Advancements in the diagnosis and management of capecitabine-induced hand-foot syndrome

Abstract

Purpose

This narrative review aims to synthesize existing evidence on hand-foot syndrome (HFS) associated with capecitabine therapy. By examining HFS pathogenesis, clinical manifestations, severity classifications, influencing factors, and management strategies, the study seeks to provide clinically actionable insights to mitigate HFS-related quality-of-life deterioration and treatment discontinuation in patients receiving this widely used capecitabine.

Methods

This narrative review summarizes recent literature on HFS caused by capecitabine, highlighting its relationship among different populations and the prevention and treatment of HFS.

Results

The review establishes that HFS manifests through sensory abnormalities (tingling, numbness) and dermatological changes (erythema, desquamation), though its precise pathophysiology remains incompletely defined. Incidence is modulated by demographic variables (age, sex, ethnicity), therapeutic variables (drug combinations, capecitabine dosage), and possibly genetic factors. The study highlights that co-administration of diclofenac demonstrates significant potential in reducing both HFS occurrence and symptom severity based on current evidence.

Conclusion

Based on critical assessment of available literature, the review concludes that the concomitant use of diclofenac with capecitabine represents an effective clinical strategy for alleviating HFS. In addition, topical urea cream, pyridoxal, lactic acid, etc. can also be used prophylactically to produce certain effects. This pharmacological approach is recommended to enhance treatment adherence and preserve patient quality of life during antineoplastic therapy.

Introduction

Capecitabine is classified as an oral antitumor metabolic antagonist within the pyrimidine analog category. Since its approval in 1998, it has been widely employed, either as monotherapy or in combination with other agents, for the treatment of colorectal, gastric, pancreatic, and breast cancers, owing to its efficacy and relatively low toxicity (Wang et al. 2021). Hand-foot syndrome (HFS), also referred to as palmoplantar erythrodysesthesia, is a prevalent side effect associated with this medication (Lassere and Hoff 2004). In a multicenter phase II trial assessing capecitabine for paclitaxel-refractory metastatic breast cancer, HFS was the sole treatment-related adverse event of grade 3 or 4 intensity reported in over 10% of participants (Blum et al. 1999). In another clinical investigation examining adjuvant capecitabine for breast cancer post-preoperative chemotherapy, the underlying mechanism of HFS in 73.4% of patients receiving capecitabine remained unclear. (Masuda et al. 2017) Clinical manifestations of HFS include numbness and a burning sensation, often described as acupuncture-like, accompanied by erythema and desquamation. In severe instances, these symptoms may progress to ulceration, adversely affecting patient adherence to treatment and potentially leading to interruptions or cessation of chemotherapy. For example,a study demonstrates that occurrence of hand-foot syndrome (HFS) during capecitabine treatment often results in treatment interruptions (26%) or treatment discontinuation (17%).The article also mentions that approximately 17.3% of patients experience grade ≥ 2 HFS. Painful erythema and cracks appear on the hands or feet, which in turn affects daily living abilities (With et al. 2023a). This, in turn, can exacerbate the deterioration of patients' quality of life and negatively influence their prognosis (With et al. 2023a; Timmers et al. 2016). Additionally, a literature review stated that the loss of fingerprints in some patients prevented them from performing daily activities such as mobile phone fingerprint recognition and processing necessary documents through fingerprint identification (Zhao et al. 2020). In addition, some countries require fingerprint identification at customs upon entry, and missing fingerprints will seriously affect travel in these countries. Therefore, it is imperative to consider preventive strategies against HFS, including the selection of appropriate medications or interventions to mitigate adverse reactions, in order to enhance patients' quality of life. The following sections summarize the mechanisms, clinical symptoms, severity grading, influencing factors, and preventive measures associated with capecitabine-induced hand-foot syndrome.

