PILOT-STUDY OF MULTIPLE CHEMOTHERAPY RESISTANCE MODULATORS PLUS EPIRUBICIN IN THE TREATMENT OF RESISTANT MALIGNANCIES

We studied the toxicity and efficacy of adding to epirubicin five resi stance modulators in the treatment of resistant solid tumors. Addition al drugs were added in successive cohorts of patients, such that cohor t 1 patients received two drugs along with their epirubicin, while coh ort 4 patients received five modulators along with their epirubicin. M etronidazole, tamoxifen (cohort 1), dipyridamole (cohort 2), ketoconaz ole (cohort 3) and cyclosporin (cohort 4) were administered with epiru bicin. A total of 22 patients were treated. Nausea and vomiting was us ually mild to moderate. There was an unexpectedly high incidence of po ssible cardiac toxicity associated with treatment, although in some pa tients it was uncertain whether or not observed cardiac events were re lated to treatment. Granulocytopenia was significant in all four cohor ts, but it was unclear whether it was increased by the modulators. The re were two febrile neutropenic events in cohorts 1 and 2 successfully treated with antibiotics, and three septic deaths (one in each of coh orts 1, 2 and 4). It was elected to discontinue enrolment on the study prematurely in light of cardiac and other toxicity seen in the first two patients accrued in cohort 4. A single response was observed. Whil e this approach is feasible, the observed toxicity and the difficulty patients experienced in ingesting the large number of prescribed pills will make further exploration of this approach difficult.