REPORTS ON SEMINARS

(1) Seminar on "Recent Progress in Drug Resistance"

This meeting, which was held in Tokyo on November 15–16, 1993, dealt with a careful examination of the basic mechanisms of various forms of drug resistance and possible means of their clinically reversing this. The first session dealt with basic information concerning MDR and PGP. Dr. Uega spoke about the molecular mechanisms of MDR and his research directed at defining the biochemistry of PGP. MDR-1 contains ten consensus sequences which could undergo N-glycosylation. He demonstrated that probably only three sites are actually N-glysocylated. He transfected mutant type GP into various cell lines and compared relative resistance to VLB, Col, Gram D, etc. Interestingly, cortisol, aldosterone, dexamethasone, and estriol are transported by human PGP (but not progesterone, estradiol, testosterone, and dehydroepiandrosterone). The inhibition of PGP by Verapamil or other calcium channel blockers or by CSA is concentration dependent. He also demonstrated that there may be several binding sites on PGP for Velban; also, that the interaction of Verapamil or CSA is different than that for Velban.
Dr. Akiyama next discussed non-PGF mediated MDR. He developed KB cell lines demonstrating high resistance to many anticancer agents associated with less accumulation of Adm or Vcr. The Multidrug Resistance Associated Protein (MRP) is a member of the ATP Binding Cassette superfamily and seems to contribute to this type of resistance (low MDR-1). However, the level of MRP gene amplification is not correlated with level of resistance, and the drugs which affect MDRS seem to be much less effective for MRP.
Dr. Susan Cole presented her research with the MDR conferred by the MRP gene product. Using a SCLC line made MDR, there is no increase in PGP (MDR-1) and little benefit to usual reversal agents. The PGP is located on chromosome 7 (similar to cystic fibrosis); MRP is on 16. Belonging to the ATP Bindery cassette superfamily, these proteins are involved in energy-dependent molecular transport across membranes and there is an enveloped hydrophilic alternating with hydrophobic regions. There is relatively little amino acid similarity with PGP or CFTR, and MRP is much larger size. She has also developed two MoAbs to identify MRP (MRP-L seems to be quite specific).
This Ab (MRP-L) does detect paraffin embedded tissues. A number of cell lines express MRP—many of them lung, but also sarcoma, leukemia, and cervix. It is possible that MRP does not work to export drugs but may change pH (but the mechanism is unclear).
Dr. Tsuruo completed this session with a discussion of PGP in CNS and new MDR reversing agents. Brain capillary endothelium express PGP (probably located in optical protein nearest the blood itself). He has identified a PGP including component (PIC) which may stimulate PGP expression. Dr. Kataoka described apoptosis resistance and its relation to drug resistance. He created a mutant line (U937 variant) which demonstrated no DNA fragmentation. He could demonstrate an association between drug resistance and lack of drug sensitivity.
Dr. Kuwano described his research relating to transcriptional control of MDR-1 and TOPO II genes as they relate to MDR. He described the MDRs present on chromosome 7. Increased MDR-1 promoter is associated with UV, TOPO I-II damage, etc. There appears to be two elements (MDR NF1 and MDR NF2) responsible for MDR-1 generation. If cells have less TOPO II, there is less clevable complex formation and greater resistance.
Dr. Beck discussed altered TOPO II and clinical drug resistance. These cells (at MDR) lack MDR-1 but have altered TOPO II. There are two isofoms of TOPO II (the product of different genes) and both have growth rate, recessively expressed resistance (? codominant), and TOPO II amount or function, ATP requirement, catalytic rate and altered ratio of isoforms. There is also less c-jun message. Newer drugs (like fostreicin) do not stabilize complexes but have no cross resistance with VP-16 or VM-26 mechanisms. It is not known whether, atMDR, this is clinically relevant. No AML or ALL mutations in TOPO II genes have been detected in 60 patients tested.
Dr. Andoh presented his studies on the mechanisms of TOPO I resistance. Using the prodrug CPT-11, he identified mutants resistant to CPT-11 (at site 533). Four defects are noted. TOPO I mutation, decreased drug transport, decreased metabolism to SN38 and decreased TOPO I levels. In a survey of tumors there was a variety of initial TOPO I levels (in general AML and gliomas have higher levels). There are no correlations between initial TOPO I level and CPT-11 sensitivity. There was, however, a positive correlation between VP-16 and ADR sensitivity and TOPO II level in stomach cancer (none found for lung or colon).
A discussion of metallothionein relevance was initiated by Dr. Imura. The content of metallothionein includes 20 cysteines. This molecule is highly inducible and binds heavy metals and scavenge-free radicals, and reacts with alkylating agents. Hence, metallothionein could interact with many anticancer agents. In animals, pretreatment with Zn or Bi (inducers of metallothionein) reduced CDDP nephrotoxicity and marrow toxicity. Is it possible that zinc could reduce the efficacy of therapy in patients? He also studied the use of proarglyglyceine to reduce MT and enhance CDDP sensitivity.
Dr. Ishikawa then presented 06 MGAT and cancer studies. This enzyme repairs a critical portion of Guanine that is damaged by alkylating agents. Liver has very high levels of 06 MG T. Using a transgeneic murine model and a potent hepatic carcinogen, the animals with higher endogenous 06 MGT seemed to be protected against carcinogenesis.
