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Comparison
of the efficacy of anti-VEGF monotherapy versus PDT and intravitreal anti-VEGF
combination treatment in AMD: a Meta-analysis and systematic review
Yao Tong1,2, Ke-Ke Zhao3, Dong
Feng4, Manas Biswal5, Pei-Quan Zhao2,
Zhao-Yang Wang2, Yun Zhang1
1Eye
Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang Province,
China
2Department
of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong University School of
Medicine, Shanghai 200092, China
3Department
of Ophthalmology, Shanghai Children’s Medical Center, Shanghai Jiaotong
University School of Medicine, Shanghai 200127, China
4Department
of Ophthalmology, The First Affiliated Hospital of College of Medicine,
Zhejiang University, Hangzhou 310006, Zhejiang Province, China
5Department
of Molecular Genetics, University of Florida, Gainesville 32610, Florida, USA
Correspondence to: Zhao-Yang
Wang. Department of Ophthalmology, Xinhua Hospital, Shanghai Jiaotong
University School of Medicine, Shanghai 200092, China. zhaokekewzy@hotmail.com.
Yun Zhang. Eye Hospital of Wenzhou Medical University, Wenzhou 325027, Zhejiang
Province, China. 15869153053@163.com
Received:
2015-12-20
Accepted: 2016-04-01
Abstract
AIM: To compare the
effect of anti-vascular endothelial growth factor (VEGF) monotherapy versus
photodynamic therapy (PDT) and anti-VEGF combination treatment in age-related
macular degeneration (AMD).
METHODS: A
computerized online search was performed using PubMed, Web of Science and the
Cochrane Library. Studies that compared anti-VEGF monotherapy with PDT and
anti-VEGF combination treatment of AMD and were designed as randomized
controlled trials were included. The means and standard deviations of the
best-corrected visual acuity (BCVA), central retinal thickness (CRT), number of
treatments and proportions of patients who gained BCVA ≥15, 10, 5, or 0 letters
at 12th month were extracted. A systematic review and Meta-analysis
of the comparison of the two approaches was conducted using Review Manager 5.2.
Subgroup. A sensitivity analysis was also performed.
RESULTS: Eight studies
were included. When the subgroup and sensitivity analysis was conducted, the
results indicated that in the findings that included the monotherapy group and
PDT (standard fluence, SF) group of Kaiser’s study, the patients in the monotherapy
group had a better BCVA compared with the combination group at 12th
month in the PDT (SF) subgroup [weighted mean difference (WMD): 3.54; 95%CI:
0.36 to 6.73; P=0.03], and there were
more patients who gained ≥15 letters of BCVA in the monotherapy group compared
with the combination group in the total result [odds ratio (OR): 1.41; 95%CI:
1.02 to 1.95; P=0.04]. The same
conclusion was obtained in the total result that included the monotherapy group
and PDT (reduced fluence, RF) group of Kaiser’s study (OR: 1.56; 95%CI: 1.13 to
2.15; P=0.007). However, there were
no significant differences in the other indexes between the two therapies.
CONCLUSION: We found that
anti-VEGF monotherapy is more effective on the recovery of visual acuity than
combination therapy and more researches with lager sample size should be
performed to study on the effect of the two therapy approaches on CRT and
number of injections.
KEYWORDS:
age-related macular degeneration; anti-vascular endothelial growth factor;
photodynamic therapy; Meta-analysis
Citation: Tong Y, Zhao KK,
Feng D, Biswal M, Zhao PQ, Wang ZY, Zhang Y. Comparison of the efficacy of anti-VEGF monotherapy versus PDT and
intravitreal anti-VEGF combination treatment in AMD: a Meta-analysis and
systematic review. Int J
Ophthalmol 2016;9(7):1028-1037
INTRODUCTION
Age-related
macular degeneration (AMD) is one of the leading causes of blindness in elderly
individuals in developed countries[1-2].
AMD affects more than 1.75 million individuals in the United States. As a
result of the rapid aging of the US population, this number will increase to
approximately 3 million individuals by 2020[3].
AMD is also a regular ophthalmic disease in elderly individuals in Asia[4].
