A randomized multicentre trial comparing sequential with alternating chemotherapy in small cell lung cancer (SCLC)

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i000 mg/g 2 i . v . d , i, vincristine (VCR) 1.3 mg/m- i . v . d , i(+ weekly the first 4 wks) and methotrexate (MTX) 20 mg/m p.o. d. 15 + 18, alternating with B: etoposide (VP-16) i00 m g / m - 2 P . O . d . 29.32, doxorubicin ~ADR) 40 mg/m i . v . d . 29 and VCR 1.3 mg/m- d. 29, followed by A d. 50, etc. 66 and 71 pts were randomized to receive an alternating or a continuous regimen, respectively. Regimen II: was identical with I for the first 7 wks when A + B wa~ followed by C: Cis-platinum (DDP) 275 mg/m i . v . d . 50, vindesin (VDS) 3 mg/m i . v . d . 50 an~ d. 64 and hexamethylmelamine (HX) 200 mg/m p.o. d. 58-71, followed by A d. 78. Regimen III was: C C ~ , CTX and VCR as in A plus VP-16 75 mg/m p . o . d . 2-5, ~. 4 wks., with addition ~f: DDP 75 mg/m i . v . d . 2^or ADR 40 mg/m- i . v . d . ½5 or VDS 3 mg/m z i . v . d . 15 or MT~ 20 mg/m p . o . d . 15 + 18 or HX 200 mg/m- p . o . d . 8-22 - returning to DDP in cyclus no six. The aims of these additions was to widen the therapeutical spectrum of an effective continuous regimen. Pts characteristics were: bone marrow disease in 41%, liver metastases in 29% (of the 83% in whom peritoneoscopy was possible), serum LDH elevated in 73% and performance status (PS) 3-4 in 32%. The differences in survival between the three groups were not significant, median values being 30, 32 and 30 wks, respectively. Complete remissions were observed in 18%, 21% and 21% of all included pts. Median survival of CRs were 64, 70 and 44 weeks, respectively, (p = 0.02 for A vs. C). The two alternating regimens are therefore supposed to lead to superior long-term results. Canadian Multicentre Randomized Trial Comparing Sequential (S) and Alternating (A) Administration of Two Non-Cross Resistant Chemotherapy Combinations in Patients with Limited Small Cell Carcinoma of the

Lung (SCCL). Feld, R., Evans, W.K., Coy, P., Hodson, I., MacDonald A.S., Osoba, D., Payne, D.G., Pater, J.L. National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario. In this trial which closed to accrual in October 1984 patients with limited SCCL were randomized to receive either23 courses of IV cyclopho~phamide (i000 mg/m ), adriamycin (50 mg/m-) and vincristine (2 mg) (CAV) fol~owed by 3 courses of VP-16 (i00 mg/m- days 1-3) and cisplatin (25 mg/m 2 days 1-3) VP/PT (S) or 6 courses of alternating CAr and VP/PT (A). Responding patients received prophylactic cranial irradiation after 3 courses of chemotherapy and thoracic irradiation after 6 courses. No maintenance chemotherapy was given. Of a total of 333 patients randomized 297 (145 on S and 152 on A) were eligible and

are currently evaluable for response after 6 courses of chemotherapy. Most patients had a good performance status (251 with ECOG 0 and i). The overall response rate was 76% (45% CR and 31% PR) after 6 courses. The CR rate for S was 42% and for A was 48%. The projected overall median survival time is 54 weeks (S 60 weeks and A 58 weeks). The overall projected 2 year survival is 19% (S 19% and A 19%). In general, the chemotherapy and radiotherapy were well tolerated but there were 7 treatment related deaths (5 on S). Neutropenia (< 500/ul) occurred in 61% of patients with approximately equal frequency on the two arms but more often on CAV. Thrombocytopenia (< 50,000/ul) occurred less frequently (10%) but was more often seen on VP/PT. Hemorrhage (< 1%) and infection (7%) were infrequent. These preliminary data suggest both methods of administering 2 non-cross resistant chemotherapy combinations are equally effective, but S may be somewhat more toxic. A Randomized Multicentre Trial Comparing Sequential With Alternating Chemotherapy in Small Cell Lun~ Cancer (SCLC). Havemann , K., Holle, R., Gropp I, C., Klapsing I, J., Becker, H., Dirks, P., Drings, P., Graubner, M., H~ssler, R., Hanse, K., Heim, M., Mende, S., Pfannschmidt, G., Schroeder, M. i. Department of Haematology/Oncology, University of Marburg, Marburg, FRG. Between July 81 and November 83, 305 patients from 15 institutions were randomized to receive either 8 cycles of sequential chemotherapy with cyclophosphamide, adriamycin and vincristine (CAV) or a strictly alternating regimen including the 3 combinations VPIV (etoposide, ifosfamide, vindesine: cycles 1,3,5), PAV (cisplatinum, adriamycin, vincristine: cycles 2, 4, 6) and CMCC (cyclophosphamide, methotrexare, CCNU: cycles 7, 8). In addition to cytostatic drug therapy, responding patients received prophylactic cranial irradiation and chest irradiation. Final results of the study are presented, with complete follow-up for all patients except long-term survivors. Patients under the alternating regimen (group B) have prolonged median survival (ii months vs. i0 months, p < 0.05) in comparison to those with sequential chemotherapy (group A), but the clinical practicability of regimen B is limited by a higher degree of side effects, especially hyperemesis. Treatment B is shown to have a significantly higher response rate (88% vs. 78%, p < 0.05) and a longer relapse-free interval, with 21% vs. 9% of patients relapse-free at one year after randomization (p < 0.01). Whether the superiority of treatment B is due to the alternating application or to the use of more effective drugs cannot be decided from the data. The standard drug combination CAV, however, can no longer be considered as optimal in the treatment of SCLC. Preliminary data of our new clinical trial using VPI (etoposide, ifosfamide) also

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indicate an advantage above CAV treatment. Supported by the BMFT.

