The Promise and Perils of Combination Therapy
A discussion of off-label treatments for age-related
GEORGE A. WILLIAMS, MD
past decade has witnessed seminal breakthroughs in our understanding of the pathogenesis
of neovascular age-related macular degeneration (AMD). The elucidation of the role
of vascular endothelial growth factor (VEGF) in particular provides a specific target
for therapeutic intervention. At present, only pegaptanib sodium (Macugen, Eyetech/Pfizer)
is FDA approved, but it seems likely other anti-VEGF treatments will be online within
the next 24 months. These therapies, along with photodynamic therapy (PDT),
with verteporfin (Visudyne,VQLT/Novartis Ophthalmics) provide retinal physicians
with a variety of treatment options. Despite these options, the treatment of neovascular
AMD remains a frustrating process for both the retinal physician and patient.
There is a strong scientific rationale for combination therapy.
Along with our improved understanding of the pathogenesis of neovascular AMD has
come the realization that neovascularization is a complex process involving multiple
cytokines, growth factors, and cell types intertwined in intricate pathways with
Combination therapy is common and often routine in the management
of diseases such as hypertension, ischemic heart disease, asthma, and cancer. Why
should neovascular AMD differ?
POSSIBLE THERAPIES FOR NEOVASCULARIZATION
Currently, the 4 available treatments for neovascular AMD are:
thermal ablative photocoagulation as described by the Macular Photocoagulation Study
(MPS),1 PDT with verteporfin,2,3
intravitreal pegaptanib sodium4,
and intravitreal triamcinolone.5
The likely availability of ranibizumab (Lucentis, Genentech) and perhaps anecortave
acetate (Retaane, Alcon) will soon add to the possible treatment permutations. Because
these therapies have different effects on neovascularization and none are individually
optimal, it seems reasonable and even compelling to consider combination therapy.
The goal of combination therapy is both to enhance efficacy and to diminish the
disadvantages of the respective treatments, such as recurrence and treatment frequency.
Today, the most frequently employed combination therapy is PDT
with verteporfin and intravitreal triamcinolone acetamide. Based on the initial
report of Richard Spaide, MD, many retinal physicians have tried this combination.5
The 2004 Practice and Trends survey of the American Society of Retina Specialists
indicates 60% of retinal physicians use this combination. The rationale for combining
PDT and triamcinolone is strong. Photodynamic therapy closes neovascular perfusion
via thrombosis and has been shown to decrease the growth of the neovascular lesion.
Unfortunately, reperfusion occurs in nearly all cases, necessitating retreatment.
Animal studies demonstrate that despite its short-term thrombotic effects, PDT also
increases VEGF expression, which may contribute to the reperfusion and leakage seen
on post-PDT fluorescein angiography. Intravitreal steroids, such as triamcinolone,
may decrease VEGF expression and thereby ameliorate post-PDT phenomena.
Although there is an increasing clinical consensus that this combination
improves efficacy and decreases retreatment frequency, there are no definitive data
from randomized clinical trials to support these contentions. Furthermore, the potential
toxicity of routine intravitreal triamcinolone acetamide such as glaucoma, cataract,
and endophthalmitis must be addressed.
Combination therapy with pegaptanib sodium and PDT was allowed
for predominantly classic lesions at individual investigator discretion in the VISION
trial.4 Approximately 22%
of patients received combination therapy with PDT and pegaptanib sodium. The VISION
trial suggests there are no safety concerns with this combination therapy. However,
patients were not randomized to PDT and the criteria for PDT treatment were not
standardized. No definitive conclusions can be made concerning the benefits of combining
pegaptanib sodium with PDT.
Combination therapy with pegaptanib and triamcinolone also
deserves consideration. Theoretically, one could expect synergy because of the different
mechanisms of action of pegaptanib sodium and triamcinolone. However, the clinical
experience to date is limited and there are no published reports on this combination.
