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A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer.

ABSTRACT: We evaluated the sequential use of carboplatin, paclitaxel and topotecan in patients with advanced, previously untreated ovarian cancer. In total, 43 patients with advanced ovarian cancer and >1 cm residual disease were treated with sequential carboplatin (area-under-the-curve (AUC) 5 days 1 and 22), paclitaxel (175 mg m(-2) days 43 and 64) and topotecan (1.5 mg m(-2) daily for 5 days from days 85, 106, 127 and 148). Median age of patients was 61 years. Median follow-up was 22.2 months (range 0.76-50.6 months). In all, 34 (79%) patients received all eight cycles of treatment and nine (21%) withdrew. Of the 29 evaluable patients, 19 (66%) responded according to WHO and 30 of 36 (83%) patients according to CA125. The best overall response (CA125 and/or WHO) was 77% (33 of 43 patients). The response rates to sequential drugs based on >50% fall in CA125 were as follows: carboplatin, 77% (30 of 39 patients); paclitaxel, 65% (15 of 23 patients); topotecan, 38% (five of 13 patients). Two patients responded to paclitaxel and one to topotecan after failure to respond to preceding chemotherapy. Median survival and time to progression was 22.24 and 10.61 months, respectively. This study demonstrates that sequential chemotherapy with just two initial courses of carboplatin is a reasonable way to introduce new agents into first-line therapy for poor prognostic ovarian cancer patients.

SUBMITTER: Guppy AE

PROVIDER: S-EPMC2410185 | biostudies-other | 2004 Feb

REPOSITORIES: biostudies-other

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Project description:BackgroundThis study was performed to assess the efficacy and feasibility of definitive chemoradiotherapy consisting of weekly doses of combined paclitaxel and carboplatin concurrent with radiation therapy, followed by 2 cycles of consolidation chemotherapy for advanced esophageal carcinoma.MethodsEligibility criteria included local, advanced, newly diagnosed and postoperative local regional lymph node metastasis; Eastern Cooperative Oncology Group (ECOG) score ≤ 2; and adequate organ function. Patients received concurrent chemoradiation therapy consisting of radiotherapy (50.4 Gy/28 Fx or 61.2 Gy/34 Fx) and concurrent paclitaxel (50 mg/m2) and carboplatin (area under the curve, AUC = 2) on days 1, 8, 15, 22 and 29. The two-cycle consolidation chemotherapy protocol was paclitaxel (175 mg/m2) plus carboplatin (AUC = 5) administered on days 57 and 85, after concurrent chemoradiotherapy.ResultsBetween August 2013 and February 2015, 65 patients with oesophageal carcinoma were enrolled in the study; 34 (52.3%) were newly diagnosed and 31 (47.6%) had postoperative local regional lymph node metastasis. The median overall survival time was 21.7 months (95% confidence interval [CI] 16.7-26.6), and the median progression-free survival time was 12.1 months (95% CI 9.0-15.3). A total of 96.9% (63/65) and 67.6% (44/65) patients completed ≥5 cycles and all 7 cycles of chemotherapy, respectively. A total of 93.8% (61/65) patients completed radiation therapy. The 1- and 2-year overall survival rates were 73.7 and 42.0%, respectively. The 1- and 2-year progression-free survival rates were 50.6 and 31.1%, respectively. Grade 3-4 toxicity during chemoradiotherapy included neutropenia (24.5%), thrombocytopenia (4.6%), fatigue (1.5%), anaemia (1.5%), radiation dermatitis (1.5%), pneumonitis (1.5%), oesophagitis (4.6%) and vomiting (1.5%).ConclusionsIn patients with locally advanced oesophageal cancer, the combination of weekly doses of paclitaxel and carboplatin was well tolerated and produced comparable results. A three-arm randomised phase III trial (NCT02459457) comparing paclitaxel in combination with cisplatin, carboplatin or 5-fluorouracil with concurrent radiotherapy is on-going at our hospital.

Project description:Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3?+?3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or???1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n?=?5) or palliative (n?=?10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n?=?4), thrombocytopenia (n?=?3) and increased GGT (n?=?3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (?22%, p?=?0.013) and decreased the Pt clearance (?-28%, p?=?0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.

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A phase II study of sequential carboplatin, paclitaxel and topotecan in patients with previously untreated advanced ovarian cancer.

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