Colonic perforation with intraluminal stents and bevacizumab in advanced colorectal cancer: retrospective case series and literature review
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* Amal Imbulgoda
* Anthony MacLean
* John Heine
* Sebastien Drolet
* Michael M. Vickers

## Abstract

**Background:** Self-expanding metal stents (SEMS) are increasingly used in the treatment of malignant large bowel obstruction in the setting of inoperable colorectal cancer. Perforation is a well-known complication associated with these devices. The addition of the vascular endothelial growth factor inhibitor bevacizumab is suspected to increase the rate, but the extent of the increase is not known.

**Methods:** We retrospectively reviewed the records of patients receiving SEMS in tertiary hospitals in Calgary, Alta., between October 2001 and January 2012.

**Results:** We reviewed the records of 87 patients with inoperable colorectal cancer who received SEMS during our study period. Nine perforations occurred in total: 4 of 30 (13%) patients who received no chemotherapy, 3 of 47 (6%) who received chemotherapy but no bevacizumab, and 2 of 10 (20%) who received chemotherapy and bevacizumab. These two patients received bevacizumab with FOLFIRI after SEMS placement, and they had peritoneal disease.

**Conclusion:** Our case series and other studies suggest that bevacizumab may increase the risk of colonic perforation in the setting of SEMS. Caution should be used when combining these therapies.

Colorectal cancer (CRC) accounted for approximately 13% of new cases of cancer in Canada in 2012.1 Approximately 15% of patients with CRC present with large bowel obstruction,2 and obstruction will develop in 8% at some point in the course of advanced disease.3 In the past, therapeutic options included emergency surgery with tumour resection and primary anastomosis or a Hartmann procedure with colostomy creation. Owing to the potential for postsurgical complications, including wound infections and anastomotic leaks, and to mortality exceeding 10%,4 the development of alternative treatment strategies have been explored.

Self-expanding metallic stents (SEMS) have been increasingly used in malignant colorectal obstruction, particularly in patients with advanced-stage cancers in whom resection is often not a feasible means of palliation. In addition, the use of SEMS as a bridge to surgery is gaining popularity in the management of resectable obstructions. Advantages include technical and clinical success rates exceeding 90%,5 stent-related mortality of less than 1%5 and possibly improved quality of life compared with palliative surgery.6,7 The potential complications of SEMS placement include stent migration, reobstruction and, the most worrisome, colonic perforation. The incidence of the latter approaches 4%5 and is a serious concern for clinicians because mortality after emergency surgery for a perforated CRC has been found to be approximately 20%–30% in recent studies.8,9

Although it does not appear that chemotherapy alone increases the risk of gastrointestinal (GI) perforation,10 there is debate as to whether the risk of perforation is increased when chemotherapy is administered to patients with stents.11–15 Of particular concern is the concurrent use of the vascular endothelial growth factor inhibitor bevacizumab with SEMS. While the addition of this agent to standard fluoropyrimide-based chemotherapy regimens has improved survival outcomes in patients with metastatic colorectal carcinoma, it has also been associated with a significantly increased risk of GI perforation, with a reported incidence of 1.9%.16

It could be expected that the combination of bevacizumab, chemotherapy and SEMS would be associated with even higher perforation rates; however, there is a paucity of literature on this topic. To investigate this possible association, we undertook a retrospective case series to determine the incidence of colonic perforation in patients with advanced-stage or locally advanced, unresectable CRC treated with SEMS in 3 tertiary hospitals in Alberta, Canada. We also performed a literature review with a particular interest on the rates of this complication with chemotherapy alone and with the addition of bevacizumab.

## Methods

Consecutive patients admitted between October 2001 and January 2012 were identified using an existing database of SEMS procedures in 3 hospitals in Calgary, Alberta. The electronic medical records for these individuals were accessed, and those who had experienced a large bowel obstruction in the setting of stage 4 or locally recurrent colorectal adenocarcinoma were included in this analysis. Patients receiving stents as a bridge to surgery as well as 1 patient who was lost to follow-up in the 6-month period following insertion were excluded. In addition to demographic details, we collected data pertaining to the stent insertion, complications, specific chemotherapy used, vital statistics outcomes and additional interventions. We obtained approval from our local research ethics committee before data collection.

