Bevacizumab in Combination With Oxaliplatin-Based Chemotherapy As First-Line Therapy in Metastatic Colorectal Cancer: A Randomized Phase III Study

Memorial Sloan-Kettering Cancer Center, 1275 York Ave, Room H-917, New York, NY 10021, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 05/2008; 26(12):2013-9. DOI: 10.1200/JCO.2007.14.9930
Source: PubMed


To evaluate the efficacy and safety of bevacizumab when added to first-line oxaliplatin-based chemotherapy (either capecitabine plus oxaliplatin [XELOX] or fluorouracil/folinic acid plus oxaliplatin [FOLFOX-4]) in patients with metastatic colorectal cancer (MCRC).
Patients with MCRC were randomly assigned, in a 2 x 2 factorial design, to XELOX versus FOLFOX-4, and then to bevacizumab versus placebo. The primary end point was progression-free survival (PFS).
A total of 1,401 patients were randomly assigned in this 2 x 2 analysis. Median progression-free survival (PFS) was 9.4 months in the bevacizumab group and 8.0 months in the placebo group (hazard ratio [HR], 0.83; 97.5% CI, 0.72 to 0.95; P = .0023). Median overall survival was 21.3 months in the bevacizumab group and 19.9 months in the placebo group (HR, 0.89; 97.5% CI, 0.76 to 1.03; P = .077). Response rates were similar in both arms. Analysis of treatment withdrawals showed that, despite protocol allowance of treatment continuation until disease progression, only 29% and 47% of bevacizumab and placebo recipients, respectively, were treated until progression. The toxicity profile of bevacizumab was consistent with that documented in previous trials.
The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved PFS in this first-line trial in patients with MCRC. Overall survival differences did not reach statistical significance, and response rate was not improved by the addition of bevacizumab. Treatment continuation until disease progression may be necessary in order to optimize the contribution of bevacizumab to therapy.

Download full-text


Available from: Florin Sirzén, Mar 23, 2014
  • Source
    • "remains currently a challenging question. The use of antiangiogenic agents as first and second-line was shown to improve overall survival[7,8]. Recently, clinical trials underlined that permanent antiangiogenic blocking as first and second-line improved overall survival[9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Anti-EGFR therapy and antiangiogenic therapies are used alone or in combination with chemotherapies to improve survival in metastatic colorectal cancer. However, it is unknown whether pretreatment with antiangiogenic therapy could impact on the efficacy of anti-EGFR therapy. We selected one hundred and twenty eight patients diagnosed with advanced colorectal cancer with a KRAS and NRAS unmutated tumor. These patients were treated with cetuximab or panitumumab alone or with chemotherapy as second or third-line. Univariate and multivariate Cox model analysis were performed to estimate the effect of a previous bevacizumab regimen on progression free survival and on overall survival during anti-EGFR therapy. In vitro studies using wild type KRAS and NRAS colon cancer cells were performed to evaluate the impact of VEGF-A on cetuximab-induced cell death. The median progression free survival (PFS) during anti-EGFR treatment was significantly different between the bevacizumab group and the non-bevacizumab group (2.8 and 4 months respectively; p = 0.003). The median overall survival from the beginning of the metastatic disease was similar in the two groups (41.3 and 42 months respectively; p = 0.7). In vitro, VEGF-A induced a resistance toward cetuximab cytotoxicity on three KRAS and NRAS wild type colon cancer cell lines in a VEGFR2 and Stat-3-dependent manner. All in all, our clinical data, supported by in vitro procedures, suggest that a previous anti-VEGF therapy decreases anti-EGFR efficacy. Although these results are observed in a limited cohort, they could be taken into consideration for a better strategy of care for patient suffering from metastatic colorectal cancer.
    Full-text · Article · Jan 2016 · Oncotarget
  • Source
    • "The current molecular target treatments for colorectal cancer include VEGF-neutralizing agents, VEGF receptor inhibitors, EGF receptor inhibitors, and tyrosine kinase-inhibiting antibodies. The clinical use of these drugs has resulted in the improvement of the prognosis of unresectable advanced colorectal cancer patients[8,29303132. Nevertheless, colorectal cancer cannot be controlled completely, and the development of new therapies is necessary. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Prokineticin 2 (PROK2) is correlated with indispensable in maintaining the homeostasis of healthy human tissues. Herein, we examined the role of PROK2 in human colorectal cancer.After total RNA extraction from 6 colorectal cancer cell lines, we examined the expression of PROK2 mRNA. For investigating angiogenesis and tumor growth in mice, the PROK2 gene was transfected into colorectal cancer cell lines having low PROK2 mRNA expression. In addition, small interfering RNA (siRNA) was transfected into colorectal cancer cell lines having high PROK2 mRNA expression for investigation of angiogenesis and tumor growth in mice.From 6 colorectal cancer cell lines studied, PROK2 mRNA expression was increased in 3 cell lines. When the PROK2 gene was transfected into the colorectal cancer cell line with low PROK2 mRNA expression, angiogenesis and tumor growth in mice increased significantly compared to the cell line with the control vector.When PROK2 siRNA was transfected into colorectal cancer cell lines with high PROK2 mRNA expression, angiogenesis and tumor growth in mice were suppressed significantly compared to the cell line with siRNA (control).This is the first report of the association of PROK2 as an angiogenic growth factor in colorectal cancer.
    Preview · Article · Jun 2015 · Oncotarget
  • Source
    • "months in the 5-FU/LV plus bevacizumab group despite the absence of oxaliplatin, compared with 5.2–5.5 months in the 5-FU/LV group. While no study has directly compared FOLFOX plus bevacizumab with 5-FU/LV plus bevacizumab, the results of previous clinical trials [3] [9] [10] indicate that the median PFS is similar with these regimens, and that 5-FU/LV plus bevacizumab is better tolerated, with a lower incidence of adverse events. These clinical results suggest that it may be unnecessary to use oxaliplatin or irinotecan in combination with 5-FU as first-line treatment and that sequential chemotherapy based on 5-FU is useful. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chemotherapeutic regimens for elderly patients with metastatic colorectal cancer (mCRC), such as bevacizumab combined with 5-fluorouracil (5-FU) and leucovorin, often exclude oxaliplatin and irinotecan owing to the risk of toxicity. However, treatment with infusional 5-fluorouracil and leucovorin requires percutaneous port-catheter placement and other precautions, causing unnecessary stress for patients as well as healthcare workers. We conducted a phase II study to evaluate the efficacy and safety of bevacizumab plus S-1 in elderly patients with previously untreated mCRC. Bevacizumab was given intravenously every two weeks, and S-1 was administered orally on days 1-28 of a 42-day cycle. The primary end-point was progression-free survival (PFS). The secondary end-points were time to treatment failure, response rate (RR), overall survival (OS), treatment completion status and safety. From October 2007 through March 2010, 56 patients were enroled. The median PFS was 9.9months, the median OS was 25.0months, and the RR was 57%. The main adverse events of grade 3 or higher were hypertension (11%), diarrhoea (9%) and neutropenia (7%). Our results suggest that combination chemotherapy with S-1 and bevacizumab can be administered safely and continuously on an outpatient basis and is therapeutically effective in elderly patients with mCRC. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Full-text · Article · Mar 2015 · European journal of cancer (Oxford, England: 1990)
Show more