Dr. Gerson provided data on his studies with 06 BG to overcome nitrosourea drug resistance. Methylation Excision Repair (MER) correlated with BCNU toxicity and MGMT is an acceptor protein to repair the chloroethyl injury. There is good correlation for colon, gastric, melanoma, and rhabdosarcomas for MGMT and BCNU toxicity. 06 BG is very effective inhibiting MGMT and sensitizes cells to BCNU. In human colon cancer there is no consistent pattern of MGMT (re gender, stage, etc). Even as little as 1 percent MGMT positive cells will regrow to nearly uniform positivity after failing BCNU therapy.
Dr. Niitsu discussed GST II as a drug resistant factor and as a tumor marker. A number of xenobiotics, radicals, and bile acids are detoxified by GST. Oncogenes (Ras, jun, fos) can also induce GST II production. He developed MoAb against several best II epitopes. For colon cancer the rate of positivity is highest in villous adenoma (1005) and lower in advanced cancer (60 percent). GST II may be measured in plasma and could serve as a tumor marker in some. He also utilized keotprofen (a NSAID) to reverse GST II induction.
Dr. Yodo provided information on thioredoxin (TRX)/ADF and studies of antiapoptosis. TRX is a redox regulator, both intracellularly and extracellularly. ADF is an ATL derived Factor, is an inducer of IL-2 R/Tax, and is related to thioredoxin of E. coli. ADF seems to be involved in both B and T cell proliferation. It also seems to scavenge reactive oxyradicals. Intracellular, the glutathione system, seems to interact with the thioreduxin systems, even though they are separate. Many kinds of stress cause the translocation of ADF from cytosol to nucleus. Oxydative stresses affect tyrosine phosphorylation, and ADF can have important membrane function. Retinoids can affect the thioreduxm system and can kill ATL cells (Thioredxun reductase is bound by retinoic acid).
Dr. Saijo described his studies of CDDP resistance and modulation. CDDP can enter the cell passively or actively and forms inter- and intra-strand cross links. A survey of six lung cancer cell lines showed that less accumulation of CDDP in NSCLC, and inconsistent increases in GSH, GST, and MT. GST II transfection does not confer universal CDDP resistance. There is a clear inverse correlation between CDDP accumulation and sensitivity. He identified a ouabain resistant mutant and compared the sensitivity to CDDP (more sensitive than the parental line) with increased Na/KATPase activity compared to the CDDP resistant line. Moreover, he demonstrated the Amphotericin B sensitized cells to CDDP, due to increasing intracellular concentration and increasing cross linking. In vivo testing is ongoing but initial studies are positive.
Dr. Howell described his research with attempts to reverse CDDP resistance. He described clinical studies of Tamoxifen with CDDP which seemed promising. In vitro demonstration of synergy with Tam + CDDP was unique, since BCNU + Tam or DTIC + Tam are antagonistic. Of the four possible Tam effects on CDDP, there was no impact or CDDP uptake, MT content, GSH content, or DNA adduct formation. Likewise, no effect was noted on intrastrand adduct repair. There was no effect on apoptosis for this combination. This synergy is observable even in CDDP resistant cell line, but if the cell is Tam resistant then the synergy is lost. There seems to be no ER interaction as well, nor on calmodulin content or function. There did seem to be some interaction with the antiestrogen binding site. A clinical trial of CDDP (100 mg/m2) q3 weeks for melanoma patients, when failing, they then receive Tam 40 mg qid x 1 then 20 mg/day x 3 weeks. The toxicity was not enhanced with Tam. Initially 3/14 responded to CDDP and thereafter 3/20 (resistant patients) responded. There is also a lower rate of resistance to the emergence of CDDP resistance (both in ovarian and melanoma cell lines). A study of I A therapy of CDDP into low blow H&N cancer patients with simultaneous Na2S2O3 peripherally. A phase I trial was initiated and therapy intensified to 150 mg/m2/week x 4 (17 patients receiving 62 infusions) and salt wasting nephropathy noted at 200 mg/m2 was not seen at 150 mg/m2 OB 22 previously untreated 9 CR, 10 PR (86 percent) and of 16 recurrent patients there were 4 CR and 6 PR (62 percent). Now they are testing this regimen with conventional course irradiation.
Dr. Spriggs discussed studies of inhibition of GSH by BSO and attempts to sensitize cells to CDDP cytotoxicity. He performed a phase I trial of BSO +LPAM. By itself BSO was not toxic even at 13 gm/m2/dose, however, myelotoxicity was worse with BSO + LPAM (compared to L-PAM alone). Even at the maximum BSO dosage, only 40 percent of GSH is inhibited.
Dr. Sone then described his research, focusing on immunologic means of inhibitory MDR-1 function. There are more than ten MoAbs that recognize extracellular and three the intracellular domain. MRK 156 and MRK 17 can demonstrate effects on MDR+ human ovarian cell lines. Both of these MoAb induce ADCC, and he is studying methods to augment this ADCC by utilizing cytokines. Using the cell line target, MCSF resulted in best enhancement of MoAb killing. He constructed a MCSF plasmid to transduce the tumor to enhance immunogenicity. Using as little as 5 percent gene modified MDR+ ovarian cancer cells transfected with MCSF, the administration of MRK-17 can be powerfully effective.
Dr. Ogawa reviewed several active new agents being studied in Japan and attempts to modify drug resistance. CPT-11 demonstrates active even in MDR 1 expressing cell lines. In NSCLC, patients with prior therapy do not respond (compared to 32 percent PR in those previously untreated). MX2 is another active agent (anthracycline analog) which is active in murine tumors resistant to DOX.