Mechanisms underlying capecitabine-induced hand-foot syndrome (HFS)

Currently, the pathogenesis of HFS is not fully understood. The mechanisms contributing to capecitabine-induced HFS primarily involve an inflammatory response mediated by cyclooxygenase (COX), as well as inflammatory responses mediated by interleukins 6 and 8. Additionally, genetic alterations, the influence of metabolic enzymes, and the accumulation of drug metabolites are also significant contributors.

Headings inflammatory response mediated by cyclooxygenase (COX)

There are three isoforms of cyclooxygenase (COX): COX-1, COX-2, and COX-3. COX-1 serves as a housekeeping enzyme consistently expressed under physiological conditions, while COX-2 is typically not expressed in normal circumstances. However, upon stimulation, mononuclear macrophages can rapidly upregulate COX-2 expression, leading to an inflammatory response. COX-2 is the key enzyme catalyzing the conversion of arachidonic acid to prostaglandin E2 (PGE2). PGE2 serves as a crucial inflammatory mediator in all typical inflammatory responses. PGE2 is generated by prostaglandin E synthase (PGES) and exerts physiological effects by binding to distinct prostaglandin E2 receptors (EPs) on the cell membrane. Related literature indicates that EP1 and EP3 are associated with inflammation-induced hyperalgesia, while EP3 also mediates inflammation-induced exudation and vasoconstriction (Yuhki et al. 2004; Miki et al. 2011). Studies (Lou et al. 2016; Zhang et al. 2011) have demonstrated that capecitabine or its metabolites can induce HFS by promoting COX-2 overexpression at the skin surface of the palms and soles. Consequently, the topical or systemic application of COX-2 inhibitors may prevent or alleviate HFS.

Headings inflammatory response mediated by interleukins 6 and 8

Certain signaling pathways, such as p38 MAPK, NF-κB, and JAK-STAT3, may contribute to capecitabine-induced HFS through the abnormal expression of interleukin-8. A mouse model of HFS confirmed that the inflammatory mechanism underlying HFS is primarily mediated by the abnormal expression of interleukin (IL)-6 or IL-8, rather than solely by COX-2 overexpression (He et al. 2022). This also demonstrates that HFS may involve multiple pathways, with interleukin being one of the key pathways among them. This finding suggests that interleukin receptor antagonists could be considered for alleviating the associated symptoms.

Headings genetically related alterations

Some researchers (Watts et al. 2022) propose that alterations in the ST6GAL1 gene are associated with capecitabine- and oxaliplatin-induced HFS. Conversely, another study (Li et al. 2021) have indicated that spermine-related DNA hypermethylation and the expression of collagen formation genes are linked to chemotherapy in patients with susceptibility factors for colorectal cancer. These findings may facilitate the implementation of personalized treatment strategies for HFS. Patients carrying the _CES1_1165-33A and _CDA_ 266 + 242G variant alleles are at an elevated risk of developing grade 2 HFS. Additionally, patients with dihydropyrimidine dehydrogenase (DPD) deficiency in certain genes exhibit a higher likelihood of experiencing HFS, along with a greater onset grade (Maillard et al. 2021; Henricks et al. 2018). A study from Ireland shows that Up to 9% of people have low levels of a working DPD enzyme and are at risk of severe toxicity from 5FU/capecitabine (Kieran et al. 2024). Therefore, prospective screening is essential to reduce the risk of life-threatening toxicity in these patients.

