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  Table of Contents  
LETTER TO THE EDITOR
Year : 2014  |  Volume : 5  |  Issue : 1  |  Page : 89-91  

Side effects of Sorafenib and sunitinib: A new concern for dermatologist and oncologist


1 Department of Dermatology, Seth GS Medical College and KEM Hospital, Mumbai, India
2 Department of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, India

Date of Web Publication30-Jan-2014

Correspondence Address:
Uday Khopkar
Department of Dermatology, OPD 117, First Floor, Old OPD Building, Seth GS Medical College and KEM Hospital,
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5178.126049

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How to cite this article:
Gole P, Madke B, Khopkar U, Kumar P, Noronha V, Yadav M. Side effects of Sorafenib and sunitinib: A new concern for dermatologist and oncologist. Indian Dermatol Online J 2014;5:89-91

How to cite this URL:
Gole P, Madke B, Khopkar U, Kumar P, Noronha V, Yadav M. Side effects of Sorafenib and sunitinib: A new concern for dermatologist and oncologist. Indian Dermatol Online J [serial online] 2014 [cited 2019 Aug 17];5:89-91. Available from: http://www.idoj.in/text.asp?2014/5/1/89/126049

Sir,

A plethora of newer anti-cancer drugs with novel mechanisms of action and less well-known side-effect profile has arrived. [1] Adjuvant chemotherapy in patients of solid organ and hematological malignancy with newer anti-cancer agents to maintain the remission has become the standard management protocol. [2] Rapidly growing cells are the collateral targets of chemotherapy, consequently the skin, hair follicles, and nail matrix are frequently affected by chemotherapy. We hereby report the cutaneous toxicity of multikinase inhibitors (MKI) and their management strategy with dose titration of anti-cancer agents, i.e., sorafenib and sunitinib.

Five patients with metastatic renal cell carcinoma with resection of involved kidney (mean age: 58.2 years; range: 43-66 years) were referred to our outpatient department from a tertiary cancer hospital or painful bullous lesions and erosions on palms, soles, and other weight-bearing areas. Out of the five patients, three patients were taking oral sorafenib 400 mg (2 × 200 mg tablets) twice daily and other two were receiving sunitinib 25 mg twice daily. The average period for development of skin toxicity was 3-6 weeks after starting the treatment. The demographic information of the patients regarding age, sex, type of malignancy, and chief dermatological complaints are summarized in [Table 1]. Mucosal involvement was not reported in any patient. Biopsy was obtained from a bulla in all the patients and from a callosity in two patients under local anesthesia after informed consent, fixed in 10% buffered formalin, embedded in paraffin and stained with hematoxylin and eosin (unnecessary) None of the patient gave history of excessive hair loss.
Figure 1: (a and b) Blister on erythematous base seen on volar aspect of palms and fingers

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Table 1: Clinical features of patients with cutaneous drug reaction secondary to anticancer agent (column for duration between start of drug and onset of skin symptoms; column for underlying malignancy not required as all were suffering from renal cell carcinoma - mentioned in starting of article)


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Tender tense vesicles, bullae and erosions on palms, soles, and fingers were seen in all patients [Figure 1]a and b, and two patients had a few bullae on ankles and knees. In patients with long-standing lesions, some of the pressure points showed painful yellowish callosities resembling circumscribed palmoplantar keratoderma. At one or two places, such callosity was seen to form the roof of the blister. Mucosal examination did not reveal any abnormality. Routine blood investigations including complete hemogram, serum biochemistry, and urinalysis were within normal reference limits.

