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Current investigations may expand PDT re-treatment indications for AMD
Physicians are aggressively exploring ways to improve clinical outcomes for patients with AMD who are treated with PDT.
Since the approval of verteporfin for photodynamic therapy in August 2001, researchers have been investigating additional potential applications for various manifestations of neovascular age-related macular degeneration. With AMD as a major cause of blindness in people over 65, the impetus for this research is clear.
The data of three clinical trials — two trials comprising the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Investigation, and the Verteporfin in Photodynamic Therapy (VIP) Trial — have defined the standards of appropriate treatment with Visudyne (verteporfin, Novartis Ophthalmics). In the United States, the treatment received regulatory approval in August 2001 for patients with predominantly classic choroidal neovascularization (CNV) in AMD, in pathologic myopia, and in the ocular histoplasmosis syndrome.
Optimization of re-treatment
In the TAP Investigation, surgeons learned that most of the visual acuity loss that occurs in eyes treated with Visudyne therapy occurs in the first 6 months after treatment initiation. In 2 years, these patients lost an average of approximately two lines of Snellen visual acuity. In contrast, eyes in the control group treated with a placebo lost an average of four lines of visual acuity within the same 2-year period.
To determine whether more frequent and earlier treatments could prevent this loss, European surgeons have began the Optimization of Treatments in PDT study. This study will try to determine whether alternative time periods of treatment with verteporfin therapy can reduce the risk of moderate and severe visual acuity loss initially after PDT.
“We are focusing on early treatment after initial treatment, to see if more therapy can stabilize or increase the visual performance in patients with predominantly classic lesions. If so, the measures of application can be redefined,” Ursula M. Schmidt-Erfurth, MD, of the University Eye Hospital in Lübeck, Germany, recently told Ocular Surgery News.
There are 15 centers currently participating in the study, which reaches across Germany, Switzerland and Austria. Currently, the study is enrolling patients in phase 3 trials. There are 158 patients enrolled, however; a goal of 200 patients will have to have been reached by April 2002 to gain statistical significance, Dr. Schmidt-Erfurth said.
Treatments will be administered to patients in 2-month intervals, as opposed to 3-month intervals, which was the standard protocol in the TAP Investigation.
“However, if we see an association between leakage and visual loss, we will try to reduce the number of treatments over time,” Dr. Schmidt-Erfurth noted.
An interim analysis will be given at the 6-month mark to determine how much treatment should be used.
The study began in 2001. Patients will be observed for 2 years.
Visudyne Early Re-treatment Trial
A similar study focusing on treatment protocol is also in progress, called the Visudyne Early Re-treatment (VER) Trial.
“The VER Trial is being conducted in the United States, as well as here in Lübeck, Vienna, Paris and Barcelona. Centers are still actively recruiting for this study as well,” Dr. Schmidt-Erfurth said.
In the VER Trial, doctors are issuing treatments every 6 weeks for the first 6 months, instead of issuing treatments every 8 weeks (2 months), as with the Optimization of Treatment in PDT Trial.
“This got many of us to question whether there might be another way of reducing the vision loss that occurs in the first 6 months after starting treatment,” said Neil M. Bressler, MD, of Johns Hopkins University in Baltimore.
As a result, Dr. Bressler and colleagues began exploring the possibility of early treatment with verteporfin therapy to reduce the risk of moderate and severe visual acuity loss 1 and 2 years after initiating therapy. They began the VER study in centers throughout Europe and North America.
In the VER study, like in the Optimization of Treatment in PDT study, treatments are given provided there is fluorescein leakage from CNV. After the 6-month period, patients receive treatments every 3 months for 2 years.
The control group is treated with the standard verteporfin therapy regimen defined by the TAP Investigation. Again, these patients will only be treated if there is fluorescein leakage from CNV. Additionally, if leakage is noticed at 1.5 or 4.5 months, patients will receive placebo with sham treatment, according to Dr. Bressler.
“Hopefully, by evaluating the different treatment intervals, we will be able to determine if more frequent and earlier treatment will improve our current outcomes when treating predominantly classic lesions,” Dr. Bressler said.
Off-label uses growing
In addition to investigative trials stretching the limits of the verteporfin therapy indications set by the TAP and the VIP trials, there are numerous possibilities for off-label use, according to Philip J. Rosenfeld, MD, PhD, of the Bascom Palmer Eye Institute at the University of Miami.
