A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC.

PURPOSE: Regorafenib is an oral multi-kinase inhibitor that offers an OS benefit to patients with mCRC refractory to standard therapy (Grothey et al., in Lancet 381:303-312, 2013), but comes with potential significant toxicities including grade 3 hand-foot skin reaction (HFSR). The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. We hypothesized that perindopril, an angiotensin-converting enzyme (ACE) inhibitor, indicated for the treatment of hypertension (Ceconi et al., in Cardiovasc Res 73:237-246, 2007), and which plays a role in preventing endothelial dysfunction, may help to prevent or reduce the severity of regorafenib-induced HFSR. PATIENTS AND METHODS: In this single-center phase II open-label trial, patients with refractory mCRC were treated with both regorafenib (160 mg/day) and perindopril (4 mg/day) for 21 days per 28-day cycle. The primary end point was to assess the proportion of patients with any grade HFSR toxicity. Secondary end points included time to development of worst (grade 3) HFSR, reduction of all grades of hypertension and all grade toxicities, as well as progression-free survival. All toxicities were evaluated using CTCAE v4.03. RESULTS: A planned interim analysis was performed after ten evaluable patients had completed their first cycle of study treatment. As 50% (5/10) experienced grade 3 HFSR, enrolment was stopped as the addition of perindopril did not lead to a reduced level of HFSR compared with regorafenib alone. Other grade 3 toxicities included hypertension (16.7%) and increased AST (16.7%). CONCLUSION: The addition of an ACE inhibitor perindopril to regorafenib did not reduce HFSR incidence or severity in patients with refractory mCRC.

A Comparison of Survival by Site of Metastatic Resection in Metastatic Colorectal Cancer.

BACKGROUND: Metastatic resection (MR) of liver-limited disease is an effective therapy for selected patients with metastatic colorectal cancer (mCRC). Despite limited data, this approach has been expanded to include MR of other sites, such as the lung, locoregional, and other distant disease (ODD). We performed a population-based study of patients with mCRC who had undergone MR and compared survival between MR of the liver and MR of other sites. METHODS: Patients with mCRC who were referred to the British Columbia Cancer Agency between 1995 and 2010 were reviewed. Patients were included if they had an R0 MR with a negative margin and no residual disease. The site of MR was classified according to collaborative staging criteria as liver, lung, locoregional, or ODD. Median overall survival (mOS) was assessed with Kaplan-Meier methods and compared using the log-rank test. A Cox proportional-hazards model was used to compare mOS, while adjusting for known prognostic factors. RESULTS: A total of 2082 patients with mCRC were identified, of whom 257 underwent R0 MR. Sites of MR included liver (65%), lung (16%), locoregional (5%), and ODD (14%). The mOS of liver, lung, locoregional, and ODD were 48.0, 42.8, 37.2, and 26.2 months, respectively (P = .087). On multivariate analysis, only MR of ODD had a significantly different survival estimate than MR of the liver (hazard ratio, 1.78; 95% confidence interval, 1.13-2.80; P = .012). CONCLUSIONS: Patients with limited lung and locoregional disease seem to have a comparable survival advantage from MR as patients with liver-limited metastases.