We write with regard to the article from Tufail et al.(1) about
treating neovascular age-related macular degeneration (ARMD). In that
paper it was concluded that intravitreal bevacizumab is a safe and
effective treatment for neovascular ARMD (up to 1 year follow-up). The
authors suggested that the much lower cost and longer duration of action
of bevacizumab compared with ranibizumab and its superiority to other
standard treatments support its implementation in selected healthcare
systems without access to ranibizumab. However, recent investigations have
raised important concerns regarding the safety of off-label intravitreal
bevacizumab in the long-term.
Measurable levels of VEGF have been detected in normal eyes,
providing evidence for a physiological expression of this angiogenic
factor in the human eye.(2) Accordingly, it was demonstrated that retinal
pigment epithelial (RPE) expression of mVEGF continues in the adult in the
absence of angiogenesis or disease.(3) This paracrine relationship
mediates the maintenance of a normal, fenestrated, quiet choriocapillaris
in the adult. In addition, the VEGF has been recognized as an important
neuroprotectant in the retinal cells.(4) Blockade of such functions may
have long-term side effects that have not been identified so far.
Intravitreal bevacizumab has been shown to cause ultrastructural
changes in the choriocapillaris; a significant reduction of
choriocapillaris endothelial cell fenestrations was seen as early as 24
hours after injection that can explain the rapid onset of response in
treated eyes.(5) However, the beneficial effect of bevacizumab in reducing
choriocapillaris fenestrations decrease over time. On the other hand,
there are evidences of harmful effects of bevacizumab on photoreceptors
and RPE. Accordingly, it has been shown that photoreceptors were damaged
in 5% of primate eyes after intravitreal injection of bevacizumab.(5) In
addition, treatment was associated with early damaging of RPE that can
further compromise outer blood-retinal barrier and choriocapillaris
function.(6-8) These adverse effects may have important clinical
implications in the context of ARMD.
The advanced form of dry ARMD or geographic atrophy is characterized
by a localized degeneration of the RPE, leading to the atrophy of the
underlying choriocapilaris and the overlying retina. This condition often
accompanies the neovascular ARMD. Since local downregulation of VEGF
synthesis by damaged RPE may aggravate geographic atrophy of
choriocapillaris, treatment with anti-VEGF agents may hasten this
pathology despite control of neovascular frond. In addition, bevacizumab
may further compromise the frail photoreceptors.
A recent randomized controlled trial has shown that intravitreal
bevacizumab and ranibizumab have comparable efficacy in the short-term.(9)
However, ranibizumab accumulates less in RPE, and hence may have less
presumed toxicity in the context of ARMD.(10) In addition, the current
dosage of intravitreal bevacizumab (1.25 mg) has shown to reduce VEGF
levels to undetectable values and below physiologic levels.(2) Therefore,
there is debate whether the current dosage is appropriate or not. Smaller
doses may cause significant clinical improvement with less adverse
effects.
In summary, although intravitreal bevacizumab injection seems
encouraging in terms of provisionally treating visual loss associated with
ARMD, it might cause RPE and/or photoreceptor injury that in turn could
aggravate the overall disease process and ultimate outcome. Therefore, it
is a debate whether the treatment has an acceptable risk–benefit ratio in
the long-term. Future studies with longer follow-up periods may elucidate
new adverse effects of this treatment modality.
References
1. Tufail A, Patel PJ, Egan C, et al; ABC Trial Investigators.
Bevacizumab for neovascular age related macular degeneration (ABC Trial):
multicentre randomised double masked study. BMJ 2010;340:c2459.
2. Funk M, Kriechbaum K, Prager F, Benesch T, Georgopoulos M,
Zlabinger GJ, Schmidt-Erfurth U. Intraocular concentrations of growth
factors and cytokines in retinal vein occlusion and the effect of therapy
with bevacizumab. Invest Ophthalmol Vis Sci 2009;50:1025-32.
3. Saint-Geniez M, Maldonado AE, D'Amore PA. VEGF expression and
receptor activation in the choroid during development and in the adult.
