Procedure's efficacy, cost fuel PDT debate in Europe

While national policies regarding treatment coverage vary, some ophthalmologists have introduced alternative treatment plans.

Photodynamic therapy with verteporfin has become a commonly practiced procedure in Europe, and multicenter trials have produced long-term results and treatment guidelines. Still, the treatment remains a subject of debate among ophthalmologists here.

Two main issues are the focus of discussion.

First is the efficacy of the treatment. In its principal application, for the wet form of age-related macular degeneration, PDT with Visudyne (verteporfin for injection, Novartis Ophthalmics) does not cure the disease, but only — and not in all cases — inhibits a symptomatic aspect of the disease (ie, choroidal neovascularization) at its advanced stage, slowing down or arresting the progression of visual loss.

Both physicians and patients often perceive this as a frustrating and disappointing result. From this viewpoint, the procedure’s results in treating neovascularization in pathologic myopia seem more rewarding, as these patients are more likely than AMD patients to improve visual acuity after verteporfin therapy.

A second issue is the high cost of the drug. European countries, and even regions within the same country, have adopted differing policies concerning registration and reimbursement, and in some areas the coverage of PDT treatment is a pressing problem.

Another subject for discussion is linked to both these issues. While PDT is generally recognized as a long-term treatment because a single session is usually effective for only a limited period of time, not all physicians agree on multiple treatment rates and modalities. Some of them have begun to investigate combining the PDT regimen with other procedures.

Combined approach

“Re-treatment criteria are extremely variable,” said Stefano Piermarocchi, MD, of Padua University. “Some investigators of the Verteporfin In Photodynamic Therapy (VIP) and Treatment of Age-Related Macular Degeneration with Photodynamic therapy Study Group (TAP) trials are modifying their re-treatment schemes because they have updated their diagnostic methods with ICG angiography and OCT. Remember that the results of VIP and TAP have only been based on fluorescein angiography.”

Dr. Piermarocchi has broad experience with PDT, and defines the treatment as “a major breakthrough in AMD and myopic degeneration.”

However, he has more recently focused his attention on a procedure combining PDT and feeder vessel treatment (FVT).

“The reduction of choroidal blood flow following PDT makes it easier to detect the feeder vessel,” he said. “We usually treat the patient with PDT and, whenever possible, we perform FVT 1 month later. We’ve found that the combination of both produces a steady decrease of leakage and flow in the choroidal new vessels and reduces the need for repeated PDT treatments. In comparison with patients treated with PDT only, there was a significantly lower rate of patients who needed a second PDT treatment after 3 months.”

“Considering that not all patients have an equally good response to PDT, that there is no evidence that multiple sessions of the treatment do or do not produce retinal damage, and that PDT treatment is extremely expensive, this option is worth further investigation,” he added.

A multicenter study comparing results of long-term PDT treatment and combination of PDT and FVT is ongoing in Italy.

Italy: provisions need definition

In Italy, the cost of treatment is a problem for some patients and practitioners. The drug and accompanying treatment have been licensed by the national authorities, and provisions have been made for the coverage of the drug on prescription in National Health Service hospitals and selected certified centers. However, regulations and reimbursement procedures are far from being clear and well-defined, according to Paolo Lanzetta, MD, of Udine University.

“The NHS covers the cost of the drug, but has not made definite provisions for the treatment. A code for ocular PDT has not yet been created, and it is not clear whether the procedure should be reimbursed on an outpatient or inpatient regimen or both,” he said.

Without clear national directives, single regional authorities have found their own solutions to the problem.

“Ocular PDT shares the same outpatient code for argon laser treatment of retinal tears, or the diagnosis related group (DRG) code for exudative AMD in case of inpatient regimen. Of course, the reimbursement rate is bound to be quite different for the two regimens,” Dr. Lanzetta said.

Recently, he added, the Tuscany region has approved a specific code for ocular PDT, which sets reimbursement to about 1,400 euros.

Dr. Lanzetta, who has participated in all stages of the VIP trial and its extension, as well as the Visudyne Early Re-treatment Trial (VER), is fairly satisfied with the results of PDT treatment. He stresses the importance of patient selection, which should be guided by a perfect knowledge of angiographic classification of CNV and by the results of the multicenter trials.

“The fact that verteporfin therapy requires multiple sessions of treatment for at least 24 months should be accepted and clearly explained to prospective patients,” he added.

