Japanese Journal of Ophthalmology

, Volume 57, Issue 3, pp 283–293 | Cite as

Two-year results of reduced-fluence photodynamic therapy combined with intravitreal ranibizumab for typical age-related macular degeneration and polypoidal choroidal vasculopathy

  • Yusaku Yoshida
  • Takeya Kohno
  • Manabu Yamamoto
  • Tasuku Yoneda
  • Hisashi Iwami
  • Kunihiko Shiraki
Clinical Investigation

Abstract

Purpose

To report the 2-year results of reduced-fluence photodynamic therapy (RF-PDT) combined with intravitreal ranibizumab (IVR) for typical age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV).

Methods

Twenty-four previously untreated eyes of 23 AMD patients with decimal best-corrected visual acuity (BCVA) of less than 0.7 received the combined therapy, followed by retreatments as needed over the subsequent 2 years. When the BCVA was better than or equal to 0.7, only 3 monthly IVR injections were performed during the retreatment.

Results

The BCVAs were maintained in 7 of 10 typical AMD eyes and in 13 of 14 PCV eyes at month 24. The mean BCVA improved in the PCV group (P < 0.05) but not in the typical AMD group. The central foveal thickness decreased in both groups (P < 0.01, P < 0.001). The mean numbers of the total PDT and IVR injections were 1.8 and 7.2 in the typical AMD group and 1.8 and 6.4 in the PCV group.

Conclusion

After RF-PDT combined therapy with administration of retreatments as needed that consisted of either 3 IVR injections alone or combined therapy, the BCVA was maintained in typical AMD and improved in PCV during a 2-year follow-up period.

Keywords

Age-related macular degeneration Polypoidal choroidal vasculopathy Ranibizumab Reduced-fluence photodynamic therapy 

Introduction

The ANCHOR and MARINA clinical trials demonstrated that monthly intravitreal injections of ranibizumab (IVR) maintained and even improved the vision of patients with age-related macular degeneration (AMD) during 24-month follow-up periods [1, 2]. However, monthly injections are an enormous burden on both patients and doctors. Thus, after a loading phase of the initial 3 monthly IVR injections, IVR retreatment was performed as needed (pro re nata, PRN) during the monthly visits in the subsequent PrONTO and SUSTAIN studies [3, 4].

In an attempt to decrease the frequency of IVR retreatment, a combination therapy that used photodynamic therapy (PDT) with verteporfin and IVR or intravitreal bevacizumab (IVB) was developed. Use of this combination therapy was expected to result in both a synergistic effect from the vasoocclusive effect of the PDT and an antiangiogenic effect from the IVR or IVB. Presently, several case series studies along with a small-scale prospective randomized study have reported finding this combination therapy to be both safe and efficacious, as well as able to potentially decrease the frequency of IVB or IVR retreatment [5, 6, 7, 8, 9, 10, 11, 12, 13, 14]. Moreover, the recent MONT BLANC [15] and DENALI [16] studies have examined the efficacy and safety of using PDT in conjunction with IVR over a 12-month period. The MONT BLANC study found no difference between the combination therapy and the IVR monotherapy in the frequency of the IVR retreatment during the PRN maintenance phase.

In the majority of these previous studies, PDT was performed using a standard light fluence rate (600 mW/cm2) for 83 s (light dose, 50 J/cm2) [5, 6, 7, 8, 9, 10, 11, 12, 14]. However, it has been reported that the standard light fluence rate (SF-PDT) can damage the choriocapillary bed that surrounds the choroidal neovascular lesion (CNV) [17]. As a result, this can lead to an upregulation of vascular endothelial growth factor (VEGF) [18], with the PDT-induced changes making it possible for the CNV to recur. Thus, a PDT method that uses a reduced light fluence rate (300 mW/cm2) for 83 s (light dose, 25 J/cm2) (RF-PDT) was subsequently developed [19]. In 2 recent studies, groups receiving RF-PDT in conjunction with IVB had significantly lower frequencies of IVB retreatment over both a 6-month [20] and a 12-month [21] period as compared with the IVB monotherapy group. However, the DENALI study showed no differences between the SF-PDT and the RF-PDT groups in either the proportion of patients with IVR treatment-free intervals over 3 months or longer or the mean number of IVR retreatments [16]. Thus, typical white AMD patients may derive no or limited clinical benefits when treated with RF-PDT or SF-PDT in conjunction with IVR.

