Verteporfin and Intravitreal Triamcinolone Acetonide Combination Therapy for Occult Choroidal Neovascularization in Age-Related Macular Degeneration

Page created by Vivian Mcguire
 
CONTINUE READING
Verteporfin and Intravitreal Triamcinolone Acetonide Combination Therapy for Occult Choroidal Neovascularization in Age-Related Macular Degeneration
Verteporfin and Intravitreal Triamcinolone
    Acetonide Combination Therapy for Occult
   Choroidal Neovascularization in Age-Related
              Macular Degeneration

                  ALBERT J. AUGUSTIN, MD, AND URSULA SCHMIDT-ERFURTH, MD

● PURPOSE:    To evaluate the efficacy and safety of pho-                   ● CONCLUSIONS: Verteporfin PDT combined with intra-
todynamic therapy (PDT) with verteporfin combined                           vitreal triamcinolone may improve the outcome of standard
with intravitreal triamcinolone (IVTA) in occult choroi-                    verteporfin PDT in the treatment of occult CNV secondary
dal neovascularization (CNV) secondary to age-related                       to AMD. An improvement in visual acuity was observed in
macular degeneration (AMD).                                                 most of the treated patients and was maintained during a
● DESIGN: Single center, nonrandomized interventional                       two-year follow-up period. Retreatment numbers were
case series.                                                                lower than expected from monotherapy trials. (Am J
● METHODS: A prospective, noncomparative, interven-                         Ophthalmol 2006;141:638 – 645. © 2006 by Elsevier Inc.
tional case series of 41 eyes of 41 patients with a                         All rights reserved.)
two-year follow-up period. Verteporfin PDT was per-
formed using the recommended standard procedure for

                                                                            P
                                                                                   HOTODYNAMIC THERAPY (PDT) WITH VERTEPORFIN IS
approved forms of AMD. A solution containing 25 mg of                               an established therapy in patients with predominantly
crystalline triamcinolone acetonide was injected intravit-                          classic subfoveal choroidal neovascularization (CNV)
really 16 hours post PDT. The procedure was repeated                        secondary to age-related macular degeneration (AMD).1–3
after three months in case of persistent CNV leakage.                       PDT with verteporfin is also useful in the treatment of
● RESULTS: The mean number of treatments needed was
                                                                            predominantly occult CNV secondary to AMD. The patients
1.8. Thirty-four eyes (82.9%) required one retreatment                      who benefited from photodynamic therapy in the Verteporfin
at three months. No additional retreatments were neces-                     in Photodynamic Therapy (VIP) Trial were occult with no
sary. Visual acuity improved gradually in most of the
                                                                            classic CNV measuring less than four Macular Photocoagu-
patients with mean values of 20/133 and 20/115 at
                                                                            lation Study (MPS) disk areas or with visual acuity worse
baseline and three months; 20/101 and 20/84 at six and
                                                                            than 20/50 at baseline.4 The treatment is well tolerated and
twelve months; and 20/83 and 20/81 at eighteen and
                                                                            visual loss can often be prevented.4 However, reactivation
twenty-four months. Eleven of 41 treated study eyes
                                                                            and persistence of CNV is not uncommon and frequent
(26.8%) underwent cataract surgery between six and
                                                                            retreatments may be required.2 Particularly in the subpopu-
fifteen months after the first treatment. Nine patients
required local or systemic glaucoma therapy because of a                    lation of purely occult lesions, outcomes may vary. In the
transient steroid induced intraocular pressure increase.                    overall population of occult lesions in the VIP trial, a mean
                                                                            loss of five lines was observed in PDT-treated eyes compared
                                                                            with a loss of 4 lines in untreated eyes.4,5 Lesions larger than
Accepted for publication Nov 26, 2005.                                      four MPS disk areas had an even worse outcome; severe
   From the Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe,     adverse events with massive vision loss were seen more
Germany (A.J.A.); and Department of Ophthalmology, University of            frequently in this subgroup.4,5
Vienna, Vienna, Austria (U.S-E.).
   Ursula Schmidt-Erfurth, MD, is an inventor on the patent on the use         The persistence and recurrence of CNV, requiring frequent
of verteporfin therapy in ocular neovascular disease under the guidelines   retreatments, can compromise the success of therapy. The
of the Wellman Laboratories of Photomedicine, Harvard Medical School,
Boston, Institutional Patent Policy and Procedures.
                                                                            pathogenesis of CNV is thought to involve not only
   The authors gratefully acknowledge Piotr Sczecsny for his scientific     photodynamic processes, but also oxidative and inflamma-
expertise and assistance with the statistical analysis.                     tory mechanisms.6,7 Such mechanisms include cell mediated
   Inquiries to Ursula Schmidt-Erfurth, MD, Department of Ophthalmol-
ogy, Medical University of Vienna, Waehringer Guertel 18-20, 1090           inflammation, leukocyte adhesion, leukocyte extravasation,
Vienna, Austria; e-mail: ursula.schmidt-erfurth@meduniwien.ac.at            and angiogenesis, features that are similar to but not

