Elsevier

Current Surgery

Volume 63, Issue 5, September–October 2006, Pages 334-337
Current Surgery

Case report
Bowel Perforation from Bevacizumab for the Treatment of Metastatic Colon Cancer: Incidence, Etiology, and Management

https://doi.org/10.1016/j.cursur.2006.06.002Get rights and content

Avastin (Bevacizumab) is a recently developed monoclonal antibody against vascular endothelial growth factor (VEGF) receptor that increases survival in patients with metastatic colorectal cancer. Bowel perforation is a known risk factor of unknown etiology associated with the use of Avastin. In this report, the incidence, risk factors, typical presentation, and management of patients with this complication is described.

Introduction

Avastin (Bevacizumab), a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) receptor, was recently approved by the Federal Drug Administration for use in metastatic colon cancer. This drug targets tumor angiogenesis, an important process in tumor growth and development. In a phase III trial of patients with metastatic colon cancer, Avastin in combination with the standard chemotherapy consisting of irinotecan (CPT-11), 5-fluorouracil (5-FU), and leucovorin (IFL) showed a 30% significant increase in overall survival compared with IFL alone (20.3 months vs 15.6 months, p ≤ 0.001) and progression-free survival by 71% (from 6.2 to 10.6 months, p ≤ 0.001).1 Other studies showed similar results with Avastin in combination with fluorouracil and leucovorin or fluorouracil alone.2 Since the release of these studies, Avastin has become a widely used intervention in patients with metastatic colon cancer.

Avastin is the first anti-angiogenesis drug used in colorectal cancer, which in contrast to conventional treatment with 5-FU, CPT-11, and oxaliplatin, does not have serious myelotoxicity or neurotoxicity.3 As VEGF is selectively present in the neovasculature of the growing tumor,4 the systemic side effects of targeting this receptor are minimized. In the initial trials of Avastin in combination with IFL, the side effects most commonly noted, over first-line therapy alone, were hypertension, proteinuria, and diarrhea. Less common serious complications such as bleeding, thromboembolic events, and bowel perforation occurred with a frequency of less than 2%.2 Bowel perforation occurred in 1.5% of patients in the phase III trial5 and in 1.6% of patients in subsequent surveillance trials, including 1367 patients receiving Avastin in combination with first-line chemotherapy.6 Thromboembolic events are also significantly higher in patients treated with Avastin versus chemotherapy alone (3.8% vs 1.7%).7

Bowel perforation in patients undergoing treatment with Avastin remains a rare but serious complication of this chemotherapeutic agent. Immediate recognition followed by surgical intervention is the best form of management for this unusual complication. In this report, the etiology, clinical presentation, risk factors, and management of bowel perforation after administration of bevacizumab for the treatment of metastatic colon cancer are investigated.

Section snippets

Case report

A 55-year-old Caucasian man with stage IIA moderately differentiated rectal adenocarcinoma presented to the Dallas Veterans Affairs Medical Center (DVAMC) with acute abdominal pain. He had initially presented to the DVAMC in August 2003 with a lower gastrointestinal bleed and a mass on digital rectal examination. Biopsies showed rectal adenocarcinoma. He underwent neoadjuvant chemoradiation with 2 cycles of 5-FU and leucovorin and 5040 cGy to the region of the tumor followed 6 weeks later by

Discussion

Avastin trials in combination with various first-line chemotherapy drugs showed bowel perforation in 1.5% to 1.6% of patients.8, 9 The location of these perforations in phase III trial patients included gastric, small bowel, and large bowel, with the most common being large bowel, as in the current case.10 A proposed common predisposing factor in the 6 patients presenting with gastrointestinal perforation during the phase III trial was intra-abdominal inflammation caused by peptic ulcer

References (21)

  • N. Ferrara

    Role of vascular endothelial growth factor in physiologic and pathologic angiogenesis: therapeutic implications

    Semin Oncol

    (2002)
  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
  • F. Kabbinavar et al.

    Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer

    J Clin Oncol

    (2003)
  • D. Simpson et al.

    Oxaliplatin: a review of its use in combination therapy for advanced metastatic colorectal cancer

    Drugs

    (2003)
  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
  • M. Kozloff et al.

    Safety of bevacizumab (BV) among patients (pts) receiving first-line chemotherapy (CT) for metastatic colorectal cancer (mCRC): preliminary results from a larger registry in the U.S

    J Clin Oncol (Meeting Abstracts)

    (2005)
  • J.R. Skillings et al.

    Arterial thromboembolic events (ATEs) in a pooled analysis of 5 randomized, controlled trials (RCTs) of bevacizumab (BV) with chemotherapy

    J Clin Oncol (Meeting Abstracts)

    (2005)
  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
  • M. Kozloff et al.

    Safety of bevacizumab (BV) among patients (pts) receiving first-line chemotherapy (CT) for metastatic colorectal cancer (mCRC): preliminary results from a larger registry in the U.S

    J Clin Oncol (Meeting Abstracts)

    (2005)
  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
There are more references available in the full text version of this article.

Cited by (83)

  • Image-guided stereotactic ablative radiotherapy for the liver: A safe and effective treatment

    2015, European Journal of Surgical Oncology
    Citation Excerpt :

    This anti-VEGFR monoclonal antibody has been associated with an increased incidence of bowel ulceration and perforation, both with and without radiotherapy. Blockage of vascularity in the bowels, resulting in hypoxia, necrosis and tissue breakdown, is probably the main cause of this toxicity.28–32 Despite several clinical factors like pre-existing liver dysfunction, prior therapy and portal vein thrombosis, accurate prediction of RILD remains a challenge.

  • Toxicity of targeted therapy: Implications for response and impact of genetic polymorphisms

    2014, Cancer Treatment Reviews
    Citation Excerpt :

    For VEGFR TKIs, the incidence rate was 1.3%, with a mortality of 28.6%, according to a meta-analysis of 5352 patients with various solid tumors treated with VEGFR TKIs [61]. The mechanism of this toxicity may involve decreased blood supply to intestinal villi by direct inhibition of VEGF signaling [101], or through micro-thromboembolism [102]. There are no studies on the correlation between this toxicity and treatment outcome, drug levels or impact of genetic polymorphisms.

  • Gallbladder perforation related to bevacizumab

    2013, Clinics and Research in Hepatology and Gastroenterology
View all citing articles on Scopus
View full text