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Sorafenib-Induced Hand, Foot, and Skin Reaction

David S. Kirwin, BS1 • John F. Linabury, MD2 • Kevin T. Wright, MD2

AFFILIATIONS:
1Yale School of Medicine, New Haven, CT
2Naval Medical Center San Diego, San Diego, CA

CITATION:
Kirwin DS, Linabury JF, Wright KT. Sorafenib-induced hand, foot, and skin reaction. Consultant. 2022;62(11):e7. doi:10.25270/con.2022.06.00006

Received November 2, 2021; accepted November 19, 2021. Published online July 14, 2022.

DISCLOSURES:
The authors report no relevant financial relationships. Drs. Wright and Linabury are a military service members. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the United States Government.” Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.

DISCLAIMER:
The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, or the US Government. The authors report that informed patient consent was obtained for publication of the images used herein.

CORRESPONDENCE:
David S. Kirwin, BS, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06437 (david.kirwin@yale.edu)


ABSTRACT:  

In September 2021, A 27 year-old male came into clinic reporting painful plantar hyperekaratosis. He recently began taking sorafenib, a multi-kinase inhibitor, targeting a desmoid tumor in the patient’s knee. He noticed new acne on his face and back since starting sorafenib. Based on the clinical presentation and relevant history, the patient was diagnosed with sorafenib induced hand foot skin reaction. Hand foot skin reaction is the most common adverse event for tyrosine kinase inhibitors involving the skin, and the adverse event which most often leads to treatment disruption. Based on his symptom severity, the patient’s current keratolytic regimen of urea lotion 10% was increased to urea lotion 40%, per the Common Terminology Criteria for Adverse Events made by the National Cancer Institute. Serendipitously, his sorafenib treatment was terminated around the same time because of ineffective tumor reduction. The keratoses and pain dissipated with sorafenib termination.

 

Case: A 27-year-old man came to the dermatology clinic in September 2021 and reported painful plantar hyperkeratosis.

The patient stated that, in June 2020, he heard a pop in his right knee while running. An orthopedist ordered a magnetic resonance imaging, which showed a 12 x 7 x 9 cm mass in the right popliteal fossa. A biopsy was performed, revealing a desmoid tumor wrapping around the popliteal artery. With the idea of shrinking the tumor before surgery, he was started in January 2021 on sorafenib 400 mg daily.

Occasionally, he used urea lotion 10% with only slight reduction in the thickness of the keratoses. He noticed intermittent skin pruritis since February 2021, shortly after sorafenib initiation. He did not note any nail changes with therapy. He did not have any changes in his chemotherapeutic regimen and was still taking sorafenib 400 mg daily. He denied taking any different chemotherapeutic agents.

The Figure shows the status of the plantar hyperkeratosis when the patient came to the dermatology clinic in September 2021: painful, thick, hyperkeratotic plaques on the bilateral plantar surfaces.

The patient also reported increased redness and bumps on his face since starting sorafenib and reported increased chest and back acne since June 2021. Anticipated completion of his 9-month treatment of sorafenib was in October 2021. Due to lack of tumor response, the patient stopped taking sorafenib in September 2021 instead of October 2021. After cessation of sorafenib, his symptoms and hyperkeratosis resolved.

A diagnosis of sorafenib-induced hand-foot skin reaction (HFSR) was made based on clinical presentation. No biopsy or other diagnostic tests were performed.

Figure. Thick, yellow, callus-like hyperkeratosis on bilateral plantar surfaces, as well as the proximal medial portion of the first toe.

Discussion. The development of targeted chemotherapy like tyrosine kinase inhibitors (TKIs) changed standard anticancer treatment for solid tumors in recent decades. Sorafenib, a multikinase inhibitor (MKI), is used for many tumors such as desmoid tumors (as seen in this patient), renal cell carcinoma (RCC), and hepatocarcinoma. TKIs are better tolerated than typical cytotoxic chemotherapy agents, such as 5-flurouricil or capecitabine, but they come with their own set of side effects. HFSR is the most common adverse event for TKIs involving the skin, and the adverse event that most often leads to treatment disruption.1,2

Estimating the incidence and risk of developing HFSR after taking a TKI is difficult, and data are mixed. Based on large phase 2/3 trials done in recent decades, one study found the incidence of sorafenib-induced HFSR ranged vastly from 10% to 62%.3 In the same study, the incidence of sunitinib-induced HFSR was between 10% and 28%.3 A separate study on regorafenib, also an MKI, found the incidence to be as high as 60.5%.4,5 In a meta-analysis that included almost 25,000 patients, Ding and colleagues6 reported the overall incidence of HFSR due to vascular endothelial growth factor TKIs to be 35%. It is clear the chance of developing HFSR depends on the specific medication used.

