Prophylactic Approach Prevents Sorafenib-Related Hand-Foot Syndrome

HCC Monitor, April 2015,

A recent phase III clinical trial has offered hope for the prophylactic management of hand-foot skin reaction in patients with hepatocellular carcinoma treated with sorafenib.

A recent phase III clinical trial has offered hope for the prophylactic management of hand-foot skin reaction in patients with hepatocellular carcinoma (HCC) treated with sorafenib (Nexavar),1which remains the only FDA-approved systemic therapy for the treatment of HCC.2

ZhengGang Ren, PhD, and colleagues from the Liver Cancer Institute at the Zhongshan Hospital of Fudan University in Shanghai, China, reported their findings in theJournal of Clinical Oncology.1

HCC is the predominant malignancy affecting the liver, accounting for approximately 85% of primary liver cancers in most regions.3Driven largely by cirrhosis of the liver or viral hepatitis, HCC is more prevalent in countries endemic for hepatitis B virus and hepatitis C virus infections, such as Africa and Asia.4While incidence in the United States has been lower compared with these geographic regions, HCC is still the fastest growing cause of cancer-related death in the United States.5—7Annually, the disease is responsible for more than 500,000 deaths across the globe.4

Less than a decade ago, systemic treatments were largely unavailable for patients affected by this malignancy. This represented a serious gap in clinical care, as many patients with the disease are diagnosed at advanced stages, precluding them from potentially curative treatment options, such as surgical resection or liver transplantation.8

The treatment paradigm shifted dramatically in late 2007, when the multikinase inhibitor sorafenib was approved by the FDA for the frontline treatment of advanced-stage HCC.2This approval was based largely on the results of two major phase III clinical trials.9,10

The use of sorafenib in these pivotal trials was able to significantly extend overall survival and time to progression for patients with advanced HCC.9,10This included a patient population in the Asia-Pacific region, where endemic hepatitis infection contributes to a heavier burden of HCC disease.10

Since 2007, sorafenib has been incorporated as a standard systemic therapy for advanced HCC in patients across the globe.11,12However, this treatment option is not without its challenges, and several important issues remain the focus of further investigation. The successful management of sorafenib-induced side effects in this population remains an important area of concern.

Side Effects Challenging Sorafenib’s Benefit

In a publication in theWorld Journal of Gastroenterology, Catherine Frenette, MD, and Robert Gish, MD, from the California Pacific Medical Center, point out that, “although sorafenib does produce some improvement in survival in HCC patients, the responses are not durable.”13This stresses the importance of balancing risk versus benefit in a setting where “significant dermatologic, gastrointestinal, and metabolic toxicities” are a factor.

“Despite prolonging survival in patients with HCC, the advantages of sorafenib are reduced by its toxicities,” corroborate Ren and colleagues in their recent publication.1These side effects often “severely affect health-related quality of life, including physical, psychological, and social well-being,” they add.

In addition to affecting quality of life from a psychosocial standpoint, side effects commonly lead to reductions in sorafenib dosing or even discontinuation of the drug entirely, which may also lessen its positive effects on survival outcome. As a result, appropriate prophylaxis and side effect management strategies are critical for optimizing patient care.

Some of the most common sorafenib-related side effects, occurring in at least 20% of the patient population, include fatigue, weight loss, diarrhea, anorexia, nausea, and abdominal pain.2Dermatologic side effects also occur frequently with the use of sorafenib, including hand-foot skin reaction (HFSR), rash or desquamation, and alopecia.

Studies have shown that diarrhea is the most commonly reported occurrence, experienced by 55% of patients taking sorafenib, with grade 3 events occurring in 10% of patients.2Among the dermatologic side effects, HFSR is reported most frequently, affecting 21% of patients taking sorafenib overall and reaching grade 3 severity in 8% of patients.

Less frequent side effects may include cardiac ischemia or infarction, reportedly observed in 2.7% of sorafenib-treated patients, compared with 1.3% in placebo-treated controls.2Treatment-emergent hypertension is also more common with sorafenib, where grade 3 hypertension events affecting 4% of treated patients were only experienced in 1% of controls. Elevated serum lipase and hypophosphatemia have also been reported.

A Focus on Hand-Foot Skin Reactions

Of these adverse outcomes, HFSR may not only be one of the most widespread, but also the most critical, as it is among the most common to contribute to early discontinuation of sorafenib use.14According to a recent meta-analysis of 24 clinical trials and over 6000 patients, HFSR occurs in 39% of patients treated with sorafenib for various types of solid tumors.15In 9% of patients, the occurrence of HFSR is deemed high-grade.

