Background for Fast Fact #520: Hand-foot syndrome (HFS), also referred to as toxic erythema of chemotherapy, palmar-plantar erythrodysesthesia, acral erythema, or hand-foot skin reaction, is a common side effect of certain kinds of systemic anti-neoplastic treatment and may result in significant pain and loss of function. Clinicians who care for patients actively receiving or who have recently received systemic cancer therapy are likely to encounter HFS. This Fast Fact will discuss identification, prevention, and unique symptom management strategies. Incidence is dose- and agent-dependent and ranges from 6-60% (higher incidences with combination treatments) (1,2).

Offending agents: Cytotoxic therapies commonly associated with HFS include 5-fluorouracil, capecitabine, doxorubicin, docetaxel, and cytarabine; tyrosine kinase inhibitors (TKIs) are another class of systemic cancer therapies which are commonly associated with HFS, particularly pazopanib, regorafenib, and cabozantinib (1,3). Other systemic cancer treatments may cause HFS as well; consult with the clinical pharmacist and oncologist.

Morbidity: Given the sensitivity of the primary affected areas (palms and soles), morbidity levels may be severe as the ability to do fundamental activities like ambulation, writing, work, etc., may be compromised. This is why HFS can limit functional capacity and lead patients to feel more dependent on others for basic tasks (4) The pathogenesis is incompletely understood but is thought to occur by leakage of the anti-neoplastic therapy out of capillaries to cause redness, pain, swelling, and blistering (4).

Presentation: HFS often develops between 1-3 weeks after chemotherapy or 2-4 weeks after initiation of a TKI (2,5). It is most evident on the fat pads of the proximal phalanges and areas prone to friction and pressure such as the groin and axillae. Patients often report tingling followed by edema, erythema and pain that can limit activities of daily living (ADL) and instrumental ADL (IADL) (4). Loss of fingerprints has been described; patients planning international travel or other relevant activities should receive appropriate counseling (6,7). Grading systems from the National Cancer Institute (NCI) are listed below: 

• Grade 1: minimal skin changes or dermatitis.
• Grade 2: skin peeling, blisters, bleeding, or edema along with pain that limits IADL.
• Grade 3: severe skin changes along with pain that limits ADL.

Diagnosis: HFS is a clinical diagnosis and biopsy is not required. The two most important conditions on the differential to rule out are acute graft-versus-host disease and Stevens-Johnson syndrome/toxic epidermal necrolysis both of which will have a more diffuse presentation (2,8,9). Consultation with dermatology should be pursued if uncertain.

Prevention: Topical 10-20% urea cream usually applied two to three times daily has been shown to help prevent HFS (10,11), as has 1% topical diclofenac applied to the hands twice daily when starting capecitabine (12). Oral celecoxib 200-400 mg twice daily for 3 to 4 months was shown to decrease the risk of all grades of HFS, it is unknown if other NSAIDs have a similar effect (11). There is inadequate evidence to support or refute use of other agents including pyridoxine and sildenafil (13-15).

Treatment: Oncologists typically monitor for and manage HFS; however, non-oncology clinicians need to be aware of it. If HFS is suspected, collaborate with the treating oncologist and clinical pharmacist. Treatment is twofold: 

1. Reduce the exposure to the offending cancer treatment either by decreasing the dose, increasing intervals between treatment, or stopping it entirely. This is recommended in patients with grade 2 or 3 HFS. Improvement and/or resolution is expected in 2-4 weeks.
2. Symptom management. High-potency topical steroids such as 0.05% betamethasone or clobetasol are indicated for grade 2 or 3 HFS. Wound care consultation is recommended in cases of desquamation. Systemic opioid therapy may be necessary for the discomfort associated with grade 2 or 3 HFS. Photobiomodulation or low-level laser therapy – 6 sessions over 2 weeks – has shown benefit in high grade HFS (16). If excessive thickening is noted of the outer skin (hyperkeratosis), 5-10% salicylic acid or 10-20% urea cream can act as a keratolytic agent (17-18).

Summary: HFS is a common side effect of cytotoxic chemotherapy and TKIs. Presenting symptoms include pain, swelling, erythema, and blistering of the hands and feet within a month of initiation of the offending agent. Topical urea, topical diclofenac and oral celecoxib can prevent HFS while HFS treatment strategies include high-potency topical steroids and anti-neoplastic therapy dose modification.

