Capecitabine, irinotecan (CAPIRI) and sunitinib in metastatic colorectal cancer

Carrato et al. [1] recently published their results of a randomized phase III trial of fl uorouracil (5-FU), leucovorin (LV) and irinotecan (FOLFIRI) plus either sunitinib or placebo in patients with metastatic colorectal cancer (mCRC). Intravenous FOLFIRI was administered every two weeks as irinotecan 180 mg/m 2 , LV 200 mg/m 2 immediately followed by 5-FU 400 mg/m 2 bolus and 5-FU 2400 mg/m 2 as a 46-hour infusion. The dosage of oral sunitinib was 37.5 mg/day in a four-weeks on/two-weeks off schedule. The study failed to demonstrate superiority for FOLFIRI plus sunitinib and showed an increased incidence of grade 3 adverse events for this combination when compared to FOLFIRI plus placebo [neutropenia (68% vs. 30%), diarrhea (16% vs. 8%, thrombocytopenia (11% vs. 1%), anemia, stomatitis, fatigue, hand-foot syndrome and febrile neutropenia). Furthermore, more deaths as a result of toxicity (n 12 vs. n 4) and signifi cantly more dose delays, dose reductions and treatment discontinuations occurred in the sunitinib arm. We performed a phase I study in a standard 3 3 trial design with capecitabine, irinotecan (CAPIRI) and sunitinib in patients with mCRC as second line treatment (NCT00777478). Both capecitabine and irinotecan were administered at a reduced starting dose (capecitabine 850 mg/m 2 on day 1 – 14 and irinotecan 200 mg/m 2 on day 1, every three weeks) due to the expected additive toxicities of the combination with sunitinib. This study was approved by the medical ethical committee and was conducted in accordance with the Principles of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent. We treated four patients at dose level 1, with sunitinib given at 25 mg/day continuously, and observed two dose limiting toxicities (DLTs): a grade 3 neutropenia lasting more than seven days and a delay of more than 14 days of the second cycle because of neutropenia and thrombocytopenia. According to protocol we subsequently treated the following patients at a lower dose level with sunitinib 12.5 mg/day continuously. Both patients at this dose level experienced neutropenia grade 3, which led to dose delays of irinotecan and dose interruptions of sunitinib and capecitabine. In one of these two patients, sunitinib was defi nitively withdrawn after cycle 4 and thereafter this patient did not experience any hematological toxicities anymore, even when the dose of irinotecan was escalated. As any clinical benefi t was not expected with lower doses of sunitinib with already reduced doses of capecitabine and irinotecan, the study was discontinued and we concluded that a combination of CAPIRI with sunitinib was not feasible. FOLFIRI, in comparison to CAPIRI, is associated with less adverse events as has been shown in a phase III trial, in which patients were randomized between treatment with FOLFIRI and CAPIRI [2]. Grade 3 to 4 nausea, vomiting, diarrhea and dehydration occurred signifi cantly more frequently in the CAPIRI arm, and neutropenia occurred more frequently in the FOLFIRI arm (43% vs. 32%). Although these data show that CAPIRI is associated with a higher incidence of toxic events, it is considered as a Acta Oncologica, 2013; 52: 1778–1790