Headings effects of metabolic enzymes

Capecitabine is metabolized in the liver to 5′-deoxyuridine (5′-DFCR), which is subsequently converted by cytidine deaminase into 5′-deoxyuridine (5′-DFUR). This compound is ultimately transformed into 5-fluorouracil (5-FU) by thymidine phosphorylase (TP), particularly within tumor tissue, leading to the destruction of cancer cells. The increased regional toxicity mediated by thymidine phosphorylase—especially in the palms and soles—and GSDME-driven pyroptosis are significant contributors to HFS. Therefore, based on this study, local application of thymidine phosphorylase inhibitor (TPI) has a certain therapeutic effect on mouse models and does not affect the efficacy of capecitabine. The decrease in tumour weight was significantly greater in the capecitabine-treated mice CAP-vehicle group (0.374 ± 0.0.095 g) and CAP-TPI group (0.316 ± 0.125 g) than in the control mice (3.026 ± 0.538 g), which suggested that topical TPI did not affect the antitumor effect of capecitabine and that TPI was well tolerated in the human colorectal cancer xenograft model. This finding not only elucidates one of the possible causes of capecitabine-induced HFS but also suggest a promising intervention strategy involving TPI to mitigate the debilitating side effects associated with capecitabine (Yang et al. 2023). However, there are currently no large-scale clinical studies to verify the efficacy and safety of topical application of related drugs.

Headings accumulation of drug metabolites

The presence of trauma to the palm and plantar skin suggests that local factors may play a significant role in the pathogenesis of related conditions. For instance, due to the rich capillary networks and increased blood flow during trauma, combined with a higher density of secretory glands, it is believed that areas subjected to repeated friction or trauma—such as the palms and soles, which are frequently engaged in daily physical activities—may exhibit higher concentrations of chemotherapy drugs (Almeida da Cruz et al. 2012; Griffin et al. 2017). Study (Huang et al. 2016) has demonstrated that capecitabine administration increases the concentration of fluorine in sweat on the skin surface, indicating potential local toxic effects. Consequently, adverse reactions may be mitigated by minimizing friction trauma, avoiding contact with warm objects, and reducing sweat secretion.

Clinical symptoms

Chemotherapy drugs can lead to clinical symptoms of hand-foot syndrome, which typically manifest 2 days to 3 weeks after treatment. Capecitabine, in particular, has been associated with symptoms lasting several months (Degen et al. 2010). The initial clinical manifestations include bilateral symmetrical numbness or tingling, burning sensations, and gradually progress to erythema and desquamation. Eventually, these symptoms can develop into ulcers and blisters accompanied by severe pain, significantly impacting daily life. These clinical manifestations commonly occur in areas of the hands and feet that are prone to friction, such as the palms, fingers, and soles (Bolognia et al. 2008; Farr and Safwat 2011). There are few reported cases of unilateral symptoms, where patients may experience partial pain on one side (Almeida da Cruz et al. 2012).

Severity grading of HFS

Currently, the National Cancer Institute Toxicity Classification (NCI-CTC) and the World Health Organization (WHO) criteria for the classification of hand-foot syndrome are frequently utilized in clinical practice (With et al. 2023a; Kwakman et al. 2020):

• **Grade I**: The patient exhibits minimal skin alterations, including numbness, dysesthesia, paresthesia, edema, erythema, and/or discomfort in the hands and/or feet; however, there is no pain.

• **Grade II**: The patient exhibits symptoms of painful erythema, desquamation, fissures, and edema in the hands and/or feet, which impact the ability to perform daily activities.

• **Grade III**: The patient exhibits severe skin alterations, including wet desquamation, edema, ulcerations, and blistering, accompanied by intense pain and significant limitations in daily self-care and work activities.

**WHO Classification**:

1. Dysesthesia/Paresthesia: Tingling sensations in the hands and feet.

2. Discomfort when holding objects, accompanied by painless swelling and erythema upon walking.

3. Painful erythema and swelling of the palms and soles, along with periungual erythema and swelling.

4. Desquamation, ulceration, blistering, and severe pain.

Influential factors

Relevant studies have demonstrated that hand-foot syndrome induced by capecitabine varies according to age, sex, drug combinations, race, and dosage. This suggests that these factors may influence the side effects associated with capecitabine.

