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 Table of Contents  
CASE REPORT
Year : 2019  |  Volume : 5  |  Issue : 1  |  Page : 34-37

Sorafenib-Induced Cutaneous Toxicities: Four Different Presentations


Department of Skin and V.D, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, Punjab, India

Date of Web Publication22-Jul-2019

Correspondence Address:
Dr. Pooja Bains
Department of Skin and V.D, Sri Guru Ram Das Institute of Medical Sciences and Research, Sri Amritsar, Amritsar, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_36_18

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  Abstract 


Sorafenib is a multikinase inhibitor which is used in the treatment of hepatocellular carcinoma and renal cell carcinoma. The cutaneous toxicities due to sorafenib can affect the daily activities of patients, resulting in interruption or dose modification of therapy. We report four cases of adverse cutaneous effects of sorafenib along with their management. The cases represent the wide spectrum of sorafenib cutaneous toxicities from mild to severe.

Keywords: Cutaneous adverse effect, hand–foot skin reaction, multikinase inhibitor


How to cite this article:
Bains P, Sharma S. Sorafenib-Induced Cutaneous Toxicities: Four Different Presentations. Indian J Drugs Dermatol 2019;5:34-7

How to cite this URL:
Bains P, Sharma S. Sorafenib-Induced Cutaneous Toxicities: Four Different Presentations. Indian J Drugs Dermatol [serial online] 2019 [cited 2019 Aug 21];5:34-7. Available from: http://www.ijdd.in/text.asp?2019/5/1/34/263097




  Introduction Top


Sorafenib is an orally active multikinase inhibitor blocking both tumor cell proliferation and angiogenesis. It selectively inhibits tyrosine protein kinases such as vascular endothelial growth factor (VEGF) receptor-2, 3; platelet-derived growth factor receptor α, β; Raf kinase; c-kit; fms-like tyrosine kinase 3 (FLT3) and rearranged in transformation (RET). This ultimately leads to the inhibition of tumor angiogenesis.[1] It was the first Food and Drug Administration (FDA) approved targeted therapy agent for cytokine-refractory diseases including hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and gastrointestinal stromal tumor (GIST). It is an oral agent administered in the dose of 400 mg BD. Despite its dramatic role as an antitumor drug, it is associated with nonnegligible adverse effects. Some of the documented cutaneous side effects include hand–foot skin reaction (HFSR), genital rash, keratoacanthomas, subungual splinter hemorrhages, alopecia, and pruritus. In a Phase II study, the most common treatment-related adverse events were fatigue (73%), rash/desquamation (66%), HFSR (62%), pain (58%), and diarrhea (58%). Alopecia (53%), stomatitis/pharyngitis (35%), dry skin (23%), flushing (16%), and edema (15%) were other noted side effects.[2] Few cases of erythema multiforme (EM) have also been reported in only 0.1% to <1% of patients.[3]

We report four cases of sorafenib-associated cutaneous adverse effects with a spectrum of presentation varying from mild to severe. Based on the literature search, the first case of Steven–Johnson syndrome (SJS) with sorafenib was reported in 2013 in a patient of metastatic RCC.[4] Another case report of SJS with sorafenib was seen in a patient of HCC, but he was on tosufloxacin concomitantly.[5] This will sensitize dermatologists and oncologists regarding the potential cutaneous adverse effect of sorafenib and aid timely intervention and decrease patient suffering.