638                                            ©   2006 BY   ELSEVIER INC. ALL   RIGHTS RESERVED.                        0002-9394/06/$32.00
                                                                                                                 doi:10.1016/j.ajo.2005.11.058
Verteporfin and Intravitreal Triamcinolone Acetonide Combination Therapy for Occult Choroidal Neovascularization in Age-Related Macular Degeneration
necessarily identical to those of wound healing.7 Evidence
is also increasing that upregulation of vascular endothelial
growth factor (VEGF) can be responsible for vascular
leakage and neovascularization.6 While demonstrating
therapeutic benefit in controlled clinical trials, PDT itself,
by triggering the generation of free radicals and lipid perox-
ides, may contribute to the oxidation-induced VEGF-
expression that has been observed in PDT treated-areas.6
PDT-induced release of VEGF enhances the decrease in
choroidal perfusion and resultant hypoxia associated with
the promotion of CNV.6 Multiple PDT applications, with
renewed choroidal alteration and angiogenic stimulation,
may trigger more persistent and accelerated regrowth and
lesion activity.6
   Intravitreal administration of a corticosteroid, such as
triamcinolone acetonide (TA), has been used for a variety
of eye diseases, for example, diabetic macular edema,8,9
retinal vein occlusion,10,11 uveitis,12,13 and AMD.14 –18 Treat-
ment with intravitreal TA (IVTA) alone was shown to
improve visual acuity in patients with exudative AMD               FIGURE 1. Occult choroidal neovascularization attributable to
with optimal outcomes observed one to three months after           age-related macular degeneration. Mean change in visual acuity
treatment.14,15 IVTA was also combined with photocoag-             (VA) from baseline to month 24 in patients suffering from
ulation in the treatment of subfoveal recurrence of CNV.16         occult choroidal neovascularization attributable to age-related
                                                                   macular degeneration and treated with a combination of pho-
More recently, verteporfin PDT with adjunct IVTA was
                                                                   todynamic therapy and triamcinolone. The mean visual acuity
suggested in pilot studies.17,18 These studies evaluated the
                                                                   at baseline significantly (P < .0001) improved from 20/133 to
effects of 4 mg intravitreal TA as an adjunct to PDT with          20/84 at the twelve-month follow-up visit. This improvement
verteporfin in the treatment of patients with subfoveal or         was maintained at the twenty-four-month visit (VA: 20/81).
juxtafoveal CNV. All studies showed beneficial effects
regarding visual acuity outcomes. The treatment was well
tolerated and no patients experienced severe visual loss.          measurement using Snellen charts, slit-lamp, and fundus
However, patient numbers were small, follow-up was limited,        examination, as well as intraocular pressure (IOP) mea-
and lesion types were ill defined.                                 surement. Fluorescein angiography (FA) was performed to
   The aim of the present study was to evaluate whether            identify the lesion type and to assess CNV leakage, using
verteporfin PDT combined with IVTA can reduce the                  the criteria described previously1,4 that included evidence
number of retreatments needed and improve visual out-              of CNV caused by AMD that extended under the geomet-
comes in patients with purely occult CNV secondary to              ric center of the foveal avascular zone. All patients were
AMD.                                                               reevaluated with fluorescein angiography every three
                                                                   months.
                                                                      Following an oral informed consent, each participant
                       METHODS                                     signed a written informed form detailing the experimental
                                                                   character of the triamcinolone procedure. The protocol of
PATIENTS SUFFERING FROM OCCULT ONLY CNV SECOND-                    the study adhered to the European Good Clinical Practice
ary to AMD were included in this prospective interven-             Guidelines and the Declaration of Helsinki.
tional case series. Recruitment was consecutive for all               PDT with verteporfin (Visudyne, Novartis Ophthal-
patients presenting in a tertiary referral center. Inclusion       mics, Basel, Switzerland) was performed according to the
criteria adhered to the recommendation of the VIP trial            recommended standard procedure for approved forms of
regarding angiographic criteria and symptoms of recent             AMD.1,2,4 Within a mean of 17 hours (16 to 18 hours) after
disease progression. The complete VIP criteria are: (1)            PDT, the patients received retrobulbar anesthesia and the
patients with macular degeneration, with subfoveal cho-            ocular surface was disinfected using polyvidone iodine
roidal neovascularization lesions measuring no greater than        solution. Retrobulbar anesthesia was performed to avoid
5400 ␮m in greatest linear dimension with occult with no           lens or retinal damage attributable to fixation problems of
classic choroidal neovascular, (2) best-corrected visual score     the patients. According to pathophysiological findings, the
of at least 50 (Snellen equivalent of 20/100), and (3)             induction of oxidative and inflammatory reactions follow-
evidence of hemorrhage or recent disease progression. At           ing PDT is necessary for vessel closure. However, this
baseline all patients underwent a standardized ophthalmo-          finally leads to enhanced VEGF expression. When starting
logic examination including best-corrected visual acuity           this case series, the rationale for designing the therapy was

