Cover Story

Practitioners, researchers continue to probe the use of anti-VEGF therapy for ROP

The use of intravitreal anti-VEGF therapy for treatment of retinopathy of prematurity has been explored in recent years; however, experts differ on its use and caution that more long-term safety and efficacy data are needed.

“This subject is one of the hottest topics presented to the pediatric ophthalmology community in 25 years and is among the most controversial. It is essential that we come to some understanding and possible protocol on how to use this medicine effectively and appropriately,” Robert S. Gold, MD, OSN Pediatrics/Strabismus Section Editor, said.

“The questions remain: When to use it and under what circumstances to use it,” he said.

The standard of care in ROP cases has historically been laser therapy, and anti-VEGF injections are typically used off label as salvage therapy or when dealing with aggressive posterior ROP, according to R.V. Paul Chan, MD, OSN Pediatrics/Strabismus Board Member.

R.V. Paul Chan, MD
Although study results are encouraging, R.V. Paul Chan, MD, advises caution when considering bevacizumab treatment for ROP.
Image: Athanason P

“We have data that it works, but as ophthalmologists who manage and treat ROP, we have to be cautious and advocate for its use in certain situations,” Dr. Chan said.

Standard of care vs. anti-VEGF

ROP largely manifests as abnormal growth of developing retinal vasculature.

Peripheral retinal ablation using either laser or cryotherapy has been proven effective on a long-term basis in a series of studies over the last 25 years, according to Graham E. Quinn, MD, MSCE, attending surgeon in the Division of Pediatric Ophthalmology at The Children’s Hospital of Philadelphia and professor of ophthalmology at the Perelman School of Medicine at the University of Pennsylvania.

“We know that ROP is a VEGF-driven disease. VEGF levels go down after laser use, and attacking it at a certain time point can stop the disease. So it makes sense to give an agent that inhibits the VEGF at a specific point in time to stop the disease. It is like a runaway train: We can put on the brakes and help give the child time to develop normal vasculature without destroying the peripheral retina,” Dr. Chan said.

Avastin (bevacizumab, Genentech) is approved by the U.S. Food and Drug Administration for the treatment of various systemic cancers and is currently used off label for ophthalmic indications such as neovascular age-related macular degeneration and diabetic retinopathy. Some investigators thought bevacizumab may also benefit ROP patients, and several case series have reported ROP regression in patients treated with bevacizumab alone or in combination with conventional laser, Dr. Chan said.

However, there are a lot of unknowns regarding anti-VEGF use for this indication.

“We don’t know the complications, we don’t know whether there is significant systemic absorption or if it affects the development of the normal vasculature, and importantly, we don’t know the side effect profile,” Dr. Chan said. “The question is not, does anti-VEGF work? We know it works for promoting regression of neovascularization. The question is, what are the side effects?”

Another area of concern is cost.

Intravitreal bevacizumab is less expensive, at an estimated $50 per injection, than laser treatment, does not require monthly injections and may help balance the cost of laser therapy, according to Dr. Quinn. But, he suggested that the additional necessary follow-up visits and inconvenience to families will contribute to the cost over the long term.

One benefit of anti-VEGF treatment is that intravitreal bevacizumab can be performed at the bedside in 2 or 3 minutes, whereas laser treatment may take up to 2 hours, requires expensive equipment and must be performed in an operating room specially equipped for laser surgery. After both laser therapy and bevacizumab therapy, infants must be followed for the first few months frequently and ultimately for years, Helen A. Mintz-Hittner, MD, professor in the Department of Ophthalmology and Visual Science at the University of Texas, Health Science Center, Houston Medical School, previously told Ocular Surgery News.

When and who to treat?

Robert S. Gold, MD
Robert S. Gold

Anti-VEGF therapies such as Macugen (pegaptanib, Eyetech/Pfizer), Lucentis (ranibizumab, Genentech) and bevacizumab have all been used to treat ROP, but when to treat, who to treat and which drug is best remain unresolved.

“Some doctors are using anti-VEGFs as soon as a baby may need treatment, which can be in zone 1, 2 or 3 for stage 1, 2 or 3 disease. Others are using it when a baby has progressed to significant retinopathy of prematurity and is too sick to be sedated for laser treatment for ROP,” Dr. Gold said.

Thomas C. Lee, MD, director of The Vision Center at Children’s Hospital Los Angeles and associate professor of ophthalmology at the Doheny Eye Institute, Keck School of Medicine, University of Southern California, said that anti-VEGF therapy is a beneficial option for certain severe cases of ROP.

