Concurrent oxaliplatin, capecitabine, and radiation therapy in the neoadjuvant therapy of rectal adenocarcinoma: can we get the right dose first?

Abstract

In the December 2005 issue of Annals of Oncology, Machiels et al. reported on a phase II study of weekly oxaliplatin, daily capecitabine Mondays through Fridays, and radiation therapy in the neoadjuvant therapy of patients with T3 or T4 or any nodally positive adenocarcinoma of the rectum [1.Machiels J.P. Duck L. Honhon B. et al.Phase II study of preoperative oxaliplatin, capecitabine and external beam radiotherapy in patients with rectal cancer: the RadiOxCape study.Ann Oncol. 2005; 16: 1898-1905Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar]. The treatment selected for this study consisted of oxaliplatin 50 mg/m2/week ×5 and capecitabine 825 mg/m2 PO BID Mondays through Fridays concurrently with conformational 3D radiation therapy 45 Gy in 25 fractions. This treatment was associated with a high rate of GI toxicity with 30% of patients developing grade 3 or 4 diarrhea and one toxic death. We argue that this dose, in the recommended schedule, is not the appropriate dose for neoadjuvant rectal chemoradiation. No rationale is provided for the starting dose on this phase II study. Furthermore, the selected two-step design was liberal in allowing the study to proceed with the initial dose-level if less than three out of the first six patients developed grade 3 or above diarrhea or febrile neutropenia. Other grade 3 to 4 toxicities such as nausea/vomiting or inability to administer a minimum threshold of radiation or chemotherapy were not considered in the dose selection or in the assessment of the safety of this combination prior to proceeding to the second-step of this study. Such liberal guidelines led to implementation of a dose-level that resulted in what we believe to be an unacceptably high rate of GI toxicity. We have recently presented our data on a phase I clinical trial of oxaliplatin, capecitabine, and radiation therapy in a similar schedule to the one described by Machiels et al. [2.Fakih M. Rajput A. Yang G. et al.A phase I and biological correlates study of capecitabine (CAP) + oxaliplatin (OX) + radiation therapy in locally advanced rectal cancer (LARC).Am Soc Clin Oncol2005. 2005; Crossref PubMed Google Scholar]. The starting dose of oxaliplatin and capecitabine was similar to the one used on Machiels phase II study; however, radiation therapy was given (conformational 3D) at 50.4 Gy in 28 fractions. We had two dose limiting toxicities consisting of G3 diarrhea in six patients treated at this dose level. A dose-level (−1) of oxaliplatin 50 mg/m2/week ×5 in combination with capecitabine 725 mg/m2 PO BID Monday–Friday and radiation was subsequently investigated in six patients with only one dose-limiting diarrhea being noted. This dose level (−1) is a more appropriate phase II dose and is currently being investigated in an ongoing phase II study. We do not believe that the additional three fractions of radiation administered in our study were the reason for our lower recommended dose as the dose-limiting diarrhea occurred within the first 45 Gy of radiation administered. We would urge against the widespread endorsement of the 50/825 mg/m2 of oxaliplatin/capecitabine dose-level given our phase I results and the high rate of GI toxicity on Machiels' study. Special caution should be exerted towards the proposed American College of Surgeons Oncology Group (ACOSOG) phase II neoadjuvant study that is recommending 50/825 mg/m2 dosing. We would hope that the long awaited safety data from the Capecitabine Oxaliplatin Radiotherapy and Excision (CORE) study would shed some further light on the tolerability of this regimen.