Aim: To compare the efficacy of low-dose transpupillary thermotherapy (TTT) and verteporfin photodynamic therapy (PDT) in patients with occult neovascular age-related macular degeneration (AMD).
Methods: Patients were randomised to receive either low-dose TTT (136 mW/mm) (and sham PDT) (n = 52) or PDT (and sham TTT) (n = 46) with retreatment if leakage was documented by fluorescein angiography. At baseline and at every follow-up, best corrected visual acuity (BCVA) was measured with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, lesion size on fluorescein angiography and foveal thickness with optical coherence tomography. The primary outcome measure was the proportion of patients who lost <15 letters at 12 months’ follow-up. Secondary outcome measures included the proportion of patients who gained ⩾0 letters, the change in mean lesion size and the change in foveal thickness at 12 months’ follow-up.
Results: The percent of patients losing fewer than 15 letters at 12 months was 75.0% in the TTT group and 73.9% in the PDT group (p>0.05). The percent of patients with preserved or improved BCVA was 36.5% in the TTT group versus 23.9% in the PDT group (p>0.05). The mean decrease in foveal thickness was 15% for TTT and 24% (p>0.05) for PDT-treated patients, and the mean increase in total lesion area was −0.7% and −1.1% (p>0.05), respectively.
Conclusion: In this prospective, randomised trial low-dose TTT and PDT appeared to be equally efficient at stabilising visual acuity in patients with occult neovascular AMD. Low-dose TTT may be considered as an alternative to PDT in this set of patients and also as an adjuvant to pharmacotherapy.
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Neovascular age-related macular degeneration (AMD) characterised by choroidal neovascularisation (CNV) is a primary cause of legal blindness in the Western world. Without treatment, prognosis is poor, resulting in a rapid and progressive loss of visual acuity and contrast sensitivity. Numerous randomised large-scale trials have shown that photodynamic therapy (PDT) with verteporfin stabilises visual acuity in patients with classic, predominantly classic and certain types of occult lesions.1 2 As to the lesions displaying occult CNV, the positive effect of PDT appeared greater in patients with either smaller lesions (⩽4 MPS disc areas) or lower levels of visual acuity (approximately ⩽20/50 in the affected eye).2 3 Limitations to PDT include its relatively high cost, the need for repeated retreatments, and the continuing visual decline that many patients experience even with treatment.
Transpupillary thermotherapy (TTT) is a technique where vascular occlusion can be induced without any photosensitive dye by delivering radiation near infrared (810 nm) to the target tissue through the pupil. TTT enables the treatment of choroidal lesions by causing a small temperature elevation (8–10°C) with subsequent intravascular thrombosis.4 Several uncontrolled small-scale trials have indicated that TTT may stabilise visual acuity in patients with neovascular AMD.5–9 The TTT4CNV study was a large prospective randomised trial comparing TTT and sham in patients with occult CNV.10 In the TTT4CNV study, no overall benefit of TTT was found, although subgroup analysis demonstrated a positive effect in patients with low baseline visual acuity (⩽20/100). There has also been controversy about the optimal intensity of the laser radiation delivered to the eye, partly because of different pigmentation of the fundus. This renders it more difficult to apply an optimal dose of TTT, thereby avoiding possible under- and overtreatment. Experimental studies indicate that TTT may inhibit CNV without collateral damage but confirms that the therapeutic window is narrow.11
Recently, new treatment options for neovascular AMD have emerged with the introduction of agents that inhibit vascular endothelial growth factor (VEGF).12–14 These treatment modalities have the potential not only to stabilise but also to improve visual acuity. Their limitations include a very high cost and the need for repeated intravitreal injections that may persist for many years, as well as a risk for intraocular complications such as endophthalmitis.
In this prospective and randomised study, we compare the effect of low-dose TTT with PDT in occult CNV secondary to AMD.
MATERIALS AND METHODS
Study design and case selection
Ninety eight patients (98 eyes) were randomly assigned (in a 1:1 ratio) to PDT with verteporfin or to TTT. To be eligble for the study the patients had to meet the following inclusion criteria: (1) age 50 years or older, (2) occult CNV under the geometric centre of the fovea. Occult CNV was defined either as a fibrovascular retinal pigment epithelium detachment (PED) or as late leakage of undetermined source, (3) lesion size of less than 5000 μm in the greatest linear dimension (GLD), (4) Best corrected ETDRS visual acuity (BCVA) corresponding to a Snellen equivalent of 20/200 to 20/25. (5) Clear ocular media. The baseline characteristics are displayed in table 1. Patients had to have the ability and willingness to understand the informed consent. Subjects were excluded if they had any condition other than AMD to account for the neovascularisation (such as pathological myopia or intraocular inflammation) or any other ocular condition that might or could have compromised vision. Patients should also not have been treated for CNV by any other means. Since this study was conducted before anti-VEGF therapies had become available this treatment option could not be offered.