References: 

1. Lacouture ME, Sibaud V, Gerber PA, et al. Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines☆. Annals of Oncology 2021;32(2):157–170; doi: 10.1016/j.annonc.2020.11.005.
2. Miller KK, Gorcey L, McLellan BN. Chemotherapy-induced hand-foot syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol 2014;71(4):787–794; doi: 10.1016/j.jaad.2014.03.019.
3. Li J, Gu J. Hand-foot skin reaction with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2017;119:50–58; doi: 10.1016/j.critrevonc.2017.09.016.
4. Kwakman JJM, Elshot YS, Punt CJA, et al. Management of cytotoxic chemotherapy-induced hand-foot syndrome. Oncol Rev 2020;14(1):442; doi: 10.4081/oncol.2020.442.
5. McLellan B, Kerr H. Cutaneous toxicities of the multikinase inhibitors sorafenib and sunitinib. Dermatol Ther 2011;24(4):396–400; doi: 10.1111/j.1529-8019.2011.01435.x.
6. Al-Ahwal MS. Chemotherapy and fingerprint loss: beyond cosmetic. Oncologist 2012;17(2):291–293; doi: 10.1634/theoncologist.2011-0243.
7. Wong M, Choo S-P, Tan E-H. Travel warning with capecitabine. Ann Oncol 2009;20(7):1281; doi: 10.1093/annonc/mdp278.
8. Nagore E, Insa A, Sanmartín O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia (‘hand-foot’) syndrome. Incidence, recognition and management. Am J Clin Dermatol 2000;1(4):225–234; doi: 10.2165/00128071-200001040-00004.
9. Lipworth AD, Robert C, Zhu AX. Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology 2009;77(5):257–271; doi: 10.1159/000258880.
10. Lan T-C, Tsou P-H, Tam K-W, et al. Effect of Urea Cream on Hand-Foot Syndrome in Patients Receiving Chemotherapy: A Meta-analysis. Cancer Nurs 2022;45(5):378–386; doi: 10.1097/NCC.0000000000001008.
11. Pandy JGP, Franco PIG, Li RK. 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; doi: 10.1007/s00520-022-07175-3.
12. Santhosh A, Sharma A, Bakhshi S, 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; doi: 10.1200/JCO.23.01730.
13. Chen M, Zhang L, Wang Q, et al. Pyridoxine for prevention of hand-foot syndrome caused by chemotherapy: a systematic review. PLoS One 2013;8(8):e72245; doi: 10.1371/journal.pone.0072245.
14. McLellan B, Ciardiello F, Lacouture ME, et al. Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management. Ann Oncol 2015;26(10):2017–2026; doi: 10.1093/annonc/mdv244.
15. Meadows KL, Rushing C, Honeycutt W, et al. Treatment of palmar-plantar erythrodysesthesia (PPE) with topical sildenafil: a pilot study. Support Care Cancer. 2015;23(5):1311–1319; doi: 10.1007/s00520-014-2465-z.
16. Latifyan S, Genot MT, Fernez B, et al. Use of low-level laser therapy (LLLT) or photobiomodulation (PBM) for the management of the hand-foot syndrome (HSF) or palmo-plantar erythrodysesthesia (PPED) associated with cancer therapy. Support Care Cancer 2020;28(7):3287–3290; doi: 10.1007/s00520-019-05099-z.
17. Wongkraisri C, Chusuwanrak K, Laocharoenkeat A, Chularojanamontri L, Nimmannit A, Ithimakin S. Randomized controlled trial on the efficacy of topical urea-based cream in preventing capecitabine-associated hand-foot syndrome. BMC Cancer. 2025;25(1):275. Published 2025 Feb 17. doi:10.1186/s12885-025-13684-1.
18. Degen A, Alter M, Schenck F, et al. The hand-foot-syndrome associated with medical tumor therapy – classification and management. J Dtsch Dermatol Ges. 2010;8(9):652-661. doi:10.1111/j.1610-0387.2010.07449.x.

Author Affiliations: Cedars-Sinai Medical Center, Los Angeles, CA.
Conflicts of Interest: None to report.
Version History:  Originally edited by Sean Marks MD; first electronically published in September 2025.