  Case Reports Top


Case 1

A 36-year-old male, diagnosed case of HCC on treatment with sorafenib 800 mg/day, was referred to skin outpatient department with the complaints of development of painful lesions on bilateral palms for 7 days. Sorafenib had been started 2 weeks back. On cutaneous examination, few pustular and bullous lesions were present on bilateral palms along with desquamation of skin on the right palm. There was sparing of bilateral soles [Figure 1]. The lesions corresponded to HFSR Grade II. The patient was managed with topical corticosteroid creams, mild keratolytics (salicylic acid 6% twice a day), and moisturizers. There was remission in lesions post 1 week of therapy without any reduction of sorafenib dose.
Figure 1: Sorafenib-induced erythematous patches with central yellow-colored blisters on the left palm and desquamation on the right palm

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Case 2

A 60-year-old male diagnosed case of HCC was treated with 400 mg of sorafenib twice a day. On the 10th day of therapy, the patient developed painful palmoplantar swelling and erythema with well-demarcated bullous plaques on palmoplantar pressure areas [Figure 2]a and [Figure 2]b. The clinical symptoms corresponded to classical features of sorafenib-induced HFSR Grade III. On treatment with topical clobetasol propionate ointment 0.05% in combination with fusidic acid twice daily, skin tenderness abated, and cutaneous lesions resolved into well-demarcated, yellow-to-brown-pigmented hyperkeratotic plaques. The dose of sorafenib was reduced to 200 mg twice a day. The patient was advised to avoid undue stress on palmoplantar pressure areas. There was no recurrence of lesions on continuation of sorafenib at reduced dose.
Figure 2: (a) Erythema and well-demarcated bullous hyperkeratotic plaques over the hand in patient with hepatocellular carcinoma on sorafenib. (b) Well-demarcated yellowish hyperkeratotic plaques and ulceration on the bilateral feet in the same patient

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Case 3

A 56-year-old male diagnosed as having RCC on treatment with 400 mg of sorafenib twice a day for 5 months along with topical treatment for HFSR suddenly had development of painful, nonitchy lesions on bilateral thighs and trunk. On dermatological examination, multiple erythematous slightly scaly, papules, and pustules were appreciated on the bilateral thighs, abdomen, and buttocks [Figure 3]a and [Figure 3]b. A skin biopsy with differential diagnosis of acute generalized exanthematous pustular eruption and psoriasiform eruption was sent for histopathological examination. It was consistent with psoriasiform eruption [Figure 4]. There was no personal or family history of psoriasis in the patient. Sorafenib was stopped, and the patient was treated with topical corticosteroids along with short course of antibiotic injection linezolid 600 mg twice a day for 5 days with relief. Sorafenib was reintroduced at a reduced dose of 200 mg twice a day after the remission of lesions without any adverse effect.
Figure 3: (a) Psoriasiform eruption on the abdomen in a patient of hepatocellular carcinoma on sorafenib. (b) Psoriasiform eruption on thighs in a patient of hepatocellular carcinoma on sorafenib

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Figure 4: Biopsy specimen exhibits psoriasiform hyperplasia in epidermis (H and E, ×100)

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Case 4

A 58-year-old female was referred to skin OPD with the complaint of tender erythematous lesions on the body along with target lesions on the palms and soles for 4 days. She had a history of left radical nephrectomy due to RCC 20 days ago. She was treated with sorafenib 400 mg twice a day. On the 10th day of sorafenib therapy, she developed erythematous macular rash with iris lesions on bilateral extremities. The lesions progressed over 2 days with the development of ulcers in the oral cavity. On dermatological examination, there were erythematous and purpuric macules on trunk, bilateral arms and legs, and target lesions on palms and soles [Figure 5]a and [Figure 5]b. Examination of mucosae revealed ulcers on the bilateral buccal mucosa but sparing of the genital mucosa. Eye examination was normal. Other than sorafenib, no new drugs were administered before the development of lesions. The patient was diagnosed as a case of Erythema multiforme due to sorafenib and admitted for further management. Histological examination of the skin biopsy sent showed a superficial, perivascular lymphocytic infiltrate and a few necrotic keratinocytes. According to the clinical picture and histopathology, the patient was diagnosed as EM, and sorafenib was stopped. The patient was started on intravenous corticosteroids, antihistamines, and topical application of corticosteroid cream (clobetasol propionate) on lesions. Her routine investigations were within normal range. In the initial 2 days of admission, lesions rapidly spread over the whole body and became confluent with newer lesions on trunk, but this was followed by remission and healing of lesions over a period of 1 week. Sorafenib was not reintroduced by oncologist.
Figure 5: (a) Erythematous to purpuric macules present on the abdomen of patient with erythema multiforme due to sorafenib (nephrectomy scar visible). (b) Target lesions present on buttocks and legs in the same patient

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We report four different presentations of cutaneous adverse effects of sorafenib.


