recent development of photodynamic therapy (PDT) for the treatment of subfoveal
choroidal neovascularisation (CNV) has provoked considerable interest amongst
UK ophthalmologists, patients, hospital managers, public health physicians
and the media. The recent publication of the Treatment of Age-related Macular
Degeneration (TAP) report1 and the further data expected soon
from this and other randomised clinical trials is likely to have a major
impact on service provision in the UK.
vast majority of cases of subfoveal CNV are caused by age-related macular
degeneration (AMD) but other causes include pathological myopia, angioid
streaks and punctate inner choroidopathy, especially in younger patients.
Until very recently confluent argon laser photocoagulation has been the
only treatment modality of proven clinical efficacy but after initial enthusiasm
its role has become restricted to the treatment of eyes with extrafoveal
CNV. In addition to PDT other therapeutic options for subfoveal CNV that
have shown promise in pilot clinical studies include radiation with photons
or protons, surgical translocation, indocyanine angiography guided laser
to feeder vessels and transpupillary thermotherapy.
for AMD is a two stage process comprising a 10 minute intravenous infusion
of 6mg/kg verteporfin followed by activation 5 minutes later by 689nm diode
laser for 83 seconds at 50J/cm2. The photosensitive verteporfin is selectively
taken up by rapidly proliferating endothelial cells within the target CNV
reaching its peak concentration at 15 minutes. Cytotoxic reactive oxygen
intermediates damage cellular proteins and cause microvascular thrombosis.2
There is no direct thermal effect.
development of PDT occurred in the fields of oncology and dermatology.
Studies of ocular experimental CNV, corneal neovascularisation and melanoma
were followed by dose ranging and safety studies in human volunteers. 3,4
Other photosensitisers are currently undergoing early clinical or pre-clinical
controlled clinical trials of PDT with verteporfin
randomised multicentre double-masked clinical trials of PDT with verteporfin
(VisudyneTM; Novartis Ophthalmics, Duluth, USA) are currently in progress,
the Treatment of AMD with Photodynamic Therapy (TAP) and Verteporfin in
Photodynamic Therapy (VIP) trials. In 1999 the one year interim results
from the TAP study were published.1 In addition unpublished
details are in the public domain giving headline results from the two year
TAP and one year VIP results.
patients with AMD and subfoveal CNV with a classic component and refracted
logMAR visual acuity (VA) between 6/12 and 6/60 (Snellen equivalent) underwent
a 2:1 randomisation between treatment and control (sham treatment). Retreatment
was applied to zones of persistent or new leakage at 3 monthly visits.
Follow-up rates were 94% at 12 and 87% at 24 months. The frequency of stable
(<15 logMAR letters lost) or improved vision in each group was: 12 months
- 61% treated, 46% placebo (p<0.001); 24 months - 53% treated, 37% placebo
(p<0.001). At 12 months a visual improvement (15 letters) occurred in
16% treated and 7% placebo patients.
predominantly classic lesions the frequency of stable/improved vision was:
12 months - 67% treated, 39% placebo (p<0.001); 24 months - 59% treated,
31% placebo (p<0,001). For lesions with no occult component frequencies
at 12 months were: 73% treated, 23% placebo (p<0.01). Treatment benefit
was also shown for secondary endpoints. Average number of treatments in
the treated group was 5.6 (3.4 in the first 12 months).
were a similar number of deaths and serious adverse events in each group.
<2% of patients were withdrawn due to adverse events. Commoner in treated
patients at 12 months were: transient visual disturbance - 18% treated,
12% placebo; injection site events - 13% treated, 0% placebo; transient
photosensitivity reactions - 3% treated, 0% placebo; low back pain - 2%
treated, 0% placebo.
patients with occult CNV with evidence of progression but no classic have
been enrolled. At the time of writing only limited results are available:
interim analysis at 12 months has not detected a significant difference
between treated and placebo groups.
patients have been enrolled into the study of CNV in pathological myopia.
The frequency of maintenance or improvement of vision at 12 months was
86% in treated patients compared to 67% in placebo patients (p=0.01).
of currently available TAP and VIP results
of the statistical of the positive results from the TAP study is made easier
when the NNT analysis of clinical effectiveness is considered. A balanced
position has been taken by the TAP study group who have recommended treatment
for patients with 50% or more classic (predominantly classic) subfoveal
CNV secondary to AMD. In this group the NNT was 3.6 at 12 months and 24
months and this compares well with an NNT calculation for the prevention
of severe visual loss after panretinal scatter photocoagulation for proliferative
diabetic retinopathy with high risk characteristics of 14.3,5
The Cochrane Eyes and Vision Group have interpreted the results as indicating
that the benefit is restricted to patients with no occult;6
the NNT improved to 2.2 in the 143 patients in this subgroup.
