Louise Yelle

Prospective Randomized Trial of Docetaxel Versus Doxorubicin in Patients With Metastatic Breast Cancer

PURPOSE This phase III study compared docetaxel and doxorubicin in patients with metastatic breast cancer who had received previous alkylating agent-containing chemotherapy. PATIENTS AND METHODS Patients were randomized to receive an intravenous infusion of docetaxel 100 mg/m(2) or doxorubicin 75 mg/m(2) every 3 weeks for a maximum of seven treatment cycles. RESULTS A total of 326 patients were randomized, 165 to receive doxorubicin and 161 to receive docetaxel. Overall, docetaxel produced a significantly higher rate of objective response than did doxorubicin (47.8% v 33.3%; P =.008). Docetaxel was also significantly more active than doxorubicin in patients with negative prognostic factors, such as visceral metastases (objective response, 46% v 29%) and resistance to prior chemotherapy (47% v 25%). Median time to progression was longer in the docetaxel group (26 weeks v 21 weeks; difference not significant). Median overall survival was similar in the two groups (docetaxel, 15 months; doxorubicin, 14 months). There was one death due to infection in each group, and an additional four deaths due to cardiotoxicity in the doxorubicin group. Although neutropenia was similar in both groups, febrile neutropenia and severe infection occurred more frequently in the doxorubicin group. For severe nonhematologic toxicity, the incidences of cardiac toxicity, nausea, vomiting, and stomatitis were higher among patients receiving doxorubicin, whereas diarrhea, neuropathy, fluid retention, and skin and nail changes were higher among patients receiving docetaxel. CONCLUSION The observed differences in activity and toxicity profiles provide a basis for therapy choice and confirms the rationale for combination studies in early breast cancer.

Phase II Clinical Trial of Ixabepilone (BMS-247550), an Epothilone B Analog, As First-Line Therapy in Patients With Metastatic Breast Cancer Previously Treated With Anthracycline Chemotherapy

PURPOSE There is a need for new agents to treat metastatic breast cancer (MBC) in patients for whom anthracycline therapy has failed or is contraindicated. This study was conducted to assess the efficacy and safety of the novel antineoplastic, the epothilone B analog ixabepilone, in patients with MBC previously treated with an adjuvant anthracycline. PATIENTS AND METHODS Patients were age >or= 18 years and had received a prior anthracycline-based regimen as adjuvant treatment. Ixabepilone as first-line metastatic chemotherapy was administered as a 40 mg/m(2) intravenous infusion during 3 hours every 3 weeks. The primary efficacy end point was objective response rate (ORR). Secondary efficacy end points included duration of response, time to response, time to progression, and survival. RESULTS All 65 patients were assessable for response. Their median age was 52 years (range, 33 to 80 years). ORR was 41.5% (95% CI, 29.4% to 54.4%), median duration of response was 8.2 months (95% CI, 5.7 to 10.2 months), and median time to response was 6 weeks (range, 5 to 17 weeks). Median survival was 22.0 months (95% CI, 15.6 to 27.0 months). Treatment-related adverse events were manageable and mostly grades 1/2: the most common of these (other than alopecia) was mild to moderate neuropathy, which was primarily sensory and mostly reversible in nature. CONCLUSION Ixabepilone is efficacious and has a predictable and manageable safety profile in women with MBC previously treated with an adjuvant anthracycline.

Phase III Open-Label Randomized Study of Eribulin Mesylate Versus Capecitabine in Patients With Locally Advanced or Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane

Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE To evaluate the roles of granisetron and dexamethasone for emesis control on days 2 through 7 after the administration of cisplatin in doses of 50 mg/m2 or greater to patients who had not previously received chemotherapy. PATIENTS AND METHODS Four hundred thirty-five eligible and assessable patients were randomized to one of two arms in a double-blind fashion: arm A; granisetron 3 mg intravenous (i.v.) plus dexamethasone 10 mg i.v. prechemotherapy followed by granisetron 1 mg orally at 6 and 12 hours, then granisetron 1 mg orally and dexamethasone 8 mg orally twice daily on days 2 through 7 (219 patients); arm B; as in arm A but with placebo substituted for granisetron on days 2 through 7 (216 patients). All patients completed diaries in which episodes of emesis and severity of nausea were recorded. RESULTS The addition of granisetron on days 2 through 7 had no discernable impact on nausea and vomiting during this period. CONCLUSION The administration of a 5-hydroxytryptamine3, receptor (5-HT3) antagonist, in this case granisetron, after 24 hours conferred no benefit. This negative result needs to be assessed in light of conflicting literature, but at present it does not appear that the routine use of these drugs in this setting is justified.

Ondansetron compared with dexamethasone and metoclopramide as antiemetics in the chemotherapy of breast cancer with cyclophosphamide, methotrexate, and fluorouracil.

BACKGROUND Although ondansetron was found to be effective as an antiemetic in numerous clinical trials of highly emetogenic combination-chemotherapy regimens that included cisplatin, its role in milder emetogenic regimens has not been fully defined. To address its use with a widely used but less emetogenic regimen, we performed a double-blind, randomized clinical trial comparing ondansetron with dexamethasone and metoclopramide in patients with breast cancer receiving chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. METHODS A total of 165 women with breast cancer from 14 Canadian centers who were about to receive this chemotherapy for the first time were randomly assigned to receive either ondansetron (n = 85) or dexamethasone plus metoclopramide (n = 80), a widely used, standard antiemetic regimen. The patients recorded the incidence of nausea, emesis, and other side effects in diaries, and these data were compared in the two groups. RESULTS The patients who received dexamethasone and metoclopramide had significantly less nausea during the first 24 hours after chemotherapy was begun. Otherwise, there were no statistically significant differences in efficacy between the regimens. The incidence of drowsiness and increased appetite was higher in the group given dexamethasone and metoclopramide. CONCLUSIONS For women with breast cancer who are being treated with cyclophosphamide, methotrexate, and fluorouracil, the efficacy of dexamethasone and metoclopramide in controlling nausea and vomiting equaled or exceeded that of ondansetron.

Abstract S6-6: A Phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes

Background: Eribulin is a non-taxane microtubule dynamics inhibitor. In a previous Phase III trial, eribulin demonstrated a statistically significant improvement in overall survival (OS) versus current treatments and a manageable toxicity profile, in heavily pre-treated patients (pts) with metastatic breast cancer (MBC). Here we report results from a Phase III trial of eribulin compared with capecitabine in earlier-line pts with MBC (NCT00337103). Patients and methods: Pts were randomized 1:1 to eribulin mesylate 1.4 mg/m 2 given on Days 1 and 8 of a 21 day cycle or capecitabine 2.5 g/m 2 /day administered orally BID on Days 1 to 14 of a 21 day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1 st , 2 nd , or 3 rd line therapy for advanced disease. The co-primary endpoints of this study were OS and progression free survival (PFS): pre-specified statistical significance at final analysis for eribulin versus capecitabine were p ≤ 0.0372 for OS and p Results: Of 1102 pts, 554 were randomized to eribulin and 548 capecitabine (375 and 380 pts were HER2[−], respectively). The median age was 54.0 years (range 24–80). Pts received study treatment as their 1 st (27.2%), 2 nd (57.4%) or 3 rd -line (14.7%) chemotherapeutic regimen in the setting of metastatic disease. The median number of treatment cycles was 6 for eribulin and 5 for capecitabine. Median OS was 15.9 and 14.5 months (hazard ratio [HR] 0.879; 95% confidence intervals [CI] 0.770–1.003; p = 0.056), and PFS (independent review) was 4.1 and 4.2 months (HR 1.079; 95% CI 0.932–1.250; p = 0.305) for eribulin and capecitabine, respectively. ORR (independent review) were 11.0% (95% CI 8.5–13.9) and 11.5% (95% CI 8.9–14.5; p = 0.849), respectively. OS for HER2(−) pts was 15.9 months for eribulin and 13.5 months for capecitabine (HR 0.838; 95% CI 0.715–0.983; p = 0.030). AEs were consistent with the known side-effect profiles of both drugs. The most common AEs for eribulin and capecitabine (>20% all grades) were neutropenia (54.2% vs 15.9%), hand-foot syndrome (0.2% vs 45.1%) alopecia (34.6% vs 4.0%), leukopenia (31.4% vs 10.4%), diarrhea (14.3% vs 28.8%), and nausea (22.2% vs 24.4%), respectively. Conclusion: In this Phase III trial, eribulin demonstrated a trend favoring improved OS, compared with capecitabine, although this improvement does not meet the pre-defined criteria for statistical significance. This study confirms eribulin as an active drug in pts with MBC, and exploratory analyses suggest possible benefits of eribulin in specific subsets of pts, sufficient to warrant further study. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S6-6.

