Safety profile of capecitabine as maintenance treatment after induction with XELOX or FOLFOX in metastatic colorectal cancer patients
Authors: C. Cremolini, R. Moretto, G. Masi, A. Falcone
Journal: Annals of Oncology (2016)

We read with interest the results of the randomized trial by Luo et al. [1.Luo H.Y. Li Y.H. Wang W. et al.Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety.Ann Oncol. 2016; 27: 1074-1081Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar], supporting the use of capecitabine as maintenance therapy following induction with XELOX or FOLFOX in Chinese metastatic colorectal cancer patients. Switching from an intravenous to an oral fluoropyrimidine is an appealing option both for patients and for physicians, especially for a potentially long-lasting treatment. Nevertheless, some concerns about tolerability of capecitabine after 5-fluorouracil (5-FU)-containing regimens were raised by previous sequence trials. In particular, an English trial [2.Hennig I.M. Naik J.D. Brown S. et al.Severe sequence-specific toxicity when capecitabine is given after fluorouracil and leucovorin.J Clin Oncol. 2008; 26: 3411-3417Crossref PubMed Scopus (20) Google Scholar] that randomized patients to adjuvant weekly 5-FU/leucovorin (LV) followed by capecitabine or the reverse sequence, in order to ascertain patients' preferences, was early interrupted due to a significantly higher incidence of grade 3 and 4 adverse events in patients assigned to the former strategy. In a similar trial conducted in Denmark [3.Pfeiffer P. Mortensen J.P. Bjerregaard B. et al.Patient preference for oral or intravenous chemotherapy: a randomised cross-over trial comparing capecitabine and nordic fluorouracil/leucovorin in patients with colorectal cancer.Eur J Cancer. 2006; 42: 2738-2743Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar], grade 3 adverse events were observed in the 48% of patients treated with capecitabine following bolus 5-FU/LV, when compared with the 19% of patients receiving capecitabine first. On the other hand, a French trial [4.Twelves C. Gollins S. Grieve R. Samuel L. A randomised cross-over trial comparing patient preference for oral capecitabine and 5-fluorouracil/leucovorin regimens in patients with advanced colorectal cancer.Ann Oncol. 2006; 17: 239-245Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar] did not report any substantial difference in terms of safety between capecitabine followed by 5-FU/LV according to the Mayo Clinic or the de Gramont schedule or the reverse sequence. It is well known that LV impairs the maximum tolerated dose of capecitabine. In addition, LV is transported into cells and converted into the polyglutammate form, with increased intracellular half-life and capable of retaining intracellular folates for prolonged periods after LV administration. This might explain the higher toxicity rate of capecitabine, when administered after 5-FU/LV [2.Hennig I.M. Naik J.D. Brown S. et al.Severe sequence-specific toxicity when capecitabine is given after fluorouracil and leucovorin.J Clin Oncol. 2008; 26: 3411-3417Crossref PubMed Scopus (20) Google Scholar]. We recognize that the tolerability profile of fluoropyrimidines may largely vary in different countries, as a consequence of both genetic (i.e. different frequency of polymorphisms involved in drug metabolism) and environmental factors (i.e. dietary habits, folate intake, fortification of cereal grain with folic acid and mandatory in the USA and UK) [5.Haller D.G. Cassidy J. Clarke S.J. et al.Potential regional differences for the tolerability profiles of fluoropyrimidines.J Clin Oncol. 2008; 26: 2118-2123Crossref PubMed Scopus (205) Google Scholar]. Nevertheless, the trial by Luo et al. [1.Luo H.Y. Li Y.H. Wang W. et al.Single-agent capecitabine as maintenance therapy after induction of XELOX (or FOLFOX) in first-line treatment of metastatic colorectal cancer: randomized clinical trial of efficacy and safety.Ann Oncol. 2016; 27: 1074-1081Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar] may help to throw light on this issue, by describing the incidence of adverse events in the maintenance arm according to the previous induction regimen (FOLFOX, N = 67 versus XELOX, N = 69). If no differences will be evident, this may reassure clinicians about the use of capecitabine following 5-FU-containing regimens, at least in Asian patients. All authors have declared no conflicts of interest.