Cutaneous Vasculopathy As an Adverse Effect of the Anti–Vascular

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OBSERVATION and several erosions (Figure 1). A punch biopsy was per- formed, and histologic analysis revealed a perivascular pre- Cutaneous Vasculopathy as an Adverse Effect dominantly lymphocytic infiltrate in the dermis and subcu- of the Anti–Vascular Endothelial Growth Factor tis (Figure 2A) as well as focal hemosiderin deposition and Agent Axitinib extravasated erythrocytes. The infiltrate was focally dense Axitinib is a targeted chemotherapeutic agent against the with lymphocytes within the vascular walls (Figure 2B), vascular endothelial growth factor (VEGF) receptor pathway. suggestive of a lymphocytic vasculopathy. Laboratory Cutaneous toxic effects of these newer targeted therapies are workup for other thrombotic, embolic, or vasculitic causes increasingly being recognized. Herein we present a case of was unrevealing. cutaneous vasculopathy associated with axitinib. His ulcerations were treated symptomatically with pet- rolatum ointment and occlusive dressings, topical lidocaine ReportofaCase| A white man in his 50s with metastatic renal ointment, and silver sulfadiazine cream but with minimal cell carcinoma presented 6 months after starting axitinib improvement. He was started on a prednisone taper, which therapy with painful lesions and discoloration on both feet. was discontinued owing to lack of improvement, as well as 1 He reported a burning sensation, exacerbated by prolonged week of strict bed rest and leg elevation. His lesions wors- periods of standing. On examination, he was found to have ened, showing increased discoloration, formation of new reticulated purpuric patches over the medial aspects of both bullae, and progression of erosions into deep painful ulcer- feet and the interdigital web spaces, with associated edema ations. The decision was made to hold axitinib treatment and initiate an empirical trial regimen of nifedipine, 20 mg, Figure 1. Cutaneous Lesions of the Left Foot in a Patient Receiving 3 times daily, and this was followed by slow improvement in Axitinib Therapy the lesions over the next month. The patient was rechal- lenged with axitinib, but 2 weeks later the lesions recurred, and so axitinib therapy was discontinued permanently. The lesions completely resolved over the next few weeks. The patient was subsequently started on ipilimumab therapy without recurrence of cutaneous symptoms.

Discussion | Axitinib is a selective inhibitor against the VEGF receptor, approved for the treatment of metastatic renal cell carcinoma after failure of prior systemic therapy. Other well- established inhibitors with activity against VEGF include sorafenib and sunitinib. Adverse effects associated with these agents include hypertension, diarrhea, fatigue, hand- Initial presentation of reticulated, purpuric patches and associated edema that foot skin reaction (HFSR), and eruption.1 By far, the most affected both feet. common cutaneous toxic effect is HFSR, which occurs in

Figure 2. Histopathologic Specimens From Left Medial Foot Lesion in a Patient Receiving Axitinib Therapy

A Original magnification ×10 B Original magnification ×40

Hematoxylin-eosin–stained specimens show partial epidermal necrosis with parakeratosis, dermal fibrosis, perivascular lymphocytic infiltrate, and extravasated erythrocytes (A) and prominent perivascular lymphocytic infiltrate with lymphocytes within the vascular wall (B).