VOL. 141, NO. 4                    VERTEPORFIN PDT     AND   TRIAMCINOLONE   IN   OCCULT CNV                                 639
FIGURE 2. Purely occult choroidal neovascularization. (Top panel) Fluorescein angiography (FA) of a patient presenting with a purely
occult choroidal neovascularization. Late FA frames demonstrated intensive leakage originating from the subfoveal lesion (Right image).
The diagnosis was consistent with a fibrovascular pigment epithelium detachment. Visual acuity at baseline was 20/63. One single course
of photodynamic therapy and intravitreal triamcinolone acetonide was performed at the baseline visit. (Bottom panel) Fluorescein
angiography (FA) documentation three months after combination treatment. The lesion appeared hypofluorescent in the early phase FA
(Left image); leakage was absent during late phase FA (Right image) and had not recurred by the 24th month.

to antagonize PDT side effects after the initiation of                  was administered intravitreally through pars plana in-
biochemical reactions necessary for vessel closure.                     jection using a 27 gauge needle. Preservative-cleared
   Subsequently, 25 mg of preservative-cleared crystal-                 TA was prepared by the institutional pharmacy using
line triamcinolone acetonide (TA), prepared from Vo-                    the method previously described by Jonas and cowork-
lon A, (Triamcinolon-Acetonide, Dermapharm AG,                          ers.14 To prevent a potentially toxic effect of a vehicle
Grünwald, Germany), in a volume of 0.2 ml solution,                     to intraocular tissues, the pharmacy prepared the solu-

640                                         AMERICAN JOURNAL       OF   OPHTHALMOLOGY                                      APRIL 2006
FIGURE 3. Occult choroidal neovascularization. (Top panel) Fluorescein angiography of a patient presenting with an occult choroidal
neovascularization. Visual acuity at baseline was 20/2000. One single course of photodynamic therapy and intravitreal triamcinolone
acetonide was performed at the baseline visit. (Bottom panel) Fluorescein angiography (FA) of this patient three months after combination
treatment. The lesion appeared hypofluorescent in the early phase FA (Left image); leakage was absent during late phase FA (Right image)
and had not recurred by the 24th month. Visual acuity improved to 20/200.

tion free of solvent agents or other vehicles. The                    points were not included in the standard observation. In
amount of administered TA was determined by high-                     case of CNV leakage, the patients were retreated at
performance liquid chromatography measurement im-                     three-month intervals using the identical procedure.
mediately following removal of the preservative. After                   The primary efficacy variable was defined as best-
injection of TA, patients were clinically controlled                  refracted visual acuity measured using Snellen charts.
including measurement of IOP at day one, two, and six,                The primary efficacy time points were the follow up
and six weeks after injection of TA. These safety time                visits at twelve months and twenty-four months follow-

VOL. 141, NO. 4                     VERTEPORFIN PDT      AND   TRIAMCINOLONE     IN   OCCULT CNV                                    641
ing the initial treatment. The mean visual acuity data at
these follow-up visits were compared with the mean

                                                                                                                                                                                                                                                                20/32–20/400
                                                                                                                                                                                                                                                    24 Months
visual acuity at the baseline visit using the paired t test

                                                                                                                                                                                                                                                                    20/81
                                                                                                                                                                                                                                                                    20/38
                                                                                                                                                                                                                                                                    20/63
                                                                              TABLE. Mean Visual Acuity (Snellen Charts) of Patients With Occult Choroidal Neovascularization Attributable to Age-Related Macular Degeneration Following Combined
to identify statistical significance.

                       RESULTS

                                                                                                                                                                                                                                                                20/32–20/400
                                                                                                                                                                                                                                                    21 Months

                                                                                                                                                                                                                                                                    20/82
                                                                                                                                                                                                                                                                    20/38
                                                                                                                                                                                                                                                                    20/63
A TOTAL OF 41 CONSECUTIVE PATIENTS SUFFERING FROM
occult CNV secondary to AMD was included into the
study. Twenty-four individuals were female and 17 male,
and the mean age of the patients was 76.2 ⫾ 5.1 year

                                                                                                         Therapy With Photodynamic Therapy and Intravitreal Triamcinolone for Each Visit During a Two-year Follow-up

                                                                                                                                                                                                                                                                20/32–20/400
(mean ⫾ standard deviation, SD, range 66 to 87 years).

