Showing papers by "Amit M. Oza published in 2000"

Phase II feasibility study of sequential couplets of Cisplatin/Topotecan followed by paclitaxel/cisplatin as primary treatment for advanced epithelial ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group Study.

Abstract: PURPOSE: Despite the improved results in advanced ovarian cancer achieved with the addition of paclitaxel to frontline therapy, there remains room for improvement. One approach is to add new agents such as topotecan. Because myelosuppression limits the delivery of topotecan with paclitaxel/cisplatin in a three-drug combination, we explored giving sequential couplets of cisplatin/topotecan followed by paclitaxel/cisplatin. PATIENTS AND METHODS: Forty-four patients with residual epithelial ovarian carcinoma after primary surgery were studied. Cisplatin 50 mg/m2 on day 1 and topotecan 0.75 mg/m2 on days 1 through 5 were administered at 21-day intervals for four cycles, followed by interval debulking surgery (if optimal debulking was not achieved with primary surgery), and then paclitaxel 135 mg/m2 over 24 hours on day 1 and cisplatin 75 mg/m2 on day 2 at 21-day intervals for four cycles. RESULTS: Such sequential couplets are feasible. Myelotoxicity was the major toxic effect, but it was of short duration. Th...

Cost-utility analysis of second-line hormonal therapy in advanced breast cancer: a comparison of two aromatase inhibitors to megestrol acetate

Abstract: Randomized trials comparing the aromatase inhibitors, anastrozole and letrozole, to megestrol acetate (MA) in postmenopausal women with advanced breast cancer demonstrated that both agents are better tolerated than MA with comparable efficacy. In addition, one trial revealed that tumor response and time to treatment failure were significantly better with letrozole. Since oncologists are faced with a choice between three agents with at least comparable efficacy but different toxicity profiles and cost, a cost-utility analysis was conducted to quantify these differences and to determine if the new agents are more cost-effective than MA. In the absence of a randomized three-arm trial, a decision model was developed to simulate the most common therapeutic outcomes. The clinical data were obtained from an overview analysis of randomized trials. Total hospital resource consumption was collected from 87 patients with advanced disease that had failed second-line hormonal therapy. Utility estimates were obtained from interviewing a random sample of 25 women from the general public and 25 female health care professionals using the Time Trade-Off technique. The model suggested a similar duration of quality-adjusted progression-free survival between drugs (letrozole 150 days, anastrozole 153 days and MA 146 days). Letrozole had an overall cost of Can$2949 per patient which was comparable to MA at Can$2966 per patient. In contrast, anastrozole was slightly more costly than MA at $Can3149 per patient, respectively. The analysis revealed that letrozole has comparable overall costs relative to MA while providing at least equivalent quality-adjusted progression-free survival. These outcomes were largely related to its higher tumor response rate, which translated to a lower proportion of patients requiring chemotherapy. Anastrozole was slightly more costly than MA and did not demonstrate superiority in quality-adjusted progression-free survival in this palliative setting.

Phase I Dose-Finding and Pharmacokinetic Study of Paclitaxel and Carboplatin With Oral Valspodar in Patients With Advanced Solid Tumors

Abstract: PURPOSE: To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic (PK) profile of paclitaxel and carboplatin when administered every 3 weeks with the oral semisynthetic cyclosporine analog valspodar (PSC 833), an inhibitor of P-glycoprotein function. PATIENTS AND METHODS: Fifty-eight patients were treated with escalating doses of paclitaxel ranging from 54 to 94.5 mg/m2 and carboplatin area under the plasma concentration versus time curve (AUC) ranging from 6 to 9 mg·min/mL, every 21 days. The dose of valspodar was fixed at 5 mg/kg every 6 hours for a total of 12 doses from day 0 to day 3. The MTD was determined for the following two groups: (1) previously treated patients, where paclitaxel and carboplatin doses were escalated; and (2) chemotherapy-naive patients, where paclitaxel dose was escalated and carboplatin AUC was fixed at 6 mg·min/mL. PK studies of paclitaxel and carboplatin were performed on day 1 of course 1. RESULTS: Fifty-eight patients were treated ...

Liarozole fumarate (R85246): in the treatment of ER negative, tamoxifen refractory or chemotherapy resistant postmenopausal metastatic breast cancer.

Abstract: Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1: 1n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozole (150-300mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0-52.3%: median duration (MD) 20 months; range 2-36.5); 25% in group 2 (95% CI 11.0-52.3%; MD 6.5 months: range 3.5-38): 11% in group 3 (95% CI 4.2-29.2%; MD 7 months; range 3-8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1-1,839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer.

Liarozole fumarate (R85246): a novel imidazole in the treatment of receptor positive postmenopausal metastatic breast cancer.

Abstract: This phase II study of liarozole fumarate (R85246, liarozole), a novel imidazole with retinomimetic and aromatase inhibitory effects, was designed to determine the efficacy and tolerability in postmenopausal women with advanced breast cancer in progression, to correlate these effects with hormonal levels, and to evaluate quality of life. Twenty-nine women with ER-positive or unknown metastatic disease who received ≥ 2 prior hormonal therapies were treated with 150–300 mg liarozole twice daily until disease progression. All patients were evaluable for toxicity and 25 for response. Four patients (16.0%, 95% CI 5.3–37.4%) had partial remission (PR) of their disease for a median of 7.4 months (range 1.2–12.9) and 7 (28%) had disease stabilization for a median of 4.8 months (1.6–16.0). Estradiol decreased from pre-treatment levels of 9.2–52 pM (mean 17.1) to below detection (9.2 pM, p=0.0005) after 1 month. Similarly estrone levels fell from 14–307 pM (mean 92.7) to below detection (9.2 pM, p=0.0001). The most common toxicity was dermatological (96.6%) with features compatible with hypervitaminosis A syndrome such as rash, pruritus, dry skin, and brittle nails. The majority of these were mild to moderate in severity. No significant improvement in quality of life scores (FLI-C) were noted. Liarozole is an active new treatment for breast cancer in patients heavily pre-treated with hormone therapies. Further studies are needed to confirm its relative efficacy in both receptor positive and negative postmenopausal breast cancer.