PARTICIPANTS

United States

Dr. William Beck
St. Jude Children's Res. Hosp.
P.O. Box 318
3 32 N. Lauderdale
Memphis, TN 38101

Dr. Susan Cole
Cancer Research Laboratories
Queen's University
Botterell Hall, Room 331
Kingston, Ontario, K7L 3N6 Canada

Dr. William Dalton
Arizona Cancer Center
University of Arizona
1515 N. Campbell Ave.
Tucson, AZ 85724

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

Dr. Stanton Gerson
Case Western Reserve
University of Med. Sch.
Univ. Hosp. of Cleveland
2074 Abington Rd.
Cleveland, OH 44106

Dr. Stephen Howell
Dept. of Medicine-0812
University of California
San Diego
9500 Gilman Drive
La Jolla, CA 92093-0812

Dr. David Spriggs
Memorial Sloan-Kettering Cancer Center
1275 York Avenue
New York, NY 10021

JAPAN

Dr. Shinichi Akiyama
University of Kagoshima
8-35-1, Sakuragaoka
Kagaoshima 890

Dr. Toshiwo Andoh
Aichi Cancer Center
1-1, Kanokoden Chikusa-ku
Nagoya 464

Dr. Nobumasa Imura
University of Kitazato
5-9-1, shirogane Minato-ku
Tokyo 108

Dr. Michihiko Kuwano
University of Kyusyu Faculty of Med.
3-1-1, Umaide Higashi-ku
Fukuoka 812

Dr. Yoshiro Niitsu
Sapporo Medical College
Nishi 16, Minami ichijyo, Chuo-ku
Sapporo 060

Dr. Makoto Ogawa (Coordinator)
Aichi Cancer Center
1-1, Kanokoden Chikusa-ku Nagoya 464

Dr. Nagahiro Saijo
National Cancer Center Hospital
5-1-1, Tsukizi Chuo-ku
Tokyo 104

Dr. Saburo Sone
University of Tokushima Faculty of Med.
2-50-1, Kuramoto-Cho
Tokushima 770

Dr. Takashi Tsuruo (Organizer)
Molecular and Cellular Biosciences
University of Tokyo
1-1-1, Yayoi Bunkyo-ku
Tokyo 113

Dr. Kazumitsu Ueda
Kyoto University Lab. of Biochemistry
Oiwake-cho Kitashirakawa Sakyo-ku
Kyoto 606-01

Dr. Junji Yodoi
University of Kyoto
Kawaramachi 53, Shogoin Sakyo-ku
Kyoto 606-01



