REPORTS ON SEMINARS

(1) Seminar on "Gastrointestinal Tumors - Biochemical Modulation and Monoclonal Antibody"
November 7-8, 1992, Tokyo, Japan

This meeting dealt with on Gastrointestinal Cancer with special attention to biochemical modulation and monoclonal antibodies. The initial discussions focused on a variety of preclinical issues. Dr. Aiba described a series of studies utilizing 5FU combinations. He reviewed the anabolism and catabolism of 5FU (a complex and dynamic series of interactions). Examining 6 human colon cancer cell lines there was significant heterogenicity in 5FU responsiveness -- overall longer exposure times (96 hrs. vs. 5 hrs.) being somewhat more effective. There was a 10-15 fold difference between the cell lines for TS levels (29 to 885) and difference in TS binding (correlating with IC50 values). Likewise, he demonstrated that 5FU resistance may be related to diminished TP/TK (activating enzymes).
Dr. Mizunuma next described studies of 5FU + LV or IFN-alpha in 3 human tumor cell line. The combination of 5FU + LV + IFN alpha was them most effective in enhancing in vitro cytotoxicity. Apparently this combination resulted in more profound TS inhibition. Apparently 5FU + LV caused increase in TK, but IFN caused a decrease. He suggested that TS inhibition may be the most important site of action.
Dr. Aiba then presented data with CPT- 11 and 5FU in which synergy was demonstrated when 5FU was given prior to CPT-11. Prior exposure to 5FU seemed to increase TOPO I (with greater sensitivity to CPT-11). A clinical trial was initiated with 5FU 750 mg/m²/d x D1-5 followed by CPT-11 200 mg/m² on D6 (as 24 hr. infusion), the sequence repeated every 3-4 weeks. The first 12 colon cancer patients were heavily pretreated (many with 5FU), but 4/12 had a PR. The historical data for CPT-11 alone suggests a 33% PR rate for this population. The dose limiting toxicity was hematologic (with relatively little diarrhea).
Dr. Sasaki described the clinically relevant 5FU + LV interactions. He described 3 clinical studies (weekly 5FU + LV), and the use of l-LV + 5FU. Combinations of LV (500 mg/m² + 5FU 600 mg/m²) given bolus every week x 6 (2 week rest). A total of 34 gastric and 32 colorectal patients were studied, Overall 9/34 gastric and 9/32 colorectal had a PR. Overall median survival was 9.1 month and 12 months, respectively for gastric and colorectal patients. Gastrointestinal toxicity predominated, but hematologic toxicity was also seen. He also described the Phase I studies of 1-LV + 5FU in which he achieved 10 µM plasma level for 2-5 hours. A randomized Phase II study utilized these data --both 1-LV schedules of 100 mg/m²/d x 5 or 250 mg/m²/week resulted in responses, while 10 mg/m²/week failed to do so. The majority of patients had leukopenia. Overall, no dramatic benefits were obvious from the use of 1-LV.
Dr. Ezaki presented data on 2 clinical trials utilizing 5FU + IFN alpha. One study utilized 5FU 750 mg/m² CI x 5d followed by weekly boluses and IFN given at 6 Mu/d tiw for colorectal cancer patients. Only 20 patients were evaluable and only I had adjuvant 5FU. Overall, 5 had PR with response duration of 2 to 6+ months. Hematologic toxicity predominated, but fever, mucositis, and diarrhea were also noted. The second study examined 5FU 350 mg/m²/d x 5 and LV 20 mg/m²/d x 5, repeated q3-4 weeks and IFN was given daily at 6 MU/d. A total of 25 patients (14 gastric and 11 colorectal) were treated and 13 had prior 5FU + LV. Of 14 gastric cancer patients 3 had PR and 1/11 colorectal patients had a CR (only the previously untreated patients with PS = 0 or 1 or 2 responded). Only 5 patients had grade 3 leucopenia (most of the 72% with fever had IFN toxicity).
