
Day 1
The first session concentrated on the physical, biological, and clinical aspects of hyperthermia. The presentations concentrated on ferromagnetic seed development as well as its use in CNS tumors, interstitial irradiation of CNS tumors with microwaves and the results of thermoradio-therapy for carcinoma of the breast and bladder. Additional papers covered the prospects for noninvasive temperature measurements using ultrasound and microwaves and the final presentations were on the use of hyperthermia to aid drug delivery from heat sensitive liposomes.
Dr. Cetas described the system he has developed for the use of thermo-regulating curie point seeds and wires. This system includes a 56-channel data acquisition system several different induction coil designs and seeds with different curie points. He described how one can predict the necessary curie point and the number of seeds based on estimates of blood flow with a computer model. The system requires that the ferroseeds be implanted between 1-1.2 cm apart. He described the importance of blood flow since below 3 ml/minute temperature is independent of low and above 30 mJ/minute it is essentially impossible to heat with thermoregulating curie point seeds. He reported initially encouraging results with the use of interstitial thermoregulating curie point seeds for malignant gliomas.
Dr. Masunaga then reported on thermoradiotherapy for carcinoma of the breast and bladder using capacitive heating or microwaves depending on the size of the lesion. He found that with the larger tumors, the best heating was with 430 MHZ microwaves or with 8 MHZ radiofrequency. The complete response rate was better for thermoradiotherapy than for radio-therapy alone. For example, in patients with primary tumors 91 percent had complete plus partial response with combined treatment and only 55 percent with radiation alone. In other studies, they reported on the use of 8 MHZ radiofrequency capacitive heating as a preoperative combined treatment with 40 Gy for bladder cancer. Patients with irradiation alone were compared to those who had thermoradiotherapy. Recurrence either locally or distantly was 11 of 41 patients treated with radiation alone and 5 of 28 patients treated with radiation plus hyperthermia.
Dr. Phillips reported on the results of interstitial 125-iodine treatment combined with hyperthermia for recurrent malignant gliomas at UCSF. Twenty-eight patients were treated with 11 showing definite improvement in the radiologic appearance of the tumor and only 6 showing tumor progression. Half the patients are still alive with a median followup of 34 weeks. Survival is similar to that achieved with higher doses of radiation alone and thermal distributions using multiple microwave antennas at 915 MHZ were excellent.
Dr. Mizushima then presented his experience with noninvasive temperature measurements using microwave radiometry. He was able to achieve resolution at 5 cm depth of one or two degrees but this could be improved to I with improved microwave design. The depth measurable could be increased with the use of lower frequencies. Accuracies as high as 0.4 C are possible.
Dr. Egawa reported on a noninvasive ultrasonic thermometry system. The system is based on ultrasound nonlinearity in the pulse reflection mode. Two ultrasound pulses of different frequencies and amplitudes are used. In practice, this pulse sequence pairing is combined with a diagnostic image ultrasound unit. Temperature measurement accuracy was expected to be about 2-3 C. It is a promising method that needs further development to reduce the uncertanties. The ability to superimpose thermometry on the anatomic information from. the ultrasound scan was very exciting as was the ability to use this with either ultrasound or microwave applicators.
Dr. Cetas then spoke on treatment planning for hyperthermia. He reviewed the various options for treatment planning including two-dimensional as well as three-dimensional, and the use of the finite element method. Problems which exist in exact prediction of temperatures include sufficient computer power to calculate enough elements, the effects of cold vessels on thermal conduction and the absolute measurement of blood flow. So far, they have developed a two-dimensional model which seems to work well in planning scanned focused ultrasound treatment. Higher capacity computers are now available which will allow three-dimensional calculations.
Drs. Nishimura and Tanaka talked about the use of cisplatinum-containing heat-sensitive liposomes and local hyperthermia. These liposomes can be designed to release at different temperatures for example with 80 percent release at 41 and none below 39 . In animal experiments, excellent concentrations in the tumor as compared to peripheral blood were shown. The heating tends to lead to higher concentrations of cisplatinum from the liposomes in the tumor as compared to other organs, except for the kidney where the total concentration is about the same as if the cisplatinum were delivered systemically withouts liposomes. Animal work shows that the liposome encapsulated cisplatinum was more effective against animal tumors than cisplatinum alone. This is a very encouraging new way to deliver localized chemotherapy.
The second session of the meeting concentrated on biological modifiers of radiation effect including radiosensitizers and colony stimulating factor. The first portion of the discussion concentrated on the development and testing of hypoxic cell sensitizers in the U.S. and in Japan with emphasis on clinical trials and on new sensitizers being prepared for the clinic.
Dr. Wasserman discussed the current status of the US/RTOG sensitizer program after a review of the rationale for chemical modifiers. The drug etanidazole, or SR 2508, appears about 4.9 times better than misonidazole in terms of the expected effectiveness versus toxicity ratio. The current active trials are in head and neck cancer where over 300 patients have been randomized to radiotherapy with and without etanidazole in Europe and about 277 patients in the U.S. Toxicity data is available as well as response data from the initial phase 11 patients and both are encouraging. The study is blinded, however, and probably neither the European nor the RTOG study data will be available for at least another year to 18 months in terms of the final outcome. SR 2508 is being looked at in phase 11 studies at other sites including bladder and prostate with intraoperative irradiation and as a continuous infusion for brachytherapy. If the head and neck trials are positive, then, of course, it will be tested in many other sites.
Dr. Mori reported on several new compounds being developed in Japan with particular emphasis on the development of an orally administered compound.
The next speaker was Dr. Kagiya who presented information on improving the tumor affinity of hypoxic cell sensitizers. He concluded that the radio-sensitizing activity in vivo of the nitroazole was proportional to the square root of the drug concentration in the tumor, whereas the acute toxicity index of the drug was proportional to the maximum brain affinity factor. He found that fluorine modifying drugs had about two times higher specific sensitizing activity than nonfluorine modified drugs and lower brain plasma partition coefficients.
The lead compound, KU 2285, showed brain concentrations as low as SR 2508 and similar LD50 values. The rate of tumor incorporation of KU 2285 was seven times greater than SR 2508. As measured by growth delay, the oral administration of KU 2285 gave a SER value about double that for the same dose of SR 2508 given intravenously. Thus, KU 2285 appears to be an excellent sensitizer for future clinical trials, particularly since it may be given orally.