Verteporfin (6 mg/m2) was infused intravenously over 10 min. Fifteen minutes after the start of infusion, diode laser treatment was performed (689 nm, 50 J/cm2 at an intensity of 600 mW/cm2) for 83 s, using a spot diameter 1000 μm larger than the greatest linear dimension (GLD) of the lesion. The GLD was measured from fluorescein angiograms. Any area of hypofluorescence due to overlying blood or a serous detachment of the RPE contiguous with CNV was considered to be part of the GLD. Sham PDT was given to all patients receiving TTT and was performed in the same way as PDT, with the exception that a glucose infusion was given instead of verteporfin.
Before starting TTT, a sham intravenous infusion of 5% dextrose in water was given over 10 min. Fifteen minutes after the start of infusion, an infrared diode laser at 810 nm (Iridex, Mountain View, CA) delivered a single spot for 60 s via a slit-lamp adaptor. The occult lesions were of a different size; some were quite large and difficult to precisely define and may have originated from one or more foci. Therefore, the Mainster wide field lens was used with a standard 3 mm spot in the laser slit lamp, which produced a spot size of 4.41 mm in diameter on the retina. The laser was selected to deliver 600 mW, corresponding to a power of 136 mW for a circular spot of 1 mm diameter. Since the temperature increases linearly with increased laser spot diameter, treatment power is also proportional to treatment spot diameter.14–16 Thus, a 1.5 mm diameter circular lesion requires half the laser power of a 3.0 mm lesion. Sham TTT was given to all patients receiving PDT and was performed in the same way as TTT, with the exception that the laser power was turned off.
Clinical assessments included BCVA (logarithmic ETDRS chart at 4 m), slit-lamp biomicroscopy of the anterior and posterior segments (funduscopy with a 78D Volk lens), IOP measurement, fluorescein angiography and optical coherence tomography (OCT; Zeiss-Humphrey). All examinations of the angiograms and OCT were performed by the same experienced ophthalmologist (AO), who was not masked to the treatment of the patient.
Each patient was examined at 6, 12, 18, 24, 36 and 48 weeks. At each visit, BCVA, slit-lamp biomicroscopy, fluorescein angiography and OCT were carried out. The follow-up was 12 months. If patients showed active CNV leakage at the time of the regularly scheduled follow-up visits, they were retreated using PDT (and sham TTT) or TTT (and sham PDT) as described above. After treatment, all patients were instructed to avoid direct sunlight and while outdoors to wear special glasses.
Main outcome measures
The main outcome measure was the proportion of patients who lost <15 ETDRS letters at 12 and 24 months’ follow-up. Secondary outcome measures were the proportion of patients who gained (⩾0) letters, the mean change in lesions size and GLD and the change in foveal thickness at 12 months’ follow-up.
The primary hypothesis was based on a difference between the treatment groups in the proportion of patients achieving the main outcome measure. We assumed that 50% of the patients treated with PDT and 80% of the patients treated with TTT would achieve the primary endpoint (loss of less than 15 letters). With a statistical power of 90% and a p value of <0.05, we estimated that a total of 96 patients would be needed (MedCalc Software, Mariakerke, Belgium). For statistical analyses, the independent Student t test and the chi-square test (to compare differences in distributions between the groups) were used.
In this study, 98 patients with occult CNV were randomly assigned to receive either low-dose TTT (n = 52) or PDT (n = 46). Fifty-one (98%) of the TTT-treated and 44 (96%) of the PDT patients completed the 12 month follow-up period. At baseline, no statistical difference was found in age, gender, visual acuity, lesion size or foveal thickness between the two groups (table 1).
At baseline, the mean BCVA was 59.7 and 60.7 ETDRS letters in the TTT and PDT groups, respectively. At 12 months, the BCVA had decreased to 52.5 letters (−7.2 letters) in TTT-treated patients and to 53.5 (−7.2 letters) in PDT-treated subjects (fig 1A, 1B).
The proportion of patients with stabilised visual acuity (lost <15 letters) was 75.0% and 73.9% in the TTT and PDT groups, respectively (p>0.05) (fig 2). The proportion of patients who gained ⩾0 letters was higher in TTT-treated patients (36.5%) than in PDT-treated patients (23.9%), but the difference was not statistically significant (p>0.05) (fig 3).
The mean lesion size and GLD at baseline were 7.84 mm2 (4.44 DA) and 3.59 mm in the TTT group vs 7.99 mm2 (4.52 DA) and 3.56 mm in the PDT group. At 12 months, the lesion size remained almost unchanged (−0.7% TTT group vs −1.1% for the PDT group). The mean foveal thickness as determined by OCT decreased by 14.4% and 24.7% in the TTT and PDT groups, respectively. These differences in secondary outcome measures between the treatment groups were not statistically significant (table 2). Leakage stop was found in 88% of TTT treated patients and in 93% of PDT treated patients. The mean number of treatments was 3.0 in the TTT group and 2.3 in the PDT group.