Histopathological examination of the lesion showed upper epidermal multi-loculated blister due to ballooning of keratinocytes [Figure 2]. In one of the biopsies, there was extensive ballooning change throughout the epidermis with necrosis and formation of sub-epidermal blister [Figure 3]. Biopsy form the long-standing callosity-like plaque showed irregular psoriasiform hyperplasia with thickened parakeratotic stratum corneum reflecting a sub-acute eczematous process [Figure 4].
Figure 2: Scanner view of skin biopsy showing ballooning degeneration of the epidermis with lymphocytic infiltrate in the upper part of the dermis (H and E, ×10)

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Figure 3: Epidermis showing hyperplastic changes and broad parakerotosis with interspersed plasma globules and sparse superficial infiltrate of lymphocytes and eosinophils. Parakeratotic layer showing large plasma globules (arrow) with severe pyknotic eosinophils (H and E, ×20)

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Figure 4: Biopsy from callosity-like plaque showing non-specific changes regular acanthosis, broad parakerotosis suggesting a long-standing lesion (H and E, ×20)

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All the patients were advised to avoid pressure on weight-bearing areas and were prescribed potent topical steroid clobetasol propionate (0.05%) ointment to be applied twice a day to affected areas until resolution. The patients were prescribed moisturizing creams and bland emollients for symptomatic relief.

Sunitinib and sorafenib are examples of a new class of anti-cancer agent namely, multi-targeted oral small molecule tyrosine kinase inhibitors, resulting in inhibition of tumor angiogenesis. Pharmacological studies have shown them to be 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. [3]

Currently, sorafenib and sunitinib are approved for treatment of metastatic renal cell carcinoma and unresectable hepatocellular carcinoma. [4],[5] Seborrheic dermatitis-like rash, pruritus, erythema, xerosis, stomatitis, subungual splinter hemorrhages, alopecia, modification of hair growth or pigmentation, skin discoloration, and hand-foot skin reaction have been reported in clinical trials of sorafenib and sunitinib. [6]

Out of all these, hand-foot skin reaction (HFSR; palmar-plantar erythrodysesthesia; acral erythema) is the most symptomatic, as it affects activities of daily living ADL in patients taking oral sorafenib and sunitinib. Other reported side-effects for sorafenib are keratoacanthoma [7],[8] leukocytoclastic vasculitis, [9] squamous cell carcinoma, [10] and alopecia. None of our cases had any other cutaneous adverse effects. HFSR associated with sorafenib and sunitinib therapy affects friction and weight-bearing acral surfaces more focally than the classic hand-foot syndrome, [11] which has been reported with capecitabine [12] cytarabine, 5-fluorouracil, and methotrexate. [13] HFSR secondary to chemotherapy has been graded by National Cancer Institute - Cancer Therapy Evaluation Program under the initiative of ? (NCI- CTCAE v3.0) [Table 2]. [14] (CTCAE expansion to be mentioned: Common Terminology Criteria for Adverse Events version 3.0).
Table 2: Grading of hand-foot skin reaction and suggested management protocol (Quote reference for findings column as it is taken from)


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From the above discussion, it is evident that grade 1 and grade 2 cutaneous reactions do not require discontinuation of treatment as majority of patient will fall in these two grades of reaction. Exact pathogenesis for hand-foot skin reaction due to MKI therapy is yet to be elucidated. Some authors have proposed direct cytotoxic effects of the drug through eccrine sweat glands correlating with acral location of this dermatoses. [15] Treatment strategy includes avoiding friction and weight, using thick cotton gloves and socks, potent topical steroid ointment mixed with moisturizing creams. For disabling pain, oral pregabalin or topical lignocaine (2%) has been advocated. [16]

Sunitinib is yet another multi-targeted tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activities and inhibits VEGFR-2, stem cell factor receptor (c-KIT), fetal liver tyrosine kinase receptor-3, and PDGFR α and β. [17] Cutaneous side-effects include acral erythema and hair depigmentation, most likely due to a direct toxic effect and blockade of stem cell factor or c-kit signaling pathway. Seborrheic dermatitis is another side-effect associated with sunitinib. [18] Hair depigmentation is a known side-effect of sunitinib due to inhibition of melanocyte function through blockage of c-Kit signaling pathway. [19]

Knowledge of dermatological side-effects of newer anti-cancer drugs having molecular specificity will enable the dermatologist and primary care physician to tackle them more efficiently and will allow the medical oncologist to titrate the offending drug in tumor burdened patients. This will aid us in rational management of cutaneous side-effects with obviating the need of withdrawing these potentially life-prolonging medications.