The next speaker was Dr. Sakamoto who spoke on the subject of the new sensitizer RK 28. Dr. Sakamoto reported on a phase I clinical trial, performed in 1988 and 1989, of this agent which is a nucleoside analog of misonidazole. The drug is similar to misonidazole in terms of toxicity and sensitization in experimental animals. The total doses reached 16 gm/m2. The main side effects were nausea and vomiting.
The subject of the conference then switched to other types of antitumor strategies using chemical and biologic modifiers. First, Dr. J.D. Chapman spoke on photodynamic therapy using hematoporphyrins. He pointed out that for cell killing, one requires adequate light, adequate amounts of the drug, and adequate levels of oxygen. Photodynamic therapy seems to kill at once damaging the mitochondria and oxidative phosphorylation process. It kills cells in vitro directly but tumor experiments in vivo suggest that the majority of the effect is through capillary injury rather than primary tumor cell kill. Treatment was given in vivo to two different experimental prostate cancers. He was able to show tumor response with a hexagonal array of light sources about 8 mm apart. He also showed that the effect was markedly enhanced by using the cytotoxicity of misonidazole against hypoxic cells.
Thus, a future strategy might be a combined use of photodynamic therapy and bioreductive agents which would kill the hypoxic cells which would be resistant to PDT.
The remainder of the session was then devoted to experience with colony stimulating factors. Dr. Friedman reported on the different types of available colony stimulating factors including those for granulocytes and for granulocytes plus monocytes. Granulocyte colony stimulating factor given before therapy reduces luekopenia. The main side effects are edema, weight gain, and myalgias. These factors are now being used in various chemotherapy studies to decrease toxicity and/or allow an increase in the intensity of the chemotherapy. The main gain noted so far in American studies is a decrease in interval between drug cycles and the ability to maintain full chemotherapy doses. Platelets remain a limiting factor.
Dr. Ogawa then reported on GCSF studies. The compound was evaluated in three sequential studies. They found that the optimal dose was 75 mcg subcutaneous daily for 14 days. The main side effect can be bone pain. Studies were evaluated by a response committee which found a very significant effect of the GCSF in accelerating the recovery from neutropenia and preventing infections during chemotherapy.
Dr. Fushiki reported on a phase 11 trial of recombinant human granulo-cyte colony stimulating factor with radiation therapy. This trial included patients whose white counts dropped below 2500 during radio-therapy who were then administered GCSF. Doses ranged from 25-75 mcg. The lower dose gave a satisfactory but slower response than the higher dose. The GCSF considerably facilitated the recovery from neutropenia caused by radiotherapy.
Day 2
The second day of the conference opened with a session on radiotherapy in combination with chemotherapy. Dr. Friedman reported on U.S. trials of combined modality therapy in non-small cell lung cancer. He presented an excellent review of recently completed and ongoing studies. Particularly interesting is the recently completed CALGB 8433 study which gave two cycles of cisplatinum and velban prior to radiotherapy and compared it to radiation therapy alone. This study showed a significant increase in survival in the group receiving the preradiation chemotherapy. It is currently being retested in a three-arm study by the RTOG with a control arm and a hyperfractionation arm both without chemotherapy. In addition, there have been a number of interesting phase 11 studies completed and many are ongoing, which suggest that simultaneous cisplatinum and VP 16 or one of the vinca alkyloids with radiotherapy or alternating with radio-therapy may give maximal response rates and should be tested in future controlled phase 111 studies.
Dr. Kimura then reported on a trial of radiation and chemotherapy for small cell lung cancer. They started radiotherapy during chemotherapy or after intensive chemotherapy and concluded that there was no significant difference between the two groups in terms of response rate although the time to chest relapse was improved in the group in which radiation was given after chemotherapy.
Dr. Okawa reported on a clinical evaluation of intra-arterial infusion chemotherapy with or without irradiation for advanced squamous cell carcinomas of the oral cavity and oropharynx. There were two studies, one with ACNU and approximately 65 Gy and another with cisplatinum and approximately 64 Gy. The survival was slightly better although not significantly so for the platinum regimen. Similar studies were conducted in pelvic tumors using 5-FU and mitomycin C with or without Adriamycin, or cisplatinum with mitomycin C with or without 5-FU. The overall response rat was 75 percent of those receiving radiotherapy and 53 percent of those with chemotherapy only. The best results were with combined cisplatinum, mitomycin C, and 5-FU.
The conference then held a short session on predictive assays in radio-therapy.
Dr. Ono covered in significant detail the use of the micronucleus assay and compared it with the agar assay for clonogenic survival. He found a good correlation in determining alpha-beta ratios. He feels that the micronucleus assay with cyt-B could rapidly discriminate between radio-resistant and radiosensitive tumor cells and primary cultures and also predict normal tissue response.
Dr. Chapman first reviewed the various potential predictors of natural history and treatment response which include intrinsic cell sensitivity, proliferation kinetics, ploidy, surface antigens, proto-oncogene expression, oxygen and heat regulated proteins, oxygen level, pH, and a number of other factors. He mentioned that the micronucleus assay may be used to predict clonogenic cell survival in view of its relative simplicity compared to the agar clonogenic assay. Proliferation assays can be carried out with prelabeling of the tumor with BUdR and calculation of the potential doubling time. Oxygen concentration can be measured with electrodes, indirectly and probably not accurately by NMR spectroscopy and by metabolism of bioreductive compounds with binding such as that seem with nitroimidazoles.
Using tritium labeled nitroimidazoles, Dr. Chapman{s group has found that melanomas and small cell lung cancers have a very high incidence of labeling with bound misonidazole. Sugar-coupled nitroimidazoles such as arabanocides and furanocides can be used to attach 123-iodine to the nitroimidazole or in vivo determination of the presence or absence of chronically hypoxic cells. Finally, he pointed out that oncogenes do, in some cases, predict greater or lesser sensitivity but it is not clear whether they will be predictive enough to replace inherent cell sensitivity measurers by more direct means such as culture or the micronucleus assay.
The Saturday afternoon session of the conference concentrated on particle radiotherapy and subsequently on an update on intraoperative radiation therapy in Japan.
