REPORTS ON SEMINARS

(1) Seminar on “Lung Cancer: Recent Treatment Strategies”
Okayama, Japan - November 12-13, 1990

The first FY 1991 bilateral meeting for Therapy occurred in Okayama on November 12 and 13, 1990. Opening remarks were presented by Drs. Kimura and Friedman who both noted the auspicious timing of this symposium to concur with the investiture of the Emperor.
The first session was devoted to Neoadjuvant Chemotherapy for NSCLC. Dr. Nishiwaki described his experience with neoadjuvant therapy utilizing CDDP (80 mg/m²) + Vindesine 3mg/m²) + Mitomycin C (8 mg/m²) q 3-4 weeks. Overall 43% PR, 8.5 months MST and 16% two year survival was noted for Stage III patients. Usually 23% of stage III patients survive five years with surgery alone. Patients for this protocol had resectable N₂ disease. Thirty-one patients entered the study receiving up to 2 cycles of CT and 28 were operated upon. Eighteen of 28 had CR or PR and 12 had No-1, 15 N₂ (pathologically documented). Only one preoperative death was noted and the survivorship appeared to be superior (but not specifically proven). This technique is both feasible and encouraging.
Dr. Green described sequential CT and RT for Stage III A or B NSCLC. Radiation alone results in a 25-30% PR rate (60 Gy) and eight months MST and 30% alive at one year. The background of CT (Pasemans, ASCO 1990) revealed that limited disease patients respond more often than those with extensive disease. Most combination CT which include CDDP give 40-90% response rates. He described CALGB study 8433 which compared RT to VLB + CDDP ---- > RT in good risk patients with regional disease. Overall survival was 11.1 months, RT = 9.7 mo. and 13.8 months for CT --- RT, in 156 randomized cases with a 27 month median F/U. Moreover, the survival is doubled for CT --- RT (24% vs. 11% at 36 mo.) A confirmatory trial is being carried out by RTOG + ECOG. The CALGB study 8831 compares CT -- RT --- CT or CT --- RT + CBDCA and the overall MST ~ 14 months. However the later CT is poorly tolerated. A series of studies will continue to examine these issues.
Dr. Hara described the Japanese experience with surgical adjuvant therapy. Utilizing CDDP based program, 96 patients were randomized (48 control and 48 CT). Three different CT were sequentially employed. Overall there was no survival difference between the two groups (likewise DFS). Recently five randomized trials were reported in Japan -- all included Stage I-III with many CT programs. The value of post-operative adjuvant CT is inconclusive.
Dr. Cox discussed a variety of issues that effect NSCLC strategies. Recognizing the different radiation schemes, hypofractionation results in only 5% complete local control rate. Hence, local control is essential. It may be that accelerated repopulation may occur after RT or CT (included clonigens). The use of 60 Gy RT conventionally administered results in 40%, 18, 13, and 7% survival at 1, 2, 3, and 5 years. Hyperfractionation overcomes accelerated repopulation (Fx =.7 to 1.3 Gy bid) theoretically. The better risk patient population fared better with higher total dose RT. He suggested that either CT or RT may result in accelerated tumor regrowth (more rapid failure and demise).
The value of CHART (Continuous Hyperfractionated Accelerated Radiation Therapy) or surgery or simultaneous CT + RT on this phenomena needs to be assessed.
Dr. Ogawa presented pilot data on two trials. The first utilized CDDP + VLB + ADRIA and 14 patients were evaluated (six with prior CT). PR was noted in two with overall MST + 13.5 months. The second study included Ifo + CDDP + VDS and was based on a pilot study in which 13/21 PR's were noted (MST = 41 + weeks). An additional 22 patients were evaluated and one CR and seven PR observed. This combination seems active and reasonably tolerable.
