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BACKGROUND Women with an existing breast carcinoma diagnosis who are found to carry a BRCA1/2 mutation have a substantial risk of developing both a contralateral breast carcinoma and ovarian carcinoma. In a newly diagnosed breast carcinoma patient, this genetic information may influence the management of her disease. To assess the volume of patients who may need genetic services at the time of diagnosis, the authors determined the proportion of women with newly diagnosed breast carcinoma at the study institution who would be eligible for genetic testing. METHODS Fifty consecutive women with new breast carcinoma who were attending a multidisciplinary clinic were interviewed. Detailed, three-generation pedigrees were collected for each patient by a genetic counselor. Three commonly used probability models were used to calculate each woman's predicted risk of harboring a germline BRCA1/2 mutation. RESULTS Eleven of 50 patients (22% [95% confidence interval, 12–36%]) were calculated to have a ≥ 10% probability of carrying a BRCA1/2 mutation by at least one mathematic model and should have been offered genetic counseling that included the discussion of genetic testing. There were considerable discrepancies between probability calculations among the three mathematic models. One of the 11 patients who was eligible for genetic testing pursued genetic counseling within 12 months of diagnosis. CONCLUSIONS At a large academic medical center, a substantial proportion of unselected women attending a multidisciplinary clinic were found to have a ≥ 10% risk of carrying a BRCA1/2 mutation. The actual number of patients eligible to receive BRCA1/2 genetic testing outweighs the number of patients seen for genetic counseling at the study institution. Finally, limited correlation was found between current predictive models. Cancer 2002;94:305–13. © 2002 American Cancer Society.

BACKGROUND Topotecan and paclitaxel are schedule dependent chemotherapeutic agents with activity against ovarian carcinoma. A Phase I–II study in which both drugs were administered concurrently by 96-hour, continuous, intravenous infusion was performed to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and efficacy of the combination. METHODS Women with ovarian or primary peritoneal carcinoma and documented recurrent disease were eligible for the study. The dose of topotecan was escalated from 1.6 mg/m2 while maintaining the paclitaxel dose constant at 100 mg/m2. Plasma concentrations of both drugs were monitored daily during the first cycle of therapy. RESULTS Forty-five patients with a median age of 54 years (range, 42–70 years) received 181 cycles of therapy. Five patients were recruited to each of four dose levels (topotecan 1.6 mg/m2, 2.0 mg/m2, 2.8 mg/m2, and 3.6 mg/m2), and an additional 25 patients were treated at the MTD (Phase II). Neutropenia and thrombocytopenia became dose limiting toxicities (DLT) at the fourth dose level. Emesis, mucositis, peripheral neuropathy, diarrhea, and alopecia were mild. Twenty patients (44%) had line-related occlusion, thrombosis, or infection. The mean values (± standard deviation) of the apparent steady-state plasma concentrations at the Phase II doses were 2.3 nM ± 0.5 nM for topotecan lactone, 5.6 nM ± 2.1 nM for total topotecan, and 40.1 nM ± 16.8 nM for paclitaxel. There were seven partial responses (Phase II) contributing to an objective response rate of 28% and a median survival time of 11.7 months (range, 0.6–20.1 months). CONCLUSIONS Topotecan at a dose of 2.8 mg/m2 and paclitaxel at a dose of 100 mg/m2 administered by concurrent, 96-hour, continuous intravenous infusions shows activity against tumors of Mullerian origin. Cancer 2001;92:1156–67. © 2001 American Cancer Society.

BACKGROUND The aim of this study was to determine the safety and activity of vinorelbine in combination with estramustine in men with androgen-independent metastatic prostate cancer. METHODS Twenty-five men with androgen-independent metastatic prostate cancer were treated with the combination of vinorelbine and estramustine. Vinorelbine 25 mg/m2 was administered by intravenous bolus on Days 1 and 8. Estramustine 140 mg was administered three times a day by mouth on Days 1 through 14. Treatment was repeated every 21 days. RESULTS A total of 132 cycles of treatment were administered. The median number of cycles per patient was 5 (range: 1–16). Mild Grade 1 or 2 gastrointestinal toxicity and fatigue were the most common adverse effects. Hematologic toxicity was minimal. Treatment resulted in a sustained > 50% decrease in serum prostate-specific antigen (PSA) in 6 of 25 patients (24% of patients; 95% confidence interval (CI) 9–45%). The median duration of PSA response was 10 weeks (range: 3–39 weeks). Of the five men with bidimensionally measurable disease, none achieved a complete or partial response. There were no documented improvements in post-treatment bone scans. Median overall survival time was 14.1 months. CONCLUSIONS The combination of vinorelbine and estramustine is a well-tolerated and modestly active regimen in men with androgen-independent metastatic prostate cancer. Cancer 2000;89:1824–8. © 2000 American Cancer Society.

