139

Influence of pretreatment clinical characteristics on the response rate to mitomycinlvindesineicisplatin (MVP) in unresectable non- small cell lung cancer Riggi M, Ruffie P, Voisin S, Monnet I, De Cremoux H, Saltiel JC et al. lnstilul Gusrave Roussy. Unire La Grange, 77176 Savlgny Le Temple. Eur J Cancer 1991;27:1238-42.

The authors report their experience with the MVP (mitomycinl vmdesine/cisplatin) regimen of the Memorial Sloan-Kettenng Cancer Center (MSKCC) which showed the highest response. rate in non-small cell lung cancer (NSCLC). The aim was to respect the original reported schedule to appreciate its activity, because the same drug combination with dose and schedule variations used by other investigators has failed to reproduce the original report results. 82 consecutive previously untreated patients with unresectable and/or m&static NSCLC received mitomycin(8mg/m2days 1,29,71), vindesine (3 mg/m2,days I. 8, IS, 22, 29, 43, 57, 71) and cisplatin (120 mg/m’, days 1, 29, 71), with evaluation on day 71. 24 objective responses were noted (29%) (2 complete response/22 partial response) (95% CI l9%-39%), without differences according to histology. Differences in median survival were noted according to the performance status and type of response. Overall survivalratesinrespondingpatients were simdartothosenoted withthe original schedules. Analysis of selection criteria showed that there were more patients with bone (P < 0.01) or hver metastases (P < 0.05), less women (P < O.OOl) and less adenocarcinoma (P < 0.001) than the MSKCC trial. A dose intensity analysis showed only a minimal differ- encein theaverageweeklydosesofvindesine (IO% lowerthan MSKCC trial: I.8 mg/m* vs. 2.25 mg/m’). Disease improvement, a subjective response criterion used in the MSKCC trial, was probably underesti- mated in the current study. We conclude that the potential benefit of chemotherapy with a three-drug combination in NSCLC is greatest in patients with stage IIlaand IlIbdiseaseor stage IV dwase wilb agood performance status and a low metastatic volume.

Activity of high-dose epirubicin in advanced non-small cell lung cancer Martoni A, Melotti B, Guaraldi M, Pannuti F. Division ofOncology, S. Orsola-Malpighi Hospital, Via Aibertoni 15. 40138 Bologna. Eur J Cancer 1991;27:1231-4.

24 patients with unresectable non-small cell lung cancer (NSCLC) ‘(14 slage IIIB and IO stage IV) with a performance status of 70% or higher and without liver metastases received 120-165 mp/m’epirubicin as an intravenous bolos every 21-28 days up to the maximum cumula- tive dose of 900 mg/m*. 6 patients (25%) (95% confidence limits 9.8- 46.7%) achieved partial remission for a median duration of 7.5 months (range: 3- 13+). The median dose actually administered per course was 120 m&n2 in responsive and non-responsive patients. The dose- limiting side-effect was neutropenia. 1 patxntreceiving the higher dose died of drug-related infection. Other non-dose-relaled grade 3 side- effects were alopecia (100%) and vomiting (17%). In 4 patients, the treatment was interrupted because of a >lO% reduction in the left ventricular ejection fraction as calculated by radionuclide angiocardi- ography. None of these patients suffered from cardiac symptoms. The median survival was IO months (range l-16). These data suggest that

epirubicin at 120-135 mg/m2may have higherantitumouractivily than

standard doses in patients with NSCLC. Further studies are needed to clarify whether OT not high-dose eplrubicin increases, the risk of cardiotoxicity compared to standard doses.

Lack of cross-resistance to fostriecin in a human small-cell lung carcinoma cell line showing topoisomerase II-related drug resis- tance De Jong S, Zijlstra JG, Mulder NH, De Vries EGE. Division ofMedical Oncology. Department ofInrernalMedicine, University Hospilal, P.O. 30.001.9700RB Groningen. Cancer Chemother Phannacol 1991;28:461- 4.

