HIGH-DOSE CHEMOTHERAPY COMBINED WITH ESCALATING DOSES OF CYCLOSPORINE-A AND AN AUTOLOGOUS BONE-MARROW TRANSPLANT FOR THE TREATMENT OF DRUG-RESISTANT SOLID TUMORS - A PHASE-I CLINICAL-TRIAL

High response rates are seen in patients undergoing dose-intensive che motherapy and autologous marrow transplantation due to the ability of the therapy to overcome inherent or acquired drug resistance, However, relapse rates are also high because this drug resistance reversal is incomplete, Because both P-glycoprotein- and platinum-induced resistan ce appear to be clinically important and can be reversed in vitro with a short exposure of cyclosporin A (CSA) at 2000 and 5000 ng/ml, respe ctively, we undertook a trial of high-dose chemotherapy with carboplat in (1500 mg/m(2)), mitoxantrone (75 mg/m(2)), and cyclophosphamide (12 0 mg/kg) over a 5-day period combined with escalating doses of CSA, Th irty-seven patients with primarily breast cancer (61% doxorubicin resi stant) and ovarian canter (85% platinum resistant) were treated with C SA given as a bolus 18 h prior to chemotherapy, followed by a 5-day in fusion at doses of 5.0-28.2 mg/kg/day and the chemotherapy, The maximu m tolerated dose of CSA was a bolus of 5.5 mg/kg and an infusion of 15 .9 mg/kg/day, which gave a mean serum CSA level of 1544 ng/ml, The dos e-limiting toxicity was severe mucositis and enteritis, leading to inf ectious complications, Nephrotoxicity was seen in 42% and, while usual ly mild and reversible, was fatal in two patients with pretreatment cr eatinine clearances < 80 ml/min, Grade III-IV isolated hyperbilirubine mia was seen in 39%, but appeared to be of no clinical significance, T he overall response rate for the 26 patients with measurable/evaluable disease was 73% and 63% for those with doxorubicin- or platinum-resis tant disease, The median overall survival and progression-free surviva l for the group were 18.1 and 8.0 months, The overall survival for the nine patients with doxorubicin-resistant breast cancer was 19.3 month s, Although we did not achieve CSA levels needed to reverse platinum r esistance in vivo, levels approaching those needed to reverse P-glycop rotein resistance were reached at the maximum tolerated dose, The stra tegy of combining dose intensity with drug resistance reversal deserve s further study, especially with the advent of potentially less toxic agents available to reverse P-glycoprotein-mediated resistance.