(2)Seminar on "Preclinical and Clinical Studies of New Anticancer Drugs"
This workshop was held February 25–26, 1994, in Kauai, Hawaii.
Dr. Tsuruo described various drugs to circumvent pleiotropic drug resistance. MS-209, which is an analog of quinoline and was developed in Japan, has shown superior activity on circumvention of pleiotropic drug resistance in vitro and in vivo experimental system and cardiac toxicity compared to verapamil. The compound was entered into a clinical phase I trial. KW-2149, which is an analog of mitomycin C has shown superior anticancer activity over the mother compound and was effective on cancer cell lines resistant to mitomycin C. The compound was not activated with P-450 and the cytocidal effect was enhanced by glutathione, which is known to act on detoxication of mitomycin C; and therefore, KW-2149 has mechanism of action different to that of the mother compound. Dr. Sikie described that Pglycoprotein has been expressed in various tissues including CNS, liver, kidney, adrenal gland, colon, and others and cells such as hemopoietic stem cells, and then presented clinical results of cyclosporin A (CSA) and PSC-833, an analog of CSA. When CSA was administered in combination with adriamycin a etoposide, grades and incidence of gastrointestinal toxicities were increased. This was judged to be related to increased AUC of these drugs and, therefore, hematologic toxicities were also enhanced.
Dr. Aiba presented results obtained in preclinical studies of a combination consisting of 5-fluorouracil (5FU) and CPT-11 using colorectal cancer cell lines. When 5FU was administered sequentially prior to CPT- 11, the cytocidal effect of drugs was synergistic, while the reversed order was less effective. A similar finding was observed in a sequence of a combination regimen consisting of edatrexate and 5FU.
Dr. Matsuda presented a summarized result of phase II trials of CPT-11 against nonsmall cell lung cancer (NSCLC). An overall response rate exceeding 20 percent was noted in previously untreated patients with NSCLC. A phase I trial, in order to determine an optimal dose of CPT-11 in combination with CDDP 80mg/m2, decided 70mg/m2 to be optimal. Phase II trial of a combination regimen consisting of CDDP 80mg/m2 CPT-11 60mg/m2 on days 1 and 8 was conduced on NSCLC. Of 59 patients, there were 1 complete response and 32 partial responses with an overall response rate of 48 percent and a median survival time was ten months.
Dr. Rothenberg reviewed CPT-11 studies in the U.S. of 45 patients with advanced colorectal cance. There were one complete response and ten partial responses with an overall response rate of 24 percent and a median survival time was more than ten months.
There was one case of attained complete response of liver metastasis lasting more than six months. Phase II trials on colorectal cancer conducted in MSKCC and the Mayo Clinic attained response rates exceeding 20 percent. CPT-11 was effective against cervical cancer. A phase I trial combining CPT-11 and 5FU plus leucovorin is in progress.
Dr. Ogawa summarized results obtained in phase II trials of SM-5887 (an analog of adriamycin) and MX-2 (an analog of carminomycin). SM-5887 exhibited significant activities on NHU; and therefore, a double blind prospective randomized trial comparing adriamycin versus SM-5887 on NHL is in progress. MX-2 demonstrated significant activities on hematologic tumors.
Dr. Baker described preclinical and clinical studies of pyrazoloacridine(PZA). PZA was effective against various solid tumor cell lines including especially hypoxic cells and dormant cells. Dose limiting toxicity (DLT) seen in phase I trials differed by schedules.
The DLT by one hour infusion was both neurotoxically and hematologically toxic, while the DLT by three-hour infusion was hematologic. Responses were seen in ovarian cancer, cervical cancer, and colorectal cancer during phase I trials.
Dr. Saijo presented results of preclinical studies on drug resistance of taxotere. They produced a resistant cell line to taxotere after repeated exposure to the drug and studies characteristic of the resistance cell line. Taxotere has cross resistance to taxol and VP 16 but not to CDDP. Verapamil reversed the resistance. In clinical trials, they treated 15 patients with NSCLC by 24 hours CV1 of taxol and obtained three partial responses (20 percent).
Dr. Friedman summarized effectiveness seen in phase II trials of taxol in the U.S. Taxol obtained response rates ranging from 20 to 50 percent in ovarian cancer, 18 to 62 percent in breast cancer, 21 to 24 percent in NSCLC, 34 percent in SCLC and 40 percent in head and neck cancer. On the other hand, the drug was not active for renal cell cancer, prostatic cancer, and colorectal cancer. Taxol was synergistic in combination with CDDP, adriamycin, edatrexate, estramustine, and others in preclinical study. Phase II trials using these combinations are in progress.
Dr. Shimosaka described results of preclinical studies of spikamycin and its analog. Spikamycin was found in a screening system of differentiation agents active against MX-1 (breast) and LX-1(lung) in nude mice. Among various analogs developed, KRN 5600 was selected as a condidated compound for clinical trials and the compound showed superior activity on both gastric cancer and colon cancer xenografts over mitomycin C. Preclinical toxicology is in progress.
Dr. Miller reviewed clinical results of cytokines used for protection of thrombocytopomia. Thrombocytopenia of grade 4 occurs 0.4 percent by CAF for breast cancer and 16 percent CAE for SCLC but mortality rates were very low. On the other hand, thrombocytopenia frequently occurs during induction chemotherapy for acute leukemia and the mortality rate was 2. Severe thrombocytopenia occurs in 100 percent in AUBMT and the mortality rate was 1.6. Therefore, thrompoietic agents are necessary for treatment in acute leukemia and AUBMT. Various cytokines are now in clinical trials. Interleukin-1 increased platelets; but toxicities such as hypotension and edema were profound and, therefore, it was judged to be not useful.
Interleukin-3 was effective for thrombocytopenia induced by chemotherapy but headache was the DLT and influenza-like symptoms occurred frequently. Clinical trials of GM-CSF, PIXY321, interleukin-6, and interleukin-11 are in progress.
Dr. Fukuoka summarized clinical results of various antimetabetites studied in Japan. A phase I trial of gemicitabine, an analog of Ara-C was concluded. The DLT was hematologic and a MTD was decided to be 1000mg/m2.
An ongoing phase II trial on NSCLC has shown a response rate exceeding 20 percent. DMDC, an analog of ARa-C, which was developed in Japan, is now in phase I trial; and the DLT appears to be hematologic.
Dr. Ariyoshi summarized clinical results of CDDP analog studied in Japan. In phase II trials 254-S exhibited significant activities on head & neck cancer, esophageal cancer, NSCLC, SCLC, ovarian cancer, and cervical cancer and; therefore, applied for commercial use. Clinical studies conducted in France indicated that 1-OHP is active on ovarian cancer, malignant melanoma, and glioma and confirmatory studies are in progress in Japan.
Dr. Rabor described results of several drugs. UFT, which is a conjugate of uracil and ftorafur, demonstrated significant activity on colorectal cancer by combining with leucovorin. Phase I trials of tomudex, a TS inhibitor, indicated that the DLT was hematologic and a MTD was 3.5mg/m2. An ongoing phase II trial has obtained responders in advanced colorectal cancer. BR-96 doxorublein is a conjugate of monoclonal antibody and doxorubien developed in order to distribute doxorubien selectively in tumor tissues. The conjugate is now in phase I trial.