However, SF-PDT has been shown to cause regression of the polypoidal lesions of polypoidal choroidal vasculopathy (PCV), which is the most common AMD subtype in Asian countries [22]. Thus, combination therapies that use SF-PDT and IVR may be suitable for treating PCV. The EVEREST study examined the efficacy of SF-PDT and IVR combination therapy in PCV patients [23]. This combination therapy was shown to be far superior with regard to the regression of the polypoidal lesions when compared with IVR monotherapy during a 6-month trial period. Thus, regression of the polypoidal lesions could contribute to a decrease in the frequency of retreatment and a better visual prognosis. However, it has been reported that SF-PDT can produce severe complications such as extensive subretinal hemorrhage in PCV [24]. Yamashita et al. [25] reported that use of RF-PDT monotherapy for PCV resulted in high regression rates for the polypoidal lesions without any extensive subretinal hemorrhage complications and an improvement in the mean best-corrected visual acuity (BCVA) at 12 months. It has also been reported that recurrence of polypoidal lesions along with enlargement of the abnormal choroidal vascular network and occurrence of type-2 choroidal neovascularization can all occur in PCV more than 1 year after the initial treatment [26, 27, 28]. Therefore, treatment outcomes after a follow-up period of longer than 1 year need to be examined.

In the current study, we reviewed the outcomes of RF-PDT plus IVR combination therapy in Japanese patients who had typical AMD or PCV and who were followed up for 2 years. The differences between the present and previous studies included our use of 3 monthly IVR injections (performed during the retreatment) and use of specific criteria for the combination therapy and IVR monotherapy during our retreatment phase. When the BCVA was less than 0.7, the combination therapy was used for the retreatment, whereas when the BCVA was better than or equal to 0.7, only 3 monthly IVR injections were performed.

Materials and methods

This was a retrospectively reviewed case series study that was approved by the ethics committee of the Osaka City University Hospital Institutional Review Board. Between April 2009 and February 2010, treatments were performed in 106 eyes of previously untreated, symptomatic Japanese AMD patients whose decimal BCVA obtained by Landolt ring tests was less than 0.7. Treatments included 33 eyes given IVR monotherapy, 19 eyes given PDT monotherapy, and 54 eyes given combined therapy with PDT and IVR (7 eyes with SF-PDT and 47 eyes with RF-PDT). Patients with a history of cerebral infarction were all given PDT monotherapy. IVR monotherapy was normally performed because of the patient’s preference. Combined therapy with SF-PDT and IVR was done for PCV cases without involvement of the foveal region. Among the 47 eyes given the combined therapy that included RF-PDT and IVR injections, a total of 24 eyes of 23 patients (12 men, 11 women) were followed up for more than 2 years. Patients’ ages ranged from 61 to 83 years, with an average of 74.4 years. The patients were followed up monthly or bimonthly for more than 2 years after their initial combination therapy. The follow-up periods ranged from 24 to 31 months, with an average of 27.5 ± 2.0 months.

Eyes were excluded from the study when massive subretinal hemorrhage was present that precluded determining the greatest linear dimension of the CNV, retinal angiomatous proliferation, or serous retinal pigment epithelial detachment unaccompanied by angiographic findings of CNV or PCV. We also excluded eyes with other diseases that cause CNV, such as high myopia with refractive error of more than −6.00 diopters, angioid streaks, and idiopathic macular CNV.

Fluorescein fundus angiography (FA) and indocyanine green fundus angiography (IA) were performed using a confocal scanning laser ophthalmoscope (Heidelberg Spectralis; Heidelberg Engineering, Heidelberg, Germany) and a digital fundus camera system (TRC50IX IMAGEnet 2000; Topcon, Tokyo, Japan). Procedures were performed before the initial combination therapy and then every 3 months until 1 year after the initial treatment. Thereafter, angiographies were performed when signs of remaining or recurrent CNV, such as subretinal fluid or intraretinal edema, were noted on optical coherence tomography (OCT). At each visit, patients underwent OCT with an RTVue device (Optovue, Fremont, CA, USA).

When polypoidal dilatations of vessels with or without abnormal choroidal vascular networks were seen on IA, PCV was diagnosed. In addition to PCV, we used FA findings to determine typical AMD patients, with individuals classified as having predominantly classic CNV, minimally classic CNV, or occult with no classic CNV.