Dr. O'Dwyer reviewed the US data with PALA modulated 5FU. Attempting to reduce UTP levels (by PALA) will theoretically increase FUTP in RNA. Other possible mechanisms of PALA include greater inhibition of TS or DNA repair. PALA also increases FdUMPT levels. Studies of PALA 250 mg/m² + 5FU 3. 6 gm/m² indicated that mucositis and diarrhea were dose limiting and 16/37 colorectal cancer patients responded. Next, studies comparing PAIA + 5FU to more standard regimens are needed. A large Phase III trial of ECOG compares 2 5FU + LV regimens with 5FU + INF alpha with 5FU alone to PAIA + 5FU. Additionally, double modulation with an antipurine (eg 6-MMPR) could enhance 5FU + PAIA. Utilizing 6MPR, PRPP could be increased due to inhibition of phosphorobosyl aminotransferase. A Phase I study was conducted and diarrhea was dose limiting with PALA 250 mg/m², MMPR 150 mg/m² and 5FU 1300 mg/² (CI for 24 hours). Phase I studies have also been performed with PAIA + 5FU + LV and PALA + 5FU + IFN alpha.
Dr. A. Benson described other clinical trials of 5FU + Levamisole. The mechanism of action is unclear since direct cytotoxicity is not observed (nor is significant modulation of 5FU effected). Generally, studies have documented only epiphenomena associated with Levamisole. Studies of high dose Levamisole + 5FU revealed neurotoxicity, nausea and vomiting. Large Phase III trials of 5FU + Levamisole in B₂, C colon cancer patients demonstrated benefits (overall survival). A randomized trial of 5FU + LEV + LV vs. 5FU + LV is ongoing as well as comparisons of all the possible combinations. He also reviewed the range of studies ongoing in the US Cooperative Groups (an enormous spectrum of activity).
Dr. Boland discussed his research in identifying novel targets for gastric cancer therapy. Studies of glycocongugates revealed that prostaglandins were important modulators of these species. Certain species (eicosanoids) can be growth regulatory. Interestingly, prostoglandins inhibited and leukotrienes stimulated the growth of a human gastric cancer cell line. Inhibitors of lipo-oxygenase suppressed cell growth. Sucrafate can increase prostoglandins (used ulcer healing) as does sofalcone (which inhibits the degradation of PG), and inhibit AGS cells. Hence, these data may be relevant to gastric cancer prevention as well.
Dr. Nakajima described a series of adjuvant and neoadjuvant studies in gastric cancer patients. Patients with Stage III or IV disease require chemotherapy in addition to surgery. He described two randomized trials of MMC in 203 treated and 225 control patients, both indicating benefits for the MMC patients. Also a combination, MFC, has been popular in Japan. A combination of "FLEP " therapy given 1A has been evaluated as a neoadjuvant. Overall, a 60% response rate was achieved and roughly 1/2 of patients were resectable. These studies will be ongoing.
Dr. Takahashi provided an overview of Japanese adjuvant trials in colorectal cancer. From 1965 to the present a series of studies utilizing fluoropyrimidine + MMC were conducted. Often, intraoperative MMC was employed, with the fluoropyrimidine given systemically for a longer period of time. Adjuvant programs had evident benefit for rectal cancer patients.
Dr. B. Levin gave a comprehensive overview of chemoprevention strategies for colon cancers. Utilizing biomarkers, it is possible to design preventive approaches (such biomarkers as BUdR or PCNA). Interesting potential preventatives include allium (garlic, leeks, onions) products. A second possible preventative is calcium, which may inhibit colorectal carcinogenesis. Likewise, NSAID such as aspirin or ibuprofen are effective preclinically. He reviewed all ongoing trials going on in the US.
A review of trials in the US for rectal cancer was provided by Dr. Levin. Clearly combinations of pelvic irradiation and chemotherapy augment the benefits of surgery. Preoperative ultrasound provides superior staying (at least for the primary tumor). Studies examining pre vs post operative XRT are being designed. For patients with smaller tumors, sphincter preservation programs are being evaluated.
Dr. Takahashi presented data on monoclonal antibodies with drug conjugates. One such MoAb is A7 (directed against 42 KD Glycoprotein) and found in 70-80% of pancreatic and colon cancers. Murine pharmacology revealed good tumor/normal tissue ratio. Imaging studies have been performed. He prepared conjugates with Neocarcinostatin (NCS), MMC, and Adriamycin. Preclinically the NCS conjugate was felt to be most useful. The A7 was linked to NCI with covalent SPOP bonding. Clinical testing has been carried out in 78 colon cancer patients -- 55 primary and 23 at metastatic sites. A7-NCS was given via IV, IA, or IP routes. No randomized studies have been performed, but some responses have been observed. Toxicities included fever (in 45%) and all patients demonstrated HAMA. Further investigation will be ongoing as he tries to improve the antigenicity characteristics of the A7 molecule.