The
pathophysiology of AMD is complex. Oxidative stress, inflammation and
angiogenesis mainly contribute to the disease progression at the molecular
level. The neovascular form of AMD (nAMD) is linked to choroidal
neovascularization (CNV), and it causes severe vision loss because of an
abnormal growth of blood vessels in the retina[5]. Vascular endothelial growth factor (VEGF), a potent
angiogenic molecule, plays an important role in the development of CNV in nAMD[6] in the tissue
microenvironment. Treatments using anti-VEGF monotherapy have been established
as the standard therapy for CNV and AMD. In these cases, patients require
multiple treatments[7] to
slow down the growth of new abnormal blood vessels. Photodynamic therapy (PDT)
is another treatment approach for AMD patients. It includes intravenous
injection of verteporfin, a photosensitizing drug, which injures newly formed
CNV and thus reduces the risk of vision loss and retards disease progression in
patients with AMD. Its efficacy and safety in nAMD have been demonstrated by
several studies[8-10].
It
was hypothesized that the combination of these two treatments may have a
synergistic effect on improving visual acuity (VA) and reducing the center
retinal thickness (CRT), the CNV and the number of anti-VEGF treatments[5,11]. Currently, there is
no consensus regarding whether combination therapy is more effective compared
with anti-VEGF monotherapy. We performed a comprehensive, computerized, online
search of the randomized controlled trials that have compared anti-VEGF
monotherapy versus PDT and anti-VEGF combination treatment in AMD. Using all
available data, a systematic review and Meta-analysis of the comparison of the
two therapies was performed to estimate the efficacy of anti-VEGF monotherapy
and combination therapy.
METHODS
Literature Search We searched
PubMed, Web of Science and the Cochrane Library using the following search
terms: (“age related macular degeneration’’ OR ‘‘AMD’’ OR “macular
degeneration”) and (‘‘PDT’’ OR ‘‘photodynamic therapy’’ OR “visudyne”) and
(‘‘anti-VEGF’’ OR ‘‘vascular endothelial growth factors’’ OR “endothelial
growth factors” OR “angiogenesis inhibitors” OR “angiogenesis inducing agents”)
and other alternative names (“macugen” OR “pegaptanib” OR “lucentis” OR “rhufab”
OR “ranibizumab” OR “bevacizumab” OR “avastin”). All related articles that were
published prior to January 31, 2015 without language or geographic limitations
were considered.
Selection Criteria Studies were
included only if they fulfilled all of the following six criteria: 1) all patients had a professional
ophthalmic examination and were diagnosed as AMD; 2) the study design was
limited to randomized controlled trials, and the full-text was available; 3)
interventions included anti-VEGF monotherapy (inner ocular injection with
ranibizumab or bevacizumab) and combined PDT and anti-VEGF therapy, and the
time of follow-up was at least 12mo; 4) endpoints included at least one of the
following: the best-corrected visual acuity (BCVA), CRT, number of treatments and
proportion of patients who gained ≥15, 10, 5, or 0 letters of BCVA at 12th
month; 5) raw data were available; and 6) for studies published by the same
group regarding the same population, only the most recent report or the report
with the largest sample size was included for the analysis.
Data Extraction Two reviewers
(Tong Y and Zhao KK) independently extracted the data and evaluated the
quality. The following variables were extracted from each study: 1) the
characteristics of the included studies, i.e.,
the name of the first author, year of publication, location, follow-up time,
mean age and sex ratio of the study participants; 2) the means and standard
deviations (SDs) of the BCVA at the endpoint; 3) the means and SDs of the CRT
at the endpoint; 4) the means and SDs of the number of treatments at the
endpoint; and 5) the proportion of patients who gained BCVA ≥15; 10; 5; 0
letters at the endpoint. An independent review and resolution by a third
reviewer (Feng D) was sought if the two reviewers disagreed.