Dr. Castro led off the discussion of particle radiotherapy with a review of the results of particle studies in the U.S. He emphasized, in particular, the results of charged particle treatment. Highlights of the presentation were the very high survival levels seen with the use of helium ion radiotherapy in chordomas, meningiomas, and chondrosarcomas of the base of skull with a 60 percent five-year disease-free survival. Similar disease-free survivals were seen for paraspinous tumors in other sites, sinus and nasopharynx tumors, and circumspinal tumors. He reported extremely high control rates for ocular melanomas in the range of 95 percent. Using high LET charged particles, i.e. neon ions, promising results have been obtained in tumors of the salivary glands, paranasal sinuses, soft tissue sarcomas, bone sarcomas, and prostate with suggestive data in melanoma and renal cell carcinoma There may also be a role for very focal high LET particle treatment in malignant gliomas.
Dr. Mishima then presented interesting information on his clinical trials with boron neutron capture therapy in malignant melanoma. He has been working primarily with p-boronophenylalanine and has shown that in experimental melanomas the tumor to blood ratio is as high as 11 after systemic administration. He has also shown responses of melanoma in the duroc pig after combined treatment with thermal neutrons and p-borono-phenylalanine.
Human trials have been carried out in several patients using peri- and intralesional injections as well as systemic administration and several complete responses have been achieved. Experiments are underway to see what the tumor to blood ratio would be to determine if the treatment would be applicable to more than very superficial lesions that can be easily directly injected.
Dr. Hatanaka then presented his experience with boron neutron capture therapy for gliomas. He has been treating patients since 1968 in Tokyo with several boron compounds and has shown an 18 percent five-year survival in a group of glioma patients of mixed histologies.
The next session concentrated on an update on intraoperative irradiation in Japan. Dr. Todoroki presented on intraoperative irradiation for advanced carcinoma of the biliary tract. A group of 200 patients showed a high rate of local failure. In a subset of 29 patients, IORT was given and 25 percent survival at five years has been observed. The IORT appears to give better survival for primaries of the gall bladder and bile duct and requires 15-20 Gy plus external beam irradiation to at least 40 Gy.
D., Okawa then presented on intraoperative radiotherapy for carcinoma of the pancreas and rectum. Seventy-five patients were treated with pancreatic cancer, 44 with IORT alone and 31 with a combination of IORT and postop external beam irradiation. The median
survival time,was 11 months for curative patients. He also reported on 41 rectal cases, all of which had preoperative irradiation with external beam plus IORT. Long-term survival was 40 percent for Dukes C lesions.
Day 3
On the last day of the conference, the first session concentrated on treatment planning systems and conformational radiotherapy. Dr. Lichter presented his three-dimensional treatment planning system developed at the University of Michigan. He traced the history of radiation oncology as it has developed as an image-based specialty, first with orthogonal X-rays, then two-dimensional CT, and finally, steps to restore the three-dimensional nature of the data. He described an outstanding set of software for using Ct, MRI, and PET data, as well as orthogonal radio-graphs and port films to display tumor and normal anatomy in three dimensions and superimpose upon it isodose distributions. The system allows for multiple conformal fields, optimization of the treatment plan, and evaluation through dose-volume histograms.
Dr. Nagata described the three-dimensional planning system on the Japanese CT simulator by Shumatsu. This unit performs CT scans then projects the selected field of irradiation upon the patient using multiple laser beams. Thus, the digitally reconstructed radiograph is projected onto the patient as if one were doing a primary simulation. Problems remaining include clinical target definition, immobilization and indexing for planning and treatment, and elimination of respiratory motion.
Dr. Tokune then reported on the use of the three-dimensional CT simulator at Keio University. He outlined the reconstruction of digital radiographs and work which is establishing the accuracy of the CT image and the recreated radiograph.
Dr. Lichter then reported in more detail on conformational therapy and the experience at the University of Michigan using their three-dimensional planning system. The use of multiple CT slices allows exact outlining of tumors such as the prostate, creating the possibility of excluding significant amounts of normal tissue and covering completely very convoluted tumor shapes such as a combination of the prostate and the seminal vesicles. He described his ability to deliver higher doses with apparently lower morbidity in prostate cancer using this technique. Although he is currently using 6-8 portals, he feels that conformational therapy will be improved by the use of multileaf collimators with automatic computer control. Faster computers and graphic displays are a necessity. Questions that remain are whether a multileaf collimator will excel over an 8 port set-up with fixed collimators.
Dr. Morita then reported on conformation radiotherapy using various systems. He reviewed the early attempts at mechanical automated con-formal therapy driven by cams and then systems using mechanical rotating blocks. He then reviewed more modern techniques for automating this kind of treatment.
The final session of the meeting concentrated on conservative treatment of breast cancer. Dr. Hiraoka reviewed 45 patients planned on the CT simulator and given irradiation after tylectomy for tumors of 2 cm diameter or less treated by quadrantectomy and axillary dissection. Cobalt 60 was used to deliver 50 Gy in 25 fractions. He discussed the problems m reducing lung irradiation and adequately treating whole breast volume.
Following this interesting presentation, Dr. Kondo reported on the progress in conservative therapy of breast cancer in Japan. Only 1 19 patients had such treatment in 1986 and by 1988, 3 percent of breast cancer was being treated by conservative methods There seems to be a great amount of resistance of Japanese surgeons to use this method. He reported on 167 patients of all stages, who received limited surgery and axillary dissection. His criteria are that the patient must have a tumor size which is not gigantic relative to the breast size and must have clear margins. His technique is to then deliver 50 Gy in 25 fractions without a boost. The results have been as good as surgery with relapse-free survival 81 percent for all stages treated. A major problem remains that the majority of women in Japan receive a classic Halsted radical mastectomy rather than more conservative therapy, particularly tylectomy and radiation.
MEETING SUMMARY
The meeting was summarized by Dr. Phillips and Dr. Abe. They agreed that a number of important areas had emerged from the exchange of information. Particular projects which could be conducted and achieved by the US-Japan group are as follows:
1. The development of better hyperthermia equipment and heating techniques.
2. The discovery and clinical testing of new radiation modifying chemicals and biologicals.
3. The development of predictive tumor assays and their evaluation.
4. The evaluation of charged particle radiotherapy with coordination between Lawrence Berkeley Laboratory, Massachusetts General Hospital, Loma Linda, and the facilities in Japan at SCUBA and at NIRS.
5. The perfection of three-dimensional treatment planning and conformal therapy.