“In Italy, verteporfin therapy is reimbursed for the treatment of predominantly classic CNV secondary to AMD and a visual acuity of 0.1 or better, and CNV due to pathologic myopia. In both cases, the lesion must be subfoveal. Reimbursement of the drug is obtained independently of the number of treatments needed. But the long waiting lists often induce patients to seek private, self-financed treatment, and in these cases cost is a relevant problem.”

France: a sufficient answer

Gabriel Coscas, MD, of the Eye University of Creteil, believes that although combinations with other treatments like FVT or thermal laser may occasionally be an option, PDT on its own is a sufficiently good answer in the cases in which it is indicated.

“It’s a relatively easy technique, and side effects and complications are rare. I have only had some cases of hemorrhage, and very few were severe and irreversible,” he said.

“Of course, efficacy depends on indications. Very late stages of the disease can only result in stabilization, but for these patients even a 60% useful stabilization represents a previously unhoped-for victory. For patients who come to us at earlier stages of the disease, within 3 months or even as little as 1 month from the onset of symptoms, even some improvement is possible. The size of the lesion is also a determining factor,” he said.

He says he is definitely satisfied with the results of the technique, which he has been using for about 4 years, from the start of the international trials.

In his opinion, the length of treatment must be assessed case by case.

“After three to four sessions I evaluate the situation with my patients and decide whether it’s worth carrying on with the treatment,” he said. “Usually, if there has been some improvement, I suggest continuing. However, if I don’t see any tangible results, I don’t go beyond the fourth session. A few cases only needed three sessions to reach some kind of improvement. In no cases have I re-treated patients more than six times.”

In France, PDT is regularly reimbursed by the health authorities for the treatment of classic or predominantly classic CNV, according to Dr. Coscas. There are no limits to the number of treatments. He said the main problem is related to CNV in myopic eyes and to occult CNV only in AMD that are still not taken in charge and that could benefit from the treatment.

Germany: different appreciation

Ursula Schmidt-Erfurth, MD, of Lübeck University, was one of the pioneers of PDT in Germany, starting with the first clinical trials in 1995. She is also satisfied with the outcomes of the treatment for the indications resulting from the VIP and TAP studies.

“We perform repeated treatments until the leakage is reduced,” she said. “It doesn’t necessarily have to be completely absent, but it has to be reduced to a level where visual acuity remains stable. At that point, we discontinue the treatment.”

Clinical results in terms of visual acuity are therefore as important as angiographic results in deciding the course of PDT, she said.

She practices in an area of Germany where coverage of PDT is a recent achievement, dating from September 2001, but she has never wanted to compromise with alternative solutions.

“Combined treatments are purely experimental. It might be an interesting approach, but prospective randomized clinical trials are necessary to prove its validity,” she said.

Other regions of Germany were more prompt in funding PDT for their residents. Veit-Peter Gabel, MD, of Regensburg University, explained that in Germany about 80% of the population is provided with health coverage by a national insurance system, while the remaining 20% are, by their own choice, privately insured.

“In many cases, within the national insurance system, reimbursement provisions for new treatments or drugs are decided by regional authorities,” he said. “Concerning PDT, the Regensburg area made provisions more than a year ago. The insurance pays for multiple treatment in patients with classic or predominantly classic CNV in AMD, and hopefully myopia will be included during the next few months. Applications for reimbursement, however, require a special and sophisticated comment on each single case. Patients can decide whether to be treated in hospitals or private practices, provided the doctor they chose is listed among those certified for PDT by the health authorities.”

Private insurance companies are also providing coverage for PDT under the same conditions. Prof. Gabel performs PDT regularly, usually two to three times for each patient, without additional procedures, but he is more satisfied with the results of the treatment in pathologic myopia than in AMD.

“In AMD, it’s better than doing nothing, but I can’t say I am satisfied. I would like to have had better results,” he said. “The endpoint of the treatment is not very clearly defined and although we perform repeated treatments, vision worsens in many cases. Since the basic disease continues its course, even if you treat the membranes the overall situation deteriorates, and this is disappointing. With pathologic myopia, positive results are more frequently achieved, and are generally more stable.”

Spain: open to alternatives

In Spain, state coverage of verteporfin treatment is provided in public hospitals. However, according to Jordi Monés, MD, of the I.M.O. Institute of Barcelona, waiting lists are a major problem.

“PDT has greatly expanded, candidates and potential candidates are dramatically increasing with the aging of the population and the number of treatments required for each patient multiply the demand,” he said.