Dr. M. Tempero described her studies of pancreatic cancer. A variety of TAA are present in pancreatic cancer (TAG 72, DUPAN, CA 19-9) which can be potentially exploited. She discussed the need for correlation of therapy to insure that tumor has adequate expression of the target Antigen. One problem is that when HAMA occurs, there may be substantial interference with other lab tests that require murine MOAB. Studies with B72.3 lnked with I¹³¹ were initially disappointing with profound hematologic toxicity and only variable imaging. By contrast cc49 or cc83 appear to be more specific. Also ABMT or peripheral stem cell rescue was employed to release hematoxicity. A very vigorous program is ongomg.
Dr. Ogawa reviewed the status of new agents being evaluated in Japan for GI cancer. There are 4 anthracyclines and 4 platinum analogues being studied. The platinum analogue 254S has been evaluated and DLT is thrombocytopenia with mild nausea, vomiting and anorexia. A similar pattern of activity was noted, compared to CDDP -- SCLC, H&N, ovarian, testis, and cervix. Of GI tumors, only esophageal cancer seemed sensitive (40% PR rate). CPT-11 has also been studied and activity demonstrated is SCLC, NSCLC, cervix, and ovarian cancer. In colorectal cancer, 12/36 patients had PR in Shimada's study and 16/64 PR's in a later study. For gastric cancer, 8/46 PR's were noted and in pancreatic cancer only 2/32 PR's seen.
Dr. Friedman presented work in progress sponsored by NCI with particular reference to therapeutic monoclonal antibodies and a new vaccine-CEA construct. The phase I studies of the vaccinia-CFA vaccine should be initiated soon and special attention will be given to patients with gastrointestinal cancers.
Overall, this conference provided a venue for a substantial exchange of information. Emphasis was placed on novel therapeutic methods. While the search for “conventional” cytotoxics will continue, increasing attention will be devoted to utilizing Monoclonal Antibodies, vaccines, and other innovative methods.

(2) Seminar on "New Drugs - Novel Structure and Tubulin Binder"
Maui, Hawaii - February 15-16, 1993

This meeting was held to discuss clinical trials with new cytotoxic agents and especially studies of tubulin binders. The first session focused on these Tubulin Binders and began with a presentation on Taxol by Dr. Donehower. He reviewed the extensive preclinical and clinical data with Taxol. The major clinical toxicities encountered include hypersensitivity, myelosuppression, alopecia, cardiac and neurologic. However with proper premedication, the incidence of hypersensitivity reaction is reduced to only 3%. Moreover, even patients with hypersensitivity can often be retreated. The cardiac toxicity is likewise rare and usually clinically insignificant. Neurotoxicity is usually manifest as sensory dysasthesias, although some motor or autonomic toxicity is also noted. Dr. Donehower also reviewed the efficacy of Taxol in patients with ovarian cancer. A series of excellent clinical studies conducted at Johns Hopkins defined the optional sequence of Taxol --- > CDDP; this order being least toxic and more efficacious. Several studies in ovarian cancer have revealed important activity. Other activity was evident in breast, NSCLC, and Head and Neck cancer patients.
Next, Dr. Saijo reported on the Japanese experience with Taxol. In vitro, he developed a Vindesine resistant cell line which was cross resistant with Taxol (but not ADM or CDDP). The mechanism of this resistance does not seem to be PGP-mediated MDR. In the H69/VDS cell line, the tubulin content increased with Verapmil. A Taxol resistant line was supersensitive to Vinca (and had no evidence of MDR and had increased tubulin) Clinically, two Phase I studies were completed in Japan and the MTD = 135 m/m² q 21 days.