Cells exhibiting decreased topoisomerase II (Topo II) activity are resistant to several drugs that require Topo II as an intermediate. These

drugs are cytotoxic due to the formation of a cleavable complex

between the drug, Topo II and DNA. Fostriecin belongs to a new class of drugs that inhibit Topo II without inducing the formation of this

cleavable complex. We tested fostriecin in three human small-cell lung carcinoma cell lines. GLC, is the parent line. GLC,/ADR is the P- glycoprotein-negative multidrug-resistant subline, which is resistant 10

several Top0 II inhibitors due to its decreased Topo II activity. GLC,/ cDDP is the cisplatin-resistant subline, which displays increased Topo II activity. Topo II activity proved to be 100% in GLC,, 35% in GLC,/ ADR and 130% in GLCJcDDP. The fostriecm concentration causing inhibition of the growth of 50% of the cells (IC,,) in the microcullure tetrazolium assay following continous incubation was 11.2,4.1 and

14.9 pM, respechvely. After I-h incubations, the IC,,was 117.8,101.3 and 219.8pM,respectively.Ourresultsindicatearelationshipbetw~n Topo II activity and fostriecin sensitivity in these closely related cell

lines. AI least in vitro, fostriecin displayed the capacity to kill cells showng resistance to drugs due to decreased Topo I1 activity. There was no relationship between this capacity and an increase in theactivity of the reduced-folate carrier system, the proposed mechanism for cellular entry of fosuiecin, since we found no correlation between the cytotoxity of fostriecin and that of methotrexate.

A randomized trial with mitomycin-Ciifosfamide versus mitomy- tin-C/vindesine versus cisplatin/etoposide in advanced non-small- cell lung cancer Gatzemeier U, Heckmayr M, Hossfeld DK, Kaukel E, Koschel G, Neuhauss R. Department of Thoracic Oncology (11 Grosshansdorf Hospifal. CenlerofPneumology andThoracic Surgery. Woehrendamm 80. D-2070 Grosshansdorf. Am J Clin Oncol Cancer Clin Trials 1991;14:405-11.

192 evaluable patients with advanced inoperable non-small-cell lung cancer were treated with either mitomycin-C/ifosfamide (A), mitomy- tin-C/vindesine (B), or cisplatin/etoposide (C) in a prospective ran- domized trial. The response rates for each treatment arm were 30.0% (A), 22.7% (B), and 25% (C), respectively. There was no statistically significant difference (p = 0.4) between treatment arms. The median survival time was 27 weeks (A), 23 weeks (B), and 25 weeks (C), respectively. With regard to toxicuy the combination mitomycin-C/ vindesine was superior to treatment arms A and C. Nausea and vomiting (WH03+4)occurredonlyin6.l%ofthepatientsversus43.3%ofthose treated with mitomycin-C/ifosfamide and 36.7% of those treated with cispIatin/etoposide. Thisdifference is statistically highly significant @ = O.OOOl). Because of its very low toxicity, especially for gasuointes- tinal symptoms, the combination mitomycin-C/vindesine was judged superior to the other combinations. None of these regimens, however. had a major impact on survival in advanced non-small-cell lung cancer.

Phase II trial of high-dose cisplatin plus etoposide plus vinblastine in non-small-cell lung cancer. A hoosier oncology group study Eklund E, Miller ME, Ansan R, Fisher WB, Einhorn LH. Hoosier Oncology Group. Walther Cancer Instirule. 3202 Noah Meridian Slreef, Indianapolis, IN 46208. Am J Clin Oncol Cancer Clin Trials 1991;14:412-5.

Fifty-one patients with advanced non-small-cell lung cancer were treated onaHoosierOncoIogy Group protocol withanaggressive. high- dose cisplatin combination chemotherapy regimen. All patients had a Kamofsky performance status of 80% or higher and had no prior chemotherapy. The drug regimen consisted of cisplatin 30 mg/mz days one through five, emposide 40 mg/m’ days one through five. and vinblastine 5 mgfm2 day one. Therapy was given every three weeks for a total of three courses. Forty-five patients were evaluable for response and an objective response was seen in I5 patients (33%) with only one complete responder. The median duration of response was 16.5 weeks. The median survival for the entire group was 29.0 weeks. Toxicity was moderately severe with two treatment-related deaths (4%). Despue an aggressive chemotherapy regimen in a favorable patient population,

there was no obvious evidence of a major therapeutic value.