FP925 : Response of ROP to Anti-VEGF – risk factors and need for combined laser

Dr.Manavi Deokrishna Sindal, Dr.nagesha,Dr.Romana Fazal

INTRODUCTION

Retinopathy of prematurity (ROP) is a vasoproliferative disorder affecting premature and sick infants with incompletely vascularized retinas. In the past few decades, the major technological improvements in neonatal care have resulted in an increased survival of more premature and low birth weight babies. This has led to the second epidemic of ROP especially in the developed world¹.In India it has been reported to be in between 6.3-44.9%.¹In the middle and low income countries, heavier and older babies are affected as a consequence of unmonitored oxygen therapy during the critical initial phases of life. Aggressive posterior ROP (AP-ROP) is a severe form of ROP located in zone I or posterior zone II of the retina, and is characterised by rapid progression to advanced stages of disease.² Even with early laser treatment as suggested in the ‘Early Treatment for ROP’ (ETROP)³ study, poor outcomes are still frequently seen in AP-ROP.⁴

There have been several encouraging reports of the use of intravitreal bevacizumab for zone 1 and zone 2 with plus disease.^5,6. Although bevacizumab appears effective in bringing resolution of zone I and posterior zone II ROP recent studies have observed late recurrence, chronic vascular arrest and incomplete peripheral vascularization needing additional laser therapy.^7-10.  We retrospectively analysed the risk factors, severity of the disease in babies who underwent monotherapy vs those needingadditional laser, and also the timing for laser and outcomes.

METHODS

This retrospective case series, was conducted at Vitreo retina department of Aravind Eye hospital, Pondicherry. The  study adhered to the tenets of the declaration of Helsinki and was approved by the institutional ethics committee. Consecutive case records of all infants who received Anti -VEGF injections for ROP between January 2013 and December 2017 were retrieved from the medical records department and screened. The main outcome measure was to evaluate the baseline characteristics and risk factors of babies who received Anti-VEGF monotherapy versus those needing additional laser i.e. combined treatment.

A total of 1957 babies were screened from January 2013 to December 2017, of which 30 babies had received Anti-VEGF bevacizumab in both eyes. The basic demographic data, birth weight, gestational age, maternal history, natal and post-natal details of hospitalization were noted at presentation, at injection, at laser and at the final follow up visit using indirect ophthalmoscopy with 28 D lens.

On screening those babies who were seen to develop APROP, as per ICROP definition or Type 1 staged ROP in zone 1 or posterior zone 2, where it was seen that the macula was not well vascularised received intravitreal bevacizumab, at diagnosis or within 24 hours. If the patient developed treatable ROP during follow-up or had vascular arrest leading to peripheral avascular areaat about 55-60 weeks postmenstrual age, laser photocoagulation was done. Near confluent burns were given with diode laser to the avascular area, under topical with minimal sedation and continuous monitoring of vitals by an anaesthetist. Following laser babies were seen at 1 week, and 1 month. All babies screened and treated for ROP are followed up later by the paediatric ophthalmology and retina departments at 6 month intervals thereafter.

RESULTS

A total of 60 eyes of 1957 babies screened for ROP from 2013-2017, needed anti-VEGF injection for posterior disease.Of the 60 eyes, 30 needed Anti-VEGF monotherapy and 30 needed combined laser – 14 eyes for treatable disease and 16 prophylactic for failure to vascularise completely. The details are given in Table1. Babies needing additional laser therapy were born more premature & had more systemic comorbidities [mean GA was 29.8wks vs 31.3wks (p<0.003)]. The combined group needed injection earlier (35wks vs 36wks, p=0.04). The mean duration to laser after injection was 112 days. No difference was noted in terms of birth weight [1417gms vs 1332gms (p=0.3)], duration of oxygen therapy and zone/ stage of disease between the groups.

Baseline characteristics	Overall (N = 60)	Injection group (N = 30)	LASER + Injection group (N = 30)	P Value
Birth weight in grams (Mean±SD)	1374.77 ± 30.57	1417.53 ± 419.40	1332.00 ± 258.98	0.360
Gestational age in weeks (Mean±SD)	30.2 ± 1.80	31.33 ± 1.85	29.80 ± 1.40	0.003
Post conceptional age at the time of injection in weeks (Mean±SD)	35.67 ± 2.27	36.20 ± 2.07	35.13 ± 2.37	0.044
Interval between injection and LASER in days (Mean±SD)	–	–	112.67 ± 71.51	–
Multiple birth
Single	36	16	20	0.455
Twins	22	12	10
History of APH	6	2	4	0.496
History of gestational diabetes in mother	0	0	0	1.000
History of maternal hypertension	6	4	2	0.293
Number of days oxygen incubation (Mean±SD)	11.35 ± 9.71	14.38 ± 11.60	8.67 ± 6.93	0.061
History of intraventricular HE	0	0	0	1.000
History of RDS	36	22	14	0.050
History of phototherapy	30	10	20	0.005
History of surfactant therapy	10	6	4	0.482
History of blood transfusion	18	8	10	0.560
History of proven sepsis	18	8	10	0.560
Mode of delivery
Normal	36	14	22	0.054
Caesarean	18	12	6

DISCUSSION

While laser therapy remains the established gold standard for treatment of ROP, use on Anti-VEGF bevacizumab has recently been shown to be efficacious in treating ROP, especially the more posterior disease.⁵ The use of Anti-VEGF was shown to be statistically more beneficial in zone 1 disease than zone 2. The main drawback of laser is the destructive nature of this modality. The ensuing permanent tissue scaring, can damage the macula when done very posteriorly leading to an undesirable outcome.