A randomized study of CDDP + VDS vs. CDDP + VDS + Ifos was discussed by Dr. Ohnoshi. An initial pilot study of the three drugs revealed a 60% response rate and MST = 10.2 months for 26 patients. In the randomized study a total of 90 patients have been randomized to date The VP is better tolerated and no significant difference in outcome has been observed.
Dr. Friedman outlined strategies for identifying new active agents. Two different approaches were described -- random screening and selective attack on known biochemical targets. Both will be pursued.
Dr. Fukuoka described a Phase III trial of CDDP (80 mg/m²) vs. CDDP + VDS (3 mg/m²). A total of 160 patients were randomized and 12% had PR with CDDP vs. 29% with CDDP + VDS. Response duration and survival were similar for both groups. He concluded that better combinations are required. Another randomized trial compared VP vs. MVP vs. EP/VM in 203 patients. The response rate was 33% for VP 43% for MVP and 19% for EP/VM but only two CR were noted. The MDR was 16-19 weeks; MST between 40 and 50 weeks. Prognostic features of note included PS, sex, stage, and weight loss
A discussion of selection and treatment outcome factors was led by Dr. Cox. In US studies, the prognostic value of performance status, extent of disease, weight loss, lymphocyte count, and bone pain has been documented. He described distinctions between AJCC and other staging systems which could explain the observed survival differences of specific studies.
Dr. Kawahara next shared data on his Phase II study of concurrent CT and RT. A total of 60 patients received MVP with RT (2 Gy/d) in a split course fashion to total of 50 to 60 Gy. Data on 38 evaluable patienis was presented; 35/38 had PR with MDR = 200 days +. Leukopenia was dose limiting in most patients and 2/38 had treatment related death. Treatment delays and dose reductions occurred.
A presentation on pathologic evaluation of variant histologies of SCLC was made by Dr. S. Aisner. Data were presented from ECOG study 1582 which examined the variant histology. Of all cases, 526 were classic SCLC and 11 ± 13 were variant (2 ± 2%). No impact on survival or time to failure was noted for the variant histology. A further data set on ongoing trials is being developed (including three NSC and three SCLC trials from ECOG, SWOG, and RTOG).
There is considerable difficulty in diagnosing NSCLC histologies. Moreover, many markers (with the exception of Bombasin) were present in both SC and NSCLC types.
A presentation by Dr. Kimura on combined RT and CT for SCLC was of interest. The combination of COMP + VAN + TRT was apparently superior to CT alone with 15 months MST and 30% alive at two years. He suggested that RT (50 Gy) should follow CT and that PCI diminished the rate of CNS metastases.
Dr. Turrisi discussed his data with a novel combination of RT and CT integration. Despite the fact that CT doses were reduced with RT, the immediate combination of CT + RT resulted in superior survival compared to CT alone. In a pilot study he gave VP-16 + CDDP x 2 with BID RT to chest and six cycles of alternating CT and PCI conclusion. Of 32 patients evaluated serious hematologic toxicity occurred in 75% (as well as esophagitis). Overall, MST = 23 months with 36 month follow ups and 17 Mo. DFS. Overall 40% survival was noted. A second pilot study of 40 patients achieved an 80% CR with similar toxicity, but 10% toxic deaths due to pneumonitis. Overall survival and DFS were similar. Four series of VP + CDDP + RT show similar local control rates. A major Phase III trial testing BID RT is ongoing.
Dr. Saijo presented two studies of the Japanese Lung Cancer CT Group. In patients who fail prior CT, the combination of VP-16 + CDDP is effective. The study can be summaried as:

CAV is statistically inferior response rate and worse leukopenia. For limited disease patients CAV/PE is slightly superior (subset analysis). No differences were noted in extensive disease. A pilot of simultaneous RT + CT was also presented in which P + E + TRT (40 Gy) was delivered to limited disease patients. A total of 60 evaluable cases have been treated -- 16 CR and 33 PR in 50 completed cases has been noted. Survival data are incomplete.
Dr. J. Aisner then presented data on drug development issues with relation to SCLC. There are many active agents already and the question arises as to how to identify new active agents. He pointed out the methodologic problems associated with new agent testing in extensive disease patients. The critical issues include good performance status patients and to employ optimal PK and PD. For example, five daily doses of V-16 is superior to 24 hour infusion. Hence interest in daily oral VP-16 is appropriate. For patients who have a late recurrence, new agents may be tested; or, alternatively new agents may be tested as 1st therapy for a fixed evaluation period.
The conference was an outstanding exchange of information and new direction for future research defined.

(2) Seminar on “New Cancer Drugs and Antimetastatic Drugs”
Hilo, Hawaii, February 9-10, 1991

This meeting took place in Hilo, Hawaii on February 9 and 10, 1991. The general topic was new therapeutic approaches and systemic agents. The first speaker, Dr. Taniguchi discussed his studies of genes related to cancer metastases. Studies of low and high metastatic potential cell lines were conducted. He identified an actin isoform by examining highly metastatic B16 subline (Ax Actin). The cDNA for Ax Actin was cloned successfully, and is one of the B Actin family (hence the new name (3M Actin). He also successfully prepared an antibody to BM Actin. He believes that BM Actin increases Actin stress fibers and decrease invasive activity (metastasis). He then described a set of experiments with V-fos oncogene transfection. These transfected cells were more highly metastatic -- no difference in matrix attachment was noted, but there was increase in matrix dissolution (procathepsin) and increase in cell motivity.
Dr. Yokota then described the genetic alterations associated with malignant progression. He described an association between chromosome 16 and various HCC (positively related to poor differentiation, tumor size, and metastases). Allelic loss is a frequent event for colon and lung cancer (and higher still in metastatic sites when compared to primary). He believes that p53 loss is an earlier event than DCC changes in colon cancer. But probably both are important. In SCC losses include 3p 14-24, 13q 12-22 (RB), 17 P13 (p53) alterations. He proposed that 3p loss is crucial to both SC and NSCLC.
Dr. Ven Narayanan discussed the search natural products with anti-HIV properties. By identifying biological targets of opportunity, a large number of candidates can be screened. Compounds are selected based upon biologic and chemical criteria and computer modeling. More than 10,000 molecules have been screened and a large number have been identified as possessing potential activity.
Dr. Tsuruo presented his studies on the interaction between cancer metastasis and platelets. By selecting subclones of colon 26 tumors, he identified the relationship between metastatic ability and platelet aggregation factor. He developed a series of MoAbs directed against platelet aggregation and these Ab's also diminished metastases. He is not able to test human tumors at this time.
Dr. Yamori discussed the relationship of growth factors and metastases. He studied several aspects of the metastatic process -- detachment, invasion, intravasation, arrest-lodgement, extravasation and proliferation. In his colon 26 system, IGF-1 appears to be an important stimulant to metastatic process. The highly metastatic lines have more IGF receptors. This may be an exploitable feature.
Dr. Narayanan discussed the status of the in vivo system in the Developmental Therapeutics Program. To date some 8,000 compounds and 5,000 natural products have been screened. Approximately 60 human cell lines have been utilized. About 80-85% of compounds screened are quickly rejected because of lack of evidence of inhibition. He also described the mechanics of the screening system and the COMPARE system. Several new leads were discussed including an elliptinium analogue, and a Japanese discreet antibiotic compound.
Dr. Seto usefully summarized the status of new Japanese antibiotics. Rhizoxin is an antibiotic that inhibits tubulin metabolism. A large series of derivatives were studied. He also described an EGF antagonist (Epiderstatin) derived from a Streptomyces species. It is structurally similar to cycloheximide. Unfortunately, this agent is in short supply. Lastly, he described studies with Lavanducyanin, an agent which stimulates certain T cells.
Dr. Von Hoff presented data on a Topioisomerase I inhibitor, Topotecan, a semisynthetic analog of Camptothecin. It has wide preclinical activity and is apparently unaffected by MDR. In colon cancer, the level of Topo I may be 16 fold higher than normal gut mucosa. There ma b y e more activity in leukemias and lymphomas -- yet untested. In vitro cloning studies indicate activity in ovary, renal, colon, and breast cancer. Phase I studies are being performed utilizing a 30 minute infusion q 3 weeks. Leukopenia has been noted, as well as mild fever, rash, nausea, diarrhea. The leukopenia is unpredictable. The pharmacokinetics have been performed in 13 patients and half life is relatively short (2-4 hours) and there is considerable variability in renal excretion (20-50% at 24 hours).
Dr. Taguchi presented his data with CPT-11, another analog of Camptothecin. This agent has been utilized in Japan in a number of Phase II studies. Three schedules were utilized 100 mg/m²/wk, 150 mg/m²/qow and 300 mg/m²/q3 weeks.
Activity was noted in 7138 lung, 4/33 breast, and 5/20 ovary cancer patients. Leukopenia was most frequent toxicity.