(3) Seminar on “New Drugs Under Development“
Volcano House, Hawaii, February 19-20, 1990
Dr. Ogawa presented new data on Anthracyclines in Japan. Three compounds are of interest. SM-5887 is in Phase II trials and appears to have superior activity to Adriamcyin and less cardiotoxicity. Leukopenia and thrombocytopenia were dose limiting. Activity was seen in NHL, breast and sarcoma, but not in gastric or NSCLC. This lack of superior activity was disappointing, but daily x 5 studies are ongoing. MX2 is another anthracycline which is active in P388/DCR cells. Leukopenia was dose limiting (12 mg/m2/dx3 q3-4 weeks). For single dose (40 mg/m2) DLT was leukopenia and nausea. ME2303 is another anthracycline with superior L1210 activity; a Phase I trial is ongoing.
Dr. Sikic presented data on Cyanomopholino-adriamycin (MRA-CN). Of interest because of intense potency, non-cross resistance, and targeted alkylation. No change in therapeutic ratio was detected. The lack of cross resistance may be due to: lipohilicity, decreased affinity for P-glycoprotein or rapid induction of injury (so that P-glycoprotein cannot detoxify). MRA-CN is retained intracellularly and is bound to DNA covalently. There is a weak interaction between MRA-CN and P Glycoprotein. In an elegant series of experiments he has dissected the various drug resistance patterns. MRA is activated by microsomes (more than MX-2).
Dr. Curt then reviewed the intramural NCI program for ---- Phase I-II activities. His report is attached.
Dr. Ota presented data on Platinum analogs under study in Japan. Two compounds of interest are 254S and DWA 2114R. Little nephrotoxicity is observed, but myelotoxicity is seen with 254S. Phase I studies have been completed for both (100 mg/m2 for 254S and 800 mg/m2 for DWA). There is less binding to protein than CisPt. Similar response rates have been noted in testis, ovary, and bladder cancer. DWA and 254S may be superior for prostate cancer. Likewise the toxicity profiles looked remarkably similar.
Dr. Taguchi presented data on a camptothecin analog CPT-11. The Phase I studies were begun in 1986 with DLT being neutropenia (nadir at 1 week with recovery by 3 weeks). Mild alopecia and gastrointestinal side effects were evident. A dosage of 200 mg/m2 was chosen for the Phase II dose.

