Hand-foot syndrome (HFS) in patients receiving capecitabine: A pharmacological explanation

Abstract

2019 Background: Use of the oral fluoropyrimidine capecitabine, which generates 5FU in tumor tissues, is currently expanding. HFS is frequently associated with administration of capecitabine. However, the underlying pharmacological mechanism of HFS is still not elucidated. In a previous experimental study, we ruled out a possible implication of 5FU catabolites (FUH2 and FBAL) in the etiology of HFS (Anti-Cancer Drugs 15: 969, 2004). The aim of this study was to investigate expression levels of thymidine phosphorylase (TP, the main activating enzyme of capecitabine) and dihydropyrimidine dehydrogenase (DPD, the rate-limiting enzyme of 5FU catabolism) in skin samples from the palm area of the hand (target zone) and from the back (control zone). Methods: Paired-skin biopsies have been planned in 12 healthy volunteers, in agreement with the local ethical committee. Expressions of TP, DPD, and Ki67 (cell proliferation marker) were analyzed by a two-step immunohistochemical method using specific monoclonal antibodies (from Calbiochem for TP, Roche for DPD and Dako for Ki67) and immunoperoxydase revelation (kit ABC Vectastain). Results: Data from the first four subjects indicate no significant difference in the strong Ki67 staining between control and target zones. TP was markedly expressed in the basal layer of the epidermis (BLE), with similar staining in control and target zones. Interestingly, in 3 cases out of 4, DPD was strongly expressed (2+, 3+) in the BLE of the control zone and much less (0, 1+) in the paired-target zone. Definitive data on 12 subjects will be presented. Conclusions: This preliminary original observation suggests that capecitabine may be locally activated in the skin due to high TP expression. The relative absence of DPD expression in the palm area may explain the specificity of HFS, which may result from a lack of local 5FU catabolism. These new data open the way to a possible pharmacological approach to limit HFS. No significant financial relationships to disclose.

Management of hand-foot syndrome induced by capecitabine

“…31 It is equally important to prospectively identify patients who may be at higher risk for HFS due to capecitabine. Although HFS has been reported to be higher in females and elderly patients with continuous infusion 5-FU, 12 this has not been noted in patients receiving capecitabine. 8,15,27,34,58 However, in order to prevent HFS and other toxicities, patients with a creatinine clearance between 30 and 50 mL/ min should receive lower starting doses (1900 mg/m 2 per day).…”

“…Ferrero et al, took paired skin biopsies from 12 healthy volunteers, using the palm area of the hand as the target zone and the back as a control zone. 12 In a preliminary report of four patients, expression of TP, DPD, and Ki-67 (a cell proliferation marker) were measured, and no differences in Ki-67 expression were found between the control and target zones. However, TP was markedly expressed in the basal layer in both zones, and in three of four cases, DPD was more strongly expressed in the control zone than in the target zone.…”

Docetaxel-associated palmar-plantar erythrodysesthesia: A case report and review of the literature

“…Dihydropyridine dehydrogenase, the rate-limiting step of 5-fluorouracil catabolism, or thymidine phosphorylase, an activating enzyme, may also be absent in the palms and soles. 31 Others propose that the accumulation of certain cytotoxic drugs in areas containing a high density of eccrine glands, such as the palms and soles, can cause PPE. 1 Finally, a trial of bevacizumab indicates that angiogenesis may play a possible role due to the higher incidence of PPE in the bevacizumab plus chemotherapy arm versus chemotherapy alone.…”