Page 2: Health Product InfoWatch - February 2017
New health product safety information
The following topics have been selected to raise awareness and, in some cases, to stimulate reporting of similar adverse reactions.
Colorectal stents and bevacizumab: increased risk of intestinal perforation
- Recent scientific publications have described an increased risk of intestinal perforation in patients receiving colorectal stents combined with bevacizumab-based chemotherapy for the treatment of colorectal cancer.
- The concurrent use of bevacizumab and colorectal stents should be considered with caution.
- Healthcare professionals are encouraged to report to Health Canada any cases of perforation suspected of being associated with the use of colorectal stents and/or bevacizumab, and to provide detailed information when describing cases.
Colorectal cancer (CRC) is one of the most common cancers worldwide and remains a major health problem.Footnote 1 In Canada, CRC accounted for approximately 13% of new cases of cancer in 2012.Footnote 2 Acute malignant colorectal obstruction is a complication of primary or metastatic CRC that can occur in 7 to 29% of patients.Footnote 1,Footnote 2,Footnote 3,Footnote 4 The optimal management of this severe clinical condition remains challenging.
Colorectal stents are a family of self-expandable metallic stents (SEMS) implanted to maintain colorectal luminal patency in the presence of colorectal obstruction. The stents are used in patients with advanced-stage cancers as an alternative to surgery for palliative care.Footnote 2 In addition, they are also used as a bridge to surgery in the management of resectable obstructions.Footnote 2,Footnote 4
One of the most important stent-related complications is intestinal perforation.Footnote 4 The incidence of perforation in patients undergoing colorectal stent placement has been reported in the literature to be between 3.8% and 6.9%, requiring a surgical intervention in 73% of cases, and leading to death in 16.3% of cases.Footnote 5
Bevacizumab is a recombinant humanised monoclonal antibody that selectively binds to and neutralises the biologic activity of human vascular endothelial growth factor.Footnote 6 In Canada, bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for first-line treatment of patients with metastatic CRC, among other indications. While the addition of this agent to standard fluoropyrimidine-based chemotherapy regimens has been reported to improve survival outcomes in patients with metastatic CRC, it has also been associated with a risk of intestinal perforation.Footnote 2,Footnote 7 Intestinal perforations have been reported in up to 2.7% of bevacizumab-treated patients with metastatic CRC.Footnote 6
While perforation is a known risk of both colorectal stents and bevacizumab therapy, recently, Health Canada identified several publications including a meta-analysis as well as retrospective case series indicating an increased risk of perforation in patients treated concomitantly with stents and bevacizumab-based chemotherapy, as compared to patients receiving chemotherapy without bevacizumab for the treatment of CRC.Footnote 2,Footnote 5,Footnote 8,Footnote 9 Based on results from the meta-analysis involving 4 086 patients who underwent colorectal stent placement, the perforation rate for patients receiving bevacizumab-based chemotherapy was 12.5%, whereas the rate of perforation for patients receiving chemotherapy without bevacizumab was 7.0%.Footnote 5 A recent Canadian study of a retrospective case series reported perforation in 2 of 10 (20%) patients receiving stents combined with bevacizumab-based chemotherapy.Footnote 2 Both patients also had peritoneal disease, and it is unclear if this may have increased the risk of perforation. For patients receiving stents and chemotherapy without bevacizumab, perforation was reported in 3 of 47 (6%) patients.
The proposed mechanism for the increased risk of intestinal perforation with concurrent therapy is that the antiangiogenic effect of bevacizumab may weaken the bowel wall and predispose the bowel to perforation by SEMS pressure.Footnote 9 Given this risk, several publications in the medical literature including the European Society of Gastrointestinal Endoscopy Clinical Guideline on SEMS have indicated that combined therapy should be carefully considered and avoided if possible.Footnote 1,Footnote 2,Footnote 4,Footnote 5,Footnote 10 Due to a similar therapeutic mechanism, other newer antiangiogenic agents may also present an increased risk of perforation when prescribed in patients with a colorectal stent implanted.Footnote 1,Footnote 4,Footnote 10 However, evidence to support this hypothesis is insufficient.
At the time of its assessment, Health Canada received 6 cases of perforation related to the use of stents and 83 cases of perforation related to the use of bevacizumab. Among these 83 cases, 3 cases reported the use of both bevacizumab and a stent. Two of the 3 cases were discussed in the literature.Footnote 2 In the third case, the patient experienced perforation at the level of his stent; however, no specific temporal information was provided on the stent insertion and the use of bevacizumab. Therefore, it was not possible to assess whether the stent was contributory to the perforation. None of the remaining cases reported with either bevacizumab or stents provided information on the concomitant use of both health products.
It is difficult to quantify the increased risk of perforation at this time, given the overall insufficient evidence due to limitations and confounding factors in the published studies. To reduce the potential risk of perforation associated with the use of these products, the concurrent use of bevacizumab and SEMS should be considered with caution.Footnote 1,Footnote 2,Footnote 4,Footnote 5,Footnote 10
Healthcare professionals are encouraged to report to Health Canada any cases of perforation suspected of being associated with the use of SEMS and/or bevacizumab. When reporting cases to Health Canada, please provide detailed information to facilitate a more thorough assessment of the potential safety issue (see "Did you know?").
Did you know?
What to include in your adverse reaction or incident reports to Health Canada concerning intestinal perforation following the use of SEMS and/or bevacizumab
It is important to include as many as possible of the following elements:
- Patient characteristics (age, sex, height and weight)
- Name of suspected health product or products if concomitant therapies are administered (including device trade/brand name, model and licence number for medical devices such as stents)
- Description of the adverse reaction or incident
- Dosing information and indication for use of the suspected health product(s)
- Therapy dates: when the use of the suspected health product(s) began and ended
- Changes to therapy with the suspected health product(s) and impact on the patient (e.g., dechallenge/rechallenge information)
- Treatment of the adverse reaction or incident (including date the adverse reaction or incident occurred and was resolved, if applicable)
- Investigations to exclude alternate causes for the adverse reaction or incident
- Relevant history and pre-existing conditions
- Relevant tests/lab data
- Other health products used (including over-the-counter and natural health products) with therapy dates and dosing information
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