Some children with zone 1 and 3 disease have a 30% fail rate despite receiving standard of care, Dr. Lee said.

“Or they go blind or develop progressive ROP. In those children, is anti-VEGF as effective? That is not clear,” Dr. Lee said.

Furthermore, concern remains about recurrence, possibly 4 to 5 months after injection, which may require more frequent follow-up. There is, however, no established recommended follow-up frequency for patients who receive anti-VEGF therapy for ROP.

According to Dr. Quinn, the treatment alters the acute phase of the disease, but there are questions regarding the uncertainty of the drug’s ocular and systemic effects.

Thomas C. Lee, MD
Thomas C. Lee

“Does the retina vascularize normally? Is the macular development normal? What are the systemic effects of anti-angiogenic drugs on neural, lung and kidney? These are major and unanswered issues,” he said.

There are various indications for the use of anti-VEGF therapy in treating ROP, according to Dr. Chan. Often, they are used when laser therapy fails and disease progresses, when laser therapy is not possible, as adjunct therapy or when treatment-requiring disease is in zone 1.

“When using [anti-VEGF therapy], we have to be very conscious of our follow-up as we will likely have to follow these children for a longer period of time than what we are used to with laser therapy. We just don’t know the long-term effects and when recurrence of disease can happen,” Dr. Chan said. There is also a question of whether laser therapy is still necessary as an adjunct when anti-VEGF therapy is used.

Study spurs discussion

A prospective, randomized clinical trial by Dr. Mintz-Hittner and colleagues, published in the New England Journal of Medicine, has advanced the knowledge base about the use of bevacizumab for treatment of ROP.

Results showed that intravitreal bevacizumab provided benefits in treating acute ROP, resulting in a lower recurrence rate than conventional laser treatment. Treatment effect was superior for zone 1 disease, but the study enrolled too few infants to show a superior treatment effect for zone 2 disease; thus, a larger clinical trial that includes both zone 1 and zone 2 disease is necessary, according to Dr. Mintz-Hittner. Further, the investigators were able to avoid damage to the peripheral retina, an inevitable result with laser treatment, which is basically a destructive treatment that ablates the peripheral avascular retina, she said.

The study included 286 eyes of 143 premature infants with acute ROP stage 3 with plus disease in zone 1 or posterior zone 2. Patients with stages 1 or 2 and stages 4 or 5 ROP in either eye were excluded. Dr. Mintz-Hittner said treating in stages 1 or 2 (without plus disease), generally in infants younger than 31 weeks adjusted age, causes an acute retinal necrosis. Treating in stages 4 or 5, generally in infants older than 45 weeks adjusted age, causes an accelerated retinal detachment. Thus, the timing of administration of anti-VEGF therapy is critical.

Dr. Mintz-Hittner and colleagues randomly assigned 140 eyes to receive 0.625 mg intravitreal injections of bevacizumab and 146 eyes to undergo peripheral retinal laser ablation.

Results showed that the recurrence rate for zones 1 and 2 combined was 4% of eyes in the bevacizumab group and 22% of eyes in the laser therapy group (P = .002). In the zone 1 group, the recurrence rate was 6% of eyes treated with bevacizumab and 42% of eyes treated with laser therapy (P = .003).

Based on the results of the trial, Dr. Mintz-Hittner said, “If you have a child with threatening ROP in zone 1, then you should at least offer this therapy to the parents of the child and explain the differences in outcome. We have seen no systemic or related toxicity of this drug that was not related to administration too early or too late, and I feel it is appropriate to use in most zone 1 cases and in some posterior zone 2 cases.”

Fast Facts

“This study clearly showed anti-VEGF therapy can be helpful for cases of zone 1 ROP in children who might have otherwise gone blind,” Dr. Lee said. “However, the appropriate application is still being discussed.”

While the results are encouraging, Dr. Chan said that the long-term complications of intravitreal bevacizumab for this indication are not fully elucidated, and there have been reports of local adverse events such as vitreous hemorrhage and progression to retinal detachment. After the injection, infection, rhegmatogenous retinal detachment and cataract are possible adverse events. Another major concern, he said, is the potential disruption of normal vascular development.

James D. Reynolds, MD, in an editorial published in the same issue of the New England Journal of Medicine as Dr. Mintz-Hittner’s study, wrote that he believes intravitreal bevacizumab therapy “will prove to be at least equal to laser therapy in clinical effectiveness for most forms of retinopathy of prematurity. As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice for zone 1 retinopathy of prematurity.”