For the combination therapy, RF-PDT was performed 3 days after the initial IVR injection, which was followed by 2 more monthly IVR injections. RF-PDT was performed 5 min after the completion of verteporfin (Visudyne; Novartis Pharma, Tokyo, Japan) injection at 6 mg/m2 of body surface area over 10 min with a light fluency rate of 300 mW/cm2 over 83 s (light dose, 25 J/cm2) using a Visulas PDT 690S system (Carl Zeiss Meditec, Jena, Germany). The half-light fluence was obtained by reducing the magnification rate of the PDT laser lens (Volk Optical, Mentor, OH, USA) from the original rate of 1.4 to a rate of 1.0. The size of the laser irradiation was determined as the greatest linear dimension (GLD) of the lesion plus 1000 μm as an extra margin on early phase FA for the type-2 CNV component and on late-phase FA for the type-1 CNV component. The area of the abnormal vascular network and polypoidal lesions on IA were included in the irradiated area in the PCV patients. When signs of remaining or recurrent CNVs, such as subretinal fluid and retinal edema on OCT and dye leakage on FA, were noted in the eyes of patients with decimal BCVA of less than 0.7 during the follow-up periods, we repeated the combination therapy consisting of RF-PDT plus 3 monthly IVR injections. If the BCVA was better than or equal to 0.7 in these cases, only the 3 monthly IVR injections were repeated.

The decimal BCVA obtained by Landolt ring tests was converted into the logarithm of the minimal angle of resolution (logMAR) for statistical analysis; a change of 0.3 or more logMAR units was considered significant. The mean BCVA at baseline was compared with the 1-, 3-, 6-, 9-, 12-, and 24-month values using the Wilcoxon signed rank test.

Central foveal thickness (CFT), defined as the distance from the inner limiting membrane to the Bruch membrane or the scleral side of the retinal pigment epithelium at the fovea, was measured manually by RTVue OCT. The baseline CFT was compared with the 3-, 6-, 9-, 12-, and 24-month values by means of a paired t test. Probability values of less than 0.05 were considered significant. The number, timing, and kinds of repeated treatments for the combination therapy or IVR monotherapy were analyzed, as were the ocular complications.

For the PCV patients, the size of the abnormal choroidal vascular network was examined on IA using a confocal scanning laser ophthalmoscope at baseline and then again at 12 and 24 months. The area of the vascular network was outlined manually on a computer monitor and the surface area calculated with inhouse software. A change of more than 20 % was considered to indicate an increase or decrease in size.

Results

On the basis of the FA findings, the CNV of the 24 eyes was classified as predominantly classic CNV in 3 eyes of 3 patients (12.5 %), minimally classic CNV in 9 eyes of 9 patients (37.5 %), and occult with no classic CNV in 12 eyes of 12 patients (50 %). On the basis of the IA findings, PCV was diagnosed in 14 eyes (58.3 %), for which FA classification suggested predominantly classic CNV in 1 eye (7.1 %), minimally classic CNV in 2 eyes (14.3 %), and occult with no classic CNV in 11 eyes (78.6 %). Pretreatment baselines for the mean age, the mean logMAR BCVA, the mean GLD, and the mean CFT of the typical AMD group, the PCV group, and all the patients combined are shown in Table 1. Details for each patient are shown in Table 2.
Table 1

Patient group characteristics at baseline

 

t-AMD (10 eyes)

PCV (14 eyes)

All (24 eyes)

Mean age (years)

72.7

75.6

74.4

Sex (male/female)

6/4

7/7

13/11

Mean VA, logMAR

0.59

0.53

0.58

 SD

0.35

0.36

0.37

 Range

0.22–1.22

0.22–1.22

0.22–1.22

Mean GLD (μm)

4218.6

4542.2

4392.8

 SD

1805.5

1517.1

1622.1

 Range

1515–7027

1750–7000

1515–7027

Mean CFT (μm)

510.1

485.1

495.5

 SD

234.5

132.8

182.6

 Range

247–966

282–827

247–966

VA visual acuity, logMAR logarithm of the minimal angle of resolution, SD standard deviation, GLD greatest linear dimension, CFT central foveal thickness, P predominantly classic type, M minimally classic type, O occult with no classic type, t-AMD typical age-related macular degeneration, PCV polypoidal choroidal vasculopathy

Table 2

Details of each patient and retreatment

Case no.

AMD type

Sex

Age, years

FA type

Baseline VA, logMAR

Retreatment (month)

