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Clinical characteristics, treatment outcomes, and prognosis in patients with MKIs-associated hand-foot skin reaction: a retrospective study

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Abstract

Background

Multikinase inhibitors (MKIs) treatment has been proven as a powerful strategy in cancer therapy. However, it is greatly hampered by its common adverse effect known as hand-foot skin reaction (HFSR), especially in patients with moderate-to-severe HFSR.

Objective

To investigate the clinical characteristics, histopathological features, treatment response, and bio-indicators of HFSR.

Methods

We retrospectively reviewed the medical records of 102 patients with moderate-to-severe HFSR resulting from MKIs therapy.

Results

The median time to development of moderate-to-severe HFSR was 18 days, which would be significantly affected by the type of MKIs and the history of HFSR. Notably, we found that HFSR was classified into three consecutive stages: erythematous lesion, yellow hyperkeratotic lesion with surrounding erythema, and hyperkeratotic lesion. Inflammation was observed in the first two stages of HFSR, but disappeared in the third stage; in contrast, the hyperkeratosis gradually became thicker from stage one to stage three. Moreover, topical medications were demonstrated as an effective therapy for HFSR, among which, the topical steroids and urea ointment treatment response rate was 37.14%, the Shouzu Ning Decoction (SND) treatment response rate was 65%, and the SND in combination with urea ointment treatment response rate was 75%, meanwhile, systemic therapies did not improve the therapeutic efficacy of topical medications alone. In addition, the serum levels of HMGB1 were found to be a potential indicator for tracking the healing process as well as predicting the prognosis of HFSR.

Conclusion

This study revealed the potential factors affecting the development of HFSR, evaluated the therapeutic response towards different strategies for treating HFSR, and identified a potential prognostic indicator of HFSR.

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Data Availability

The datasets used during the current study are available from the corresponding author on reasonable request.

References

  1. Yang J, Yan J, Liu B (2018) Targeting VEGF/VEGFR to modulate antitumor immunity. Front Immunol 9:978

    Article  PubMed  PubMed Central  Google Scholar 

  2. Liu G, Chen T, Ding Z, Wang Y, Wei Y, Wei X (2021) Inhibition of FGF-FGFR and VEGF-VEGFR signalling in cancer treatment. Cell Prolif 54(4):e13009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Jayson GC, Kerbel R, Ellis LM, Harris AL (2016) Antiangiogenic therapy in oncology: current status and future directions. Lancet 388(10043):518–529

    Article  CAS  PubMed  Google Scholar 

  4. Ding F, Liu B, Wang Y (2020) Risk of hand-foot skin reaction associated with vascular endothelial growth factor-tyrosine kinase inhibitors: a meta-analysis of 57 randomized controlled trials involving 24,956 patients. J Am Acad Dermatol 83(3):788–796

    Article  CAS  PubMed  Google Scholar 

  5. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A (2021) Using the Common Terminology Criteria for Adverse Events (CTCAE - version 5.0) to evaluate the severity of adverse events of anticancer therapies. Actas Dermosifiliogr (Engl Ed) 112(1):90–92

    Article  CAS  PubMed  Google Scholar 

  6. Chanprapaph K, Rutnin S, Vachiramon V (2016) Multikinase inhibitor-induced hand-foot skin reaction: a review of clinical presentation, pathogenesis, and management. Am J Clin Dermatol 17(4):387–402

    Article  PubMed  Google Scholar 

  7. Freites-Martinez A, Lacouture ME (2018) Dermatologic Adverse Events. In: Olver I (ed) The MASCC Textbook of Cancer Supportive Care and Survivorship. Springer International Publishing, Cham, pp 597–620

    Chapter  Google Scholar 

  8. McLellan B, Ciardiello F, Lacouture ME, Segaert S, Van Cutsem E (2015) Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management. Ann Oncol 26(10):2017–2026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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

    Article  CAS  PubMed  Google Scholar 

  10. Anderson RT, Keating KN, Doll HA, Camacho F (2015) The hand-foot skin reaction and quality of life questionnaire: an assessment tool for oncology. Oncologist 20(7):831–838

    Article  PubMed  PubMed Central  Google Scholar 

  11. Lacouture ME, Sibaud V, Gerber PA et al (2021) Prevention and management of dermatological toxicities related to anticancer agents: ESMO Clinical Practice Guidelines. Ann Oncol 32(2):157–170

