The Clinical Benefits of Transpupillary Thermotherapy for the Treatment of Subfoveal Occult Choroidal Neovascularization

A review of transpupillary thermotherapy to treat neovascular AMD.

The Clinical Benefits of Transpupillary Thermotherapy for the Treatment of Subfoveal Occult Choroidal Neovascularization
A review of transpupillary thermotherapy to treat neovascular AMD.

Age-related macular degeneration (AMD) is a leading cause of severe vision loss among the elderly throughout the world. Available treatments for neovascular AMD now include laser photocoagulation,1 photodynamic therapy (PDT) with verteporfin (Visudyne, QLT/Novartis, Vancouver, Canada),2 and intravitreal injections of biopharmaceutical agents that inhibit vascular endothelial growth factor (VEGF).3 The first anti-VEGF agent to be approved by the FDA is pegaptanib sodium (Macugen, Eyetech/Pfizer, New York, NY). These treatments result in avoidance of 3 lines of loss of vision in approximately 61%–70% of patients after 1 year of treatment compared to conventional laser photocoagulation of subfoveal choroidal neovascularization (CNV), which typically results in severe loss of vision immediately after treatment. The future remains exciting, in that other treatments, such as ranibizumab (Lucentis, Genentech, San Francisco, CA), offer promise to patients suffering from the neovascular consequences of AMD.


Suprathreshold laser photocoagulation was the mainstay for a small minority of patients with neovascular AMD prior to the development of PDT with verteporfin and anti-VEGF treatment with pegaptanib sodium. One significant impetus for the development of alternative treatments was the drastic reduction in visual acuity (VA) following ablative treatments for CNV. In the late 1990s, before these new treatments came to market, interest developed in subthreshold laser photocoagulation protocols for the treatment of occult subfoveal CNV.4 Subthreshold protocols were developed, and were given the name transpupillary thermotherapy (TTT). Emphasis was placed on the treatment of subfoveal occult CNV because there were no treatment alternatives for this form of the disease, which represented the large majority of patients with exudative AMD.

Figure. A patient treated with transpupillary thermotherapy at baseline and at the 24-month follow-up.


Strong interest in TTT exists, as neovascular AMD is a worldwide problem. Pharmacologically-based treatments are expensive and can be difficult to deliver, particularly to elderly individuals, relative to laser-based treatments. Therefore, TTT can play a significant role in the management of neovascular AMD (Figure).

Transpupillary thermotherapy is applied using a large spot slit-lamp delivery system and an infrared (810 nm) laser (IRIDEX Corporation, Mountainview, CA). Typically, the power is of low intensity (less than 800 mW), over 60 seconds duration for a 3-mm spot.

Larger spot sizes can be delivered with newer slit-lamp delivery systems. Advantages of TTT that were recognized early on included: infrequent occurrence of severe loss of vision immediately after treatment, unlike what occurs with suprathreshold laser protocols when applied to the fovea; apparent resorption of subretinal and intraretinal fluid as evidenced on optical coherence tomography (OCT); apparent stabilization and, in some instances, improvement of VA. Numerous peer-reviewed case series, from clinical investigators worldwide, of treated patients were consistent with these observations. These findings proved to be impetus for the TTT4CNV Clinical Trial which was initiated in March 2000 with the aim to show the safety and efficacy of TTT in a multicentered, randomized, prospective, sham-controlled study.

Results From the TT4CNV Clinical Trial
Elias Reichel, MD

During the 2005 ARVO meeting in Fort Lauderdale, FL, Elias Reichel, MD, presented the results of the TTT4CNV trial on behalf of the TTT4CNV Study Group. The TTT4CNV trial was initiated in March 2000 with the aim to show the safety and efficacy of transpupillary thermotherapy (TTT) in the treatment of neovascular age-related macular degeneration.

The study was conducted at 22 enrolling centers across the United States. Only patients who had occult CNV, �10% classic CNV, �3 mm greatest diameter (<1.8 disc diameter), and who were 50 years of age or older with a VA of 20/50–20/400 (20-65 ETDRS letters) were included.

The randomized (1 eye/patient), masked (patient, VA & FA examiners, Reading Center), 2/3 treated (800 mW; 60 seconds; 3 mm), 1/3 sham controlled (O mw; 60 seconds; 3 mm) study consisted of 69% females with a mean study age of 79 years. The mean VA was 58 letters and angiographic characteristics of enrolled patients were 81% pure occult, 13% with up to 10% classic, and 6% with 10% or more classic.

The same treatment dose was used for all eyes regardless of lesion and patient characteristics, and follow-up examinations were conducted at 1, 3, 6, 12 and 24 months. Only 1 retreatment was allowed at 3 months at the investigator's discretion (50% of eyes were retreated).

Overall there was no significant difference in severe vision loss one month after treatment (9/196).


The TTT4CNV Clinical Trial was recently concluded. General observations from this clinical trial confirmed that TTT treatment did not result in a significant difference in immediate severe loss of vision when compared to the sham treated group and the risk of severe vision loss was less than 5%. This substantiates the idea that subthreshold photothermal protocols can be used to treat the macula with a very low risk of severe vision loss. Further, all efficacy trends favored TTT when compared to the sham group, though the primary efficacy endpoint of avoidance of moderate vision loss did not meet statistical significance. The secondary efficacy endpoint of visual improvement was achieved and was statistically significant.

In light of the favorable trends in the intent-to-treat group, a subgroup analysis was performed on those patients who had baseline VAs of 20/100 or worse.5 The rationale for this analysis was based upon the fact that the majority of patients who were described in previously published case series had 20/100 vision or worse (Table).6-11 Further, the subgroup of patients with 20/100 vision or worse showed significant benefit in the TAP studies and in the SST Study (Group H). In the subgroup of patients with best-corrected baseline VA of 20/100 or worse, it was determined that TTT had an increasingly beneficial effect over time, using a longitudinal analysis of time by treatment interaction and this was statistically significant. There was approximately a 2-line difference in VA, favoring patients who were treated with TTT, at the Month 24 point. In this subgroup of patients with poorer vision, there were no patients in the sham group who showed at least 1 line of improvement, whereas 20% in the TTT group did.

These findings demonstrate that subthreshold laser photocoagulation can be used to treat occult CNV underneath the fovea and that the natural history can be altered with this technique. The subgroup of patients with baseline VA of 20/100 or worse showed a benefit to TTT when compared to natural history.

Transpupillary thermotherapy remains a cost effective and easy to implement treatment that does not require multiple treatment sessions over a prolonged period of time. Transpupillary thermotherapy serves a worldwide need for an inexpensive and easy to deliver method of altering the natural history of occult CNV. Further advances in noninvasive techniques in measuring temperature and appropriate laser dosimetry may result in further refinements of this treatment technique.


Elias Reichel, MD is vice chair, Department of Ophthalmology, Tufts University School of Medicine; director of vitreoretinal diseases and surgery service and director of the vitreoretinal Fellowship at the New England Eye Center, Boston, MA. Dr. Reichel is a consultant for IRIDEX and serves as an advisor to Eyetech, Genetech, and Novartis. He can be reached by e-mail at



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