                                                                                                                                                                                                                                                    18 Months

                                                                                                                                                                                                                                                                    20/83
                                                                                                                                                                                                                                                                    20/39
                                                                                                                                                                                                                                                                    20/63
VIP-criteria were met in all patients except that eyes
presenting with a visual acuity lower than 20/200 were also
included.4 Twenty-six (63.4%) of the study eyes were
phakic and 15 (36.6%) were pseudophakic. The study eye

                                                                                                                                                                                                                                                                20/32–20/400
of each of the 41 patients was treated primarily and

                                                                                                                                                                                                                                                    15 Months
documented as study eye, the fellow eye was treated in five

                                                                                                                                                                                                                                                                    20/87
                                                                                                                                                                                                                                                                    20/39
                                                                                                                                                                                                                                                                    20/80
patients, but data were excluded from the study documen-
tation for the second eye.
   Most of the study eyes, 34 of 41 eyes (82.9%) required
one additional treatment at three months because of

                                                                                                                                                                                                                                                                20/32–20/400

                                                                                                                                                                                                                                                                                     *Patients who failed to read any letters (counting fingers or hand motion) are arbitrarily assigned to 20/2000.37
                                                                                                                                                                                                                                                    12 Months
persistent leakage originating from the CNV lesion. Com-

                                                                                                                                                                                                                                                                    20/84
                                                                                                                                                                                                                                                                    20/39
                                                                                                                                                                                                                                                                    20/80
plete resolution of leakage was seen in all eyes by three to
six months, and no patient required additional retreat-
ments after the 6-month interval. Thus, the mean number
of treatments was 1.83 for the study eye. The median size

                                                                                                                                                                                                                                                                20/32–20/400
of lesions before first combination was 3600 ␮m (range 800
                                                                                                                                                                                                                                                    9 Months

                                                                                                                                                                                                                                                                    20/89
                                                                                                                                                                                                                                                                    20/38
                                                                                                                                                                                                                                                                    20/80
to 7100 ␮m); 34 of 41 eyes showed persistent leakage after
three months. The median size of lesions of these 34
patients was 3200 ␮m (range 1200 to 4700 ␮m).
   Figure 1 presents data on best-corrected visual acuity
                                                                                                                                                                                                                                                                20/32–20/400

(mean, SD) for the study eyes during the two-year fol-
                                                                                                                                                                                                                                                    6 Months

                                                                                                                                                                                                                                                                   20/101

low-up period after the first treatment. The mean visual
                                                                                                                                                                                                                                                                   20/39
                                                                                                                                                                                                                                                                   20/80

acuity at baseline was 20/133 (SD 20/57) and significantly
(P ⬍ .0001) improved to 20/84 at the twelve-month
follow-up visit. The improvement in visual acuity was
                                                                                                                                                                                                                                                                20/40–20/2000*

maintained throughout the twenty-four-month follow-up
with a mean visual acuity of 20/81 (SD 20/38) at the final
                                                                                                                                                                                                                                                    3 Months

                                                                                                                                                                                                                                                                    20/115

                                                                                                                                                                                                                                                                    20/100
                                                                                                                                                                                                                                                                    20/44

visit. Notably, the mean visual acuity at the twenty-four-
month visit also represented a significant improvement in
comparison with baseline values.
   The mean visual acuity of the study eye before treatment
                                                                                                                                                                                                                                                                20/40–20/2000*

was 20/133 (range 20/40 to 20/2000). Visual acuity im-
                                                                                                                                                                                                                                                                    20/133

                                                                                                                                                                                                                                                                    20/100
                                                                                                                                                                                                                                                    Baseline

proved gradually in all of the patients except for nine
                                                                                                                                                                                                                                                                    20/57

patients. Mean visual acuity was 20/115, 20/101, 20/89,
20/83, and 20/81 at three, six, twelve, eighteen, and twenty-
four months, respectively.
   At twelve months, 43% of the 18 patients remained
                                                                                                                                                                                                                                                                Standard deviation

stable (⫾1 line), after twenty-four months, 41.5% of the
17 patients remained stable. The percentage of patients
who improved 3 or more lines was 29.3% (12 patients) at
                                                                                                                                                                                                                                                                Median
                                                                                                                                                                                                                                                                Range

twelve months and 31.7% (13 patients) at twenty-four
                                                                                                                                                                                                                                                                Mean

months. The percentage of patients who gained 6 or more
lines at twelve and twenty-four months was 9.8% (4