222 JAMA Dermatology February 2016 Volume 152, Number 2 (Reprinted) jamadermatology.com

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approximately 20% to 30% of patients.1,2 Characteristically, 5. Jain L, Sissung TM, Danesi R, et al. Hypertension and hand-foot skin HFSR presents as painful, hyperkeratotic, erythematous reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib. J Exp Clin Cancer Res. 2010;29:95. plaques on the palms and soles in areas subject to increased 6. Kiuru M, Schwartz M, Magro C. Cutaneous thrombogenic vasculopathy pressure. Other mucocutaneous effects described with anti- associated with bevacizumab therapy. Dermatol Online J. 2014;20(6): VEGF agents include keratoacanthoma, squamous cell carci- 13030/qt41f655g9. noma, splinter subungual hemorrhages, hair depigmenta- tion, and stomatitis.2 Both systemic and cutaneous toxic effects of axitinib are Intermittent Vismodegib Therapy consistent with other agents in the same class, with a signifi- in Basal Cell Nevus Syndrome cant incidence of HFSR.3,4 Hand-foot skin reaction has been The use of intermittent vismodegib therapy is a promising and proposed to result from blockade of VEGF receptor and platelet- sustainable medical alternative to the current mainstream sur- derived growth factor receptor in areas repeatedly subject to gical management of basal cell nevus syndrome (BCNS). We subclinical trauma, disrupting normal vascular repair pro- report our clinical experience with intermittent vismodegib cesses in fibroblasts and endothelial cells.4 While the acral le- therapy in 2 patients with BCNS. sions in the present patient were distinct from HFSR, it is pos- sible that a similar process was responsible. Inhibition of VEGF Report of Cases | Patient 1 is a white man in his 40s, and patient leads to increased vascular tone,1 and so dysregulated vaso- 2 is a white woman in her 50s. Vismodegib therapy was started constriction in the skin may disrupt normal tissue repair.4 In- in both cases because the basal cell carcinoma (BCC) lesions deed, hypertension in patients treated with concurrent in both patients were becoming more aggressive, were appear- sorafenib and bevacizumab, a monoclonal antibody against ing more frequently, and could not be managed as easily with VEGF, was found to be a risk factor for developing HFSR.5 Va- surgical and other nonsurgical treatments. sodilatory agents such as nifedipine may therefore be useful The intermittent vismodegib dosing was first adminis- for both hypertension and cutaneous lesions. One patient tered to patient 1 circumstantially; adverse effects in his case treated with bevacizumab developed hemorrhagic ulcers and resulted in patient noncompliance with the prescribed non- purpuric patches on the lower legs, termed thrombogenic intermittent regimen. However, the dramatic improvement vasculopathy,6 further supporting a direct VEGF-mediated ef- prompted us to suggest intermittent therapy to both fect. In the midst of continued characterization of toxic ef- patients. The Table contains the dosing regimen, number of fects profiles of newer oncologic agents, our case represents BCCs before and after vismodegib therapy, and adverse a distinct cutaneous vasculopathy associated with the anti- effects. Both patients agreed to a lifelong intermittent vis- VEGF agent axitinib. modegib regimen but not lifelong continuous daily therapy owing to its adverse effects. The dosing interval was indi- Veronica J. Shi, BA vidualized to adverse-effect tolerability and so differs Anjela Galan, MD between our patients. Ian D. Odell, MD, PhD Jennifer N. Choi, MD Discussion | An autosomal dominant disorder, BCNS is typi- cally due to mutation of the PTCH1 tumor suppressor gene, re- Author Affiliations: Department of Dermatology, Yale University School of sulting in uncontrolled upregulation of the sonic hedgehog Medicine, New Haven, Connecticut (Shi, Galan, Odell, Choi); Department of pathway and carcinogenesis. Although surgical excisions of- Pathology, Yale University School of Medicine, New Haven, Connecticut (Galan). fer the highest cure rate and lowest rate of recurrence, the on- Corresponding Author: Jennifer N. Choi, MD, Department of Dermatology, going repetitive traumatic procedures cause cosmetic disfig- Yale University School of Medicine, 333 Cedar St, Laboratory for Medicine and Pediatrics 5040, New Haven, CT 06510 ([email protected]). urement and lower patients’ quality of life. Vismodegib is an oral smoothened antagonist approved in Published Online: October 28, 2015. doi:10.1001/jamadermatol.2015.3209. 2012 by the US Food and Drug Administration for metastatic, Conflict of Interest Disclosures: None reported. locally advanced, or inoperable BCC. The adverse effects in- Additional Contributions: We are indebted to Edward W. Cowen, MD, MHSc, Dermatology Branch, Center for Cancer Research, National Cancer Institute, clude muscle spasms, alopecia, dysgeusia, weight loss, fa- National Institutes of Health, Bethesda, Maryland, for discussion and tigue, nausea, and constipation. In addition, vismodegib is comments on the manuscript. Dr Cowen received no compensation for his embryotoxic and teratogenic. Barrier contraception was rec- contributions. ommended to our patients during and for 7 months after treat- 1. Cohen RB, Oudard S. Antiangiogenic therapy for advanced renal cell ment, and a second method of contraception was advised for carcinoma: management of treatment-related toxicities. Invest New Drugs. 2012;30(5):2066-2079. our female patient. 1 2. Ishak RS, Aad SA, Kyei A, Farhat FS. Cutaneous manifestations of Tang et al reported a dropout rate of 54% owing to anti-angiogenic therapy in oncology: review with focus on VEGF inhibitors. Crit adverse effects in a study of vismodegib treatment for Rev Oncol Hematol. 2014;90(2):152-164. patients with BCNS. The concept of drug holiday is sup- 3. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib ported by Ally et al,2 who found that 2 of 3 patients who took versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase a 3-month break from vismodegib therapy had similar effi- 3 trial. Lancet. 2011;378(9807):1931-1939. cacy of odontogenic cyst shrinkage compared with patients 4. Fischer A, Wu S, Ho AL, Lacouture ME. The risk of hand-foot skin reaction to axitinib, a novel VEGF inhibitor: a systematic review of literature and undergoing continuous vismodegib treatment. The intermit- meta-analysis. Invest New Drugs. 2013;31(3):787-797. tent regimen was better tolerated vis-à-vis muscle cramps

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