treatment of type 1 retinopathy of … · treatment of type 1 retinopathy of prematurity with...

TREATMENT OF TYPE 1 RETINOPATHYOF PREMATURITY WITH INTRAVITREALBEVACIZUMAB (AVASTIN)PAOLA DORTA, MD, ANDRES KYCHENTHAL, MD

Purpose: The purpose of this study was to report a noncomparative consecutive caseseries of eyes with type 1 retinopathy of prematurity treated only with intravitreal bevaci-zumab (Avastin).

Methods: Twelve consecutive eyes of 7 premature infants, with type 1 retinopathy ofprematurity as stated in the Results of the Early Treatment for Retinopathy of PrematurityRandomized Trial, were treated with only one intravitreal injection of bevacizumab (0.625mg). RetCam pictures were used to document the cases.

Results: Nine eyes had zone I and 3 eyes had zone II retinopathy of prematurity. Theinfants weighed between 600 and 1,100 grams (mean, 846.57 g). The gestational ageranged from 23 weeks to 28 weeks (mean, 25.57 weeks). All eyes showed regression of thedisease with no additional treatment needed.

Conclusion: Intravitreal bevacizumab is a useful therapy for type 1 retinopathy ofprematurity. However, additional studies are needed to define the role of Avastin as thefirst-line therapy, in combination, or after the failure of laser photocoagulation.

RETINA 30:S24–S31, 2010

Great improvements have been made in the man-agement of retinopathy of prematurity (ROP)

since the initial therapeutic approach described in theCryotherapy for Retinopathy of Prematurity study.1,2 Amore appropriate time for therapeutic intervention wasdefined by the Early Treatment for Retinopathy of Pre-maturity Randomized Trial,3 and better screening strat-egies with the use of digital imaging systems are nowavailable.4,5 All of this, together with the use of laserphotocoagulation6–9 and vitreoretinal surgery,10–13 havecontributed to significant increases in favorable out-comes and decreases in child blindness secondaryto ROP.

Conventional therapy (laser photocoagulation) pro-duces excellent results in zone II, but too many zoneI cases still may have an unfavorable result with thistreatment.14–18 Even in cases in whom there is afavorable anatomic result, functional outcome mightbe poor, mainly in aggressive posterior (ROP) zone I

cases in whom vascular retinal development does notoften reach the macular area. Currently, 90% of ourpatients with ROP correspond to low-birth-weight in-fants, and zone I now represents 35% of our ROP-treated cases.

The search for complementary or alternative treat-ments seems necessary for these infants. The well-known role of vascular endothelial growth factor(VEGF)19 as well as the availability of anti-VEGFdrugs resulted in their use in ROP. Several reportsinvolving the use of anti-VEGF drugs, specificallybevacizumab (Avastin, Genentech, San Francisco,CA), in cases with ROP have been published.20–23

After applying bevacizumab, successful resultswere achieved in three clinical situations before itwas used as a first-line therapy. The drug was givento a group of patients after progression of thedisease despite laser photocoagulation. A secondgroup of patients included cases in which bevaci-zumab was used before vitrectomy because of thepresence of retinal detachment and vascular activitywhen the patient was first seen. A third clinicalsituation involved posterior zone I cases withoutmacular development in whom bevacizumab wasused shortly after laser treatment. In these cases, wedid not laser the area where the macula should

From the Department of Ophthalmology, Hospital de NiñosRoberto del Rio, Santiago, Chile.

Presented in part at the Association of Pediatric Retinal Sur-geons Meeting, Hawks Key, FL, January 2009.

The authors have no financial interest in the material presented.Reprint requests: Paola Dorta, MD, Servicio de Oftalmología,

Hospital de Ninos Roberto del Río, Av. Vitacura 5900 of 404Santiago, Chile; e-mail: [email protected]

S24

develop, but instead, provided there was vascularactivity, bevacizumab was injected after photoco-agulation so as not to risk an unfavorable resultbecause of insufficient laser treatment. This studyreports a noncomparative, consecutive case study of12 eyes with type 1 ROP treated with only oneintravitreal injection of bevacizumab (Avastin).

