Choroidal neovascularization (CNV) is a common cause of adult-onset blindness, most commonly associated with age-related macular degeneration (AMD). In its earliest stages, AMD is characterized by minimal visual impairment and the presence of large drusen and other pigmentary abnormalities on ophthalmoscopic examination. As AMD progresses, 2 distinctively different forms of degeneration may be observed. The first, called the atrophic, areolar or dry form, evolves slowly. Atrophic AMD is the most common form of degeneration and is often a precursor of the second form, the more devastating exudative neovascular form, also referred to as disciform or wet degeneration. The wet form is distinguished from the atrophic form by serous or hemorrhagic detachment of the retinal pigment epithelium and the development of choroidal neovascularization (CNV), sometimes called neovascular membranes. Risk of developing severe irreversible loss of vision is greatly increased by the presence of CNV.
The pattern of CNV, as revealed by fluorescein or indocyanine angiography, is further categorized as classic or occult. For example, classic CNV appears as an initial lacy pattern of hyperfluorescence followed by more irregular patterns as the dye leaks into the subretinal space. Occult CNV lacks the characteristic angiographic pattern, either due to the opacity of coexisting subretinal hemorrhage or, especially in CNV associated with AMD, by a tendency for epithelial cells to proliferate and partially or completely surround the new vessels. Interestingly, lesions consisting only of classic CNV carry a worse visual prognosis than those composed of only occult CNV, suggesting that the proliferative response that obscures new vessels may also favorably alter the clinical course of AMD.
There is ongoing research interest in the use of transpupillary thermotherapy to treat subfoveal choroidal neovascularization with an “occult” angiographic pattern. Transpupillary thermotherapy (TTT) is a technique in which heat is delivered to the choroid and retinal pigment epithelium through the pupil using a modified diode laser. This laser technique contrasts with the laser used in standard photocoagulation therapy, in that TTT uses a lower power laser for more prolonged periods of time and is designed to gently heat the choroidal lesion, thus limiting damage to the overlying retinal pigment epithelium.
Laser photocoagulation has been used to treat CNV, however, patients with subfoveal lesions are generally not candidates for this treatment due to the risk of an immediate reduction in central vision, outweighing any treatment advantage. Photocoagulation of macular drusen is addressed in policy No. 9.03.11.

Photodynamic therapy (see policy No. 9.03.08) has been used with success in treating subfoveal CNV; the treatment has shown the greatest success in treating patients with classic CNV (as opposed to occult CNV), as defined angiographically. Photodynamic therapy as a treatment of CNV uses a nonthermal laser designed to activate verteporfin, the photosensitizing agent.
Treatment of choroidal neovascularization with anecortave acetate is addressed in policy No. 9.03.16.

Transpupillary thermotherapy is considered investigational as a treatment of choroidal neovascularization.

In 2002, a new CPT tracking code was introduced to specifically describe transpupillary thermotherapy and to differentiate this therapy from other laser treatments of choroidal neovascularization, i.e., photodynamic therapy (CPT code 67221) and laser photocoagulation (67220) as follows:

0016T: Destruction of localized lesion of choroid (e.g., choroidal neovascularization), transpupillary thermotherapy.

Plans may continue to see this service coded incorrectly with 67220.

BlueCard/National Account Issues

Some state or federal mandates (e.g., FEP) prohibit plans from denying technologies approved by the U.S. Food and Drug Administration (FDA) as investigational. Since the laser used in this procedure (an adaptation of the laser used for standard photocoagulation) is FDA approved, Plans may have to consider the coverage eligibility on the basis of medical necessity alone for some lines of business.

There are minimal published data regarding transpupillary thermotherapy. Reichel and colleagues reported on a case series of 16 eyes in 15 patients who presented with occult subfoveal choroidal neovascularization secondary to age-related macular degeneration. (1) Three eyes showed a 2 or more line improvement in visual acuity over a period of 6 to 25 months. Visual acuity remained stable in 9 treated eyes. The remaining 4 eyes showed a decline in visual acuity. Newson and colleagues reported on a case series of 44 eyes in 42 patients consisting of 12 eyes with classic CNV and 32 eyes with occult CNV. (2) The mean follow-up was 6 months. The mean change in vision in those with classic and occult CNV was –0.75 and –0.66 Snellen lines, respectively.