Dr. Chan said that the editorial “caused some controversy in our community.

“We have to be careful about this statement. Laser is still very much a part of our armamentarium for this disease. Most of us will advocate for [bevacizumab’s] use in progressive disease, zone 1 ROP or new vessels in the iris, in cases when we can’t laser it, etc.,” he said. “But if you are treating standard, run-of-the-mill treatment-requiring ROP, I believe that most of us who manage this disease will still advocate for laser.”

The long-term effects of anti-VEGF use in ROP remain to be seen. Dr. Mintz-Hittner said that it has been used for this indication for more than 6 years around the world, and even though outcome data are not available, no systemic adverse events have been reported in this population to date.

“We don’t know the long-term outcomes, but philosophically, I don’t think we can withhold this therapy from patients until we get long-term data 9 years from now, whether you are participating in a randomized clinical trial or not,” she said. “Some children cannot be moved to a study site; however, the number of zone 1 cases keeps increasing due to increased survival of very small infants, and some considerations of anti-VEGF therapy for these patients, their parents and society is appropriate.”

Timeline for adoption unclear

When asked if they are any closer to using anti-VEGFs to treat ROP and whether they will ever be used on label for this indication, most experts interviewed by OSN agree that the answers are equivocal. Studies evaluating the dose of bevacizumab, the timing of treatment, vision outcomes and safety data are warranted.

“Avastin represents an important addition to our armamentarium, and application should be considered carefully on a case-by-case basis. Laser, I believe, will continue to be an important main stage in ROP cases until more is learned about anti-VEGF use in ROP,” Dr. Lee said.

Use of anti-VEGF injections in cases of ROP should be used “compassionately for failed laser or poor view. Otherwise we should only be using it in the setting of an adequately sized, randomized, controlled and masked clinical trial,” Dr. Quinn said.

The important questions of who to treat, what to treat and when to treat will still remain, according to Dr. Gold.

“It’s a great medication and it works very well, but we don’t know the long-term effect,” he said. – by Tara Grassia

POINT/COUNTER
How soon after discharge do you see an infant who had stage 1 or 2 ROP but reached near complete vascularization and was improving as expected without treatment?

*
Lindstrom's Perspective
All ophthalmologists should be familiar with ROP and its treatments

References:

  • Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. 2007;114(5):855-859.
  • Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group.. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615.
  • Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, Salazar-Teran N, Chan RV. Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity. Retina. 2008;28(3 Suppl):S19-25.
  • Reynolds JD. Bevacizumab for retinopathy of prematurity. N Engl J Med. 2011;364(7):677-678.
  • Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity [published online ahead of print Sept. 17, 2011]. Am J Ophthalmol. doi:10.1016/j.ajo.2011.07.005.

  • R.V. Paul Chan, MD, can be reached at New York-Presbyterian Hospital, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, New York, NY, 10021; 646-962-2540; fax: 646-962-0609; email: roc9013@med.cornell.edu.
  • Robert S. Gold, MD, can be reached at the Pediatric Ophthalmology and Adult Eye Muscle Disorders Eye Physicians of Central Florida, 790 Concourse Parkway South, Suite 200, Maitland, FL 32751; 407-767-6411; fax: 407-767-8160; email: rsgeye@aol.com.
  • Thomas C. Lee, MD, can be reached at The Vision Center at Children’s Hospital Los Angeles, 4650 Sunset Blvd. #88, Los Angeles, CA 90027; 323-361-2299; fax: 323-361-3515; email: tleemd@gmail.com.
  • Helen A. Mintz-Hittner, MD, can be reached at Robert Cizik Eye Clinic, 6400 Fannin St., Suite 1800, Houston, TX 77030; 713-559-5277; fax: 713-559-5290; email: helen.a.mintz-hittner@uth.tmc.edu.
  • Graham Quinn, MD, MSCE, can be reached at Division of Pediatric Ophthalmology, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, PA 19104; 215-590-4594; email: quinn@email.chop.edu.
  • Disclosures: Drs. Chan, Gold, Mintz-Hittner and Quinn have no relevant financial disclosures. Dr. Lee is a non-paid consultant for Endo Optiks.

The use of intravitreal anti-VEGF therapy for treatment of retinopathy of prematurity has been explored in recent years; however, experts differ on its use and caution that more long-term safety and efficacy data are needed.