For 18 evaluable renal cell cancer patients no responses were seen. For hematologic malignancy patients, a daily x 3 or 8 day (bid) schedule was employed. Twenty-three lymphoma and 9 leukemia patients were treated and 35% and 0% responded, respectively. For lung cancer, SCLC had 36% response rate, but for NSCLC only previously untreated patients responded. For patients with ovarian and cervical cancer 24% responded overall.
Dr. Raber presented data on Taxol studies he has been performing. The acute dose limiting toxicity was neutropenia. A breast cancer study (25 patients) revealed 12/25 responders (MDR = 5 months). Very substantial responses were seen even in patients failing activity on Adriamycin. So far 3/15 PR have been seen in NSCLC patients.
Dr. Ogawa presented new agents being tested in Japan. A totally synthesized anthracycline (SM 5887) has demonstrated activity. Another agent MX-2 has also been tested in these diseases:

Likewise, a third anthracycline ME2303 is undergoing Phase II testing. A platinum analogue, 254-S, has dose limiting myelosuppression and relatively mild nephrotoxicity. Preliminary evidence of antitumor effects were noted in SC and NSCLC as well as head and neck and gynecologic cancer.
Dr. Glick discussed the use of WR2721 as a radioprotector, chemoprotector, and chemosensitizer. Considerable data exist on the preclinical rationale and there is evidence of diminished toxicity. Leukopenia resulting from cytoxan was improved with WR2721. A major randomized trial of cytoxan + platinum with or without WR2721 is ongoing.
This conference was a successful blending of basic and clinical investigation. Considerable new information on chemotherapy was shared and new opportunities for research defined.

(3) Seminar an “Role of Growth Factors in Cancer Treatment”
Napa, California - March 18-19, 1991

This meeting between U.S. and Japanese investigators was held on March 18-19, 1991, in Napa, California, to discuss the use of hematopoietic growth factors.

M. Ogawa, M.D., Chemotherapy Center, Tokyo
The first session was devoted to the use of CSF's in Bone Marrow Transplantation (BMT) and Dr. Ogawa was the first speaker. He described a Phase II trial of G-CSF in Autologous BMT (AuBMT). Using historical controls the time to recovery of WBC counts was reduced from 25 to 14-17 days (200-400 vg/m²). A second study utilized 300 vg/m²/d x 14 in a variety of tumors (7/37 with purged bone marrow), and showed the same trends. A third study of 53 patients utilized three different preparatory regimens. Currently he uses G-CSF to mobilized PBSC and using ACF chemotherapy he noted 2/20 CR (with induction) and the use of G-CSF, AuBMT, and PBSC dramatically decreased neutropenic period.

