Sorafenib-associated hand-foot skin reaction: practical advice on diagnosis, mechanism, prevention, and management

References

• Wilhelm S, Carter C, Lynch M, et al. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006;5(10):835–844.
   PubMed Web of Science ®Google Scholar
• Marino D, Zichi C, Audisio M, et al. Second-line treatment options in hepatocellular carcinoma. Drugs Context. 2019;8:212577.
   PubMedGoogle Scholar
• Hulin A, Stocco J, Bouattour M. Clinical pharmacokinetics and pharmacodynamics of transarterial chemoembolization and targeted therapies in hepatocellular carcinoma. Clin Pharmacokinet. 2019;58(8):983–1014.
   PubMedGoogle Scholar
• Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–390.
   PubMed Web of Science ®Google Scholar
• Kuzuya T, Ishigami M, Ishizu Y, et al. Clinical characteristics and outcomes of candidates for second-line therapy, including regorafenib and ramucirumab, for advanced hepatocellular carcinoma after sorafenib treatment. Hepatol Res. 2019;49:1054–1065.
   Web of Science ®Google Scholar
• Gauthier A, Ho M. Role of sorafenib in the treatment of advanced hepatocellular carcinoma: an update. Hepatol Res. 2013;43(2):147–154.
   PubMed Web of Science ®Google Scholar
• Guliani A, Daroach M, Aggarwal D, et al. Severe hand–foot skin reaction and erythema multiforme-like lesions due to sorafenib. Postgrad Med J. 2018;94(1115):535–536.
   PubMed Web of Science ®Google Scholar
• Dehneshin N, Raissi H, Hasanzade Z, et al. Using molecular dynamics simulation to explore the binding of the three potent anticancer drugs sorafenib, streptozotocin, and sunitinib to functionalized carbon nanotubes. J Mol Model. 2019;25(6):159.
   PubMed Web of Science ®Google Scholar
• Dehneshin N, Raissi H, Hasanzade Z, et al. Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma. Hepatology. 2016;64(3):774–784.
   PubMed Web of Science ®Google Scholar
• Wang Z, Dai J, Yan J, et al. Targeting EZH2 as a novel therapeutic strategy for sorafenib-resistant thyroid carcinoma. J Cell Mol Med. 2019;23(7): 4770–4778.
   Web of Science ®Google Scholar
• Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64(19):7099–7109.
   PubMed Web of Science ®Google Scholar
• Abdelgalil AA, Alkahtani HM, Al-Jenoobi FI. Sorafenib. Profiles Drug Subst Excip Relat Methodol. 2019;44:239–266.
   PubMedGoogle Scholar
• Wilson MA, Zhao F, Letrero R, et al. Correlation of somatic mutations and clinical outcome in melanoma patients treated with carboplatin, paclitaxel, and sorafenib. Clin Cancer Res. 2014;20(12):3328–3337.
   PubMed Web of Science ®Google Scholar
• Giglio V, Viale M, Bertone V, et al. Cyclodextrin polymers as nanocarriers for sorafenib. Invest New Drugs. 2018;36(3):370–379.
   PubMed Web of Science ®Google Scholar
• Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7(10):3129–3140.
   PubMed Web of Science ®Google Scholar
• Chang YS, Adnane J, Trail PA, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol. 2017;59(5):561–574.
   Google Scholar
• Ito Y, Sasaki Y, Horimoto M, et al. Activation of mitogen-activated protein kinases/extracellular signal-regulated kinases in human hepatocellular carcinoma. Hepatology. 1998;27(4):951–958.
   PubMed Web of Science ®Google Scholar
• Villanueva A, Newell P, Chiang DY, et al. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007;27(1):55–76.
   PubMed Web of Science ®Google Scholar
• Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130(4):1117–1128.
   PubMed Web of Science ®Google Scholar
• Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41(5):864–880.