Statistical Analysis Data were
collected and analyzed using Review Manager 5.2 software. We calculated the
pooled odds ratios (ORs) and 95% confidence intervals (CIs) for the dichotomous
outcomes, as well as the weighted mean differences (WMDs) and 95% CIs for the
continuous outcomes. The differences between the monotherapy and combination
groups were displayed via forest
plot. Q-statistic and I2
statistic were used to measure the difference in the between-study
heterogeneity. If the heterogeneity was statistically significant (P<0.1 and I2>50%), we chose a random-effects model. Otherwise,
a fixed-effects model was used. Furthermore, a subgroup analysis was conducted
to determine the effect of the fluence used in the PDT therapy, and a
sensitivity analysis was performed because of the different design of Kaiser et al’s[17] study.
RESULTS AND DISCUSSION
Literature Search Forty-eight
relevant studies were identified by our initial search, which included 8
studies eligible for inclusion in the review[12-19]. The follow-up times in all studies comprised
12mo. In some cases, raw data were kindly provided by the author[13], and some were procured
from Novartis’ data on file[15,17].
Figure 1 is a flow diagram of the selection of eligible studies. The characteristics
of the included studies are summarized in Table 1. The combined sample size for
this Meta-analysis was 800, which included 409 individuals in the monotherapy
group and 391 individuals in the combination group. The average ages ranged
from 65.3 to 79.1y in the monotherapy group and 63.2 to 80.3y in the
combination group. The gender ratios (male/female) of the two groups varied
from 0.53 (16/30) to 1.6 (8/5) in the monotherapy group and 0.36 (13/36) to 2.0
(12/6) in the combination group. All included studies comprised randomized
controlled trials; 3 studies were conducted in America, 4 studies were
conducted in Europe, and 1 study was conducted in Korea. Table 1 indicates the
features of the included studies. Table 2 presents the means and SDs of the BCVA,
the CRT, the numbers of treatments of the patients at 12th month and
the proportion of the patients who gained BCVA ≥15, 10, 5, 0 letters at 12th
month in the included studies.
Table
1 The feature of
included studies
First author |
Public year |
Study type |
Location |
Follow-up (mo) |
Groups |
Patients (n) |
Mean age (a) |
Gender radio (M/F) |
Therapy |
Larsen[15] |
2012 |
RCT |
Europe |
12 |
Monotherapy |
133 |
75.5 |
59/74 |
IVR (3+PRN) |
Combination |
122 |
76.8 |
44/78 |
PDT (SF1+PRN); IVR (3+PRN) |
|||||
Kaiser[17] |
2012 |
RCT |
America |
12 |
Monotherapy |
112 |
NR |
NR |
IVR (11) |
PDT (SF) combination |
104 |
NR |
NR |
PDT (SF1+PRN); IVR (3+PRN) |
|||||
PDT (RF) combination |
105 |
NR |
NR |
PDT (RF1+PRN); IVR (3+PRN) |
|||||
Krebs[16] |
2013 |
RCT |
Austria |
12 |
Monotherapy |
24 |
77.71 |
NR |
IVR (3+PRN) |
Combination |
20 |
80.25 |
NR |
PDT (SF1+PRN); IVR (3+PRN) |
|||||
Vallance[13] |
2010 |
RCT |
UK |
12 |
Montherapy |
9 |
NR |
NR |
IVR (3+PRN) |
Combination |
9 |
NR |
NR |
PDT (SF1+PRN); IVR (3+PRN) |
|||||
Lim[14] |
2012 |
RCT |
Korea |
12 |
Monotherapy |
13 |
66.7 |
8/5 |
IVB (3+PRN) |
Combination |
23 |
68.9 |
12/6 |
PDT (SF1+PRN); IVB (3+PRN) |
|||||
Williams[12] |
2012 |
RCT |
American |
12 |
Monotherapy |
27 |
79.1 |
NR |
IVB (1+PRN) |
PDT (RF) combination |
29 |
79.3 |
NR |
PDT (RF1+PRN); IVB (1+PRN) |
|||||
Costagliola[19] |
2010 |
RCT |
Italy |
12 |
Monotherapy |
45 |
65.3 |
20/25 |
IVB (1+PRN) |
PDT (RF) combination |
40 |
63.2 |
18/22 |
PDT (RF1+PRN); IVB (1+PRN) |
|||||
Datseris[18] |
2015 |
RCT |
America |
12 |
Monotherapy |
46 |
74 |
16/30 |
IVB (1+PRN) |
PDT (RF) combination |
49 |
73 |
13/36 |
PDT (RF1+PRN); IVB (1+PRN) |
RCT:
Randomized control trials; Monotherapy: Group which accept anti-VEGF treatment
only; PDT (SF): PDT with standard fluence; PDT (RF): PDT with reduced fluence; BCVA:
Best-corrected visual acuity; CRT: Central retinal thickness; IVR: Intravitreal
ranibizumab; IVB: Intravitreal bevacizumab; PRN: As needed; NR: No record.