Invest Ophthalmol Vis Sci 2006;47:3135-42.
4. Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth
factor-A is a survival factor for retinal neurons and a critical
neuroprotectant during the adaptive response to ischemic injury. Am J
Pathol 2007;171:53-67.
5. Peters S, Heiduschka P, Julien S, et al; Tu¨bingen Bevacizumab
Study Group. Ultrastructural findings in the primate eye after
intravitreal injection of bevacizumab. Am J Ophthalmol 2007;143:995–1002.
6. Spitzer MS, Wallenfels-Thilo B, Sierra A, et al; Tuebingen AQ : 1
Bevacizumab Study Group. Antiproliferative and cytotoxic properties of
bevacizumab on different ocular cells. Br J Ophthalmol 2006;90:1316–1321.
7. Sayanagi K, Ikuno Y, Soga K, et al. Marginal crack after
intravitreal bevacizumab for myopic choroidal neovascularization. Acta
Ophthalmol 2009;87:460–463.
8. Chan CK, Abraham P, Meyer CH, et al. Optical coherence tomography-
measured pigment epithelial detachment height as a predictor for retinal
pigment epithelial tears associated with intravitreal bevacizumab
injections. Retina 2010 Feb;30:203-11.
9. Subramanian ML, Ness S, Abedi G, Ahmed E, Daly M, Feinberg E, et
al. Bevacizumab vs ranibizumab for age-related macular degeneration: early
results of a prospective double-masked, randomized clinical trial. Am J
Ophthalmol 2009;148:875-82.e1.
10. Klettner AK, Kruse ML, Meyer T, et al. Different properties of
VEGF-antagonists: bevacizumab but not ranibizumab accumulates in RPE
cells. Graefes Arch Clin Exp Ophthalmol 2009; 247:1601–1608.
Competing interests:
None declared
Competing interests:
No competing interests
18 June 2010
Mohammad H Nowroozzadeh
Ophthalmologist
Poostchi Ophthalmology Research Center, Zand St., Shiraz, Iran, Postal code: 7134997446
Rapid Response:
Intravitreal Bevacizumab for Neovascular ARMD
We write with regard to the article from Tufail et al.(1) about
treating neovascular age-related macular degeneration (ARMD). In that
paper it was concluded that intravitreal bevacizumab is a safe and
effective treatment for neovascular ARMD (up to 1 year follow-up). The
authors suggested that the much lower cost and longer duration of action
of bevacizumab compared with ranibizumab and its superiority to other
standard treatments support its implementation in selected healthcare
systems without access to ranibizumab. However, recent investigations have
raised important concerns regarding the safety of off-label intravitreal
bevacizumab in the long-term.
Measurable levels of VEGF have been detected in normal eyes,
providing evidence for a physiological expression of this angiogenic
factor in the human eye.(2) Accordingly, it was demonstrated that retinal
pigment epithelial (RPE) expression of mVEGF continues in the adult in the
absence of angiogenesis or disease.(3) This paracrine relationship
mediates the maintenance of a normal, fenestrated, quiet choriocapillaris
in the adult. In addition, the VEGF has been recognized as an important
neuroprotectant in the retinal cells.(4) Blockade of such functions may
have long-term side effects that have not been identified so far.
Intravitreal bevacizumab has been shown to cause ultrastructural
changes in the choriocapillaris; a significant reduction of
choriocapillaris endothelial cell fenestrations was seen as early as 24
hours after injection that can explain the rapid onset of response in
treated eyes.(5) However, the beneficial effect of bevacizumab in reducing
choriocapillaris fenestrations decrease over time. On the other hand,
there are evidences of harmful effects of bevacizumab on photoreceptors
and RPE. Accordingly, it has been shown that photoreceptors were damaged
in 5% of primate eyes after intravitreal injection of bevacizumab.(5) In
addition, treatment was associated with early damaging of RPE that can
further compromise outer blood-retinal barrier and choriocapillaris
function.(6-8) These adverse effects may have important clinical
implications in the context of ARMD.