Dr. Raber next discussed his clinical experience with Taxotere. He performed an initial Phase I and a series of Phase II studies. The Phase I study schedule was daily x 1-5 administered as a short bolus (1 hour), and cycles q21 days. The DLT was granulocytopenia and mucositis, and the 1 hour schedule was utilized in the U.S. Phase II studies initially. However, the Phase II toxicity experience is somewhat confusing -- hypersensitivity seem to be a common problem, as were skin rashes (37% courses) and peripheral edema (20-30% courses). A number of developmental questions remain, including identifying the best dosage and schedule and determining whether pretreatment antiallergic therapies might be useful.
Dr. Tsuruo, discussed another microtubular agent -- palmitoyl rhizoxin developed in Japan. Rhizoxin is derived from a fungus and is a macrolide. The palmitoyl analogues demonstrates an improved preclinical antitumor profile. Its binding site on tubulin is the same as that for the Vincas, but the palmitoyl analogue may be less affected by the MDR phenotype. Interestingly, the LDL receptor may be necessary for this drugs transport into the cell. He also described other preclilaical studies of MDR reversing agents in Japan. He hypothesized that it may be that multiple MDR modifiers may be needed to clinically reverse MDR (eg. MRK-16 + Cyclosporin overcome MDR and give far better entry of VCR).
Spikamycin and its analogues were discussed by Dr. Takaku. These interesting new agents have both differentiating effects and antitumor properties. Efficacy has been demonstrated in MX-1 and LX-1 xenograft models. Analogues of spikamycin (with longer saturated side chains) have better antitumor activity. In mice, hematologic toxicity was noted at higher dosages. Hepatotoxicity was also notable with decreased synthetic ability as well as LFT abnormalities.
The second session dealt with another important family of agents the Camptothecins. Dr. Raber presented clinical studies with Topotecan a Topoismoerase I inhibitor being evaluated in the US. Two Phase I studies were conducted -- the appropriate dosage being 10-12 mg/m² over 24 hours and 10 mg/m² over 96 hours (lenkemia). The Phase II studies were conducted at 1.5 mg/m²/d x 5 q21 days. A total of 28 ovarian cancer patients who were CDDP-resistant and 4 PR were noted. In NSCLC, 2/19 PR were noted (all previously untreated); the data are too preliminary for SCLC. In acute leukemia there was a 19% objective response rate. Overall, this drug has promising activity.
Dr. F. Fukuoka described studies in Japan of CPT-11. A Phase I study of weekly therapy demonstrated that diarrhea was dose limiting in 4/8 patients at 125 mg/m². Unfortunately, the diarrhea and leukopenia were somewhat unpredictable. A Phase II study of 73 NSCLC patients was completed and 23 had a PR with median response duration of 15 weeks. In SCLC, 41 patients (most of whom had prior chemotherapy) were treated and 13 responses seen. In colorectal cancer, 17/63 patients had PR. Likewise, in ovarian cancer patients 13/55 had PR (all patients had prior therapy), and 13/55 cervix patients had a PR. Finally, a Phase I study of CPT- 11 + CDDP was conducted and 80 mg/m² of CDDP was given on Day 1 with increasing doses of CPT-11 administered q week x 3 (repeated every 4 weeks). In this combination study, overall 14/26 patients responded, all with NSCLC (Dose = 60 mg/m²/week + 80 mg/m²). This combination wm be pursued in NSCLC. A study of VP16 + CPT-11 was also conducted and responses were noted. Of interest, there seemed to be a good correlation between SN-38 serum peak levels (the active metabolite of CPT-11) and the major toxicity, diarrhea.
Dr. A. List described an integrated series of studies conducted at the University of Arizona examining MDR in a range of hematologic malignancies. For patients with large cell lymphoma, only 1/49 were PGP + initially while 7/10 were PGP + at relapse. Clinical exposure to ADR/VCR induced PGP (which was also related to duration of exposure). A series of trials tested whether verapamil plus chemotherapy resulted in responses, and 4/10 PGP + patients responded. De novo leukemia has about 20% incidence of PGP + (this increases with worse risk groups). Patients with poor risk karyotypes had evidence of MDR; as were those with CD34 + blasts and those with monocytic phenotype or in malignant T cells (CO58, etc.). Other prognosis factors include age, s phase etc. In CML Blastic B cells and in ALL, the CD34 + cells were not associated with MDR. One trial of Ara-C 3 gm/d x 5 plus CSA (Day 6-8) plus Daunomycin 45 mg/m2/d x 4 was carried out, and 40 poor risk patients were treated. Approximately 75% had PGP postivity, and response rates are pending.