“This subject is one of the hottest topics presented to the pediatric ophthalmology community in 25 years and is among the most controversial. It is essential that we come to some understanding and possible protocol on how to use this medicine effectively and appropriately,” Robert S. Gold, MD, OSN Pediatrics/Strabismus Section Editor, said.

“The questions remain: When to use it and under what circumstances to use it,” he said.

The standard of care in ROP cases has historically been laser therapy, and anti-VEGF injections are typically used off label as salvage therapy or when dealing with aggressive posterior ROP, according to R.V. Paul Chan, MD, OSN Pediatrics/Strabismus Board Member.

R.V. Paul Chan, MD
Although study results are encouraging, R.V. Paul Chan, MD, advises caution when considering bevacizumab treatment for ROP.
Image: Athanason P

“We have data that it works, but as ophthalmologists who manage and treat ROP, we have to be cautious and advocate for its use in certain situations,” Dr. Chan said.

Standard of care vs. anti-VEGF

ROP largely manifests as abnormal growth of developing retinal vasculature.

Peripheral retinal ablation using either laser or cryotherapy has been proven effective on a long-term basis in a series of studies over the last 25 years, according to Graham E. Quinn, MD, MSCE, attending surgeon in the Division of Pediatric Ophthalmology at The Children’s Hospital of Philadelphia and professor of ophthalmology at the Perelman School of Medicine at the University of Pennsylvania.

“We know that ROP is a VEGF-driven disease. VEGF levels go down after laser use, and attacking it at a certain time point can stop the disease. So it makes sense to give an agent that inhibits the VEGF at a specific point in time to stop the disease. It is like a runaway train: We can put on the brakes and help give the child time to develop normal vasculature without destroying the peripheral retina,” Dr. Chan said.

Avastin (bevacizumab, Genentech) is approved by the U.S. Food and Drug Administration for the treatment of various systemic cancers and is currently used off label for ophthalmic indications such as neovascular age-related macular degeneration and diabetic retinopathy. Some investigators thought bevacizumab may also benefit ROP patients, and several case series have reported ROP regression in patients treated with bevacizumab alone or in combination with conventional laser, Dr. Chan said.

However, there are a lot of unknowns regarding anti-VEGF use for this indication.

“We don’t know the complications, we don’t know whether there is significant systemic absorption or if it affects the development of the normal vasculature, and importantly, we don’t know the side effect profile,” Dr. Chan said. “The question is not, does anti-VEGF work? We know it works for promoting regression of neovascularization. The question is, what are the side effects?”

Another area of concern is cost.

Intravitreal bevacizumab is less expensive, at an estimated $50 per injection, than laser treatment, does not require monthly injections and may help balance the cost of laser therapy, according to Dr. Quinn. But, he suggested that the additional necessary follow-up visits and inconvenience to families will contribute to the cost over the long term.

One benefit of anti-VEGF treatment is that intravitreal bevacizumab can be performed at the bedside in 2 or 3 minutes, whereas laser treatment may take up to 2 hours, requires expensive equipment and must be performed in an operating room specially equipped for laser surgery. After both laser therapy and bevacizumab therapy, infants must be followed for the first few months frequently and ultimately for years, Helen A. Mintz-Hittner, MD, professor in the Department of Ophthalmology and Visual Science at the University of Texas, Health Science Center, Houston Medical School, previously told Ocular Surgery News.

When and who to treat?

Robert S. Gold, MD
Robert S. Gold

Anti-VEGF therapies such as Macugen (pegaptanib, Eyetech/Pfizer), Lucentis (ranibizumab, Genentech) and bevacizumab have all been used to treat ROP, but when to treat, who to treat and which drug is best remain unresolved.

“Some doctors are using anti-VEGFs as soon as a baby may need treatment, which can be in zone 1, 2 or 3 for stage 1, 2 or 3 disease. Others are using it when a baby has progressed to significant retinopathy of prematurity and is too sick to be sedated for laser treatment for ROP,” Dr. Gold said.

Thomas C. Lee, MD, director of The Vision Center at Children’s Hospital Los Angeles and associate professor of ophthalmology at the Doheny Eye Institute, Keck School of Medicine, University of Southern California, said that anti-VEGF therapy is a beneficial option for certain severe cases of ROP.

Some children with zone 1 and 3 disease have a 30% fail rate despite receiving standard of care, Dr. Lee said.

“Or they go blind or develop progressive ROP. In those children, is anti-VEGF as effective? That is not clear,” Dr. Lee said.

