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Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: a meta-analysis of randomized controlled trials

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Abstract

Purpose

Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are common toxicities of several systemic cancer treatments. Multikinase inhibitor–induced HFSR is distinguished from chemotherapy-induced HFS in terms of pathogenesis, symptomatology, and treatment. Multiple trials have investigated the efficacy of preventive strategies such as COX-inhibitors, pyridoxine, and urea cream; however, no consensus has been made. This meta-analysis evaluated data from high-quality trials to provide strong evidence in forming recommendations to prevent systemic cancer therapy–induced HFS/HFSR.

Methods

A systematic search of PubMed, Embase, Cochrane, clinical trials databases, and hand searching were utilized to identify randomized trials (RCTs) investigating prophylactic strategies for HFS/HFSR in cancer patients receiving systemic treatment. Trials published until August 2021 were included. Using the random effects model, pooled odds ratios were calculated for rates of all-grade and severe HFS/HFSR. Subgroup analysis based on type of cancer treatment given was done.

Results

Sixteen RCTs were included (N=2814). For all-grade HFS/HFSR, celecoxib (OR 0.52, 95% CI 0.32–0.85, p=0.009) and urea cream (OR 0.48, 95% CI 0.39–0.60, p<0.00001) both showed statistically significant risk reduction. Celecoxib was effective in preventing HFS in patients who received capecitabine (50.5% vs 65%, p=0.05), while urea cream was effective in both capecitabine HFS (22.3% vs 39.5%, p=0.02) and sorafenib-induced HFSR (54.9% vs 71.4%, p<0.00001). Pyridoxine at higher doses showed a trend towards benefit in preventing all grade HFS (69.6% vs 74.1%, p=0.23).

Conclusions

Urea cream and celecoxib are both effective in preventing HFS/HFSR in patients receiving systemic cancer treatment. Particularly, celecoxib is more effective in preventing all-grade capecitabine-induced HFS, while urea cream shows more benefit in preventing moderate to severe sorafenib-induced HFSR. Studies investigating optimal dosing for celecoxib and urea cream are recommended. There is inadequate evidence to make recommendations regarding pyridoxine.

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Data availability

All data generated or analyzed during this study are included in this published article and referenced articles are listed in the “References” section.

Code availability

Not applicable.

References

  1. Yap Y, Kwok L, Syn N et al (2017) Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine–induced hand-foot syndrome: a randomized clinical trial. JAMA Oncol 3(11):1538–1545. https://doi.org/10.1001/jamaoncol.2017.1269

    Article  PubMed  PubMed Central  Google Scholar 

  2. Nikolaou V, Syrigos K, Saif MW (2016) Incidence and implications of chemotherapy related hand-foot syndrome. Expert Opin Drug Saf 15(12):1625–1633. https://doi.org/10.1080/14740338.2016.1238067

    Article  CAS  PubMed  Google Scholar 

  3. Degen A, Alter M, Schenck F et al (2010) The hand-foot-syndrome associated with medical tumor therapy - classification and management. J Dtsch Dermatol Ges 8(9):652–661. https://doi.org/10.1111/j.1610-0387.2010.07449.x

    Article  PubMed  Google Scholar 

  4. Macedo LT, Lima JP, dos Santos LV, Sasse AD (2014) Prevention strategies for chemotherapy-induced hand-foot syndrome: a systematic review and meta-analysis of prospective randomised trials. Support Care Cancer 22(6):1585–1593. https://doi.org/10.1007/s00520-014-2129-z

    Article  PubMed  Google Scholar 

  5. Yadav N, Madke B, Kar S, Prasad K (2015) Liposomal doxorubicin-induced palmoplantar erythrodysthesia syndrome. Indian Dermatol Online J 6(5):366–368. https://doi.org/10.4103/2229-5178.164488

    Article  PubMed  PubMed Central  Google Scholar 

  6. Yang CH, Lin WC, Chuang CK et al (2008) Hand-foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol 158:592–596. https://doi.org/10.1111/j.1365-2133.2007.08357.x

    Article  CAS  PubMed  Google Scholar 

  7. Demirdag HG, Ayanoglu BT, Armagan BY (2019) Evaluation of hand-foot syndrome and hand-foot skin reaction. Turk Arch Dermatol Venereol 52:28–31. https://doi.org/10.4274/turkderm.galenos.2018.98624

