Loading
Capecitabine, liposomal doxorubicin and tablets such as sorafenib and regorafenib can make the palms and soles red, sore, peeling or blistered. From the start, avoid rubbing, heat and long soaks, wear well-fitting shoes and moisturise daily; with sorafenib, a 10 per cent urea cream from day one helps. If hands or feet become painful or limit what you do, stop capecitabine and call your team.
Hand-foot syndrome (HFS) from capecitabine and pegylated liposomal doxorubicin, and hand-foot skin reaction (HFSR) from multikinase inhibitors, are managed by prevention, inspection at every cycle, and dose modification by CTCAE grade. Labels set the dose rules: capecitabine is withheld for grade 2 or worse until grade 0 to 1 and restarted at 100, 75 or 50 per cent of the current dose by occurrence (grade 2) or at 75 or 50 per cent (grade 3), and patients are told to stop the tablets themselves at grade 2; liposomal doxorubicin is delayed up to 2 weeks for grade 2 or worse and reduced by 25 per cent after grade 3; regorafenib is reduced to 120 mg at the first grade 2 HFSR and to 80 mg if it recurs, and interrupted for at least 7 days at grade 3.
For prevention, general measures (avoiding friction, heat and water exposure, fitted gloves and footwear, regular emollients) are universal advice without randomised proof. 10 per cent urea cream three times daily from day 1 of sorafenib lowered any-grade HFSR (56.0 against 73.6 per cent) and grade 2 or worse HFSR (20.7 against 29.2 per cent) in an open trial of 871 people; a blinded trial of 20 per cent urea was not significant on its primary measure. With capecitabine, oral celecoxib reduces grade 2 or worse HFS in network meta-analyses but carries cardiovascular and gastrointestinal risk; topical diclofenac gel reduced grade 2 to 3 HFS from 15.0 to 3.8 per cent in the D-TORCH trial and leads the 2026 network meta-analysis, but a 2026 real-world study found no benefit and a Japanese phase 3 trial is under way. Pyridoxine does not work. The ESMO 2021 guideline could not be read.
Why: Pressure, friction and heat bring the reaction on where the skin is under most stress; moisturising keeps the skin supple. These measures are safe, though no trial has proved them on their own.
“Preventive measures (grade 0) include avoiding mechanical or chemical stress, limiting water exposure, wearing appropriately fitted gloves, regular use of emollients, and patient education.”
International Journal of Clinical Oncology 2025 · expert review; no randomised trial of these measures alone
Why: The reaction is often under-reported; seeing it early allows a short break before it becomes severe.
“As its incidence may be underestimated, the panel recommended that providers carry out visual inspections of the palms of the hands and soles of the feet in addition to taking history on HFS-related symptoms prior to each cycle.”
ESMO Open 2023 · international expert panel recommendation, ungraded
Why: Urea softens the thickened skin where the reaction starts; in a large trial it lowered the chance of a reaction and delayed it.
“UBC prophylaxis in patients with advanced HCC starting sorafenib reduced HFSR rates, extended the time to first occurrence of HFSR, and improved patient quality of life compared with BSC.”
Journal of Clinical Oncology 2015 · randomised open-label trial, n = 871
Why: An anti-inflammatory gel blocks a step in the inflammation behind the reaction; one randomised trial found it prevented most moderate cases, but a later study in routine care did not.
“Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003).”
Journal of Clinical Oncology 2024 · single-site randomised double-blind trial, n = 264
Why: Several trials found that it does not prevent the reaction.
“Pyridoxine Most RCTs on pyridoxine showed negative results, and multiple systematic reviews and meta-analyses have shown insufficient efficacy [ 59 , 60 ].”
International Journal of Clinical Oncology 2025 · systematic reviews and meta-analyses
Why: Stopping at once lets the skin recover quickly; continuing makes it worse and can lead to a longer break.
