Polypoidal choroidal vasculopathy (PCV), a subtype of neovascular AMD, is characterized by serosanguinous pigment epithelial detachment (PED) with relatively fewer drusen.^1-3 It is more prevalent among Asians as compared to whites.^1,4,5 Imaging techniques comprising fundus fluorescein angiography (FFA) and indocyanine green angiography (ICG) have provided the opportunity to diagnose this rare condition with greater certainty, with the latter being the gold standard diagnostic modality.^6,7

With the introduction and widespread usage of anti-VEGF agents, the previously popular photodynamic therapy using verteporfin (vPDT) now is being used less commonly. The gain of visual acuity (VA) at 1 year has been noted to fade over 3 years and longer following PDT.⁸ However, studies showed fewer anti-VEGF injections with combination PDT and anti-VEGF injection at baseline.⁹ The concerns regarding long-term efficacy, high cost, need of specialized equipment, and side effects with repeat PDT have led to receding interest in vPDT.

Multiple previous studies have compared anti-VEGF agents with vPDT. EVEREST II and PLANET studies are the latest multicenter trials in the continuum, evaluating anti VEGF agents with combination therapy including vPDT. Though both were multicenter, randomized controlled trials (RCT), differences existed in methodology, treatment protocols, and results. Here we aim to decipher both the studies and elucidate key points from both trials, based on data presented to date.

OVERALL STUDY DESIGN

The EVEREST II trial is a 24-month multicenter study of 322 Asian participants. Twelve-month data have been reported. This study compared the monotherapy of ranibizumab 0.5mg/0.05mL (Lucentis; Genentech) with combination therapy of ranibizumab and vPDT. Photodynamic therapy was performed at baseline along with 3 monthly ranibizumab injections followed by treatment on a PRN basis.¹⁰ In the PLANET study, on the other hand, aflibercept (Eylea; Regeneron) was compared with combination therapy of aflibercept and deferred vPDT. The study protocol involved 3 monthly injections of aflibercept (2mg/0.05mL). The follow-up protocol was treat and extend (T&E) as compared to PRN in EVEREST II. The study included patients from the Asia Pacific region and Europe. The vPDT therapy was given as a rescue therapy after 3 months in the PLANET study as compared to baseline vPDT in EVEREST II.^10,11

BASELINE CHARACTERSTICS

The mean age of patients in both studies was >65 years, with the mean being 68.2 and 68.0 years in monotherapy and combination arms, respectively, in EVEREST II. The patients in the PLANET study had a mean age of 70.8 and 70.4 years in the respective groups.^10,11 Both of the studies had a male preponderance in both study arms. Patients in EVEREST II had a baseline VA of 61.2±13.9 (mean±SD) and 61.1±12.6 letters in the monotherapy and combination arms, respectively. This was slightly better compared to the PLANET study, where patients had a mean baseline VA of 57.7±11.3 and 59.0±11.5 letters in the aflibercept and aflibercept+vPDT arms, respectively. Screening failure occurred in up to 34% of patients in the EVEREST study, because the diagnosis of PCV involved a central reading center, which made the diagnosis in accordance to clinically defined criteria in EVEREST II. The PLANET study involved the study center only, not the centralized image reading center. So, there might be a component of uncertainty in the diagnosis of PCV, with some cases of neovascular AMD being erroneously diagnosed as PCV in the PLANET study. This applies to the decision for rescue therapy as well.

METHODOLOGY AND INCLUSION AND EXCLUSION CRITERIA

EVEREST II incorporated 12-month results of 2 subgroups including ranibizumab (0.5mg/0.05mL) with sham PDT and ranibizumab (0.5mg/0.05mL) with vPDT. Similar to EVEREST II, patients in PLANET study received 3 monthly injections of aflibercept and were further retreated when criteria were fulfilled. The PLANET study, unlike EVEREST II, involved aflibercept injections at an interval of 8 weeks, which after 12 months were treated on a T&E regimen (data have not yet been presented).

PDT was administered only as a rescue therapy and not given at the primary visit in the PLANET study. Considering the fact that only 6% and less than 15% of patients satisfied the criteria for rescue treatment in the PLANET study at 12 weeks and 52 weeks, respectively, PDT at baseline may not be mandated and can be considered overtreatment on extrapolating the results.

On the other hand, the percentage of patients in EVEREST II that required rescue PDT were 71.2% and 38.9% in the sham PDT and vPDT subgroups, respectively. A total of 61% and 26.8% patients received only a single vPDT/sham PDT in the respective study arms in EVEREST II over 12 months. Thus the possible limitations of ranibizumab monotherapy needs to be analyzed and the role of vPDT especially does appear helpful, whereas the same observation was not noted in aflibercept monotherapy.