Age and sex

Research indicates that the maximum concentration (Cmax) of capecitabine is significantly higher in women than in men (Ilich et al. 2016; Wagner et al. 2021). Notably, capecitabine does not exhibit antiproliferative activity in vivo, and the Cmax value of 5-fluorouracil (5-FU), which possesses antitumor activity, was not significantly different between the sexes. Age (ranging from 26 to 65 years) was negatively correlated with capecitabine Cmax, indicating that the concentration of the capecitabine metabolite 5-FU in elderly patients is relatively high, thereby increasing the likelihood of developing hand-foot syndrome. Consequently, it is essential to provide timely protective measures (Gressett et al. 2006; Kang et al. 2010; Shafiei et al. 2023).

Drug combinations

The incidence of HFS varies with different drug combinations. For instance, the incidence rates for capecitabine monotherapy range from 50 to 60%, while combinations with docetaxel show rates of 56–63% (Farr and Safwat 2011). The use of renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACE-Is) or type II angiotensin receptor blockers, may protect the vascular endothelium and influence the development of HFS (Takahashi et al. 2019; Kanbayashi et al. 2023).

Ethnicity

Compared to white populations, African American patients exhibit a higher incidence of HFS, which may present as hyperpigmentation. A study state that African-Americans showed significantly reduced peripheral blood mononuclear cell DPD enzyme activity compared with Caucasians (0.26 ± 0.07 and 0.29 ± 0.07 nmol/min/mg, respectively; P = 0.002). The prevalence of DPD deficiency was threefold higher in African-Americans compared with Caucasians (8.0% and 2.8%, respectively; P = 0.07) (Mattison et al. 2006).Understanding these differences is crucial, as HFS is more prevalent among Black patients than their white counterparts (Lou et al. 2016; Miller et al. 2014; Narasimhan et al. 2004; Nikolaou et al. 2016).

Dosage

The dose-toxicity relationship of capecitabine in breast cancer patients has not been fully elucidated. A systematic review and meta-analysis (Nishijima et al. 2016) revealed that capecitabine administered alone at a dose of 1000 mg/m² twice daily resulted in a higher incidence of toxicity compared to a dose of 1250 mg/m².

Prevention and control measures

Dose adjustment and cessation of drug use

For dose adjustments of capecitabine in the event of HFS, the following recommendations are based on the FDA-approved XELODA package insert:

• Grade 1 HFS: Maintain the original dose.

• Grade 2 HFS: Interrupt treatment until symptoms resolve to Grade 0 or 1, then resume at 100% of the original dose. For subsequent occurrences, reduce the dose to 75% and then to 50%. If a fourth occurrence happens, discontinue treatment.

• Grade 3 HFS: Interrupt treatment until symptoms resolve to Grade 0 or 1, then continue at 75% of the original dose. For subsequent occurrences, reduce to 50% and discontinue after a third occurrence.

• Grade 4 HFS: Permanently discontinue treatment.

Through appropriate dose adjustments, the progression of HFS can be effectively alleviated; however, these adjustments may impact the patient's treatment process and could affect progression-free survival (PFS) and overall survival (OS). Therefore, the use of drugs and other preventive measures should be prioritized.

