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Note: The first paragraph of this article incorrectly identifies the data as pertaining to zone I ROP although it actually represents the overall results. Please see the invited letter at the end of this article, which provides a correction and discusses the implications.
Should bevacizumab (Avastin) supplant laser for treating zone I retinopathy of prematurity? Earlier this year, the BEAT-ROP investigators reported that, in infants with zone I stage 3+ disease, the recurrence rate with intravitreal bevacizumab was 4 percent, compared with 22 percent with laser therapy.1 Based on these results, the language in an accompanying editorial was emphatic: “Intravitreal bevacizumab should become the treatment of choice for zone I retinopathy of prematurity.”2
That statement set off an intense debate that shows no signs of receding any time soon. Indeed, 10 years from now, the treatment paradigm for zone I ROP may well have shifted toward antiangiogenic therapy. At the moment, however, significant questions remain.
Gathering the Evidence
In 2004, the FDA approved bevacizumab for metastatic colon cancer, and the first published reports on the use of bevacizumab for ROP appeared in 2007. With continuing research, further evidence supporting its use has emerged.
Retrospective reports. Beginning in 2007, several retrospective reports presented experience with infants with aggressive posterior ROP (AP-ROP). This type of ROP often has an unfavorable outcome with standard laser therapy and progresses rapidly to complete retinal detachment. Thus, even though these reports involved only a small number of infants, the news that intravitreal bevacizumab could induce regression of AP-ROP without retinal detachment drew considerable attention.
Prospective case series. The first prospective case series was published in 2008, involving 18 eyes of 13 infants. These patients were divided into three groups: those who had stage 4a or 4b disease and had not responded to conventional treatment; those with threshold ROP who were difficult to treat with conventional therapy because of poor ocular media clarity; and those who had high-risk prethreshold or threshold disease. After injection of bevacizumab, neovascular regression was observed in 17 of 18 eyes.3
Randomized trial. BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) was the first prospective, controlled, randomized trial of one dose of bevacizumab (0.625 mg) for one ROP stage (stage 3+), without combining laser and bevacizumab in the same infant.
For the study, investigators enrolled 150 infants with zone I or zone II posterior stage 3+ disease, for a total sample of 300 eyes (286 were included in the final analysis). The patients were randomly assigned to receive bilateral injections of 0.625 mg of bevacizumab or bilateral laser therapy; the primary outcome was ROP recurrence in one or both eyes requiring re-treatment before the 54-week mark.
Six of the 140 eyes in the bevacizumab group experienced a recurrence compared with 32 of the 146 eyes in the laser group. The treatment effect was more pronounced in infants with zone I disease; in this subset, two eyes treated with bevacizumab experienced a recurrence versus 23 eyes treated with laser. Four cases of complications (one of corneal opacity and three of lens opacity) were observed; all occurred in association with conventional laser therapy for zone II disease.
What About the Parents?
One wild card in this debate is the influence of concerned parents. Will they push bevacizumab to the forefront of ROP treatment? Here’s what Drs. Mintz-Hittner, Quinn and Wallace have to say about their experience to date.
Dr. Mintz-Hittner: “I’m hearing from knowledgeable and insistent parents who report that they’re going to their local hospital IRB boards and asking for a one-time compassionate dose of bevacizumab—and telling them, ‘If you don’t, I’ll move my child.’ The hospitals are complying because they don’t want to lose these babies.”
Dr. Quinn: “We have not heard from parents who want to do this. I have met with our neonatologist and worked out a system for handling possible cases, and we have prepared a separate consent form for bevacizumab on a compassionate-use basis.”
Dr. Wallace: “I haven’t had any parent-initiated queries myself, although I’ve heard that other ophthalmologists have. I bring it up myself with parents and tell them, ‘This is a new treatment. This is what we do and don’t know. We don’t have long-term outcome data.’”
Promising Results, Continuing Concerns
As promising as the BEAT-ROP results are, they don’t necessarily mean that bevacizumab is ready for prime time for zone I or zone II disease, some observers say. In particular, many clinical researchers note that the study had several limitations. The BEAT-ROP manuscript clearly acknowledges one issue: “Our sample was sufficiently large to show significant efficacy of intravitreal bevacizumab for zone I disease but not for zone II posterior disease.” Other lingering questions include safety, long-term outcomes and even appropriate dosage.