   PubMed Web of Science ®Google Scholar
• Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhib its tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res. 2006;66(24):11851–11858.
   PubMed Web of Science ®Google Scholar
• Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–134.
   PubMed Web of Science ®Google Scholar
• White PT, Cohen MS. The discovery and development of sorafenib for the treatment of thyroid cancer. Expert Opin Drug Discov. 2015;10(4):427–439.
   PubMed Web of Science ®Google Scholar
• Higuchi Y, Motoki T, Ishida H, et al. Sorafenib treatment for papillary thyroid carcinoma with diffuse lung metastases in a child with autism spectrum disorder: a case report. BMC Cancer. 2017;17(1):775.
   PubMedGoogle Scholar
• Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26(29):4714–4719.
   PubMed Web of Science ®Google Scholar
• Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28(14):2323–2330.
   PubMed Web of Science ®Google Scholar
• Zhu YJ, Zheng B, Wang HY, et al. New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin. 2017;38(5):614–622.
   PubMed Web of Science ®Google Scholar
• Wang XQ, Fan JM, Liu YO, et al. Bioavailability and pharmacokinetics of sorafenib suspension, nanoparticles and nanomatrix for oral administration to rat. Int J Pharm. 2011;419(1–2):339–346.
   PubMedGoogle Scholar
• Grieb BC, Goff LW, Goyal L, et al. Evolving landscape of systemic therapy for hepatocellular carcinoma: breakthroughs, toxicities, and future frontiers. Am Soc Clin Oncol Educ Book. 2019;39:248–260.
   PubMedGoogle Scholar
• Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10(1):25–34.
   PubMed Web of Science ®Google Scholar
• Iyer R, Fetterly G, Lugade A. Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010;11(11):1943–1955.
   PubMed Web of Science ®Google Scholar
• Sahai S, Swick BL. Hyperkeratotic eruption, hand-foot skin reaction, facial erythema, and stomatitis secondary to multi-targeted kinase inhibitor sorafenib. Int J Dermatol. 2010;49(10):1203–1206.
   PubMed Web of Science ®Google Scholar
• Wu S, Chen JJ, Kudelka A, et al. Incidence and risk of hypertension with sorafenib in patients with cancer: a systematic review and meta-analysis. Lancet Oncol. 2008;9(2):117–123.
   PubMed Web of Science ®Google Scholar
• Funakoshi T, Latif A, Galsky MD. Risk of hypertension in cancer patients treated with sorafenib: an updated systematic review and meta-analysis. J Hum Hypertens. 2013;27(10):601–611.
   PubMed Web of Science ®Google Scholar
• Li Y, Li S, Zhu Y, et al. Incidence and risk of sorafenib-induced hypertension: a systematic review and meta-analysis. J Clin Hypertens (Greenwich). 2014;16(3):177–185.
   PubMed Web of Science ®Google Scholar
• Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27(20):3312–3318.
   PubMed Web of Science ®Google Scholar
• Choueiri TK, Schutz FA, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28(13):2280–2285.
   PubMed Web of Science ®Google Scholar
• Stadler WM, Figlin RA, McDermott DF, et al. Safety and efficacy results of the advanced renal cell carcinoma sorafenib expanded access program in North America. Cancer. 2010;116(5):1272–1280.
   PubMed Web of Science ®Google Scholar
• Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676.
   PubMed Web of Science ®Google Scholar
• Chen HX, Cleck JN. Adverse effects of anticancer agents that target the VEGF pathway. Nat Rev Clin Oncol. 2009;6(8):465–477.
   PubMed Web of Science ®Google Scholar
• Gao B, Yeap S, Clements A, et al. Evidence for therapeutic drug monitoring of targeted anticancer therapies. J Clin Oncol. 2012;30(32):4017–4025.
   PubMed Web of Science ®Google Scholar
• Boudou-Rouquette P, Narjoz C, Golmard JL, et al. Early sorafenib-induced toxicity is associated with drug exposure and UGTIA9 genetic polymorphism in patients with solid tumors: a preliminary study. PLoS One. 2012;7(8):e42875.
