Hand-Foot Skin Reaction with Sunitinib: A Rare Case Report with Review of Literature.

Newer multi-kinase inhibitors (MKI) like sunitinib have changed the therapy of patients of renal cell carcinoma, hepatocellular carcinoma, and gastrointestinal stromal tumor. The use of sunitinib also led to cutaneous toxicity, known as hand-foot skin reaction (HFSR). We report a case of hand-foot skin reaction (HFSR) in an Indian patient being treated with sunitinib. Respective literature on this disorder is also reviewed. Copyright:

Introduction

Adverse cutaneous drug reactions (ACDR) are common in dermatological practice. There are a plethora of newer anticancer drugs though there is limited information on adverse effects of them.

Sunitinib is one of the newer multi-kinase inhibitors (MKI), an important inhibitor of tumor angiogenesis, a selective inhibitor of vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3, platelet-derived growth factor receptor (PDGFR)-β, Raf, FLT-3, and C- kit.[1] It is approved mainly for renal cell carcinoma, hepatocellular carcinoma, and gastrointestinal stromal tumor.[2]

The use of sunitinib also led to cutaneous toxicity, known as hand-foot skin reaction (HFSR), which differs from the hand-foot syndrome (HFS), which is caused by many older cytotoxic drugs.[3] There are few reports stating that sunitinib can produce a hand-foot skin reaction, but the occurrence of that in Indian subcontinent is rare. We report a case of hand-foot skin reaction (HFSR) in an Indian patient being treated with sunitinib. Respective literature on this disorder is also reviewed.

Case Report

A 58-year-old male patient presented in the outpatient with a complaint of eruptions with pain and burning sensation of extremities. He had multiple tender and painful blisters and hyperkeratotic plaques on palms and soles. Yellow-colored callus-like hyperkeratotic plaques were present on the undersurface of the great toes [Figure 1a, 1b], at the palmer aspect of 4th metacarpophalangeal joint [Figure 2a]. Blisters were on sides of 2nd toes and dorsum of one foot - sites likely had friction with chappal footwear [Figure 1c]. Blisters were surrounded by erythema [Figure 1d]. He had ulcerated and crusted lesions on extensor of elbows [Figure 2c], on dorsum of foot [Figure 1c], at lower back just above the gluteal cleft, and mucosal lesions involving angles of the mouth (like angular cheilitis).

Figure 1

a,b- Yellow-colored callus-like hyperkeratotic plaques. c- Blisters are on side of 2nd toes and dorsum of one foot. d- Blister surrounded by erythema

Figure 2

a- Hyperkeratotic plaques. b - Erythema on finger tips. c- Ulcerated and crusted lesions on extensor of elbows. d- Angular cheilitis

The patient had metastatic renal cell carcinoma for that he was on sunitinib therapy. Treatment with sunitinib started 1 month back, 37.5 mg daily for two weeks followed by 50 mg daily. Ten days after dose escalation, these lesions developed and gradually increased in number. The patient complained of pain and burning sensation of limbs also. He was not taking any other drug regularly.

His hemoglobin was 9.5 g%, serum urea was 54.2 mg, and uric acid was 7.90 mg, other parameters were within normal limits. Based on the history and clinical examination, a diagnosis of hand-foot skin reaction (HFSR) was made. Other differential diagnoses were erythromelalgia, graft-versus-host disease, chemotherapy-induced Raynaud's syndrome, erythema multiforme, and other cutaneous drug reactions. We were unable to perform a biopsy as the patient's condition didn't permit. Also, we were unable to do a rechallenge test as the patient did not give consent or was not admitted to our indoor patient department.

He was advised for dose reduction of sunitinib. Also, advised to avoid friction, given vitamin B-complex, topical antibiotics, paraffin, and betamethasone oint. All the lesions became less within 14 days with above management with improvement of physical discomfort also [Figure 3a-e].

Figure 3

a- Subsiding hyperkeratotic lesion and erythema. b- Subsiding crusted lesion. c- Subsiding hyperkeratotic lesion. d- Subsiding blister lesion, leaving minimal change. e- Crusted healed lesion at lower back

Discussion

In hand-foot syndrome caused by traditional chemotherapeutic drugs like 5FU, doxorubicin,[3] or capecitabine (28%–74%), docetaxel, etc.,[3] there is a prodrome of dysesthesia in most of the patients that progresses to a burning pain (which may be severe) followed by well-defined swelling and erythema. The symmetric erythema is more marked over the pads of the distal phalanges. The hands are usually more severely affected than the feet, and rarely, outside the palmer and plantar regions with fine desquamation. Lesions worsen with continued therapy, and after withdrawal, a gradual clearing of symptoms occurs over a period of 2 weeks.[3]