Although fewer than 20% of patients with neovascular AMD present
with MPS-eligible extrafoveal or juxtafoveal well-defined lesions, thermal laser
is often effective in the short-term ablation of these lesions.1
Unfortunately, the high incidence of recurrent neovascularization limits the long-term
visual benefit. Combination therapy with pegaptanib sodium or triamcinolone to prevent
recurrence is an obvious option. Again, the clinical experience with this combination
is limited. Furthermore, the low incidence of MPS-eligible lesions will make clinical
THE FUTURE OF COMBINATION THERAPY
As newer treatments become available, the possible therapeutic
combinations increase. The obvious question is how can we determine the safety and
efficacy of all possible combination therapies in the absence of confirmatory clinical
trials? The answer is that we cannot. The rapid development of new therapies makes
it increasingly difficult to design clinical trials that will be relevant at the
time of their completion. Furthermore, as multiple treatments are approved, how
do we determine which treatment or combination of treatments is the appropriate
standard of care against which new treatments are to be evaluated? In the current
era of limited resources, we cannot answer all the questions. We must therefore
come to a consensus to determine the most important questions. Although this requires
the participation of retinal physicians in conjunction with industry and government,
it is the retinal physicians as patient advocates who must drive this process.
Combination therapy also raises ethical issues. Patients with
neovascular AMD are desperate and vulnerable. They fear blindness as much or more
than stroke, myocardial infarction, or AIDS.6,7
Retinal physicians who suggest combination therapy are obligated to take the time
to explain the known benefits as well as the limitations of monotherapy, the rationale
for combination therapy and the uncertainties concerning efficacy and risk. The
Ophthalmic Mutual Insurance Corporation also suggests for risk management reasons
that patients be informed when drugs such as triamcinolone are used off-label.8
Some retinal physicians and, in my experience, many patients are uncomfortable with
the uncertainties of combination therapy, and off-label drug use. If so, they should
be confident that monotherapy according to current coverage criteria with either
PDT or pegaptanib sodium are the only proven treatments.
The substantial cost (See "The Economic Impact of Combination
Therapy and AMD", page 48) of treating neovascular AMD demands that ophthalmologists
use evidence-based treatment criteria to determine which patients will benefit from
which treatment and, just as importantly, which patients will not. Well-executed
case series and single-center trials can provide useful and important information.
They are the genesis of medical progress. Only retinal physicians skilled in the
diagnosis and treatment of neovascular AMD are capable of critically evaluating
and applying treatment results from a variety of sources to a specific patient.
Retinal physicians therefore need flexibility in the coverage criteria for the treatment
of neovascular AMD to pursue optimal treatments.
Economic Impact of Combination Therapy and AMD
loss from AMD is a demographic time bomb. The Eye Disease Prevalence Research Group
estimates that in the United States in 2000 there were 1.75 million people with
advanced AMD defined as neovascular or central geographic atrophy.9
Perhaps even more ominously, 7.3 million people are estimated to be at high risk
for developing advanced AMD. By 2020, nearly 3 million people are projected to have
advanced AMD with the majority having neovascular AMD.10
Prior to the introduction of verteporfin therapy in 2000, less than 20% of eyes
with neovascular AMD were treatable. Today, with therapeutic options including verteporfin,
pegaptanib sodium, and triamcinolone virtually all de novo cases of neovascular
AMD can be treated. As a result, the treatment of neovascular AMD will consume an
increasing amount of healthcare resources and is likely to become 1 of the leading
line items in Medicare expenditures.