Safety and pharmacokinetics. Potential systemic toxicity is one of the most pressing questions. Long-term safety “has to be the overriding concern,” said Graham E. Quinn, MD, professor of ophthalmology at the Children’s Hospital of Philadelphia, University of Pennsylvania. “You don’t want to save the eye only to hurt the baby.”
A 2007 report on the pharmacokinetics of bevacizumab found that the half-life of 1.25 mg is 4.32 days in a rabbit eye. In addition, small amounts were detected in the serum and the fellow eye—although, the researchers note, “because humans have a larger serum compartment than rabbits, systemic exposure may be less.”4
The lack of clarity on pharmacokinetics in infants worries Dr. Quinn. “I would think that would be the subject of a phase 1 study. If babies are being treated, then those babies should also have their blood levels determined so that we know how long the drug lasts.”
David K. Wallace, MD, MPH, professor of ophthalmology and pediatrics at Duke Eye Center, also expressed concern. “We don’t know how much bevacizumab gets into the infant’s circulation and how it might affect the development of critical structures such as the brain, lungs, kidneys and gastrointestinal tract.” In contrast, he said, “We’re doing pretty well with laser and have no reason to believe that laser itself has any systemic side effects.”
Larger, longer studies needed. According to the BEAT-ROP report, it would take a fairly large sample size—well over 3,000 infants—to fully address systemic toxicity issues. But even at this point, with the smaller BEAT-ROP cohort, “When we look for systemic toxicity, we don’t see it,” said lead researcher Helen A. Mintz-Hittner, MD, professor of ophthalmology and visual science at the University of Texas Health Science Center in Houston. “So far, it isn’t an issue,” even with the oldest BEAT-ROP participants, who are now four years old. However, she acknowledged that this “remains an unanswered question in terms of 10-year data.”
Dr. Mintz-Hittner said that the BEAT-ROP investigators are now completing a five-year follow-up. “We’re specifically looking at toxicity issues and evaluating development, lung status and kidney function.”
Ocular outcomes. Unlike laser, bevacizumab doesn’t destroy the peripheral retina or induce cystoid macular edema. Still, more needs to be learned about the drug’s long-term effect on ocular health when given early in life. “With bevacizumab, we may have a treatment that’s easier to administer, but we don’t yet have a handle on the ocular outcome,” Dr. Quinn said. “For instance, there are no data on the visual fields; that is speculative at this stage of the game.”
In the next phase of BEAT-ROP, investigators will be conducting “extremely detailed exams on such markers as visual fields, color vision and contrast sensitivity,” Dr. Mintz-Hittner said. “We’re doing a full structural evaluation of the eyes, including OCT, fundus photography and fluorescein angiography.”
All of this will be completely masked to the BEAT-ROP researchers. This approach may alleviate some of the criticisms of the first BEAT-ROP report: Although the study was controlled, it was not masked because the laser therapy left recognizable marks. “Ophthalmologists making the decision to re-treat knew which eye was which,” Dr. Quinn noted. “Even the most earnest and conscientious investigators might be biased.”
Protocol for follow-up. Some of Dr. Quinn’s concerns regarding long-term outcome stem from his discussions with his colleagues who have used this treatment in other countries, particularly those in South America. “What concerns me is hearing people talk about treating the disease and then seeing it smolder and eventually reactivate. Essentially, they don’t know when the baby really is good to go and feel that they should follow the baby every two weeks for many months, perhaps as long as eight months. This makes me a little wary.”
There’s no question that careful follow- up is essential, Dr. Mintz-Hittner said. “Late recurrence tends to take place around 50 weeks’ postmenstrual age and can be treated with another injection. But the reality is that if you’re following these infants according to the recommendations of the Early Treatment for Retinopathy of Prematurity (ETROP) study, you’re going to catch any recurrence, whether it occurs after laser or bevacizumab.”
Dosage. The BEAT-ROP investigators used 0.625 mg, which is one-half of the adult dose. “We could probably go to one-quarter of the adult dose, but that would take another study,” Dr. Mintz-Hittner said, adding that sample size would be an issue. “You might need 1,000 infants for a head-to-head dosage comparison.”
Making the Treatment Decision
At the moment, the decision to use bevacizumab may well come down to the individual physician’s comfort zone.
“Bevacizumab has been wonderful in many developing countries where there isn’t access to a laser or to an ophthalmologist who can administer laser,” Dr. Wallace said. “In these instances, it has saved the vision of many babies who otherwise might have gone blind.”
