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Review Ocular Oncology Non-surgical Drug Therapy for Locally Advanced Periocular Cancer Margaret L Pfeiffer, 1,2 Omar Ozgur, 1 and Bita Esmaeli 1 1. Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, US; 2. Ruiz Department of Ophthalmology and Visual Science, The University of Texas Medical School at Houston, Houston, Texas, US T argeted treatment with sonic hedgehog inhibitors for locally advanced basal cell carcinoma (BCC) has significantly improved our ability to preserve ocular function and avoid orbital exenteration in patients with locally advanced BCC of orbital and perioribtal area. Epidermal growth factor receptor inhibitors can be considered as non-surgical treatment in elderly patients with locally advanced or metastatic squamous carcinoma of the orbit who are not good candidates for surgery. Topical application of imiquimod in the periocular region can be considered for cases of recurrent in situ lentigo maligna; however, an intense soft tissue reaction and conjunctival and eyelid injection and irritation are expected side effects. Keywords Basal cell carcinoma, squamous cell carcinoma, targeted therapy, vismodegib, erlotinib Disclosure: Margaret L Pfeiffer, Omar Ozgur and Bita Esmaeli have nothing to declare in relation to this article. No funding was received in the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: May 29, 2016 Accepted: August 21, 2016 Citation: US Ophthalmic Review, 2016;9(2):97–9 Corresponding Author: Bita Esmaeli, Orbital Oncology & Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1488, Houston, Texas 77030, US. E: Medical therapies for periocular tumors are emerging as alternatives to traditional surgical excision and radiation. These relatively new drugs are good options in patients who are unable or unwilling to undergo surgery, with locally advanced lesions, or, as in the case of basal cell nevus syndrome, with multitudes of large symptomatic tumor burden. Targeted drugs that are currently approved by the US Food and Drug Administration (FDA) include hedgehog pathway inhibitors for basal cell carcinoma (BCC), epidermal growth factor receptor (EGFR) inhibitors for squamous cell carcinoma (SCC), and topical agents such as imiquimod and 5-fluorouracil for BCC, SCC, and lentigo maligna melanoma. Here we discuss the current evidence for the use of these drugs in the periocular region. Hedgehog pathway inhibitors for basal cell carcinoma The hedgehog pathway is involved in fetal development and postnatal tissue regulation and has been identified as pathogenic in BCC. Mutations in the Patched-1 transmembrane receptor and a downstream receptor, smoothened, have been implicated in sporadic BCC and in basal cell nevus syndrome and lead to cellular proliferation, tumorigenesis, and angiogenesis. 1 Two targeted hedgehog pathway inhibitors are approved by the FDA for treatment of locally advanced or metastatic BCC: vismodegib and sonidegib. Although no reports exist about the use of sonidegibin periocular BCC, vismodegib has been successfully used and reported in several series of patients with locally advanced or metastatic periocular BCC or with basal cell nevus syndrome with symptomatic periocular lesions. These studies used the approved oral dose of 150 mg daily. In the three largest series, a majority of patients had some response to treatment. 2–4 Taken in aggregate, these studies reported results in 27 patients. Twenty-four had locally advanced periocular BCC, and three had basal cell nevus syndrome with symptomatic periocular lesions. Of these patients, 13 (48%) had a complete response, 14 (52%) had a partial response, three (11%) had stabilization of disease, and one progressed. Two patients with initial responses—one complete, one stable—later developed progressive disease at 38 and 16 months after starting treatment, respectively. The definitions of partial response differed in each paper: in one, response was quantified by percentage change lesion size (reported at 15–90%), 2 in the second, defined as at least a 30% decrease in the sum of diameters of target lesions, taking as a reference the baseline sum of diameters; 3 and, in the third, ‘at least 40% decrease in tumor size on clinical and/or radiologic evaluation.’ 4 A complete response had disappearance of all target lesions. 2–4 Follow-up ranged in these studies from a mean of 7.3 to 12.5 months. 2–3 Adverse events are commonly reported with vismodegib use. In the pivotal study that led to FDA approval of vismodegib for BCC, all 104 patients experienced adverse events. These were categorized as mild to moderate in half of the patients and included muscle spasms (71.2%), alopecia (65.4%), dysgeusia (53.8%), anorexia (50.0%), fatigue (40.4%), and nausea (32.7%). 5,6 The common adverse TOU CH MED ICA L MEDIA 97