The Clinical
Benefits of Transpupillary Thermotherapy for
the Treatment of Subfoveal
Occult Choroidal Neovascularization
A
review of transpupillary thermotherapy to treat neovascular AMD.
ELIAS REICHEL, MD
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.
TREATMENTS FOR NEOVASCULAR
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.
|
TRANSPUPILLARY THERMOTHERAPY
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.
|
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).
|
|
|
|
TTT4CNV CLINICAL TRIAL
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 ereichel@tufts-nemc.org.
REFERENCES
1. Macular Photocoagulation
Study Group. Laser photocoagulation of subfoveal neovsacular lesions of age-related
macular degeneration: updated findings from two clinical trials. Arch Ophthalmol.
1993;111:1200-1209.
2. Photodynamic therapy of
subfoveal choroidal neovascularization in age-related macular degeneration with
verteporfin: one-year results of 2 randomized clinical trials – TAP report.
Arch Ophthalmol. 1999;117:1329-1345.
3. Gragoudas ES, Adamis AP,
Cunningham ET Jr, Feinsod M, Guyer DR. Pegaptanib for neovascular age-related macular
degeneration. N Eng J Med. 2004;351:2805-2816.
4. Reichel E, Berrocal AM,
Ip M, Kroll AJ, Desai V, Duker JS, Puliafito CA. Transpupillary thermotherapy of
occult subfoveal choroidal neovascularization in patients with age-related macular
degeneration. Ophthalmology. 1999;106:1908-1914.
5. Reichel E, Musch DC, Blodi
BA, Mainster MA, TTT4CNV Study Group. Results from the TTT4CNV Clinical Trial. Investigative
Ophthalmology in Visual Science. 2005;Abstract:2311.
6. Park CH, Duker JS, Mainster
MA, Puliafito CA, Reichel E. Transpupillary thermotherapy (TTT) of occult choroidal
neovascularization: a retrospective, noncomparative case series of fifty-seven eyes.
Semin Ophthalmol. 2001;16:66-69.
7. Friberg
TR, Pandya A,
Nazari K. Transpupillary thermotherapy (TTT) fir age-related macular degeneration.
Semin Ophthalmol. 2001;16:70-80.
8. Ahuja
RM, Benner JD, Schwartz JC, Butler JW, Sterdl SM. Efficacy of occult subfoveal choroidal neovascularization
in age-related macular degeneration. Semin Ophthalmol. 2001;16:81-85.
9. Algvere PC, Libert C,
Seregard S. Transpupillary thermotherapy of occult CNV with no or minimally classic
CNV in age-related macular degeneration. Semin Ophthalmol. 2001;16:90-96.
10. Thach AB, Sipperley JO,
Dugel PU, Sneed SR, Park DW, Cornelius J. Large-spot size transpupillary thermotherapy
for the treatment of occult choroidal neovascularization associated with age-related
macular degeneration. Arch Ophthalmol. 2003:121;817-820.
11. Newsom
RB, McAlister JC,
Saeed M, McHugh JDA. Transpupillary thermotherapy (TTT) for the treatment of choroidal
neovascularization. Br J Ophthalmol. 2001;85:173-178.
Retinal Physician, Issue: July 2005