Diseases Studied Patients Enrolled
Lung 52
GI 70
Breast 29
H&N 15

Most lung patients were NSC and with prior therapy and an overall 20% PR rate was noted, Iasting only I month duration. Responses were noted in ovarian and cervical cancers, in breast, gastric, and colon cancer patients. For the hematologic malignancies a total of 71 patients were treated. For acute leukemias only I ALL responded but responses were seen in NHL and HD.
A second drug, an ellipticine compound (SUN 4599) was developed by Suntory. It is a Topo II inhibitor. More active than Ellipticine or Elliptinium in L1210 and P388, it is active in B16 and Colon 38. DLT was hypotension and tachycardia. Creatinine clearance and proteinuria was noted as well as LFT abnormalities. Evaluation is ongoing.
Dr. Beck described non-P Glycoprotein mechanisms of MDR. Atypical MDR had affected the cytotoxicity of many natural products (not Vinca), no change in drug accumulation, no change in Pgp and MDR gene. Many drugs affect Topo II-AMSA, Dox, VP-16, Mitoxantrone, Ellipticine, Amonafide, and Fostreicin. He has demonstrated 2 means of epipodophylotoxin resistance -- Pgp and Topo II. Atypical MDR can be modulated by HN2. VU, CN MRA but not by verapamil or chloroquinone. Further studies will be needed to characterize the clinical spectrum.
Dr. Ando then discussed Topo I resistance and Camptothecin resistance. Topo I does not require ATP and causes single strand-DNA interactions. Resistant cells have been isolated in which 2 single point mutations in the central conserved region substitute a single amino acid. These regions are likely important to cleavage strand passage. There appears to be no structural DNA abnormality in either Northern or Southern blots. Topostin is a new Topo I inhibitor which may affect resistance. Mutated Topo I may be the major cause of CPT resistance. Topo II drugs may be a useful means of circumventing Topo I resistance. Clinical studies will be planned.
Dr. Dalton described methods of overcoming drug resistance in myeloma. He has correlated P170 with Dox resistance and the MRK-16 Ab seems to be an excellent probe. In untreated patients about 96% are Pgp negative; however if treated with Vcr or Dox nearly half demonstrate resistance. Patients were treated with VAD + Verapamil; 22 patients were treated and 5 had a clinical response (of short duration). New studies will be used to examine R-verapamil (1/5 cardiotoxicity of L verapamil). Quinine + R-verapamil may also be tested, as well as cyclosporin. A cell line resistant to Dox + Verapamil was resistant to VP16, CDDP, and L-PAM but not to Vinca. Three other cell lines resistant to Mitoxantrone had no increase in Pgp.
Dr. Shimoyama described studies to MoAb directed against MDR cells. Both MRK16 and MRK20 have some potential to predict clinical sensitivity.
Dr. Kuwano described methods of circumventing MDR drug resistance. Common properties of MDR reversal include high affinity for P170, cationic and amphipathic, lysosomaltrophic but not necessarily Ca2 channel blockers. Two synthetic isoprenoids can potentiate Bleo and Adriamycin. Both in vitro and in vivo studies support this effect. Other compounds of interest are the dihydropyridines. Even in non MDR experiments there was increase in survival (even in sensitive tumor lines). He also has examined MDR gene manipulation for both MDR gene amplification or message increase. He constructed synthetic oligonucleotides that will be tested.
Dr. Ozols described GSH interaction-free radical destruction and binding to electrophilic agents. BSO is capable of decreasing GSH and potentiates CDDP and L-PAM effects. BSO makes CDDP and Nitrosoureas more nephrotoxic! But it helps potentiate CBDCA and L-PAM. Aphidicolin also potentiates CDDP. A Phase I trials of BSO + LPAM is ongoing. Studies of Ethacrinic acid to inhibit GST; aphidicolin to inhibit DNA polymerase, and inactivation of O6-alkylaguanine transferase in MER + tumors (chlorozotocin followed by BCNU) may provide useful clues. Proposed studies include evaluation of the following:

Study Probes
GSH DNA Polymerase a, b
GSTransferase ERCC1, ERCC2
GST isozyme patterns GST MRNA
Metallothiornine
MDR-1
Her-2/neu

Dr. Tsuruo presented the final paper on General Strategies of Drug Resistance. He stressed the need to develop new agents of higher specificity and efficacy. Pgp is a type of ATPase and can be manipulated. He has chimeric antibody MRK-16 which has ADCC activity. Testing will be carried out at NCI. Another possible target is CP22 which is important Ca2 channel regulators ways of circumventing MDR are rhizoxin derivatives, ME2303 and MX-2, CP-11.
This conference successfully integrated clinical and preclinical drug development topics.


SEMINAR AGENDA AND PARTICIPANTS

(1) SEMINAR ON “RESEARCH DIRECTIONS OF NEW BRM AND COMBINATION TREATMENT”
Holiday Inn, Union Square, San Francisco, November 13-14, 1989

AGENDA
ORGANIZERS:
Dr. Michael Friedam
Dr. Makoto Ogawa

November 13 (Monday)
8:55 A.M. Welcome Remarks Drs. M. Friedman and
M. Ogawa
Session I Growth Factors and Chemotherapy
Chairperson: Dr. M. Ogawa
9:00-9:30 Phase I-II Study of rhG-CSF in Chemotherapy for Lung Cancer Dr. N. Saijo
9:30-10:00 CSF plus Chemotherapy Dr. W. Peters
10:00-10:30 Discussion/Coffee Break
10:30-11:00 Phase I-II Study of rhG-CSF in Malignant Lymphoma and Solid Tumors Dr. M. Ogawa
11:00-11:30 Overview of CSF Trial in U.S.A. Dr. M. Friedman
11:30-12:00 Discussion
12:00-1:00 LUNCH
Chairperson: Dr. M. Friedman
1:00-1:30 CSF's in BMT Dr. F. Appelbaum
1:30-2:00 Phase I-II Study of rhG-CSF in BMT Dr. T. Masaoka
2:00-2:30 Discussion/Coffee Break
2:30-3:00 rhG-CSF on Hematologic Disorders Dr. H. Mizoguchi
3:00-3:30 Discussion
Session II Cytokines and Chemotherapy
Chairperson: Dr. D. Levitt
4:00-4:30 Interferons and Cytotoxic Drugs Dr. K. Ezaki
4:30-5:00 Interferon Plus 5-FU Dr. S. Wadler
5:00-5:30 Discussion
5:30 ADJOURN

