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.

Inflammation and psychosocial factors mediate exercise effects on sleep quality in breast cancer survivors: pilot randomized controlled trial.

OBJECTIVE: To improve mechanistic understanding, this pilot randomized controlled trial examined mediators of an exercise intervention effects on sleep in breast cancer survivors (BCS). METHODS: Forty-six postmenopausal BCS (≤Stage II, off primary treatment) were randomized to a 3-month exercise intervention or control group. Intervention included 160 min/week of moderate intensity aerobic walking, twice weekly resistance training (resistance bands), and six discussion groups (to improve adherence). Blinded assessments at baseline and post-intervention included sleep disturbance (PSQI and PROMIS®), objective sleep quality (accelerometer), serum cytokines, accelerometer physical activity, cardiorespiratory fitness, body composition, fatigue, and psychosocial factors. Mediation was tested using Freedman-Schatzkin difference-in-coefficients tests. RESULTS: When compared with control, the intervention group demonstrated a significant increase in PSQI sleep duration (i.e., fewer hours of sleep/night) (d = 0.73, p = .03). Medium to large but non-significant standardized effect sizes were noted for PSQI daytime somnolence (d = -0.63, p = .05) and accelerometer latency (d = -0.49, p = .14). No statistically significant mediators were detected for PSQI sleep duration score or accelerometer latency. Daytime somnolence was mediated by tumor necrosis factor-alpha (mediated 23% of intervention effect, p < .05), interleukin (IL)-6:IL-10 (16%, p < .01), IL-8:IL-10 (26%, p < .01), and fatigue (38%, p < .05). Mediating or enhancing relationships for several of the sleep outcomes were noted for accelerometer physical activity, PROMIS® fatigue, exercise social support, and/or physical activity enjoyment. CONCLUSIONS: Inflammation and psychosocial factors may mediate or enhance sleep response to our exercise intervention. Further study is warranted to confirm our results and translate our findings into more effective interventions aimed at improving sleep quality in BCS.

Biobehavioral factors mediate exercise effects on fatigue in breast cancer survivors.

PURPOSE: This study aimed to examine mediators of fatigue response to an exercise intervention for breast cancer survivors in a pilot randomized controlled trial. METHODS: Postmenopausal breast cancer survivors (n = 46; ≤stage 2), off primary treatment, and reporting fatigue and/or sleep dysfunction were randomized to a 3-month exercise intervention (160 min·wk of moderate-intensity aerobic walking, twice weekly resistance training with resistance bands) or control group. Six discussion group sessions provided behavioral support to improve adherence. Fatigue, serum cytokines, accelerometer physical activity, cardiorespiratory fitness, sleep dysfunction, and psychosocial factors were assessed at baseline and 3 months. RESULTS: The exercise intervention effect sizes for fatigue were as follows: fatigue intensity d = 0.30 (P = 0.34), interference d = -0.38 (P = 0.22), and general fatigue d = -0.49 (P = 0.13). Using the Freedman-Schatzkin difference-in-coefficients tests, increase in fatigue intensity was significantly mediated by interleukin 6 (IL-6) (82%), IL-10 (94%), IL-6/IL-10 (49%), and tumor necrosis factor-α (TNF-α):IL-10 (78%) with reduced sleep dysfunction increasing the relationship between intervention and fatigue intensity rather than mediating intervention effects (-88%). Decrease in fatigue interference was mediated by sleep dysfunction (35%), whereas IL-10 and pro-anti-inflammatory cytokine ratios increased the relationship between intervention and interference (-25% to -40%). The reduction in general fatigue was significantly mediated by minutes of physical activity (76%), sleep dysfunction (45%), and physical activity enjoyment (40%), with IL-10 (-40%) and IL-6/IL-10 (-11%) increasing the intervention-fatigue relationship. In the intervention group, higher baseline fatigue, anxiety, depression, and perceived exercise barrier interference predicted a greater decline in fatigue interference and/or general fatigue during the intervention. CONCLUSIONS: Biobehavioral factors mediated and enhanced intervention effects on fatigue, whereas psychosocial factors predicted fatigue response. Further study is warranted to confirm our results and to improve understanding of relationships that mediate and strengthen the intervention-fatigue association.

Effects of a physical activity behavior change intervention on inflammation and related health outcomes in breast cancer survivors: pilot randomized trial.