Methods

Between August and December 2008, 12 eyes of 7premature infants with type 1 ROP were treated con-secutively with a single intravitreal injection of bev-acizumab (0.625 mg). Type 1 ROP was defined ac-cording to the Early Treatment of Retinopathy ofPrematurity Study3 as one of the following conditions:zone I, any stage ROP with plus disease; zone II, stage3 ROP without plus disease; or zone III, stage 2 or 3ROP with plus disease.

Bevacizumab injection was preferred to laser treat-ment in these patients because the disease was soposterior as to preclude macular vascularization, visu-alization was hindered by a persistent tunica vasculosalentis and vitreous haze, or they were too ill for lasertreatment.

Two patients were screened by the authors andthe other five referred from other neonatal units. Allpatients were treated within 72 hours of reachingtype 1 ROP. No eyes with any stage of retinaldetachment or congenital ocular anomaly were in-cluded. Preoperative examinations and follow-upwere performed using indirect ophthalmoscopy andthe RetCam Imaging System (Clarity Medical Sys-tems, Pleasanton, CA).

The use of bevacizumab in our patients with ROPwas discussed and approved by members of the Na-tional Neonatal Network. In all cases, written in-formed consent form was obtained from the guardiansbefore the injections were administered.

The injections were administered in an operatingroom under the care of a pediatric anesthesiologist.Sterile unit doses of bevacizumab (Avastin) were pre-pared in a compounding pharmacy under aseptic con-ditions and placed in a tuberculin syringe. A dose of0.625 mg was injected 1 mm posterior to the limbusafter the instillation of 10% povidone–iodine. Besidessystemic and local perioperative complications, welooked for complications specifically related to intra-vitreal injections.

Results

This series included 12 eyes of 7 premature infants,5 boys and 2 girls. The infants weighed between 600and 1,100 g (mean, 846.6 g). The gestational ageranged from 23 weeks to 28 weeks (mean, 25.6weeks) (Table 1).

Nine eyes (75%) had zone I ROP. Of these, threewere classified as aggressive posterior ROP. Threeof the 12 eyes (25%) had zone II ROP. Bevaci-zumab was injected, on average, at 34 weeks forzone I cases and at 40 weeks for zone II cases. Alleyes showed regression of the disease with no needfor additional treatment.

We observed that the vascularization of the retinaafter the regression of the ROP after the bevacizumabinjection followed a normal, although slower patternwith no evidence of vascular arrest or persistent cic-atricial changes. However, not all eyes had reachedthe ora during the follow-up period.

Regarding macular architecture, no evidence ofmacular drag or distortion was found nor were anypersistent cicatricial changes observed in this series ofcases. No complications attributable to the bevaci-zumab were seen in any of our patients. An epiretinalhemorrhage was seen in one eye as a consequence ofthe injection procedure. The hemorrhage spontane-ously reabsorbed without consequence.

Table 1. Summary of the Data of the Study Group

Case BW (g)GA

(Weeks)Age at Bevacizumab

Injection (Weeks) ROP Zone Treated Eye Sex

1 1,100 28 32.6 Zone I (AP-ROP) OD-OS M2 760 23 32.1 Zone I (AP-ROP) OD-OS M3 650 24 34.3 Zone I OS* M4 890 26 38.6 Zone I OD-OS M5 1,056 26 32.3 Zone I (AP-ROP) OD-OS F6 870 28 40.3 Zone II OD-OS M7 600 24 40.0 Zone II OD† FMean 846.6 25.6 35.7

BW, birth weight; GA, gestational age; AP-ROP, aggressive posterior ROP; OD, right eye; OS, left eye; M, male; F, female.*OD of patient 3 received laser treatment.†OS of patient 7 did not develop type 1 ROP.