November 14 (Tuesday)
Chairperson: Dr. K. Ezaki
9:00-9:30 LAK plus IL2 Dr. Y. Kimoto
9:30-10:00 IL2 Plus Other Agents Dr. W. Urba
10:00-10:30 Discussion/Coffee Break
10:30-11:00 Interferon-B Plus IL2 Dr. N. Saijo
11:00-11:30 Interferon-a Plus IL2 Dr. D. Levitt
11:30-12:00 Discussion
12:00-1:00 LUNCH
Session III New Directions of Investigation
Chairperson: Dr. W. Urba
1:00-1:30 Interleukin-I Study Dr. F. Takaku
1:30-2:00 Discussion/Coffee Break
2:00-2:30 Some Topics in Cytokine Studies Dr. M. Ogawa
2:30-3:00 Levamisole Plus 5-FU Dr: M. Friedman
3:00-3:30 Discussion
4:00 Closing Remarks Drs. M. Friedman and
M. Ogawa


PARTICIPANTS

JAPAN
Dr. Makoto Ogawa
Cancer Chemotherapy Center
Kami-ikebukuro, Toshima-ku, Tokyo 170

Dr. Fumimaro Takaku
Tokyo University, Hongo Bunkyo-ku, Tokyo 113

Dr. Hideaki Mizoguchi
Tokyo Women's Medical College
Hirakawa-cho, Shinjuku-ku, Tokyo 162

Dr. Toru Masaoka Osaka Adult Medical Center
Nakamichi Higashinari-ku Osaka 537

Dr. Nagahiro Saijo
National Cancer Center, Tsukiji Chuo-ku Tokyo 140

Dr. Yasuhiko Kimoto
Research Institute for Microbial Disease
Osaka University, Yamadaoka Suita-shi Osaka 565

Dr, Kohji Ezaki
Fujita-Gakuen Health University
School of Medicine Dengakugakubo, Kutsukake-cho
Toyoake-shi Aichi 470-11

UNITED STATES

Dr. Frederick R. Appelbaum
Fred Hutchinson Cancer Research Center
1124 Columbia Street, Room 318 Seattle WA 98104

Dr. Scott Wadler
Department of Oncology
NW 460 Montefiore Medical Center
Bronx, New York 10467

Dr. Michael A. Friedman
Cancer Therapy Evaluation Program
National Cancer Institute, Executive Plaza
North Room 742 Bethesda, Maryland 20892

Dr. Daniel Levitt
Hoffman-LaRoshe Nutley, New Jersey 07110

Dr. William P. Peters
Bone Marrow Transplantation Unit Duke University
Medical Center, Box 3961 Durham, NC 27710

Walter J. Urba
Clinical Services Program Resources, Inc.
National Cancer Institute, Frederick Cancer Research Facility
Building 560, Room 11-62 Frederick, MD 21701



(2) SEMINAR ON “FRONTIERS OF RADIOTHERAPY AND THE COMBINED MODALITIES”
Park Hotel, Kyoto, March 16-18, 1990

AGENDA

ORGANIZERS:
Dr. Theodore Phillips
Dr. Mitsuyuki Abe
FRIDAY - MARCH 16
8:45-9:00 INTRODUCTION: Drs. Phillips and Abe
Hyperthermia:Physical, Biological, and Clinical Aspects
Moderators: Drs. Cetas and Egawa
9:00-9:45 Ferromagnetic seed hyperthermia Dr. Cetas
9:25-9:50 Clinical results of thermoradiotherapy for carcinoma of the breast and the urinary bladder Dr. Masunaga
9:50-10:15 Interstitial hyperthermia for CNS tumors Dr. Phillips
10:15-10:30 Break
10:30-10:55 Present status and prospect for clinical applications of noninvasive temperature measurements Dr. Mishima
10:55-11:20 Noninvasive ultrasonic thermometry Dr. Egawa
11:20-11:45 Treatment planning for hyperthermia Dr. Cetas
11:45-12:05 Drug delivery system using temperature sensitive large liposomes in combination with localized hyperthermia Dr. Nishimura
12:05-12:25 Concomitant therapy with cisplatinum-containing heat-sensitive liposomes and local hyperthermia Dr. Tanaka
12:25-12:35 Discussion
12:35-2:00 Lunch
Modifiers of Biological Effects of Radiation; Sensitizers and CSF
Moderators: Drs. Wasserman and Mori
2:00-2:25 Update on the U.S. sensitizer progr Dr. Wasserman
2:25-2:50 Update on sensitizer studies in Japan Dr. Maori
2:50-3:15 Fluorine-modified nitroimidazole KU2285: Characteristics of pharmacology and radiosensitizing activity in vivo Dr. Kagiya
3:15-3:40 Fundamental and phase I clinical studies of new hypoxic radiosensitizer RK-28 Dr. Sakamoto
3:40-3:55 Break
3:55-4:20 Curative treatment of photon-resistant rat prostate carcinomas by interstitial photodynamic therapy Dr. Chapman
4:20-4:45 Colony stimulating factors - The U.S. experience Dr. Friedman
4:45-5:10 Colony stimulating factors- The Japanese experience Dr. Ogawa
5:10-5:35 Clinical effects of recombinant human granulocyte colony stimulating factors on neutropenia induced by radiation Dr. Fushiki
5:35-5:45 Discussion
6:00 Reception at Park Hotel