VA at month 12

VA at month 24

VA change

3

6

9

12

15

18

21

24

1

t-AMD

f

78

P

0.52

IVRa

IVRa

IVRa

0.40

0.30

2

t-AMD

m

65

M

0.30

−0.18

−0.30

3

t-AMD

m

78

M

0.22

0.15

-0.18

4

t-AMD

f

69

M

0.40

0.70

0.82

5

t-AMD

m

67

M

1.00

Comb

0.82

1.05

6

t-AMD

f

80

O

1.10

Comb

1.10

1.40

7

t-AMD

f

76

M

0.40

Comb

0.05

−0.08

8

t-AMD

m

78

M

0.40

Comb

Comb

Comb

0.82

0.82

9

t-AMD

m

73

M

1.22

Comb

Comb

0.70

1.05

10

t-AMD

m

63

P

0.30

IVR

IVR

IVR

0.05

−0.18

11

PCV

m

70

P

1.22

0.70

0.52

12

PCV

f

83

O

1.10

Comb

IVR

IVR

0.52

0.70

13

PCV

f

83

O

0.22

Comb

0.00

0.22

14

PCV

f

78

O

0.22

IVR

Comb

0.00

−0.08

15

PCV

m

72

M

0.70

0.70

0.52

16

PCV

m

81

O

1.10

Comb

1.15

0.52

17

PCV

f

80

O

0.30

Comb

0.40

0.15

18

PCV

m

79

O

0.52

0.40

0.30

19

PCV

f

78

O

0.30

0.05

0.00

20

PCV

m

77

O

0.30

Comb

Comb

0.10

0.70

21

PCV

m

66

O

0.30

IVR

−0.08

−0.18

22

PCV

m

61

O

0.22

IVR

Comb

Comb

Comb

0.05

0.22

23

PCV

f

80

O

0.40

Comb

0.22

0.40

24

PCV

f

71

M

1.15

1.00

0.82

AMD age-related macular degeneration, FA fluorescein fundus angiography, VA visual acuity, logMAR logarithm of the minimal angle of resolution, t-AMD typical AMD, PCV polypoidal choroidal vasculopathy, m male, f female, P predominantly classic choroidal neovascularization, M minimally classic choroidal neovascularization, O occult choroidal neovascularization with no classic component, IVR intravitreal ranibizumab monotherapy, Comb combined therapy with IVR and reduced-fluence photodynamic therapy, improved, unchanged, deteriorated

aPatient rejected additional photodynamic therapy and chose IVR monotherapy

Eyes with typical AMD (Fig. 1)

BCVA

In the typical AMD group, BCVA improvement was seen in 3 eyes (30 %) at month 12 and in 4 eyes (40 %) at month 24. The baseline BCVA continued to be maintained in 8 eyes (80 %) at month 12 and in 7 eyes (70 %) at month 24 (Fig. 2). The overall mean logMAR BCVA of the 10 eyes was 0.59 ± 0.35 (range, 0.22–1.22) at baseline, 0.46 ± 0.40 (range, −0.18 to 1.10; P = 0.21) at month 12, and 0.47 ± 0.59 (range, −0.30 to 1.40; P = 0.33) at month 24 (Fig. 3; Table 3).
Fig. 1

A representative patient (case 3) with typical age-related macular degeneration. ad Fundus color photographs obtained at baseline, month 3, month 12, and month 24, respectively. The best-corrected decimal visual acuities were 0.6, 0.9, 0.7, and 1.5 at baseline, month 3, month 12, and month 24, respectively. The subretinal hemorrhage present at baseline had disappeared by month 3. eh Optical coherence tomographies performed at baseline, month 3, month 12, and month 24, respectively. The serous retinal detachment and subretinal high reflectivity present at baseline had disappeared by month 3 and did not recur up to month 24. ik Fluorescein angiographies obtained at baseline, month 3, and month 12, respectively. The dye leakage from minimally classic choroidal neovascularization present at baseline had disappeared by month 3 and had not recurred by month 12

Fig. 2

Proportion of the 10 eyes in the typical age-related macular degeneration group that exhibited changes in best-corrected visual acuity (BCVA). Each bar represents each of the 10 eyes. The dark-gray box indicates an improved BCVA of more than 0.3 logMAR units, the light-gray box indicates a stable BCVA, and the white box indicates a decreased BCVA of more than 0.3 logMAR units

Fig. 3

Time course of the mean best-corrected visual acuity (BCVA) converted into logMAR units for the typical age-related macular degeneration (t-AMD) and the polypoidal choroidal vasculopathy (PCV) groups. Square t-AMD, triangle PCV, *P < 0.05; **P < 0.01. The P values were derived from the Wilcoxon signed rank test calculated versus the baseline. The error bar indicates ±1 standard deviation of the mean

Table 3

Mean BCVA and CFT during the 24-month follow-up period

 

Baseline

Post-photodynamic therapy (month)

1

3

6

9

12

24

Typical AMD

 Mean BCVA, logMAR

0.59

0.55

0.47

0.43

0.48

0.46

0.47

  SD

0.35

0.36

0.41

0.45

0.14

0.40

0.59

  Range

0.22–1.22

0.00–1.15

−0.08–1.15

−0.18–1.10

−0.08–1.15

−0.18–1.10

−0.30–1.40

  P value

NA

0.53

0.11

0.05

0.17

0.21

0.33

 Mean CFT (μm)

