The Effect on Surgical Complications of Bevacizumab Added to Neoadjuvant Chemotherapy for Breast Cancer: NRG Oncology/NSABP Protocol B-40.

BACKGROUND: NRG Oncology/NSABP trial B-40 tested the impact of adding bevacizumab (bev) to neoadjuvant chemotherapy for operable breast cancer. Secondary endpoints included rates of surgical complications after surgery in patients who did or did not receive bev. METHODS: A total of 1206 women with HER2-negative operable breast cancer were randomly assigned to receive one of three different docetaxel-plus-anthracycline-based regimens, without or with bev (15 mg/kg every 3 weeks) for the first 6 of 8 cycles and for 10 doses postoperatively. Surgical complications were assessed from date of surgery through 24 months following study entry. RESULTS: Early surgical complications were significantly more frequent in the bev group (25.4 vs. 18.9%; trend test p = 0.008), but most were grade 1-2. Early noninfectious wound dehiscences were infrequent and not significantly different (5.4 vs. 3.1%; trend test p = 0.15). Long-term noninfectious wound complications were significantly higher for patients receiving bev (11.8 vs. 5.1%; trend test p = 0.0007), but the incidence of grade ≥3 wound dehiscence was low in both groups (<1%). Among 193 patients undergoing expander or implant reconstructions, 19 (19.6%) of 97 in the bev-receiving group versus 10 (10.4%) of 96 in the non-bev group had grade ≥3 complications (Pearson, p = 0.11). CONCLUSIONS: Overall, adding bev increased surgical complications, but most serious complications were not significantly increased. In particular, the need for surgical intervention in patients undergoing breast reconstruction with prosthetic implants was higher with bev but was not statistically significantly different. With precautions, bev can be used safely perioperatively in patients undergoing surgery for breast cancer.

Toxicity-Related Factors Associated With Use of Services Among Community Oncology Patients.

PURPOSE: Community oncology practices frequently manage chemotherapy-associated toxicities, which may disrupt treatment, impair quality of life, and induce unplanned service use. We sought to understand the patterns and correlates of unplanned health care service use among patients receiving first-cycle chemotherapy at five community-based ambulatory oncology practices. PATIENTS AND METHODS: A survey study examined the dichotomous outcome of unplanned service use, defined as oncologist visits, emergency department visits, and hospitalizations, resulting from toxicity-related factors. Newly diagnosed patients with breast, lung, head and neck, or colorectal cancer or non-Hodgkin lymphoma were recruited during the first chemotherapy cycle. Before beginning the second cycle of chemotherapy, patients completed a questionnaire that measured unplanned service use and overall distress, plus severity of nausea, vomiting, diarrhea, constipation, mouth sores, intravenous catheter problems, pain, fever and chills, extremity edema, and dyspnea on a 5-point scale (1, did not experience; 5, disabling). Medical record reviews captured chemotherapy doses, comorbid conditions, and supportive care interventions. Mixed-effects logistic regression was used to identify factors associated with unplanned service use, with random effects specified for each clinic. RESULTS: Among 106 patients (white, 98%; female, 74.5%; mean age ± standard deviation, 60 ± 11 years), frequently reported toxicities were pain, nausea, diarrhea, and constipation. Thirty-six patients (34%) reported unplanned service use: 29% reported oncologist visits, 14% reported emergency department visits, and 8% reported hospitalizations. Factors significantly associated with unplanned service use were high patient-reported distress and receipt of colony-stimulating factor. CONCLUSION: Service use resulting from toxicity-related factors occurs frequently in community oncology settings. Monitoring toxicity patterns and outcomes can inform proactive symptom management approaches to reduce toxicity burden between scheduled visits.

Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial.