T. Masaoko, M.D., Osaka Adult Disease Center
Dr. Masaoka presented his studies of Allogeneic BMT with G-CSF, utilizing G-CSF from three different sources (CHO cells, E.coli, and chemically modified). Prior to initiating his multiinstitutional studies he evaluated the sensitivity of AML or CML cells to G-CSF. In general he found that normal cells were more stimulated by G-CSF than AML or CML cells. He tested G-CSF in vivo, testing AML or CML patients to attempt to shorten the period of neutropenia see if their blasts were stimulated. The BMT was followed in 3-5 days by G-CSF 300 g/m²/d.

Days of fever were higher in placebo group after day 10. The GVHD rates were similar as were the risks of leukemia relapse There seemed to be no deleterious effects of using G-CSF.

James Armitage, M.D., University of Nebraska
Dr. Armitage presented his data on GM-CSF in BMT transferase. The most common clinical situations in which autologous BMT has been used are NHL, ALL AML. HD, Breast currently. Currently about 60-100 AlloBMT and 4000 AuBMT are preformed yearly in the United States. There are no data from this experience to support the initial concern that GM-CSF might stimulate NHL growth and relapse.
In AuBMT the use of GM-CSF shortens the period of neutropenia (by about 7 days) and decreases the risk sepsis. A Phase III study of Rhu-GM-CSF at 250 vg/m²/d x 21 d showed faster myeloid engraftment in ALL or NHL patients, shorter hospitalization (by about one week), less antibiotics. A cost estimate is that about $3000/day is an average cost for ABMT -- and therefore a 10-15% savings might be envisioned. The GM-CSF might cost about $3000 per course. As noted above, there was no evidence for GM-CSF promoting NHL relapse. Dr. Armitage is exploring use of GM-CSF in increasing peripheral blood stem cell harvest (up to 200 fold with chemotherapy naive patients primed with Cytoxan). Unanswered questions include the effects of GM-CSF on leukocyte function and its use together with other growth factors in either ABMT or to mobilize PBSC.

David R. Parkinson, M.D., National Cancer Institute
Dr. Parkinson described the development plans for IL-3. Preclinical data suggest that IL-3 followed by GM-CSF may both enhance GM-CSF effects on neutrophil recovery and accelerate platelet recovery. It appears that IL-3 stimulates a more primative hematopoietic population -- its administration in patients dramatically increases both basophil and eosinophil numbers and therefore increase (massively) histamine levels. There may be a platelet stimulatory effect for IL-2 used alone, but it requires a relatively long period of time. An initial Phase I study with Immunex material showed the predominance side effect to be headaches of potential concern is the fact that there are IL-3 receptors in various lymphocyte populations, and some patients with non-Hodgkins lymphoma may have had acceleration of tumor growth on IL-3. One treatment approach will utilize 3-7 days of IL-3 priming, then followed by GM-CSF. A number of Phase I studies are being planned to investigate the effect of IL-3 on recovery from single agent chemotherapy with (Cytoxan, ThioTEPA or 5-FU), and combination studies of IL-3 and GM-CSF have already been approved.

M. Fukuoka, M.D., Osaka Prefectural Habakino Hospital
Dr. Fukuoka next discussed his studies of dose intensity in lung cancer patients. Extensive SCLC patients were treated with CDDP 25 mg/m², VCR 1 mg Dox 40 mg/m², VP-16 80 mg/m²/dx3 in a weekly or q2 week schedule ("CODE"). Patients were ranodmized to receive either CODE or CODE + G-CSF (daily except for D1). So far 45 patients have been entered and 32 patients are evaluable.

Median F/U is only 3-19 months.

As noted above, the period of neutropenia was reduced with G-CSF. The PS was less without G-CSF, and there were more febrile episodes without G-CSF. A major Phase III study comparing CODE + G-CSF vs. CAV/PE were conducted. For patients with NSCLC, Mitomycin C, 8 mg/m² D1, VDS 3 mg/m² D1 + 8, CDDP 80 mg/m² D1; all repeated q3 weeks. A total of 64 patients were evaluable for each group, and 48% response rate was noted. A more intense program with CDDP 100 mg/m² D1 + 8 with MV has been initiated with significant extramedullary toxicity noted.