642                                       AMERICAN JOURNAL      OF   OPHTHALMOLOGY                                                                                                                                                                                                                                                                                                                       APRIL 2006
patients). No deterioration in visual acuity was observed in        relatively high. For the subgroup of cases with occult with
any of the patients during the two-year observation period.         no classic CNV in the VIP trial, verteporfin-treated patients
   Figure 2 shows a characteristic finding in a patient suffering   received an average of 3.1 treatments (of a possible total of
from occult CNV treated with IVTA. The patient required             four) before the follow-up at month twelve and an average
one combination treatment, and during twenty-four month             of 1.8 in the second twelve months.4 In comparison, a
follow-up, the lesion became inactive. Accordingly, vision          recently published study reports a mean number of 5.6
increased from 20/63 to 20/32 and remained stable.                  retreatments in patients with classic subfoveal CNV during
   Figure 3 shows a characteristic finding in a patient suffering   a period of two years.2
from occult CNV treated with IVTA. The patient required                There are several hypothesis for the persistence of CNV
one combination treatment, and during twenty-four month             and the need of retreatments after PDT monotherapy. One
follow-up, the lesion became inactive. Accordingly, vision          of the mechanisms of photodynamic action is the produc-
increased from 20/2000 to 20/200 and remained stable.               tion of oxidative radicals, thus enhancing a major patho-
   Generally, treatments were well tolerated. Eleven of 41          genic process of CNV induction. Following PDT, the acute
treated study eyes (26.8%) underwent cataract surgery               oxidative damage represents a much more powerful reac-
between months 6 and 15 after the first treatment; 11 of            tion than the chronic life-long photodynamic light-induced
the 26 phakic study eyes (42.3%) underwent cataract                 process that eventually leads to CNV.6 Each PDT retreat-
surgery. One of these patients was treated with Yttrium             ment may acutely enhance the long lasting disease process
Aluminum Garnet (YAG) laser capsulotomy six months                  and increase the amount of photoreceptor loss. After the
after the cataract surgery. Three untreated fellow eyes also        acute phase of the PDT reaction, oxidation- or ischemia-
had cataract surgery at eighteen to twenty-one months and           induced expression of VEGF, VEGF receptor 3, and
one untreated fellow eye was treated with YAG laser                 pigment epithelium-derived factor was described in the
capsulotomy.                                                        PDT-treated areas.6 This effect may represent another sub-
   A transient IOP-increase was observed in nine eyes,              acute and longer lasting stimulus for neovascular growth and
which was controlled by topical monotherapy in seven                leakage and induce inflammatory reactions. In experimental
patients. Two patients required intermittent systemic ther-         studies, PDT was shown to induce a rapid inflammatory
apy using carboanhydrase inhibitors. The median IOP was             response including infiltration of leukocytes, increased ex-
15 at baseline visit (range 11 to 19 mm Hg), 16 at follow-up        pression of cytokines for example, intracellular adhesion
visit after three months (range 11 to 34 mm Hg), 15 at              molecule (ICAM)-1 and interleukin (IL)-6.19 Following
follow-up visit after 6 and 9 months (range 10 to 42 mm             application of PDT using standard parameters to the
Hg and 10 to 19 mm Hg, respectively), 16 at follow-up               macula of human eyes, histologic studies have identified
visit after twelve months (range 11 to 20 mm Hg), and 15            thrombotic occlusion of the choriocapillary layer; charac-
at follow-up visits after twenty-four months (range 11 to 18        teristic hypofluorescence seen in indocyanine green (ICG)
mm Hg). Complications attributable to the injection                 angiography was clearly consistent with a thrombosis of
procedure such as pseudoendophthalmitis, retinal detach-            choriocapillaries and individual larger vessels.20 Choroidal
ment, retinal tears, or vitreous hemorrhage were not                hypoperfusion and resulting tissue hypoxia may represent
observed.                                                           an angiogenic stimulus responsible for CNV progression
                                                                    and may be enhanced by PDT-induced release of VEGF.6
                                                                       Corticosteroids have antiproliferative, anti-inflamma-
                     DISCUSSION                                     tory and angiostatic effects and are known to decrease
                                                                    vascular permeability.21–23 The rationale for the present
THE PRESENT STUDY ILLUSTRATES THE USEFULNESS OF                     study was to combine verteporfin PDT with an antiinflam-
verteporfin PDT combined with IVTA in the treatment of              matory and/or antiangiogenetic drug thus antagonizing
occult CNV secondary to AMD. The treatment course                   VEGF-expression and inflammatory reactions in the sub-
with a mean number of 1.8 treatments needed during a                acute phase following PDT. IVTA alone has been used in
two-year period is favorable. In addition, visual acuity            a number of conditions, including AMD and macular
improved in most of the patients, consistent with pilot             edema of different origins.14,24 Several approaches have
results from small studies using verteporfin PDT com-               been employed to administer corticosteroids, for example,
bined with IVTA in other CNV subgroups.17,18 This                   intravitreal injections, implants, periocular, or systemic
study includes a well-defined population of eyes with               administration. Although the mode of action is not fully
purely occult lesions and clearly demonstrates that the             clarified for IVTA, promising results have been obtained in
improvement in visual acuity and absence of leakage                 the treatment of intraocular proliferative, edematous, and
was maintained throughout the twenty-four-month fol-                neovascular diseases.14 –16,25,26 Most studies have reported
low-up visit.                                                       beneficial effects on visual acuity from the use of either 4 mg
   Verteporfin PDT alone is effective in the treatment of           or 25 mg IVTA.14 –16,25,26 However, in the case of AMD
occult CNV secondary to AMD, but the number of                      associated with CNV, the effect was mostly anatomical
retreatments necessary for CNV closure was found to be              and did not translate into functional improvement: IVTA

