[Off-label Use Review ②] Diclofenac gel reduces chemotherapy side effects by 75% — The D-TORCH trial
Hand-Foot Syndrome and topical NSAIDs: Diclofenac gel prevents chemotherapy side effects — The impact of the D-TORCH trial
Introduction: The 'invisible' suffering of chemotherapy
Hand-Foot Syndrome (HFS) is a cutaneous adverse event of chemotherapy that causes erythema, pain, swelling, blisters, and desquamation on the palms and soles. Its formal name is palmar-plantar erythrodysesthesia (PPE). While not a life-threatening side effect, severe cases significantly impair activities of daily living (ADL), forcing dose reductions, treatment interruptions, or discontinuation of chemotherapy. In other words, it is a clinically significant side effect that threatens the continuity of cancer treatment,.
The most well-known causative agent is capecitabine (Xeloda®), with an incidence reported between 22% and 75%. Other causes include continuous intravenous 5-FU, doxorubicin (especially liposomal formulations), and tyrosine kinase inhibitors such as sorafenib and regorafenib.
Conventionally, there has been evidence for the prevention of HFS using urea cream (10-20%) or oral celecoxib, but celecoxib has been difficult to use proactively due to concerns regarding cardiovascular risk. This is where topical diclofenac gel—an inexpensive and easily accessible preventive method—comes in.
1. Pathophysiology of HFS and the involvement of COX-2
Although the exact pathogenesis of HFS has not been fully elucidated, the currently prevailing hypotheses are as follows.
① Local drug accumulation hypothesis: Because thymidine phosphorylase (TP), the enzyme that converts capecitabine into its active metabolite (5-FU), is highly expressed in the skin of the palms and soles, high concentrations of 5-FU are produced locally in these areas, damaging keratinocytes.
② COX-2 mediated inflammation hypothesis: Keratinocyte damage caused by capecitabine increases the expression of COX-2 (cyclooxygenase-2), and the inflammatory response mediated by prostaglandins is amplified in the palms and soles. Some view the essence of HFS as 'inflammation localized to the palms and soles'.
This 'COX-2 mediated inflammation' hypothesis is the pharmacological basis for HFS prevention using NSAIDs.
2. Evidence for oral celecoxib: Effective but difficult to use
HFS prevention using COX-2 inhibitors was first studied with oral celecoxib (Celebrex®).
Zhang et al. (2012) — Annals of Oncology
A prospective randomized phase III trial involving 139 patients with stage II/III colorectal cancer. Comparing capecitabine ± celecoxib, the incidence of Grade 1 or higher HFS was 74.6% in the capecitabine-only group and 57.4% in the celecoxib combination group (P=0.034), while Grade 2 or higher was 29.6% vs 14.7% (P=0.035), respectively. Multivariate analysis showed that celecoxib use was the only independent factor for HFS prevention (Grade 1 or higher: HR 0.556, Grade 2 or higher: HR 0.414).
Meta-analysis (Pandy et al., 2022 — Support Care Cancer)
In a meta-analysis of 16 RCTs (total 2,814 patients), celecoxib significantly reduced the risk of developing all-grade (OR 0.52, 95% CI 0.32–0.85) and moderate-to-severe (Grade 2 or higher) HFS caused by capecitabine.
Problems with celecoxib
Celecoxib may increase the risk of cardiovascular events such as myocardial infarction and stroke, raising concerns about long-term administration to cancer patients—especially the elderly or those with cardiovascular risk factors. There is also a risk of peptic ulcers. For this reason, despite the evidence, the reality is that prescribing celecoxib for the purpose of HFS prevention is not done routinely.
3. The emergence of topical diclofenac: The D-TORCH trial
Background and concept
If celecoxib (an oral COX-2 inhibitor) is effective in preventing HFS, could topical NSAIDs, which can inhibit COX-2 locally, be expected to have a similar effect? This hypothesis led to the D-TORCH trial. Diclofenac gel (1%) is an inexpensive topical NSAID that is also available as an OTC drug, and because systemic absorption is low, concerns regarding cardiovascular risk are significantly reduced.
D-TORCH trial (Santhosh et al., 2024 — J Clin Oncol)
Study Overview: A phase III, double-blind, placebo-controlled RCT conducted at a single center in India. 264 patients scheduled for capecitabine-based treatment for breast or gastrointestinal cancer were randomly assigned to either the 1% diclofenac gel group (131 patients) or the placebo gel group (133 patients).
Intervention Method: Participants applied diclofenac gel or placebo gel to the palmar and dorsal surfaces of both hands twice daily for 12 weeks (4 courses of capecitabine). The amount applied per application was 1 FTU per side of each hand. It should be noted that application to the soles of the feet was not performed.
Primary Endpoint: Incidence of Grade 2 or higher HFS (CTCAE v5.0).
Results:
Endpoint | Diclofenac Group | Placebo Group | Difference (95% CI) | P-value | Grade 2-3 HFS | 3.8% | 15.0% | 11.2% (4.3–18.1) | 0.003 | Grade 1-3 HFS (All Grades) | 6.1% | 18.1% | 11.9% (4.1–19.6) | — | HFS-related dose reduction | 3.8% | 13.5% | 9.7% (3.0–16.4) | —
The relative risk reduction is approximately 75%, and the NNT (Number Needed to Treat) for preventing Grade 2 or higher HFS is calculated to be approximately 9.
Safety: No serious adverse events related to diclofenac gel were reported. As it is a topical formulation, cardiovascular and gastrointestinal risks associated with systemic NSAIDs are minimized.
Subgroup Analysis: The efficacy of diclofenac gel was consistent across all subgroups, including by gender, by breast/gastrointestinal cancer, and by monotherapy/combination therapy.
