Topical diclofenac did not prevent clinically significant hand-foot syndrome in patients taking capecitabine, challenging earlier randomised evidence supporting its prophylactic use.
Topical diclofenac has failed to reduce capecitabine-induced hand-foot syndrome in a prospective real-world study, with researchers concluding the treatment should not routinely be used for prophylaxis.
The two-centre DICLO-HFS study found grade 2 or worse hand-foot syndrome (HFS) occurred in 16.9% of patients using prophylactic diclofenac, compared with 13.8% of those receiving active monitoring alone.
The difference was not statistically significant (OR 1.28, 95% CI 0.52-3.10; p=0.591), and diclofenac also failed to delay the onset of clinically significant HFS.
Writing in JCO Global Oncology, the Turkish researchers said the findings contrasted with the phase III D-TORCH trial, which previously reported a reduction in grade 2 or worse HFS among patients receiving capecitabine monotherapy who used prophylactic topical diclofenac.
HFS is a common toxicity of capecitabine characterised by erythema, dysesthesia, swelling, and desquamation of the palms and soles.
Although it is rarely life-threatening, it can substantially affect daily functioning and quality of life and lead to chemotherapy dose modification or discontinuation.
“The pathophysiology of capecitabine-related HFS is incompletely understood,” the researchers wrote.
“Local accumulation of cytotoxic metabolites in the skin and inflammatory signalling pathways – particularly those involving cyclo-oxygenase-2 (COX-2), interleukin-6 (IL-6), and interleukin-8 (IL-8) – are considered central contributors.
“Systemic COX-2 inhibition with celecoxib has demonstrated preventive efficacy against capecitabine-related HFS; however, long-term use is limited by concerns regarding cardiovascular and gastrointestinal toxicity.
“Consequently, topical diclofenac, a locally acting COX-2 inhibitor with a favourable safety profile, has emerged as a pragmatic and widely accessible prophylactic option for supportive symptom management.”
The prospective observational study included 151 adults with colorectal or gastric cancer treated at two centres in Türkiye between July 2023 and February 2024.
Of these, 71 used 1% topical diclofenac on their hands and feet twice daily throughout capecitabine treatment, while 80 received active monitoring without prophylactic topical treatment.
Unlike the earlier randomised trial, the study was designed to examine diclofenac under routine clinical conditions and included patients receiving capecitabine in combination with oxaliplatin as well as those undergoing chemoradiotherapy.
The median age was 64 years and 63% of participants were men. Almost half had colon cancer, 36% had rectal cancer, and 17% had gastric cancer. Three-quarters received capecitabine in combination with oxaliplatin, while 26% received monotherapy.
After a median follow-up of 19.1 weeks, median time to grade 2 or worse HFS was 8.0 weeks with diclofenac and 9.4 weeks with active monitoring, with no significant difference between the groups.
Nor did diclofenac reduce the need for capecitabine dose reductions due to HFS. Dose reductions occurred in 33.8% of patients receiving diclofenac and 25.0% of those undergoing active monitoring (OR 1.53, 95% CI 0.76-3.10; p=0.235).
Grade 3 HFS was uncommon, occurring in 4% and 2.5% of the respective groups, and there were no grade 4 or 5 events.
The analysis did, however, identify two potential markers of greater HFS risk.
Women had almost four times the odds of developing grade 2 or worse HFS compared with men after adjustment (OR 3.87, 95% CI 1.48-10.17; p=0.006).
Patients receiving capecitabine monotherapy similarly had nearly four times the odds compared with those receiving combination therapy (OR 3.97, 95% CI 1.52-10.32; p=0.005).
The researchers cautioned that these findings should be interpreted in light of the observational design and relatively small number of HFS events, but said the factors could potentially help identify patients requiring closer toxicity monitoring.
Topical diclofenac itself appeared safe, with no dermatological or systemic adverse reactions attributed to the drug. Other treatment-related adverse events occurred at similar frequencies and severity in the two groups.
“The most common treatment-related adverse events were thrombocytopenia (33%), neutropenia (30%), mucositis (25%), and diarrhea (15%),” the researchers wrote.
“The frequency and severity of adverse events were similar between study groups. No adverse dermatologic or systemic reactions attributable to topical diclofenac were observed.”
The researchers suggested several factors could explain the discrepancy with D-TORCH, including differences in study design, patient populations, treatment regimens, adherence monitoring, and follow-up.
The real-world cohort was more heterogeneous than a randomised trial population, and adherence to diclofenac was based on patient self-report. Physician-directed treatment allocation also meant selection bias and residual confounding could not be excluded.
The results nevertheless leave clinicians without a clear standard for preventing a toxicity that can compromise capecitabine treatment.
Other approaches under investigation include systemic celecoxib, methylcobalamin supplementation, and topical corticosteroids, but the authors said no preventive strategy had yet been established as definitive.
“Although topical diclofenac remains safe and easily accessible, our findings suggest that routine prophylactic use in patients receiving capecitabine-based chemotherapy is not currently supported,” the researchers concluded.
“Recent investigations evaluating alternative preventive strategies further underline the ongoing unmet clinical need in this field.
“Future randomised studies directly comparing available prophylactic approaches across different clinical settings are warranted to establish an evidence-based standard for toxicity prevention.”
