A randomised clinical study of verapamil in addition to combination chemotherapy in small cell lung cancer

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Abstract
Proliferation of drug resistant tumour following chemotherapy is the principal cause of treatment failure in small cell lung cancer (SCLC). Verapamil has been shown to partially restore drug sensitivity in tumour cells rendered resistant in vitro. The results of the first large-scale randomised study of a resistance modifying drug given in conjunction with chemotherapy in cancer patients are reported. Two hundred and twenty-six patients have been entered. All patients received four cycles of cyclophosphamide (750 mg m-2), doxorubicin (40 mg m-2) and vincristine (1.4 mg m-2) on Day 1 and etoposide (75 mg m-2) on Days 1, 2 and 3, repeated at 21 day intervals. Those patients randomised to the verapamil arm received oral verapamil 120 mg qid for 5 days with each course of chemotherapy. Similar numbers of cycles of protocol treatment were given in both arms with over 75% of patients completing all four cycles. There were no significant differences in general toxicities between the two arms, except for more severe alopecia in the verapamil treatment group (P = 0.045). There was no significant difference in cardiovascular or haematological toxicity, although the median nadir white cell count after Cycle 1 chemotherapy was lower in the verapamil arm (P = 0.065) and there were significantly more dose reductions after Cycle 1 in the verapamil arm (P = 0.031). No statistically significant differences in response (P = 0.582) or survival (P = 0.290) data were seen. The absence of a significant improvement in response or survival using verapamil may relate to the low blood levels of verapamil seen in the clinic (0.8 microM), in contrast to those known to be maximally active in vitro (> 6 microM) or to the presence of other cellular mechanisms by which drug resistance develops.