### Statistical analysis

For comparisons between groups, we performed a Fisher exact test using STATA statistical software version 13.1.

## Results

Of the 87 patients meeting our inclusion criteria, 30 had not received chemotherapy, 47 had received chemotherapy but not bevacizumab (18 before SEMS, 28 after, 1 unknown), and 10 received chemotheraphy and bevacizumab (3 before, 6 after, 1 unknown; Table 1). The patients who did not receive chemotherapy tended to be older and had worse performance status and lower baseline carcinoembryonic antigen (CEA) values. In the bevacizumab group, a relatively large proportion of patients had peritoneal involvement (40%), with both perforations in this group occurring in the setting of peritoneal disease.

View this table:
[Table 1](http://canjsurg.ca/content/58/3/167/T1)

Table 1 
Baseline demographic and clinical characteristics of the study sample

Perforations occurred in 4 (13%) patients with SEMS who did not receive chemotherapy, 3 (6%) with SEMS who received chemotherapy but not bevacizumab, and 2 (20%) with SEMS who received chemotherapy and bevacizumab (Table 2). We found no differences in perforation rates between the chemotherapy plus bevacizumab and the chemotherapy alone groups (*p* = 0.21), between the chemotherapy plus bevacizumab and the no chemotherapy groups (*p* = 0.63), or between the chemotherapy alone and the no chemotherapy groups (*p* = 0.42). Perforations occurred in 4 of 36 (11%) patients who received chemotherapy with or without bevacizumab after stenting compared with 1 of 18 (6%) patients who had received systemic therapy before the procedure. Total complication rates (including reobstructions and migrations) were 16% in the no chemotherapy group, 27% in the chemotherapy without bevacizumab group and 50% in the chemotherapy plus bevacizumab group.

View this table:
[Table 2](http://canjsurg.ca/content/58/3/167/T2)

Table 2 
Complications of patients with SEMS

Mean survival times since stenting were 101 days in the no chemotherapy group, 277 days in the chemotherapy without bevacizumab group and 226 days in the chemotherapy plus bevacizumab group (Table 3). The chemotherapy regimens administered to 5 patients with perforations included 5-fluorouracil/folinic acid (FU/FA; *n* = 1), FOLFOX (*n* = 2) and FOLFIRI plus bevacizumab (*n* = 2).

View this table:
[Table 3](http://canjsurg.ca/content/58/3/167/T3)

Table 3 
Mean survival (d) of patients from insertion of SEMS

Data pertaining to the 2 patients with perforations who received FOLFIRI plus bevacizumab are presented in Table 4. Features in common include peritoneal involvement and a history of exposure to FOLFIRI plus bevacizumab chemotherapy within the previous 2 weeks. Patient 2 perforated during her first treatment cycle. Location of stricture, initial CEA, time from stenting until perforation and outcome were markedly different between these patients.

View this table:
[Table 4](http://canjsurg.ca/content/58/3/167/T4)

Table 4 
Demographic and clinical characteristics of patients who experienced a perforation with bevacizumab

## Discussion

Multiple studies have established that an increased risk of perforation exists with the addition of bevacizumab to chemotherapy in patients with CRC.16–18 A recent meta-analysis of randomized controlled trials encompassing more than 3000 patients with metastatic CRC showed a perforation rate of 15 of 1491 (1.0%) in patients treated with and 2 of 1508 (0.1%) in patients treated without bevacizumab added to standard 5-FU-based chemotherapy regimens.17 A large observational cohort study of nearly 2000 patients treated with bevacizumab reported a perforation rate of 1.9%.16 In another meta-analysis, Geiger-Gritsch and colleagues18 reported a 4-fold higher risk of GI hemorrhage or perforation with bevacizumab. In a phase II NSABP C-10 trial,19 perforation occurred in 1 of 86 (1.2%) patients; this patient had an intact primary tumour and received mFOLFOX6 chemotherapy with bevacizumab.