VOL. 141, NO. 4                     VERTEPORFIN PDT     AND   TRIAMCINOLONE   IN   OCCULT CNV                                 643
inhibited neovascular growth in an experimental model of              intravitreal corticosteroid. This increase could be con-
laser-induced CNV, a model of limited value for age-                  trolled by topical monotherapy or short-term systemic
related CNV.23 In sub- and juxtafoveal CNV eyes, a single             therapy. Published studies have reported elevation in
IVTA resulted in 55% stabilization, but 33% of eyes                   intraocular pressure in 30% to 50% of patients treated with
experienced vision loss.26 In predominantly occult lesions,           IVTA during the first three months after the injection.31,32
CNV enlargement was reduced to 31% in the IVTA group                  The corticosteroid-induced elevation in intraocular pres-
compared with 70% growth in the control group with only               sure can usually be controlled with topical medication.31 In
minor effects on vision outcome.25 A single IVTA course               comparison, the incidence of cataracts in the Treatment of
in predominantly classic lesions reduced lesion growth, but           AMD in Photodynamic Therapy (TAP) investigation, was
showed no difference in vision outcome at twelve                      14.9% for verteporfin-treated patients compared with
months.27 Following IVTA using a high dose of 25 mg,                  15.0% for patients receiving placebo (P ⫽ 1.00); in the
visual acuity increased after each injection, but the overall         VIP AMD trial, the incidence of cataracts was 13.3%
effect was transient during follow-up.28 Obviously, the               and 8.8% in verteporfin- and placebo-treated patients,
effects of IVTA alone are not appropriate to achieve                  respectively (P ⫽.285).36
persistent absence of CNV leakage together with vision                   This interventional case series had several limitations,
stabilization or even improvement.                                    including lack of standardized protocol refractions/visual
   Preliminary experience with combination of PDT and                 acuity testing, lack of randomization, and absence of a
IVTA seems to promise improved visual outcome and                     control group. Without a control group, the number of
lower retreatment rates. Spaide and associates18 found that           patients who may have improved or remained stable
in patients not pretreated with PDT alone, an increase of             without treatment can not be determined.
at least 3 lines was seen in 33% at six months, the mean                 In conclusion, there is a need for more effective new
change in VA was 2.4 lines.                                           treatments of occult CNV secondary to AMD. If vertepor-
   After a mean follow-up of eighteen months, combina-                fin monotherapy is being used, the need for multiple
tion therapy resulted in vision gain in 7%, stabilization in          retreatments is a significant concern. Future treatments are
50%, and vision loss in 43% of all patients.17 Numbers or             likely to include combinations of PDT with corticoste-
retreatment needed to achieve absence of leakage using                roids, angiostatic corticosteroids, or antiangiogenetic/anti
combination therapy ranged from 1.2 to 2.7, significantly             permeability drugs. Prospective, randomized, and controlled
lower than with PDT monotherapy.                                      studies are needed to further evaluate the benefit of combi-
   In our study population, verteporfin PDT combined                  nation strategies (Table).
with IVTA was well tolerated. However, at the current
state it must be highlighted that the use of IVTA in any
condition still is experimental and that the experience
from its use in various conditions is based on small                                        REFERENCES
uncontrolled studies.29 Potential complications of IVTA
include cataract progression and increased intraocular                 1. TAP Study Group. Photodynamic therapy of subfoveal cho-
pressure.14,17,25,27,29 –32 Rare cases of endophthalmitis have            roidal neovascularization in age-related macular degeneration
                                                                          with verteporfin. One-year results of two randomized clinical
also been reported after IVTA.29,33 This side-effect might
                                                                          trials—TAP Report 1. Arch Ophthalmol 1999;117:1329 –1345.
be related to the content of alcohol in the original                   2. TAP Study Group. Photodynamic therapy of subfoveal cho-
formulation. In a study of commercially available depot                   roidal neovascularization in age-related macular degeneration
corticosteroids, Hida and associates34 found that the de-                 with verteporfin. One-year results of two randomized clinical
velopment of proliferative vitreoretinopathy in some cases                trials—TAP Report 2. Arch Ophthalmol 2001;119:198 –207.
could be the result of retinal necrosis and repair processes           3. Wormald R, Evans J, Smeeth L, Henshaw K. Photodynamic
caused by these vehicles. Concentrations of benzyl alcohol,               therapy for neovascular age-related macular degeneration
the preservative in intravitreal triamcinolone, higher than               (Cochrane Review). The Cochrane Library, Issue 2, John
1 mmol/l have been found to reduced the b-wave in                         Wiley and Sons, Ltd, Philadelphia, PA, 2004.
electroretinography.35 When alcohol was extracted before               4. Verteporfin in Photodynamic Therapy Study Group. Verte-
intravitreal administration in our study, endophthalmitis                 porfin therapy of subfoveal choroidal neovascularization in
or even mild inflammation did not occur at all. In the                    age-related macular degeneration: two-year results of a ran-
                                                                          domized clinical trial including lesions with occult with no
present study, 26.8% of the study eyes underwent cataract
                                                                          classic choroidal neovascularization—Verteporfin in Photody-
surgery between six and fifteen months after the first
                                                                          namic Therapy Report 2. Am J Ophthalmol 2001;131:541–560.
combined treatment. In the pilot study by Rechtman and                 5. Treatment of Age-Related Macular Degeneration with
coworkers using 4 mg intravitreal TA , three out of six                   Photodynamic Therapy (TAP) and Verteporfin in Photo-
phakic eyes developed cataract.17 In another study with 4                 dynamic Therapy (VIP) Study Groups. Effect of lesion
mg IVTA and laser treatment, no significant effect on                     size, visual acuity, and lesion composition on visual acuity
cataract progression was observed.16 In our series, nine                  change with and without verteporfin therapy for choroidal
patients suffered from a transient increased IOP due to the               neovascularization secondary to age-related macular de-