BACKGROUND: The goal of this pilot study was to determine the magnitude and direction of intervention effect sizes for inflammatory-related serum markers and relevant health outcomes among breast cancer survivors (BCSs) receiving a physical activity behavior change intervention compared with usual care. METHODS: This randomized controlled trial enrolled 28 stage I, II, or IIIA BCSs who were post-primary treatment and not regular exercisers. Participants were assigned to either a 3-month physical activity behavior change intervention group (ING) or usual care group (UCG). Intervention included supervised aerobic (150 weekly minutes, moderate-intensity) and resistance (2 sessions per week) exercise that gradually shifted to home-based exercise. Outcomes were assessed at baseline and 3 months. RESULTS: Cardiorespiratory fitness significantly improved in the ING versus the UCG (between-group difference = 3.8 mL/kg/min; d = 1.1; P = .015). Self-reported sleep latency was significantly reduced in the ING versus the UCG (between group difference = -0.5; d = -1.2; P = .02) as was serum leptin (between-group difference = -9.0 ng/mL; d = -1.0; P = .031). Small to medium nonsignificant negative effect sizes were noted for interleukin (IL)-10 and tumor necrosis factor (TNF)-α and ratios of IL-6 to IL-10, IL-8 to IL-10, and TNF-α to IL-10, whereas nonsignificant positive effect sizes were noted for IL-6 and high-molecular-weight adiponectin. CONCLUSIONS: Physical activity behavior change interventions in BCSs can achieve large effect size changes for several health outcomes. Although effect sizes for inflammatory markers were often small and not significant, changes were in the hypothesized direction for all except IL-6 and IL-10.

Better exercise adherence after treatment for cancer (BEAT Cancer) study: rationale, design, and methods.

Most breast cancer survivors do not engage in regular physical activity. Our physical activity behavior change intervention for breast cancer survivors significantly improved physical activity and health outcomes post-intervention during a pilot, feasibility study. Testing in additional sites with a larger sample and longer follow-up is warranted to confirm program effectiveness short and longer term. Importantly, the pilot intervention resulted in changes in physical activity and social cognitive theory constructs, enhancing our potential for testing mechanisms mediating physical activity behavior change. Here, we report the rationale, design, and methods for a two-site, randomized controlled trial comparing the effects of the BEAT Cancer physical activity behavior change intervention to usual care on short and longer term physical activity adherence among breast cancer survivors. Secondary aims include examining social cognitive theory mechanisms of physical activity behavior change and health benefits of the intervention. Study recruitment goal is 256 breast cancer survivors with a history of ductal carcinoma in situ or Stage I, II, or IIIA disease who have completed primary cancer treatment. Outcome measures are obtained at baseline, 3 months (i.e., immediately post-intervention), 6 months, and 12 months and include physical activity, psychosocial factors, fatigue, sleep quality, lower extremity joint dysfunction, cardiorespiratory fitness, muscle strength, and waist-to-hip ratio. Confirming behavior change effectiveness, health effects, and underlying mechanisms of physical activity behavior change interventions will facilitate translation to community settings for improving the health and well-being of breast cancer survivors.

A randomized phase II study of paclitaxel and bevacizumab with and without gemcitabine as first-line treatment for metastatic breast cancer.

BACKGROUND: The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB). PATIENTS AND METHODS: In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m(2) (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m(2) (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life. RESULTS: Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia (P = .001) and dyspnea (P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) (P = .021), FACT-B Social/Family Well-being (P = .041), and Breast Cancer-Additional Concerns (P = .008) scores than patients treated with PB+G. CONCLUSION: The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated.

Reduced barriers mediated physical activity maintenance among breast cancer survivors.

To better understand mechanisms of physical activity (PA) behavior change in breast cancer survivors, we examined mediation of a successful PA behavior change intervention by social cognitive theory (SCT) constructs. Our exploratory study randomized 41 breast cancer survivors to receive the 3-month intervention (INT) or usual care (UC). We used the Freedman and Schatzkin approach to examine mediation of intervention effect on PA 3 months postintervention by changes in SCT constructs from baseline to immediately postintervention. Compared with UC, the INT group reported lower barriers interference (mean difference = -7.8, 95% CI [-15.1, -0.4], d = -0.67, p = .04) and greater PA enjoyment (mean difference = 0.7, 95% CI [0, 1.5], d = 0.61, p = .06). Barriers interference mediated 39% (p = .004) of the intervention effect on PA 3 months postintervention. PA enjoyment was not a significant mediator. Reducing barriers to PA partially explained our intervention effect.

Insight in the prediction of chemotherapy-induced nausea.