Table
2 Means and SDs of
examination results of patients in each included study at 12th month
Study (first author) |
Groups |
Patients (n) |
Means of BCVA (SD, letter) |
CRT (SD, μm) |
Treatments n (SD) |
Patients gained BCVA [letter, n
(%)] |
|||
≥15 |
≥10 |
≥5 |
≥0 |
||||||
Larsen[15] |
Monotherapy |
132 |
59.4 (18.8) |
232 (54.54) |
5.1 (2.01) |
34 (25.8) |
51 (38.6) |
69 (52.3) |
87 (65.9) |
PDT(SF) combination |
121 |
57.1 (18.3) |
219.9 (61.05) |
4.8 (2.03) |
22 (18.2) |
45 (37.2) |
61 (50.4) |
86 (71.1) |
|
Kaiser[17] |
Monotherapy |
110 |
63 (18.88) |
284.59 (75.49) |
NR |
45 (41.1) |
65 (58.9) |
72 (65.3) |
87 (78.9) |
PDT(SF) combination |
103 |
59 (17.47) |
292.92 (79.27) |
NR |
32 (31.3) |
50 (48.2) |
57 (55.4) |
77 (74.7) |
|
PDT(RF) combination |
105 |
59 (18.03) |
305.72 (80.45) |
NR |
26 (24.7) |
45 (42.4 |
62 (58.8) |
74 (70.6) |
|
Krebs[16] |
Monotherapy |
22 |
57.09 (24.61) |
291.87 (70.00) |
7.17 (2.44, n=24) |
NR |
NR |
NR |
NR |
PDT(SF) combination |
19 |
46.89 (28.30) |
268.83 (90.81) |
5.8(2.31, n=20) |
NR |
NR |
NR |
NR |
|
Vallance[13] |
Monotherapy |
9 |
59.44 (11.05) |
233.11 (47.93) |
4.6 (0.96) |
1 (11.1) |
3 (33.3) |
NR |
NR |
PDT(SF) combination |
9 |
52.78 (18.74) |
193.67 (37.52) |
4.3 (0.82) |
1 (11.1) |
1 (11.1) |
NR |
NR |
|
Lim[14] |
Monotherapy |
13 |
NR |
239.3 (129.37) |
3.3 (0.46) |
NR |
NR |
NR |
NR |
PDT(SF) combination |
23 |
NR |
211.89 (128.89) |
3.22 (0.42) |
NR |
NR |
NR |
NR |
|
Williams[12] |
Monotherapy |
27 |
NR |
NR |
NR |
9 (33) |
NR |
NR |
NR |
PDT(RF) combination |
29 |
NR |
NR |
NR |
9 (31) |
NR |
NR |
NR |
|
Costagliola[19] |
Monotherapy |
45 |
57 (18) |
223 (72) |
NR |
21 (47) |
NR |
NR |
NR |
PDT(RF) combination |
40 |
61 (16) |
244 (60) |
NR |
14 (35) |
NR |
NR |
NR |
|
Datseris[18] |
Monotherapy |
46 |
NR |
286.00 (57.99) |
NR |
20 (43.5) |
NR |
NR |
NR |
PDT(RF) combination |
49 |
NR |
290.84 (96.26) |
NR |
21 (42.8) |
NR |
NR |
NR |
Monotherapy:
Group which accept anti-VEGF treatment only; Combination: PDT and anti-VEGF
combination treatment; PDT (SF): PDT with standard fluence; PDT (RF): PDT with
reduced fluence; BCVA: Best-corrected visual acuity; CRT: Central retinal
thickness; NR: No record or record is incomplete.
Figure
1 The literature
search process.