644                                       AMERICAN JOURNAL       OF   OPHTHALMOLOGY                                        APRIL 2006
generation–TAP and VIP Report 1. Am J Ophthalmol                         implications for molecular degeneration. Clin Exp Immunol
      2003;136:407– 418.                                                       2000;121:458 – 465.
 6.   Schmidt-Erfurth U, Schlötzer-Schrehard U, Cursiefen C, et          22.   Penfold PL, Wong JG, Gyory J, Billson FA. Effects of
      al. Influence of photodynamic therapy on expression of vascular          triamcinolone acetonide on microglial morphology and
      endothelial growth factor (VEGF), VEGF receptor 3, and                   quantitative expression of MHC-II in exudative AMD. Clin
      pigment epithelium-derived factor. Invest Ophthalmol Vis Sci             Exp Ophthalmol 2001;29:188 –192.
      2003;44:4473– 4480.                                                23.   Ciulla TA, Criswell AH, Danis RP, Hill TE. Intravitreal
 7.   Kent D, Sheridan C. Choroid neovascularization: a wound                  triamcinolone acetonide inhibits choroidal neovasculariza-
      healing perspective. Molecular Vision 2003;9:747–755.                    tion in a laser-treated rat model. Arch Ophthalmol 2001;
 8.   Jonas JB, Hayler JK, Sofker A, Panda-Jonas S. Intravitreal               119:399 – 404.
      injection of crystalline cortisone as adjunctive treatment of      24.   Penfold PL. Intravitreal triamcinolone in recurrence of
      proliferative diabetic retinopathy. Am J Ophthalmol 2001;                choroidal neovascularization. Editorial. Br J Ophthalmol
      131:468 – 471.                                                           2002;86:600 – 601.
 9.   Martidis A, Duker JS, Greenberg PB, et al. Intravitreal            25.   Danis RP, Ciulla TA, Pratt LM, Anliker W. Intravitreal
      triamcinolone for refractory diabetic macular edema. Oph-                triamcinolone in exudative age-related macular degenera-
      thalmology 2002;109:920 –927.                                            tion. Retina 2000;20:244 –250.
10.   Greenberg PB, Martidis A, Rogers AH, et al. Intravitreal           26.   Challa JK, Gillies MC, Penfold PL, et al. Exudative macular
      triamcinolone acetonide for macular edema due to central                 degeneration and intravitreal triamcinolone: 18 month fol-
      retinal vein occlusion. Br J Ophthalmol 2002;86:247–248.                 low-up. Aust N Z J Ophthalmol 1998;26:277–281.
11.   Ip MS, Kumar KS. Intravitreous triamcinolone acetonide as          27.   Gillies MC, Simpson JM, Billson FA, et al. Safety of an
      treatment for macular edema from central retinal vein occlu-             intravitreal injection of triamcinolone: results from a ran-
      sion. Arch Ophthalmol 2002;120:1217–1219.                                domized clinical trial. Arch Ophthalmol 2004;122:336 –340.
12.   Antcliff RJ, Spalton DJ, Stanford MR, et al. Intravitreal          28.   Jonas JB, Kreissig I, Degenring R. Repeated intravitreal
      triamcinolone for uveitic cystoid macular edema: an optical              injections of triamcinolone acetonide as treatment of pro-
      coherence tomography study. Ophthalmology 2001;108:                      gressive age-related macular degeneration. Graefes Arch
      765–772.                                                                 Clin Exp Ophthalmol 2002;240:873– 874.
13.   Young S, Larkin G, Branley M, Lightman S. Safety and               29.   Peyman GA, Moshfeghi DM. Intravitreal triamcinolone
      efficacy of intravitreal triamcinolone for cystoid macular edema         acetonide. Editorial. Retina 2004;24:488 – 490.
      in uveitis. Clin Experiment Ophthalmol 2001;29:2– 6.               30.   Gillies MC, Simpson JM, Luo W, et al. A randomized
14.   Jonas JB, Kreissig I, Hugger P, et al. Intravitreal triamcino-           clinical trial of a single dose of intravitreal triamcinolone
      lone acetonide for exudative age related macular degenera-               acetonide for neovascular age-related macular degeneration:
      tion. Br J Ophthalmol 2003;87:462– 468.                                  one-year results. Arch Ophthalmol 2003;121:667– 673.
15.   Penfold P, Gyory J, Hunyour A, Billson FA. Exudative               31.   Jonas JB, Kreissig I, Degenring R. Intraocular pressure after
      macular degeneration and intravitreal triamcinolone. A pilot             intravitreal injection of triamcinolone acetonide. Br J Oph-
      study. Aus NZ J Ophthalmol 1995;26:277–281.                              thalmol 2003;87:24 –27.
16.   Ranson NT, Danis RP, Ciulla TA, Pratt L. Intravitreal              32.   Wingate RJB, Beaumont PE. Intravitreal triamcinolone and
      triamcinolone in subfoveal recurrence of choroidal neovas-               elevated intraocular pressure. Aust N Z J Ophthalmol 1999;
      cularization after laser treatment in macular degeneration.              27:431– 432.
      Br J Ophthalmol 2002;86:527–529.                                   33.   Moshfeghi DM, Kaiser PK, Scott IU, et al. Acute endoph-
17.   Rechtman E, Danis RP, Pratt LM, Harris A. Intravitreal                   thalmitis following intravitreal triamcinolone acetonide in-
      triamcinolone with photodynamic therapy for subfoveal                    jection. Am J Ophthalmol 2003;136:791–796.
      choroid neovascularization in age related macular degenera-        34.   Hida T, Chandler D, Arena JE, Machemer R. Experimental
      tion. Br J Ophthalmol 2004;88:344 –347.                                  and clinical observations of the intraocular toxicity of commer-
18.   Spaide RF, Sorenson J, Maranan L. Combined photody-                      cial corticosteroid preparations. Am J Ophthalmol 1986;101:
      namic therapy with verteporfin and intravitreal triamcinolone            190 –195.
      acetonide for choroidal neovascularization. Ophthalmology          35.   Walter P, Luke C, Sickel W. Antibiotics and light responses in
      2003;110:1517–1525.                                                      superfused bovine retina. Cell Mol Neurobiol 1999;19:87–92.
19.   Gollnick SO, Evans SS, Baumann H, et al. Role of cytokines         36.   Azab M, Benchaboune M, Blinder KJ, et al. Verteporfin
      in photodynamic therapy-induced local and systemic inflam-               therapy of subfoveal choroidal neovascularization in age-
      mation. Br J Cancer 2003;88:1772–1779.                                   related macular degeneration: meta-analysis of 2-year safety
20.   Schmidt-Erfurth U, Laqua H, Schlötzer-Schrehard U, et al.                results in three randomized clinical trials: Treatment Of
      Histopathological changes following photodynamic therapy in              Age-Related Macular Degeneration with Photodynamic Ther-
      human eyes. Arch Ophthalmol 2002;120:835– 844.                           apy and Verteporfin In Photodynamic Therapy Study Report 4.
21.   Penfold PL, Wen L, Madigan MC, et al. Triamcinolone                      Retina 2004;24:1–12.
      acetonide modulates permeability and intercellular adhesion        37.   Holladay JT. Proper method for calculating average visual
      molecule-1 (ICAM-1) expression of the ECV304 cell line:                  acuity. J Refrac Surg 1997;13:388 –391.

