title: Mitoxantrone combined with paclitaxel as salvage therapy for platinum-refractory ovarian cancer: laboratory study and clinical pilot trial.
abstract: This report describes preclinical and early clinical investigations of the mitoxantrone/paclitaxel combination (NT) for patients with platinum-refractory ovarian cancer. The preclinical activity of NT was studied ex vivo, evaluating native tumor specimens with the ATP tumor chemosensitivity assay. Of 24 tumors tested, 20 (83%) were sensitive to NT, whereas 7 (29%) responded to mitoxantrone and 8 (33%) responded to paclitaxel. In the majority of tumors assayed (19 of 24), potentiating or major independent effects between both agents were found. Subsequently, a clinical pilot trial of NT was initiated for patients with platinum-refractory ovarian cancer. Patients had failed one to four (median, two) prior chemotherapy regimens. In 11 cases, NT was administered every three weeks with 8 mg/m2 mito-xantrone and 180 mg/m2 paclitaxel (NT-I). Seven patients were treated biweekly with 6 mg/m2 mitoxantrone and weekly with 100 mg/m2 paclitaxel (NT-II). During 92 NT courses, myelosuppression with leucopenia, anemia, and thrombocytopenia was the limiting toxicity, occurring more frequently with NT-II. No patient required hospitalization due to any life-threatening complication. Five complete and nine partial remissions were observed with both NT-I and NT-II, accounting for an overall 78% response rate, with a median progression-free survival of 40 weeks. One patient showed early progression during therapy. Currently, three patients (NT-I, two; NT-II, one) have died due to progressive relapsed ovarian cancer, so that the median overall survival is not reached after a median follow-up of 40.5+ weeks. Both schedules were found to be equal in terms of response rate and overall survival. NT is highly active and practical for salvage treatment of ovarian cancer. NT-II may be preferred due to both clinical activity and patients' acceptance. However, NT-I seems to be a less myelotoxic alternative. Both schedules warrant further clinical investigation.
authors.affiliation: Department of Gynecology and Obstetrics, University of Cologne Medical Center, D-50931 Cologne, Germany.
authors.forename: C M
authors.initials: CM
authors.lastname: Kurbacher
authors.forename: H W
authors.initials: HW
authors.lastname: Bruckner
authors.forename: I A
authors.initials: IA
authors.lastname: Cree
authors.forename: J A
authors.initials: JA
authors.lastname: Kurbacher
authors.forename: L
authors.initials: L
authors.lastname: Wilhelm
authors.forename: G
authors.initials: G
authors.lastname: Pöch
authors.forename: D
authors.initials: D
authors.lastname: Indefrei
authors.forename: P
authors.initials: P
authors.lastname: Mallmann
authors.forename: P E
authors.initials: PE
authors.lastname: Andreotti
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology*; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010865:Pilot Projects; D012074:Remission Induction; D016879:Salvage Therapy; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008942:Mitoxantrone; D017239:Paclitaxel; D002945:Cisplatin