Systemic medication

Celecoxib

The mechanism of HFS has been most extensively studied in relation to COX-2.Thus, Some researchers have demonstrated in a prospective randomized phase III clinical trial that celecoxib can effectively prevent capecitabine-related HFS. In this study, patients with stage II and III colorectal cancer who received standard capecitabine chemotherapy were randomized into two groups: one group received capecitabine combined with celecoxib, while the other group received capecitabine alone. The results indicated that the use of celecoxib significantly reduced the incidence of grade 1 and 2 HFS, establishing it as an effective and safe method for preventing capecitabine-related HFS. Researchers compared all the adverse events in the study and found that the incidence of ≥ grade 1 and ≥ grade 2 HFS differed significantly between the capecitabine group and capecitabine/celecoxib (74.6% versus 57.4%, P = 0.034, 29.6% versus 14.7% P = 0.035). The difference in the incidence of grade 3 HFS between the groups was not significant (8.5% versus 2.9% P = 0.303). And in the multivariate Cox proportional hazards regression analysis to detect all the clinical factors that were potential prognostic factors: The result showed that use of celecoxib was the only factor that affected the incidence of ≥ grade 1 HFS [hazard ratio (HR): 0.556, 95% confidence interval (CI) 0.392–0.790, P = 0.001)] and ≥ grade 2 HFS (HR: 0.414, 95% CI 0.224–0.765, P = 0.005.) Additionally, a recent randomized controlled parallel study confirmed celecoxib's superior efficacy: during the study period, 16 patients (72.7%) in the control group developed HFS, whereas only 8 patients (36.4%) in the celecoxib group exhibited this symptom (P = 0.015). This finding is consistent with previously reported efficacy data (Kettana et al. 2025). Notably, celecoxib was particularly effective in preventing all grades of capecitabine-induced HFS (Zhang et al. 2011, 2012; Gressett et al. 2006; Pandy et al. 2022). However, concerns regarding its cardiotoxicity persist, as it may lead to myocardial infarction and other long-term effects (Kwakman et al. 2020; Solomon et al. 2005; Caldwell et al. 2006). For example, a meta-analysis showed that the odds ratio of myocardial infarction with celecoxib compared to placebo was 2.26 (95%confidence interval 1.0–5.1) (Caldwell et al. 2006).

Traditional Chinese medicine drug preparations

The management of hand and foot syndrome (HFS) in Traditional Chinese Medicine (TCM) encompasses the external application of various herbal preparations, including safflower (10 g), angelica (20 g), purple grass (20 g), cassia (10 g), rhubarb (20 g), peony (20 g), purple (10 g), purslane (20 g), and bitter bath (20 g). Additionally, an internal decoction composed of astragalus and cassia root is recommended (Zhao et al. 2014). In traditional Chinese medicine, differences among practitioners often lead to variations in prescribed dosages. Therefore, the reliance on symptomatic TCM approaches has resulted in a paucity of high-quality randomized controlled trials that investigate the preventive and therapeutic effects of Chinese medicine on HFS. However, no large-scale prospective clinical trials have yet been conducted to validate the therapeutic efficacy of traditional Chinese medicine for HFS, and the relationship between the two requires further investigation.

Topical medications

Diclofenac

The incidence of HFS is closely linked to cyclooxygenase-2 (COX-2) activity. While celecoxib has demonstrated efficacy in preventing HFS, its potential systemic side effects restrict its routine use. In contrast, topical diclofenac is associated with a minimal risk of systemic adverse effects. A single-center phase III randomized double-blind trial (Santhosh et al. 2024) involving 264 patients assigned participants to receive either topical diclofenac gel (n = 131) or a placebo (n = 133). The occurrence of Grade 2 or 3 HFS was noted in 3.8% of the diclofenac group, compared to 15.0% in the placebo group (absolute difference, 11.2%; 95% confidence interval [CI], 4.3–18.1; P = 0.003). Furthermore, the incidence of Grade 1–3 HFS was lower in the diclofenac group (6.1%) than in the placebo group (18.1%; absolute risk difference, 11.9%; 95% CI, 4.1–19.6%). Additionally, the frequency of capecitabine dose reductions due to HFS was lower in the diclofenac group (3.8%) compared to the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0–16.4). These results indicate that topical diclofenac is a more effective intervention for HFS induced by capecitabine (Santhosh et al. 2024). Additionally, a recent randomized, double-blind, placebo-controlled Phase III study evaluated whether diclofenac sodium 0.1% cream (distinct from the diclofenac gel used in the D-TORCH study) could prevent capecitabine-induced HFS.This experiment is currently undergoing further research and follow-up (Iimura et al. 2025).