Further data are needed to confirm these preliminary results. The TTT4CNV Study is a nationwide study involving 22 centers that was started in March 2000 (http://www.eyesight.org/Research/Research-TTT/research-ttt.html). A total of 336 patients with symptomatic occult CNV that shows signs of exudation are being recruited. Two thirds of eyes will be treated and one third will receive sham treatment. Patients will be followed up for 2 years.

Updated reviews of the peer-reviewed literature based on the MEDLINE database in 2003 and 2005 identified no publications on clinical trials for transpupillary thermotherapy for treatment of CNV that would change the policy statement. One prospective nonrandomized study of 21 eyes with idiopathic CNV reported 81% of patients treated with TTT were improved or stabilized at a mean of 5.1 months follow-up. (3) Three other nonrandomized studies of TTT in eyes with CNV related to ARMD were reported. (4-6) Nagpal and colleagues reported on TTT for CNV in 160 eyes (99 classic and 61 occult) of patients of Indian descent. (4) The authors reported in classic CNV, 29.3% improved, 39.4% stabilized, and 31.3% deteriorated at 12 months’ follow-up. In occult CNV, 19.6% improved, 57.4% stabilized, and 22.9% deteriorated. Nagpal and colleagues concluded that there was effectiveness with TTT in Indian eyes, which responded to lower energy levels than did Caucasian eyes in their experience. In Thach et al, 69 eyes with occult CNV were treated with TTT. (5) After a minimum of 6 months’ follow-up, 71% of patients improved or stabilized. Finally, in the Algvere study of TTT in predominately occult CNV, 8% improved, 40.7% stabilized, and 51.3% deteriorated after 12 months’ follow-up. (6) Algvere and colleagues reported minimally classic CNV responded poorly to TTT. While there appears to be some improvement or stabilization in occult CNV in these studies, further study is needed to demonstrate that improvements in health outcomes occur with acceptable levels of adverse effects with TTT over the natural course of the disease.

In addition, in a presentation at the American Academy of Ophthalmology meeting in October 2004, in New Orleans, Iridex Corporation announced preliminary results of the TTT4CNV study. Iridex reported preliminary results did not show TTT for CNV resulted in significant benefit over sham treatment. Only 47% of 303 patients who received TTT for CNV had modest or severe vision loss after 2 years, compared with 43% in those who received sham treatment. Further analysis of the data will be performed, according to Iridex Chief Executive Theodore Boutacoff. Therefore, the policy statement is unchanged.

An October 2005 TEC Special Report on the treatment of age-related macular degeneration supports the conclusions given above noting TTT, when used alone, has not been efficacious. (7) A trial combining triamcinolone with TTT is currently in progress.

2006-2007 Update

A search of the MEDLINE database for the period of October 2005 through January 2007 found no evidence to support a change in the policy statement. TTT is being studied outside of the U.S. for patients with occult choroidal neovascularization who are not candidates for phototherapy. Two small randomized trials (28 and 25 patients) reported no benefit of TTT in preventing further visual loss in patients with occult choroidal neovascularization, while a case series reported macular burn as a complication of TTT in 8.6% of 35 patients available for follow-up. (8-10) One randomized (not blinded) study of 26 patients did not find a statistically significant improvement for combination treatment with triamcinolone and TTT in comparison with TTT alone. (11)