BACKGROUND: NSABP B-40 was a 3 × 2 factorial trial testing whether adding capecitabine or gemcitabine to docetaxel followed by doxorubicin plus cyclophosphamide neoadjuvant chemotherapy would improve outcomes in women with operable, HER2-negative breast cancer and whether adding neoadjuvant plus adjuvant bevacizumab to neoadjuvant chemotherapy regimens would also improve outcomes. As reported previously, addition of neoadjuvant bevacizumab increased the proportion of patients achieving a pathological complete response, which was the primary endpoint. We present secondary patient outcomes, including disease-free survival, a specified endpoint by protocol, and data for distant recurrence-free interval, and overall survival, which were not prespecified endpoints but were collected prospectively. METHODS: In this randomised controlled trial (NSABP B-40), we enrolled women aged 18 years or older, with operable, HER2-non-amplified invasive adenocarcinoma of the breast, 2 cm or greater in diameter by palpation, clinical stage T1c-3, cN0, cN1, or cN2a, without metastatic disease and diagnosed by core needle biopsy. Patients received one of three docetaxel-based neoadjuvant regimens for four cycles: docetaxel alone (100 mg/m(2)) with addition of capecitabine (825 mg/m(2) oral twice daily days 1-14, 75 mg/m(2) docetaxel) or with addition of gemcitabine (1000 mg/m(2) days 1 and 8 intravenously, 75 mg/m(2) docetaxel), all followed by neoadjuvant doxorubicin and cyclophosphamide (60 mg/m(2) and 600 mg/m(2) intravenously) every 3 weeks for four cycles. Those randomly assigned to bevacizumab groups were to receive bevacizumab (15 mg/kg, every 3 weeks for six cycles) with neoadjuvant chemotherapy and postoperatively for ten doses. Randomisation was done (1:1:1:1:1:1) via a biased-coin minimisation procedure to balance the characteristics with respect to clinical nodal status, clinical tumour size, hormone receptor status, and age. Intent-to-treat analyses were done for disease-free survival and overall survival. This study is registered with ClinicalTrials.gov, number NCT00408408. FINDINGS: Between Jan 5, 2007, and June 30, 2010, 1206 patients were enrolled in the study. Follow-up data were collected from Oct 31, 2007 to March 27, 2014, and were available for overall survival in 1186 patients, disease-free survival in 1184, and distant recurrence-free interval in 1181. Neither capecitabine nor gemcitabine increased disease-free survival or overall survival. Median follow-up was 4·7 years (IQR 4·0-5·2). The addition of bevacizumab significantly increased overall survival (hazard ratio 0·65 [95% CI 0·49-0·88]; p=0·004) but did not significantly increase disease-free survival (0·80 [0·63-1·01]; p=0·06). Four deaths occurred on treatment due to vascular disorder (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), sudden death (docetaxel plus capecitabine followed by doxorubicin plus cyclophosphamide group), infective endocarditis (docetaxel plus bevacizumab followed by doxorubicin plus cyclophosphamide and bevacizumab group), and visceral arterial ischaemia (docetaxel followed by doxorubicin plus cyclophosphamide group). The most common grade 3-4 adverse events in the bevacizumab group were neutropenia (grade 3, 99 [17%]; grade 4, 37 [6%]), hand-foot syndrome (grade 3, 63 [11%]), and hypertension (grade 3, 60 [10%]; grade 4, two [<1%]) and in the non-bevacizumab group were neutropenia (grade 3, 98 [16%]; grade 4, 36 [6%]), fatigue (grade 3, 53 [9%]), and hand-foot syndrome (grade 3, 43 [7%]). INTERPRETATION: The addition of gemcitabine or capecitabine to neoadjuvant docetaxel plus doxorubicin plus cyclophosphamide does not seem to provide any benefit to patients with operable breast cancer, and should not change clinical practice in the short term. The improved overall survival with bevacizumab contradicts the findings of other studies of bevacizumab in breast cancer and may indicate the need for additional investigation of this agent. FUNDING: National Institutes of Health, Genentech, Roche Laboratories, Lilly Research Laboratories, and Precision Therapeutics.

North Central Cancer Treatment Group/Alliance trial N08CA-the use of glutathione for prevention of paclitaxel/carboplatin-induced peripheral neuropathy: a phase 3 randomized, double-blind, placebo-controlled study.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a significant side effect of taxane and platinum-based chemotherapy. Several studies have supported the potential benefit of glutathione for the prevention of platinum-induced CIPN. The current trial was designed to determine whether glutathione would prevent CIPN as a result of carboplatin/paclitaxel therapy. METHODS: In total, 185 patients who received treatment with paclitaxel and carboplatin were accrued between December 4, 2009 and December 19, 2011. Patients were randomized to receive either placebo (n = 91) or 1.5 g/m(2) glutathione (n = 94) over 15 minutes immediately before chemotherapy. CIPN was assessed using the European Organization for Research and Treatment of Cancer Quality-of-Life (EORTC-QLQ) 20-item, CIPN-specific (CIPN20) sensory subscale and the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. RESULTS: There were no statistically significant differences between the 2 study arms with regard to: 1) peripheral neurotoxicity, as assessed using both the EORTC-QLQ-CIPN20 (P = .21) and the CTCAE scales (P = .449 for grade ≥2 neurotoxicity; P = .039 for time to development of grade ≥2 neuropathy, in favor of the placebo); 2) the degree of paclitaxel acute pain syndrome (P = .30 for patients who received paclitaxel every 3-4 weeks and P = .002, in favor of the placebo, for patients who received weekly paclitaxel); 3) the time to disease progression (P = .63); or 4) apparent toxicities. Subgroup analyses did not reveal any evidence of benefit in any particular subgroup. CONCLUSIONS: The results from this study do not support the use of glutathione for the prevention of paclitaxel/carboplatin-induced CIPN.

Randomized trial to assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer.

PURPOSE: Hot flashes occur in approximately 80% of androgen-deprived men. Few intervention studies have been conducted to relieve hot flashes in men. PATIENTS AND METHODS: Eligible androgen-deprived men were randomly assigned to one of four daily regimens (2 × 2 factorial design) for 12 weeks: milk protein powder and placebo pill, venlafaxine and milk protein powder, soy protein powder and placebo pill, or venlafaxine and soy protein powder. The primary end point was hot flash symptom severity score (HFSSS), defined as number of hot flashes times severity. The secondary end point was quality of life (QoL), assessed by using the Functional Assessment of Cancer Therapy-Prostate. RESULTS: In all, 120 men age 46 to 91 years participated. Most were white (78%) and overweight or obese (83%). Toxicity was minimal. Neither venlafaxine nor soy protein alone or in combination had a significant effect on HFSSS. Soy protein, but not venlafaxine, improved measures of QoL. CONCLUSION: In androgen-deprived men, neither venlafaxine nor soy proved effective in reducing hot flashes. Interventions that appear effective for decreasing hot flashes in women may not always turn out to be effective in men.