Pyridoxal

Concerning vitamin B6 (pyridoxal), both domestic and international clinical studies have shown that it does not significantly prevent or delay the onset of Grade 2 or higher HFS (Kang et al. 2010; Toyama et al. 2018; Braik et al. 2014; Yap et al. 2017; Huang et al. 2018; Lian et al. 2021). Nevertheless, for patients receiving capecitabine, Muhammad Wasif Saif (2011) has suggested administering pyridoxal at a dosage of 50 mg twice daily upon the onset of Grade 2 HFS, with the possibility of increasing the dosage to 100 mg twice daily if necessary. Patients may be treated three times daily with doses reaching up to 150 mg for Grade 2–3 HFS, yielding favorable outcomes.Although dose escalation has been observed to alleviate HFS in several cases, this may be related to patient-specific factors and is subject to potential confounding variables. Based on the currently available higher-level evidence from controlled trials, pyridoxal remains non-indicative for the treatment of HFS (Lian et al. 2021).

Topical urea cream, lactic acid, and mapisal

A meta-analysis incorporating United States, Germany, United Kingdom, Singapore, China, Iran, Japan, Korea, and Thailand indicates that (Huang et al. 2018) indicated that topical urea/lactate was ineffective in preventing capecitabine-induced HFS of Grades 1, 2, or 3 (Grade 1: RR = 0.88, 95% CI = 0.41–1.88, I = 62.8%; Grade 2: RR = 0.80, 95% CI = 0.41–1.57, I = 0.0%; Grade 3: RR = 0.53, 95% CI = 0.13–2.15, I = 0.0%). The results for the prevention of capecitabine-induced Grade 2 HFS were similarly unimpressive (Grades 1–3: RR = 0.81, 95% CI = 0.52–1.26, I = 53.0%; Grade 2: RR = 0.74, 95% CI = 0.41–1.32, I = 0.0%). Due to the small sample size, subgroup analysis was not conducted in this study. However, when the sample size was increased (Lan et al. 2022), urea cream demonstrated a beneficial effect in reducing the incidence of severe HFS. In a recent phase II randomized study (Wanichtanom et al. 2024), the combination of aloe gel and urea cream was applied topically; in this cohort, 86.7% of patients experienced Grade 0–1 HFS, while 13.3% experienced Grade 2–3 HFS. In the 10% urea cream group, 64.5% of patients had Grade 0–1 HFS, and 35.5% had Grade 2–3 HFS (Mann–Whitney U test, p = 0.045). The incidence of all HFS grades was 46.7% in the A + U group and 71% in the U group. The proportion of patients with Grade 2–3 HFS was significantly lower in the combined treatment group. Since 2011, ointments containing various antioxidants have shown high free radical protection factors; however, their efficacy is not as pronounced as that of 10% urea cream (Hofheinz et al. 2015).

Silymarin

A meta-analysis (Kao et al. 2022; Elyasi et al. 2017) indicated that topical silymarin exhibited the most significant effect (odds ratio [OR]: 0.08; 95% confidence interval [CI]: 0.01–0.71). One study showed that the silymarin group had a 40% incidence of HFS at week 9, compared to 60% in the placebo group (P = 0.03) (Elyasi et al. 2017).

Local heparin

In a clinical study conducted by Analia Rodriguez-Garzotto et al. (2022), it was reported that the median time to treatment with topical heparin (TH) was 7.6 weeks (range = 3.6–41.6 weeks), and the median time to response was 3.01 weeks (95% CI = 2.15–3.97). At the conclusion of the treatment, 19 out of 21 patients (90.48%) exhibited a response, demonstrating one or more reduced HFS grades. No patients experienced adverse effects associated with TH, and none discontinued chemotherapy.However, this study was not a controlled trial and involved a small number of patients. Therefore, further large-scale prospective clinical trials are needed to validate its feasibility.

