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The experience of moving from doing an 'empty review' to a pioneer trial

Tuesday, 25 Oct 2016

In this news item, Dr Stephen Gichuhi of the University of Nairobi describes how authorship of a Cochrane Review led to his identification of an important knowledge gap in the management of ocular surface squamous neoplasia disease and his research to address it.

In 2005, I was invited to attend the first Reviews for Africa Programme (RAP) at Cochrane South Africa. One had to prepare a topic related to HIV/AIDS beforehand. There was no shortage of questions around ocular HIV-related conditions. One, in particular, bothered me a lot. We saw far too many tumours of the conjunctiva, the thin membrane that covers the white of the eye. Working in the national referral hospital also meant that we received the worst of them; late and large. Surgical excision was the mainstay of treatment but recurrence was an issue. Large tumours needed radical surgery such as enucleation (removal of the eyeball) or exenteration that involves removing the eye and all the orbital contents - the outcome is usually unsightly. I didn’t enjoy doing this operation. I went into ophthalmology to save eyes and restore vision. Here, we were losing.

I found no randomized controlled trials in people living with HIV. We were treating a serious disease based on case reports and case series, the lowest level of evidence in the evidence hierarchy.  It was difficult to draw conclusions from these reports. Doses varied widely, inclusion criteria varied, there were no comparison groups so bias could not be ruled out. I was disheartened to write an ‘empty review’ but was encouraged by Jimmy Volmink and others that this was a significant finding in that we had identified a knowledge gap.

After the review was published in 2007, I started thinking about doing a trial in Africa. In 2011 I got funding from the British Council for Prevention of Blindness through the Sir John Wilson Fellowship. This would allow me to do a PhD at the London School of Hygiene and Tropical Medicine and conduct a series of integrated studies on ocular surface squamous neoplasia (OSSN) in Kenya. We set off in earnest working in four eye-care centres in different regions of Kenya. The enthusiasm of clinicians in my country and study participants was a great boost. Everyone who heard about this project couldn’t wait for the results. It touched on something that clearly concerned them. Most textbooks we read referred to this as a rare disease of elderly men but in Africa it was different. We had the highest incidence in the world. Over two thirds (67%) of affected patients were women, young (mean age 41 years) and 74% were living with HIV. OSSN is an orphan disease that hardly received attention from both HIV programmes and eye care programmes. As it usually only affects one eye it is not an important cause of blindness. HIV health worker training programmes hardly mentioned OSSN.

The PhD project consisted of a series of six integrated studies on the epidemiology and management of OSSN. We conducted a systematic review of the epidemiology of OSSN in Africa and in 2013 updated the 2007 Cochrane review where we found one cross-over trial of mitomycin C (MMC) but it enrolled elderly males who were probably uninfected with HIV. We conducted a randomised placebo-controlled trial of 5-Fluorouracil (5FU) chemotherapy eye drops given after surgery to investigate if this could reduce the recurrence of the lesions. The trial results were astounding. Post-operative topical 5FU substantially reduced recurrence of OSSN and was well-tolerated.  Treatment with 5FU was associated with fewer OSSN recurrences (10.6% versus 36.2%) than placebo (odds ratio 0.21, 95% confidence interval 0·07 to 0·63, P = 0·01).

The results were recently published in The Lancet Global Health (Gichuhi S, Macharia E, Kabiru J, et al. Topical fluorouracil after surgery for ocular surface squamous neoplasia in Kenya: a randomised, double-blind, placebo-controlled trial. The Lancet Global Health; 4(6): e378-85).

Here is a link to the open-access paper:


A commentary recognized that our research filled an important knowledge gap in the management of this disease.

Stephen Gichuhi
Department of Ophthalmology, University of Nairobi

This news article was first published in the Cochrane South Africa newsletter, Volume 18 (No. 1) July/August 2016