Phase II, Randomized Trial Comparing Bevacizumab Plus Fluorouracil (FU)/Leucovorin (LV) With FU/LV Alone in Patients With Metastatic Colorectal Cancer

Abstract

The encouraging results of this randomized trial support further study of bevacizumab 5 mg/kg plus chemotherapy as first-line therapy for metastatic colorectal cancer.

Antiangiogenic agents and late anastomotic complications

“…In randomized phase II and III trials, the incidence of bowel perforation under bevacizumab therapy, independently of surgery, was around 1-2%, significantly higher than in control patients [4,6]. In the BRiTE observational study, a 1.7% gastrointestinal perforation rate was observed among the 1,960 assessable patients with metastatic colorectal cancer treated with first-line chemotherapy and bevacizumab.…”

“…The last stage is the maturation process, characterized by an increase in collagen content and tensile strength [15]. In phase II and III studies, the surgical wounds were exposed to bevacizumab therapy only during the maturation phase, that is, more than 28 days after surgery [4][5][6].…”

“…Preclinical studies have demonstrated deleterious effects of agent targeting vascular endothelial growth factor (VEGF) on the healing of ventral hernias and colonic anastomoses [1][2][3]. In fact, major surgery less than 28 days before the beginning of therapy has been an exclusion criterion in colorectal phase II and III studies with bevacizumab [4][5][6]. In the pivotal phase III trial in metastatic colorectal cancer, wound-healing complications occurred in 10 out of 75 (13%) bevacizumab-treated patients undergoing surgery compared to 1 out of 29 (3.4%) control patients.…”

Mechanisms of adverse effects of anti-VEGF therapy for cancer

“…Fatal pulmonary haemorrhage occurred in two patients in a trial of sunitinib in metastatic NSCLC (Socinski et al, 2006), and the agent is not approved for this form of cancer. Patients with metastatic colorectal cancer who receive bevacizumab plus chemotherapy generally have a higher incidence of serious haemorrhage (3 -9%) than those on chemotherapy alone (Kabbinavar et al, 2003;Hurwitz et al, 2004;Giantonio et al, 2005;Gordon and Cunningham, 2005;Kabbinavar et al, 2005;Hurwitz and Saini, 2006) (Other information at: http://www.avastin-info.com/portal/eipf/pb/avastin/ com/clinicalslidekit). Haemorrhagic events of all types had a higher incidence in patients on sorafenib (15%) than on placebo (8%).…”

Angiogenesis inhibitors in clinical development; where are we now and where are we going?

“…In these studies, the increased incidence of thromboembolic complications, bleeding episodes (some of which were lethal), hypertension and proteinuria was the reason for concern (Burnstein et al, 2002;Miller et al, 2002;Yang et al, 2002;Kabbinavar et al, 2003). Two randomised phase III studies combining bevacizumab with standard cytotoxic treatment in patients with metastatic breast cancer showed disappointing results (Miller et al, , 2003, but a recently presented randomised phase III study in 800 previously untreated patients with metastatic colorectal cancer comparing treatment with irinotecan, 5-fluorouracil and leucovorin (IFL) and IFL combined with bevacizumab given every 2 weeks showed increased response rates, prolonged time to progression and significantly increased survival with no increased incidence of thromboembolic complications .…”