Dexamethasone improves the efficacy of granisetron in the first 24 h following high-dose cisplatin chemotherapy

The object of the study was to determine whether dexamethasone improved the efficacy of the serotonin receptor (5-HT3) antagonist granisetron in controlling acute (within 24 h) emesis in cancer patients receiving high-dose cisplatin chemotherapy and to ascertain whether continuation of granisetron after 24 h reduces the occurrence of delayed emesis. This randomised, double-blind, multicentre, three-arm study was conducted at 21 medical centres. A group of 292 nausea- and emcsis-free patients with cancer, who had never had chemotherapy and were scheduled to receive at least 50 mg/m2 cisplatin, were given 3 mg granisetron i.v. in a 15-min infusion with or without 10 mg dexamethasone i.v. completed 5 min prior to high-dose cisplatin and 1 mg granisetron p.o. at +6 h and +12 h. Primary study end-points were control of emesis and nausea. Patients completed a self-report diary every 6 h for the first 24 h. At the end of the 24-h period, the patients who received dexamethasone had a significantly higher complete protection rate from emesis (64% compared to 39%) than those who received no steroid. Similarly, the dexamethasone-treated group had a significantly higher complete plus partial (0–2 emetic episodes) protection rate (84% compared to 64%). This study shows that dexamethasone markedly enhances the antiemetic efficacy of granisetron for acute-onset emesis in high-dose cisplatin chemotherapy.

Chemotherapy-induced emesis: quality of life and economic impact in the context of current practice in Canada.

In this study, we estimated the proportion of patients who experience chemotherapy-induced nausea and vomiting (CINV) in current practice and evaluated the impact of CINV on quality of life and cost in Canada. Patients receiving highly emetogenic chemotherapy were recruited from 4 Canadian oncology centers. Patients used diaries to record information on their activities, incidence of nausea and vomiting, and health resources consumed each day for 5 days following chemotherapy. They also completed the Functional Living Index-Emesis (FLIE) questionnaire and a health utility instrument before chemotherapy and 5 days later. Of the 323 patients recruited, 266 (82%) completed their diary. On day 1, 26% of patients reported nausea or vomiting (acute emesis). From day 2 to day 5 after chemotherapy, 44% reported nausea or vomiting (delayed emesis). Patients who experienced nausea or vomiting during the study period had a decrease in FLIE score of 22% and a decrease in health utility of 15%. Patients with nausea or vomiting reported an average of 19 hours per cycle during which they were unable to perform their normal activities. Also, friends or relatives spent an average of 10 hours helping these patients. Incremental medical costs per patient experiencing CINV were

Activity and Safety of the Antiestrogen EM-800, the Orally Active Precursor of Acolbifene, in Tamoxifen-Resistant Breast Cancer

61 Canadian. Including productivity losses, total incremental costs were

Phase II Multicenter Trial of Anthracycline Rechallenge With Pegylated Liposomal Doxorubicin Plus Cyclophosphamide for First-Line Therapy of Metastatic Breast Cancer Previously Treated With Adjuvant Anthracyclines

592 Canadian per patient. Despite use of antiemetics, CINV remains problematic, impacting the quality of life of patients with cancer and increasing costs.