   PubMed Web of Science ®Google Scholar
• Zhang L, Zhou Q, Ma L, et al. Meta-analysis of dermatological toxicities associated with sorafenib. Clin Exp Dermatol. 2011;36(4):344–350.
   PubMed Web of Science ®Google Scholar
• Zhang HL, Qin XJ, Wang HK, et al. Clinicopathological and prognostic factors for long-term survival in Chinese patients with metastatic renal cell carcinoma treated with sorafenib: a single-center retrospective study. Oncotarget. 2015;6(34):36870–36883.
   PubMedGoogle Scholar
• Gomez P, Lacouture ME. Clinical presentation and management of hand-foot skin reaction associated with sorafenib in combination with cytotoxic chemotherapy: experience in breast cancer. Oncologist. 2011;16(11):1508–1519.
   PubMed Web of Science ®Google Scholar
• Chu D, Lacouture ME, Fillos T, et al. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol. 2008;47(2):176–186.
   PubMed Web of Science ®Google Scholar
• Lee JH, Chung YH, Kim JA, et al. Genetic predisposition of hand-foot skin reaction after sorafenib therapy in patients with hepatocellular carcinoma. Cancer. 2013;119(1):136–142.
   PubMed Web of Science ®Google Scholar
• Beldner M, Jacobson M, Burges GE, et al. Localized palmar-plantar epidermal hyperplasia: a previously undefined dermatologic toxicity to sorafenib. ONCOLOGIST. 2007;12(10):1178–1182.
   PubMed Web of Science ®Google Scholar
• Autier J, Escudier B, Wechsler J, et al. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor. Arch Dermatol. 2008;144(7):886–892.
   PubMed Web of Science ®Google Scholar
• Degen A, Alter M, Schenck F, et al. The hand-foot-syndrome associated with medical tumor therapy–classification and management. Jddg. 2010;8(9):652–661.
   Google Scholar
• Yang CH, Lin WC, Chuang CK, et al. Hand-foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol. 2008;158(3):592–596.
   PubMed Web of Science ®Google Scholar
• Chanprapaph K, Rutnin S, Vachiramon V, et al. Multikinase inhibitor-induced hand-foot skin reaction: a review of clinical presentation, pathogenesis, and management. Am J Clin Dermatol. 2016;17(4):387–402.
   PubMed Web of Science ®Google Scholar
• Common Terminology Criteria for Adverse Events (CTCAE) v4.03. US Department of health and human services. National Institute of Health. National Cancer Institute. 2009 May 28.
   Google Scholar
• Pragasam V, Verma R, Vasudevan B. Sorafenib and sunitinib: A dermatologist’s perspective. Indian Dermatol Online J. 2014;5(1):1–3.
   PubMedGoogle Scholar
• Azad NS, Aragon-Ching JB, Dahut WL, et al. Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy. Clin Cancer Res. 2009;15(4):1411–1416.
   PubMed Web of Science ®Google Scholar
• Chang WT, Lu SN, Rau KM, et al. Increased cumulative doses and appearance of hand-foot skin reaction prolonged progression free survival in sorafenib-treated advanced hepatocellular carcinoma patients. Kaohsiung J Med Sci. 2018;34(7):391–399.
   PubMed Web of Science ®Google Scholar
• Reig M, Torres F, Rodriguez-Lope C, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol. 2014;61(2):318–324.
   PubMed Web of Science ®Google Scholar
• Ponziani FR, Bhoori S, Germini A, et al. Inducing tolerability of adverse events increases sorafenib exposure and optimizes patient’s outcome in advanced hepatocellular carcinoma. Liver Int. 2016;36(7):1033–1042.