Bevacizumab added to neoadjuvant chemotherapy for breast cancer.

BACKGROUND: Bevacizumab and the antimetabolites capecitabine and gemcitabine have been shown to improve outcomes when added to taxanes in patients with metastatic breast cancer. The primary aims of this trial were to determine whether the addition of capecitabine or gemcitabine to neoadjuvant chemotherapy with docetaxel, followed by doxorubicin plus cyclophosphamide, would increase the rates of pathological complete response in the breast in women with operable, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and whether adding bevacizumab to these chemotherapy regimens would increase the rates of pathological complete response. METHODS: We randomly assigned 1206 patients to receive neoadjuvant therapy consisting of docetaxel (100 mg per square meter of body-surface area on day 1), docetaxel (75 mg per square meter on day 1) plus capecitabine (825 mg per square meter twice a day on days 1 to 14), or docetaxel (75 mg per square meter on day 1) plus gemcitabine (1000 mg per square meter on days 1 and 8) for four cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for four cycles. Patients were also randomly assigned to receive or not to receive bevacizumab (15 mg per kilogram of body weight) for the first six cycles of chemotherapy. RESULTS: The addition of capecitabine or gemcitabine to docetaxel therapy, as compared with docetaxel therapy alone, did not significantly increase the rate of pathological complete response (29.7% and 31.8%, respectively, vs. 32.7%; P=0.69). Both capecitabine and gemcitabine were associated with increased toxic effects--specifically, the hand-foot syndrome, mucositis, and neutropenia. The addition of bevacizumab significantly increased the rate of pathological complete response (28.2% without bevacizumab vs. 34.5% with bevacizumab, P=0.02). The effect of bevacizumab on the rate of pathological complete response was not the same in the hormone-receptor-positive and hormone-receptor-negative subgroups. The addition of bevacizumab increased the rates of hypertension, left ventricular systolic dysfunction, the hand-foot syndrome, and mucositis. CONCLUSIONS: The addition of bevacizumab to neoadjuvant chemotherapy significantly increased the rate of pathological complete response, which was the primary end point of this study. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00408408.).

Phase I study of involved-field radiotherapy preceding autologous stem cell transplantation for patients with high-risk lymphoma or Hodgkin's disease.

PURPOSE: This Phase I study was designed to evaluate the tolerability of involved-field radiotherapy (IFRT) to areas of persistent disease in patients with high-risk Hodgkin's disease and non-Hodgkin's lymphomas before autologous stem cell transplantation (ASCT). METHODS AND MATERIALS: Thirty-one patients with primary refractory or relapsed Hodgkin's disease (n = 13) and non-Hodgkin's lymphoma (n = 18) were treated with IFRT followed by high-dose chemotherapy and ASCT. All patients had bulky disease (> or =5 cm) and/or an inadequate response to salvage chemotherapy. The IFRT dose was escalated to a maximum of 36 Gy. Dose-limiting toxicity was defined as Grade 3-4 Bearman toxicity (life-threatening/fatal toxicity occurring within 28 days of ASCT). The chemotherapy regimen consisted of cyclophosphamide, etoposide, and carmustine. RESULTS: The delivered dose of IFRT was 20 Gy in 9 patients, 28-30 Gy in 20, and 32-36 Gy in 2 patients to mediastinal (n = 19) and nonmediastinal (n = 12) sites. The median interval between IFRT completion and ASCT was 19 days. One patient developed Bearman Grade 3 hepatic toxicity. No other Grade 3 or 4 Bearman toxicity was observed. An increased requirement for i.v. narcotics was observed in patients treated with mediastinal IFRT vs. nonmediastinal IFRT (p = 0.02). A trend toward increased mucositis severity was seen in patients previously treated with a larger number of chemotherapy agents (p = 0.09) and in those with a shorter interval between IFRT and ASCT (p = 0.12). Pulmonary toxicity was more common in patients treated with mediastinal IFRT than in those treated with nonmediastinal IFRT (21% vs. 0%, p = 0.13). The 2-year overall and progression-free survival rate was 70% and 49% for all patients, 84% and 50% for patients with Hodgkin's disease, and 59% and 47% for patients with non-Hodgkin's lymphoma, respectively. CONCLUSION: The maximal tolerated dose of IFRT was not reached when Grade 3-4 Bearman toxicity was dose limiting. Increased pulmonary toxicity and mucositis severity was seen after mediastinal IFRT compared with nonmediastinal IFRT. Because local control was excellent, higher doses of IFRT are not recommended. The absolute benefit of IFRT in this patient population needs investigation in future studies.