S25TREATMENT OF TYPE 1 ROP WITH BEVACIZUMAB ● DORTA AND KYCHENTHAL

Patient 1 was born at 28 gestational weeks. This casehad posterior zone I ROP (aggressive posterior ROP)and developed type 1 ROP at 32-weeks postmenstrualage, 4 weeks after birth. On the day of the bevacizumabtreatment, retinal vascularization did not even reachthe macular area (Figure 1A). At 35.6-weeks post-menstrual age, retinal vessels reached the fovealarea (Figure 1B). At 46-weeks postmenstrual age(14 weeks after the bevacizumab injection), retinalvascularization reached zone III (Figure 1C).

Patient 2 also presented zone I ROP, and the bev-acizumab injection was administered at 32-weekspostmenstrual age, when the baby developed type 1ROP (Figure 2A). One week after the procedure, atotal regression of the vascular activity at the anteriorsegment was observed (Figure 2B). There was a small

epiretinal hemorrhage that was spontaneously reab-sorbed. At 43-weeks postmenstrual age, the retinalvascularization reached zone III (Figure 2C).

The left eye of patient 3 presented a posterior zoneI ROP, and bevacizumab was given at 34-week post-menstrual age. When the ridge started to regress, thelimit between the vascular and avascular retina lookedvery neat, giving the impression of a neovascular stripadvancing toward the avascular area (Figure 3A).Such a situation was observed in most cases. Normal-looking vascularization reached zone III at 46-weekpostmenstrual age (Figure 3B). When this patient wasreferred, he had a vitreous hemorrhage in the righteye. Laser photocoagulation and bevacizumab weregiven at the same time. This eye had a favorableoutcome and is not part of this series.

Fig. 1. Case 1: Posterior zoneI ROP (aggressive posteriorROP). (A) Bevacizumab in-jection with type 1 ROP at32-weeks postmenstrual age,4 weeks after birth. Retinalvascularization did not evenreach the macular area. (B)At 35.6-weeks postmenstrualage, retinal vessels reached thefoveal area. (C) At 46-weekspostmenstrual age (14 weeksafter the bevacizumab injec-tion), retinal vascularizationwas observed within zone III.

S26 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2010 ● VOLUME 30 ● NUMBER 4

Patient 4 already had an important ridge andinitial fibrosis at the time of the bevacizumab injec-tion at 38.5-weeks postmenstrual age (Figure 4A);however, there was adequate regression without any

traction development after the injection at 39.8weeks (Figure 4). Patient 5 presented with aggres-sive posterior ROP, and bevacizumab was injectedat 32.3-weeks postmenstrual age. Figure 5 shows

Fig. 3. Case 3: Zone I ROP.Bevacizumab was given at 34-weeks postmenstrual age. (A)When the ridge started to re-gress, the limit between thevascular and avascular retinalooks very neat, giving the im-pression of a neovascular stripadvancing toward the avasculararea. (B) Normal-looking vas-cularization reached zone III at46 weeks.

Fig. 2. Case 2: Posterior zoneI ROP. (A) Bevacizumab in-jection was given at 32-weekspostmenstrual age when thebaby developed type 1 ROP.(B) Regression of the vascu-lar activity at the anterior andposterior segments was ob-served 1 week after the pro-cedure. (C) At 43-weekspostmenstrual age, the reti-nal vascularization reachedzone III.


images of the right and left eyes taken 6 weeks afterthe bevacizumab injection. There is a marked vas-cular strip moving toward the avascular retina,which, previous to this study, would have promptedus to perform photocoagulation.