Thomas Shea, M.D., University of California at San Diego Medical Center
Dr. Shea described his studies with PBSC and dose intense CT. Preclinically the use of either G or GM-CSF can enhance PBSC effects. Patients receiving CBDCA (1200 mg/m²), PBSC, and GM-CSF on a regular schedule were studied. A total of 18 patients have successfully been treated with this program. He is planning to use IL-3 primed GM-CSF to increase the efficiency of PBSC harvest for CBDCA therapy (1200 mg/m²).

A. Urabe, M.D., Teikyo University
Dr. Urabe discussed the use of erythropoietin (EPO) in cancer patients. He presented data on erythropoetin levels in iron deficiency anemia, aplastic anemia, and in various malignant states. In contradistinction to the erythropoietin deficiency state observed in patients with the anemia of renal failure, erythropoietin levels are not low, but vary with the hemoglobin. In patients with malignant lymphoma, myeloma, or solid tumors however, the levels of erythropoietin are inappropriately low for the hemoglobin, suggesting a potential beneficial effect for erythropoietin.

H. Mizoguchi, M.D., Tokyo Women’s Medical College
Dr. Mizoguchi discussed the biology of MegCSF and thrombopoietin (TPO). Two types of factors are required for thrombopoiesis -- MegCSF and Meg POT (stimulates maturation of megakaryocytes). MegPOT increases size of megs, ploidy, enzyme content and may be identical to TPO. The combination IL-7 and IL-3 resulted in increase plts (IL-7 alone did not); hence IL-7 has MegPDT activity. IL-9 alone is similar to IL-7, but no increase with IL-3 + IL-7. On the other hand IL-11, but enhanced colony formation induced by IL-3, IL-3 + GM-CSF have MegCSF activity, IL6, IL7, IL11, TPO, MCSF have MegPOT activity.

Peter Greenberg, M.D., Stanford University Medical Center
Dr Peter Greenberg discussed myelodysplastic syndrome therapies. He reviewed the natural histories of the good and poor prognostic types of MDS. In vitro data suggested that both G or GM-CSF could induce differentiation of MDS cells. The responding cells more often had normal cytogenetics and that G-CSF had more differentiation potential compared to GM-CSF; by contrast GM-CSF had more proliferative potential. Dr. Greenberg studied 19 patients with MDS treated with G-CSF and noted increase in neutrophil and erythrocyte counts in these patients is beginning to study the use of G-CSF + EPO. A major Phase III study of G-CSF in MDS patients will examine whether the high risk MDS population can be helped by this approach to therapy.

F. Takaku, M.D., National Hospital Center
Dr. Takaku provided a unique perspective on the hematopoietic growth factors. He described the uses of G-CSF in both BMT and CT situations. Of eight previously chemotherapy refractory AML patients, four had CR to G-CSF + Ara-C. The explanation for this observation is not known. He also demonstrated the ability of G-CSF to stimulate PMN's to make IFN-alpha. We know relatively little about possible direct cytotoxic effects of M-CSF, but it may induce cytotoxicity by TNF-mediated NO production, or by some more direct mechanism. Future directions in this fieled as summarized by Dr. Takakuo included assessment and prevention of adverse effects of currently used cytokines and the search for new cytokines.

H. Saito, M.D., Nagoya University
Dr. Saito discussed the use of G-CSF in various hematologic malignancies.
G-CSF receptors are present on most myeloid cell lines but usually relatively few binding sites or low affinity. In contrast, lymphoid or most non-hematopoietic cell lines do not express G-CSF receptors, with the exception of two choriocarcinoma cell lines; this is very different from the GM-CSF receptor which has a wider distribution of expression in solid tumor cell lines. Dr. Saito presented a Phase III, blind study of G-CSF in non-Hodgkin's lymphoma.