Royal College of Ophthalmologists Guidelines |
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Photodynamic therapy for subfoveal choroidal neovascularisation |
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The 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. The 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.
PDT 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.
Initial 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 trials.
Randomised controlled clinical trials of PDT with verteporfin
Two 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.
TAP study
609 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.
For 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).
There 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.
VIP study
339 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.
120 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).
Implications of currently available TAP and VIP results
Clinical indications
Interpretation 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
Indicated Probably indicated Possibly indicated Not indicated To 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.
No 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.
Service development in the UK
Estimating 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.
For 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.
Health 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.
Summary
Current 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.
Simon Harding St Paul's Eye Unit, Royal Liverpool University Hospital
Email: simonharding1@compuserve.com
Mr 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.
References:
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