Two years ago Phil Rosenfeld of the Bascom Palmer Eye Institute gave a talk on vascular endothelial growth factor (VEGF) inhibitor treatment strategies. In it, he used a slide of the classic Gary Larson Far Side cartoon of a woman studying veterinary medicine. The chapter on horse ailments revealed that the common cure was “shoot the horse”. Phil’s thesis was that for choroidal neovascularization (CNV), VEGF-inhibitors was the equivalent of “shoot the horse.” Irrespective of origin, size, or type, ranibizumab or bevacizumab was the answer for CNV. To a large extent, this has borne out well. We transitioned from an era of limiting visual loss to 15 or fewer letters to an era of average gain of visual acuity for 3 major subtypes of CNV, with 1/3 or more gaining 15 letters.
The catch was that for both the MARINA (occult or minimally classic) and ANCHOR (predominantly classic), patients received monthly injections of ranibizumab for 24 months. In the eye. I promise, it doesn’t hurt. Not that much. Even before these results were released in 2005, the race was underway to build a “better” treatment protocol. For whom “better” refers to is hotly debated. Many retina specialists decry the volume of patients that are flowing through their offices and how they are deluged with patients waiting for intravitreal injections and occupying precious parking spaces. Others lament the toll placed on patients and their caregivers to have to come to the office each month just to gain vision. We all fear the effect that the cumulative cost of monthly dosing is placing on the Centers for Medicare/Medicaid Services, as we suspect that it will adversely impact us, sooner rather than later.
Both the PrONTO and PIER protocols required 3 monthly loading doses. The PrONTO protocol utilizes p.r.n. dosing thereafter for optical coherence tomography (OCT) or visual acuity changes noted on monthly follow-ups or fluorescein angiographic leakage at quarterly follow-up. The PIER protocol, usually minus the photodynamic therapy, follows with quarterly dosing after the initial three injections. The label for ranibizumab advises monthly injections; alternately, 4 loading injections plus quarterly dosing is sufficient, albeit visual acuity loss is to be expected versus monthly dosing.
Phil has studied this area more extensively than anyone, and he now advocates one of two strategies, both which involve monthly injections until there is no fluid visible on OCT. Real world strategy 1 (aka PrONTO style) follows with monthly examinations with treatment when the fluid reappears. The patient’s follow-up interval is then changed to the length of time at which fluid appeared prior to the first p.r.n. injection. Real world strategy 2 (aka Treat and Extend) adds one more injection after the fluid has been vanquished. Then, patients are seen at 1 month, treated regardless of OCT findings. If the OCT is dry at 2 months, treat and have the patient return in 3 months. Repeat until one determines the length of time for fluid recurrence, and then use that as the length of follow-up. This is an interesting and appealing strategy because it keeps the physician in the loop regarding treatment decisions while maximizing patient comfort.
One other treatment regimen that I recently heard about is 3 monthly injections followed by monthly examinations and treatment for visual acuity decline or OCT findings. The catch here is that the entire reinduction of 3 monthly injections is performed when the p.r.n. treatment is initiated. Follow-up is then initiated at this length of failure.
So what do the papers say? Unfortunately, the picture remains fuzzy. The MARINA and ANCHOR are two large multicenter, randomized, double-masked, controlled trials that show unequivocal support for the monthly dosing regimen. The PIER results demonstrated superiority to sham, but still resulted in average loss of visual acuity at 1 and 2 years follow-up. The PrONTO trial showed a mean gain of visual acuity at 2 years, with an average of 5.6 treatments in the first year. This trial, while promising, was single-center, non-randomized, uncontrolled, and open-label. Its applicability to the general AMD population is guarded.
Sage advice? Unfortunately, I have none. I have tried all of these strategies, and have since reverted to monthly dosing for two main reasons. One, nothing equals the visual acuity results. Two, the visual acuity analysis of the MARINA trial demonstrated that 50% of their three-line gainers did not gain those 3 lines until between months 5-12. Therefore, for my patients with occult and minimally classic lesions, I encourage them to wait at least 12 injections before abandoning hope. Upwards of 95% of my patients are comfortable with monthly dosing. In the end, I bow to the wishes of the individual patient. My concern is that the “horse” is like Jason Vorhees in the Friday 13th movie franchise and I will run out of bullets or (money).
DMM serves on advisory boards for Genentech and Novartis.
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