“Instruct patients experiencing grade 2 palmar-plantar erythrodysesthesia syndrome or greater to stop taking XELODA immediately and to contact their healthcare provider.”
H2-Pharma, via DailyMed (US National Library of Medicine) 2026 · US prescribing information
Why: Lowering the dose after a reaction makes a repeat less likely while keeping the treatment going.
“Withhold XELODA and then resume at same or reduced dose or permanently discontinue based on severity and occurrence”
H2-Pharma, via DailyMed (US National Library of Medicine) 2026 · US prescribing information (Table 1)
Why: The reaction usually appears after two or three cycles and settles with a delay; a lower dose makes it less likely to return.
“Delay DOXIL liposomal infusion for the first episode of Grade 2 or greater HFS”
Baxter, via DailyMed (US National Library of Medicine) 2026 · US prescribing information
Why: The reaction is most common in the first cycle; stepping the dose down lets most people continue.
“Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia syndrome (PPES)] that is recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a minimum of 7 days for Grade 3 HFSR”
Bayer, via DailyMed (US National Library of Medicine) 2026 · US prescribing information
Why: Steroid creams calm the inflammation and urea softens the hard skin; Western guidelines recommend them, though no trial has tested them for this.
“Various guidelines recommend high potent topical steroid therapy for grade ≥ 2 HFS/HFSR [ 13 , 14 ], and such is used in clinical practice, although no RCTs have been conducted.”
International Journal of Clinical Oncology 2025 · guideline recommendation cited by the review; no randomised trials
Why: S-1 is a different fluoropyrimidine tablet that causes much less hand-foot syndrome, so treatment can continue at full strength.
“In patients who experience pain and/or functional impairment due to HFS during treatment with capecitabine or infusional 5-FU, a switch to S-1 is recommended without prior dose reduction of capecitabine/5-FU.”
ESMO Open 2023 · international expert panel recommendation, ungraded
How care is usually carried out, read from the guidelines and standards cited. Your own team's protocol and their judgement come first; this page is for understanding it, not for doing it yourself.
Dose modification by grade, from each drug's label, is the core of management, with inspection of hands and feet at every cycle and early self-stopping of capecitabine at grade 2. For prevention, the strongest single result is 10 per cent urea cream from day 1 of sorafenib (large open trial; a blinded trial of 20 per cent urea was not significant on its main measure). For capecitabine, two network meta-analyses agree that oral celecoxib reduces moderate to severe HFS but its cardiovascular and gastrointestinal risks limit routine use; topical diclofenac had the strongest effect in the 2026 network meta-analysis and in one randomised trial, but a 2026 real-world study found no benefit and a confirmatory phase 3 trial (J-DIRECT) is under way, so it is reasonable to offer but not yet established. Urea cream beat an antioxidant ointment for capecitabine in one trial. Pyridoxine does not work. The ESMO 2021 dermatological toxicity guideline, which is the main international guideline, could not be read.
H2-Pharma, via DailyMed (US National Library of Medicine) 2026 · Baxter, via DailyMed (US National Library of Medicine) 2026 · Bayer, via DailyMed (US National Library of Medicine) 2026 · Journal of Clinical Oncology 2015 · European Journal of Cancer 2020 · BMJ Supportive & Palliative Care 2022 · BMJ Supportive & Palliative Care 2026 · Journal of Clinical Oncology 2024 · JCO Global Oncology 2026 · Journal of Clinical Oncology 2015 · International Journal of Clinical Oncology 2025 · ESMO, Annals of Oncology 2021
Where it differs: Celecoxib 200 mg twice daily alongside capecitabine to prevent HFS.
Evidence: The 2022 network meta-analysis (15 trials, 2715 patients) found only celecoxib significantly prevented grade 2 or worse HFS (odds ratio 0.29); the 2026 network meta-analysis also found a reduction (risk ratio 0.46). The Japanese review advises limiting it because of cardiovascular and gastrointestinal risk with long-term use.
