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.

Peritoneal carcinomatosis of gastrointestinal origin: natural history and treatment options.

BACKGROUND: Peritoneal carcinomatosis (PC) is a challenging consequence of certain malignancies, associated with a poor prognosis and limited treatment options. Generally, PC has been treated similarly to metastatic cancers of the primary tumor, but associated with worse outcomes when compared to other sites of metastatic disease from the same primary tumor site. With supportive care alone, the median survival with PC is 3-6 months. More recently, a limited number of centers have reported success with cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in a subset of patients with PC, resulting in improved survival compared with historical controls. OBJECTIVES: This paper outlines the natural history of PC, and surgical, chemotherapeutic, and combined modality treatment options, with a focus on PC of colorectal (CRC) and appendiceal origin. RESULTS: At this time, the 'standard' treatment for PC remains incompletely defined. As such, the optimal management strategies for both 'localized' and unresectable disease is unclear. CS + HIPEC is a promising treatment with a significant survival benefit of 10 months over systemic therapy alone demonstrated in a clinical trial of patients with CRC. CONCLUSION: Well-designed clinical trials need to continue to be offered to improve care and determine the optimal treatment strategies for PC.