The advanced form of dry ARMD or geographic atrophy is characterized
by a localized degeneration of the RPE, leading to the atrophy of the
underlying choriocapilaris and the overlying retina. This condition often
accompanies the neovascular ARMD. Since local downregulation of VEGF
synthesis by damaged RPE may aggravate geographic atrophy of
choriocapillaris, treatment with anti-VEGF agents may hasten this
pathology despite control of neovascular frond. In addition, bevacizumab
may further compromise the frail photoreceptors.
A recent randomized controlled trial has shown that intravitreal
bevacizumab and ranibizumab have comparable efficacy in the short-term.(9)
However, ranibizumab accumulates less in RPE, and hence may have less
presumed toxicity in the context of ARMD.(10) In addition, the current
dosage of intravitreal bevacizumab (1.25 mg) has shown to reduce VEGF
levels to undetectable values and below physiologic levels.(2) Therefore,
there is debate whether the current dosage is appropriate or not. Smaller
doses may cause significant clinical improvement with less adverse
effects.
In summary, although intravitreal bevacizumab injection seems
encouraging in terms of provisionally treating visual loss associated with
ARMD, it might cause RPE and/or photoreceptor injury that in turn could
aggravate the overall disease process and ultimate outcome. Therefore, it
is a debate whether the treatment has an acceptable risk–benefit ratio in
the long-term. Future studies with longer follow-up periods may elucidate
new adverse effects of this treatment modality.
References
1. Tufail A, Patel PJ, Egan C, et al; ABC Trial Investigators.
Bevacizumab for neovascular age related macular degeneration (ABC Trial):
multicentre randomised double masked study. BMJ 2010;340:c2459.
2. Funk M, Kriechbaum K, Prager F, Benesch T, Georgopoulos M,
Zlabinger GJ, Schmidt-Erfurth U. Intraocular concentrations of growth
factors and cytokines in retinal vein occlusion and the effect of therapy
with bevacizumab. Invest Ophthalmol Vis Sci 2009;50:1025-32.
3. Saint-Geniez M, Maldonado AE, D'Amore PA. VEGF expression and
receptor activation in the choroid during development and in the adult.
Invest Ophthalmol Vis Sci 2006;47:3135-42.
4. Nishijima K, Ng YS, Zhong L, et al. Vascular endothelial growth
factor-A is a survival factor for retinal neurons and a critical
neuroprotectant during the adaptive response to ischemic injury. Am J
Pathol 2007;171:53-67.
5. Peters S, Heiduschka P, Julien S, et al; Tu¨bingen Bevacizumab
Study Group. Ultrastructural findings in the primate eye after
intravitreal injection of bevacizumab. Am J Ophthalmol 2007;143:995–1002.
6. Spitzer MS, Wallenfels-Thilo B, Sierra A, et al; Tuebingen AQ : 1
Bevacizumab Study Group. Antiproliferative and cytotoxic properties of
bevacizumab on different ocular cells. Br J Ophthalmol 2006;90:1316–1321.
7. Sayanagi K, Ikuno Y, Soga K, et al. Marginal crack after
intravitreal bevacizumab for myopic choroidal neovascularization. Acta
Ophthalmol 2009;87:460–463.
8. Chan CK, Abraham P, Meyer CH, et al. Optical coherence tomography-
measured pigment epithelial detachment height as a predictor for retinal
pigment epithelial tears associated with intravitreal bevacizumab
injections. Retina 2010 Feb;30:203-11.
9. Subramanian ML, Ness S, Abedi G, Ahmed E, Daly M, Feinberg E, et
al. Bevacizumab vs ranibizumab for age-related macular degeneration: early
results of a prospective double-masked, randomized clinical trial. Am J
Ophthalmol 2009;148:875-82.e1.
10. Klettner AK, Kruse ML, Meyer T, et al. Different properties of
VEGF-antagonists: bevacizumab but not ranibizumab accumulates in RPE
cells. Graefes Arch Clin Exp Ophthalmol 2009; 247:1601–1608.
Competing interests:
None declared
Competing interests: No competing interests