BACKGROUND A Phase I study was initiated to determine the maximum tolerated dose of weekly gemcitabine combined with monthly, fixed-dose docetaxel. METHODS Patients with metastatic solid tumors were treated with docetaxel, 60 mg/m2, on Day 1 every 28 days. Gemcitabine was administered on Days 1, 8, and 15 and underwent dose adjustment in cohorts of 3–6 patients. At the maximum tolerated dose, 11 additional patients were enrolled. RESULTS Twenty-six patients received 85 cycles of therapy. At the first dose level, the planned gemcitabine dose on Days 1, 8, and 15 was 800 mg/m2. Two of the 6 patients treated at this dose level experienced dose-limiting toxicities (DLTs) requiring the reduction of gemcitabine to 600 mg/m2 per dose and the administration of ciprofloxacin, 500 mg orally twice daily, on Days 8–18. At the second dose level the first 3 patients experienced no DLTs and the dose of gemcitabine was increased to 700 mg/m2. Two of the 6 patients treated at the 700 mg/m2 dose level experienced DLTs. Eleven additional patients were enrolled at the recommended Phase II dose of gemcitabine (600 mg/m2). At this dose level, Grade 3/4 (according the National Cancer Institute's common toxicity criteria) neutropenia and thrombocytopenia occurred in 12.5% and 2.1% of cycles, respectively. Grade 3 and 4 nonhematologic toxicities were uncommon. Three of seven evaluable patients with pancreatic carcinoma had evidence of significant antineoplastic activity (three partial responses). In addition, two complete responses (one patient with gastric carcinoma and one patient with ovarian carcinoma) and one partial response (patient with hepatocellular carcinoma) were noted in patients with other solid tumors. CONCLUSIONS The regimen comprised of docetaxel, 60 mg/m2, on Day 1 and gemcitabine, 600 mg/m2, on Days 1, 8, and 15 with ciprofloxacin on Days 8–18 every 28 days is safe, well tolerated, and active. Cancer 2000;88:180–5. © 2000 American Cancer Society.

BACKGROUND: The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced-stage epithelial ovarian cancer (EOC) who were receiving dose-intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule. METHODS: Patients with stage III/IV EOC received cyclophosphamide 750 mg/m2, followed by a 24-hour infusion of paclitaxel 250 mg/m2 and cisplatin 75 mg/m2 on Day 2. Filgrastim began on Day 3 at 10 μg/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel. RESULTS: Sixty-two patients were enrolled. Thirty-two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent-to-treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow-up of 11.4 years, the median progression-free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel. CONCLUSIONS: The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Oncology Group suggest that further study is warranted of dose-dense or dose-intense paclitaxel regimens in women with newly diagnosed, advanced-stage EOC. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND Tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene) cytidine; FMdC] is a novel nucleoside analog with potent antiproliferative and antitumor activity in preclinical studies. A tolerable safety profile and clinical activity have been shown in Phase I and Phase II clinical studies. The purpose of the current open-label, Phase I dose-escalation trial was to evaluate the combination of tezacitabine and 5-fluorouracil (5-FU) in the treatment of patients with advanced solid tumors. METHODS Twenty-four patients with a variety of advanced solid tumors for which there was no curative therapy were enrolled. Bolus infusion tezacitabine was administered on Day 1 of a 14-day cycle at escalating doses of 150–350 mg/m2, with continuous infusion 5-FU (CI 5-FU) given on Days 1–7 at a fixed dose of 200 mg/m2 per day. Patients underwent objective tumor evaluation by radiologic methods or clinical examination at baseline and after every fourth treatment cycle. RESULTS The maximum tolerated dose of the combination therapy was determined to be tezacitabine, 200 mg/m2, with CI 5-FU, 200 mg/m2 per day. The toxicities were manageable, the most notable being transient severe (National Cancer Institute Common Toxicity Criteria Grade 3 or 4) neutropenia in 23 patients (96%). Eleven (55%) of the 20 assessable patients had partial responses or stabilization of disease. The highest response rate was in patients with primary tumors of esophageal origin. CONCLUSIONS Tezacitabine at a dose of 200 mg/m2 in combination with CI 5-FU at a dose of 200 mg/m2 per day was relatively well tolerated and had clinical activity in patients with advanced solid tumors, particularly in patients with esophageal and other gastrointestinal carcinomas. Cancer 2005. © 2005 American Cancer Society. Cancer 2005. © 2005 American Cancer Society.