Capecitabine is a novel fluoropyrimidine carbamate which is selectively activated after oral administration to 5-fluorouracil (5-FU) by a sequential triple enzyme pathway in liver and tumor cells. The cytotoxic activity of the metabolized 5-FU depends on thymidylate synthase (TS) inhibition, leading to defective DNA synthesis. Capecitabine has shown promising activity in all tumor types sensitive to 5-FU and is therefore investigated in many clinical trials. Since we observed an increase of mean corpuscular volume (MCV) of red blood cells under therapy with capecitabine, the current investigation aimed to quantitate this effect and to elucidate the underlying mechanisms. A total of 154 patients suffering from advanced cancer received capecitabine (2500 mg/m2/day for 14 days every 21 days) either as monotherapy, or in combination with other antineoplastic agents or biological response modifiers. During 3 consecutive cycles of therapy a complete blood cell count including the red cell indices MCV, mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration was performed before each application of capecitabine. In addition, vitamin B12, folic acid and homocysteine were determined to define their role in increasing MCV. Restaging was performed after 9 weeks. Within 9 weeks, a statistically significant increase of MCV (without other hematologic abnormalities or clinical symptoms) could be observed (p<0.0001). Vitamin B12, folic acid and homocysteine levels did not change significantly during the observation period. When comparing the different increases of MCV during 9 weeks (deltaMCV) with respect to tumor response, deltaMCV tended to higher values in patients with tumor remission or stable disease than in patients with tumor progression. We conclude that serum levels within the normal range rule out severe deficiencies of vitamin B12, folic acid or homocysteine as an account of macrocytemia. We therefore hypothesize that an increased MCV (without concomitant anemia) in patients receiving capecitabine might be due to the 5-FU-induced TS inhibition also in erythroid precursor cells. Whether this increase in MCV might serve as a surrogate marker for tumor response has to be evaluated in further investigations.
Copyright 2003 Lippincott Williams & Wilkins