The costs associated with the treatment of AMD
are driven primarily by 2 factors: the allowable reimbursement of the drugs and
the increase in physician services, which are necessary for the diagnosis, drug
administration, and treatment follow-up. At present, both of these factors have
an adverse effect on the calculation of the sustainable growth rate (SGR), which
is used to determine the yearly update to the conversion factor. The conversion
factor translates the Resource Based Relative Value Scale valuation of all combination
therapy procedures into dollars. It is projected that if the current SGR methodology
remains in effect, there will be a 40% decrease in Medicare physician payment rates
by 2013. The net effect is that in 2013, physician payment rates will be 20% lower
than they were in 1990 when the SGR process began. Therefore, there is a consensus
among policy makers that the SGR process requires revision or replacement. However,
there is no consensus on how to change the present system or how to pay for any
change. Since 2002, yearly congressional action has superseded the SGR mandated
cuts at the cost of over $60 billion. In the absence of a permanent fix to the SGR
process, it is unknown whether Congress will continue to choose to override the
In 2005, projected total Medicare expenditures
will be approximately $325 billion. Of that total, physicians receive approximately
$80 billion and ophthalmologists about $5 billion. Therefore, the net effect of
ophthalmology-related increases in general and AMD-related increases in particular
on the SGR calculation are minimal. However, within ophthalmology the treatment
costs of AMD will become a substantial portion of overall ophthalmology-related
expenditures. At present, protocol treatment costs range between approximately $8000
for PDT and $12,000 for pegaptanib sodium per new case of neovascular AMD. These
costs include the drugs and subsequent necessary physician services such as treatment,
imaging studies, and office visits. Although it is too soon to know the relative
use of PDT versus pegaptanib sodium, in 2003 approximately 40000 patients received
PDT. The broader FDA label and coverage criteria for pegaptanib sodium will result
in substantially greater utilization. If one conservatively assumes that only 50%
of the estimated 200000 new cases of CNV/year are treated with either modality at
an average cost of $10,000 per patient, the total cost is approximately $1 billion/year.
Furthermore, since all of these patients require follow-up and some require additional
treatment beyond 1 year, the cumulative costs are even greater.
With these costs for monotherapy as
a baseline, it is apparent why payers are concerned about the costs of combination
therapy. Obviously, if patients receive per protocol treatment with both PDT and
pegaptanib sodium, the increased costs are substantial. However, combination therapy
also has the potential to lower costs. For example, if the combination of intravitreal
triamcinolone and PDT decreases the frequency of PDT retreatment, drug costs would
A. Williams, MD, is chair of the Department of Ophthalmology at Williams Beaumont
Hospital and director at Beaumont Eye Institute located in Royal Oak, Mich.. Dr.
Williams has no financial interest in the information contained in this article.
He can be reached by e-mail at GWilliams@beaumont.edu.
1. American Academy of Ophthalmology. Preferred Practice Pattern.
Age-Related Macular Degeneration. 2003.
2. TAP Study Group. Photodynamic therapy of subfoveal choroidal
neovascularization in age-related macular degeneration with verteporfin . TAP report
#1. Arch Ophthalmol. 1999;117:1329-1345.
3. VIP Study Group. Verteporfin therapy of subfoveal choroidal
neovascularization in age-related macular degeneration. VIP Report #2. Am J Ophthalmol.
4. Gragoudas ES et al. Pegaptanib sodium for neovascular age-related
macular degeneration. N Engl J Med. 2004; 351:2805-2816.
5. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy
with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization.
6. Williams RA, Brody BL, Thomas RG, et al. The psychosocial
impact of macular degeneration. Arch Ophthalmol. 1998;116: 420-514.
7. Brown MM, Brown GC, Sharma S, et al. Quality of life and systemic
comorbidities in patients with ophthalmic disease. Br J Ophthalmol. 1002;86:8-11.
8. Craven ER, Moran EC. Medicolegal implications of using off-label
drugs and devices . OMIC publication archives. Ophthalmic Mutual Insurance Company,
Winter 1996. http://www.omic.com/resources/risk-man.
9. Eye Diseases Prevalence Research Group. Prevalence of age-related
macular degeneration in the United States. Arch Ophthalmol. 2004;122:564-572.
10. Age-Related Eye Disease Study Research Group. Potential public
health impact of Age-Related Eye Disease Study Results. Arch Ophthalmol.
Retinal Physician, Issue: September 2005