A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

BACKGROUND: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. FINDINGS: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. CONCLUSIONS: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. CLINICAL TRIAL INFORMATION: NCT00520975.

A randomized phase III double-blind placebo-controlled trial of first line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

Background: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Nausea and disturbed sleep as predictors of cancer-related fatigue in breast cancer patients: a multicenter NCORP study.

PURPOSE: Cancer-related fatigue (CRF) is a prevalent and distressing side effect of cancer and its treatment that remains inadequately understood and poorly managed. A better understanding of the factors contributing to CRF could result in more effective strategies for the prevention and treatment of CRF. The objectives of this study were to examine the prevalence, severity, and potential predictors for the early onset of CRF after chemotherapy cycle 1 in breast cancer patients. METHODS: We report on a secondary data analysis of 548 female breast cancer patients from a phase III multi-center randomized controlled trial examining antiemetic efficacy. CRF was assessed by the Brief Fatigue Inventory at pre- and post-chemotherapy cycle 1 as well as by the four-day diary. RESULTS: The prevalence of clinically relevant post-CRF was 75%. Linear regression showed that pre-treatment CRF, greater nausea, disturbed sleep, and younger age were significant risk factors for post-CRF (adjusted R2 = 0.39; P < 0.0001). Path modeling showed that nausea severity influenced post-CRF both directly and indirectly by influencing disturbed sleep. Similarly, pre-treatment CRF influenced post-CRF directly as well as indirectly through both nausea severity and disturbed sleep. Pearson correlations showed that changes in CRF over time were significantly correlated with concurrent changes in nausea severity (r = 0.41; P < 0.0001) and in disturbed sleep (r = 0.20; P < 0.0001). CONCLUSION: This study showed a high prevalence (75%) of clinically relevant CRF in breast cancer patients following their initial chemotherapy, and that nausea severity, disturbed sleep, pre-treatment CRF, and age were significant predictors of symptom.

5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial.

BACKGROUND: Despite widespread use of short-acting antagonists for the 5-hydroxytryptamine (5-HT) receptor, about 50% of patients given moderately emetogenic chemotherapy have delayed nausea. We aimed to assess whether a 5-HT-receptor antagonist was more effective than was prochlorperazine for control of delayed nausea and delayed vomiting caused by doxorubicin. METHODS: 691 patients who previously had not had chemotherapy and who were scheduled to receive doxorubicin were given a short-acting 5-HT-receptor antagonist and dexamethasone before doxorubicin (day 1), and were randomly assigned to one of three regimens for days 2 and 3: 10 mg prochlorperazine taken orally every 8 h; any first-generation 5-HT-receptor antagonist (except palonosetron) taken as standard dose intravenously or orally; or 10 mg prochlorperazine taken as needed. Nausea and vomiting were assessed by use of a home record. The primary endpoint was mean severity of delayed nausea. The secondary endpoint was quality of life. Analyses were done by intention to treat. FINDINGS: 519 (77%) of the 671 evaluable patients had delayed nausea, with a mean severity of 3.33 (95% CI 3.22-3.44). 161 (71%) of 226 patients assigned prochlorperazine every 8 h reported delayed nausea (mean severity 3.37 [3.16-3.58]), as did 179 (79%) of 226 patients assigned 5-HT-receptor antagonists (3.29 [3.09-3.48]) and 179 (82%) of 219 patients assigned prochlorperazine as needed (3.33 [3.15-3.50]); groups did not differ in mean severity (p=0.853, one-way ANOVA). Patients allocated prochlorperazine every 8 h had less delayed nausea than did those allocated 5-HT-receptor antagonists (p=0.05, t test) and those allocated prochlorperazine as needed (p=0.009, t test). INTERPRETATION: Short-acting 5-HT-receptor antagonists are no better than is prochlorperazine in control of delayed nausea caused by doxorubicin. Although fewer patients taking prochlorperazine report delayed nausea, the proportion was unacceptably high.