510.1

NA

290.9

327.9

312.3

312.9

309.7

  SD

234.5

NA

129.2

194.1

154.0

139.6

135.9

  Range

247–966

NA

121–549

122–836

131–610

133–552

133–535

  P value

NA

NA

<0.001

<0.01

<0.001

<0.01

<0.01

PCV

 Mean BCVA, logMAR

0.58

0.53

0.45

0.42

0.39

0.37

0.35

  SD

0.38

0.37

0.38

0.35

0.36

0.38

0.29

  Range

0.22–1.22

0.15–1.15

0.00–1.15

0.00–1.15

−0.08–1.22

−0.08–1.15

−0.18–0.82

  P value

NA

0.13

<0.05

<0.01

<0.01

<0.01

<0.05

 Mean CFT (μm)

485.1

NA

204.0

276.4

219.6

226.0

216.1

  SD

132.8

NA

44.7

124.6

62.8

76.3

61.5

  Range

282–827

NA

135–332

177–676

139–345

140–460

131–357

  P value

NA

NA

<0.001

<0.01

<0.001

<0.001

<0.001

BCVA best-corrected visual acuity, logMAR logarithm of the minimal angle of resolution, CFT central foveal thickness, SD standard deviation, AMD age-related macular degeneration, PCV polypoidal choroidal vasculopathy

No significant improvement in the mean BCVA was observed throughout the 24-month period.

CFT

The mean CFT of the 10 eyes significantly decreased from 510.1 ± 234.5 μm (range, 247–966 μm) at baseline to 290.9 ± 129.2 μm (range, 121–549 μm; P < 0.001) at month 3. This decreased CFT was maintained up to month 24 (Fig. 4; Table 3).
Fig. 4

Time course of the mean central foveal thickness (CFT) of the typical age-related macular degeneration (t-AMD) group and the polypoidal choroidal vasculopathy (PCV) group. Square t-AMD, triangle PCV; *P < 0.01; **P < 0.001. The P values were derived from a paired t test calculated versus the baseline. Error bar indicates 95 % confidence interval of the mean

Number of retreatments

Retreatments were performed in 7 of the 10 eyes (70 %) during the 2-year follow-up period (Table 2). Of these 7 eyes, 6 were retreated within the first 12 months, with 4 eyes undergoing the combination therapy and 2 eyes retreated with IVR monotherapy (Table 2). The mean number of the total PDT sessions was 1.5 (range, 1–2) during the first 12-month period and 1.8 (range, 1–4) during the 2-year period. The mean number of the total IVR injections was 5.1 (range, 3–9) during the first year and 7.2 (range, 3–12) during the 2-year period.

Eyes with PCV (Fig. 5)

BCVA

Of the 14 eyes of the PCV group, BCVA improvement was seen in 1 eye (7.1 %) at month 3, 3 eyes (21.4 %) at month 12, and 7 eyes (50.0 %) at month 24 (Fig. 6). Deterioration of the BCVA was seen in only 1 eye at month 24. Thus, the baseline BCVA was maintained in 14 eyes (100 %) at month 12 and in 13 eyes (92.9 %) at month 24. The mean logMAR BCVA of the 14 eyes with PCV improved from 0.58 ± 0.38 (range, 0.22–1.22) at baseline to 0.45 ± 0.38 (range, 0.00–1.15; P < 0.05) at month 3. This significant improvement in the BCVA was maintained up to month 24 (Fig. 3; Table 3).
Fig. 5

A representative patient (case 18) with polypoidal choroidal vasculopathy. ad Fundus color photographs obtained at baseline, month 3, month 12, and month 24, respectively. The best-corrected decimal visual acuities were 0.3, 0.3, 0.4, and 0.5 at baseline, month 3, month 12, and month 24, respectively. Subretinal hemorrhage present at baseline disappeared in conjunction with a decrease in the hard exudates by month 3. eh Optical coherence tomographies performed at baseline, month 3, month 12, and month 24, respectively. The intraretinal cystic edema, subretinal fluid, and high reflectivity present at baseline had all disappeared by month 3 and did not recur up to month 24. ik Fluorescein angiographies were performed at baseline, month 3, and month 12, respectively. The late dye leakage from occult choroidal neovascularization present at baseline had disappeared by month 3, resulting in dye staining at month 3 and month 12. ln Indocyanine green angiographies performed at baseline, month 3, and month 12, respectively. Polypoidal lesions (arrows) present at baseline had disappeared by month 3 and did not recur up to month 12

Fig. 6

Proportion of the 14 eyes in the polypoidal choroidal vasculopathy group that exhibited changes in best-corrected visual acuity (BCVA) from baseline. Each bar represents each of the 14 eyes. The dark-gray box indicates improved BCVA of more than 0.3 logMAR units, the light-gray box indicates a stable BCVA, and the white box indicates a decreased BCVA of more than 0.3 logMAR units

CFT

The mean CFT of the 14 eyes with PCV exhibited a significant decrease from 485.1 ± 132.8 μm (range, 282–827 μm) at baseline to 204.0 ± 44.7 μm (range, 135–332 μm; P < 0.001) at month 3. This significant CFT decrease was maintained up to month 24 (Fig. 4; Table 3).

