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Raising the bar in retinopathy of prematurity treatment

      The treatment of retinopathy of prematurity (ROP) has evolved significantly with the introduction of anti-vascular endothelial growth factor (VEGF) agents, and with new treatment paradigms there continue to be questions regarding the long term local and systemic sequelae after anti-VEGF therapy. In selected ROP patients, treatment is necessary to prevent vision-threatening complications such as macular dragging and tractional retinal detachment.
      Treatment options include cryotherapy, laser photocoagulation, and, more recently, intravitreal injection of anti-VEGF agents.
      • Mintz-Hittner HA
      • Kennedy KA
      • Chuang AZ
      BEAT-ROP Cooperative Group
      Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.
      • Stahl A
      • Lepore D
      • Fielder A
      • et al.
      Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial.
      • Good WV
      Early Treatment for Retinopathy of Prematurity Cooperative Group
      Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial.
      • Sankar MJ
      • Sankar J
      • Chandra P.
      Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity.
      • Stahl A
      • Krohne TU
      • Eter N
      • Oberacher-Velten I
      • Guthoff R
      • Meltendorf S
      • Ehrt O
      • Aisenbrey S
      • Roider J
      • Gerding H
      • Jandeck C
      • Smith LEH
      • Walz JM
      Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) Study Group. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial.
      Recent evidence has consolidated the promising results seen with laser photocoagulation and anti-VEGF therapy, deeming cryotherapy treatment essentially obsolete.
      • Mintz-Hittner HA
      • Kennedy KA
      • Chuang AZ
      BEAT-ROP Cooperative Group
      Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.
      • Stahl A
      • Lepore D
      • Fielder A
      • et al.
      Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial.
      • Good WV
      Early Treatment for Retinopathy of Prematurity Cooperative Group
      Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial.
      • Sankar MJ
      • Sankar J
      • Chandra P.
      Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity.
      • Stahl A
      • Krohne TU
      • Eter N
      • Oberacher-Velten I
      • Guthoff R
      • Meltendorf S
      • Ehrt O
      • Aisenbrey S
      • Roider J
      • Gerding H
      • Jandeck C
      • Smith LEH
      • Walz JM
      Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) Study Group. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial.
      The Early Treatment for Retinopathy of Prematurity trial has defined the standard treatment recommendations for Type 1 ROP, including Zone I ROP (any stage with plus disease or Stage 3 with no plus disease) and Zone II ROP, Stage 2 or 3, with plus disease.
      • Good WV
      Early Treatment for Retinopathy of Prematurity Cooperative Group
      Final results of the Early Treatment for Retinopathy of Prematurity (ETROP) randomized trial.
      While laser therapy has improved anatomic and visual outcomes, there are limitations as it may cause permanent peripheral visual field deficits and may induce clinically significant myopia. Moreover, there are clinical situations where laser therapy may be limited, such as media opacity, aggressive posterior disease, and inability for the patient to tolerate general anesthesia, if that is being considered.
      The Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity (BEAT-ROP) study compared laser treatment to intravitreal bevacizumab (IVB) and found superiority with IVB in the primary outcome of treatment failure (defined as recurrence of neovascularization necessitating retreatment by 54 weeks postmenstrual age) in Zone I Stage 3 with plus disease compared to conventional laser ablation. The BEAT-ROP study, however, found no difference between laser versus IVB for Zone II disease.
      • Mintz-Hittner HA
      • Kennedy KA
      • Chuang AZ
      BEAT-ROP Cooperative Group
      Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity.
      Following this trial, further studies evaluating the utility of anti-VEGF have increased the evidence available and a Cochrane systematic review from 2016, evaluating the effects of IVB and intravitreal ranibizumab (IVR) monotherapy found that IVB/IVR has not necessarily improved short‐term structural outcomes (partial or complete retinal detachment and ROP recurrence) but significantly reduced the risk of refractive error development at 30 months of age.
      • Sankar MJ
      • Sankar J
      • Chandra P.
      Anti-vascular endothelial growth factor (VEGF) drugs for treatment of retinopathy of prematurity.
      With more recent evidence from RAINBOW, CARE ROP Study, and the Pediatric Eye Disease Investigator Group (PEDIG), new treatment paradigms with anti-VEGF for ROP treatment with anti-VEGF-therapy have been supported.
      • Stahl A
      • Lepore D
      • Fielder A
      • et al.
      Ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW): an open-label randomised controlled trial.
      ,
      • Stahl A
      • Krohne TU
      • Eter N
      • Oberacher-Velten I
      • Guthoff R
      • Meltendorf S
      • Ehrt O
      • Aisenbrey S
      • Roider J