Dr. George Morstyn presented an overview of G-CSF use in various clinical situations. One issue being addressed is the value of G-CSF as a therapy for patients with febrile neutropenia. If patients had 4 afebrile days and had a ANC > 500/mm³, they were considered successfully treated. G-CSF reduced the number of febrile days but had relatively little overall clinical impact. Dr. Morstyn also discussed the studies of SCF (stem cell factor). SCF is a tyrosine kinase, the ligand of the C-Kit receptor and acts synergistically with many other factors (IL6, G-CSF, EPO, etc.) and acts on CD34 + progenitors. Patients with MDS and Aplastic Anemia have high endogenous levels of SCF. Murine studies demonstrate that GCSF + SCF will cause increase quantitative and qualitative peripheral blood stem cells. In baboons, a lower dose of GCSF + SCF is far better than higher dose of SCF or GCSF alone. Interestingly, combinations of SCF + IL3, G and GM-CSF seem to most effectively produce more stem cells. In patients, the toxicity of SCF was principally skin reactions and respiratory symptoms (25-50 g/d). No respiratory symptoms were noted with 10 g/kg/d.
Dr. Ariyoshi reviewed new antimetabolities being studied in Japan. To date, three antifols have been studied, including Edatrexate, Trimetrexate, and TNP 351. Edatrexate at doses of 30 mg/m²/week x 3 repeated q 4 weeks was tested in breast, lung, head and neck, and stomach cancer patients. Relatively poor activity has been noted so far. Studies of Timetrexate are also being conducted. TNP-351 (Takeda Pharmaceuticals) has a number of attractive features (eg. preclinical panel activity) and the Phase I study has been competed. Phase II trials in breast, lung, and GI cancers are ongoing. Three fluoropyrimidine drugs are being studied in Japan (including BDF-A2, which has some activity in breast, lung, and stomach cancer). Another analog is S-1, an oral tablet form of Ftorafur. The Phase I study of S-1 is just now beginning. Lastly, a number of cytidine analogues were described. For example, Gemcitibine had modest activity in NSCLC (3/54 PR at 800-1000 g/m²). Another analogue, DMDC was also presented although Phase I trials are just beginning.
Dr. Makoto Ogawa discussed several new platinum analogues including 254-S which is water soluble and has dose limiting thrombocytopenia and comparatively little nephrotoxicity. Activity was seen in patients with head and neck cancer, esophageal cancer, testis, SCLC, cervical and ovarian, urothelial, and NSCLC. Overall there was general similarity to CBDCA. In a Phase III study, 254S was no better than CDDP in NSCLC (both utlized with Vindesine). Another analogue studied was DW A2114R and neutropenia was dose limiting (along with a little hepatotoxicity). Disappointingly, this agent had little activity except in patients with ovarian cancer (~30% PR). TRK-710 is yet another analogue being tested since it may be active against CDDP-resistant tumors. Phase I trials are ongoing.
Dr. H. Scher reviewed the data with Suramin. The toxicities were unusal and included keratopathy (with glycosaminoglycan deposition) neuropathy (possibly related to peak blood level), rash, myopathy, and infection. Initially, considerable problems existed in efforts to define a safe and acceptable dosage and schedule (since this drug has such peculiar pharmacokinetics). Many different schedules were evaluated, and efficacy has been noted in prostate, lymphomas and trials are ongoing in breast cancer and with radiation therapy. Currently, an emperic dosing scheme is being utilized and seems to be convenient and safe.
Dr. A. Matsuda discussed new pyrimidine nucleoside derivatives being studied preclinically in Japan. These new agents would be chemically stable until incorporation into DNA. One such agent, referred to DMDC (analogues of 2/-deoxycytidine), has broad in vitro activity. Such analogues are relatively resistance to deamination but little in vivo data exist.
Dr. M. Friedman concluded the meeting by cataloguing the new agents being studied by the NCI. Most attractive of these were Pyrazolooacridine, Clomesone, Pencloimidine, and Fostreicin.
Overall, the meeting proved to be an effective forum for information exchange.