VOL. 141, NO. 4                        VERTEPORFIN PDT       AND   TRIAMCINOLONE     IN   OCCULT CNV                                      645
Biosketch
Albert J. Augustin, MD, is a Professor of Ophthalmology and Chairman of the Department of Ophthalmology at Klinikum
Karlsruhe, Medical Education Center of the University of Freiburg, Germany. His research interests include age-related
macular degeneration, diabetic retinopathy, and retinal ischemia. Dr Augustin has been involved in many prospective
clinical studies and is a member of numerous professional organizations, including the American Academy of Ophthalmology,
the International Society of Eye Research, and the American Society of Retina Specialists.

645.e1                                  AMERICAN JOURNAL    OF   OPHTHALMOLOGY                                 APRIL 2006
Biosketch
Ursula Schmidt-Erfurth, MD, is a Professor in Ophthalmology and the Chairman of the Department of Ophthalmology
and Optometry at the University of Vienna, Austria. Her clinical work includes general ophthalmology with a specific
focus in medical and surgical retina. During her fellowship at the Harvard Medical School in Boston, she initiated research
in photodynamic therapy for the treatment of ocular neovascular disease and became an inventor of verteporfin therapy.
She is also one of the founders of the TAP (treatment of age-related macular degeneration using photodynamic therapy)
and VIP (verteporfin in photodynamic therapy) study groups. Her research interests include the development of novel
imaging modalities as well as pharmacologic strategies in the treatment of chorioretinal disease. Another focus of her
research interest is retinal imaging and pharmacologic strategies to treat neovascular disease of retina and choroid. She
is a principal investigator and member of the study advisory boards for the clinical trials using antiangiogenic agents such
as Macugen and Lucentis. Dr Schmidt-Erfurth has published extensively in peer-reviewed journals and is a member of
multiple national and international ophthalmological societies such as the American Academy of Ophthalmology, the
Macula Society, the Retina Society, the Club Jules Gonin, Euretina, and others. She has received a number of prestigious
research awards including the Roger Johnson Award, the Achievement Award of the American Academy, the Carl Zeiss
Research Award, the Fight-for-Sight Award, and the Christiansen Award.

VOL. 141, NO. 4                  VERTEPORFIN PDT    AND   TRIAMCINOLONE   IN   OCCULT CNV                           645.e2
You can also read