Physical protection

Patients are advised to minimize friction between their hands and feet to avoid contact with overheated or warm objects. In hot weather, it is recommended that patients allow their skin to breathe as much as possible and avoid direct sun exposure to prevent an increase in skin temperature. For individuals prone to sweating, it is advisable to refrain from wearing excessively tight gloves and shoes. Instead, patients should opt for properly fitting cotton socks to reduce pressure and friction on the palms and soles, thereby minimizing physical damage to the skin. Additionally, the use of soft and comfortable insoles can provide protection to the skin of the feet during strenuous exercise or activities that may cause skin irritation (Degen et al. 2010; Law et al. 2015; Suzuki et al. 2018; Nagore et al. 2000).

Main content table and evaluation of the literature

The main content of the experimental literature is presented in Table 1. For quality assessment, we applied the Cochrane risk of bias assessment tool in Revman 5.4, with the results presented in Fig. 1. We consider the risk to be high for experiments involving traditional Chinese medicine due to individual variations and issues with result reporting.

Table 1.

Summary of key experimental literature

	Counrtry	Population	Chemotherapydrug	Interventionprophylaxis		Comparator		Outcomes
				Event	Total	Event	Total
Zhang et al. 2012	China	N = 150 Stages II and III colorectal cancer patients	Capecitabine-based CAPEOX	39(57.4%)	N = 68 Celecoxib 200 mg two times per day	53(74.6%)	N = 71 No celecoxib	Celecoxib prevents all-grade HFS (57.4% vs 74.6% p = 0.034) and moderate to severe HFS (14.7% vs 29.6% p = 0.035)
Kettana et al. 2025	Egypt	N = 44 stage II colorectal cancer patients	Capecitabine	8 (36.4%)	N = 22 Celecoxib 200 mg two times per day	16 (72.7%)	N = 22 No celecoxib	16 patients (72.7%) in the control group versus 8 patients (36.4%) in the celecoxib group developed HFS (P = 0.015)
Santhosh et al. 2024	India	N = 264 breast or GI cancer	Capecitabine-based treatment	5 (3.8%)	N = 131 1% topical diclofenac (Enzoflam)	20 (15.0%)	N = 133 Placebo gel	3.8% of the diclofenac group, compared to 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3–18.1; P = 0.003)
Kang et al. 2010	Korea	N = 360 GI tract cancers	Capecitabine-based treatment	147(81.7%)	N = 180 Pyridoxine 100 mg twice per day	140(77.8%)	N = 180 A placebo of identical appearance	HFS of any grade developed in 147 (81.7%) of 180 patients in the placebo group and 140 (77.8%) of 180 in the pyridoxine group Grade 2 or worse HFS developed in 55 (30.6%) of 180 placebo-treated patients and in 57 (31.7%) of 180 pyridoxine patients The cumulative dose of capecitabine to grade 2 or worse HFS was not different between the two groups (median not reached in either group; hazard ratio [HR] = 0.95; P = 0.788)
Toyama et al. 2018	Japan	N = 135 advanced or metastatic breast cancer	Capecitabine-based treatment	45(68.2%)	N = 67 Pyridoxine 60 mg per day	49(73.1%)	N = 68 No pyridoxine	All-grade HFS was observed in 45 (68.2%) and 49 (73.1%) patients in the pyridoxine and no pyridoxine groups,respectively
Braik et al. 2014	America	N = 77	Capecitabine-based treatment	10 (26%)	N = 38 Pyridoxine 100 mg/day	8 (21%)	N = 39 placebo	HFS developed in 10 of 38 (26%) patients in the pyridoxine group and in 8 of 39 (21%) patients in the placebo group (P = .0.547).Therefore, the risk of HFS was 5 percentage points higher in pyridoxine group (95% CI for difference, −13 percentage points to + 25 percentage points)
Yap et al. 2017	Singapore	N = 210 breast, colorectal, and other cancers	Capecitabine-based treatment	33 (31.4%)	N = 105 pyridoxine (200 mg)	39 (37.1%)	N = 105 placebo	The incidence of grade 2 or higher HFS did not differ (P = 0 .38) between the placebo group (39 of 105 [37.1%]; 95% CI, 27.9–46.4%) and the pyridoxine group (33 of 105 [31.4%]; 95%CI 22.6%-40.3%)
Wanichtanom et al. 2024	Thailand	N = 61 Rectal cancer,colorectal, and other cancers	Capecitabine-based treatment	14(46.7%)	N = 30 Aloe Vera plus Urea cream	22(71%)	N = 31 Urea cream	The incidence of all HFS grades was 46.7% in the A + U group and 71% in the U group
Hofheinz et al. 2015	German	N = 152 GI tumors or breast cancer	Capecitabine-based treatment	30 (39.5%)	N = 76 Mapisal	17 (22.4%)	N = 76 Urea cream	Thirty of 76 patients (39.5%) receiving Mapisal experienced HFS (grades 1/2/3 [% of total events: 66.7/26.7/6.7];). In the urea arm, only 17 of 76 patients (22.4%) reported HFS (grades 1/2/3 [%: 52.9/41.2/5.9]). Thus, the proportion of participants experiencing HFS was significantly higher in the Mapisal group (stratified common odds ratio, 2.37; 95% CI 1.14 to 4.84; P = 0.02)
Elyasi et al. 2017	Iran	N = 40 gastrointestinal cancer	Capecitabine-based treatment	8(40%)	N = 20 Silymarin	12(60%)	N = 20 placebo	The HFS incidence rate in the silymarin group was 40% in Week 9, compared to 60% in the placebo group. (P = 0.03)
Zhao et al. 2014	China	N = 92 gastric cancer,lung cancer,breast cancer, colon cancer, rectal cancer	Capecitabine, sorafenib, and gefitinib	7(11.7%)	N = 60 Modified Taohong-siwu decoction to soak hands and feet for 30 min, once daily	16(50%)	N = 30 100 mg pyridoxine orally, twice daily	The effective rate of relief was 88.3% in group A, which was significantly higher than the 50% in group B (P = 0.00)