    Article  Google Scholar 

  8. McLellan B, Ciardiello F, Lacouture ME, Segaert S, Van Cutsem E (2015) Regorafenib-associated hand-foot skin reaction: practical advise on diagnosis, prevention, and management. Ann Oncol 26:2017–2026. https://doi.org/10.1093/annonc/mdv244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0, November 2017, National Institutes of Health, National Cancer Institute. Available at: https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf. Accessed 27 Mar 2018

  10. Ai L, Xu Z, Yang B, He Q, Luo P (2019) Sorafenib-associated hand-foot skin reaction: practical advice on diagnosis, mechanism, prevention, and management. Expert Rev Clin Pharmacol 12(12):1121–1127. https://doi.org/10.1080/17512433.2019.1689122

    Article  CAS  PubMed  Google Scholar 

  11. Lian S, Zhang X, Zhang Y, Zhao Q (2021) Pyridoxine for prevention of hand–foot syndrome caused by chemotherapy agents: a meta-analysis. Clin Exp Dermatol 46:629–635. https://doi.org/10.1111/ced.14486

    Article  CAS  PubMed  Google Scholar 

  12. Chen JC, Wang JC, Pan YX et al (2020) Preventive effect of celecoxib in sorafenib-related hand-foot syndrome in hepatocellular carcinoma patients, a single-center, open-label, randomized, controlled clinical phase III trial. Am J Cancer Res 10(5):1467–1476 Published 2020 May 1

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ren Z, Zhu K, Kang H et al (2015) Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol 33(8):894–900. https://doi.org/10.1200/JCO.2013.52.9651

    Article  CAS  PubMed  Google Scholar 

  14. Wang C, Rang G, An L et al Preventive effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma: a randomized controlled trial. Hepatology 62:1

  15. Lee YS, Jung YK, Kim JH et al (2020) Effect of urea cream on sorafenib-associated hand-foot skin reaction in patients with hepatocellular carcinoma: a multicenter, randomised, double-blind controlled study. Eur J Cancer 140:19–27. https://doi.org/10.1016/j.ejca.2020.09.012

    Article  CAS  PubMed  Google Scholar 

  16. Higgins JPT, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD et al (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials BMJ 343:d5928. https://doi.org/10.1136/bmj.d5928

  17. Köhne CH, De Greve J, Hartmann JT et al (2008) Irinotecan combined with infusional 5-fluorouracil/folinic acid or capecitabine plus celecoxib or placebo in the first-line treatment of patients with metastatic colorectal cancer. EORTC study 40015. Ann Oncol 19(5):920–926

    Article  PubMed  Google Scholar 

  18. Zhang RX, Wu XJ, Wan DS et al (2012) 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 23(5):1348–1353. https://doi.org/10.1093/annonc/mdr400

    Article  CAS  PubMed  Google Scholar 

  19. Chen M, Zhang L, Wang Q, Shen J (2013) Pyridoxine for prevention of hand-foot syndrome caused by chemotherapy: a systematic review. PLoS One 8(8):e72245. https://doi.org/10.1371/journal.pone.0072245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kang YK, Lee SS, Yoon DH et al (2010) Pyridoxine is not effective to prevent hand-foot syndrome associated with capecitabine therapy: results of a randomized, double-blind, placebo-controlled study. J Clin Oncol 28(24):3824–3829. https://doi.org/10.1200/JCO.2010.29.1807

    Article  CAS  PubMed  Google Scholar 

  21. Von Gruenigen V, Frasure H, Fusco N et al (2010) A double-blind, randomized trial of pyridoxine versus placebo for the prevention of pegylated liposomal doxorubicin-related hand-foot syndrome in gynecologic oncology patients. Cancer 116(20):4735–4743. https://doi.org/10.1002/cncr.25262

    Article  CAS  Google Scholar 

  22. Corrie PG, Bulusu R, Wilson CB et al (2012) A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications. Br J Cancer 107(4):585–587. https://doi.org/10.1038/bjc.2012.318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Braik T, Yim B, Evans AT et al (2014) Randomized trial of vitamin B6 for preventing hand-foot syndrome from capecitabine chemotherapy. J Community Support Oncol 12(2):65–70. https://doi.org/10.12788/jcso.0017

