AIM: To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease.

METHODS: We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test.

RESULTS: Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups.

CONCLUSION: Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone.

Peritoneal spread from colorectal cancer occurs in 10%-15% of patients with metastatic colorectal cancer (mCRC)[1]. These patients typically have a high disease burden with increased morbidity and a worse prognosis than patients without peritoneal disease[2-4].

Gastrointestinal perforation is a well-documented side effect of bevacizumab, a humanized monoclonal antibody and occurs at a rate of 1%-2%. In the BRITE registry[5], 37 of 1953 metastatic colorectal patients had a gastrointestinal perforation. On multivariate analysis, risk factors associated with gastrointestinal perforation included intact primary tumour and prior adjuvant radiotherapy. The risk of gastrointestinal perforation may be enhanced in the presence of chemotherapy related gastrointestinal toxicity or by bevacizumab induced changes in tumour vasculature. A meta-analysis found gastrointestinal perforation occurs with the use of bevacizumab in other tumour types with the highest relative risk seen with intra-abdominal cancers including colorectal, ovarian, pancreatic and renal cell cancers compared to breast, lung and glioblastoma[6].

The rates of gastrointestinal perforation in phase III trials have been reported in ovarian cancer which like colorectal cancer has a predilection for peritoneal spread. In the OCEANS trial[7] and the AURELIA trial[8] the rate of gastrointestinal perforation was 0.8% and 2.2% respectively, in patients receiving bevacizumab and chemotherapy. In a univariate analysis of patients receiving bevacizumab in the GOG 0218 trial[9]-inflammatory bowel disease, small bowel surgery or large bowel surgery at time of primary resection was associated with an increased risk of gastrointestinal perforation. The increased risk of gastrointestinal perforation in patients with intra-abdominal tumours, bowel surgery or bowel obstruction have led some investigators to urge caution in using bevacizumab in patients with peritoneal metastases[6,10,11].

Our study aimed to assess the gastrointestinal safety outcomes of bevacizumab and systemic chemotherapy in mCRC patients with peritoneal disease in three cohorts, including both clinical trial and non-trial patients. The Australasian Gastrointestinal Trials Group (AGITG) MAX trial[12] included patients with peritoneal disease and hence was an ideal study for our analysis.

Despite the advances in the treatment of metastatic colorectal cancer, the prognosis of patients with peritoneal disease remains poor. This analysis suggests that the addition of bevacizumab to chemotherapy does not increase the rate of gastrointestinal perforations in patients with metastatic colorectal cancer and peritoneal metastases. Specifically, no gastrointestinal perforations were seen in the patients with peritoneal disease in the MAX study and the NSWCC cohort, and in the TRACC registry bevacizumab use was not associated with an increased rate of gastrointestinal perforation. The addition of bevacizumab to standard first-line chemotherapy is associated with longer PFS in patients with peritoneal disease treated in the trial and non-trial settings. There was a consistent PFS benefit seen across studies, with the hazard ratios ranging from 0.61 to 0.75, with statistical significance only seen in the TRACC registry. However, the AGITG MAX clinical trial was not powered to detect statistically significant improvements in PFS within the peritoneal subgroup. Significant differences in prognostic variables, as well as selection bias may have led to the significant survival differences associated with bevacizumab use in the TRACC registry and the NSWCC cohort. Both the TRACC registry and NSWCC cohorts demonstrated a > 50% usage of bevacizumab alongside a range of chemotherapy regimens by clinicians.

Multiple risk factors have been associated with an increased risk of gastrointestinal perforations. Intra-abdominal tumours such colorectal, ovarian, pancreatic and renal cell cancers have been associated with an elevated risk of gastrointestinal perforation compared to non-abdominal cancers such as breast and lung cancers[6,11]. In the BRITE registry[5] the rate of gastrointestinal perforation in all patients with mCRC was 1.9% with an elevated risk on multivariate analysis seen in patients with an intact primary tumour and prior adjuvant radiation. Given the increased risk of gastrointestinal perforations in patients with mCRC investigators have postulated various mechanisms including predisposing GI toxicity from chemotherapy, pelvic irradiation, intact primary tumour, peritoneal metastases and bevacizumab-induced changes in tumour vasculature. To our knowledge the risk of gastrointestinal perforation in patients with peritoneal disease has been poorly described. The AGITG MAX trial is the only randomised Phase III trial comparing a bevacizumab containing arm to a non-bevacizumab containing arm where the outcomes of peritoneal disease patients are described. Although others have performed analyses of patients with peritoneal metastases in randomised trials, these were not comparisons of the addition of bevacizumab to chemotherapy[3,4,14]. In most cases safety analyses were not reported.

Our analysis presents outcomes of patients in a clinical trial as well as outcomes in patients treated in typical community cancer centres. Rates of gastrointestinal perforations were available from all three cohorts and indicate that bevacizumab appears to be as safe in the peritoneal disease subgroup as compared to patients without peritoneal disease. Furthermore, despite previous series suggesting an elevated risk[6,10,11], clinicians appear to be comfortable in using bevacizumab in patients with peritoneal disease as reflected in the number of patients with peritoneal disease recruited to MAX and the proportion of bevacizumab-treated patients in the TRACC registry not being impacted by the presence or absence of peritoneal disease. The weaknesses of the analysis include the small patient numbers in each cohort. In Australia, bevacizumab has been publicly funded since 2009 and thus the numbers of patients with peritoneal disease who had access to bevacizumab in the NSWCC were small. Nevertheless, this analysis represents the largest analysis of gastrointestinal perforations in patients with peritoneal disease.

There is significant discordance seen in the OS effects. The median OS in the MAX trial is longer in the capecitabine alone arm, however, the curves cross before and after the median with a HR = 0.89. Use of post-progression therapy was minimal in the MAX trial, suggesting imbalances in subsequent therapy do not explain the discordance between the impact on PFS and OS. Nonetheless, the OS findings of the subgroup of patients with peritoneal metastases are consistent with the overall MAX trial results. While a statistically significant improvement in OS was seen in the TRACC registry, this may be due to differences in prognostic factors between the bevacizumab and non-bevacizumab treated patients given the non-randomised nature of the registry, which likely account for at least some of this gain. Such an imbalance in patient prognostic factors may also have explained the inconsistency in data from the BRITE registry[15], which showed a far larger survival gain with bevacizumab beyond progression in all patients with metastatic colorectal cancer than was seen in the randomised TML trial[16]. Although the difference in survival is large in the NSWCC cohort there are known significant baseline differences between the groups and these factors may account for the difference seen.

Alternative routes of bevacizumab administration may be helpful for patients with peritoneal disease, with case reports of intraperitoneal administration of bevacizumab with significant symptomatic benefit mainly in ovarian cancer patients[17-19]. However, we are unaware of any data related to the safety and efficacy of this approach in metastatic colorectal cancer. The results of ongoing trials are eagerly awaited[20].

In conclusion, this analysis of metastatic colorectal cancer patients with peritoneal disease reveals similar findings across a clinical trial and routine practice cohorts. The combination appears to be safe to use, without an increase in rate of gastrointestinal perforations observed in any of the cohorts. From our analysis, patients with metastatic colorectal cancer to the peritoneum should not be excluded from receiving bevacizumab.