The Case for TTT
Current studies and clinical experience show it to be an effective, safe and economically viable treatment.
BY FAREED ALI, M.D., FRCS(C)

The past 5 years have brought a revolution in the treatment options available for subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Although no single treatment modality has been shown to be highly effective for all types of CNV, some treatments do offer significant benefits to many patients. One of the most efficacious -- and economically viable -- is Transpupillary Thermotherapy (TTT). TTT stabilizes visual acuity in a significant percentage of these patients, preventing or minimizing the deterioration typically seen when no treatment is applied.

Here, I'd like to present an overview of the clinical and practical aspects of TTT for the many ophthalmologists who are contemplating offering this procedure to their AMD patients.

Performing TTT

TTT is a subthreshold diode laser treatment requiring an 810-nm diode infrared laser. (This laser can also be used for other treatments.) It prevents further visual loss in about 70% to 80% of AMD patients who have CNV. About 10% will notice some improvement in their vision after treatment, and about 20% will require a second treatment.

Here's what's involved if you decide to offer this procedure to your patients:

First, create appropriate patient expectations. The patient needs to understand that the primary goal of TTT is not to improve vision but to prevent further deterioration of vision. Before treating the patient, detail the statistics regarding success rate and re-treatment (mentioned above).

Deliver treatment. TTT is performed at the slit lamp; the laser is delivered through the pupil via a contact lens placed on the cornea.

During the procedure, the laser spot diameter should be large enough to cover the entire area displaying CNV, with the treatment spot centered on the CNV. In most cases a 3.0-mm spot size is used, with a power setting of 800 mW. The laser is applied for 60 seconds.

Patients should be told to expect to feel some mild warmth around their eye, but if they feel any actual pain or uncomfortable heat they should let you know. If they do report pain or uncomfortable heat, reduce laser power by about 10% and continue treatment.

Left: Before TTT, vision 20/800. Right: 3 months after TTT, vision 20/80. Note the lack of any laser-induced retinal damage.

Ideally, treatment should not produce any change in the color of the retina. (See images, above.) Whitening of the retina indicates that the power setting is too high. This is a rare occurrence, but if it happens, reduce power by at least 10% and continue treatment.

Post-treatment. The patient's vision may be blurred for a few hours after the treatment, but there's no need to use any eye drops or take any special precautions. Generally, you should have patients come in for a follow-up visit 6 to 12 weeks post-treatment.

(For more information about the possibility of treating the patient a second time, see "Should You Re-Treat?" on page 71.)

Mechanisms of Action

The fact that TTT is a subthreshold treatment may be a cause for concern for surgeons who haven't had experience with other subthreshold retinal laser treatments, such as soft drusen treatment or micropulsed diode laser therapies. It does take a "leap of faith" to believe that a retina with serious disease can be treated with a subthreshold laser, without the use of additional pharmacological agents. However, this is one of the most satisfying aspects of TTT: It's a minimally invasive treatment that produces dramatic results. It doesn't induce any changes in the retina, and the patient isn't subjected to any risk of systemic side-effects. (See images above.)

Using TTT to treat CNV in AMD has its historical origins in the earliest photodynamic therapy (PDT) trials (Reichel et al., Ophthalmic Surg 1994, 25(3):195-201). These trials involved the use of intravenous indocyanine green dye and an 810-nm infrared laser as the photoactivator. Researchers observed that some of the patients in the placebo arm of the trial exhibited beneficial changes in their CNV. This led to the use of an infrared laser without any drug infusion as a treatment for CNV (Reichel et al., Ophthalmology 1999, 106:1908-1914). Since then, the recommended parameters for TTT have been used on thousands of patients with clearly demonstrated safety and efficacy.

There are several theories regarding the mechanism of action of TTT. Its effectiveness has been attributed to:

► the induction of apoptosis in the endothelial cells of abnormal vessels

► free radical reactions in vascular tissues, causing sclerosis and thrombosis of abnormal vessels

► high temperatures within retinal tissue inhibiting vascular endothelial growth factor (VEGF) and enhancing the effectiveness of some inhibitors of angiogenesis

► the role of heat shock proteins. These are induced by high temperatures and help protect the neurosensory retina during TTT.

(For more information on these theories, see Mainster and Reichel, Ophthalmic Surg Lasers 2000, 31:359-373).

It's likely that a combination of all of these factors is involved. In any case, the efficacy of the treatment is well established.

Left: Red-free photo before TTT. Right: Red-free photo 3 months after TTT shows lack of any laser-induced RPE damage.
Left: Late phase fluorescein angiogram before TTT. Right: Late phase fluorescein angiogram 3 months after TTT shows resolution of subretinal blood and leakage.

Laser Power Settings

Some ophthalmologists have expressed reservations about using TTT on the grounds that the power settings used seem arbitrary and uncertain. However, the recommended parameters are based on both initial histopathological studies (Brancato et al., Lasers Light Ophthalmol 1988, 2:73-78) and a vast amount of empirical clinical data. They've been used in thousands of eyes with remarkably consistent clinical results and an excellent safety record.

