IN-VITRO DRUG-TESTING OF OVARIAN-CANCER USING THE HUMAN TUMOR COLONY-FORMING ASSAY - COMPARISON OF IN-VITRO RESPONSE AND CLINICAL OUTCOME

The purpose of this study was to assess the prognostic value of in vit ro drug chemosensitivity testing using the Hamburger-Salmon human tumo r colony-forming assay (HTCA) in fresh tumor samples obtained from new ly diagnosed patients with stage II-IV ovarian cancer undergoing maxim um cytoreductive surgery and prior to platinum-based chemotherapy. The HTCA was performed on fresh ovarian cancers obtained from 93 patients at their initial exploratory laparotomy to evaluate in vitro sensitiv ity to cisplatin, carboplatin, and cyclophosphamide following a 1-hr d rug exposure. Prospective clinical follow-up was performed on all pati ents with the primary study endpoints being pathologically proven comp lete response at second-look surgery and disease-free and overall surv ival durations. In vitro drug sensitivity was strongly dose-dependent. At a concentration of 5 mu g/ml only 23% of tumor samples were sensit ive (as defined by a greater than or equal to 50% decrease in tumor co lony-forming units compared to controls) to cisplatin; 13% of tumors w ere sensitive to carboplatin at a concentration of 50 mu g/ml and 11% to 4-OH-cyclolphosphamide at a concentration of 1 mu g/ml. At doses wh ich were 10 times the previously stated concentrations, the sensitivit y rates to cisplatin, carboplatin, and 4-OH-cyclophosphamide increased to 72, 63, and 53%, respectively. Subjects were categorized as having drug-sensitive disease if HTCA results showed in vitro drug sensitivi ty to at least one of the agents used in their primary chemotherapy. M ultivariate analysis failed to show any advantage in clinical response rate, progression-free interval, or survival duration for patients wi th drug-sensitive disease compared to drug-resistant disease; however, there was evidence of a trend toward an enhanced pathologically prove n complete response rate in patients who had chemosensitive tumors in vitro. Second-look surgery was performed in 28 of 55 patients with opt imal surgical resections and no clinical evidence of disease at the co mpletion of their primary chemotherapy. Fifty percent (5/10) of patien ts with drug-sensitive disease achieved a pathologic complete response , while only 3/18 (17%) patients with drug-resistant tumors had a docu mented pathologic complete response (P = 0.13). As reported in other o varian cancer studies, patient characteristics which were found to be significantly associated with survival were stage of disease (II-III v s IV), optimal primary surgical resection (i.e., <I cm(2) residual tum or) vs suboptimal resection, clinical measurability of disease at init iation of chemotherapy, and response to primary chemotherapy. In concl usion, in vitro drug sensitivity, as measured by the HTCA, does not ap pear to be an independent prognostic factor for survival in patients w ith stage II-IV epithelial ovarian cancer who undergo standard treatme nt with tumor debulking surgery and primary platinum-based chemotherap y. Further studies are indicated to determine whether in vitro drug se nsitivity is an independent prognostic factor for pathologically prove n complete response at second-look surgery. (C) 1994 Academic Press, I nc.