Two new drugs, of multi targeted kinase inhibitor group, sorafenib and sunitinib, have emerged as significant causes of HFS.[3] Here disease is more likely to present as localized patches not only on pressure-bearing aspects of the palms and soles but also on areas that rub against neighboring surfaces, such as the lateral soles and web spaces, in comparison with traditional HFS.[4] Male and female genital involvement is also noted.[5] Several patients on multi targeted kinase inhibitors also developed simultaneous scalp dysesthesia, angular cheilitis, perianal rashes, and facial erythema resembling seborrheic dermatitis, although it was unclear whether these rashes shared common pathogenesis with the concomitant HFS.[3] A bullous variant probably represents a severe form of the syndrome.[3] This group of features coined a separate name—hand-foot skin reaction (HFSR).[4] Our patient developed dysesthesia at the beginning, followed by blisters with surrounding erythema, callus-like blister, or hyperkeratotic plaque. He had lesions on pressure points (sole of feet, elbow), at the same time in areas of friction i.e., sides of toes, undersurface of fingers [Figure 1c, 1d, 2a]. In addition to that, he had angular cheilitis also [Figure 2d]. Lesions on feet were more than on hands, as opined for HFSR caused by sunitinib[3]

Different clinical presentations lead to the discussion of different mechanisms for development of hand foot skin reaction and HFS, one of them is the excretion of the drug through the sweat glands that leads to a high concentration in the areas of the skin around the sweat glands.[4] But significant levels of kinase-inhibitor may not be present in sweat collected from patients' palms.[6] Another theory is hand-foot skin reaction due to multi kinase inhibitor (MKI) may be caused by drug leakage from capillaries damaged by subclinical trauma.[7] This hypothesis was backed by observation like lesions on fingertips produced by the friction of Blackberry handheld device.[8] Our patient also had blisters on the friction areas of footwear or joints.

The diagnosis of HFSR is usually made from the clinical presentation, in those patients with a history of taking MKI drugs.[3]

Time of onset of HFSR is usually between 3–6 weeks of treatment.[3] Our patient also developed lesions near the end of the fourth week. By the Adverse Drug Reaction (ADR) Probability Scale (Naranjo scale), the causality of using sunitinib and the development of HFSR in our patient is probable (score 5).

According to The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI-CTCAE v 4.0)[9] severity of HFSR is up to Grade 3, not life-threatening and is reversible [Table 1].

Table 1

NCI-CTCAE v 4.0 Severity Grade of HFSR

Grade 1	Grade 2	Grade 3
Minimal skin changes or dermatitis (e.g., erythema, edema, or hyperkeratosis) without pain	Skin changes (e.g., peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; limiting instrumental ADL	Severe skin changes (e.g., peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; limiting self care ADL

ADL-Activities of daily living

Using this terminology is helpful in guiding therapeutic decisions as well as communicating with the treating oncologist.

HFSR can significantly impact the quality of life (QoL). For that, dose modification or treatment discontinuation may be required. Furthermore, continuous MKI treatment in Grade 1 or 2 toxicities can progress to Grade 3. So, it is required for clinicians to closely monitor patients receiving MKI with HFSR and be aware of prevention and management strategies that may reduce its incidence, duration, and severity.[10]

Recommendations for treatment are as follows [Table 2].[11]

Table 2

Recommendations for treatment[11]

Grade	Recommendations	Change in dose
Gr-1	Avoid hot water.	Maintain current dose of MKIs
	Use moisturizing cream
	Thick cotton gloves and socks
	20%-40% urea cream
Gr-2	As with grade 1, clobetasol 0.05% ointment. 2% lidocain	Dose reduction of 50% for 7-28 days
Gr-3	Codeine; pregabaline for pain. As per Gr 1 and 2.	Interrupt treatment for 7 days and until improvement

Gr-Grade; MKI-Multikinase inhibitor

Plantar hyperkeratosis is a putative risk factor for HFSR, and controlling them with adequate foot care may help to reduce the development of HFSR,[12] though the debatable, prophylactic application of exfoliating products to the calluses and prophylactic pyridoxine (vitamin B) are in use.[13]

HFSR due to sunitinib is rarely reported from India and to our knowledge, it is the first case of bullous lesion with HFSR patient from India. The incidence of the development of such severe skin reaction is high in the phase III clinical trial, but data from the Indian context is rare.

Patients taking medications that have propensity to develop HFSR should be informed for the potential development of this condition. Awareness about the probability of such reactions helps to counter/prevent/minimize the distressing condition.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.