A randomized trial of anticoagulation with warfarin and of alternating chemotherapy in extensive small-cell lung cancer by the Cancer and Leukemia Group B.

Abstract

The Cancer and Leukemia Group B (CALGB) conducted a prospective randomized trial to evaluate the role of warfarin and alternating chemotherapy in extensive small-cell lung cancer (SCCL). After stratification for sex and performance status, patients were randomly assigned to receive chemotherapy with methotrexate, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH), cyclophosphamide, and lomustine (CCNU) (MACC), or MACC plus warfarin (MACC + W), or mitomycin, etoposide, cisplatin, and hexamethylmelamine alternating with MACC (MEPH/MACC). Warfarin was given continuously to maintain a prothrombin time of one and one half to twice the control values. A total of 328 patients were enrolled, and 294 were evaluable. There was a statistically significant advantage in objective response rates (complete [CR] and partial responses [PR], respectively) for MACC + W (17% and 50%) as compared with MACC alone (8% and 43%) or MEPH/MACC (10% and 38%) (P = .012). Both failure-free survival (P = .054 Wilcoxon test) and overall survival (P = .098 Wilcoxon test) were higher on MACC + W (median, 6.6 months and 9.3 months, respectively), as compared with MACC (5.0 months and 7.9 months) and MEPH/MACC (5.0 months and 7.9 months). Toxicity was comparable among the three arms, except for increased hemorrhagic events on MACC + W, which were life-threatening in four patients (4%), and lethal in two others (2%). These data support the role of warfarin in the treatment of SCCL, but do not establish its mechanism of action. Warfarin deserves further studies in SCCL, particularly in patients with limited disease.

Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent

“…A total of 19 trials fulfilled the criteria of selection (Table 1; Eagan et al, 1981;Fukuoka et al, 1986Fukuoka et al, , 1991Evans et al, 1987;Haveman et al, 1987;Wolf et al, 1987;Chahinian et al, 1989;Sculier et al, 1990aSculier et al, , 1993Goodman et al, 1990;Smith et al, 1990;Wampler et al, 1991;Kanitz et al, 1992;Roth et al, 1992;Farris et al, 1993;Sculier et al, 1993;Joss et al, 1994;Veronesi et al, 1994;Souhami et al, 1997;Urban et al, 1999). One trial was rejected due to the fact that patients had received chemotherapy prior to randomization as it was a second-line chemotherapy study (O'Bryan et al, 1990).…”

“…Supported by a grant from the French League Against Cancer (Hérault committee). Overall Eagan, 1981Fukuoka, 1986 Haveman, 1987Evans, 1987Chahinian, 1989 Sculier, 1990Goodman, 1990Fukuoka, 1991 Smith, 1990Wampler, 1991Kanitz, 1992Roth, 1992 Sculier, 1993Farris, 1993Veronesi, 1994Joss, 1994Souhami, 1997 Urban, 1999 Meta-analysis of cisplatin in SCLC 13 …”

Impact of Venous Thromboembolism and Anticoagulation on Cancer and Cancer Survival

“…In another study, 328 patients with small-cell lung cancer receiving chemotherapy were randomly assigned to concurrent warfarin or not. 162 A significant improvement in objective tumor response was observed with a trend toward improved overall survival. A subsequent study of warfarin in 347 patients with limited-stage small-cell lung cancer demonstrated no significant improvement in response rate, disease-free, or overall survival.…”

Coagulation and cancer: Implications for diagnosis and management

“…94,96 Experimental and clinical studies suggest that heparin and vitamin K antagonists are effective compounds for the prevention of metastases. 33,107 Data from randomised trials suggest that small-cell lung cancer (SCLC) consistently responds to heparin and vitamin K antagonist, but several other tumors, including non small-cell cancer (NSCLC), colon and prostate cancer, do not respond to warfarin 13,11,55,111,117 and do not produce thrombin. 118 Further studies are needed to confirm the existing data and to determine whether haparin, vitamin K antagonists or platelet aggregation inhibitors effectively prevent the formation of metastatic tumors.…”