    Article  CAS  PubMed  Google Scholar 

  12. Luo P, Yan H, Chen X et al (2020) s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide. Cell Res 30(9):779–793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Perucci LO, Sugimoto MA, Gomes KB, Dusse LM, Teixeira MM, Sousa LP (2017) Annexin A1 and specialized proresolving lipid mediators: promoting resolution as a therapeutic strategy in human inflammatory diseases. Expert Opin Ther Targets 21(9):879–896

    Article  CAS  PubMed  Google Scholar 

  14. Wang S, Zhang Y (2020) HMGB1 in inflammation and cancer. J Hematol Oncol 13(1):116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yang Q, Zang HM, Xing T et al (2021) Gypenoside XLIX protects against acute kidney injury by suppressing IGFBP7/IGF1R-mediated programmed cell death and inflammation. Phytomedicine 85:153541

    Article  CAS  PubMed  Google Scholar 

  16. Shinohara N, Nonomura N, Eto M et al (2014) A randomized multicenter phase II trial on the efficacy of a hydrocolloid dressing containing ceramide with a low-friction external surface for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma. Ann Oncol 25(2):472–476

    Article  CAS  PubMed  Google Scholar 

  17. Melosky BL, Lim HJ, Davies JM et al (2019) A phase II trial of the effect of perindopril on hand-foot skin reaction (HFSR) incidence and severity in patients receiving regorafenib for refractory mCRC. Cancer Chemother Pharmacol 83(3):411–417

    Article  CAS  PubMed  Google Scholar 

  18. Jatoi A, Ou FS, Ahn DH et al (2021) Preemptive versus reactive topical clobetasol for regorafenib-induced hand-foot reactions: a preplanned analysis of the ReDOS trial. Oncologist 26(7):610–618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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

    Article  CAS  PubMed  Google Scholar 

  20. 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

    Article  CAS  PubMed  Google Scholar 

  21. Shou L, Shao T, Zhao F, Chen S, Chen Q, Shu Q (2021) The efficacy and safety of the Shouzu Ning Decoction treatment for multi-kinase inhibitors-associated severe hand-foot skin reaction. Cancer Manag Res 13:45–53

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yan SJ, Li Y, Li ZL, Chen Y, Zhang XH, Xiao L (2019) A case report for severe hand-foot skin reaction caused by chemotherapy with actinomycin D in a patient with oculocutaneous albinism. Onco Targets Ther 12:1851–1855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Porta C, Paglino C, Imarisio I, Bonomi L (2007) Uncovering Pandora’s vase: the growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clin Exp Med. 7(4):127–134

    Article  CAS  PubMed  Google Scholar 

  24. Lee WJ, Lee JL, Chang SE et al (2009) Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol 161(5):1045–1051

    Article  CAS  PubMed  Google Scholar 

  25. Lacouture ME, Reilly LM, Gerami P, Guitart J (2008) Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol 19(11):1955–1961

    Article  CAS  PubMed  Google Scholar 

  26. Yang CH, Lin WC, Chuang CK, Chang YC, Pang ST, Lin YC 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(3):592–596

    Article  CAS  PubMed  Google Scholar 

  27. Chen J, Shao T, Zhang Y, Shou L, Shu Q (2023) External application of Shouzuning. Decoction in the treatment of grade 3 hand-foot skin reaction caused by apatinib. Chin J Integr Tradit West Med 43(03):298–302

    Google Scholar 

  28. Lv Q, Xing Y, Liu J et al (2021) Lonicerin targets EZH2 to alleviate ulcerative colitis by autophagy-mediated NLRP3 inflammasome inactivation. Acta Pharm Sin B 11(9):2880–2899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Tang P, Liu H, Lin B et al (2020) Spatholobi Caulis dispensing granule reduces deep vein thrombus burden through antiinflammation via SIRT1 and Nrf2. Phytomedicine 77:153285

    Article  CAS  PubMed  Google Scholar 

  30. Shi S, Liu Z, Xue Z, Chen X, Chu Y (2020) A plasma metabonomics study on the therapeutic effects of the Si-miao-yong-an decoction in hyperlipidemic rats. J Ethnopharmacol 256:112780