Patient 6 was a sick baby (sepsis, patent ductusarteriosus, severe pulmonary dysplasia); there wasevidence of fibrosis at the time of treatment at 40.3-week postmenstrual age (Figure 6A). Regression wasslower, and after 3-week postbevacizumab injections(43.3 weeks) (Figure 6B), anterior and posterior seg-ment activities were still present. However, despite hispoor systemic condition, there was no need for furthertreatment. Retinal vascularization reached zone III at48.3 weeks (Figure 6C). Patient 7 was born at 24weeks and weighed 600 g. She developed a zone II,type 1 ROP; bevacizumab was injected into the right

eye at 40-weeks postmenstrual age with completeregression of the disease.

Discussion

Retinopathy of prematurity represents an importantcause of pediatric blindness24 in the world. The moreposterior forms of the disease may have bad outcomesdespite adequate treatment.14–18 Hence, the use ofanti-VEGF drugs in the context of a vasoproliferativedisorder was a logical approach. Good results havebeen obtained in patients with wet macular degener-ation and diabetic retinopathy25,26 and also in a seriesof patients with ROP.20–23

This clinical information, together with the goodresults that we obtained with the bevacizumab injec-tions as a complementary treatment before this series,

Fig. 4. Case 4: (A) Initial fi-brosis and ridge at the time ofthe bevacizumab injection at38.5-weeks postmenstrual age.(B) Adequate regression with-out any traction developmentwas observed after the injec-tion at 39.8 weeks.


Fig. 6. Case 6: (A) Evidence of fibrosis at the time of treatment at 40.3-weeks postmenstrual age. (B) Regression was slower, and after 3-weekpostbevacizumab injections (43.3 weeks), anterior and posterior segment activities were still present. (C) Despite a poor systemic condition, there wasno need for further treatment, and retinal vascularization reached zone III at 48.3 weeks.

Fig. 5. Case 5: Aggressiveposterior ROP. Bevacizumabwas injected at 32.3-weekspostmenstrual age. Images ofthe right and left eyes weretaken 6 weeks after bevaci-zumab injection. There is amarked vascular strip movingtoward the avascular retina,which, previous to this study,would have prompted us toperform photocoagulation.


led us to the use of this drug as a first-line therapy. Inthis series, intravitreal anti-VEGF drugs allowed afavorable outcome in all cases with no additionaltreatment required. Laser therapy, however, is a de-structive procedure. Therefore, if the same results canbe obtained with this more conservative treatment,then many potential benefits may be obtained by usingsuch a therapy, including more visual field and lessrefractive errors together with overall better vision forthese eyes.

The specific clinical situations of these cases eitherprevented the use of laser treatment or the likelihoodof a favorable outcome was too reduced. This, addedto our step approach experience, supported the choiceof offering a bilateral treatment.

Notwithstanding this, potential systemic side ef-fects from the use of anti-VEGF drugs in infantsremain a big concern. Monitoring of possible centralnervous system, cardiac, or renal adverse effects prob-ably should be part of any prospective trial of anti-VEGF agents for ROP. Nonetheless, we have seen nocomplications attributable to the bevacizumab injec-tions in any of our patients.

Doubtless, many questions are raised by this andother similar studies. What role will bevacizumab playin ROP? Are there any systemic side effects that arenot yet known? Will bevacizumab prove to providebetter functional outcomes?

For the time being, we believe that photocoagu-lation for type 1 ROP might not be the best first-linetherapy for every case. Furthermore, the availabilityof anti-VEGF drugs forces us to establish the bestchoice for each patient. Given the available data,bevacizumab injection may be currently preferredto laser treatment in patients with disease that is tooposterior as to preclude macular vascularization,visualization is hindered by a persistent tunica vas-culosa lentis and vitreous haze, or they are too illfor laser treatment. Developing studies might ex-pand these indications.

In conclusion, intravitreal bevacizumab is a usefultherapy for type 1 ROP. However, additional studiesneed to be performed to define the role of bevaci-zumab as the first-line therapy, in combination withlaser, or after the failure of laser photocoagulation.

Key words: antivascular endothelial growth fac-tor, Avastin, bevacizumab, RetCam, retinopathy ofprematurity.

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