Best-corrected Visual Acuity Figure 2 shows
the forest plots of the effect on the BCVA. We performed a subgroup analysis to
determine the effect of the fluence used in the PDT therapy, and a sensitivity
analysis was performed because Kaiser et
al’s[17] study has
three groups: monotherapy group, PDT (standard fluence, SF) group and PDT
(reduced fluence, RF) group; we discussed the results that included the
monotherapy group and PDT (SF) group of Kaiser’s study, as well as the results
that included the monotherapy group and PDT (RF) group of Kaiser et al’s[17] study.
Figure
2A shows the results that included the monotherapy group and PDT (SF) group of Kaiser et al’s[17] study. In the PDT (SF) subgroup, the patients in
the monotherapy group exhibited a better BCVA compared with the combination
group at 12th month (WMD: 3.54; 95%CI: 0.36 to 6.73; P=0.03), with no evidence of
heterogeneity (I2=0%, P=0.77). The PDT (RF) subgroup included
only one study[19] (WMD:
-4.00; 95%CI: -11.23 to 3.23, P=0.28).
In the total result, the mean difference in the BCVA was not significant
between the monotherapy and combination groups (WMD: 2.32; 95%CI: -0.60 to
5.23; P=0.12), with no significant
heterogeneity (I2=14%, P=0.33).
Figure
2B shows the results that included the monotherapy group and PDT (RF) group of
Kaiser’s study. In the PDT (SF) subgroup, the mean difference in the BCVA was
not significant between the monotherapy and combination groups (WMD: 3.34;
95%CI: -0.87 to 7.54; P=0.12), with
no evidence of heterogeneity (I2=0%,
P=0.47). In the PDT (RF) subgroup,
the mean difference in the BCVA was not significant between the monotherapy and
combination groups (WMD: 1.46; 95%CI: -2.62 to 5.53; P=0.48), with significant heterogeneity (I2=69%, P=0.07).
Overall, the mean difference in the BCVA was not significant between the
monotherapy and combination groups (WMD: 2.37; 95%CI: -0.56 to 5.29; P=0.11), with no significant heterogeneity
(I2=22%, P=0.27).
Figure
2 Forest plots of
the effect on the BCVA A: Comparison of BCVA at 12th
month between monotherapy group and combination group [including monotherapy
group and PDT (SF) group of Kaiser et al’s[17] study]; B: Comparison of
BCVA at 12th month between monotherapy group and combination group [including
monotherapy group and PDT (RF) group of Kaiser et al’s[17]
study].
Central Retinal Thickness Figure 3 shows
the forest plots of the effect on the CRT. We also performed subgroup and
sensitivity analyses. Figure 3A shows the results that included the monotherapy
group and PDT (SF) group of Kaiser et al’s[17] study. In the PDT (SF)
subgroup, the mean difference in the CRT was not significant between the
monotherapy and combination groups (WMD: 9.25; 95%CI: -1.70 to 20.21; P=0.10), with no significant
heterogeneity (I2=28%, P=0.24). The PDT (RF) subgroup was also
not significantly different between the two groups (WMD: -13.91; 95%CI: -34.93
to 7.12; P=0.19), with no significant
heterogeneity (I2=0%, P=0.45). In the total result, the mean
difference in the CRT was not significant between the monotherapy and
combination groups (WMD: 4.31; 95%CI: -5.40 to 14.03; P=0.38), with no significant heterogeneity (I2=39%, P=0.13).
Figure
3B shows the results that included the monotherapy group and PDT (RF) group of
Kaiser’s study. In the PDT (SF) subgroup, the CRT was thinner in the
combination group compared with the monotherapy group (WMD: 15.99; 95%CI: 3.11
to 28.87; P=0.01), with no evidence
of heterogeneity (I2=0%, P=0.62). In the PDT (RF) subgroup, the
CRT was thinner in the monotherapy group compared with the combination group
(WMD: -17.54; 95%CI: -32.36 to -2.73; P=0.02),
with no significant heterogeneity (I2=0%, P=0.67). In the total result, the mean
difference in the CRT was not significant between the monotherapy and
combination groups (WMD: 1.79; 95%CI: -15.60 to 19.18; P=0.84), with significant heterogeneity (I2=56%, P=0.03).