   PubMed Web of Science ®Google Scholar
• Wang E, Xia D, Bai W, et al. Tumor hypervascularity and hand-foot-skin reaction predict better outcomes in combination treatment of TACE and Sorafenib for intermediate hepatocellular carcinoma. BMC Cancer. 2019;19(1):409.
   PubMedGoogle Scholar
• Chanprapaph K, Pongcharoen P, Vachiramon V. Cutaneous adverse events of epidermal growth factor receptor inhibitors: A retrospective review of 99 cases. Indian J Dermatol Venereol Leprol. 2015;81(5):547.
   PubMed Web of Science ®Google Scholar
• Liu HB, Wu Y, Lv TF, et al. Skin rash could predict the response to EGFR tyrosine kinase inhibitor and the prognosis for patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS ONE. 2013;8(1):e55128.
   PubMed Web of Science ®Google Scholar
• Lee SW, Lee TY, Yang SS, et al. Specific adverse events predict survival rates in a Chinese population diagnosed with hepatocellular carcinoma and treated with sorafenib. JGH Open. 2018;3(1):10–16.
   PubMed Web of Science ®Google Scholar
• Lacouture ME, Wu S, Cetal R. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008;13(9):1001–1011.
   PubMed Web of Science ®Google Scholar
• Nagore E, Insa A, Sanmartin O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia (‘hand-foot’) syndrome. Incidence, recognition and management. Am J Clin Dermatol. 2000;1(4):225–234.
   PubMedGoogle Scholar
• Jacobi U, Waibler E, Schulze P, et al. Release of doxorubicin in sweat: first step to induce the palmar-plantar erythrodysesthesia syndrome. Ann Oncol. 2005;16(7):1210–1211.
   PubMed Web of Science ®Google Scholar
• Milano G, Etienne-Grimaldi MC, Mari M, et al. Candidate mechanisms for capecitabine-related hand-foot syndrome. Br J Clin Pharmacol. 2008;66(1):88–95.
   PubMed Web of Science ®Google Scholar
• Senapati J, Devasia AJ, Ganapule A, et al. Sorafenib induced hand foot skin rash in FLT3 ITD mutated acute myeloid leukemia-a case report and review of literature. Mediterr J Hematol Infect Dis. 2014;6(1):e2014016.
   PubMedGoogle Scholar
• Morita E, Lee DG, Sugiyama M, et al. Expression of c-kit ligand in human keratinocytes. Arch Dermatol Res. 1994;286(5):273–277.
   PubMed Web of Science ®Google Scholar
• Lammie A, Drobnjak M, Gerald W, et al. Expression of c-kit and kit ligand proteins in normal human tissues. J Histochem Cytochem. 1994;42(11):1417–1425.
   PubMed Web of Science ®Google Scholar
• Jain L, Gardner ER, Figg WD, et al. Lack of association between excretion of sorafenib in sweat and hand-foot skin reaction. Pharmacotherapy. 2010;30(1):52–56.
   PubMed Web of Science ®Google Scholar
• Massey PR, Okman JS, Wilkerson J, et al. Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature. Support Care Cancer. 2015;23(6):1827–1835.
   PubMed Web of Science ®Google Scholar
• Pontén F, Ren Z, Nistér M, et al. Epithelial-stromal interactions in basal cell cancer: the PDGF system. J Invest Dermatol. 1994;102(3):304–309.
   PubMed Web of Science ®Google Scholar
• Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. Faseb J. 2004;18(2):338–340.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Eskens FA, Steeghs N, Verweij J, et al. Phase I dose escalation study of telatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 3, platelet-derived growth factor receptor beta, and c-Kit, in patients with advanced or metastatic solid tumors. J Clin Oncol. 2009;27(25):4169–4176.
   PubMed Web of Science ®Google Scholar
• Lacouture ME, Reilly LM, Gerami P, et al. Hand–foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol. 2008;19(11):1955–1961.
