Topical fluorouracil after surgery for ocular surface squamous neoplasia in Kenya: a randomised, double-blind, placebo-controlled trial

Abstract

SummaryBackgroundOcular surface squamous neoplasia (OSSN) is an aggressive eye tumour particularly affecting people with HIV in Africa. Primary treatment is surgical excision; however, tumour recurrence is common. We assessed the effect of fluorouracil 1% eye drops after surgery on recurrence.MethodsWe did this multicentre, randomised, placebo-controlled trial in four centres in Kenya. We enrolled patients with histologically proven OSSN aged at least 18 years. After standard surgical excision, participants were randomly allocated to receive either topical fluorouracil 1% or placebo four times a day for 4 weeks. Randomisation was stratified by surgeon, and participants and trial personnel were masked to assignment. Patients were followed up at 1 month, 3 months, 6 months, and 12 months. The primary outcome was clinical recurrence (supported by histological assessment where available) by 1 year, and analysed by intention to treat. The sample size was recalculated because events were more common than anticipated, and trial enrolment was stopped early. The trial was registered with Pan-African Clinical Trials Registry (PACTR201207000396219).FindingsBetween August, 2012, and July, 2014, we assigned 49 participants to fluorouracil and 49 to placebo. Four participants were lost to follow-up. Recurrences occurred in five (11%) of 47 patients in the fluorouracil group and 17 (36%) of 47 in the placebo group (odds ratio 0·21, 95% CI 0·07–0·63; p=0·01). Adjusting for passive smoking and antiretroviral therapy had little effect (odds ratio 0·23; 95% CI 0·07–0·75; p=0·02). Adverse effects occurred more commonly in the fluorouracil group, although they were transient and mild. Ocular discomfort occurred in 43 of 49 patients in the fluorouracil group versus 36 of 49 in the placebo group, epiphora occurred in 24 versus five, and eyelid skin inflammation occurred in seven versus none.InterpretationTopical fluorouracil after surgery substantially reduced recurrence of OSSN, was well-tolerated, and its use recommended.FundingBritish Council for Prevention of Blindness and the Wellcome Trust.

Extending far and wide: the role of biopsy and staging in the management of ocular surface squamous neoplasia

“…While we, like others, found no significant difference in outcomes between excisional biopsy vs chemotherapy, tumour extent (regardless of depth of invasion or treatment) seemed to play a role—as recurrent or persistent tumours were larger on average than tumours that did not recur. This trend toward larger size in recurrent tumours agrees with prior studies that have shown a significant relationship between increased recurrence and larger baseline tumour diameter …”

“…In our study, we found no significant difference in tumour outcomes when comparing invasive and non‐invasive lesions, even when primary treatment modality was accounted for. This is consistent with larger retrospective studies that found no significant difference in recurrence of invasive vs non‐invasive OSSN tumours . Additionally, a recent multicentre retrospective study demonstrated that tumour stage did not reliably predict initial treatment decisions, as both excision and chemotherapy were successfully utilized as treatment modalities for invasive and non‐invasive lesions, despite their histopathologic differences .…”

“…This trend toward larger size in recurrent tumours agrees with prior studies that have shown a significant relationship between increased recurrence and larger baseline tumour diameter. 20,21 Although the recent AJCC 8th edition staging criteria more strongly emphasize biopsy with histopathologic analysis for the evaluation of OSSN, we found that tumour outcomes were similar regardless of depth of invasion or treatment, and that initial tumour size-rather than histopathologic analysis-may be more useful for understanding potential risk of recurrence and the need for more aggressive management and more cautious follow-up. As our study is limited by its non-randomized, retrospective nature and relatively small sample size, future investigations with larger patient populations and randomized trials would be useful to more extensively evaluate the clinical relevance of the AJCC 8th edition in the diagnosis and management of patients with OSSN.…”

“…This is consistent with larger retrospective studies that found no significant difference in recurrence of invasive vs non-invasive OSSN tumours. 20,21 Additionally, a recent multicentre retrospective study demonstrated that tumour stage did not reliably predict initial treatment decisions, as both excision and chemotherapy were successfully utilized as treatment modalities for invasive and noninvasive lesions, despite their histopathologic differences. 22 Thus, although routine staging and histopathologic analysis of OSSN tumours has been previously recommended in order to guide treatment planning, 15,16 our findings suggest that a biopsy of each tumour in order to determine specific histopathologic characteristics may not be necessary in order to make effective management decisions and achieve reasonable treatment response and cure.…”

Ocular surface squamous neoplasia in HIV-infected patients: current perspectives

“…However, postoperative topical 5-FU drops have been shown to reduce the recurrence of OSSN in HIV patients. 52 , 90 …”