Disappearance of polypoidal lesions on IA

Polypoidal lesions disappeared in 10 of the 14 eyes (71.4 %), with the remaining 4 eyes (28.6 %) exhibiting a reduction at month 3. Only 1 eye (case 21) showed recurrence of the polypoidal lesion at month 6, although this subsequently disappeared after retreatment with IVR monotherapy. Of the 4 eyes that exhibited a reduction in the polypoidal lesions at month 3, 2 eyes (cases 14 and 24) showed persistence of the polypoidal lesion without exudative changes. One of the remaining eyes showed an increase in the polypoidal lesion at month 6, although it subsequently disappeared after retreatment with the combination therapy. The remaining eye showed a persistent polypoidal lesion even after retreatment that included 3 sessions of combination therapy and 1 session of IVR monotherapy. Overall, the polypoidal lesions disappeared in 11 eyes (78.6 %) and remained in 3 eyes (21.4 %) at month 24.

Change in the size of the abnormal choroidal vascular network on IA

The size of the abnormal choroidal vascular network increased by more than 20 % in 4 of the 14 eyes (28.6 %) and decreased similarly in 2 eyes (14.3 %) at month 12. Of the 8 eyes examined by IA at month 24, 2 eyes showed an increase, while 2 other eyes exhibited a decrease in size from baseline.

Number of retreatments

Of the 14 eyes with PCV, retreatment was performed in 9 eyes (64.3 %) during the 2-year follow-up period (Table 2). In addition, 7 eyes (50.0 %) needed retreatment within the first year, with 8 of the 9 eyes (88.9 %) receiving combination therapy, while the remaining eye underwent IVR monotherapy. The mean numbers of the overall treatment sessions for PDT and IVR were 1.4 (range, 1–2) and 4.7 (range, 3–9) during the first year and 1.8 (range, 1–4) and 6.4 (range, 3–15) during the 2-year period.

Complications

BCVA deterioration of more than 0.3 logMAR units was noted in 1 eye (case 4) within 3 months of the initial combination therapy. The deterioration of the BCVA was due to a loss of photoreceptors that occurred despite the disappearance of the subfoveal exudative changes. No eyes exhibited any decrease in BCVA shortly after retreatment with the combination therapy. Extensive post-PDT subretinal hemorrhage was absent after both the initial and the retreatment combination therapy. In 1 of the 14 eyes with PCV (7.1 %) (case 15), a new small subretinal hemorrhage of one-half disc diameter was initially observed and then disappeared by month 3. Indocyanine green fundus angiography showed post-PDT hypofluorescence in 5 of the 24 eyes (20.8 %) during the 2-year period. The post-PDT hypofluorescence appeared after the initial combination therapy in 4 eyes (16.7 %), while in the remaining eye (case 8), the hypofluorescence appeared at month 6 after the second combination therapy. No serious ocular or general adverse events such as intraocular infection, retinal detachment, or cerebrovascular or cardiac events were observed during the 24-month follow-up period.

Discussion

As compared with previous studies, one of the major differences in the current treatments was our use of 3 monthly IVR injections during the retreatment phase. For the ANCHOR and MARINA studies, the mean BCVA increased up until month 3, after which the initial 3 monthly IVR injections finally suppressed the neovascular activity and vascular leakage in the CNV patients. This improvement usually occurs in conjunction with the disappearance of the exudative changes, which takes place after the first or second IVR injection. On occasion, we have observed cases in which the BCVA continued to improve after the exudative changes had disappeared. Thus, since a single injection of IVR would probably be insufficient for ensuring full improvement of the BCVA during the retreatment phase, we decided to administer 3 monthly injections of IVR during both the IVR monotherapy and the combination therapy retreatment.

In our patients, the CFT decreased significantly at month 3 in both the typical AMD group and the PCV group. This decrease was maintained throughout the 2-year follow-up period in both groups. However, the time course for the mean BCVA showed a discrepancy between the typical AMD group and the PCV group. The PCV group exhibited a significant improvement in the mean BCVA from month 3 until month 24. Although the mean BCVA in the typical AMD patient group was maintained at about 0.1 logMAR units better than the baseline BCVA throughout the 2-year follow-up period, no significant improvement in mean BCVA resulted from the combination therapy despite the 3 monthly IVR injections performed during the retreatments.