This prospective study, randomising subjects with occult neovascular AMD to low-dose TTT or PDT, showed that the two treatment modalities yielded visual results that were almost identical. During a follow-up of 12 months, no significant differences between the two groups emerged. The results further show that in both groups of patients, the mean change in MPS disc areas, foveal thickness and cessation of fluorescein leakage remained the same over time.
The mode of action of TTT compared with PDT reveals different features. PDT induces immediate thrombosis and cessation of perfusion, particularly in areas of neovascularisation.17 18 PDT treatment of experimental CNV in the mouse has confirmed the acute closure of vessels after 1 and 7 days but also that treated areas remain vascularised to some extent even at high light doses.19 In patients treated with PDT, angiography has indicated a closure of choroidal vessels proceeding over as long as 1 week.20 Following TTT targeted to experimental CNV in the mouse eye, transmission electron microscopy confirmed the presence of vascular occlusion at 1 day and significant reduction, and persistent vascular occlusion, of the CNV at 7 days.11 In patients with subfoveal CNV, FA and ICG demonstrated a hypofluorescent area corresponding to the laser spot and absence of angiographic leakage at 1–2 weeks.21
Experience indicates that the TTT radiation power is crucial for the maintenance of retinal function and in avoiding putative cellular damage. In the initial TTTrCNV study, a laser power of 800 mW (for a 3 mm retinal spot) was used in patients with neovascular AMD.5 However, in later investigations on occult CNV, it was observed that a power of 800 mW induced a greater visual loss than 600 mW.7 Animal experiments further indicate that the therapeutic window of TTT is quite narrow, showing inhibition of experimental CNV without morphological retinal damage within a limited range of laser power (in this experimental setting a laser power of 50 mW induced vascular occlusion in CNV without causing retinal damage, whereas outer layer disruption occurred at 80 mW).11 Therefore, in the present clinical study, the laser power was reduced to 136 mW/mm (retinal spot diameter) as compared with 248 mW/mm in some other studies.5 10
The main outcome measure was not met in this study, that is that low-dose TTT would prove superior to PDT at stabilising BCVA. In fact, the two treatments behaved remarkably similar in this set of patients. Based on this outcome, it may have been preferable to design a non-inferiority study instead. However, such a study would have required approximately 300 patients per treatment group.22 Furthermore, the similar outcome in the two groups suggests that any difference found in a study using a larger sample size would probably be small and not clinically relevant. Regarding the secondary outcome measures, there was a trend in favour of TTT (eg, the proportion of patients with preserved or improved BCVA and the mean increase in total lesion area) although none of the parameters were statistically significant.
The VIP2 study (Verteporfin in Photodynamic Therapy Study) was a randomised clinical trial comparing the effect of PDT with placebo (sham PDT) in patients with occult CNV.2 This study concluded that PDT was significantly better than placebo in patients with smaller lesions (<4DA) or lower BCVA (less than 65 letters, Snellen equivalent <20/50). In the VIP2 study, the proportion of patients with stabilised BCVA (losing <15 letters) was 54% (PDT group) and 39% (placebo group). In the present study, we compared the effect of TTT and PDT in a similar set of patients with occult CNV. The proportion of patients with stabilised BCVA was much higher in our study (75.0% and 73.9% in the TTT and PDT groups, respectively) than those reported in the VIP2 study. In our study, we did not include a placebo group prohibiting a direct comparison with the VIP2 study. Nevertheless, our results compare very favourably to those of the VIP2 study (the placebo group lost more than 20 letters in the VIP2 study compared with seven letters for both treatments in our study), indicating that both low-dose TTT and PDT are indeed superior to placebo in this set of patients with occult CNV.
Anti-VEGF agents (eg, pegaptanib, ranibizumab and bevazimab) have now become most valuable treatment modalities in neovascular AMD. However, for optimal effect, these agents require intravitreal injections every 4 or 6 weeks for a considerable period of time. In order to reduce the burden of this treatment on the patient as well as on the healthcare system, the development of strategies aimed at reducing the number of intravitreal injections will be critical. Combination therapy is one such attractive possibility. For example, the use of PDT as an adjuvant to ranibizumab or bevazicumab has been suggested to decrease the need for repeated intravitreal injections.23–25 Also, this combination may prove beneficial regarding control of lesion growth, and ideally the need for long-term retreatments may be reduced. Several randomised multicentre trials are now being planned to address this promising concept. Our present finding indicating that low-dose TTT is equipotent to PDT suggests that TTT may also be considered as an adjuvant therapy to intravitreal pharmacotherapy. The fact that the cost of TTT is negligible makes this possibility even more attractive. However, this concept needs to be further investigated in randomised clinical trials.
Competing interests: None.
Ethics approval: This investigation was approved by the Local Ethics Committee at the Karolinska Institutet.
Patient consent: All patients included gave their informed consent to participate.
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