As a result, there are many affluent patients in private practices like the I.M.O. Institute, where fast, efficient and qualified services are provided.

As a principal investigator in the international PDT trials, Dr. Monés has been performing the treatment for 5 years, and regards it as a precious opportunity for people who would have had no hope in preserving their eyesight in the past. He thinks, however, that multiple treatment is a crucial issue, and not primarily for financial reasons.

“We cannot be rigid about a procedure. If an alternative treatment improves results, we should make the most of it,” he said. “I personally evaluate what’s best at each stage of the lesion, and occasionally combine PDT with feeder vessel treatment, macular translocation or laser photocoagulation.

“However, most of the time we perform PDT until the lesion is stabilized. Sometimes the final outcome is favorable in spite of initial poor responses to treatment. Thus, we encourage continuing PDT even if the first treatments seem not to be effective. Basically, the aim is to achieve maximum efficacy and visual results. If with this we avoid some of the cost of re-treatment, fine, but this is not a primary reason.”

Portugal: cost a major concern

On the other hand, treatment costs are a major concern in some countries.

“Due to the very high cost of Visudyne, only few public hospitals have been allocated funds for the treatment by the health authorities,” said Rufino Silva, MD, of Coimbra University. “It’s mainly the case of university hospitals in major cities, like Lisbon, Coimbra and Porto. Some private practices are also performing the treatment, but the entire burden of the expenses is carried by the patients. Reimbursement from private insurance companies is the exception, because only a few citizens can afford private insurance anyway.”

He added that the cost of PDT is limiting the number of patients receiving the treatment. Some physicians, he said, do not feel that the correlation between cost and benefit is positive for patients who pay for themselves, and therefore do not prescribe the treatment.

In spite of problems, PDT is widespread in Portugal, and doctors are fighting government policy on this matter. Dr. Silva himself has been performing PDT for 2 years, and is fairly satisfied with the results. There are cases where he combines the treatment with transpupillary thermotherapy (TTT).

“They are mainly patients with a bad prognosis, with CNV and exudation increasing in spite of the treatment, severe visual loss and visual acuity 20/400 or less. An improvement in visual acuity is not expected in these patients even with the stopping of leakage, and TTT is a less expensive option that we can offer them.”

U.K.: treatment under review

Although PDT was granted a license in the United Kingdom in July 2000, the situation of service provisions is still undecided. The treatment is currently under review by various bodies who advise the National Health Service. The National Institute for Clinical Excellence has initially discouraged national financing of PDT for the cure of AMD and said the need for continued treatment is a key issue in determining whether the treatment will be cost-effective in clinical practice. However, it is still under review, and a final decision will be made shortly.

“The situation is fluid, but at present the NHS does not finance PDT, except in some centers under a named patient basis program. Those of us who are involved with macular disease do not agree with this policy,” said Peter A.M. Hamilton, MD, of London.

“Because the NHS is not funding the treatment, all my patients are private patients, either covered by private health insurance or self-funded,” he explained. “The majority of them have only one treatment, only three have been re-treated twice and one patient has had PDT three times. I am not combining PDT with other procedures.”

Despite the low number of treatments, he said he is satisfied with his results.

[Editor's note: See related article.]

Switzerland: well-established practice

“Switzerland was the first country in Europe to grant a license to Visudyne and PDT,” said Leonidas Zografos, MD, of the Jules Gonin University Eye Hospital in Lausanne. “It was in our clinic and in the HCUG of Geneva that the first cases of PDT were performed, back in 1994, for the phase 1-2 clinical trials preceding VIP and TAP.”

Funding provisions have followed. In Switzerland, health care coverage is entirely private but mandatory for all citizens, he said. Since June 2000, all insurance companies have officially approved reimbursement for PDT, with no limits to the number of treatments.

“Our government has authorized PDT on the basis of a statistic forecast of the number of cases to be treated annually until the end of 2002,” said Guy Donati, MD, of Geneva University Hospital. “A budget has been approved, and at the established date the health authorities will verify if the number of predicted cases was more or less correct. So far, there have been no problems with reimbursement, because we are largely within the limits of allocated funds and the number of cases treated in the past 2 years has been lower than forecast.”

Point on alternative procedures

PDT is a well-established practice in Switzerland, where more than 20 lasers are currently available for the procedure.

