A new study, published earlier this month in the New England Journal of Medicine , describes the use of intravitreal Avastin to treat Retinopathy of Prematurity (ROP) in premature infants.
This study was widely covered by the press, but I would like to reproduce just a few of the presentations to provide you with the information necessary to best understand the results of this study.
A quick summary of the study was reported by Review of Ophthalmology, Retina Online .
Treatment of ROP with IVB
A prospective, controlled, randomized, stratified, multicenter trial was conducted to assess intravitreal bevacizumab (IVB) monotherapy for zone I or zone II posterior stage 3+ (i.e., stage 3 with plus disease) retinopathy of prematurity (ROP).
Infants were randomly assigned to receive IVB (0.625 mg in 0.025 ml of solution) or conventional laser therapy, bilaterally, and the primary ocular outcome was recurrence of retinopathy of prematurity in one or both eyes requiring retreatment before 54 weeks' postmenstrual age.
A total of 150 infants (300 eyes) were enrolled; 143 infants survived to 54 weeks' postmenstrual age, and the 7 infants who died were not included in the primary-outcome analyses. It was noted that ROP recurred in 4 infants in the bevacizumab group (6 of 140 eyes [4%]) and 19 infants in the laser-therapy group (32 of 146 eyes [22%], p=0.002). A significant treatment effect was found for zone I ROP (p=0.003) but not for zone II disease (p=0.27).
IVB monotherapy, as compared with conventional laser therapy, in infants with stage 3+ ROP showed a significant benefit for zone I but not zone II disease. Futhermore, development of peripheral retinal vessels continued after treatment with IVB, but conventional laser therapy led to permanent destruction of the peripheral retina. This trial was too small to assess safety.
Source: Mintz-Hittner HA, Kennedy KA, Chuang AZ; for the BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364(7):603-615 .
In addition, Retina Online also provided a discussion of the accompanying editorial from the NEJM
Bevacizumab and ROP: Editorial
This editorial discusses the use of bevacizumab in the treatment of retinopathy of prematurity (ROP), with particular focus on the study above by Mintz-Hittner and colleagues, which compares intravitreal bevacizumab (IVB) to conventional laser therapy. It points out that in comparing IVB to an effective, established treatment, there are three concerns: efficacy, safety and practicality and that with regard to the Mintz-Hittner, et al. study, as compared with conventional laser therapy in treating patients with zone I ROP, IVB represents a true breakthrough in disease management.
The editorial also notes that the safety of therapy for ROP involves not only the eye, but also potentially profound systemic issues. Bearing in mind the pharmacokinetics of bevacizumab, the extensive experience with adults taking this drug and the study by Mintz-Hittner and colleagues, it seems reasonable to assume that IVB is safe; however, continued vigilance will be important as use of the drug continues. With respect to ocular health with the use of IVB, the editorial mentions that timing of the injection is critical, as injection too early in the disease process may interfere with necessary retinal vascularization and injection too late may accelerate the cicatricial phase of ROP and lead to early retinal detachment.
In light of previous work and its confirmation in a robust clinical trial, the use of IVB as monotherapy is superior to laser therapy in treating zone I ROP and is possibly superior in treating posterior zone II disease, the editorial concludes. The author goes on to speculate that IVB therapy will prove to be at least equal to laser therapy in clinical effectiveness for most forms of ROP and that, as our experience with the drug grows, its indications and relative contraindications will be refined. In the meantime, IVB should become the treatment of choice for zone I ROP.
Source: Reynolds JD. Bevacizumab for retinopathy of prematurity. N Engl J Med 2011;364(7):677-678.
However, the most complete coverage of the study results were reproduced in Medical News Today, and was the work of a representative of the University of Texas Health Science Center at Houston, Meredith Raine, where the study took place.
Medical News Today
In Treating A Leading Cause Of Childhood Blindness, Drug Therapy Shows Significant Benefit
18 Feb 2011
A readily available, inexpensive drug therapy showed a significant benefit in treating premature infants with the worst and historically most difficult-to-treat cases of retinopathy of prematurity.