In our institution we use bevacizumab as monotherapy for babies who on screening are diagnosed with APROP or Zone 1 or posterior Zone 2 disease, where we feel laser treatment is very likely todamage macula. Those babies developing Zone 2 anterior disease continue to receive laser therapy as per ETROP guidelines. We continue to observe our babies after Anti-VEGF monotherapy till we note any of three possible outcomes – complete vascularisation, arrest of vascularisation or development of treatable disease. When retinal vascularisation proceeds till a certain extent to periphery, after which an arrest of further development is noted,there is still no  consensus on the management of such cases. We observe such cases till 55 to 60 weeks postmenstrual age, where after we perform an evaluation under sedation and prefer to laser the remaining avascular area. A certain subset of babies, who initially had a more stormy post-natal period show development of treatable ROP in a more anterior location. As now the  macular area is well vascularised, we perform laser photocoagulation in such cases. All babies are eventually followed up at 6 month intervals with the paediatric and retina departments.

Lee et al ¹¹ in their paper describe the simultaneous use of laser and bevacizumab vs. only laser. They note rapid resolution of plus disease and better vascularisation in their cases. In our series, we noted not only rapid resolution of active ROP, but also good vascularisation. Laser has been shown to cause more occurrence of refractive error. ¹² The avoidance of laser initially, can prevent unnecessary laser in a lot of infants. Hu et al ¹⁰describe treatment with laser for recurrence of ROP after bevacizumab monotherapy. While they needed laser in some cases and surgery in others, none of our cases needed surgery.

The drawback of our study is its retrospective nature and lack of imaging in our cases. This study shows that Anti-VEGF as an initial monotherapy, with later close monitoring with a need to basis laser treatment is an excellent treatment option for babies with APROP or very posterior disease. Need for prolonged follow-up is an inconvenience, that can be overcome with good counselling and detailed discussions of condition with parents.

References

1. Zin A, Gole GA. Retinopathy of prematurity-incidence today. ClinPerinatol 2013;40:185–200.
2. Drenser KA, Trese MT, Capone A Jr. Aggressive posterior retinopathy of prematurity. Retina 2010;30(4 Suppl):S37–40.
3. Good WV, Hardy RJ. The multicenter study of Early Treatment for Retinopathy of Prematurity (ETROP). Ophthalmology 2001;108:1013–14.
4. Vinekar A, Trese MT, Capone A Jr. Evolution of retinal detachment in posterior retinopathy of prematurity: impact on treatment approach. Am J Ophthalmol 2008;145:548–55.
5. Azad R, Chandra P. Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity. Indian J Ophthalmol 2007;55:319; author reply 20.
6. Mintz-Hittner HA, Kennedy KA, Chuang AZ. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011; 364:603-15.
7. Tahija SG, Hersetyati R, Lam GC, Kusaka S, McMenamin PG. Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. Br J Ophthalmol. 2014 Apr;98(4):507-12.
8. Padhi TR, Besirli CG. Re: Lepore et al.: Intravitreal bevacizumab versus laser treatment in type 1 retinopathy of prematurity: report on fluorescein angiographic findings (Ophthalmology 2014;121:2212-9). Ophthalmology. 2015 Aug;122(8):e47-8.9.     
9.   Patel RD, Blair MP, Shapiro MJ, Lichtenstein SJ. Significant treatment failure with intravitreous bevacizumab for retinopathy of prematurity. Arch Ophthalmol. 2012 Jun;130(6):801-2.10.  
10. Hu J, Blair MP, Shapiro MJ, Lichtenstein SJ, Galasso JM, Kapur R. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol. 2012 Aug;130(8):1000-6. Erratum in: Arch Ophthalmol. 2013 Feb;131(2):212.11. 
11.   Lee JY, Chae JB, Yang, SJ et al. Effects of intravitreal bevacizumab and laser in retinopathy of prematurity therapy on the development of peripheral retinal vessels. Graefes Arch ClinExpOphthalmol. 2010 Sep;248(9):1257-62.
12. Geloneck MM, Chuang AZ, Clark WL, et al. refractive outcomes following bevacizumab monotherapy compared with conventional laser treatment: a randomised clinical trial. JAMA ophthalmol. 2014 Nov;132(11):1327-33.