PARTICIPANTS

United States

Dr. Laurence Baker
Wayne State University
3990 John R Street
1 Brush South
Detroit, Michigan 48201-2018

Dr. Martin Raber
University of Texas Cancer Center
Box 92
1515 Holcombe Boulevard
Houston, Texas 77030-4009

Dr. Mace Rothenberg
University of Texas Health Science Center at San Antonio
Division of Oncology, (111-J)
7703 Floyd Curl Drive
San Antonio, Texas 78284-7701

Dr. Branimir Sikic
Stanford University
Oncology Division—Room M-211
Stanford, California 94305-1901

Dr. Langdon Miller
National Cancer Institute
Executive Plaza North, Room 715
Bethesda, Maryland 20892

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

JAPAN

Dr. Keisuke Aiba
Cancer Chemotherapy Center
1-37-1 Kami-ikebukuro Toshima-ku
Tokyo 170

Dr. Yutaka Ariyoshi
Aichi Cancer Center
1-1. Kanokoden Chikusa-ku
Nagoya 464

Dr. Masahiko Fukuoka
Osaka City General Hospital
2-13-22 Miyakojimahondori, Miyakojima-ku
Osaka 534

Dr. Noriyuki Masuda
Habikino Hospital
3-7-1 Habikino, Habikino-city
Osaka 583

Dr. Makoto Ogawa
Aichi Cancer Center
111 Kanokoden Chikusa-ku
Nagoya 464

Dr. Nagahiro Saijo
National Cancer Center Hospital
5-1-1 Tsukizi Chuo-ku
Tokyo 104

Dr. Akihiro Shimosaka
Kirin Brewery Company
Nikko Motoyoyogi Bldg, 30-13
Motoyoyogi-cho, Shibuya-ku
Tokyo 150

Dr. Takashi Tsuruo
Molecular and Cellular Bioscience,
University of Tokyo
1-1-1 Yayoi Bunkyo-ku
Tokyo 113