      • Gerding H
      • Jandeck C
      • Smith LEH
      • Walz JM
      Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) Study Group. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial.
      Positive features of anti-VEGF may include the development of continued peripheral retinal vascularization while stimulating regression of pathologic neovascular proliferation and potentially allowing for improved visual function following stabilization and regression of disease. While promising results regarding anti-VEGF are being found in pooled study data for Zone I disease, there is still no consensus on the treatment of choice for treatment-requiring ROP. Recent reports highlight the presence of vascular abnormalities and the presence of peripheral avascular retina following intravitreal anti-VEGF therapy.
      • Stahl A
      • Krohne TU
      • Eter N
      • Oberacher-Velten I
      • Guthoff R
      • Meltendorf S
      • Ehrt O
      • Aisenbrey S
      • Roider J
      • Gerding H
      • Jandeck C
      • Smith LEH
      • Walz JM
      Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity (CARE-ROP) Study Group. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial.
      These cases may require additional treatment with repeat anti-VEGF or laser photocoagulation and no guidelines have been established regarding which modality should be utilized as the rescue. Importantly, the overall safety, including mortality, neurodevelopment, or delayed systemic effects of anti-VEGF therapy, is yet to be established. Currently, there is no definitive evidence to support adverse systemic events in systematic reviews of the literature but long-term follow-up studies are needed and causality may be difficult to determine without large data sets.
      Increasing success in neonatal care has reduced premature infants' mortality, thus necessitating optimal treatment strategies to grant the best outcomes possible extending into childhood and adulthood. Treatment successes likely will no longer solely be determined by anatomic outcomes and the degree of refractive error, binocularity, and more sensitive aspects of vision are now being evaluated. In a retrospective cross-sectional study by Manuchian et al. featured in this issue, binocularity outcomes when comparing laser ablation and anti-VEGF treatment are being reported for the first time. The authors found a statistically significant increased rate of cumulative binocularity disrupting events in the laser-treated group (e.g amblyopia, anisometropia) and a non-statistically significant trend towards better binocularity rates and levels in anti-VEGF treated infants. The two groups were comparable in terms of degree of disease; however, there were significantly more plus-disease eyes treated with anti-VEGF, highlighting the paradigm changes in ROP care. This study included Type 1 ROP and Type 2, if there were characteristics concerning for progression to Type 1, also demonstrating the new strategies taking place.
      In the pursuit to avoid blindness secondary to ROP, and despite therapeutic advances, the study by Manuchian et al, highlights that we are currently in need of more data and well-designed studies to best understand the functional outcomes after anti-VEGF therapy for ROP. The ideal treatment paradigm should limit potential adverse sequelae and abnormal anatomical and functional outcomes. In that vein, clinical trials and studies aiming to determine the optimal treatment strategy for ROP require meticulous independent variable selection criteria and analysis, as these can confound the outcome variables. At the time of treatment, differences in gestational and chronological age, disease severity, and factors preventing adequate treatment delivery (e.g., media opacity or inexperience with laser ablation in infants) can significantly influence result interpretation. As differences in outcomes between Zone I and Zone II treatment have been found, studies adequately powered to evaluate each treatment strategy in each zone would be optimal given the fact that many physicians may be inclined to treat outside the parameters of Type 1 ROP in particular clinical situations. Further randomised controlled trials, such as those being initiated by the DRCR Retina Network will provide additional data to evaluate treatment strategies. Although anti-VEGF agents have been used for ROP for over a decade, more needs to be learned about best treatment strategy with anti-VEGF agents (monotherapy or in conjunction with laser therapy), dosing of anti-VEGF agents, treatment beyond Type I ROP, and short- and long-term structural results as well as long-term functional outcomes. Ideally, trials should be extensive multicentre studies to allow for adequate sample sizes and diverse populations to determine clinically significant differences. This would allow us to elucidate treatment indications for both primary treatment (monotherapy or combined anti-VEGF/laser therapy) and rescue treatment (laser vs. anti-VEGF) and perhaps Type I and II ROP definitions will evolve. We expect that future studies will provide reliable data on refraction, binocularity, and related visual outcomes and ultimately allow us to raise the bar in ROP treatment.

      References

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        • Lepore D
        • Fielder A
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