In patients with SEMS, the overall perforation rate was found to be 3.76% in a large pooled analysis encompassing 54 studies (1198 patients) in the pre-bevacizumab era.5 This study included patients stented for palliation as well as patients stented as a bridge to surgery. In comparison, we found (excluding patients treated with bevacizumab) a much higher rate of perforation (9%) in the present study. This higher rate could be related to the selected population including only palliative and poor surgical risk patients. Other healthier patients and those with a lower burden of disease having a stent as a bridge to surgery were not included in our series. Similarly, patients who did not receive chemotherapy had a higher perforation rate than those who received chemotherapy (13% v. 6%). Generally, patients who are unfit for chemotherapy are older and have worse performance status and possibly more advanced primary tumours. In the setting of palliative chemotherapy, several small studies have reported similar results (Table 5).

View this table:
[Table 5](http://canjsurg.ca/content/58/3/167/T5)

Table 5 
Selected studies of perforation following SEMS insertion for advanced colorectal cancer

Since both bevacizumab and SEMS are associated with colonic perforations, it would be expected that the combination of bevacizumab, chemotherapy and the use of SEMS would be associated with even higher perforation rates. In 1 case series including 9 patients treated with SEMS and chemotherapy, the only 2 patients to receive bevacizumab were the only individuals to experience perforations.21 Small and colleagues22 reported in a retrospective study that 4 perforations occurred in 23 (17.4%) patients who received the drug after SEMS insertion compared with 14 in 207 (6.8%) patients who did not receive it; however, this difference was not statistically significant (*p* = 0.06). In addition, another study revealed a 50% perforation rate in 8 patients who received bevacizumab with a stent in situ.23 Our finding of 2 perforations in 10 patients fits within the range found in these prior studies.

In our series the 2 patients who experienced a perforation while treated with bevacizumab had peritoneal disease. It remains unclear if peritoneal disease increases the risk of GI perforation with bevacizumab in the setting of CRC. In patients with ovarian cancer, GI perforations occur at a rate of more than 5%.24 As these patients frequently have abdominal carcinomatosis, some groups24,25 have hypothesized that bevacizumab-related perforation occurs more frequently in these individuals because of peritoneal disease. Proposed mechanisms include necrosis of the tumour deposited in the intestinal wall, microperforation due to bowel obstruction24 and aggressive surgical cytoreduction causing injury.25 Some of these mechanisms would apply to CRC as well. Intuitively, radial pressure on the bowel wall from a stent could lead to erosion and, subsequently, perforation.

The timing of administration of systemic therapy in relation to SEMS insertion may influence the risk of perforation. In patients receiving chemotherapy with or without bevacizumab after stenting, perforations occurred in 11% compared with only 6% in patients who had received systemic therapy before the procedure. This finding could be due to tumour response, resulting in the stent eroding through a weakened bowel wall. However, this mechanism could also apply to systemic therapy given before stenting. All of the patients who received chemotherapy with or without bevacizumab before stenting in our study had last been treated 50 or more days before stenting; many patients who received chemotherapy with or without bevacizumab after stenting were treated within a month of stenting. Thus, it may be the proximity in time of the chemotherapy in relation to the procedure that may be most important. Further studies are required to investigate this possibility.

### Limitations

The small number of patients with SEMS who received chemotherapy and bevacizumab limits our study, as in other reports on this topic. Owing to these small numbers and the retrospective nature of our study, we were unable to control for measured (and unmeasured) variables that may have increased the perforation risk. However, the use of bevacizumab in this clinical setting is increasing, and the risk of perforation remains a major concern. Further, our study involved only 1 health region in Canada, which may limit the generalizability of our results.

## Conclusion

Self-expanding metallic stents are part of the armatorium for malignant colorectal obstruction, especially in a palliative setting. However, the risk of perforation remains a major concern. Our study adds further evidence of a higher risk of colonic perforation when bevacizumab is administered to patients in this setting. Further studies involving larger numbers of patients and multiple centres are needed to confirm this risk. Oncologists should carefully consider the perforation risk associated with bevacizumab, especially in patients with SEMS.

## Footnotes

*   **Competing interests:** None declared.

*   **Contributors:** A. Imbulgoda, A. MacLean, J. Heine and M. Vickers designed the study. A. Imbulgoda, A. MacLean and S. Drolet acquired the data, which A. Imbulgoda and M. Vickers analyzed. A. Imbulgoda and M. Vickers wrote the article, which all authors reviewed and approved for publication.

*   Accepted November 11, 2014.

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