VISUAL ACUITY GAIN

The monotherapy arm (PRN) using ranibizumab had a mean gain in VA (±SD) of 5.1±1.1 ETDRS (Early Treatment of Diabetic Retinopathy Study) letters as compared to combined therapy of ranibizumab and vPDT which had a VA gain of 8.3±1.0 ETDRS letters in EVEREST II. The percentage of patients with BCVA ≥69 ETDRS letters was 69.0% and 58.8% in the ranibizumab+vPDT and ranibizumab arms, respectively. However, patients in the PLANET study had a VA gain of 10.7±11.3 ETDRS letters in monotherapy (bimonthly injections after loading dose) with aflibercept compared to the combination arm of aflibercept and vPDT where VA gain of 10.8±10.7 letters was obtained. At 52 weeks, a total of 33.1% and 36.6% of patients (P=.46) gained ≥15 letters in the aflibercept and AFL+vPDT groups, respectively. The perecentage of patients in EVEREST II with ≥15 letters gain was less (24.5% in the combination and 14% in the montherapy arm). Whether the higher baseline BCVA of 61.2 (EVEREST II) vs 57.7 letters (PLANET) played a role in the differential visual gain is difficult to predict.

NUMBER OF INJECTIONS AND INTERVENTIONS

The total number of injections (mean±SD) required in the monotherapy and combination arms were 7.3±3.3 and 5.2±2.5, respectively, in EVEREST II. In the PLANET study, however, patients needed 8.1±1.3 injections in the aflibercept monotherapy arm and 8.0±0.9 in the aflibercept+vPDT combination arm. The difference in number of total intravitreal injections can be explained by treatement protocols. While EVEREST II involved injections on a PRN basis, PLANET study patients received injections every 8 weeks after the first 12 weeks. The mean numbers of follow-up visits in EVEREST II and PLANET were 12 and 8, respectively. The lower number of visits can be attributable to the frequency of aflibercept injections in PLANET, while patients in EVEREST II were followed up every month.

The patients in EVEREST II had a mean of 6.7 and 9.6 interventions in the monotherapy and combination arms, respectively (active/sham PDT+anti-VEGF injections), indicating that vPDT may play a significant role in reducing the total number of ranibizumab injections over 12 months. In the PLANET study, however, the number of interventions did not vary between the 2 groups (8.3 vs 8.2 in the monotherapy and combination arms, respectively). The plausible explanation for this may be either superior efficacy of aflibercept or employing vPDT as a rescue therapy rather than at the initial visit.

POLYP REGRESSION

In the PLANET study, the percentages of patients with no active polyps at week 52 were 81.7% and 88.9% in the monotherapy and combination therapy arms, respectively. Complete polyp regression was seen in 39% and 45% in the monotherapy and combination therapy arms, respectively. The mean number of polyps reduced by 52% (3.48 to 1.66) and 58% (3.93 to 1.65) in the aflibercept monotherapy and aflibercept + vPDT groups, respectively. Similarly, the mean area of polyps also showed a reduction of 66% (0.21 mm² to 0.07 mm²) and 58% (0.19 mm² to 0.08 mm²) in the respective groups.

In EVEREST II, polyp inactivation was seen in 50% and 79.5% of study patients whereas complete polyp regression was seen in 34.7% and 69.3% in the monotherapy and combination therapy groups, respectively. Activity of polyps was defined as evidence of polyps on ICGA with both new or persistent fluid on OCT. The difference in polyp regression pattern may be due to conservative ICGA criteria used by the reading center while in clinical settings decisions may be based on ICGA and other imaging techniques as well. In the PLANET study, ICGA was performed at baseline and at month 12. Moreover, accessibility to ICGA is limted in real-life settings.

REDUCTION IN CENTRAL MACULAR THICKNESS

In terms of anatomic improvement involving reduction of central subfield thickness (CST), the aflibercept and aflibercept+vPDT arms had a comparable reduction of 137.7 µm and 143.5 µm at 52 weeks in PLANET study. In EVEREST II, combination and monotherapy arms had a reduction of 151.5 µm and 106.3 µm in CST, respectively.

CONCLUSION

EVEREST II reported the superiority of combination treatment, with both ranibizumab and vPDT complementing each other leading to fewer ranibizumab injections and lower cost. Anti-VEGFs also downregulate VEGF thus antagonizing the VEGF spike induced by vPDT. The results of the PLANET study suggest that aflibercept monotherapy is noninferior to aflibercept combined with vPDT. Whether the results of EVEREST II and PLANET studies can be extrapolated and directly translated into clinical practice remains to be seen. In clinical experience as well, aflibercept appears to have better anatomical and visual outcome in PCV. However, repeated injections and multiple repeat injections could be economically challenging in real-life situations. On the other hand, vPDT does lead to regression of polyps and improvement in BCVA; however, BCVA gain is not sustained long term and side effects including post-PDT hemorrhage, secondary choroidal neovascular membrane, and progressive RPE and choriocapillaris are also known to occur with repeat PDT. Furthermore, whether polyp regression prevents or delays any future recurrence is not known. The persistence of branching vascular network and the associated chronic exudation leads to poor visual outcomes in recurrent PCV cases. Polyp regression or polyp inactivation as a treatment endpoint is still not understood. With regards to selecting an anti-VEGF injection between ranibizumab and aflibercept, a head-to-head comparison trial could pave the way for a much more accurate conclusion. RP

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