(3)Seminar on "Breast Cancer—Adjuvant and Neoadjuvant Approaches"
The third US-Japan meeting on therapy was held in Oakland, California, on March 10–11 1994. This meeting dealt with features of adjuvant approaches and neoadjuvant approaches utilizing new techniques. It began with discussions of breast cancer patients, and Dr. Fisher described two decades of research with the NSABP. He demonstrated the efficacy of cancer as an adjuvant and proper dose intensity as important. Based upon solid preclinical data, study B-18 evaluated pre- versus postoperative adjuvant cancer on all patients receiving surgery. Correlations with ER, ploidy, size, other markers, nodal status, and a response of primary tumors are of real interest. Study B 18 completed accrual (1500 patients) in April 1993 and 80 percent of patients responded to preoperative cancer (38 percent complete response) and only 4 percent had progressive disease. The best responses were seen in the smaller primary tumor size. There also seemed to be some downstaging of lymph node status with preoperative cancer. He hopes to determine if preoperative complete response rate is a true surrogate for overall, long-term survival.
Dr Tajima next presented his data with high-dose therapy supported by PBSC for breast cancer patients. Based upon data largely derived from U.S. studies, enthusiasm for this approach increased. At Takai University, 22 patients were treated with HDCT and ABMR; and in an uncontrolled trial, there appeared to be some advantage. The doses of Cytoxan + Adriamycin + ACNU were only modest initially, but escalated in more recent trials.
Dr. Ogawa presented an overview of adjuvant trials in gastric cancer patients. The initial study (714 patients) was flawed by a 26 percent exclusion rate, and the Mitomycin C group had a better survival. In subsequent studies MFC + Ft seemed to be superior (two separate protocols). In general, somewhat more Stage I-II patients are being diagnosed and these patients have a better outcome compared to Stage III or IV. It is not possible to show benefits for adjuvant therapy for Stage IV or I patients and only inconsistent findings have been noted for Stage II or III patients.
Dr. Noto presented data on immunochemotherapy for colorectal cancer patients utilizing PSK (a nonspecific immunopotentiator extracted from a fungus). Patients received either MMC + 5FU or in combination with PSK for three years. There was no particular abrogation of recurrence pattern. Overall, however, the number of patients in each group was quite small.
Dr. Nakai discussed his studies in 139 patients with HCL who underwent hepatic resection between 1981–1993; about 50 percent could be resected for "cure." As expected, most patients failed locally in liver ruminant. Patients at high risk of failure of local primary therapy received 1A chemotherapy. Since 1990, 23 cases (Stage III) were treated with 1A CT (ADM, MMC, 5FU, CDDP alone or in various combinations). It is clear that postresection 1A CT can be safely given with possible demonstration of benefits.
This session was concluded by Dr. Haller who reviewed the U.S. experience in a comprehensive manner. He discussed the prognostic factors of relevance—stage, gender, T levels, etc., and described the available chemotherapy. Clearly, the addition of leucovorin to 5FU results in superior response rates. Also, protracted IV infusion seemed to have better response rates. The use of 5FU + Levamisole provides a 57 percent vs. 41 percent survival rate of seven years for Dukes' C patients (for B2 patients the trends are similar but not statistically significant). Interestingly, the use of intraportal 5FU immediately postoperative does confer some survival benefit but no improvement in hepatic recurrence (as the initial site of failure).
Dr. Hirabayashi discussed approaches to patients with gynecologic cancers in Japan. For patients with advanced ovarian cancers, temporary blockage of vessels was achieved intraoperatively to examine tissue extraction. For 66 Stage III or IV patients, PAC was utilized preoperatively and only one patient had a complete response and 47 had partial responses. For patients with cervical cancer, combinations of CDDP with other agents yielded high partial response rates (~80 percent). A total of 49 Stage II-IV cervical cancer patients were treated with CDDP + IFOS + PEPBLEO and a 70 percent response rate noted. He believes that neoadjuvant approaches are ideal for both cervical and ovarian cancer patients.