Furthermore, concern remains about recurrence, possibly 4 to 5 months after injection, which may require more frequent follow-up. There is, however, no established recommended follow-up frequency for patients who receive anti-VEGF therapy for ROP.

According to Dr. Quinn, the treatment alters the acute phase of the disease, but there are questions regarding the uncertainty of the drug’s ocular and systemic effects.

Thomas C. Lee, MD
Thomas C. Lee

“Does the retina vascularize normally? Is the macular development normal? What are the systemic effects of anti-angiogenic drugs on neural, lung and kidney? These are major and unanswered issues,” he said.

There are various indications for the use of anti-VEGF therapy in treating ROP, according to Dr. Chan. Often, they are used when laser therapy fails and disease progresses, when laser therapy is not possible, as adjunct therapy or when treatment-requiring disease is in zone 1.

“When using [anti-VEGF therapy], we have to be very conscious of our follow-up as we will likely have to follow these children for a longer period of time than what we are used to with laser therapy. We just don’t know the long-term effects and when recurrence of disease can happen,” Dr. Chan said. There is also a question of whether laser therapy is still necessary as an adjunct when anti-VEGF therapy is used.

Study spurs discussion

A prospective, randomized clinical trial by Dr. Mintz-Hittner and colleagues, published in the New England Journal of Medicine, has advanced the knowledge base about the use of bevacizumab for treatment of ROP.

Results showed that intravitreal bevacizumab provided benefits in treating acute ROP, resulting in a lower recurrence rate than conventional laser treatment. Treatment effect was superior for zone 1 disease, but the study enrolled too few infants to show a superior treatment effect for zone 2 disease; thus, a larger clinical trial that includes both zone 1 and zone 2 disease is necessary, according to Dr. Mintz-Hittner. Further, the investigators were able to avoid damage to the peripheral retina, an inevitable result with laser treatment, which is basically a destructive treatment that ablates the peripheral avascular retina, she said.

The study included 286 eyes of 143 premature infants with acute ROP stage 3 with plus disease in zone 1 or posterior zone 2. Patients with stages 1 or 2 and stages 4 or 5 ROP in either eye were excluded. Dr. Mintz-Hittner said treating in stages 1 or 2 (without plus disease), generally in infants younger than 31 weeks adjusted age, causes an acute retinal necrosis. Treating in stages 4 or 5, generally in infants older than 45 weeks adjusted age, causes an accelerated retinal detachment. Thus, the timing of administration of anti-VEGF therapy is critical.

Dr. Mintz-Hittner and colleagues randomly assigned 140 eyes to receive 0.625 mg intravitreal injections of bevacizumab and 146 eyes to undergo peripheral retinal laser ablation.

Results showed that the recurrence rate for zones 1 and 2 combined was 4% of eyes in the bevacizumab group and 22% of eyes in the laser therapy group (P = .002). In the zone 1 group, the recurrence rate was 6% of eyes treated with bevacizumab and 42% of eyes treated with laser therapy (P = .003).

Based on the results of the trial, Dr. Mintz-Hittner said, “If you have a child with threatening ROP in zone 1, then you should at least offer this therapy to the parents of the child and explain the differences in outcome. We have seen no systemic or related toxicity of this drug that was not related to administration too early or too late, and I feel it is appropriate to use in most zone 1 cases and in some posterior zone 2 cases.”

Fast Facts

“This study clearly showed anti-VEGF therapy can be helpful for cases of zone 1 ROP in children who might have otherwise gone blind,” Dr. Lee said. “However, the appropriate application is still being discussed.”

While the results are encouraging, Dr. Chan said that the long-term complications of intravitreal bevacizumab for this indication are not fully elucidated, and there have been reports of local adverse events such as vitreous hemorrhage and progression to retinal detachment. After the injection, infection, rhegmatogenous retinal detachment and cataract are possible adverse events. Another major concern, he said, is the potential disruption of normal vascular development.

James D. Reynolds, MD, in an editorial published in the same issue of the New England Journal of Medicine as Dr. Mintz-Hittner’s study, wrote that he believes intravitreal bevacizumab therapy “will prove to be at least equal to laser therapy in clinical effectiveness for most forms of retinopathy of prematurity. As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice for zone 1 retinopathy of prematurity.”

Dr. Chan said that the editorial “caused some controversy in our community.