  Discussion Top


The common cutaneous side effects of sorafenib include desquamation of skin, HFSR, alopecia, dry skin, seborrheic dermatitis, angular cheilitis, and perianal dermatitis.[6] One of the most common cutaneous side effects, HFSR, is characterized by well-demarcated, tender, erythematous papules, and plaques with blisters or hyperkeratotic, callus-like formations on palmoplantar surfaces, friction prone sites, and distal phalanges.[7] It is graded into three grades according to the level of severity.[7] Grade I has tingling, painless swelling, erythema, or discomfort of the hands/feet without any difficulty in carrying out normal daily activities. Grade II has skin changes including peeling, blisters, bleeding, edema, or hyperkeratosis with pain limiting activities of daily living. Grade III is defined as severe painful hand/foot skin eruptions that prevent the patient from working or performing daily activities. HFSR usually appears during the first 6 weeks of treatment of sorafenib, more commonly as early as 1–2 weeks after treatment is started.[8] It can be managed with topical treatment or dose reduction or discontinuation of sorafenib therapy depending on the severity of eruption. In Case 1, the patient had Grade II HFSR due to sorafenib which was managed without dose reduction of sorafenib, while Case 2 had HFSR Grade III managed with reduction in sorafenib dose to half. Adjuvant topical therapy had to be given in both cases. The lesions responded well to treatment in both cases. These two cases represent the most commonly encountered adverse effect of HFSR (10%–63%)[2] in patients on sorafenib.

Case 3 was a biopsy-proven case of psoriasiform eruption. The temporal relationship between the initiation of sorafenib and onset of cutaneous eruption along with negative personal and family history of psoriasis points toward the diagnosis of sorafenib-induced psoriasiform eruption. The pathogenesis of development of psoriasiform eruption in patients on sorafenib cannot be fully explained and seems paradoxical. Sorafenib blocks the activity of VEGF, a cytokine which is known to be elevated in patients of psoriasis.[9] A theory is that sorafenib might alter the keratinocyte proliferation and differentiation by an unknown mechanism resulting in psoriasiform eruption.[9] The case reports of sorafenib-induced psoriasiform eruption in patients with no prior history of psoriasis are very few in literature, and further research into understanding the mechanism involved is required.[9],[10]

Case 4 was of sorafenib-induced EM in a 58-year-old female of RCC. Sorafenib has a good safety profile, but with the widespread use of this drug, more reports of EM due to sorafenib are seen in the literature.[11],[12] According to a recent Japanese study, EM was reported in 25% of 36 patients.[12] The population-related pharmacogenomics might contribute to the higher rate of adverse events of antitumor agents between patients in Japan and those in other regions.[13] EM and SJS are a Type IV allergy; therefore, sorafenib cannot be readministered to a patient who has this skin rash. Hence, it is important to continue sorafenib therapy while treating any nonallergic skin reaction; however, patients who experience EM induced by sorafenib cannot continue sorafenib. In a case report, on giving challenge with 100 mg of sorafenib after 3 weeks of complete resolution of EM, there was reappearance of rash within 24 h of sorafenib dose.[3] The average duration between sorafenib commencement and onset of lesions, according to various studies, is 8–15 days. In our patient, the rash started on the 10th day of starting treatment, similar to other reported cases. There has been a single case report of EM-like rash with sorafenib from India, in which there was no reappearance of rash on reintroduction of drug.[14] No case report of EM with sorafenib has been reported from India. The appearance of more severe rash has been associated with better treatment outcomes, although we were unable to establish this relationship in our patient as the patient was lost to follow-up. There is a need to study more cases and investigate the incidence of EM in Indian population due to sorafenib and clinician should be aware of this possible complication, so that early interventions can be made.