|Indications for Photodynamic Therapy with Verteporfin
subfoveal/juxtafoveal CNV secondary to AMD, predominantly
classic, VA6/60 or better, lesions <5400um
CNV secondary to pathological myopia
lesions greater than 5400 um subject to limitations of
laser spot size
juxtrapapillary lesions with subfoveal extension; CNV
from other causes
<50% classic; pure occult; RPE tears
date the TAP and VIP studies have not demonstrated a clinically significant
benefit for lesions with minimally (<50%) classic or no classic and
so the treatment of these lesions is not indicated. Conversely the 12 month
data on pathological myopes has shown a statistically significant benefit
and probably justifies inclusion of this cause of CNV at least at this
stage. Whether the results in myopes can be generalised into other causes
of CNV such as punctate inner choroidopathy and angioid streaks remains
unclear. Further work on case selection is required. Indications based
on the currently available date are summarised in the table.
major safety issues have been identified in verteporfin PDT. A transient
visual loss developing by 48 hours and persisting up to 4 weeks is seen
in some patients. A potential longer term effect on the RPE needs to be
borne in mind: some atrophy was seen after multiple treatments administered
at 2-4 week intervals over a 3 month period but not during the TAP study.
development in the UK
the numbers of patients that might meet criteria for verteporfin PDT is
difficult as no direct data exist. Information from BD registrations 7
and observational data on classification of lesion components8
is available but limited. If 5% of eyes with new exudative AMD remain extrafoveal
and treatable with confluent laser then it seems reasonable that a further
30% might be eligible for PDT giving a rough estimate of 5,000 patients
per annum in England and Wales.
verteporfin PDT to be established in the UK under the NHS the capacity
of the hospital eye service will need to expand. Training of ophthalmologists
and photographers in stereoscopic angiography will be required as will
an increase in numbers of medical, nursing and other ancillary staff. Several
centres in the UK are far advanced in business planning/service development
to meet the anticipated need.
authorities and other purchasers have adopted varying positions on PDT
while they consider proposals for service contracts. The treatment is relatively
expensive if the TAP protocol is adhered to but the cost is likely to fall.
Guidance on the implementation of PDT has been issued by two UK bodies.
He Safety and Efficacy Register of New Interventional Procedures (SERNIP)
group have categorised the treatment of classic CNV as 'B' - efficacy established,
further evaluation required to establish safety. A Royal College of Ophthalmologists
working party have recommended that treatment should commence in a limited
number of centres with retinal expertise, access to stereoscopic angiography
and experience in collecting data in clinical trials. The National Institute
for Clinical Effectiveness (NICE) will not consider the treatment in the
near future. A national database of outcomes and adverse events should
help provide information to purchasers and regulators and act as a surveillance
system for SERNIP.
evidence supports the use of PDT with verteporfin for a proportion of patients
with subfoveal CNV. To minimise the danger of indiscriminate use at this
early stage in the introduction of PDT, treatment should be restricted
to those patients in whom a treatment benefit has been definitely demonstrated.
Further research is needed to establish the optimum treatment regime, its
cost-effectiveness and its impact on health services.
Harding St Paul's Eye Unit, Royal Liverpool University Hospital Email:
Harding has received departmental research funding from QLT/CIBA Vision
in his capacity as principal investigator of a clinical centre within the
TAP and VIP studies. He has no proprietary, commercial or financial interest
in any photodynamic therapy agent or device.
group. Photodynamic therapy of subfoveal choroidal neovascularisation in
age-related macular degeneration with verteporfin. One-year results of
2 randomised clinical trials - TAP report 1. Arch Ophthalmol 1999;
Mechanisms of tumour necrosis induced by photodynamic therapy. J Photochem
Photobiol B 1989; 3: 299-318
JW, Schmidt-Erfurth U, Sickenberg M, et al. Photodynamic therapy with verteporfin
for choroidal neovascularisation caused by age-related macular degeneration:
results of a single treatment in a phase 1 and 2 study. Arch Ophthalmol
U, Miller JW, Sickenberg M, et al. Photodynamic therapy with verteporfin
for choroidal neovascularization caused by age-related macular degeneration:
results of a single treatment in a phase 1 and 2 study. Arch Ophthalmol
1999; 1999; 117:1177-1187
Harding SP. Is it time for a national screening programme for sight-threatening
diabetic retinopathy? Editorial Eye 1999; 13:129-130
R, Evans J, Smeeth L. Photodynamic therapy for neovascular age-related
macular degeneration (Cochrane Review). Cochrane Eyes and Vision
Group. In: The Cochrane Library, Issue 3, 2000. Oxford: Update Software.
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