Topical COX inhibitor mitigates capecitabine-associated HFS in GI cancer patients

Topical diclofenac gel significantly reduced the incidence of hand-foot syndrome (HFS) in patients with gastrointestinal (GI) cancer receiving capecitabine, according to findings from the exploratory subgroup analysis of the D-ToRCH* trial.

“Also called palmar-plantar erythrodysesthesia syndrome, HFS is a dose-limiting side effect of capecitabine in patients with GI cancer,” said the researchers. Though not life-threatening, HFS involves painful symptoms, including peeling, blistering, bleeding, ulcerations, and swelling, as well as hyperpigmentation of the palms and soles, skin thickening, and loss of sensation. [Oncol Rev 2020;14:442]

This range of symptoms could greatly impair quality of life (QoL) and require dose adjustments or, in some cases, permanent discontinuation of capecitabine.

The efficacy of the oral cyclo-oxygenase-2 (COX-2) inhibitor celecoxib in reducing the incidence of capecitabine-associated HFS has already been established, but it has not been adopted in clinics due to its reported cardiac and GI toxicities. [Support Care Cancer 2014;22:1585-1593; Celecoxib. www.ncbi.nlm.nih.gov/books/NBK535359, accessed August 16, 2023]

In hopes of finding a more tolerable alternative, the investigators postulated that a topical agent such a diclofenac – an extensively used COX inhibitor in osteoarthritis – could be an alternative to avoid these toxicities. “Diclofenac has been used for several decades in osteoarthritis and has a long-term safety record. Its cardiac safety is well known,” the researchers said.

The overall study sample included 264 patients (median age 47 years, 71 percent female) with breast (56 percent) or GI (44 percent) cancers who were on capecitabine, alone or in combination with other agents. Participants were randomized 1:1 and were instructed to apply either topical diclofenac 1% or a matched placebo gel BID. Half of the participants had stage 4 disease. [ESMO GI 2023, abstract P-202]

 

GI cancer subgroup

The most common primary GI cancer was colon cancer (n=64), followed by stomach (n=18) and peri-ampullary cancer (n=14).

In this subgroup, topical diclofenac significantly reduced the incidence of grade ≥2 HFS compared with placebo (3.7 percent vs 14.5 percent; p=0.05). A comparison between arms yielded a relative risk of 0.26 (95 percent confidence interval, 0.06–1.15 percent), translating to a 74-percent reduction in the risk of developing grade ≥2 HFS with the study drug.

All secondary outcomes aligned with the primary endpoint. The incidence of any-grade HFS was lower with diclofenac vs placebo (3.7 percent vs 16.1 percent; p=0.031). Capecitabine dose reduction due to HFS was less common with the study drug compared with placebo (3.7 percent vs 14.5 percent).

 

Overall cohort

Overall, other causes of capecitabine dose reduction were mucositis, diarrhoea, and myelosuppression. The percentage of participants who cut their capecitabine dose was doubled in the placebo vs the diclofenac arm (30.8 percent vs 16.1 percent).

According to the researchers, capecitabine dose reduction is an important secondary outcome as it might have important implications for oncologic benefits.

Diclofenac was consistently favoured over placebo across all other subgroups**, with relative risks ranging between 0.09 and 0.51.

Mean increase in HFS14*** score was greater with placebo than with diclofenac (8.7 vs 2.3).

 

A new standard of care?

The findings in the GI subgroup are generally in line with that observed in the overall analysis.

“This is the first study that convincingly established the role of a topical COX inhibitor for HFS prevention. Moving forward, we feel that this should be the new standard of care for the prevention of capecitabine-associated HFS,” the researchers concluded.

They added that medical oncology outpatient departments should regularize the utilization of topical diclofenac.