In the United States, he said, “Many of us are using bevacizumab in cases of very posterior, very severe, rapidly progressing ROP. Some of these AP-ROP cases, in our anecdotal experience, don’t respond quite as well to laser.” However, he’s reluctant to make a wholesale move to bevacizumab without “additional, high-quality evidence” in its favor. “Most cases of type 1 [stages 1, 2 and 3] ROP in this country do very well with laser.”
“I think it would be wonderful if bevacizumab were the panacea that is suggested in the BEAT-ROP report and the editorial, but I don’t think life is as clear-cut as that,” Dr. Quinn said. “Right now, I can look a parent in the eye and say, ‘I know what the side effects are with laser, based on study data. Granted, your baby is a sample of one, but overall, I know that your baby will likely respond in a certain fashion. Let’s go the proven route first until we have a handle on this new treatment possibility.’”
Not surprisingly, Dr. Mintz-Hittner has a different perspective. “I do feel that it’s not a destructive technique,” she said. “It results in less myopia and leaves the peripheral retina and macula intact, with potentially better visual fields and visual acuity. Of course, people want the 10-year follow-up data now, and we don’t have that yet. But then the question is, can you withhold a therapy that’s so superior for another 10 years?”
1 Mintz-Hittner, H. A. et al. N Engl J Med 2011;364(7):603–615.
2 Reynolds, J. D. N Engl J Med 2011;364(7): 677–678.
3 Quiroz-Mercado, H. et al. Retina 2008;28(3 suppl):S19–25.
4 Bakri, S. J. et al. Ophthalmology 2007;114(5): 855–859.
Drs. Mintz-Hittner, Quinn and Wallace report no related financial interests.
Learn More in Orlando
The use of bevacizumab for ROP is bound to be one of the most widely discussed topics in Orlando. Make sure to attend one of the following events to hear more.
- The debate begins on Friday, Oct. 21, at 1:35 p.m., at the Retina Subspecialty Day, in a panel discussion with six experts, titled “Snow White and the Six Dwarfs: Anti-VEGF for ROP.”
- On Saturday, Oct. 22, at 12:07 p.m., Dr. Mintz-Hittner presents the keynote lecture, “Avastin for ROP,” at the Pediatrics Subspecialty Day. In addition, several relevant instruction courses will be presented during the Annual Meeting:
- Management of High-Risk ROP in the 21st Century: Thermal-Destructive vs. Pharmacologic Treatment (Sunday, Oct. 23, 3:15 to 5:30 p.m.; course 240).
- ROP Screening and Treatment: What You Wanted to Know but Were Afraid to Ask (Monday, Oct. 24, 2011, 10:15 a.m. to 12:30 p.m.; course 354).
- Overview of Utilization of Bevacizumab (Avastin) for ROP (Monday, Oct. 24, 3:15 to 5:30 p.m.; course 429).
Bevacizumab for ROP Data Clarification
I read the October story “Study of Bevacizumab for ROP Sparks Controversy” with great interest, in part because the writer attributed the initiation of the “intense debate” to my New England Journal of Medicine editorial.
My editorial was an objective assessment of the efficacy, safety and practicality of intravitreal bevacizumab (IVB) for ROP based on pharmacokinetic data, previous small case series and the BEAT-ROP trial. While the latter multicenter, randomized trial had flaws, it was nonetheless superior to previous work and underwent rigorous review by the NEJM editorial staff. From this information IVB is obviously practical, and it appears at least as safe for the eye as conventional laser therapy (CLT). I also noted the unknown systemic safety of this treatment and pointedly stated that such concerns were “potentially profound.”
However, the efficacy of IVB over CLT was dramatic, especially for zone I ROP. The BEAT-ROP trial looked at recurrence rate of disease following treatment and reported that data in terms of infants and not eyes. The results were as follows:
|Posterior zone II
Unfortunately, the EyeNet article mentioned only the overall results as listed in the abstract, but mistakenly referred to those results as the zone I results. This mischaracterization of the treatment effect dramatically undervalues the true efficacy difference in zone I and, by association, undervalued the basis for my editorial opinion. IVB is practical, safe for the eye, and dramatically more efficacious for true zone I ROP. The speculative systemic safety issues do not offset the major improvement in preventing blindness in zone I ROP. We have much to learn about IVB, and I support more research and more evidence-based results.
James D. Reynolds, MD