Effective drug management of PVR remains unfulfilled goal

February 23, 2017

Article

The bottom line about pharmaceutical management of proliferative vitreoretinopathy (PVR) is that many different drugs have been tried, but so far nothing has been proven effective for treating PVR or reducing its risk, said Demetrios G. Vavvas, MD, PhD, at the inaugural Retina World Congress.

Introducing a discussion of published studies and case series reporting on pharmaceutical management of PVR, Dr. Vavvas told attendees: “Welcome to the graveyard.” Ending his review, he acknowledged that the picture he painted was “bleak.”

Dr. Vavvas admitted that though he cannot predict the future, he is an optimist by nature and is hopeful that researchers will eventually identify effective pharmacotherapy for PVR management. Success, however, will require better knowledge of PVR pathogenesis and awareness of the probable flaws of previously attempted strategies.

“There are several reasons why we have yet to identify effective pharmaceutical agents for the management of PVR," said Dr. Vavvas, Monte J. Wallace Ophthalmology Chair in Retina and associate professor of ophthalmology, Harvard Medical School, Boston.

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"First, we do not fully understand how it develops," he said. "Furthermore, the preclinical models used to investigate potential therapies are imprecise and do not really recapitulate what happens in patients in vivo. Therefore, it is not surprising that an agent that looks promising for treating PVR induced experimentally by a single factor fails in clinical trials."

In addition, available histopathological studies have looked at epiretinal and subretinal membrane specimens, but they overlook the presence and role of intraretinal fibrosis that causes retinal stiffness and shortening, he noted.

“Furthermore, many of the clinical trials of pharmaceutical intervention for PVR did not take into account that PVR develops through a long-term, continuous process that cannot be effectively interrupted by a single or short-term intervention," Dr. Vavvas said. "So, in addition to identifying an appropriate agent, there is a need to figure out the appropriate dosing, timing, and duration of treatment. Likely, there is also a need for combination therapy.”

Treatments tried

The pharmaceutical agents that have been investigated for management of PVR can be categorized by their mechanism of action as being anti-inflammatory or antiproliferative.

More recently, there is interest in molecular targeting using modalities directed against specific cytokines that have been identified as involved in the pathway to the development of PVR, but so far none of those approaches has been studied clinically.

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Anti-inflammatory treatment has centered mostly on the use of corticosteroids, and results have been reported from studies investigating oral prednisone or a corticosteroid added to the infusate intraoperatively.

“Despite the absence of conclusively positively results in studies that were published between 1998 and 2012, there are some investigators who still want to explore a potential benefit of anti-inflammatory treatment, if given long term,” Dr. Vavvas said.

He noted there are proposed studies that use more intensive and extensive anti-inflammatory regimens or the extended-release dexamethasone implant (Ozurdex, Allergan).

A recently published case series reported some good results using the latter agent as an adjunct to silicone oil tamponade. Nevertheless, it was not a randomized controlled trial, Dr. Vavvas said.

Antiproliferative agents that have been used for management of PVR include intravitreal 5-fluorouacil (5-FU) in combination with low molecular weight heparin, radiation, intravitreal daunorubicin, oral retinoic acid, oral colchicine, and intravitreal injection of a ribozyme against proliferating cell nuclear antigen, even intravitreal aspirin.

Unfortunately, most did not show any significant effect on reoperation rate, and of interest one of the 5-FU studies showed a potential toxicity in vision in patients with macula-on status.

The study investigating oral retinoic acid, which was a randomized controlled trial, showed likely the most encouraging results. During follow-up to at least 1 year after surgery with silicone oil for primary rhegmatogenous retinal detachment and PVR, there were significant differences favoring the group treated with oral retinoic acid for 8 weeks versus controls in measures of retinal attachment macular pucker formation, and ambulatory vision.

This study, however, included only 35 eyes, and thus needs to be verified by a larger study. The group at Wills Eye is planning a follow-up study to verify the prior study results, he noted.

Methotrexate

Most recently, there is interest in using methotrexate which is both antiproliferative and anti-inflammatory. Several years ago, Dean Eliott, MD, at Massachusetts Eye and Ear Infirmary, Boston, started a phase I/II trial that considers the issue of dosing and PVR chronicity.

Dr. Eliott’s work takes into account that methotrexate, like all small molecules, has a short half-life in the vitreous and that PVR is a long-term disease, Dr. Vavvas said. He noted that Dr. Eliott seems to be achieving some benefit administering repeated (weekly) intravitreal methotrexate injections into the silicone oil-filled vitreous cavity over a period of about 3 months.

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“However, there is a need for a larger controlled study,” Dr. Vavvas said. “A published, uncontrolled series that included 29 eyes reported that using a single intravitreal methotrexate in the infusion appears to be safe.”

Dr. Vavvas has no relevant financial interests to disclose.