Figure
3 Forest plots of
the effect on the CRT A: Comparison of CRT at 12th
month between monotherapy group and combination group(including monotherapy
group and PDT (SF) group of Kaiser et al’s[17] study); B: Comparison
of CRT at 12th month between monotherapy group and combination group
[including monotherapy group and PDT (RF) group of Kaiser et al’s[17] study].
Number of Treatments Figure 4 shows
the forest plots of the effect on the number of treatments. The mean difference
in the number of treatments was not significant between the monotherapy and
combination groups (WMD: 0.20; 95%CI: -0.05 to 0.45; P=0.12), with no significant heterogeneity (I2=12%, P=0.33).
Figure
4 Comparison of
number of treatments between monotherapy group and combination group.
Best-corrected Visual Acuity More Than
15, 10, 5, or 0 Letters Figure
5 shows the forest plots of the proportion of patients who gained ≥15 letters
of BCVA at 12th month. Subgroup and sensitivity analyses were
performed.
Figure
5A shows the results that included the monotherapy group and PDT (SF) group of
Kaiser et al’s[17] study. In the PDT (SF) subgroup, the proportion of
patients who gained ≥15 letters of BCVA in the monotherapy group was increased
compared with the combination group (OR: 1.53; 95%CI: 1.02 to 2.31; P=0.04), with no significant
heterogeneity (I2=0%, P=0.96). The PDT (RF) subgroup was not
significantly different between the two groups (OR: 1.23; 95%CI: 0.73 to 2.08; P=0.43), with no significant
heterogeneity (I2=0%,
P=0.74). In the total result, the proportion of patients who gained ≥15 letters
of BCVA in the monotherapy group was increased compared with the combination
group (OR: 1.41; 95%CI: 1.02 to 1.95; P=0.04),
with no significant heterogeneity (I2=0%,
P=0.95).
Figure
5B shows the results that included the monotherapy group and PDT (RF) group of
Kaiser et al’s[17] study. The PDT (SF) subgroup was not significantly
different between the two groups (OR: 1.53; 95%CI: 0.85 to 2.77; P=0.16), with no evidence of
heterogeneity (I2=0%, P=0.77). In the PDT (RF) subgroup, the
proportion of patients who gained ≥15 letters of BCVA in the monotherapy group
was increased compared with the combination group (OR: 1.57; 95%CI: 1.06 to
2.31; P=0.02), with no significant heterogeneity (I2=0%, P=0.50).
In the total results, the proportion of patients who gained ≥15 letters of BCVA
in the monotherapy group was increased compared with the combination group (OR:
1.56; 95%CI: 1.13 to 2.15; P=0.007),
with no significant heterogeneity (I2=0%,
P=0.78).
Figure
5 Forest plots of the proportion of patients who gained ≥15 letters of BCVA at 12th
month
A: Comparison between
monotherapy group and combination group [including monotherapy group and PDT
(SF) group of Kaiser et al’s[17] study]; B: Comparison
between monotherapy group and combination group [including monotherapy group
and PDT (RF) group of Kaiser et al’s[17] study].
A
subgroup analysis, sensitivity analysis and discussion were also conducted in
the analysis of the effect of the proportion of patients who gained ≥10, 5, 0
letters of BCVA at 12th month. With the exception of the proportion
of patients who gained ≥10 letters in the monotherapy group, which was
increased compared with the PDT (RF) combination group in Kaiser’s study
(Figure 6B), all other comparisons were not significantly different (Figures
6-8).
Figure
6 Forest plots of
proportion of patients who gained ≥10 letters of BCVA at 12th
month A: Comparison between monotherapy group
and combination group [including monotherapy group and PDT (SF) group of Kaiser et al’s[17] study]; B: Comparison between monotherapy group and
combination group [including monotherapy group and PDT (RF) group of Kaiser et al’s[17] study].
Figure
7 Forest plots of proportion of patients who gained ≥5 letters of BCVA at 12th
month
A: Comparison between monotherapy group and combination group [including
monotherapy group and PDT (SF) group of Kaiser et al’s[17]
study]; B: Comparison between monotherapy group and combination group [including
monotherapy group and PDT (RF) group of Kaiser et al’s[17]
study].