“Results may be controversial, because efficacy is not 100%, but PDT has undergone official investigation in multicenter trials on hundreds of patients,” Dr. Donati said. In his opinion, this is the main crucial difference with other types of procedure, like the combined FVT.

“Combining PDT and FVT is a very interesting idea, and I do it occasionally, as do most of my colleagues in Switzerland. However, it is important to recognize the difference. When we do PDT we are dealing with an evidence-based procedure, and we are on the safe side also from a medical-legal point of view. With alternative procedures, we stand in an area which is not yet well-defined,” he pointed out.

A second important difference with PDT is that the FVT can only be applied in a limited number of cases.

Cost-effectiveness

Indications for PDT are widening. The VIP study has demonstrated that occult membranes, which are the vast majority, may also benefit from the treatment, Dr. Donati said.

“Efficacy, in these cases, is even more controversial, because it doesn’t go beyond 50%. However, we must consider that nothing had so far proven effective for occult neovascularization. It’s a big step forward,” he said.

This new possible application of PDT is undergoing evaluation in many countries, but reticence is great, because the social costs of the treatment, which are already so high, would rise immensely.

However, the social and economic burden and the impact on the quality of life of AMD are factors that deserve more attentive consideration from all governments, according to Dr. Lanzetta.

For Your Information:

• Stefano Piermarocchi, MD, can be reached at Università degli Studi di Padova, Istituto di Oftalmologia, Via Giustiniani 2, Padua, Italy; +(39) 049-821-2134; fax: +(39) 049-875-5168; e-mail: stefano.piermarocchi@unipd.it. Dr. Piermarocchi has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Paolo Lanzetta, MD, can be reached at Department of Ophthalmology, University of Udine, Viale Venezia, 410, 33100 Udine, Italy; +(39) 0432-239-268; fax: +(39) 0432-239-313; e-mail: paolo.lanzetta@dsc.uniud.it. Dr. Lanzetta has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Gabriel Coscas, MD, can be reached at University of Paris XII, Eye University Clinic of Creteil, 40 Avenue de Verdun, 94010 Creteil, France. +(33) 1-45-17-52-25; fax: +(33) 1-45-17-52-27; e-mail: gabriel.coscas@libertysurf.fr. Dr. Coscas has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• 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: schmidterfurth@ophtha.mu-Lübeck.de. Ocular Surgery News cannot confirm whether Dr. Schmidt-Erfurth has a direct financial interest in any of the products mentioned in this article or if she is a paid consultant for any of the companies mentioned.
• Veit-Peter Gabel, MD, can be reached at Augenklinik der Universitaet, Franz-Josef-Strauss Allee 11, 93042 Regensburg, Germany; +(49) 941-944-9201; fax: +(49) 941-944-9202. Ocular Surgery News cannot confirm whether Dr. Veit-Peter Gabel has a direct financial interest in any of the products mentioned in this article or if he is a paid consultant for any of the companies mentioned.
• Jordi Monés, MD, can be reached at Institut de Microcirurgia Ocular, Munner 10, 08022 Barcelona, Spain; +(34) 93-253-1500; fax: +(34) 93-417-1301; e-mail: jordi_mones@comb.es. Dr. Monés has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Rufino Silva, MD, can be reached at Ophthalmology Department, Hospital of the University of Coimbra, Praceta Mota Pinto, 3000 Coimbra, Portugal; +(351) 2-39-70-1182 /+(351) 9-64-09-9210; fax: +(351) 2-39-82-6625; e-mail: rufino.silva@oftalmologia.co.pt. Ocular Surgery News cannot confirm whether Dr. Silva has a direct financial interest in any of the products mentioned in this article or if he is a paid consultant for any of the companies mentioned.
• Peter A.M. Hamilton, MD, can be reached at 149 Harley St., London W1G 6BN, England; +(44) 20-7935-4444; fax: +(44) 20-7935-3061; e-mail: eyehamilton@msn.com. Dr. Hamilton has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
• Leonidas Zografos, MD, can be reached at Hopital Ophtalmique Jules Gonin, 15 Ave. de France, 1004 Lausanne, Switzerland; +(41) 21-626-8111; fax: +(41) 21-626-8889. Dr. Zografos has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned. Guy Donati, MD, can be reached at Eye Hospital of Geneva – HCUG, 22 rue Alcide Jentzer, 1205 Geneva, Switzerland; +(41) 79-448-0018; fax: +(41) 22-839-3385. Dr. Donati has no direct financial interest in the products mentioned in this article, nor is he 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.