Effective conservative management of locally advanced conjunctival melanoma using initial systemic therapy

Abstract

Conjunctival melanoma (CM) comprises 2% to 5% of all ocular tumours, and 5% to 7% of ocular melanomas. The annual incidence of CM is 0.2 to 0.8 per million amongst Caucasians, in which population the usual age range of presentation is 55 to 65 years. The standard of care for the initial management of localized CM is no-touch surgical excision with a minimum 2 to 4 mm margin. Locally advanced disease involving orbit invasion is more challenging to manage and has traditionally been regarded as an indication for radical curative-intent surgery (orbital exenteration). Here we report a case of locally advanced and recurrent CM that has been managed successfully for the last 3.5 years using systemic targeted therapy. A 53-year-old Caucasian male presented in January 2016 to the ocular oncology unit with a biopsy confirming locally advanced CM (AJCC stage T3B) of the right eye invading the anterior orbit and upper tarsal plate. The tumour had been excised in December 2015. Visual acuities were 6/7.5 and 6/6 in the right and left eye, respectively. Staging investigations including fluorodeoxyglucosepositron emission tomography scanning revealed no metastatic disease. Mutation testing (Ion Torrent Ampliseq Cancer Gene Panel v2.0) of formalin-fixed paraffin-embedded tissue confirmed a classical BRAF (V600E) mutation. During the multidisciplinary discussion, three aspects of the patient's own preferences were identified: first, ocular removal may affect his employment as a licensed occupational operator of heavy equipment; second, satisfactory binocular vision as an enthusiastic recreational cricket player; and third, importance of normal cosmesis for lifestyle reasons. On the other hand, it was explained to the patient that surgical exenteration could well represent the only plausible curative intervention. Against that reasoning, however, it was also conceded that even proceeding to exenteration would not guarantee a cure, since subsequent locoregional and/or metastatic recurrence remained a possibility. After informed discussion and consent, the patient was offered initial management using systemic therapy targeting V600E-mutant BRAF, consisting of dabrafenib and trametinib. Patient understood that the provisional plan would be for substitution of immunotherapy (eg, anti-PD1 plus ipilimumab) with the aim of achieving a further period of long-term control, albeit not necessarily a cure. The possibility of using initial immunotherapy was also discussed, though it was pointed out that a rapid initial tumour shrinkage might be more reliably achieved using mutation-targeting kinase inhibitors, and hence this approach was chosen. Fortunately, a complete clinical and radiologic remission of disease was evident by April 2016 (Figure 1A,B). From May 2016, the clinical course was complicated by drug-related fever and abnormal liver function tests, which was at first managed with a combination of treatment delay, dose reduction, and/or steroid cover. A small recurrence on the upper lid was resected during this period, and histopathology confirmed CM recurrence (Figure 1C). By early 2017, persistent fevers and liver function abnormalities triggered a switch to vemurafenib and cobimetinib, which proved to be better tolerated. Repeat conjunctival biopsies performed on 12 July 2017 showed no histological evidence of melanoma. FDG-PET imaging and clinical review in October 2017 likewise demonstrated no evidence of local or systemic disease. The last review in March 2019 showed no detectable disease both clinically (Figure 1D) and radiologically. The patient remained asymptomatic on the above regimen with visual acuity of 6/7.5 in the affected eye, and eastern cooperative oncology group (ECOG) performance status. This case adds to the limited literature on locally advanced CM managed with systemic treatment. One recent study reported three cases of locally advanced CM initially treated with drugs; molecular testing of one of these patients showed no somatic mutations in BRAF, KIT or NRAS genes, but with a complete response to Received: 15 August 2019 Revised: 4 October 2019 Accepted: 18 November 2019