High incidence of severe hand–foot syndrome during capecitabine–docetaxel combination chemotherapy

Y. H. Park*,1, B.-Y. Ryoo1, H. J. Lee1, S. A. Kim2 and J.-H. Chung2

1 Medical Oncology, Korea Cancer Center Hospital, Seoul; 2 Pharmacology, Kohwang Medical Research Institute, Seoul, Republic of Korea

*E-mail: yhpark@kcch.re.kr

5-Fluorouracil (5-FU) remains one of the most widely used chemotherapeutic agents in the treatment of malignancies of the gastrointestinal tract, breast, head and neck. The development of new 5-FU-related agents with improved anticancer effect is of significant clinical interest. Capecitabine (Xeloda"), a recently developed oral antineoplastic agent, has been demonstrated to possess enhanced antitumor effect and augmented tolerability over 5-FU [1]. This drug is being widely used on its own in the treatment of stomach, colorectal and breast cancers.

Grade 3 hand–foot syndrome, one of the major dose-limiting toxicities of capecitabine, has been reported in only 9.9% of patients with metastatic breast cancer undergoing capecitabine-only therapy who have previously undergone paclitaxel therapy [2]. Due to such a low percentage of patients experiencing this and other toxic effects, this drug is regarded as manageable and is not considered to have life-threatening toxicity. This agent is currently undergoing clinical trials on the feasibility of its application in combination with other agents. Taxanes have been shown to upregulate thymidine phosphorylase in vitro, and their toxicities have been shown not to overlap with those of capecitabine [3]. Combination chemotherapy utilizing capecitabine with a taxane has been proposed as a treatment for metastatic breast cancer and has been shown to be of great efficacy [4].

We administered capecitabine in conjunction with doxetaxel to patients with advanced gastric cancer for a total of four therapeutic cycles. Pyridoxine 300 mg was administered to these patients to prevent hand–foot syndrome. Nonetheless, grade 3 hand–foot syndrome was observed in ~52% (12 out of 23 cases) of the patients. This figure is far higher than the value of 24% reported for metastatic breast cancer patients [4]; ethnicity is suspected to underly this significant difference, although there may be other reasons.

It has been reported that patients who experience severe 5-FU toxicity possess the common IVS14+1G->A mutation at the NdeI restriction site of exon 14 of the DPYD gene, causing a deficiency in dihydropyrimidine dehydrogenase activity [5]. We performed RFLP (restriction fragment length polymorphism) analysis of the restriction site in the patients examined, but the G->A point mutation was not observed in any of the patients, with or without grade 3 hand–foot syndrome. This result suggests that the severity of hand–foot syndrome is probably not associated with the IVS14+1G->A mutation.

Y. H. Park1*, B.-Y. Ryoo1, H. J. Lee1, S. A. Kim2, J.-H. Chung2

1Medical Oncology, Korea Cancer Center Hospital, Seoul; 2Pharmacology, Kohwang Medical Research Institute, Seoul, Republic of Korea (*E-mail: yhpark@kcch.re.kr)

References

1. Van Cutsem E, Findlay M, Osterwalder B et al. Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study. J Clin Oncol 2000; 18: 1337–1345.[Abstract/Free Full Text]

2. Blum JL, Jones SE, Buzdar AU et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485–493.[Abstract/Free Full Text]

3. Sawada N, Ishikawa T, Fukase Y et al. Induction of thymidine phosphorylase activity and enhancement of capecitabine efficacy by taxol/taxotere in human cancer xenografts. Clin Cancer Res 1998; 4: 1013–1019.[Abstract]

4. O’Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20: 2812–2823.[Abstract/Free Full Text]

5. Van Kuilenburg AB, Muller EW, Haasjes J et al. Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G->A mutation causing DPD deficiency. Clin Cancer Res 2001; 7: 1149–1153.[Abstract/Free Full Text]





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