In the pivotal phase III trials using sorafenib in the setting of HCC, any grade HFSR was reported at 21% and 45%.9,10Grade 3 events occurred in 8% and 11% of patients, respectively, in these studies. Rates were even greater in 2 recent trials of sorafenib in Asian patients with HCC, where any grade HFSR reached 72% and 82%.16,17Varying incidence rates for this side effect may be influenced by differences in tumor type, patient performance status, gender, or the starting dose in each respective clinical trial.

Symptoms associated with HFSR may become apparent as early as during the first few weeks of therapy. One report documented a median onset of 18.4 days following sorafenib initiation, with a range in development time from 3 days to 8 weeks.18“HFSR usually develops 2 to 4 weeks after initiation of treatment with a tyrosine kinase inhibitor,” noted Ren, “with the risk being highest at 5 weeks, followed by a gradual decline.”1

The onset of symptoms is typically characterized by painful hyperkeratotic lesions on the palms of the hands or soles of the feet, where rings of erythema localize around regions of pressure or flexure.13Keratinocyte necrosis, dermal edema, parakeratosis, and hyperkeratosis are all common manifestations of the disorder.19Patients may experience feelings of tingling, swelling, numbness, and painful blistering or ulceration.

One of the early signs of HFSR, mild hyperkeratosis, may be the only symptom to occur following sorafenib use. Alternatively, HFSR can progress to the point of severely impairing a patient’s ability to carry out activities of daily living.1In either case, no consensus has been reached on the best supportive measures for managing sorafenib-induced HFSR.19,20

Interventions for Sorafenib-Induced HFSR

Studies investigating potential interventions have included the removal of hyperkeratotic tissue, application of emollients or exfoliating agents, limiting the area to hot water exposure, or protecting the feet with well-fitting shoes and cotton socks.15,20In the absence of improvement, reducing the dose of sorafenib or discontinuing use has been recommended, at least until resolution of HFSR to grade 1 or below.21,19

In 2008, an international interdisciplinary panel of experts attempted to establish evidence-based best practices in managing HFSRs to multikinase inhibitors, such as sorafenib.19Their recommendations included the incorporation of over-the-counter and prescription-strength topical agents, such as creams and moisturizers. In particular, creams containing urea have been reportedly useful in offering relief from the hyperkeratotic symptoms of HFSR.19

Although efforts have been made to consolidate recommendations for the management of this condition, measures with documented prophylactic benefit have remained elusive for many years. “Despite relatively high HFSR rates,” noted Ren and colleagues, “the management of HFSR has been reactive rather than proactive.”1

Taking a Proactive Approach

In answer to this shortcoming, Ren and colleagues aimed to systematically test the ability of a topical agent to prevent the onset or severity of sorafenib-induced HFSR in a phase III setting.1Theirs is the first randomized controlled trial evaluating prophylactic methods, applied before the appearance of HFSR-related symptoms in patients being treated for HCC.

In an open-label setting, the authors enrolled nearly 875 patients with advanced HCC, representing populations from 64 treatment centers throughout China. For up to 12 weeks, patients were treated with best supportive care (BSC), either alone or in combination with a 10% urea-based cream (UBC). Treatment began on day 1 of sorafenib therapy and was assessed every 2 weeks thereafter, with a follow-up at 14 weeks. Those who developed HFSR were allowed to begin using therapeutic creams, including UBC, to help mitigate their symptoms.

In addition to monitoring for the onset of HFSR, participants also completed the Hand-Foot Reaction Quality of Life (HF-QoL) questionnaire. This 48-question self-assessment aimed at gathering feedback on the condition of the patient’s hands, feet, and other regions of the body, as well as any impact their symptoms may be having on sleep, mood, social life, and daily activity.

Results demonstrate that the incidence of any grade HFSR was significantly reduced in those patients receiving prophylactic UBC treatment, when compared with BSC alone. An incidence rate of 73.6% for those on BSC was reduced to 56.0% for patients applying the UBC proactively. This was also the case for HFSR events at or exceeding grade 2, where incidence significantly decreased from 29.2% to 20.7% with the addition of UBC.

The preventative use of UBC also prolonged median time to first occurrence of HFSR, from 34 days in patients receiving BSC alone to 84 days in the BSC plus UBC-treated group. A 34% reduction in risk of onset through week 12 was concomitant with improved quality of life. Patient responses on the HF-QoL questionnaire demonstrated that the use of UBC was able to lower symptom burden and reduce the impact of HFSR on daily activities.

Although the underlying mechanisms responsible for sorafenib-associated HFSR remain unknown, the investigators detected a correlation between elevated AST levels and increased risk of HFSR. This association did not, however, minimize the treatment effect achieved with UBC. “Abnormal AST may reflect underlying liver disease in these patients,” the authors noted, “which may interfere with liver metabolism of sorafenib and enhance its plasma concentration.”