Figure
8 Forest Plots of
proportion of patients who gained ≥0 letters of BCVA at 12th
month
A: Comparison between monotherapy group and combination group [including
monotherapy group and PDT (SF) group of Kaiser et al’s[17]
study]; B: Comparison between monotherapy group and combination group [including
monotherapy group and PDT (RF) group of Kaiser et al’s[17]
study].
DISCUSSION
The
aim of our study is to compare the efficacy of PDT and intravitreal anti-VEGF
monotherapy versus PDT and anti-VEGF combination treatment in AMD. Three of the
eight included studies compared reduced fluence PDT and anti-VEGF combination
therapy with anti-VEGF monotherapy, whereas the other three included studies
compared standard fluence PDT and anti-VEGF combination therapy with anti-VEGF
monotherapy; Kaiser et al’s[17] study compared both the
standard and reduced fluence PDT and anti-VEGF combination therapy with
anti-VEGF monotherapy. Thus, we performed subgroup and sensitivity analyses and
discussed the results that included the monotherapy group and the PDT (SF)
group of Kaiser’s study and the results that included the monotherapy group and
the PDT (RF) group of Kaiser’s study. When we included the different groups of
Kaiser’s study in the sensitivity analysis, the results were different in the
different subgroups.
Kaiser et al’s[17] study
demonstrated that monotherapy may lead to a better BCVA compared with
combination therapy. In Krebs et al’s
study[16], the patients
in the monotherapy group gained a mean of 5.1 letters, whereas the patients in
the combination group lost a mean of 7.1 letters at 12th month after
the accepted different treatments. Larsen et
al’s[15] study also
indicated that monotherapy is superior in VA recovery. Vallance et al’s[13] study exhibited similar results, but the difference
was not significant. However, in Costagiliola et al’s[19]
study, the improvement in VA was greater in the combination group compared with
the monotherapy group, but the difference was not statistically significant
either. When a Meta-analysis was performed for these studies, we determined
that both the combination therapy and the anti-VEGF monotherapy improved the
BCVA at 12th month. In the sensitivity analysis, in the PDT (SF)
subgroup of the results that included the monotherapy group and PDT (SF) group
of Kaiser et al’s[17] study, the patients in the anti-VEGF monotherapy
group exhibited a better BCVA compared with the combination group at 12th
month. Furthermore, the Meta analysis of the proportions of patients who gained
≥15, 10, 5, 0 letters in the BCVA indicated that more patients gained ≥15
letters in the BCVA in the monotherapy group compared with the combination
group. This finding may indicate that anti-VEGF monotherapy may improve BCVA
better than the combination treatment. However, this finding may also be
affected by the design of Kaiser et al’s[17] study: ranibizumab
monotherapy was administered monthly and 12 times in total in the monotherapy
group, which may lead to a better therapeutic effect compared with other
studies while patients in other studies accepted less treatments. However, in
the results that included the monotherapy group and PDT (SF) group of Kaiser’s
study, there was no significant difference in the BCVA between the two groups
in the PDT (RF) subgroup and the total result. In the results that included the
monotherapy group and PDT (RF) group of Kaiser’s study, both subgroups were not
significantly different in the BCVA between the two groups. There were no
differences in the ratios of the patients who gained more BCVA ≥10, 5, 0
letters between the two groups.