SATURDAY -MARCH 17
Radiotherapy in combination with chemotherapy
Moderators: Drs. Friedman and Ogawa
9:00-9:25 Radiotherapy with chemotherapy in the treatment of lung cancer Dr. Friedman
9:25-9:50 Chemotherapy combined with radiotherapy for small cell lung cancer Dr. Kimura
9:50-10:15 Clinical evaluation of intra-arterial infusion chemotherapy with or without radiation Dr. Okawa
10:15-10:25 Discussion
10:25-10:45 Break
Predictive Analysis
Moderators: Drs. Chapman and Sakamoto
10:40-11:05 Predictive analysis in radiotherapy Dr. Ono
11:05-11:30 The relative importance of various predictive assays in determining radiation treatment outcome Dr. Chapman
11:30-11:40 Discussion
11:40-1:20 Lunch
Particle Analysis
Moderators: Drs. Castro and Tsunemoto
1:20-1:45 The results of particle studies in the United States Dr. Castrao
1:45-2:10 The results of particle studies in Japan Dr. Tsunemoto
2:10-2:35 The results of proton therapy in Tsukuba Dr. Tsuji
2:35-3:00 Treatment planning problems in particle therapy Dr. Castro
3:00-3:25 New thermal neutron capture therapy for malignant melanoma using melanogenesis seeking 10B compound Dr. Mishima
3:25-3:50 History and present status of boron neutron capture therapy for brain tumors and bone and liver cancers Dr. Hatanaka
3:50-4:05 Discussion
4:05-4:15 Break
Uodate on Intraoperative Radiation Therapy
Moderator: Dr. Abe
4:15-4:40 Intraoperative radiation therapy for advanced carcinoma of the biliary tract Dr. Todoroki
4:40-5:05 Intraoperative radiotherapy for carcinoma of the pancreas and rectum Dr. Okawa
5:05-5: 15 Discussion

SUNDAY - MARCH 18
Treatment Planning System and Conformational Radiotherapy
Moderators: Drs. Lichter and Morita
8:30-8:55 Three-dimensional planning system Dr. Lichter
8:55-9:20 Three-dimensional system-The CT simulator Dr. Nagata
9:20-9:45 Three-dimensional planning using CT simulator Dr. Tokune
9:45-10:10 Conformational therapy Dr. Lichter
10:10-10:35 Conformational radiotherapy Dr. Morita
10:35-10:45 Discussion
10:45-11:00 Break
Conservative Treatment of Breast Cancer
Moderators: Drs. Phillips and Takahashi
11:00-11:25 Conservative treatment for early breast cancer: Use of CT simulator in radio-therapy treatment planning Dr. Hiraoka
11:25-11:50 A Japanese experience of breast conservation therapy Dr. Kondo
11:50-12:00 Discussion
12:00-12:10 Meeting Summary Drs. Phillips and Abe

PARTICIPANTS

JAPAN
Mitsuyuki Abe, M.D.
Professor and Chairman
Department of Radiology
Faculty of Medicine
Kyoto University
606 Kyoto

Sunao Egawa, M.D.
Chief, Department of Radiation Therapy
National Cancer Center Hospital
104 Tokyo

Ikuo Kimura, M.D.
Department of Internal Medicine
Faculty of Medicine, Okayama University
700 Okayama

Yutaka Mishima, M.D.
Department of Dermatology
School of Medicine
Kobe University 650 Kobe

Makoto Ogawa, M.D.
Head, Cancer Chemotherapy Center
Japanese Foundation for Cancer Research
170 Tokyo

Kiyohiko Sakamoto, M.D.
Department of Radiology
Faculty of Medicine, Tohoku University
980 Sendai

Hiroshi Tsunemoto, M.D.
Derector, National Institute of Radiological Sciences
260 Chiba

Japanese Speakers
Masato Fushiki, M.D.
Department of Radiology
Faculty of Medicine
Kyoto University, 606 Kyoto

Hiroshi Hatanaka, M.D.
Department of Neurosurgery
Teikyo University Medical School
173 Tokyo

Masahiro Hiraoka, M.D.
Department of Radiology
Faculty of Medicine
Kyoto University, 606 Kyoto

Tsutomu Kagiya, Ph.D.
Department of Hydrocarbon Chemistry
Faculty of Engineering
Kyoto University, 606 Kyoto

Makoto Kondo, M.D.
Department of Radiology
Medical School of Keio University
160 Tokyo

Shin-ichiro Masunaga, M.D.
Department of Radiology
Faculty of Medicine
Kyoto University, 606 Kyoto

Shizuo Mizushina, Ph.D.
Research Institute of Electronic
Shizuoka University
Graduate School of Electronic Science and Technology, 432 Hamamatsu

Tomoyuki Mori
Department of Radiation Oncology
Tokai University School of Medicine
259-1 1, Isehara

Kozo Morita, M.D.
Chief, Department of Radiation Therapy
Aichi Cancer Center
464 Nagoya

Yasushi Nagata, M.D.
Department of Radiology
Faculty of Medicine
Kyoto University 606 Kyoto

Yasumasa Nishimura, M.D.
Department of Radiology
Faculty of Medicine Kyoto University, 606 Kyoto

Tomohiko Okawa, M.D.
Division of Clinical Oncology
Department of Radiology
Tokyo Women’s Medical College 162 Tokyo

Koji Ono, M.D.
Department of Radiology
Faculty of Medicine
Kyoto University, 606 Kyoto

Yoshimasa Tanaka, M.D.
Chairman, Department of Radiology
Kansai Medical University, 570 Osaka