Dr. Eisenberger described studies being performed for prostate cancer patients. Patients with more extensive local disease, high PSA, or high Gleason's score are good candidates for combined (neo-adjv) approaches. Nomograms have been developed to try to distinguish between PSA elevations associated with local versus distant recurrences. Combinations of LHRH + Flutamide are superior to LHRH alone especially in good risk, low volume Stage D patients. It has been suggested that diploid patients may also have a better prognosis. Studies of a gene therapy using a GM-CSF infected autologous vaccine are soon to be initiated.
Dr. Akazu reviewed the studies on intravesical therapy for superficial bladder cancer patients. It appears that while the initial recurrence post TURB can be prolonged, overall recurrence rate and survival are not affected. This seems to be true for ADM or MMC. BCG has an exceedingly high complete response rate (60 percent for T1 and 80 percent for CIS) and is reasonably well tolerated. He also noted that GST M genotype may be more sensitive to carcinogens (for both lung and bladder). A randomized trial for Ta or T1 patients utilizing placebo control or BPL was totally negative.
Dr. Kotake concluded this session on GU cancers with his discussion of innovative endocrine approaches to prostate cancer patients. Thirty patients with B2 or C disease received four months of endocrine therapy followed by prostatectomy and then adjuvant endocrine therapy. It was not clear that significant downstaging occurred. A similar study using radiation as the primary modality was initiated and a 60 percent five-year survival rate was noted.
Dr. Inuyama presented a discussion of adjuvant treatment of head and neck cancer patients. He described a phase II neoadjuvant trial of maxillary sinus carcinoma utilizing CDDP + Pepbleomycin given via the temporal artery followed by RT + 1A 5FU and then surgery (if possible). Complete response was noted in 12/28 to neoadjuvant therapy (12/20 also had partial response). Overall, there was a 53 percent five-year survival. A second study of concurrent RT + CBDCA on a total of 43 evaluable patients (various primary sites) with 53 having Stage III–IV disease was described (40 Gy + 100 mg/m2/week). Of special interest were 29 laryngeal cancer patients—93 percent were NED at three years and 20/29 had larynx preservation. A randomized study is being planned. Finally, he presented data on VFT for adjuvant therapy for stage II–IV (Mo) receiving surgery. A total of 398 were randomized and the three-year survival was indistinguishable (73 vs. 78 percent) as was the DFS (73 vs. 66 percent).
Dr. Forastierre offered a presentation dealing with esophageal cancer. She noted the changing epidemiology–move adenoma, ge junction, etc. There are three different approaches being pursued–chemo, surgery and chemoradiation alone. For preoperative CT, 40–60 percent respond but few complete responses and there was no discernible impact on survival. There are also two studies of chemoradiation which demonstrate superior survivorship (compared to RT alone). There was, however, a substantial local failure rate (44 percent at one year). Using pre-operative CT (5FU 300 mg/d CIVI for 21 days, CDDP 100mg/m2 for three weeks, Velban 1 mg/m2/d x 3 for three weeks), combined with hyperfractionated thoracic RT in 43 patients, 36 had a potentially curative resection and about 30-35 pecent five-year survival. Even patients with positive resection were alive at five years.
Dr. Robert Livingston reviewed a series of studies of locally advanced (but not metastatic) NSCLC patients. In general, less extensive disease responded better to CDDP based therapy. One study of CDDP (100 mg/m2) + VLB 5 mg/m2/wk k5 in ten patients demonstrated better survival (14 vs. 9 mo M ST and 10 percent vs. 7 percent five-year survival). Chuno radiation is now standard treatment for Stage III patients. One study of COD 50 mg/m2 Day 1, 8, 29, 35 + VP16 50 mg/m2 Day 1–5, 29–35 plus RT preceeding thoracotomy (if appropriate), demonstrated about 25 percent three years survival. A randomized study compared to CT & RT has been initiated to help determine the value of surgery.