In
all included studies, the CRT was reduced at 12th month using both
approaches. However, it remains unclear which approach is better. For example,
in Kaiser et al’s[17] study, a decrease in the mean CRT was identified
for the ranibizumab monotherapy (172.2 µm), PDT (SF) combination (151.7 µm),
and PDT (RF) combination (140.9 µm) groups from the baseline at 12th
month (P=0.400 and 0.050 for the SF
and RF combination groups, respectively). In Costagliola et al’s[19]
study, the mean change from baseline in the center point thickness was
approximately 107 µm in the monotherapy group and 77 µm in the combination
group through 12mo (P=0.002 and 0.003
for the monotherapy and combination groups, respectively). However, in Krebs et al’s[16] study, the retinal thickness decreased 81.49 µm in
the monotherapy group and 138.2 µm in the combination group (P value was not provided). In Larsen et al’s[15] study, the mean change in the CRT at 12th
month was reduced 115.3 µm in the combination group and 107.7 µm in the monotherapy
group, which was not significantly different between the groups. In Vallance et al’s[13] study, the mean CRT was reduced by 138 µm in the
combination group and 103 µm in the monotherapy group (P=0.57). In the sensitivity analysis, in the results that included
the monotherapy group and PDT (SF) group of Kaiser’s study, there was no
significant difference between the two groups. In the results that included the
monotherapy group and PDT (RF) group of Kaiser’s study, the CRT was thinner in
the combination group compared with the monotherapy group in the PDT (SF)
subgroup, and the result was opposite in the PDT (RF) subgroup. This finding is
likely a result of the fluence of the PDT or was affected by the design of
Kaiser’s study as previously discussed. In the total result, there was no
significant difference in these two groups. Overall, the findings were opposite
and were not significantly different in several included studies; thus,
additional studies with larger sample sizes should be conducted to determine
which approach has a better effect on the CRT.
The
treatment approaches are different in several included studies; thus, we
performed a Meta-analysis for four studies that used the same approach and had
complete data to compare the number of treatments between the two groups. Krebs
et al’s[16] study considered that a significant reduction in
the number of required intravitreal injections may be achieved by additional
PDT treatment; however, we did not identify a significant difference in the
number of treatments between the two groups in the total result. In Larsen et al’s[15] study, the patients received 4.8 ranibizumab
injections, on average, in the combination group versus 5.1 injections, on
average, in the monotherapy group in 12mo; the mean number of ranibizumab
retreatments was 1.9 in the combination group and 2.2 in the monotherapy group
(P=0.14). In Vallance et al’s[13] study, after the initial injection, both groups
required a mean of 1.3 retreatments with ranibizumab over the 12mo of the trial.
Datseris et al[18] and Costagliola et al’s [19]
studies indicated that low fluence PDT and anti-VEGF combination therapy
significantly reduced the reinjection rate compared with monotherapy. Williams et al’s[12] study also considered that low fluence PDT and
anti-VEGF combination therapy may lead to fewer reinjections; however, the
difference was not significant based on a Chi-square test. Additional studies
with larger sample sizes should be performed to determine whether low fluence
PDT and anti-VEGF combination therapy may reduce the number of injections.
In Si
et al’s[20] study, they compared a combination of ranibizumab
and photodynamic therapy with ranibizumab monotherapy in the treatment of AMD
and obtained similar results compared with the current study. The differences
between our studies are that we included ranibizumab and bevacizumab as the
anti-VEGF therapy and eight studies were included in our analysis.
In
conclusion, we determined that anti-VEGF monotherapy is better for visual
recovery compared with combination therapy. As some included studies suggested,
low fluence PDT combined with anti-VEGF therapy may reduce the frequency of
reinjection. Fewer injections may be useful to reduce the risk of side effects
and the financial burden to patients; however, it may not improve VA similar to
anti-VEGF monotherapy. To determine the best therapeutic schedule, it is
advisable to consider the patient’s demand and the doctor’s proper judgments
based on the practical situation of the patient. We did not identify
significant differences in the other indexes between the two therapeutic
approaches. More researches with lager sample size should be performed to study
on the effect of the two therapy approaches on CRT and number of injections.
ACKNOWLEDGEMENTS
Yao
Tong conceived of the study and participated in its design; analysis and
interpretation of data and drafted the manuscript. Zhao-Yang Wang participated
in design the study. Ke-Ke Zhao and Dong Feng participated in performed the
statistical analysis. Manas Biswal helped to amend the mistakes of grammar. Pei-Quan
Zhao and Yun Zhang helped to revise the manuscript.
Foundations:
Supported
by the National Natural Science Funds of China (No.81371040);
Shanghai Pujiang Program (No.15PJD028).
Conflicts
of Interest: Tong
Y,
None; Zhao KK, None; Feng D, None; Biswal M, None; Zhao PQ,
None; Wang ZY, None; Zhang Y, None.
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