Takashi Tokoroki, M.D.
Department of Surgery
Institute of Clinical Medicine
University of Tsukuba, 305 Ibaraki

Koichi Tokuue, M.D.
Department of Radiology
National Tochigi Hospital 320 Utsunomiya

Hirohiko Tsujii, M.D.
The Particle Radiation Medical Science Center
University of Tsukuba, 305 Ibaraki

UNITED STATES

Theodore L. Phillips, M.D.
Department of Radiation Oncology
University of California Long Hospital
Room L75 San Francisco
California 94143-0226

Allan S. Lichter, M.D.
Department of Radiation Oncology
University of Michigan Medical Center
Room B2C490, Box 0010
Ann Arbor, Michigan 48109

Todd H. Wasserman, M.D.
Mallinckrodt Institute of Radiology
510 South Kingshighway Blvd.
St Louis, Missouri 631 10

Joseph Castro, M.D.
Department of Radiation Oncology
Lawrence Berkeley Laboratory
Bldg. 55, Room 121, Berkeley, California 94720

Thomas C. Cetas, Ph.D.
Department of Radiation Oncology
University of Arizona
Health Science Center Tucson, Arizona 85724

J. Donald Chapman, Ph.D.
Department of Radiation Oncology
Cross Cancer Institute
11560 University Avenue Edmonton, AB T6G 1Z2
Canada

Michael A. Friedman, M.D.
Associate Director for Cancer Therapy Evaluation Program, National Cancer Institute
Executive Plaza North Room 742
Bethesda Maryland 20892



(3) SEMINAR ON “NEW DRUGS UNDER DEVELOPMENT”
Volcano House, Hawaii, February 19-20, 1990

AGENDA
February 19
8:55 Opening Remarks Drs. M. Friedman and
M. Ogawa
Session I-New Drug Under Development
Chairperson: Dr. M. Ogawa
9:00-9:45 Phase I NCI Sponsored Trials Dr. M. Friedman
10:00-10:45 New Anthracyclines Dr. M. Ogawa
10:45-11:30 New Anthracyclines Dr. B. Sikic
11:30-12:00 Discussion
12:00-1:00 LUNCH
Chairperson: Dr. M. Friedman
1:00-1:30 Phase I-II Activities in the Clinical Center Dr. G. Curt
1:45-2:30 New Cisplatins Dr. K. Ota
2:30-3:15 CPT-II and Other Drugs Dr. T. Taguchi
3:15-3:45 Discussion
Session II Circumvention of Drug Resistance
Chairperson: Dr. T. Tsuruo
3:45-3:50 Drug Resistance Association with Topoisomerase Dr. W. Beck
4:30-5:15 Clinical Potential of Topoisomerase Inhibitors Camptotecin resistance and its circumvention Dr. T. Andoh
5:15-5:45 Discussion
5:45 Adjourn

February 20
Session II Circumvention of Drug Resistance
Chairperson: Dr. B, Sikic
9:00-9:45 Overcoming Resistance in Myeloma Dr. W. Dalton
9:45-10:30 Detection of MDR Cancer Cells by Monoclonal Antibody Dr. M. Shimoyama
10:30-11:00 Discussion
11:00-11:45 Circumvention of Drug Resistance Dr. M. Kuwano
12:00-1:00 Lunch
Chairperson: Dr. G. Curt
1:00-2:15 BSO/L-PAM and PALA/5-FU Dr. R Ozols
2:15-3:00 Perspective of Drug Resistance Research Dr. T. Tsuruo
3:00-4:00 General Discussion of Drug Resistance
4:00 Closing Remarks Drs. M. Friedman and
M. Ogawa
4:15 Adjourn


PARTICIPANTS

JAPAN

Dr. Makoto Ogawa
Cancer Chemotherapy Center
Kamiikebukuro, Toshima-ku Tokyo 170

Dr. Takashi Tsuruo Tokyo University
Yayoi 1-1-1, Bunkyo-ku, Tokyo 140

Dr. Kazuo Ota
Nagoya Memorial Hospital
Hirabari 4-305, Tenpaku, Nagoya 468

Dr. Tesuo Taguchi
Research institute for Microbial Disease
Osaka University, Yamadaoka
Suita-ku, Osaka 565

Dr. Toshio Ando Aichi Cancer Center
Kakoden 1-1, Chigusa-ku
Nagoya 464

Dr. Masanori Shimoyama
National Cancer Center Tsukiji
5-1-1 Chuo-ku Tokyo 140

Dr. Michihiko Kuwano
Medical College of Oita
Idaigaoka 1-1506
Hazama-cho Oita-gun Oita 879-56

UNITED STATES

Robert Ozols, M.D.
Chairman, Department of Medical Oncology
Fox Chase Cancer Center, 7701 Burholme Avenue
Philadelphia. Pennsylvania 19111

Warren Ross, M.D.
Dean’s Office, University of Florida
College of Medicine, Box J-215, J.H. Miller Health Center
Gainesville, Florida 32610

Branimir I. Sikic, M.D.
Division of Oncology M-211
Stanford University Medical Center
Stanford, California 94305

William Dalton, M.D.
University of Arizona Cancer Center
Tucson, Arizona 85724

Greg Curt, M.D.
Associate Director, Clinical Oncology Program
National Cancer Institute
Bethesda, Maryland 20892

Michael Friedman, M.D.
Associate Director, Cancer Therapy Evaluation Program
National Cancer Institute, Executive Plaza
North Bethesda, Maryland 20892