In a phase III randomised Diclofenac Topical in Reducing Capecitabine-associated HFS (D-TORCH) study, topical diclofenac was significantly associated with lower grade 2 or 3 hand-foot syndrome (HFS) rates compared with placebo in patients with breast and gastrointestinal cancers treated with oral capecitabine.
This was associated with less frequent dose reductions of capecitabine and a better HFS-related quality-of-life (QoL). The findings are published by Dr. Atul Batra of the Department of Medical Oncology, BRAIRCH, AIIMS in Delhi, India and colleagues on 27 February 2024 in the JCO.
HFS is a dose-limiting side effect of capecitabine. The authors wrote in the background that several strategies have been evaluated for capecitabine-associated HFS. The placebo-controlled study did not demonstrate the efficacy of urea-based cream in preventing capecitabine-associated HFS; the other study lacked a placebo control and reported superiority over mapisal, an antioxidant cream. Celecoxib showed efficacy to prevent HFS in an open-labelled randomised controlled study. The mechanism postulated was the inhibition of the COX-2 enzyme, which is upregulated because of underlying inflammation in HFS. However, systemic side effects of celecoxib have limited routine prescription.
Topical diclofenac gel, commonly used in osteoarthritis, acts by inhibiting the COX-2 enzyme locally with minimal risk of systemic adverse events. The study investigators planned the single-site phase III randomised double-blind D-TORCH study with the hypothesis that topical diclofenac will prevent HFS. They enroled patients with breast or gastrointestinal cancers who were planned to receive capecitabine-based treatment.
The study participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary endpoint was the incidence of grade 2 or 3 HFS according to Common Terminology Criteria for Adverse Events version 5, which was compared between the two groups using simple logistic regression.
In total, 131 patients were randomly assigned to receive topical diclofenac gel and 133 to receive placebo. Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group with absolute difference of 11.2% (95% confidence interval [CI] 4.3 to 18.1; p = 0.003).
Grade 1-3 HFS was lower in the diclofenac group than in the placebo group, 6.1% versus 18.1% with absolute risk difference of 11.9% (95% CI 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%) with absolute risk difference of 9.7% (95% CI 3.0 to 16.4).
The authors commented that a dose of topical diclofenac used in this study was empirically halved of that used in osteoarthritis. Diclofenac application and HFS assessment were limited to hands in this study. Capecitabine-associated HFS is more common in hands because of a high concentration of thymidine phosphorylase in palms, the enzyme responsible for the conversion of capecitabine to its active form, fluorouracil, postulated in the pathophysiology of HFS. Duration of topical diclofenac use in the study was limited to 12 weeks, as most patients develop HFS by this time.
Further studies are needed to evaluate this treatment alongside other cancer treatments commonly associated with HFS.
The results were previously presented at the ASCO 2023 Annual Meeting.
Alkem Laboratories Limited provided the diclofenac gel and matched placebo for this study. The Indian Association of Supportive Care in Cancer provided partial funding for the study. The study protocol was developed during the ACORD protocol development workshop in 2020.
Reference
Santhosh A, Sharma A, Bakhshi S, et al., on behalf of the D-TORCH Trial Investigators. Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial. JCO; Published online 27 February 2024. DOI: https://doi.org/10.1200/JCO.23.01730