Canadian Multicenter Randomized Trial Comparing Standard (SD) and Alternating (A) Combination Chemotherapy in Extensive Small Cell Lung Cancer (SCLC). Evans, W.K., Murray, N., Feld, R., Coy, P., Clarke, D., Levitt, M., Shelley, W., Pater, J. National Cancer Institute of Canada Clinical Trials Group, Kingston, Ontario. Patients with extensive SCLC were randomized to receive either 6 ~ourses of i.v. cyclophosphamide 1009 mg/m-, doxorubicin (adriamycin) 50 mg/m- and vincristine 2 mq (CAV) at 3 week interval~ or CAV alternating with VP-I~ 100 mg/m- days 1-3 and cisplatin 25 mg/m days 1-3 q 3 weeks for 6 treatment cycles. Responding patients received prophylactic cranial irradiation after 3 courses of chemotherapy. No maintenance chemotherapy was given and thoracic irradiation was only used to palliate persistant or recurrent local symptoms. Two hundred and thirteen of 230 patients randomized prior to Sept. i, 1984 were eligible for study (i01 on SD; 112 on A). Most had a good performance status (62% ECOG 0, l) and the two groups were well balanced for known prognostic factors. Of the 187 patients evaluable for response, 57% were classified as responders after 6 courses (17% CR; 34% PR). The response rate (CR + PR) was higher on A (61% vs 39%, p<.01) and the median progression free survival was also superior (A=30 wks SD=23 wks, p=0.001). The median survival time of the whole group was 37 wks (A=40 wks, SD=34 wks, p=0.056). The frequency of thrombocytopenia and severe GI toxicity was slightly greater on A but the frequency of neutropenia and infection was less. This preliminary analysis suggests that A is a better treatment approach for extensive SCLC.

Feasibility of in Vitro Growth and Chemosensitivity Testing (CT) of Small Cell Lung Cancer (SCLC) Cells in a Prospective Clinical Trial. Ihde, D., Oie, H., Russell, E., Linnoila, I., Carney, D., Minna, J., Gazdar, A. NCINavy Med. Oncol. Br., Natl. Cancer Inst. and Naval Hosp., Bethesda, MD 20814, U.S.A. Staging procedures performed in SCLC patients (pts) seldom yield specimens containing sufficient clonogenic tumor cells to perform CT for even a single drug. We have tried to circumvent this problem by using cell culture techniques to expand the number of tumor cells before CT with a dye exclusion assay. To determine the frequency with which in vitro CT data could be generated in SCLC pts, we initiated a prospective clinical trial in pts

with untreated extensive stage or recurrent tumor. Only routine staging procedures (bone marrow, paracentesis, biopsy of peripheral nodes or subcutaneous nodules, peritoneoecopic liver biopsy) were used to obtain tumor samples in all but 2 cases. Tumor-containing specimens could be procured from 19 (76%) of 25 consecutive untreated pts. A major surgical procedure would have been required in the remaining 6. Sufficient cell growth to allow CT of 7 or more drugs, usually at 3 concentrations, occurred in specimens from 9 pts (47% of pts with positive specimens). In 9 pts with recurrent SCLC in whom positive specimens were cultured, cell amplification that permitted CT was observed in material from 5 pts (55%). Sufficient cells to generate CT data never resulted unless cytology of the submitted specimen or gross appearance in the culture flask suggested malignant cells were present. In 2 instances C T could be performed after only a few days in culture; the remaining tests were done after 3-10 weeks. There was a wide spectrum of sensitivity to individual drugs among different pts. We conclude that prospective collection of in vitro CT data is feasible with routine staging procedures in a large fraction of pts with newly diagnosed extensive stage or recurrent SCLC.

Anticancer Drug Sensitivity of Lung Cancer Using The Tt~nor Stem Cell Assay. Hiraki, S., Ohnoshi, T., Kishimoto, N., Numata, T°, Kimura, I. Second Department of Medicine, Okayama University Medical School, Okayama, Japan. It would be helpful for successful chemotherapy of cancer patients to know accurate in vitro anticancer drug sensitivity. The purpose of the present study was evaluate the tumor stem cell assay reported by Salmon et al for the selection of effective drugs for individual patients with lung cancer and for the in vitro phase II screening of new anticancer drugs. Specimens were obtained by aspiration of pleural effusions and bone marrows and biopsy of the primary and metastatic tumors. Tumor cells were exposed to drugs for one hour prior to plating. Each drug was tested at two or three dose levels which were achievable clinically. Drugs tested in the present study were adriamycin, aclarubicin, THP-adriamycin, mitoxantrone, 40497S (active form of ifosfamide), mitomycin C and methotrexate. Seventy~eight specimens were obtained from patients with lung cancer and tested drug sensitivity by the assay. Of 78 specimens, 57 (73%) formed at least five colonies per plate. In the analysis of colony growth rates according to histological types, small cell carcinoma was 85%, squamous cell carcinoma 78%, adenocarcinoma 68% and large cell carcinoma 67%. Of these 57 specimens, 39 formed more than 30 colonies in control plates and were able to test drug