(3) Seminar on “Breast Cancer - New Therapies”
Oaldand, California - March 8-9, 1993

This meeting dealt with a variety of emerging scientific issues related to breast cancer therapy. The first speaker was Dr. Tominaga who pointed out that breast cancer incidence is rising in Japan (currently, 20,000 patients per year) and the peak incidence is in the 40-49 age range. Most Japanese patients are Stage II and most have invasive ductal carcinoma (only 1% lobular carcinoma). Previous data indicates better survivorship for Japanese women compared to US women (Stage for Stage). For Stage I patients there is a 90% 5 year survival, and 84% for Stage II. Data on EGF, P53, Her2/neu and other possible prognostic factors were described. Vessel density also seems to be potentially useful prognostic factor.
Next, Dr. Koyama described a series of adjuvant chemotherapy trials in Japan. Even early studies (in the 1960's) of MMC + Cytoxan demonstrated statistically significant benefits. Another large, multinstitutional trial indicated that Tamoxifen + Ftorafur was better than Ftorafur alone (3% overall survival advantage). As expected, ER + and post menopausal patients benefited most from Tamoxifen. Other prognostic factors were generally similar to those described in US studies (eg ER and nodal status).
Dr. Henderson discussed studies of factors which predict for response to chemotherapy. He pointed out the difficulty in assigning prognostic significance (only ER, nodal status and primary size are clearly relevant). Only 4-5% of node negative patients are totally without any single dire prognostic factors. In one study (CALGB 8869), Erb B-2 appeared to be correlated with response, treatment, overall survival, and relapse free survival. In this series, more intensive chemotherapy seemed to be more effective in the erbB-2 overexpressor. There may be an association between erb B-2 and Topoisomerase II levels, but is still to be fully described.
Dr. Tokuda discussed the role of c erbB-2 as a prognostic factor in Japanese patients and as a therapeutic target. Based upon a small series, the prognostic value of C-erb-B2 could not be confirmed. Utilizing a humanized MoAb (Ab405) from Genentech, preclinical studies have been performed with erbB-2 expressing tumors there was definite tumor inhibition not for erbB-2 negative). Another study of bispecific Ab (anti-erb B-2 plus antiCD3) attempted to capitalize on immunologic killing potential. A clinical trial of this bispecific antibody is being initiated in breast cancer patients.
Dr. C. Bena discussed his research on Her2/neu biology and breast cancer. The erbB-2 receptor is a tyrosine kinase and cells with excess may be resistant to chemotherapy and immune killing. His studies are defining the clinical utility of this receptor.
Dr. Mukaiyama presented his studies of p Glycoprotein (MDR) in breast cancer patients. In general patients with breast or ovary cancer have low initial expressions of PGP (as opposed to stomach or colon cancer patients). Using a variety of techniques (Northern blots, Amplimer RT-PCR) MDR could be detected. After exposure to an anthracycline, up to 50-75% or more of tumors are MDR+. Three MDR modulators were studies (N-1379, AHC-52, MS-075). A study of N1379 + Adria has been conducted (N1379 is similar Verapmil but is nearly insoluble). Studies have also been planned for PSC833.
Dr. Waldman described his cytogenetic studies of breast cancer. He utilizes In situ hybridization (FISH) and can identify larger centromeric and small (cosmid) sites as well. There may be a large number of abnormalities in any particular epithelial tumor. As expected LDH on 17 is associated with more Bord labeling. He has identified a terminal 17 deletion which may be more specific than P53 loss. Chromosomally tumors are dramatically heterogenic. Commonly, loss IP, gain 1q, 8q (Myc), 11q, 12q, 17 P loss (P53) have been noted.
Dr. Cullen described studies if ILGF in breast cancer. IGF-1 is the normal product of liver in response to GH, while IGF-2 is a fetal growth factor. IGF-1 is a tyrosine kinase receptor (IGF-2 has an unknown purpose). Both are strong mitogens in tumors. IGF2 seems to be produced in the stroma, rather than the epithelium (tumor fibroblasts seem to produce more IGF2), IGF was more often made in normal fibroblasts. Overall, 15/16 benign fibroblasts make IGF-1, 11/16 malignant fibroblasts make IGF2. The tumor fibroblasts also can make the erbB2 receptor (gp30 or heregulin); roughly in 50%. If you block the IGF receptors on epithelium, you block growth (much more so than IGF1). One Phase I study of Pentosan (which may interfere with receptor dimorization and prevent phosphorylation) has been completed and low doses may be effective at interring with IGF systems. IGF binding protein 1 has been produced and can block IGF2 mitogenesis (competitive). Thirdly peptide analogs of the IGF domain may be effective.