Study Limitations
It is a single-center study, and multi-center trials are needed to verify external validity.
Application to the soles of the feet was not performed (it is unclear whether results for the feet can be extrapolated from hand-only application).
The patient population was in India, and differences in skin characteristics between races may affect the results.
Applicability to causative agents other than capecitabine (such as sorafenib) has not been examined.
4. Comparison with other preventive measures
Urea cream (10–20%)
Meta-analyses have shown that urea cream is also effective in preventing HFS caused by capecitabine and sorafenib (Lan et al., 2022, Cancer Nursing; OR 0.48, P<0.00001). Its moisturizing effect, which keeps the stratum corneum flexible, and its mild keratolytic action are considered to be the mechanisms. It is widely used because it is inexpensive, easily accessible, and has almost no side effects.
Pyridoxine (Vitamin B6)
Although it was once widely used for HFS prevention, its efficacy was not demonstrated in RCTs, and it is not recommended in current evidence-based guidelines.
Topical steroids
Used for inflammation management after onset, but there are few RCTs for preventive purposes.
Conclusion of network meta-analysis
In a 2022 network meta-analysis, the only intervention that showed a statistically significant difference in preventing Grade 2 or higher HFS was celecoxib (OR 0.29, 95% CrI 0.13–0.68). However, this analysis did not include the D-TORCH trial (published in 2024). If the results of the D-TORCH trial are added, topical diclofenac is expected to be positioned as a strong option.
5. Implications for prescription handling and medication guidance
Scenarios encountered in the pharmacy
If diclofenac gel (such as Voltaren® Gel) is prescribed along with capecitabine, or if a patient consults you saying, 'The doctor told me to apply over-the-counter diclofenac gel,' it may be for the purpose of HFS prevention.
Specific guidance on application method (based on the D-TORCH trial)
Apply to clean, dry skin
Apply to both the palm and back of both hands
The amount for one application is 1 FTU per side of one hand
Apply twice daily
Do not apply to wounds, eczema, or infected areas
Do not wash hands after application (to keep the active ingredient on the skin)
Do not layer sunscreen or other topical medications on the same area
Avoid contact with eyes, nose, and mouth
Key points for patient explanation
'This is a medication to prevent skin problems on the hands caused by anticancer drugs.'
'It is known as a pain reliever for joints, but here it is used to prevent inflammation of the hands.'
'Unlike oral NSAIDs, this is a topical medication, so systemic side effects are very rare.'
If symptoms appear on the hands (redness, pain, swelling, blisters), please consult a doctor as soon as possible.
Points to note
Contraindicated in patients with a history of NSAID allergy.
Concomitant use with oral NSAIDs or aspirin was an exclusion criterion in the D-TORCH trial.
Preventive effect on the soles of the feet has not been verified (in the D-TORCH trial, it was applied only to the hands).
6. Summary: Inexpensive, safe, and effective—a three-pronged preventive method
The efficacy of NSAIDs for hand-foot syndrome (HFS) is based on the pathological hypothesis of HFS as "COX-2-mediated inflammation." While efficacy was previously demonstrated with oral celecoxib, routine use was difficult due to concerns regarding cardiovascular risk.
The D-TORCH trial, published in J Clin Oncol in 2024, showed that an extremely simple intervention—topical application of 1% diclofenac gel—reduced the risk of developing Grade 2 or higher HFS from capecitabine by 75% (3.8% vs 15.0%, P=0.003) and also suppressed the need for dose reductions of the anticancer drug. Its characteristics—an NNT of approximately 9, no serious side effects, and being inexpensive and easily accessible—make the barrier to clinical implementation very low.
Although there are limitations, such as it being a single-center trial and the application to the soles of the feet remaining unverified, it is worthy of attention as one of the most accessible HFS preventive measures currently available. Future multi-center follow-up studies and investigations into its application for other causative drugs (such as sorafenib) are expected.
Many patients receiving cancer chemotherapy use multiple drugs, and the role of pharmacists in managing side effects is significant. The knowledge that a familiar drug like diclofenac gel can be an "unsung hero" in maintaining the continuity of cancer treatment is something every pharmacist should know.
Key References
Santhosh A et al. Topical diclofenac for prevention of capecitabine-associated hand-foot syndrome: a double-blind randomized controlled trial. J Clin Oncol. 2024;42(15):1821-1829. PMID: 38412399
Zhang RX et al. Celecoxib can prevent capecitabine-related hand-foot syndrome in stage II and III colorectal cancer patients: result of a single-center, prospective randomized phase III trial. Ann Oncol. 2012;23(5):1348-1353. PMID: 21940785
Zhang RX et al. The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study. J Cancer Res Clin Oncol. 2011;137(6):953-957. PMID: 21113620
Pandy JGP et al. Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: a meta-analysis of randomized controlled trials. Support Care Cancer. 2022;30(11):8655-8666. PMID: 35655045
Lan TC et al. Effect of urea cream on hand-foot syndrome in patients receiving chemotherapy: a meta-analysis. Cancer Nurs. 2022;45(5):378-386. PMID: 34483284
Lin EH et al. Retrospective study of capecitabine and celecoxib in metastatic colorectal cancer: potential benefits and COX-2 as the common mediator in pain, toxicities and survival? Am J Clin Oncol. 2006;29(3):232-239. PMID: 16755175
Kwakman JJM et al. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncol Rev. 2020;14(1):442. PMID: 32431787
Lacouture ME et al. Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines. Ann Oncol. 2021;32(2):157-170.
This article is intended to provide information based on research papers and does not recommend individual diagnosis, treatment, or prescriptions. The prevention and management of hand-foot syndrome should be carried out under the responsibility of the prescribing physician. HFS prevention using topical diclofenac gel is not an approved indication in Japan.