Significant Association between Hand-Foot Syndrome and Efficacy of Capecitabine in Patients with Metastatic Breast Cancer

Abstract

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is a promising treatment for colorectal, breast and gastric cancers, but often causes hand-foot syndrome (HFS), the most common dose-limiting toxicity. The current study was conducted to investigate the relationship between HFS and efficacy of capecitabine in 98 patients with metastatic breast cancer. Possible associations between HFS and efficacy endpoints, including time-to-treatment failure (TTF), tumor response in metastatic lesions and changes in tumor markers, were investigated retrospectively using electronic medical records. The TTF of group with HFS of grade 1 and ≥2 was significantly longer than that of group with no HFS, respectively (hazard ratio (HR), 0.39; 95% confidence interval (CI), 0.18-0.87 for group with grade 1; HR, 0.42, 95% CI, 0.19-0.90 for group with grade ≥2). Significantly higher disease control rates for the liver metastasis were observed in patients with HFS (grade 1 and greater) than in those without HFS (92.9 vs. 42.9%, p 0.009). Furthermore, prevention of increases in tumor marker levels (carcinoembryonic antigen (CEA), carbohydrate antigen 15-3 (CA15-3) and National Cancer Center-Stomach-439 (NCC-ST439)) was evident in patients with HFS. This study clearly showed a significant correlation between HFS and some efficacy markers of capecitabine therapy in patients with metastatic breast cancer, and suggests that early dose adjustment based on severity of HFS might improve efficacy. Studies are needed to explore predictive biomarkers for HFS/efficacy, so that capecitabine therapy can be further tailored to patient response.Key words capecitabine; hand-foot syndrome; efficacy; electronic medical record Capecitabine is administered as an oral fluoropyrimidine prodrug in the treatment of a number of cancers, including breast and gastrointestinal cancers. 1) Capecitabine generates 5-fluorouracil (5-FU) preferentially in tumor tissue through a three-step enzymatic process. In the first step, capecitabine is hydrolyzed by carboxylesterase (CES) in the liver to produce the 5′-deoxy-5-fluorocytidine (5′-DFCR). In the second step, 5′-DFCR is converted to 5′-deoxy-5-fluorouridine (5′-DFUR) by cytidine deaminase (CDA), which is highly active in liver and tumor tissues.2) In the final step, 5′-DFUR is converted to 5-FU by thymidine phosphorylase (TP), a rate-limiting enzyme. Dihydropyrimidine dehydrogenase (DPYD), a ratelimiting catabolic enzyme of the pyrimidines, is also involved in the degradation pathway of capecitabine.1,3) Since TP activity is 3-10 times higher in tumor cells than in the normal tissues, 2,4) selective conversion of capecitabine to 5-FU in tumor tissues minimizes systemic exposure to 5-FU relative to exposures associated with intravenous (i.v.) 5-FU/leukovorin regimens. Thus, capecitabine is associated with a lesser incidence of 5-FU-related severe toxicities, such as diarrhea, stomatitis, nausea, alopecia and neutropenia, while maintaining equivalent or superior efficacy compared with the IV regimens. 5-7)The most com...

Quality of Life under Capecitabine (Xeloda®) in Patients with Metastatic Breast Cancer: Data from a German Non-Interventional Surveillance Study

“…The most common adverse event that led to termination was HFS. However, no negative impact of HFS on the global QoL could be detected, possibly in part due to the patients knowing that HFS is a predictive factor with regard to an increased DCR and prolonged PFS and overall survival, which has been confirmed during several investigations in colorectal cancer [14,15] and also in metastatic breast cancer [16]. Compared to other side effects, physicians possibly accord a higher relevance to HFS than patients do.…”

“…HFS is mostly associated with local pressure sensitivity and paresthesia, up to blistering and skin detachments. Several investigators already stressed a significant correlation between HFS and some efficacy markers of capecitabine [7], suggesting that HFS may be a positive indicator of cellular activity.…”

A network meta-analysis for toxicity of eight chemotherapy regimens in the treatment of metastatic/advanced breast cancer

“…Hence, the lower toxicity of paclitaxel is reasonable due to its specific therapeutic targets. For patients with metastatic triple-negative breast cancer, cisplatin + gemcitabine regimen might be an alternative or even the favorable first-line chemotherapy strategy when compared with the more established paclitaxel + gemcitabine regimen [42]. For women with metastatic breast cancer, doxorubicin and paclitaxel as first-line therapy has an obvious advantage over FAC in the aspects of response rate, median time to progression, as well as in overall survival [43].…”

A simple home-based self-monitoring tool for early detection of hand-foot syndrome in cancer patients

“…HFS is not life threatening, but can seriously reduce the quality of life (QOL) (8,9). Most reports describing patients with severe HFS indicate that this condition results in poor compliance and/or discontinuation of cancer treatment (9)(10)(11)(12)(13).…”