Can diclofenac prevent Hand-Foot Syndrome (HFS)?
Hand-Foot Syndrome (HFS), commonly known as palmar-plantar erythrodysesthesia (PPE), can be caused by capecitabine. This condition is characterised by redness (erythema), swelling (oedema) and can progress to blister formation and significant pain with a risk of discontinuation or delay of life-saving treatment. Typical causative agents include oral fluoropyrimidine, capecitabine and some other chemotherapy agents. Prior studies have indicated incidence rates vary between 22-77% and differ depending on the research reviewed.
Capecitabine is commonly utilised in many cancers, including breast, colorectal and gastric cancer and is a 5-fluorouracil pro drug. This means that it selectively transformed to its active moiety by the enzyme thymidine phosphorylase. While the cause of this syndrome is poorly understood, it is thought that capecitabine alters keratinocytes and induces cell death (1). Toxicity from capecitabine can impair a patient’s quality of life and functionality.
Historically, celecoxib, a COX-2 inhibitor, demonstrated a 61% decrease in moderate to severe HFS and 53% in all grade HFS. Issues with using celecoxib include increased cardiovascular event risk, GI bleeding and ulceration. This led to the ASCO AKHIL et al. presentation with oral diclofenac. Abstract 12005.
AKHIL et al. study is a double-blinded, randomised, placebo-controlled trial and the first randomised clinical trial looking at topical diclofenac to prevent HFS of grade two or higher. This research was conducted in India.
It was hypothesised that 1% topical diclofenac would decrease the incidence of HFS in capecitabine (grade 2 or higher) by 15% versus placebo. The primary endpoint was to compare the efficacy of topical diclofenac vs placebo in preventing HFS. Secondary objectives include prevention of all grade HFS, time to development of HFS, patient-reported outcomes, adherence with the application, safety profile and dose reduction of capecitabine.
Inclusion criteria included patients over 18, the commencement of capecitabine for breast and gastrointestinal malignancy, starting dose >1000 mg/m2 BD 14 days on and seven off with a life expectancy greater than 12 weeks. ECOG had to be 0-2, and the patient must commence treatment <14 days from randomisation. Adherence to trial protocol was essential.
Exclusion criteria included patients with pre-existing neuropathy grade 2 or higher, other dermatological conditions, allergy or anaphylaxis to NSAID, history of asthma, urticaria or different allergic-type reactions, pregnancy, and lactating women.
Administration of diclofenac occurred as follows: The participants administered 1gm of topical 1% diclofenac gel or placebo surface twice a day on the dorsal and palmar aspect of the hand until the development of HFS or four cycles of treatment, whichever came sooner.
Two hundred sixty-three patients were randomised to topical diclofenac (n=130) or placebo (n=133). The incidence of HFS with G2 or higher was 3.8% in the diclofenac arm versus 15% in the placebo arm. All grades of HFS were lower in the intervention arm vs the placebo arm (6.1% vs 18.1%). In the stratified subgroups, including men, women, and breast and GI cancers, combination therapy, the diclofenac arm had a lower incidence of HFS.
Source (https://meetings.asco.org/abstracts-presentations/2267830
Dose reductions of capecitabine were 3.8% in the intervention arm versus 15% in the placebo arm.
In summary, topical diclofenac prevents HFS in all grades for patients receiving capecitabine. It also minimised dose reductions. Ongoing questions remain, including the long-term use of diclofenac in patients with metastatic disease, dose administration duration, HFS breakdown in combination therapy, risk of cardiac toxicity if used long term and whether this can be used to treat rather than prevent HFS.
(2) https://conferences.asco.org/am/abstracts-posters
(3) https://ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.12005
(4) https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-022-06353-2
· 10.1200/JCO.2023.41.16_suppl.12005 – Link to article (subscription may be required)