   PubMed Web of Science ®Google Scholar
• Robert C, Soria JC, Spatz A, et al. Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol. 2005;6(7):491–500.
   PubMed Web of Science ®Google Scholar
• Zimmerman EI, Gibson AA, Hu S, et al. Multikinase inhibitors induce cutaneous toxicity through OAT6-mediated uptake and MAP3K7-driven cell death. Cancer Res. 2016;76(1):117–126.
   PubMed Web of Science ®Google Scholar
• Méndez-Blanco C, Fondevila F, García-Palomo A, et al. Sorafenib resistance in hepatocarcinoma: role of hypoxia-inducible factors. Exp Mol Med. 2018;50(10):134.
   PubMedGoogle Scholar
• Iyer RV, Maguire O, Kim M, et al. Dose-dependent sorafenib-induced immunosuppression is associated with aberrant NFAT activation and expression of PD-1 in T cells. Cancers (Basel). 2019;11(5):E681.
   PubMed Web of Science ®Google Scholar
• Wang P, Tan G, Zhu M, et al. Hand-foot skin reaction is a beneficial indicator of sorafenib therapy for patients with hepatocellular carcinoma: a systemic review and meta-analysis. Expert Rev Gastroenterol Hepatol. 2018;12(1):1–8.
   PubMed Web of Science ®Google Scholar
• Le Grazie M, Biagini MR, Tarocchi M, et al. Chemotherapy for hepatocellular carcinoma: the present and the future. World J Hepatol. 2017;9(21):907–920.
   PubMed Web of Science ®Google Scholar
• Zhang W, Cai J, Wu B, et al. pH-responsive hyaluronic acid nanoparticles coloaded with sorafenib and cisplatin for treatment of hepatocellular carcinoma. J Biomater Appl. 2019;34(2):219–228.
   Web of Science ®Google Scholar
• Tovoli F, Ielasi L, Casadei-Gardini A, et al. Management of adverse events with tailored sorafenib dosing prolongs survival of hepatocellular carcinoma patients. J Hepatol. 2019; pii: S0168-8278(19)30482-9. doi:10.1016/j.jhep.2019.08.015. [Epub ahead of print].
   PubMedGoogle Scholar
• Saito K, Ikeda M, Kojima Y, et al. Lipid profiling of pre-treatment plasma reveals biomarker candidates associated with response rates and hand-foot skin reactions in sorafenib-treated patients. Cancer Chemother Phaemacol. 2018;82(4): 677–684.
   PubMed Web of Science ®Google Scholar
• Reig M, Boix L, Torres F, et al. Towards personalised approach in systemic treatment for hepatocellular carcinoma. the value of AGT M235T gene polymorphism. J Hepatol. 2018;68:S197.
   Web of Science ®Google Scholar
• Ren Z, Zhu K, Kang H, et al. 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. 2015;33(8):894–900.
   PubMed Web of Science ®Google Scholar
• ClinicalTrails.gov [Internet]. South Korea Guro: Korea University Guro Hospital; [cited 2019 Oct 30]. Avaliable from: https://clinicaltrials.gov/ct2/show/NCT03212625
   Google Scholar
• Shinohara N, Nonomura N, Eto M, et al. 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. 2014;25(2):472–476.
   PubMed Web of Science ®Google Scholar
• Li M, Su Y, Zhang F, et al. A dual-targeting reconstituted high density lipoprotein leveraging the synergy of sorafenib and antimiRNA21 for enhanced hepatocellular carcinoma therapy. Acta Biomater. 2018;75:413–426.
   PubMed Web of Science ®Google Scholar
• Naganuma A, Hoshino T, Ohno N, et al. ß-hydroxy-ß-methyl butyrate/L-arginine/L-glutamine supplementation for preventing hand–foot skin reaction in sorafenib for advanced hepatocellular carcinoma. In Vivo. 2019;33(1):155–161.
   PubMed Web of Science ®Google Scholar