Gemcitabine Plus Bevacizumab Compared With Gemcitabine Plus Placebo in Patients With Advanced Pancreatic Cancer: Phase III Trial of the Cancer and Leukemia Group B (CALGB 80303)

Abstract

Purpose The combination of gemcitabine plus bevacizumab produced a 21% response rate and a median survival of 8.8 months in a multicenter phase II trial in patients with metastatic pancreatic cancer. These encouraging data led Cancer and Leukemia Group B (CALGB) to conduct a double-blind, placebo-controlled, randomized phase III trial of gemcitabine/bevacizumab versus gemcitabine/placebo in advanced pancreatic cancer patients. Patients and Methods Eligible patients had no prior therapy for advanced disease, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, no tumor invasion of adjacent organs, and no increased bleeding risk. The primary end point was overall survival. Patients were stratified by performance status, extent of disease, and prior radiotherapy. Patients received gemcitabine at 1,000 mg/m2 over 30 minutes on days 1, 8, and 15 every 28 days and bevacizumab at 10 mg/kg or placebo on days 1 and 15 every 28 days. Results Between June 2004 and April 2006, 602 patients were enrolled onto the study and 535 were treated. Median overall survival was 5.8 months for gemcitabine/bevacizumab and 5.9 months for gemcitabine/placebo (P = .95). Median progression-free survival was 3.8 and 2.9 months, respectively (P = .07). Overall response rates were 13% and 10%, respectively. Patients with a performance status of 0, 1, and 2 survived a median of 7.9, 4.8, and 2.4 months, respectively. The only statistically significant differences in grades 3 and 4 toxicity occurred for hypertension (10% v 3%; P < .001) and proteinuria (5% v 1%; P = .002); venous thrombosis grade ≥ 3 was equivalent in both arms (14% and 15%, respectively). Conclusion The addition of bevacizumab to gemcitabine does not improve survival in advanced pancreatic cancer patients.

Myoferlin plays a key role in VEGFA secretion and impacts tumor‐associated angiogenesis in human pancreas cancer

“…Unfortunately, they failed to show any survival benefit for bevacizumab or axitinib in combination with gemcitabine. 43,44 However, these studies did not consider separately patients with a high basal production of VEGFA which correlates with better progression-free and overall survival in bevacizumab-treated patients versus those receiving placebo. 45 In another study, the pretreatment plasma VEGFA levels were described as ranging from 0 to 462 pg/ml, 30 underlying the heterogeneity of this parameter in patients.…”

Simultaneous inhibition of the ubiquitin-proteasome system and autophagy enhances apoptosis induced by ER stress aggravators in human pancreatic cancer cells

“…2 Currently, gemcitabine is the mainstay of therapy; however, response rates are less than 20%. 3 Thus, this lack of effective therapeutic strategies urgently raises the need for novel systemic treatments.…”

Risk of Serious Neutropenic Events in Cancer Patients Treated with Bevacizumab: A Meta-analysis

“…After evaluating each remaining study, 22 RCTs were selected for the meta-analysis (Hurwitz et al, 2005;Sandler et al, 2006;Escudier et al, 2007;Herbst et al, 2007;Karrison et al, 2007;Miller et al, 2007;Allegra et al, 2009;Baar et al, 2009;Moehler et al, 2009;Reck et al, 2009;Robert et al, 2009;Van Cutsem et al, 2009;Brufsky et al, 2010;Burger et al, 2010;Kang et al, 2010;Kelly et al, 2010;Kindler et al, 2010;Miles et al, 2010;Okines et al, 2010;Rini et al, 2010;Tebbutt et al, 2010;Zalcman et al, 2010). The selection process is summarized in Figure 1.…”