    Article  CAS  PubMed  Google Scholar 

  24. Ota M, Tatsumi K, Suwa H et al (2014) The effect of pyridoxine for prevention of hand-foot syndrome in colorectal cancer patients with adjuvant chemotherapy using capecitabine: a randomized study. Hepatogastroenterology 61(132):1008–1013

    PubMed  Google Scholar 

  25. Yap YS, Kwok LL, Syn N et al (2017) Predictors of hand-foot syndrome and pyridoxine for prevention of capecitabine-induced hand-foot syndrome: a randomized clinical trial. JAMA Oncol. 3(11):1538–1545. https://doi.org/10.1001/jamaoncol.2017.1269

    Article  PubMed  PubMed Central  Google Scholar 

  26. Toyama T, Yoshimura A, Hayashi T et al (2018) A randomized phase II study evaluating pyridoxine for the prevention of hand-foot syndrome associated with capecitabine therapy for advanced or metastatic breast cancer. Breast Cancer 25(6):729–735. https://doi.org/10.1007/s12282-018-0879-z

    Article  PubMed  Google Scholar 

  27. Watanabe K, Ishibe A, Watanabe J et al (2020) The effect of TJ-28 (Eppikajutsuto) on the prevention of hand-foot syndrome using capecitabine for colorectal cancer: the Yokohama Clinical Oncology Group Study (YCOG1102). Indian J Gastroenterol 39(2):204–210. https://doi.org/10.1007/s12664-020-01039-6

    Article  PubMed  Google Scholar 

  28. Wolf SL, Qin R, Menon SP et al (2010) Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. J Clin Oncol 28(35):5182–5187. https://doi.org/10.1200/JCO.2010.31.1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hoffheinz RD, Gencer D, Schulz H et al (2015) Mapisal versus urea cream as prophylaxis for capecitabine-associated hand-foot syndrome: a randomized phase III trial of the AIO quality of life working group. J Clin Oncol 33(22):2444–2449. https://doi.org/10.1200/JCO.2014.60.4587

    Article  CAS  Google Scholar 

  30. Gomez P, Lacouture ME (2011) Clinical presentation and management of hand-foot skin reaction associated with sorafenib in combination with cytotoxic chemotherapy: experience in breast cancer. Oncologist 16(11):1508–1519. https://doi.org/10.1634/theoncologist.2011-0115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Harris R, Breyer M (2006) Update on cyclooxygenase-2 inhibitors. CJASN 1(2):236–245. https://doi.org/10.2215/CJN.00890805

    Article  CAS  PubMed  Google Scholar 

  32. Chalermchai T, Tantiphlachiva K, Suwanrusme H, Voravud N, Sriuranpong V (2010) Randomized trial of two different doses of pyridoxine in the prevention of capecitabine-associated palmar-plantar erythrodysesthesia. Asia Pac J Clin Oncol 6(3):155–160. https://doi.org/10.1111/j.1743-7563.2010.01311.x

    Article  CAS  PubMed  Google Scholar 

  33. Lauman MK, Mortimer J (2001) Effect of pyridoxine on the incidence of palmar plantar erythroderma (PPE) in patients receiving capecitabine. In Proc Am Soc Clin Oncol 20(1):392a

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Authors and Affiliations

  1. Cancer Institute, Section of Medical Oncology, St. Luke’s Medical Center, Quezon City, Philippines

    Jessa Gilda P. Pandy, Paula Isabel G. Franco & Rubi K. Li

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  1. Jessa Gilda P. Pandy
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  2. Paula Isabel G. Franco
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All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to Jessa Gilda P. Pandy.

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Ethics approval

The study was approved by the Ethics Review Committee of the St. Luke‘s Medical Center. Patient consent was not required. This study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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The authors declare no competing interests.

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Pandy, J.G.P., Franco, P.I.G. & Li, R.K. Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: a meta-analysis of randomized controlled trials. Support Care Cancer 30, 8655–8666 (2022). https://doi.org/10.1007/s00520-022-07175-3

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