Risk of hand-foot skin reaction with sorafenib: A systematic review and meta-analysis

Background. Hand-foot skin reaction (HFSR) is a dose-limiting toxicity associated with sorafenib, an oral multi-kinase inhibitor with clinical activity against solid tumors. This study was conducted to determine the risk of developing HFSR among patients receiving sorafenib. Patients and Methods. Databases from Pubmed, Web of Science, and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through July, 2007 were searched to identify relevant studies. Eligible studies were prospective clinical trials using single agent sorafenib. The summary incidence rate and the relative risk (RR) were calculated using random-effects model. Results. A total of 4 883 patients in 11 trials with metastatic tumors were included for analysis. Among patients receiving sorafenib, the summary incidence of all-grade HFSR was 33.8% (95% CI: 24.5–44.7%) with significant difference between patients with RCC and non-RCC malignancy (RR 1.52, 95% CI: 1.32–1.75%, p<0.001). The incidence of high-grade HFSR was 8.9% (95% CI: 7.3–10.7%). In addition, sorafenib was associated with a significant increased risk of HFSR with RR of 6.6 (95% CI: 3.7 to 11.7, p<0.001) in comparison with controls. Conclusion. There is a significant risk of HFSR associated with sorafenib. Proper management and further study are recommended to reduce the risk.

[1]  Bonnie-Mae Gerbrecht.  Current Canadian Experience With Capecitabine: Partnering With Patients to Optimize Therapy , 2003, Cancer nursing.

[2]  P. Russo.  Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma , 2006 .

[3]  J. Verweij,et al.  The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. , 2006, European journal of cancer.

[4]  M. Ratain,et al.  Phase I study of pegylated liposomal doxorubicin, paclitaxel, and cisplatin in patients with advanced solid tumors. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  F. Pontén,et al.  Epithelial-stromal interactions in basal cell cancer: the PDGF system. , 1993, The Journal of investigative dermatology.

[6]  D. Miller,et al.  Oral dexamethasone attenuates Doxil-induced palmar-plantar erythrodysesthesias in patients with recurrent gynecologic malignancies. , 2004, Gynecologic oncology.

[7]  Jeffrey S. Morris,et al.  Effect of celecoxib on capecitabine-induced hand-foot syndrome and antitumor activity. , 2002, Oncology.

[8]  T. Kuo,et al.  Hand-foot syndrome and seborrheic dermatitis-like rash induced by sunitinib in a patient with advanced renal cell carcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Dirk Strumberg,et al.  Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  S. Wilhelm,et al.  BAY 43-9006: preclinical data. , 2002, Current pharmaceutical design.

[11]  R. Figlin,et al.  The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial in North America: Safety and efficacy , 2007 .

[12]  M. Ratain,et al.  Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis , 2006, British Journal of Cancer.

[13]  G. Scambia,et al.  Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia ('hand-foot' syndrome). , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[14]  H. Tilg,et al.  The kinase inhibitor imatinib--an immunosuppressive drug? , 2007, Current cancer drug targets.

[15]  R. Lloyd,et al.  MC044h, a phase II trial of sorafenib in patients (pts) with metastatic neuroendocrine tumors (NET): A Phase II Consortium (P2C) study , 2007 .

[16]  B. Schwartz,et al.  Phase I study of BAY 43-9006 (sorafenib), a Raf kinase and VEGFR inhibitor, combined with irinotecan (CPT-11) in advanced solid tumors , 2005 .

[17]  L. Ellis,et al.  Angiopoietins and their role in colon cancer angiogenesis. , 2002, Oncology.

[18]  E. Kohn,et al.  Increased efficacy and toxicity with combination anti-VEGF therapy using sorafenib and bevacizumab. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  M. Buyse,et al.  Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factors. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  N. Normanno,et al.  Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. , 2006, The oncologist.

[21]  W. Gerald,et al.  Expression of c-kit and kit ligand proteins in normal human tissues. , 1994, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[22]  R. Figlin,et al.  Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. , 2007, The New England journal of medicine.

[23]  M. Lacouture,et al.  Hand-foot and stump syndrome to sorafenib. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  J. Hainsworth,et al.  Bevacizumab, erlotinib, and imatinib in the treatment of patients (pts) with advanced renal cell carcinoma (RCC): A Minnie Pearl Cancer Research Network phase I/II trial , 2005 .

[25]  O. Garrone,et al.  Topical dimethylsulfoxide for the prevention of soft tissue injury after extravasation of vesicant cytotoxic drugs: a prospective clinical study. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  D. Strumberg,et al.  Pooled safety analysis of BAY 43-9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome? , 2006, European journal of cancer.

[27]  Agustin A. Garcia,et al.  Bevacizumab in the management of solid tumors , 2007, Expert review of anticancer therapy.

[28]  J. Ioannidis,et al.  Quantitative Synthesis in Systematic Reviews , 1997, Annals of Internal Medicine.

[29]  M. Sugiyama,et al.  Expression of c-kit ligand in human keratinocytes , 1993, Archives of Dermatological Research.

[30]  Fergal J. Moloney,et al.  The frequency and significance of thiopurine S‐methyltransferase gene polymorphisms in azathioprine‐treated renal transplant recipients , 2006, The British journal of dermatology.

[31]  J. Llovet,et al.  Sorafenib Improves Survival in Hepatocellular Carcinoma: Results of a Phase 3 Randomized, Placebo-Controlled Trial , 2007 .

[32]  C. Fabian,et al.  Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion , 1990, Investigational New Drugs.

[33]  D. Amadori,et al.  Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  E. Rock,et al.  Approval Summary: Sunitinib for the Treatment of Imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma , 2007, Clinical Cancer Research.

[35]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[36]  J. Lademann,et al.  Release of doxorubicin in sweat: first step to induce the palmar-plantar erythrodysesthesia syndrome? , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  M. Erkişi,et al.  Palmar-plantar erythrodysesthesia due to docetaxel-capecitabine therapy is treated with vitamin E without dose reduction. , 2006, Breast.

[38]  Peter Vajkoczy,et al.  Combined inhibition of VEGF‐ and PDGF‐signaling enforces tumor vessel regression by interfering with pericyte‐mediated endothelial cell survival mechanisms , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  N. Laird,et al.  Meta-analysis in clinical trials. , 1986, Controlled clinical trials.

[40]  J. Lokich,et al.  Chemotherapy-associated palmar-plantar erythrodysesthesia syndrome. , 1984, Annals of internal medicine.

[41]  Alain Spatz,et al.  Cutaneous side-effects of kinase inhibitors and blocking antibodies. , 2005, The Lancet. Oncology.

[42]  W. Burgdorf,et al.  Peculiar acral erythema secondary to high-dose chemotherapy for acute myelogenous leukemia. , 1982, Annals of internal medicine.

[43]  D. Frye,et al.  Capecitabine: nursing implications of a new oral chemotherapeutic agent. , 1999, Oncology nursing forum.

[44]  D. V. Von Hoff,et al.  Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with taxotere. , 1993, Journal of the National Cancer Institute.

[45]  M. Gore,et al.  Phase I trial of BAY 43-9006 (sorafenib) combined with dacarbazine (DTIC) in metastatic melanoma patients , 2005 .