PARTICIPANTS

United States

Dr. Robert Livingston
University of Washington
UW Medical Center, Room 3945
1959 NE Pacific Street
Seattle, Washington 98195-0001

Dr. Arlene Forastiere
Johns Hopkins Oncology Center
600 N. Wolfe Street
Baltimore, Maryland 21287-0002

Dr. Daniel Haller
University of Pennsylvania
6 Penn Center Plaza
3400 Spruce Street
Philadelphia, Pennsylvania 19103-2901

Dr. Bernard Fisher
University of Pittsburgh
School of Medicine
3550 Terrace Street
Room 914
Pittsburgh, Pennsylvania 15261

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

JAPAN

Dr. Yukio Inuyama
Professor, Hokkaido University
School of Medicine
7-15 Uyonishi Kita-ku-Kita
Sapporo 060

Dr. Tomoo Tajima
Professor, Tokai University
School of Medicine
Boseidai Isehara City
Kanagawa 259-11

Dr. Kakehiro Nakai
Professor, Wakayama Medical College
27 Kyubancho Wakayama City
Wakayama 640

Dr. Higeyuki Akaza
Associate Professor
University of Tsukubsa City 305

Dr. Toshihiko Kotake
The Center for Adult Disease, Osaka
1-3-1 Nakamichi Higashinari-ku Osaka 537

Dr. Kohiji Hirabayashi
National Fukuyama Hospital
4-14-17 Okinoue-cho Fukuyama City 720

Dr. Makoto Ogawa
Aichi Cancer Center
1-1 Kanokoden Chikusa-ku Nagoya 464