    Article  CAS  PubMed  Google Scholar 

  31. Li HY, Sun H, Zhang AH et al (2022) Therapeutic effect and mechanism of Si-Miao-Yong-An-Tang on Thromboangiitis Obliterans based on the urine metabolomics approach. Front Pharmacol 13:827733

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Treesirichod A, Chuenboonngarm S, Kritsanaviparkporn C (2022) The efficacy and safety of 20% urea cream and 10% urea cream in the treatment of acanthosis nigricans in adolescents, a randomized comparative double-blind study. J Cosmet Dermatol 21(7):2859–2864

    Article  PubMed  Google Scholar 

  33. Yang H, Wang H, Andersson U (2020) Targeting inflammation driven by HMGB1. Front Immunol 11:484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zheng W, Shi H, Chen Y, Xu Z, Chen J, Jin L (2017) Alteration of serum high-mobility group protein 1 (HMGB1) levels in children with enterovirus 71-induced hand, foot, and mouth disease. Medicine (Baltimore) 96(17):e6764

    Article  CAS  PubMed  Google Scholar 

  35. Xue J, Suarez JS, Minaai M et al (2021) HMGB1 as a therapeutic target in disease. J Cell Physiol 236:3406–3419

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the Key Pilot Program of Integrative Chinese and Western Medicine for Refractoriness Disease (Gastric Cancer), the Project of science and technology of Traditional Chinese Medicine of Zhejiang Province (NO. 2020ZB076, 2022ZB113), the Scientific Research Fund of Zhejiang Provincial Education Department (Y202145970), and "the Postgraduate Scientific Research Fund" of Zhejiang Chinese Medical University (2021YKJ03).

Author information

Author notes

  1. Liumei Shou, Jialu Chen, and Tianyu Shao contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China

    Liumei Shou, Shuyi Chen & Qijin Shu

  2. The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China

    Liumei Shou, Jialu Chen, Tianyu Shao, Yao Zhang, Shuya Zhao & Shuyi Chen

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  1. Liumei Shou
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Contributions

Qijin Shu: Conception, edited the manuscript, provided study patients and provided the funding. Liumei Shou: Designed the research, edited the manuscript, provided study patients and provided the funding. Jialu Chen: Manuscript writing, collected and assembled data, conducted data analysis and interpretation. Tianyu Shao: Manuscript writing, conducted data analysis and interpretation. Yao Zhang: Collected and assembled data. Shuya Zhao: Collected and assembled data. Shuyi Chen: Provided study patients. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Qijin Shu.

Ethics declarations

Ethics approval

This study was approved by the ethics committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2021–10-11 / 2021-KL-169–01). And the study of patient serum samples was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang Chinese Medical University (2017–06-19 / 2017-X-046). This study was performed in accordance with the Ethical Standards of the World Medical Association Declaration of Helsinki.

Consent to participate

This is a retrospective study. The ethics committee of the First Affiliated Hospital of Zhejiang Chinese Medical University has confirmed that it is not necessary to obtain consent. And for 19 patients of blood donors, signed informed consent was obtained.

Consent to publish

The authors affirm that human research participant provided informed consent for publication of the images in Fig. 2.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

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Supplementary Information

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520_2023_7830_Fig4_ESM.png

Supplementary file1 Supplemental Figure 1. Boxplot of the onset time in different tumor types. There was no statistically significant difference in the onset time of HFSR between primary cancer (P = .248). NSCLC, Non small-cell lung cancer; SCC, squamous cell carcinoma. (PNG 1538 kb)

High resolution image (TIFF 2367 kb)

520_2023_7830_Fig5_ESM.png

Supplementary file2 Supplemental Figure 2. ANXA1, ANXA5 and IGFBP7 concentrations in the serum of patients were respectively measured by ELISA before and after treatment. ANXA5 decreased significantly in serum levels after HFSR treatment in both the remission group and no-remission group, with no significant difference (P = .919). ***P < 0.001, *P < 0.05 (PNG 358 kb)

High resolution image (TIFF 388 kb)

Supplementary file3 (DOCX 21 kb)

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Shou, L., Chen, J., Shao, T. et al. Clinical characteristics, treatment outcomes, and prognosis in patients with MKIs-associated hand-foot skin reaction: a retrospective study. Support Care Cancer 31, 375 (2023). https://doi.org/10.1007/s00520-023-07830-3

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