Fluorouracil limited to use in high-risk cases

April 1, 2008

Intravitreal medical adjunctive therapy for routine cases in patients undergoing vitrectomy for rhegmatogenous retinal detachment currently does not seem to be beneficial. Studies find that 5-fluorouracil may be associated with systemic toxicity and its use may be limited to high-risk patients.

New Orleans-Intravitreal medical adjunctive therapy for routine cases of rhegmatogenous retinal detachment currently does not seem to be beneficial. There are concerns about potential toxicity from fluorouracil (5-FU), and its use should be limited to high-risk cases, according to G. William Aylward, MD, who spoke at the American Academy of Ophthalmology annual meeting.

The questions that Dr. Aylward raised are: what can be done to stop proliferative vitreoretinopathy (PVR), and what is the best adjunctive therapy after it has developed?

Regarding adjunctive therapy, Dr. Aylward explained that Mark Blumenkrantz, MD, showed that 5-FU has a beneficial effect on PVR in an animal model. One dose of 5-FU was reported to have a long-term effect on fibroblast function in tissue culture.

Dr. Aylward and colleagues at Moorfields Eye Hospital in the past investigated the effects of low-molecular-weight heparin and 5-FU. These drugs were chosen because they work on the formation of the matrix in PVR and on migration and proliferation of the cellular component, he explained.

In the first study, published in 2001, the investigators evaluated if heparin and 5-FU could prevent PVR in patients with high-risk disease; they also evaluated the effect of the drugs administered by infusion for up to 1 hour to a subset of patients undergoing vitrectomy to treat PVR. "We found a clinically and statistically significant difference in reduced PVR in the treatment group. No complications developed that were related to the treatment," he stated.

A study was undertaken of the same combination treatment to treat established PVR. The study included two groups of patients: those with severe PVR with retinectomy and those with less severe disease who received a scleral buckle. "We found no difference in the rate of retinal re-attachment either clinically or statistically. Although this was disappointing, retinal re-attachment, while it is important to the surgeon and the patient, is not a good end point for what we were trying to discover, which was reduced PVR," he said.

Dr. Aylward described what he meant using two cases. In one case with mild PVR this was considered a failure because of a small break at the entry site. In another case with large membranes covering the retina, this was considered a success because there was no retinal break.

In the same study, they looked at macular pucker, which he considered a more accurate end point. "We found a small treatment difference with macular pucker. There may have been some effect of treatment but this did not translate into a benefit for the patient," he said.

A study of 5-FU was carried out by David Charteris, MD, and Louisa Wickham, MD, of adjuvant therapy to prevent PVR in all patients. Among 600 enrolled patients, the investigators were not able to identify a significant difference in the primary or the final success rates. "A very worrying finding was that the visual acuity was reduced in the macular on treatment group. This is an interesting observation that remains unexplained. It does indicate a potential problem with 5-FU. While it is uncertain if the visual acuity decrease was a sign of toxicity, the result is worrying," Dr. Aylward commented.

He also pointed out that 5-FU can be absorbed systemically from the vitrectomy fluid; investigators have reported metabolites in urine samples. This indicates that only one infusion for a short period can be problematic.

"The current cocktail may be beneficial in high-risk cases, but has no benefit in established cases of PVR or in routine cases because of possible toxicity. Progress in this area will be seen in combination therapies and drug-delivery systems. Right now, adjunctive therapy for routine use in routine cases does not seem to have a role," Dr. Aylward concluded.