2008 Update
A search of the MEDLINE database was performed for the period of February 2007 through April 2008. Two studies from Asia (one small controlled trial and one case series) were identified; both studies indicated that the rationale for utilizing TTT was the lower cost of this treatment in comparison with photodynamic therapy (PDT) with verteporfin. (12, 13) In the controlled trial, patients chose PDT or TTT after an explanation of the costs, benefits and risks of each treatment. (12) Sixteen patients (16 eyes) selected PDT and 14 patients (16 eyes) selected TTT; treatments were repeated if there was evidence of dye leakage at follow-up. The average pre-treatment visual acuity was similar in the two groups. At six months follow-up visual acuity loss was 15 letters or less in 14 (87%) eyes treated with TTT and 13 (81%) eyes treated with PDT; however, more patients with good initial visual acuity (20/63 or greater) had a loss of 2 or more lines following TTT (4 of 4), than following PDT (1 of 6). Although the authors concluded that patients with good initial visual acuity should be treated with PDT, the study is limited by selection bias and small subject number. Larger prospective studies are needed to evaluate whether TTT may be an acceptable option in comparison with photodynamic therapy. Evidence is insufficient to determine whether TTT is as beneficial as the established alternative; the policy statement is unchanged.
Preferred Practice Patterns (practice guidelines) on photodynamic therapy from the American Academy of Ophthalmology (AAO) indicate that there is insufficient evidence to guide treatment recommendations for transpupillary thermal therapy. (14)

References:

1. Reichel E, Berrocal AM, Ip M et al. Transpupillary thermotherapy of occult subfoveal choroidal neovascularization in patients with age-related macular degeneration. Ophthalmology 1999; 106(10):1908-14.
2. Newson RS, McAlister JC, Saeed M et al. Transpupillary thermotherapy (TTT) for the treatment of choroidal neovascularization. Br J Ophthalmol 2001; 85(2):173-8.
3. Kumar A, Prakash G, Singh RP. Transpupillary thermotherapy for idiopathic subfoveal choroidal neovascularization. Acta Ophthalmol Scand 2004; 82(2):205-8.
4. Nagpal M, Nagpal K, Sharma S et al. Transpupillary thermotherapy for treatment of choroidal neovascularization secondary to age-related macular degeneration in Indian eyes. Indian J Ophthalmol 2003; 51(3):243-50.
5. Thach AB, Sipperley JO, Dugel PU et al. Large-spot size transpupillary thermotherapy for the treatment of occult choroidal neovascularization associated with age-related macular degeneration. Arch Ophthalmol 2003; 121(6):817-20.
6. Algvere PV, Libert C, Lindgarde G et al. Transpupillary thermotherapy of predominantly occult choroidal neovascularization in age-related macular degeneration with 12 months follow-up. Acta Ophthalmol Scand 2003; 81(2):110-7.
7. TEC Special Report: Current and evolving strategies in the treatment of age-related macular degeneration. Technology Evaluation Center. October 2005.
8. Gustavsson C, Agardh E. Transpupillary thermotherapy for occult subfoveal choroidal neovascularization: a 1-year, prospective randomized pilot study. Acta Ophthalmol Scand 2005; 83(2):148-53.
9. Myint K, Armbrecht AM, Mon S et al. Transpupillary thermotherapy for the treatment of occult CNV in age-related macular degeneration: a prospective randomized controlled pilot study. Acta Ophthalmol Scand 2006; 84(3):328-32.
10. Rougier MB, Francois L, Fourmaux E et al. Complications and lack of benefit after transpupillary thermotherapy for occult choroidal neovascularization: 1-year results. Retina 2005; 25(6):784-8.
11. Agurto-Rivera R, Diaz-Rubio J, Torres-Bernal L et al. Intravitreal triamcinolone with transpupillary therapy for subfoveal choroidal neovascularization in age related macular degeneration. A randomized controlled pilot study [ISRCTN74123635]. BMC Ophthalmol 2005; 5:27.
12. Tewari HK, Prakash G, Azad RV et al. A pilot trial for comparison of photodynamic therapy and transpupillary thermotherapy for the management of classic subfoveal choroidal neovascularization secondary to age-related macular degeneration. Indian J Ophthalmol 2007; 55(4):277-81.
13. Zhang X, Zhu X, Wang D et al. Low-power transpupillary thermotherapy combined with intravitreal triamcinolone acetonide for subfoveal choroidal neovascularization. Ophthalmic Res 2007; 39(4):241-2.
14. American Academy of Ophthalmology. Age-Related Macular Degeneration, Preferred Practice Pattern. San Francisco: American Academy of Ophthalmology, 2006. Available at www.aao.org/ppp. 

Choroidal Neovascularization, Transpupillary Thermotherapy
Transpupillary Thermotherapy