Increased mean corpuscular volume of erythrocytes predicts the response to metronomic cyclophosphamide, capecitabine and bevacizumab treatment: Is it true for capecitabine treatment or more?

Abstract

We read with great interest the article by Dellapasqua et al. about the increased erythrocyte mean corpuscular volume (MCV) with metronomic cyclophosphamide, capecitabine and bevacizumab treatment as a predictor of response.1Dellapasqua S. Bagnardi V. Bertolini F. Sandri M.T. Pastrello D. Cancello G. et al.Increased mean corpuscular volume of red blood cells predicts response to metronomic capecitabine and cyclophosphamide in combination with bevacizumab.Breast. 2012; 21: 309-313Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar The authors had found that 61% (42 of 69) of the metastatic breast cancer patients developed macrocytosis on the 24th week of the treatment and had chosen that time point as a landmark on which patient rate had reached a plateau for macrocytosis (MCV ≥ 100 fl). Time to progression was longer among patients who developed macrocytosis than patients who did not (72 vs. 43 weeks). Predicting the response at the 6th month (24th week) of the treatment might not be an early time point as the authors mentioned that macrocytosis was an early surrogate marker of response. We have recently shown that early increment of erythrocyte MCV at 9th week of capecitabine monotherapy (2500 mg m−2; for 14 days every 21 days) might predict treatment response on 75 metastatic breast cancer patients.2Arslan C. Aksoy S. Dizdar O. Kurt M. Güler N. Ozisik Y. et al.Increased mean corpuscular volume of erythrocytes during capecitabine treatment: a simple surrogate marker for clinical response.Tumori. 2011; 97: 711-716PubMed Google Scholar Drugs interacting on DNA biosynthesis, especially antimetabolites, might cause macrocytosis. Capecitabine treatment in various solid tumours and breast cancer populations was shown to cause macrocytosis which might be related with tymidilate synthesis.2Arslan C. Aksoy S. Dizdar O. Kurt M. Güler N. Ozisik Y. et al.Increased mean corpuscular volume of erythrocytes during capecitabine treatment: a simple surrogate marker for clinical response.Tumori. 2011; 97: 711-716PubMed Google Scholar, 3Wenzel C. Mader R.M. Steger G.G. Pluschnig U. Kornek G.V. Scheithauer W. et al.Capecitabine treatment results in increased mean corpuscular volume of red blood cells in patients with advanced solid malignancies.Anti-Cancer Drugs. 2003; 14: 119-123Crossref PubMed Scopus (31) Google Scholar, 4Karvellas C.J. Sawyer M. Hamilton M. Mackey J.R. Effect of capecitabine on mean corpuscular volume in patients with metastatic breast cancer.Am J Clin Oncol. 2004; 27: 364-368Crossref PubMed Scopus (24) Google Scholar Continuous usage of drug and ongoing effect on DNA synthesis might be an important factor on the occurrence of macrocytosis. A 14-day schedule of capecitabine treatment has been shown to cause macrocytosis. Metronomic treatment schedule of capecitabine treatment might increase erythrocyte MCV levels due to continuous effect on DNA synthesis with a high probability as the authors mentioned. However, macrocytosis might not be related with capecitabine only but also other treatment agents such as bevacizumab, cyclophosphamide or erlotinib. The authors referred to a study of capecitabine treatment on gastrointestinal cancer patients.5Sun J.F. Wu R.R. Norris C. Noone A.M. Amankawa-Sakyi M. Slack R. et al.Safety of chronic low-dose capecitabine as maintenance therapy in gastrointestinal cancers.Gastrointest Cancer Res. 2009; 1: 134-140Google Scholar Capecitabine treatment on gastrointestinal cancer patients for macrocytosis might not be suitable due to the possible broken integrity of the gastrointestinal system and potential vitamin B12 deficiency. In this study, patient population was not homogeneous with regard to the treatment agents and/or doses in contrast to what the authors mentioned (23 patients received bevacizumab 15 mg kg−1 IV every 21 days plus cyclophosphamide 50 mg po once daily, capecitabine 500 mg po thrice daily, and 46 patients received bevacizumab 10 mg kg−1 IV every 14 days, plus capecitabine 500 mg po thrice daily, cyclophosphamide 50 mg po once daily plus erlotinib 100 mg po once daily ± trastuzumab IV). Studies with single agent capecitabine treatment might show the effect of capecitabine on macrocytosis clearer than treatment with combination regimens on breast cancer patients. Authors state that they have no conflict of interest.