Background

The pathophysiology of hand-foot syndrome (HFS) includes activation of cyclooxygenase (COX)-2, leading to an upregulation of the inflammatory cascade. No clinical trials have assessed the role of topical non-steroidal anti-inflammatory drugs (NSAIDs) in preventing HFS.

General Aim

To determine the efficacy and safety of topical diclofenac in reducing the incidence of HFS in patients receiving capecitabine .

Primary Objective (Endpoint)

To compare the effect of topical diclofenac with placebo in preventing clinically significant HFS (incidence of NCI CTCAEv5.0 grade 2 or higher HFS)

Secondary Objectives (Endpoint)

To compare the effect of topical diclofenac with placebo on:

1.     Incidence of NCI CTCv5.0 all grade HFS

2.     Time to develop grade ≥2 HFS (from start of capecitabine)

3.     Patient-reported outcomes (PROs) (HFS-14 questionnaire)

4.     Adherence with diclofenac/ moisturiser application (self-reported)

5.     Capecitabine dose reductions, delays and cessation due to HFS (number of patients with dose modifications due to HFS)

6.     Safety profile (NCICTCv5.0 all grade HFS)

Tertiary Objective (Endpoint)

7. To correlate the occurrence and severity of HFS with COX-2 levels     (Serum COX-2 levels) and polymorphism of DPPD enzyme

Design

Randomized double-blind, placebo-controlled parallel group study

Target population

Patients with any stage breast or gastrointestinal cancers, who are starting capecitabine monotherapy. Key exclusion criteria include pre-existing dermatological conditions, peripheral neuropathy and known allergy to NSAIDs.

Study treatments

Experimental arm: Twice daily application of 1 gm 1% topical diclofenac to the palmar and dorsal surface of both hands for 12 weeks or > grade 2 HFS, whichever is earlier

Control arm: Twice daily application of matched placebo to the palmar and dorsal surface of the both hands for 12 weeks or > grade 2 HFS, whichever is earlier

Assessments

HFS  will be assessed by the treating physicians every 3 weeks in the clinic. All participating physicians will be trained in grading HFS. Photographs will be taken at baseline and every 3 weeks and will be reviewed by an independent blinded investigator to confirm grading of HFS. PROs will be recorded and serum COX-2 levels will be measured at two time points: baseline and 12 weeks or > grade 2 HFS, whichever is earlier

Statistical considerations

With 120 patients in each study arm, there will be at least 80% power to detect a difference in HFS rates  at a two-sided 0.05 significance level, using a chi-square test. This assumes that the rate of grade 2 or higher HFS is 30% in the control arm and 15% in the experimental arm. Assuming approximately 10% attrition, we plan to recruit 264 patients (randomised 1:1 to each treatment).