Fig. 1.

Literature quality assessment

Summary

Currently, the underlying mechanisms of HFS induced by capecitabine remain poorly understood. Potential contributing factors may include epoxygenase (COX)-mediated inflammation, interleukin-6 and interleukin-8 mediated inflammatory responses, genetic variations, the accumulation of metabolic enzymes and drug metabolites, as well as patient-specific factors such as age, sex, drug combinations, race, and dosage. Although HFS is not life-threatening, it can lead to dose reductions or discontinuation of treatment in severe cases, thereby impacting the efficacy of the drugs. Various strategies have been employed to prevent or treat HFS; however, their effectiveness is often suboptimal. For instance, while pyridoxal and certain other medications may show efficacy, their long-term use can result in significant side effects, as observed with celecoxib. Furthermore, some treatments lack adequate clinical research to substantiate their use. For traditional Chinese medicine, its efficacy often varies due to individual differences, and further large-scale clinical studies are needed to verify its efficacy and safety. However, Topical diclofenac, as a locally applied drug, is effective and has fewer adverse reactions than other methods.

We believe that, as the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice in 2020: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles (With et al. 2023b). We can also conduct relevant tests before administering medication to medication to control dosage to achieve a certain preventive effect.

When administering medication, we recommend that for patients without significant underlying conditions, regardless of whether HFS occurs, local application of diclofenac combined with physical therapy should be initiated early for prevention. If HFS occurs and diclofenac combined with physical therapy fails to provide adequate relief, COX-2 inhibitors such as celecoxib may be considered; however, caution is advised for patients with cardiovascular disease. Additionally, for patients who do not respond to the above measures, further options such as Topical Urea Cream, Lactic Acid, and Mapisal may be explored.

Author contributions

BC: Writing–original draft, Writing—review and editing. XW: Writing—review and editing. LM: Supervision, Validation, Funding acquisition, Visualization, Writing—review and editing.

Funding

This research was funded by Natural Science Foundation Program of Jilin Province, grant number YDZJ202501ZYTS093.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.