The power settings do need to be adjusted for patients with varying RPE pigmentation because of race. However, these changes can be grouped into broad categories; power settings don't need to be altered for each individual patient. For example, excellent results are achieved by lowering the power 25% when treating patients of East Asian ethnicity, and by lowering the power by 30% for patients of Indian/South Asian descent (Ali, IRIS Med Appl Newsletter 2003, 8(1):1-8).

Because the only significant variable is the laser power setting, it makes sense that TTT should result in very consistent treatment effects and a wide safety profile. (In contrast, PDT involves such variables as drug dosage, laser fluence, laser exposure times and time interval between treatments.)

A Proven Treatment?

A multicenter randomized clinical trial of TTT (the TTT4CNV trial) is currently underway. Doctors sometimes wonder whether the procedure should be performed before the results of this trial are known.

In fact, TTT isn't considered to be an experimental procedure; the lasers that are used to perform TTT are all FDA-approved devices, and the procedure itself has been used for treating CNV in AMD for more than 5 years. (It was used for treating intraocular tumors before that, as described by Oosterhuis et al., Arch Ophthalmol 1995, 113:315-321.) In addition, numerous smaller studies support the efficacy and safety of this procedure. (For a partial list, see "Clinical Data: An Overview" on page 68.)

Ultimately, it's up to each ophthalmologist to determine if he or she is comfortable performing any given procedure. However, there's plenty of precedent for performing ophthalmic procedures that haven't been evaluated by a formal, randomized clinical trial.

The most obvious example is the use of lasers to treat diabetic retinopathy. Panretinal laser photocoagulation for diabetic retinopathy was first proposed in the late 1960s, but the beneficial effects weren't proven in a randomized trial until the Diabetic Retinopathy Study in the mid-1970s.

Similarly, the beneficial effects of laser treatment for diabetic macular edema weren't rigorously proven until the completion of the Early Treatment Diabetic Retinopathy Study in the late 1980s. Many thousands of patients had sight-saving laser photocoagulation procedures before these studies were completed.

Furthermore, many ophthalmic procedures that are commonly performed today, such as macular hole surgery and phacoemulsification, haven't been evaluated through formal randomized trials. Selective laser trabeculoplasty (SLT) has also been widely accepted in the glaucoma community, even though a randomized clinical trial evaluating its efficacy has only recently been started.

Economic Considerations

TTT is gaining wide acceptance around the world; it's currently in use in more than 50 countries. It's also approved for reimbursement in 17 states in the United States and covered under the public health insurance plans in Canada.

Part of the reason for TTT's wide acceptance is the fact that it's economically viable:

► Offering TTT doesn't involve any ongoing costs. The only cost to the surgeon is the initial cost of the laser, and the laser can also be used for many other procedures that treat diabetic retinopathy and glaucoma.

► TTT doesn't require any additional office space.

► Performing the procedure doesn't require any specially trained staff.

► TTT takes only a couple of minutes, so it can be performed by one doctor working in a busy clinic.

By comparison, the high cost of the drugs required for PDT has been an obstacle for individual patients and national health plans throughout the world. Many of the new pharmacological treatments for AMD currently undergoing clinical trials in the United States will also face this obstacle.

A Valuable Alternative

When choosing which treatment options to offer your AMD patients in the current healthcare environment, practical and economic considerations, as well as clinical efficacy, need to be taken into account. TTT has a lot to offer in all of these areas. My experience -- along with the clinical evidence to date -- shows that TTT is safe and effective, and the economic benefits are clear.

In addition:

► Because it involves no significant set-up time, additional equipment or additional support staff, it's particularly well-suited for a busy retinal practice with limited space or resources.

► TTT is a valuable treatment option for patients with classic CNV for whom PDT is not a viable option.

► TTT makes treatment possible in parts of the world where there's limited access to PDT.

► TTT is an excellent option for elderly patients. It requires no intravenous access, can be performed in a relatively short period of time, requires minimal follow-up and has no risk of systemic side-effects.

I believe that any ophthalmologist who wants to offer patients with AMD a comprehensive range of treatment options should consider incorporating TTT into his or her practice.

Dr. Fareed Ali is director of clinical research at the Canadian Centre for Advanced Eye Therapeutics in Toronto, Canada. He has no financial interest in any of the products or therapies mentioned in this article.

Should You Re-Treat?

The decision to re-treat should be based on a number of factors, including patient symptoms, visual acuity, biomicroscopic retinal examination and retinal imaging tests such as Optical Coherence Tomography (OCT) and fluorescein angiography. OCT has been particularly useful in demonstrating reduction in subretinal fluid post-TTT. (See images below). Note that leakage found using fluorescein angiography doesn't necessarily indicate a need for re-treatment, especially in cases of occult CNV. If the patient reports improvement, visual acuity hasn't worsened, and you find less subretinal exudation (clinically and on OCT), then TTT probably shouldn't be repeated even if you find some residual angiographic leakage. If you're using TTT for the first time, observe your first series of patients closely; carefully examine the pre- and post-TTT retinal photographs, angiograms and OCT scans. Keep a record of your patients' rate of vision stabilization and their re-treatment rates. Then compare your rates to the averages presented and published by experienced users. If your stabilization rates are much lower and your retreatment rates are much higher than the reported averages, re-evaluate the parameters you're using. Left: OCT of patient before TTT. Right: OCT of same patient 3 months after TTT shows significant reduction in subretinal fluid.