 
   References Top

1.Kamil N, Kamil S, Ahmed SP, Ashraf R, Khurram M, Ali MO. Toxic effects of multiple anticancer drugs on skin. Pak J Pharm Sci 2010;23:7-14.  Back to cited text no. 1
    
2.Alley E, Green R, Schuchter L. Cutaneous toxicities of cancer therapy. Curr Opin Oncol 2002;14:212-6.  Back to cited text no. 2
    
3.Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327-37.  Back to cited text no. 3
    
4.van der Veldt AA, Haanen JB, van den Eertwegh AJ, Boven E. Targeted therapy for renal cell cancer: Current perspectives. Discov Med 2010;10:394-405.  Back to cited text no. 4
    
5.Biró K, Küronya Z. Recent advancements in the treatment of renal cell carcinoma - Focus on international guidelines. Magy Onkol 2010;54:369-76.  Back to cited text no. 5
    
6.Bhojani N, Jeldres C, Patard JJ, Perrotte P, Suardi N, Hutterer G, et al. Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma. Eur Urol 2008;53:917-30.  Back to cited text no. 6
    
7.Kong HH, Cowen EW, Azad NS, Dahut W, Gutierrez M, Turner ML. Keratoacanthomas associated with sorafenib therapy. J Am Acad Dermatol 2007;56:171-2.  Back to cited text no. 7
    
8.Jantzem H, Dupre-Goetghebeur D, Spindler P, Merrer J. Sorafenib-induced multiple eruptive keratoacanthomas. Ann Dermatol Venereol 2009;136:894-7.  Back to cited text no. 8
    
9.Chung NM, Gutierrez M, Turner ML. Leukocytoclastic vasculitis masquerading as hand-foot syndrome in a patient treated with sorafenib. Arch Dermatol 2006;142:1510-1.  Back to cited text no. 9
    
10.Dubauskas Z, Kunishige J, Prieto VG, Jonasch E, Hwu P, Tannir NM. Cutaneous squamous cell carcinoma and inflammation of actinic keratoses associated with sorafenib. Clin Genitourin Cancer 2009;7:20-3.  Back to cited text no. 10
    
11.Lee WJ, Lee JL, Chang SE, Lee MW, Kang YK, Choi JH, et al. Cutaneous adverse effects in patients treated with the multitargeted kinase inhibitors sorafenib and sunitinib. Br J Dermatol 2009;161:1045-51.  Back to cited text no. 11
    
12.Vasudevan B. An unusual case of capecitabine hyperpigmentation: Is hyperpigmentation a part of hand-foot syndrome or a separate entity? Indian J Pharmacol 2010;42:326-8.  Back to cited text no. 12
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13.Nagore E, Insa A, Sanmartín O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia ('hand-foot') syndrome. Incidence, recognition and management. Am J Clin Dermatol 2000;1:225-34.  Back to cited text no. 13
    
14.National Cancer Institute. Common terminology criteria for adverse events v3.0. Available from: http://www.ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. [Last accessed 2011 Feb 12].  Back to cited text no. 14
    
15.Lai SE, Kuzel T, Lacouture ME. Hand-foot and stump syndrome to sorafenib. J Clin Oncol 2007;25:341-3.  Back to cited text no. 15
    
16.Lacouture ME, Wu S, Robert C, Atkins MB, Kong HH, Guitart J, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 2008;13:1001-11.   Back to cited text no. 16
    
17.Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003;2:471-8.  Back to cited text no. 17
    
18.Yang CH, Lin WC, Chuang CK, Chang YC, Pang ST, Lin YC, et al. Hand-foot skin reaction in patients treated with sorafenib: A clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol 2008;158:592-6.  Back to cited text no. 18
    
19.Moss KG, Toner GC, Cherrington JM, Mendel DB, Laird AD. Hair depigmentation is a biological readout for pharmacological inhibition of KIT in mice and humans. J Pharmacol Exp Ther 2003;307:476-80.  Back to cited text no. 19
    


    Figures

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

  [Table 1], [Table 2]


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