Dr. Adachi discussed the use of dose-intensity chemotherapy for patients with advanced breast cancer. Commonly, Stage IV patients receive conventional cytoxan + adriamycin + Tamoxifen (CPA 100 mg/m²/d po to Adria 20 mg/m²/wk + 2q 4 + Tam 20 mg/d). Patients have also received a Phase I-II trial of epirubicin + CPA + GCSF. Doses of 130 mg/m2 of EPI, 1000 mg/m² CPA and GCSF (2 g/kg) were achieved (q 3 weeks). Overall 68% of patients responded (22% CR).
The discussion of the Japanese experience with PBSC support was led by Dr. Mukaiyama. A series of studies utilizing ThioTEPA and Epirubicin have been conducted (especially for breast cancer patients). Responses were noted and toxicity was acceptable. Unfortunately, the survival was not dramatically increased. New anthracycline analogues with less cardiotoxicity are being evaluated.
Dr. Tajima reviewed the Japanese experience with high dose chemotherapy in the adjuvant setting. A total of 59 patients (32 Stage II, 22 Stage III) were evaluated. Of 24 patients with 10+ nodes, 34% had 10 year DFS. Although not a randomized study, these results seemed superior when compared to historical control. The regimen consists of CPA 1.6 gm/m², Adria 80 mg/m², ACNU 3 mg/kg q 3-4 weeks. Currently, he is utilizing a CPA + Epirubicin conditioning regimen, followed by a double high dose program including ThioTEPA, CPA, Epirubicin with ABMT + PBSC. In order to assure that reinfused marrow is not contaminated, MoAbs (IIL-1 or CAM 5.2) were used to screen the marrows.
Dr. Davidson presented her experience with high dose programs in patients with Stage IV disease. Overall about 20% have CR, 10-20% will have DFS and 5-10% will die of acute toxicity. Possible options to improve outcome include sequential intense therapy, biomodulation and resistance reversal. Attempts to enhance autologous GVD (to improve efficacy), she has evaluated cyclosporine and/or interferon gamma. Combination of CSA 2.5 mg/kg/d + IFN gamma 0.025 mg/m²/d resulted in significant GVHD in 50% of patients. She also has studied Novobiocin inhibition of repair of damage caused by BCNU and CDDP. Novobiocin has been included in a pilot ABMT (CPA + ThioTEPA) program.
Dr. Norton described the evaluation of the Taxanes into breast cancer therapy. Taxol is an active agent even in refractory patients (at doses of ~200 mg/m² q3 weeks). The problem of trying to integrate Taxol into combination regimens is considerable and he has modeled optimal adjuvant scenarios. Currently he proposes to give Adria 90 mg/m² q2 weeks x 3, Taxol 250 mg/m² q3 wks x 3, CPA 3 GM/m² q 2 weeks x 3 (all with GCSF). The sequence is purposeful (based on MDR emergence and the ability of alkylators to eliminate residuaL disease). He also has data that antiEGF MoAb + DOX a Taxol is powerfully synergistic. This combination will be further explored.
Dr. Ogawa reviewed new agents being studied in Japan which may be relevant for breast cancer patients. One agent, 254S is a water soluble platinum which is relatively inactive in breast cancer patients. Another platinum analogues in DWA 2114R which also had minimal antitumor activity (in heavily pretreated patients ). MX-2 is a doxorubicin analogues administered of 20 patient and 1 CR and 3 PR were noted. A Phase I trial of Taxol has also been administered; and a dose of 150 mg/m² was identified as generally tolerable. Finally, CPT-11 is a Topoisomerase I inhibitor which results in 4/24 responses in breast cancer patients (ICR, 3PR response = 60-200 days).



SEMINAR AGENDA AND PARTICIPANTS

(1) Seminar on "Gastrointestinal Tumors - Biochemical Modulation and Monoclonal Antibody"
November 7-8, 1992 Hotel Grand Palace, Tokyo, Japan

AGENDA