BMJ Supportive & Palliative Care 2022 · BMJ Supportive & Palliative Care 2026 · International Journal of Clinical Oncology 2025
Where it differs: 1 per cent diclofenac gel twice daily from the start of capecitabine as routine practice, compared with active monitoring, in two centres.
Evidence: Prospective observational study of 151 people: grade 2 or worse HFS 16.9 per cent with diclofenac against 13.8 per cent with monitoring (not significant); the authors concluded the findings do not support routine diclofenac prophylaxis. Not randomised.
Where it differs: 10 per cent urea cream as the preventive cream for capecitabine, compared with Mapisal, an antioxidant ointment.
Evidence: Randomised phase 3 trial of 152 evaluable people: any-grade HFS in 6 weeks 22.4 per cent with urea against 39.5 per cent with the ointment. There was no untreated control group.
Where it differs: Topical steroids are not used for grade 1 HFS, and lidocaine patches and antiseptic solutions are not used for grade 3, unlike Western guidance; urea cream used with caution because of irritation.
Evidence: Narrative review of 53 articles by a Japanese pharmacist-led group; based on differences in skin type and lack of Asian safety data rather than trials.
Capecitabine often makes the hands and feet sore and peeling, and the usual answer is a lower dose. In one randomised trial, a cheap diclofenac gel rubbed on the palms cut moderate or worse hand-foot syndrome from 15 to under 4 per cent and halved dose cuts. A later study in routine care found no benefit, and a larger Japanese trial on palms and soles is under way.
| Recommendation | Grade, as printed | Source |
|---|---|---|
| Urea cream 10 per cent reduced grade 2 or worse HFSR with sorafenib “as was the incidence of grade ≥ 2 HFSR (20.7% v 29.2%, respectively; OR, 0.635; 95% CI, 0.466 to 0.866; P = .004).” | randomised open-label trial, P = .004 | Journal of Clinical Oncology 2015 |
| Urea cream 20 per cent did not significantly reduce cumulative HFSR in a blinded trial with sorafenib “The urea cream group showed a trend towards a lower cumulative incidence of any-grade HFSR (log-rank, P = 0.247) and severe HFSR of grade II or higher (log-rank, P = 0.394) without statistical significance.” | randomised double-blind trial, not significant on cumulative incidence | European Journal of Cancer 2020 |
| Topical diclofenac and celecoxib reduced moderate to severe HFS in the 2026 network meta-analysis “Both topical diclofenac (RR 0.26, 95% CI 0.10 to 0.66) and celecoxib (RR 0.46, 95% CI 0.26 to 0.84) significantly reduced the risk of moderate to severe HFS compared with placebo.” | network meta-analysis of 13 RCTs, 1983 patients | BMJ Supportive & Palliative Care 2026 |
| Only celecoxib prevented moderate to severe HFS in the 2022 network meta-analysis “The analysis showed only celecoxib could significantly prevent the incidence of moderate to severe HFS (grade ≥2) (OR 0.29, 95% CrI 0.13 to 0.68).” | Bayesian network meta-analysis of 15 RCTs, 2715 patients | BMJ Supportive & Palliative Care 2022 |
| Topical diclofenac did not reduce grade 2 or worse HFS in routine care “In this prospective real-world study, prophylactic topical diclofenac did not reduce clinically significant capecitabine-induced HFS or delay its onset compared with active monitoring.” | prospective observational study, n = 151, not significant | JCO Global Oncology 2026 |
Shares the tags protocol, skin-toxicity, supportive-care.
Shares Sorafenib, Capecitabine and the tags protocol, supportive-care.
Shares Capecitabine and the tags protocol, supportive-care.
Shares Vitamin B6 (pyridoxine) for hand-foot syndrome and other uses, Capecitabine and the tag supportive-care.
Shares the tags protocol, supportive-care.
Shares the tags protocol, supportive-care.
Shares the tags protocol, supportive-care.
Shares the tags protocol, supportive-care.