Sorafenib response rate and disease control rate were comparable between study groups, indicating that the use of UBC did not alter the efficacy of multikinase inhibitor treatment. Perhaps surprisingly given the beneficial effects observed for those using the UBC, the addition of UBC did not reduce the need for sorafenib dose reduction or interruption.

The relatively short duration of UBC treatment in this study may have been responsible for the lack of improvement in sorafenib discontinuation and other variables. In addition, the patients’ ability to switch from the control group to UBC treatment after the onset of HFSR symptoms may have masked the effects of UBC on these endpoints.

The Future of Sorafenib Side Effect Management in HCC

In their discussion, the authors emphasize that the inability of patients in the control arm to use alternative, non—urea-based creams before the onset of HFSR may have impacted the study results. Due to this study design, it is difficult to say whether the benefits of UBC were a direct result of the urea component, or simply a benefit of applying the cream itself.1This represents an important area of discrimination for the future.

Another potential limitation of the UBC study may be the lack of a central review process to avoid subjective differences during symptom evaluation. Due to the acute nature of HFSR symptom onset, central review was not optimal for patient care in this setting. The nonblinded nature of the study may also be a limitation, and the authors call for additional randomized studies to be performed in a blinded, placebo-controlled manor to further assess the benefits of this prophylactic measure.

Overall, proper side effect management in sorafenib-treated patients with HCC remains an important area of consideration that is “critical for promoting uninterrupted treatment,” noted Dr. Ahmed Kaseb, MD, from the Hepatocellular Carcinoma Program at the University of Texas M.D. Anderson Cancer Center.14Prophylactic measures in these individuals warrant further investigation, where they may continue to aid in reducing the rates and severity of HFSR and other adverse reactions, extending the time before onset of painful symptoms, and improving overall patient quality of life. “With proactive management and diligent follow-up in the early months of therapy,” Kaseb added, “long-term [sorafenib] treatment is feasible.”14


  1. 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.
  2. FDA Approval for Sorafenib Tosylate.Natl Cancer Inst. Accessed March 13, 2015.
  3. El-Serag HB. Epidemiology of hepatocellular carcinoma.Clin Liver Dis. 2001;5(1):87-107.
  4. Cicalese L. Hepatocellular Carcinoma.. Accessed March 24, 2015.
  5. Seeff LB. Introduction: the burden of hepatocellular carcinoma.Gastroenterology. 2004;127(5 suppl 1):S1-S4.
  6. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005.J Clin Oncol. 2009;27(9):1485-1491.
  7. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis.Gastroenterology. 2007;132(7):2557-2576.
  8. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma.Lancet. 2003;362(9399):1907-1917.
  9. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma.N Engl J Med. 2008;359(4):378-390.
  10. Cheng A-L, Kang Y-K, 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.
  11. Bruix J, Sherman M, American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: an update.Hepatol Baltim Md. 2011;53(3):1020-1022.
  12. Song P, Tobe RG, Inagaki Y, et al. The management of hepatocellular carcinoma around the world: a comparison of guidelines from 2001 to 2011.Liver Int. 2012;32(7):1053-1063.
  13. Frenette C, Gish R. Targeted systemic therapies for hepatocellular carcinoma: clinical perspectives, challenges and implications.World J Gastroenterol. 2012;18(6):498-506.
  14. Kaseb AO, Kulik LM. Sorafenib in the Continuum of Care for Hepatocellular Carcinoma: Challenges in Defining Optimal Practice. In: Kaseb A, ed.Hepatocellular Carcinoma - Future Outlook. InTech; 2013. Accessed March 13, 2015.
  15. Zhang T, Ding X, Wei D, et al. Sorafenib improves the survival of patients with advanced hepatocellular carcinoma: a meta-analysis of randomized trials.Anticancer Drugs. 2010;21(3):326-332.
  16. Ogasawara S, Kanai F, Obi S, et al. Safety and tolerance of sorafenib in Japanese patients with advanced hepatocellular carcinoma.Hepatol Int. 2011;5(3):850-856.
  17. Kudo M, Imanaka K, Chida N, et al. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma.Eur J Cancer Oxf Engl 1990. 2011;47(14):2117-2127.
  18. Lee WJ, Lee JL, Chang SE, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib.Br J Dermatol. 2009;161(5):1045-1051.
  19. Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib.The Oncologist. 2008;13(9):1001-1011.
  20. Anderson R, Jatoi A, Robert C, Wood LS, Keating KN, Lacouture ME. Search for evidence-based approaches for the prevention and palliation of hand-foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs).The Oncologist. 2009;14(3):291-302.
  21. Autier J, Escudier B, Wechsler J, Spatz A, Robert C. Prospective study of the cutaneous adverse effects of sorafenib, a novel multikinase inhibitor.Arch Dermatol. 2008;144(7):886-892.