Photodynamic therapy found to slow visual loss in patients with macular

Issue: December 1999

---David G. Miller, MD

Dr. Miller: What I’d like to talk about is photodynamic therapy with Visudyne (verte porfin, QLT PhotoTherapeutics and CIBA Vision). In standard laser therapy, the laser beam comes in, travels through the retina, which is transparent, heats up the retinal pigment epithelium (RPE) and burns the retina as well as the blood vessels, photoreceptor cells and RPE. It destroys the underlying membrane, of course, but anything else on top of that is also destroyed.

This works quite well for the extrafoveal lesions but, unfortunately, a very small percentage of patients are candidates for laser surgery. In fact, less than 20% of patients with wet macular degeneration have neovascular lesions that are treatable with the standard laser.

FDA panel recommends Visudyne

BETHESDA, Md. – On November 17, as this issue of Primary Care Optometry News was going to press, an advisory panel to the Food and Drug Administration (FDA) recommended approval of Visudyne (verteporfin for injection, QLT Phototherapeutics and CIBA Vision).

The panel reviewed controlled clinical trials of photodynamic therapy (PDT) using Visudyne. Based on the better preservation of vision in the PDT-treated group versus the control group, the panel recommended approval of PDT for patients with predominantly classic subfoveal choroidal neovascularization as a result of age-related macular degeneration.

Of the patients in which 12-month follow-up data could be obtained, 61.2% of the 535 Visudyne-treated patients lost less than 15 letters of visual acuity (based on the ETDRS visual acuity measure) versus 44.5% of the placebo control patients. Treated patients lost an average of only 9.9 ETDRS letters at 12 months, compared with 20.8 letters in the control group, which received laser treatment following an injection of 5% dextrose placebo. Retreatment was deemed necessary in a number of patients, with 90% being retreated at 3 months postoperatively, 80% at 6 months, 70% at 9 months and 64% at 12 months.

“The benefit is not huge, and it is temporary,” said panel chair Donald S. Fong, MD, of the Kaiser Permanente Medical Center in Baldwin Park, Calif. He supported approval, though, because treatment did abate the loss of vision. The panel agreed and recommended FDA approval.

“Given the outcome of today’s panel meeting, we are confident that the FDA will grant us approval within the priority time frame, which means February 2000,” said Luzi von Bidder, president of the worldwide ophthalmic business unit of CIBA Vision Corp.

The concept of photodynamic therapy is well established; it has been used to treat skin cancer. A dye is injected into the venous system and is circulated through the body. The dye will accumulate within any abnormal vasculature, such as in a tumor or skin cancer. You then hit that area with a diode laser, which would activate the dye and make it chemically reactive, thus destroying the tumor or at least shutting down the blood flow. The theory behind the treatment is that as long as this material accumulated only in abnormal tissue, the normal tissue should be unaffected.

Performing the procedure

Before beginning, the target area must be calculated by using the angiogram, measuring in millimeters. We can treat a lesion up to about 6.5 mm in diameter, or about 3 disc diameters. The medication dose is calculated, mixed into a saline solution and diluted in dextrose solution, then it is infused over 10 minutes. You wait 5 more minutes for the dye to circulate through the body and it will accumulate itself in the neovascular tissue underneath the retina.

The beam is targeted on the size needed to obliterate the membrane. One continuous spot is shot, and it takes about 1.5 minutes.

This is performed as an outpatient procedure. When the patient returns home, he or she need only avoid exposure to sunlight. The drug has a half-life of 2 to 5 hours and is eliminated from the bloodstream in about 24 hours. The treatment itself has not been found to cause much visual loss or damage.

Safety and efficacy trials have been completed, and the data showed in these somewhat short trials that there was a benefit to this treatment compared to observation. The dosing of the medication and the energy of the laser was varied in these earlier trials to find the optimum dose and light time. It was determined that 6 mg/m²was the optimum dose and 50J/cm² was the optimum energy of the laser. They also found that though the choroidal neovascularization is occluded it was usually temporary, reopening on the angiogram a few weeks later. Re-treatment was successful at closing them down and preserving vision.

Two phase 3 trials began in 1997. The first phase 3 trial was called TAP: treatment of age-related macular degeneration with photodynamic therapy; the other was VIP: verteporfin in photodynamic therapy.

The TAP patients included those with subfoveal neovascular membranes and some classic component present within the membrane. The vision had to be 20/200 or better. Six hundred patients were enrolled and first-year data has been released.

The VIP trial allowed patients with macular degeneration, but also those with pathological myopia. It also allowed lesions that were occult only into the trial, which was the big distinction between TAP and VIP, or 3a and 3b.

TAP trial indicates benefits

The VIP trial began a bit later than the TAP, so I do not have data on it. The patients in the control arm of the TAP trial were injected with a sugar solution and received the laser light. The patients in the treatment arm received re-treatments every 3 months if necessary. The TAP trial results at 12 months show a definite statistical benefit to receiving the injections of the Visudyne, as opposed to being injected with the sugar solution.

On average, in the first year, patients received 3.4 treatments. In most patients, the lesions continued to leak, so they required re-treatment. At the end, patients who were treated showed less than three lines of vision loss when compared to those not treated. So there is still visual loss in the treatment group, but it’s not as great. This was shown to be statistically significant based on the number of patients enrolled in the study.

Another, more impressive, endpoint was the number of patients who actually improved vision. The patients who received the treatment had about a 16% or 17% chance of improving vision by one line or more, where those who did not had only a 7% or 8% chance of their vision improving. And this, too, is shown to be statistically significant.

The procedure was well tolerated and patients had no adverse outcomes or unexpected side effects causing significant dropout from the trial. About 2% of the patients in each arm of the study disenrolled themselves.

New retinal rotation

I wanted to discuss another procedure called retinal rotation or retinal translocation. This procedure involves moving the retina to a new location so the abnormal vessels are no longer located underneath it. You pick the fovea up and essentially move it down or up. Then you can always come back and laser the choroidal neovascularization safely because then it’s extra foveal, by definition.

Sutures are placed in the sclera, as if placing a scleral buckle almost on the outside of the eye. A vitrectomy is performed and a retinal detachment created by placing a cannula into the retina and ballooning it up. You actually have to detach the entire superior retina, temporal retina and inferior temporal retina.

Once the retina is freely floating, the sutures are tied up on the outside. This is the scleral imbrication. By tightening these sutures you make a fold in the sclera, and also a fold in the eye wall, so you need less retina to cover the same amount of space. When the retina flattens itself back down, which it does automatically because there are no large holes in it, those holes created by making the detachment are very small, essentially self sealing. The eye is filled with air and it flattens out, and the retina shifts down.

The procedure is relatively invasive and risky. The retinal detachment rate associated with the procedure is 5% to 10%. And these detachments are severe, with a lot of proliferated vitreoretinopathy; they can be very difficult to fix. Another unique complication is a macular fold. If that redundancy in the retina doesn’t fall to the bottom and winds up in the macula, you have very poor vision.

For Your Information:

David G. Miller, MD, is a retinal specialist with Retina Associates of Cleveland Inc. He can be reached at 26900 Cedar Road, Suite 303, Beachwood, OH 44122; (216) 831-5700; fax: (216) 831-1959. Dr. Miller has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.