  Conclusion Top


Since its approval by the FDA, sorafenib has been found to be effective in the treatment of RCC, HCC, and GIST. As dermatologists, we need to be able to recognize the many adverse effects that can be caused by sorafenib. There is a growing need for more closer interaction between oncologists and dermatologists to describe and report newer side effects and accordingly prescribe preventive and curative measures to the patient.

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.



 
  References Top

1.
1. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, 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;64:7099-109.  Back to cited text no. 1
    
2.
Ratain MJ, Eisen T, Stadler WM, Flaherty KT, Kaye SB, Rosner GL, et al. Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2006;24:2505-12.  Back to cited text no. 2
    
3.
MacGregor JL, Silvers DN, Grossman ME, Sherman WH. Sorafenib-induced erythema multiforme. J Am Acad Dermatol 2007;56:527-8.  Back to cited text no. 3
    
4.
Ikeda M, Fujita T, Amoh Y, Mii S, Matsumoto K, Iwamura M, et al. Stevens-Johnson syndrome induced by sorafenib for metastatic renal cell carcinoma. Urol Int 2013;91:482-3.  Back to cited text no. 4
    
5.
Choi MK, Woo HY, Heo J, Cho M, Kim GH, Song GA, et al. Toxic epidermal necrolysis associated with sorafenib and tosufloxacin in a patient with hepatocellular carcinoma. Ann Dermatol 2011;23:S404-7.  Back to cited text no. 5
    
6.
Kong HH, Turner ML. Array of cutaneous adverse effects associated with sorafenib. J Am Acad Dermatol 2009;61:360-1.  Back to cited text no. 6
    
7.
Robert C, Sibaud V, Mateus C, Cherpelis BS. Advances in the management of cutaneous toxicities of targeted therapies. Semin Oncol 2012;39:227-40.  Back to cited text no. 7
    
8.
Porta C, Paglino C, Imarisio I, Bonomi L. Uncovering Pandora's vase: The growing problem of new toxicities from novel anticancer agents. The case of sorafenib and sunitinib. Clin Exp Med 2007;7:127-34.  Back to cited text no. 8
    
9.
González-López MA, González-Vela MC, Yáñez S, Fernández-Llaca H, Val-Bernal JF. Psoriasiform skin eruption associated with sorafenib therapy. Indian J Dermatol Venereol Leprol 2011;77:614-5.  Back to cited text no. 9
    
10.
Diamantis ML, Chon SY. Sorafenib-induced psoriasiform eruption in a patient with metastatic thyroid carcinoma. J Drugs Dermatol 2010;9:169-71.  Back to cited text no. 10
    
11.
Sohn KH, Oh SY, Lim KW, Kim MY, Lee SY, Kang HR, et al. Sorafenib induces delayed-onset cutaneous hypersensitivity: A case series. Allergy Asthma Immunol Res 2015;7:304-7.  Back to cited text no. 11
    
12.
Bilaç C, Müezzinoǧlu T, Ermertcan AT, Kayhan TC, Temeltaş G, Oztürkcan S, et al. Sorafenib-induced erythema multiforme in metastatic renal cell carcinoma. Cutan Ocul Toxicol 2009;28:90-2.  Back to cited text no. 12
    
13.
Kodaira M, Takahashi S, Takeuchi K, Yuasa T, Saotome T, Yonese J, et al. Sorafenib-induced erythema multiforme for metastatic renal cell carcinoma. Ann Oncol 2010;21:1563-5.  Back to cited text no. 13
    
14.
Guliani A, Daroach M, Aggarwal D, Radotra BD, Kumaran MS. Severe hand-foot skin reaction and erythema multiforme-like lesions due to sorafenib. Postgrad Med J 2018;94:535-6.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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