Clinical manifestations of HFSR usually appear within 4 weeks of initiation of the culprit medication.7 As the name implies, the palms and soles are classically involved, as well as other areas of consistent friction. The typical appearance of HFSR is callus-like, hyperkeratotic plaques on an erythematous base in areas of friction, including the metatarsals (as seen in this patient), heels (as seen in this patient), the fingertips, and joint surfaces.8

Importantly, HFSR is usually painful, helping to differentiate between other pathologies on the differential diagnosis, which includes tinea pedis and tinea manuum, dyshidrotic eczema, contact dermatitis, and psoriasis. Burning is another typical symptom of HFSR, with lower tolerance to contact with hot surfaces.1 HFSR can present similarly to hand-foot syndrome (HFS). However, HFS is usually caused by cytotoxic chemotherapy agents, whereas HFSR is usually caused by TKIs. HFS is typically more severe and less localized than HFSR. Lastly, HFS has a higher predilection for the palms than the soles, whereas HFSR typically involves the soles more than the palms (as seen in this patient).9

HFSR is a clinical diagnosis. Biopsies are not necessary. Severity grading is assessed by the Common Terminology Criteria for Adverse Events made by the National Cancer Institute. The grade of severity often drives treatment recommendations.

Management of TKI-induced HFSR depends mostly on severity, with consideration to the patient’s need to stay on current chemotherapy and current dose.1,10 Medications to treat HFSR focus on symptoms and include keratolytics for hyperkeratosis, analgesics for pain, and topical corticosteroids for inflammation.5,11 In particular, treating areas of lacerated skin with disinfectants is paramount for these immunocompromised patients. Dose reduction is needed when symptoms significantly affect the patient’s quality of life.12 In alignment with the HFSR grading system, dose reduction is considered for grade 2 HFSR and needed for grade 3 HFSR.5 With proper management, and dose reduction if needed, patients have an excellent recovery and prognosis from sorafenib-induced HFSR.

A silver lining exists for patients with HFSR. There is evidence that development of HFSR leads to better chemotherapeutic outcomes.10 A study by Nakano and colleagues13 in Japan found sorafenib-induced HFSR in metastatic RCC patients was predictive of tumor response and progression-free survival. A separate study done in the Czech Republic found a similar increase in overall survival and progression-free survival among patients with metastatic RCC treated with sunitinib.14

Patient outcome. Our case patient had partial benefit from urea 10% lotion, but we recommended increasing the keratolytic to urea 40% cream as needed. The patient reported 2 months later at a telemedicine follow-up that the urea 40% cream was more effective. At his most recent follow-up in late September 2021, he reported that the sorafenib treatment was terminated because of ineffective tumor reduction. He discussed his options with an oncologist for alternative targeted therapies and more traditional chemotherapeutics before surgical revaluation. The plantar keratoses and painful symptoms resolved with termination of sorafenib, further corroborating the diagnosis of sorafenib-induced hand, foot, skin reaction.

References

1. 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. Oncologist. 2008;13(9):1001-1011. doi:10.1634/theoncologist.2008-0131

2. 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. doi:10.1001/archderm.144.7.886

3. Lipworth AD, Robert C, Zhu AX, Hand-foot syndrome (hand-foot skin reaction, palmar-plantar erythrodysesthesia): focus on sorafenib and sunitinib. Oncology. 2009;77(5):257-271. doi:10.1159/000258880

4. Belum VR, Wu S, Lacouture ME, Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis. Invest New Drugs. 2013;31(4):1078-1086. doi:10.1007/s10637-013-9977-0

5. McLellan B, Ciardiello F, Lacouture ME, Segaert S, Cutsem EV. Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management. Ann Oncol. 2015;26(10):2017-2026. doi:10.1093/annonc/mdv244

6. Ding F, Liu B, Wang Y. 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. 2020;83(3):788-796. doi:10.1016/j.jaad.2019.04.021

7. McLellan B, Kerr H. Cutaneous toxicities of the multikinase inhibitors sorafenib and sunitinib. Dermatol Ther. 2011;24(4):396-400. doi:10.1111/j.1529-8019.2011.01435.x

8. Miller KK, Gorcey L, McLellan BN, Chemotherapy-induced hand-foot syndrome and nail changes: a review of clinical presentation, etiology, pathogenesis, and management. J Am Acad Dermatol. 2014;71(4):787-794. doi:10.1016/j.jaad.2014.03.019

9. Bolognia JL, Schaffer JV, Cerroni L, eds. Chapter 21. Dermatology. 4th ed. Elsevier; 2018:363-368. doi:10.1111/pde.13439  

10. Lacouture B. Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors. UpToDate. Updated Jan 25, 2022. Accessed April 5, 2022. https://www.uptodate.com/contents/hand-foot-skin-reaction-induced-by-multitargeted-tyrosine-kinase-inhibitors

11. Manchen E, Robert C, Porta C. Management of tyrosine kinase inhibitor-induced hand-foot skin reaction: viewpoints from the medical oncologist, dermatologist, and oncology nurse. J Support Oncol. 2011;9(1):13-23. https://doi.org/10.1016/j.suponc.2010.12.007

12. Nardone B, Hensley JR, Kulik L, et al. The effect of hand-foot skin reaction associated with the multikinase inhibitors sorafenib and sunitinib on health-related quality of life. J Drugs Dermatol. 2012;11(11):e61-65.

13. Nakano K, Komatsu K, Kubo T, et al. Hand-foot skin reaction is associated with the clinical outcome in patients with metastatic renal cell carcinoma treated with sorafenib. Jpn J Clin Oncol. 2013;43(10):1023-1029. doi:10.1093/jjco/hyt110

14. Poprach A, Pavlik T, Melichar B, et al. Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study. Ann Oncol. 2012;23(12):3137-3143. doi:10.1093/annonc/mds145