PURPOSE: To identify risk factors for chemotherapy-related nausea. METHODS: We examined risk factors for nausea in 1,696 patients from three multicenter studies conducted from 1998 to 2004. All patients were beginning a chemotherapy regimen containing cisplatin, carboplatin, or doxorubicin. Nausea was assessed on a 1-7 scale four times a day for 4 days by diary. RESULTS: First, average nausea for breast cancer patients receiving doxorubicin (mean = 2.31) was significantly greater than for other patients receiving doxorubicin (mean = 1.82), patients receiving cisplatin (mean = 1.88), and patients receiving carboplatin (mean = 1.45), Ps < 0.01. Second, mean nausea decreased steadily with age, P < 0.0001. Third, patients rating themselves more susceptible to nausea had significantly more nausea (adjusted mean = 2.51) than patients rating themselves less susceptible (adjusted mean = 1.92) and were 2.8 times more likely to experience severe nausea, Ps < 0.0001. Fourth, expected nausea was a significant predictor of average nausea, P = 0.034, but not severe nausea, P = 0.31. Last, no evidence that gender is a significant predictor of nausea in 299 patients with gender neutral cancers, P = 0.35. CONCLUSIONS: Specific patient characteristics, especially younger age and perceived susceptibility to nausea, can help clinicians in the early identification of patients who are more susceptible to treatment-related nausea.

Physical activity and health outcomes three months after completing a physical activity behavior change intervention: persistent and delayed effects.

PURPOSE: We previously reported the effectiveness of a 12-week physical activity behavior change intervention for breast cancer survivors postintervention with this report, aiming to determine delayed and/or persistent effects 3 months after intervention completion. METHODS: Forty-one sedentary women with stage I, II, or IIIA breast cancer currently receiving hormonal therapy were randomly assigned to receive the 12-week Better Exercise Adherence after Treatment for Cancer intervention or usual care. Assessments occurred at baseline, postintervention, and 3 months postintervention. RESULTS: Weekly minutes of greater than or equal to moderate intensity physical activity measured by accelerometer showed a significant group by time interaction (F = 3.51; P = 0.035; between group difference in the mean change from baseline to 3 months postintervention, 100.1 minute, P = 0.012). Significant group by time interactions also showed sustained improvements from baseline to 3 months postintervention in strength (F = 3.82; P = 0.027; between group difference, 11.2 kg; P = 0.026), waist-to-hip ratio (F = 3.36; P = 0.041; between group difference, -0.04; P = 0.094), and social well-being (F = 4.22; P = 0.023; between group difference, 3.9; P = 0.039). A delayed reduction in lower extremity dysfunction 3 months postintervention was noted (F = 3.24; P = 0.045; between group difference in the mean change from postintervention to 3 months follow-up; P = -7.6; P = 0.015). No group by time effect was noted for fitness, body mass index, percent fat, bone density, total quality of life (Functional Assessment of Cancer Therapy-General), fatigue, endocrine symptoms, cognitive function, or sleep. CONCLUSIONS: The intervention resulted in sustained improvements in physical activity, strength, central adiposity, and social well-being with lower extremity function benefits appearing 3 months after intervention completion. Testing translation in a multisite study is warranted.

A randomized trial to increase physical activity in breast cancer survivors.

PURPOSE: Interventions to increase physical activity among breast cancer survivors are needed to improve health and quality of life and possibly to reduce the risk of disease recurrence and early mortality. Therefore, we report the feasibility and preliminary outcomes of a pilot randomized trial designed to increase physical activity in sedentary breast cancer survivors receiving hormone therapy. METHODS: Forty-one sedentary women on estrogen receptor modulators or aromatase inhibitors for stage I, II, or IIIA breast cancer were randomly assigned to receive a 12-wk multidisciplinary physical activity behavior change intervention or usual care. RESULTS: Recruitment was 34%, intervention adherence was 99%, and complete follow-up data were obtained on 93%. Most participants (93%) were white with mean age of 53 +/- 9 yr. Differences favoring the intervention group were noted for accelerometer physical activity counts (mean difference = 72,103; 95% confidence interval (CI) = 25,383-119,000; effect size (d) = 1.02; P = 0.004), aerobic fitness (mean difference = 2.9; 95% CI = -0.1 to 5.8; d = 0.64; P = 0.058), back/leg muscle strength (mean difference = 12.3; 95% CI = 0.4-15.9; d = 0.81; P = 0.017), waist-to-hip ratio (mean difference = -0.05; 95% CI = -0.01 to -0.08; d = -0.77; P = 0.018), and social well-being (mean difference = 2.0; 95% CI = 0.3-3.8; d = 0.76; P = 0.03). However, the intervention group also reported a greater increase in joint stiffness (mean difference = 1.1; 95% CI = 0.1-2.2; d = 0.70; P = 0.04). CONCLUSIONS: A behavior change intervention for breast cancer survivors based on the social cognitive theory is feasible and results in potentially meaningful improvements in physical activity and selected health outcomes. Confirmation in a larger study is warranted.

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.

Phase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer.

PURPOSE: We conducted a phase II clinical trial to determine the clinical efficacy and safety of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients were eligible if they had measurable disease, no prior chemotherapy for metastatic disease, and a performance status