A phase II and pharmacokinetic study of weekly 72-h topotecan infusion in patients with platinum-resistant and paclitaxel-resistant ovarian carcinoma.

BACKGROUND: As suggested by preclinical trials, prolonged administration of topotecan, a reversible inhibitor of topoisomerase-I, may have a therapeutic advantage. Following a phase I trial of weekly 72-h topotecan infusion, we performed a phase II trial utilizing this schedule in ovarian carcinoma. METHODS: Eligibility included platinum-/paclitaxel-resistant ovarian carcinoma, measurable disease, and adequate hematologic, renal, and hepatic function. A dose of 2.0 mg/m(2) of topotecan was administered as a 72-h infusion weekly via an ambulatory pump. Plasma topotecan concentrations were determined prior to and at the completion of each weekly course. RESULTS: Twenty-four patients were entered and 23 patients were evaluable for toxicity and response. Two hundred eighteen weekly courses of therapy were administered (median 7 weeks, range 4-46 weeks). Toxicity was mild with grade 3 leukopenia, neutropenia, and anemia occurring in 13, 13, and 17% of patients, respectively. Two of 23 patients (9.1%) (CI 1-28%) had partial responses of 2 and 3 months' duration and 6 had stable disease. Steady state plasma topotecan lactone concentrations were a median of 1.2 ng/ml (range 0.4-8.00 ng/ml) following the first week of infusion. Steady state topotecan lactone concentrations after the first week of infusion were highest in 2 patients with partial responses. Mean steady state plasma topotecan lactone concentrations after the first week of infusion were 4.6, 2.0, and 1.3 ng/ml for partial response, stable disease, and progressive disease, respectively. An analysis of variance of steady state plasma topotecan concentrations after the first week of infusion over all administered cycles demonstrated a significant difference in steady state plasma topotecan lactone concentrations between patients with partial response and stable disease and between partial response and no response (significant at the 0.05 level after adjustment for multiple comparisons). Controlling for cycle number, steady state topotecan lactone concentrations are significantly greater for patients with responding or stable disease than those with progressive disease (P = 0.0003) and have a lower bound of > or = 1.9 ng/ml (95% confidence level). CONCLUSION: Steady state topotecan lactone concentrations are associated with responding or stable disease in platinum- and paclitaxel-resistant ovarian cancer. Steady state topotecan concentrations could potentially be utilized to modify tumor exposure and response.

Tolerance of twenty-four hour paclitaxel and carboplatin as first-line therapy in ovarian, peritoneal and fallopian tube carcinoma.

Rose PG, Fusco N, Fluellen L, Rodriguiz M. Tolerance of twenty-four hour paclitaxel and carboplatin as first-line therapy in ovarian, peritoneal and fallopian tube carcinoma. A combination of a platinum and taxane are accepted as standard first-line therapy for ovarian cancer. However, both 24-h paclitaxel and cisplatin and 3-h paclitaxel and carboplatin have significant neurotoxicity. The present study was undertaken to determine the toxicity of 24-h paclitaxel and carboplatin as first-line therapy. Ovarian, peritoneal, and fallopian tubal carcinoma patients treated with 24-h paclitaxel and carboplatin as first-line therapy were retrospectively reviewed. Paclitaxel was administered at a dose of 135 mg/m2 as a 24-h infusion followed by carboplatin at an AUC of 5 every 21 days. Toxicity was graded according to NCI Common Toxicity Scale. Fourteen patients with ovarian, peritoneal or tubal carcinoma were studied. Twelve were treated primarily with paclitaxel and carboplatin and two were originally treated with paclitaxel and cisplatin for two cycles but switched to paclitaxel and carboplatin for severe cisplatin-associated toxicities. A total of 86 courses were administered (median 6, range 1-9). Hematologic toxicity was the principal toxicity with neutropenic fever occurring in 8 patients (57%). The duration of neutropenia was brief and no septic deaths occurred. Following paclitaxel dose reduction to 110 mg/m2 neutropenic sepsis did not recur except in one patient with recurrent C. difficile colitis. The two patients who switched from paclitaxel/cisplatin to paclitaxel/carboplatin reported better tolerance of the chemotherapy regimen. Among the 13 patients with ovarian and peritoneal carcinoma 100% achieved a clinical complete response. Although associated with a high incidence of neutropenia, this regimen had rare severe or chronic toxicities in particular neurotoxicity and a high response rate.

Ninety-six-hour infusional paclitaxel as salvage therapy of ovarian cancer patients previously failing treatment with 3-hour or 24-hour paclitaxel infusion regimens.

PURPOSE: To test the hypothesis that prolonged infusion of paclitaxel (96 hours) might overcome resistance to shorter infusion schedules (3 or 24 hours) in ovarian cancer. PATIENTS AND METHODS: A total of 30 patients with advanced ovarian cancer (24 patients), primary carcinoma of the peritoneum (four patients), or fallopian tube cancer (two patients) who previously had received paclitaxel administered on either a 3-hour or 24-hour schedule were treated with the agent delivered as a 96-hour infusion (30 to 35 mg/m2/d x 4 days) on an every 3-week program. RESULTS: Although the regimen generally was well tolerated, no objective responses were observed. CONCLUSION: In patients with ovarian cancer who have shown resistance to shorter paclitaxel infusion schedules, ninety-six hour infusional paclitaxel is an inactive treatment strategy. This makes it less likely that protracted infusion of paclitaxel will improve outcome when used as part of primary therapy of ovarian cancer. An ongoing randomized study will answer that question.

Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma.

PURPOSE: The combination of paclitaxel and a platinum compound is the most active first-line regimen for advanced ovarian carcinoma. The current study was undertaken to evaluate this combination in the re-treatment of patients with ovarian or peritoneal carcinoma who had disease recurrence > or = 6 months following this combination. METHODS: Twenty-five patients with recurrent ovarian or peritoneal carcinoma > or = 6 months after a complete clinical response with first-line paclitaxel and platinum chemotherapy were studied. Recurrent disease was documented by computed tomography (CT), elevated CA 125 level, or surgical findings. Second-line chemotherapy consisted of paclitaxel 135 mg/m2 as a 24 hour infusion and carboplatin at an area under the concentration-time curve (AUC) of 5 to 6 every 21 days. Response to therapy was classified as measurable or assessable. RESULTS: The median time to recurrence after first-line therapy was 10 months (range, 6 to 30). Among 20 measurable and assessable patients, 14 (70%) demonstrated a complete clinical response and four (20%) a partial clinical response. The response rate with measurable disease was 91% and with assessable disease was 89%. The median progression-free interval for all patients was 9.0+ months (range, 2 to 15). The median progression-free interval for patients with measurable or assessable disease was 9.0+ months and for nonassessable disease was 7.0+ months. Fifteen patients (60%) have developed recurrence after secondary therapy at a median interval of 9.0 months (range, 2 to 15). Only two patients have died with a median survival after secondary therapy of 10.0+ months (range, 2.0 to 21.0+). CONCLUSION: The use of this combination, in this sensitive population, has a high response rate and long progression-free interval. In a chemotherapy-sensitive population, the activity of alternative second-line agents must be interpreted with this perspective.