A similar lack of BCVA improvement was reported in the 6-month follow-up of another study in which patients were treated with a half-fluence rate of RF-PDT combined with IVB therapy [20]. In that study, IVB monotherapy and a quarter-fluence rate of RF-PDT in conjunction with IVB therapy resulted in a significant improvement in the BCVA at month 6. In other studies, the combination of RF-PDT with IVB therapy was performed only during the initial therapy period. However, the results of those studies showed an improvement in vision similar to that seen with IVB monotherapy at 12 months [21] and at 24 months [13]. Thus, these findings suggest that IVR monotherapy or a quarter-fluence rate of RF-PDT therapy combined with IVR or IVB might have been a better choice during the maintenance phase for the typical AMD patients in our current study. Additionally, the lack of significant improvement in vision in our typical AMD group could also have been related to the interval between visits. To ensure that our patients would not be inconvenienced during their treatment, we allowed them to set their own visit intervals, which ranged from 4 to 8 weeks. Thus, these bimonthly visits could very well have delayed prompt intervention that might have prevented the deterioration in the patients’ vision due to the recurrence of CNV activity.

Recently, the MONT BLANC study demonstrated the noninferiority of SF-PDT combination therapy followed by PRN retreatments for BCVA at month 12 [15]. Additionally, the MONT BLANC and DENALI [16] studies showed no major benefits when using SF-PDT or RF-PDT in conjunction with IVR, even when the number of retreatment sessions was taken into consideration. The authors suggested that the benefit of the combination therapy might be limited in typical AMD patient cases. However, the results may not be applicable for patients of different races. In addition, IVR monotherapy with monthly injections is known to cause an increase in the rate of recurrence of cerebral infarction. Thus, a modification of the standard combination therapy, similar to our currently used treatment or that reported in another study [29], or perhaps a triple therapy that uses an intravitreous steroid [30], may be worth examining with regard to decreasing the frequency of IVR retreatments. In our typical AMD patients, the combination therapy with RF-PDT and the 3 monthly injections of IVR followed by the PRN IVR retreatment with or without RF-PDT maintained but did not improve the BCVA at month 24. However, since only a very small number of patients were examined and no controls were included in our study, a definitive conclusion cannot be drawn from the current results.

Contrary to the mean BCVA results seen for our typical AMD group, the PCV group showed encouraging results for the combination therapy that used RF-PDT with 3 monthly injections of IVR followed by PRN IVR retreatments with or without RF-PDT. The mean logMAR BCVA was significantly improved at month 3, with this improvement maintained until month 24. The number of eyes exhibiting BCVA improvement increased from 1 of the 14 eyes (7.1 %) at month 3 to 3 (21.4 %) at month 12 and to 7 (50.0 %) at month 24. Additionally, the initial BCVA was maintained in all 14 eyes up to month 12 and in 13 eyes up to month 24. The improvement in the mean BCVA and the proportion of eyes in which vision was maintained were similar to those previously reported for the studies on PCV that used SF-PDT and IVB or IVR combination therapy [31, 32, 33, 34, 35, 36] or RF-PDT and IVB combination therapy [37]. However, the significant improvement in mean BCVA seen at month 12 disappeared at month 24 in both an SF-PDT monotherapy study [26] and an SF-PDT and IVB or IVR combination study [35]. In our study, 6 patients underwent retreatment during the second year, 1 patient (case 11) underwent IVR monotherapy, and 5 patients underwent combination therapy. Since both therapies included 3 monthly IVR injections during all of the retreatments, these 3 monthly IVR injections might have effectively suppressed the exudative activity of PCV [38], thereby contributing to the continuous BCVA improvement seen throughout the 24 months.

