Randomized double-blind, placebo-controlled study of topical diclofenac in the prevention of hand-foot syndrome in patients receiving capecitabine (the D-TORCH study)

Abstract

Introduction Hand-foot syndrome (HFS) is a common cutaneous side effect of capecitabine therapy. Apart from oral cyclooxygenase-2 (COX-2) inhibitor (celecoxib), there are no proven strategies for the prevention of HFS. However, celecoxib is associated with significant cardiotoxicity. To date, no study has evaluated the role of topical COX inhibitor, diclofenac. In this study, we aim to compare topical 1% diclofenac gel with placebo in the prevention of capecitabine-induced HFS. Methods This is a randomized, placebo-controlled, double-blind, parallel-group superiority trial: the Diclofenac Topical in Reducing Capecitabine induced HFS (D-TORCH) study. A total of 264 patients with breast and gastrointestinal malignancies will be randomly allocated (stratified by sex and type of therapy [monotherapy or combination regimen with capecitabine]) to receive either 1% topical diclofenac or placebo that will be applied over the palmar and dorsal surface of the hands twice daily whilst taking capecitabine for 12 weeks. The patients will be followed up until the end of four cycles. The primary objective of this study is to compare the effect of topical diclofenac with placebo in preventing HFS (incidence of NCI CTCAEv5.0 grade 2 or higher HFS). The secondary objective is to compare the effect of topical diclofenac with placebo on preventing all grades of HFS (incidence of NCI CTCv5.0 all grade HFS), time to develop HFS (from the start of capecitabine), patient-reported outcomes (PROs) (HF-HRQoL questionnaire), adherence with the application (self-reported), capecitabine dose changes (number of patients with dose modifications due to HFS) and safety profile (NCICTCv5.0 all grade HFS) Discussion The D-TORCH study aims to determine if 1% topical diclofenac reduces the incidence of grade 2 or higher HFS in patients receiving capecitabine. To date, there have been a lot of trials for hand-foot syndrome prevention using agents like pyridoxine, vitamin E, carvedilol, and various polyherbal formulations, but none has been found successful. If the trial meets the primary end point, 1% topical diclofenac will be the new standard of care for HFS prevention. Trial registration Clinical Trials Registry of India CTRI/2021/01/030592. Prospectively registered on January 19, 2021

Capecitabine-Induced Genital Hand-Foot Syndrome Treated With Topical Tacrolimus

“…However, the associated toxicity may often affect gastrointestinal, hematologic, and integumentary systems; HFS is a common adverse reaction, often involving focal irritation, erythema, and peeling of the hands or feet [2,7]. Prior studies state that as many as three in four patients develop some degree of HFS, although HFS involving the genitals is notably rare and has only been reported in a handful of prior case studies; it is even rarer in patients who have not yet received radiotherapy [3,8]. According to the National Cancer Institute (NCI) grading of HFS toxicity, higher grades (grade 3) represent more significant adverse cutaneous effects and symptomatology; our patient developed grade 2 toxicity in the feet and hands [9].…”

“…HFS classically presents in the hand and feet, and its presentation in the genital region (causing balanitis) is extremely rare and not well characterized. Given the debilitating nature of the disease and the significant effects on the quality of life, early recognition and treatment of the condition is essential to avoid long-term interruption of potentially outcome-modifying chemotherapy [3][4][5]. In this report, we discuss a unique case of capecitabine-induced HFS involving the genitals, which resolved with local tacrolimus therapy after initial treatment failure with topical steroids and discontinuation of capecitabine.…”

“…The mechanism of action of HFS is not fully understood, but it is believed to occur on the palms and soles due to the transportation of drugs from the eccrine sweat glands to the stratum corneum, where the drugs accumulate and ultimately cause a local cutaneous reaction [1]. This reaction is often characterized initially by paresthesia, which is followed by erythema, edema, and blistering of the hands and feet with resultant epidermal necrosis [2,3]. HFS classically presents in the hand and feet, and its presentation in the genital region (causing balanitis) is extremely rare and not well characterized.…”

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial

“…The study protocol was published earlier. 23 This was an investigator-initiated, single-institution, phase III, randomized, double-blind, placebo-controlled study conducted from February 2021 to January 2023 at the All India Institute of Medical Sciences, New Delhi, India.…”

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“…The 3, 6 and12 months-PFS was similar in both arms, however, patients in the experimental dose, had a significantly milder toxicity profile. D-TORCH was a study assessing the role of 1% topical diclofenac preventing capecitabine associated hand-foot-syndrome [ 33 , 34 ]. A total of 20 patients developed hand-foot syndrome, 6 (7.8%) in the diclofenac arm and 14 (19.7%) in the placebo arm (p = 0.034).…”