“We have to be careful about this statement. Laser is still very much a part of our armamentarium for this disease. Most of us will advocate for [bevacizumab’s] use in progressive disease, zone 1 ROP or new vessels in the iris, in cases when we can’t laser it, etc.,” he said. “But if you are treating standard, run-of-the-mill treatment-requiring ROP, I believe that most of us who manage this disease will still advocate for laser.”

The long-term effects of anti-VEGF use in ROP remain to be seen. Dr. Mintz-Hittner said that it has been used for this indication for more than 6 years around the world, and even though outcome data are not available, no systemic adverse events have been reported in this population to date.

“We don’t know the long-term outcomes, but philosophically, I don’t think we can withhold this therapy from patients until we get long-term data 9 years from now, whether you are participating in a randomized clinical trial or not,” she said. “Some children cannot be moved to a study site; however, the number of zone 1 cases keeps increasing due to increased survival of very small infants, and some considerations of anti-VEGF therapy for these patients, their parents and society is appropriate.”

Timeline for adoption unclear

When asked if they are any closer to using anti-VEGFs to treat ROP and whether they will ever be used on label for this indication, most experts interviewed by OSN agree that the answers are equivocal. Studies evaluating the dose of bevacizumab, the timing of treatment, vision outcomes and safety data are warranted.

“Avastin represents an important addition to our armamentarium, and application should be considered carefully on a case-by-case basis. Laser, I believe, will continue to be an important main stage in ROP cases until more is learned about anti-VEGF use in ROP,” Dr. Lee said.

Use of anti-VEGF injections in cases of ROP should be used “compassionately for failed laser or poor view. Otherwise we should only be using it in the setting of an adequately sized, randomized, controlled and masked clinical trial,” Dr. Quinn said.

The important questions of who to treat, what to treat and when to treat will still remain, according to Dr. Gold.

“It’s a great medication and it works very well, but we don’t know the long-term effect,” he said. – by Tara Grassia

POINT/COUNTER
How soon after discharge do you see an infant who had stage 1 or 2 ROP but reached near complete vascularization and was improving as expected without treatment?

*
Lindstrom's Perspective
All ophthalmologists should be familiar with ROP and its treatments

References:

  • Bakri SJ, Snyder MR, Reid JM, Pulido JS, Singh RJ. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology. 2007;114(5):855-859.
  • Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group.. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med. 2011;364(7):603-615.
  • Quiroz-Mercado H, Martinez-Castellanos MA, Hernandez-Rojas ML, Salazar-Teran N, Chan RV. Antiangiogenic therapy with intravitreal bevacizumab for retinopathy of prematurity. Retina. 2008;28(3 Suppl):S19-25.
  • Reynolds JD. Bevacizumab for retinopathy of prematurity. N Engl J Med. 2011;364(7):677-678.
  • Sato T, Wada K, Arahori H, et al. Serum concentrations of bevacizumab (Avastin) and vascular endothelial growth factor in infants with retinopathy of prematurity [published online ahead of print Sept. 17, 2011]. Am J Ophthalmol. doi:10.1016/j.ajo.2011.07.005.

  • R.V. Paul Chan, MD, can be reached at New York-Presbyterian Hospital, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, New York, NY, 10021; 646-962-2540; fax: 646-962-0609; email: roc9013@med.cornell.edu.
  • Robert S. Gold, MD, can be reached at the Pediatric Ophthalmology and Adult Eye Muscle Disorders Eye Physicians of Central Florida, 790 Concourse Parkway South, Suite 200, Maitland, FL 32751; 407-767-6411; fax: 407-767-8160; email: rsgeye@aol.com.
  • Thomas C. Lee, MD, can be reached at The Vision Center at Children’s Hospital Los Angeles, 4650 Sunset Blvd. #88, Los Angeles, CA 90027; 323-361-2299; fax: 323-361-3515; email: tleemd@gmail.com.
  • Helen A. Mintz-Hittner, MD, can be reached at Robert Cizik Eye Clinic, 6400 Fannin St., Suite 1800, Houston, TX 77030; 713-559-5277; fax: 713-559-5290; email: helen.a.mintz-hittner@uth.tmc.edu.
  • Graham Quinn, MD, MSCE, can be reached at Division of Pediatric Ophthalmology, The Children’s Hospital of Philadelphia, 34th and Civic Center Blvd., Philadelphia, PA 19104; 215-590-4594; email: quinn@email.chop.edu.
  • Disclosures: Drs. Chan, Gold, Mintz-Hittner and Quinn have no relevant financial disclosures. Dr. Lee is a non-paid consultant for Endo Optiks.