In our study, 7 of the 14 eyes with PCV (50.0 %) needed retreatments during the first 12-month period. This retreatment frequency was within the 36–55 % range reported for earlier studies in which previously untreated PCV patients received combination therapy of SF- or RF-PDT and IVB or IVR [31, 33, 35, 36, 37]. During the first 12 months of our study, the mean numbers of total RF-PDT sessions and IVR injections were 1.4 and 4.7, respectively. Once again, these numbers were within previously reported ranges for the administration of combination therapies, i.e., from 1.31 to 1.9 sessions for SF- or RF-PDT and from 1.59 to 4.2 injections for IVB or IVR [30, 31, 32, 33, 34, 35, 36]. However, we were unable to directly compare the frequency of the retreatment sessions with those of previous reports because our criteria for the retreatment with PDT and IVR injection differed from those of the prior studies. In those studies [31, 32, 34, 35, 36], PDT retreatments were applied in eyes with remaining or recurrent polypoidal lesions or in eyes with fluorescein dye leakage. In our study, combination therapy was used for eyes with decimal visual acuity of less than 0.7, while eyes with decimal visual acuity better than or equal to 0.7 received only IVR monotherapy. In addition, since the 3 monthly injections of IVR were all performed during the retreatment sessions, regardless of whether combination therapy or IVR monotherapy was used, the mean number of IVR injections was increased by two as compared with patients undergoing a single IVB or IVR injection during the retreatment. Again, it was our initial supposition that 3 monthly injections of IVR would indeed suppress the exudative and neovascular activities more strongly than would just a single injection. However, the necessity of administering 3 monthly injections of IVR for every retreatment still needs to be closely examined.

In the EVEREST study [23], the BCVA changes were similar among the combination therapy, PDT monotherapy, and IVR monotherapy groups. While the combination therapy tended to require a smaller number of retreatments for both the verteporfin/sham PDT and IVR/sham injection as compared with the IVR monotherapy, it should be noted that the EVEREST study period was only 6 months. Since exudative changes recur with or without polyp recurrence more than 1 year after the initial treatment in PCV patients [26, 27, 28], a clinical trial with a follow-up period of longer than 6 months needs to be undertaken.

Previous studies have stated that RF-PDT combination therapy in PCV patients would be expected to decrease post-PDT complications such as extensive subretinal hemorrhage [24] and choriocapillary nonperfusion of the irradiated area [17]. In line with this, Yamashita et al. reported finding a reduction in severe post-PDT subretinal hemorrhage when using RF-PDT monotherapy for PCV [25]. Additionally, other studies have shown that combination therapy with SF-PDT and IVB also reduced the occurrence of subsequent subretinal hemorrhages [31, 32]. However, a later study reported on a patient who had extensive subretinal hemorrhage after receiving combination therapy with SF-PDT and IVR [36]. Therefore, our combination therapy with RF-PDT and IVR might be a good alternative treatment for reducing extensive subretinal hemorrhage. Indeed, with the exception of a patient with a small 0.5 disc diameter-sized subretinal hemorrhage at 1 month after the initial combination therapy, we found no extensive subretinal hemorrhages after our initial combination therapy or retreatments in 13 PCV patients. This finding of only 1 of 14 patients (7.1 %) with post-PDT subretinal hemorrhage is much less than the 21 % frequency found for the 28 study eyes that showed post-PDT small subretinal hemorrhages within 1 disc area in Yamashita et al.’s [25] RF-PDT monotherapy study. Their study also showed improvement in the mean BCVA and a small number (1.3) of mean treatment sessions during the 12-month follow-up period. Unfortunately, since only a small number of treated PCV eyes were included in our current study, the ability of RF-PDT and IVR combination therapy to reduce post-PDT subretinal hemorrhage has yet to be definitively proven. Post-PDT hypofluorescence on IA is another complication associated with PDT [17]. Yamashita et al. [25] reported finding mild-to-moderate nonperfusion of the choriocapillaries in 57 % of the 28 PCV patients who received RF-PDT monotherapy, with this nonperfusion disappearing 3 months later. Since the hypofluorescence on IA was seen in 5 of our 24 patients’ eyes (20.8 %), this mild-to-moderate hypofluorescence appears to be inevitable, even with RF-PDT, in some patients.

The initial treatment in our study used a combination therapy of RF-PDT and 3 monthly injections of IVR followed by PRN retreatment with 3 monthly IVR injections with or without RF-PDT. This treatment was able to maintain the initial mean BCVA of patients with typical AMD for 2 years. The same treatment regimen also significantly improved the mean BCVA and helped maintain the improvement in the PCV patients for 2 years. Although more patients will need to be examined if the effectiveness of our treatment strategy for typical AMD is to be definitively proven, our present results still support recommended use of this treatment in PCV patients. However, because the number of patients examined in our current study was only small and because there were no controls, a larger scale clinical trial with a follow-up period of longer than 2 years will need to be undertaken to definitively prove its findings.

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Copyright information

© Japanese Ophthalmological Society 2013

Authors and Affiliations

  • Yusaku Yoshida
    • 1
  • Takeya Kohno
    • 1
  • Manabu Yamamoto
    • 1
  • Tasuku Yoneda
    • 1
  • Hisashi Iwami
    • 1
  • Kunihiko Shiraki
    • 1
  1. 1.Department of Ophthalmology and Visual Science, Graduate School of MedicineOsaka City UniversityOsakaJapan

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