He said he has found positive results with patients suffering from occult CNV with no classic CNV, idiopathic CNV, CNV secondary to angioid streaks and post-inflammatory CNV. In general, visual acuity outcomes in younger patients with a range of subfoveal CNV seem to be better than in older patients with AMD and CNV.
Susan Bressler, MD, of the Wilmer Eye Institute of Johns Hopkins University, summarized the 2-year results of a large subgroup of patients who participated in the VIP Trial. The subgroup included patients with occult lesions with no classic CNV. Based on the subgroup analysis from this study, verteporfin therapy reduced the risk of moderate and severe vision loss in these eyes with either lower levels of initial vision (less than 20/50) or smaller initial lesion size (less than four disc areas). All primary and secondary outcomes were significantly in favor of verteporfin at the 2-year examination in this subgroup, she said.
Dr. Rosenfeld said that the off-label use seems promising. “In the coming months, we will hear more about off-label cases being performed,” he added.
Proceed with caution
Most of the treatment therapies and off-label uses being examined in the United States and Canada are being used on a much smaller scale in Europe, according to Dr. Schmidt-Erfurth.
“There are so many competing studies at the moment. Not all of the data from the States are being well-received. Europeans are skeptical of the new therapies for PDT,” she said.
Europeans are exploring alternative indications, but minimally in comparison to other parts of the world, Dr. Schmidt-Erfurth added.
It is possible that less experimentation with PDT is being done in Europe because reimbursement regulations for therapies do not always cover the cost of PDT technology, she said.
“Most doctors are covered only if they are treating someone in the classic indication approved and defined by the TAP Trial. However, there are numerous cases outside the approved realm of predominantly classic CNV, CNV due to myopia, or occult-only CNV lesions that are not accounted for,” she said.
For such reasons, Dr. Schmidt-Erfurth advises caution when treating and diagnosing patients with AMD.
Topography and OCT imaging
“Topography is a novel diagnostic technique, which was newly developed for the three-dimensional imaging of vascular structures,” Dr. Schmidt- Erfurth said.
Dr. Schmidt-Erfurth documents the photodynamic changes of CNV with a scanning laser ophthalmoscope. According to her, the images presented reveal “important discrepancies” between three-dimensional features, giving a precise configuration of the vascular structures.
“Sometimes, early hypofluorescence appears as prominent pooling of extravagate. Or, after multiple PDT treatments, persistent hyperfluorescence imposes as a perfusion defect,” she said.
Carefully distinguishing between elements is key to appropriate assessment of treatment outcomes, she added.
Additionally, Dr. Schmidt-Erfurth values the data generated by examinations with Optical Coherence Tomography (OCT).
“OCT offers imaging that monitors intraretinal and subretinal fluid, which may guide surgeons when considering re-treatments,” she said.
In fact, she noted that consistent OCT patterns were found in the follow-up in the TAP and VIP studies, which “allows a staging of tissue response.”
With use of these tests, decisions for treatment and alternative indications for PDT may be achieved with considerable certainty, she said.
For Your Information:
- Ursula M. Schmidt-Erfurth, MD, can be reached at Augenklinik Der Univ., Ratzeburger Allee 160, Lübeck D-23538, Germany; +(49) 451-500-2229; fax: +(49) 451-500-3085; e-mail: uschmidterfurth@ophtha.mu-Lübeck.de. Dr. Schmidt-Erfurth has a direct financial interest in products mentioned in this article; she is a patent holder on Visudyne.
- Neil M. Bressler, MD, can be reached at 550 N. Broadway, 9th floor, Ste 902, Baltimore, MD 21205 U.S.A.; +(1) 410 955-3518; fax: +(1) 410-955-0845; e-mail: nbressler@jhmi.edu. Dr. Bressler has been a consultant to QLT and Novartis ophthalmics. The terms of this agreement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
- Philip J. Rosenfeld, MD, PhD, can be reached at the Bascom Palmer Eye Institute at 900 NW 17th Street, Miami, FL 33136 U.S.A.; +(1) 305-326-6148; fax: +(1) 305-326-6417; e-mail: prosenfeld@med.miami.edu. Ocular Surgery News was unable to confirm whether Dr. Rosenfeld has a direct financial interest in the products mentioned in this article or whether he is a paid consultant for any companies mentioned
- Novartis Ophthalmics, distributor of Visudyne, can be reached at 11695 Johns Creek Pkwy, Duluth, GA 30097 U.S.A.; +(1) 770-905-1000; fax: +(1)770-905-1883. Visudyne is a trademark of Novartis AG.