The results of a multicenter clinical trial led by researchers at The University of Texas Health Science Center at Houston (UTHealth) are published in the Feb. 17 issue of The New England Journal of Medicine.
Retinopathy of prematurity is a leading cause of childhood blindness worldwide. In the immature retina of babies born before 30 weeks' gestational age, the disease results in disorganized growth of retinal blood vessels, which can lead to scarring and retinal detachment.
In this study, Helen A. Mintz-Hittner, M.D., the Alfred W. Lasher, III, Professor in the Department of Ophthalmology and Visual Science at the UTHealth Medical School, and colleagues compared the use of intravitreal bevacizumab, an anti-vascular endothelial growth factor, to conventional laser treatment.
The study investigators treated infants with acute retinopathy of prematurity affecting zone I and posterior zone II - the retinal zones with the highest rate of treatment failure.
Data on the outcomes of 143 infants enrolled in the study showed that, among infants with zone I disease, the recurrence rate was 6 percent with intravitreal bevacizumab and 42 percent with conventional laser therapy. The drug therapy resulted in mild anatomical retinal abnormality in just one eye of 31 infants, whereas conventional laser treatment resulted in a mild structural abnormality in 16 eyes and severe abnormality in two eyes of 33 infants.
"When I started working with babies almost 40 years ago, there was nothing we could do for those with retinopathy of prematurity," said Mintz-Hittner, the study's principal investigator. "We've gone from nothing to a real solution. It you are careful and administer this therapy appropriately in stage 3+, you can get wonderful outcomes."
Mintz-Hittner, an attending physician at Children's Memorial Hermann Hospital and the Robert Cizik Eye Clinic, stressed that timing is critical with this drug therapy. If administered too early, in stages 1 and 2 of the disease, it can cause retinal dystrophy. Given too late, in stages 4-5 of the disease, the drug can accelerate retina detachment.
"In that window, as the abnormal vessels begin to proliferate but before the retinal begins to detach, that's when you want to treat," Mintz-Hittner said.
In addition to the significantly reduced recurrence rate for patients with retinopathy of prematurity in zone I, Mintz-Hittner said, compared with conventional laser therapy, the drug therapy appears to do the best job preserving vision. Plus, when administered, there is no need to intubate the baby and there is a faster recovery.
"Our first available treatment for babies with retinopathy of prematurity was cryotherapy," Mintz-Hittner said. "It was very painful and it wiped out all posterior ocular layers. The visual field was decreased and myopia or nearsightedness occurred. It was a long procedure - 2 to 3 hours - requiring intubation. With laser treatment, you still had to intubate, which could cause major setbacks for the baby, and field loss and myopia still occurred, but it was less painful and only destroyed the inner retinal layers."
"With this drug therapy, we use a few drops of anesthetic to numb the eye. We take a syringe with a tiny needle and administer a small amount of the drug directly into the eye. The whole process takes two to three minutes, and you begin to see results within 24 hours," she said. "The abnormal vessels virtually disappear and then normal vessels begin to grow out again. The field of vision is preserved and myopia is less."
The results of the study were so promising that Children's Memorial Hermann Hospital has discontinued the use of conventional laser therapy and now offers only the drug therapy to premature infants with this type of retinal disease.
"As compared with conventional laser therapy in treating patients with zone I retinopathy of prematurity, intravitreal bevacizumab represents a true breakthrough in disease management," James D. Reynolds, M.D., wrote in an accompanying editorial in The New England Journal of Medicine."...Intravitreal bevacizumab should become the treatment of choice for zone I retinopathy of prematurity." Reynolds is with the Department of Ophthalmology at the University of Buffalo in Buffalo, N.Y.
Compared with laser therapy, Mintz-Hittner cautioned, the drug therapy does require longer follow-up, "You must follow the child for at least 16 weeks following the injection to make sure there isn't a recurrence. Approximately 4 percent of patients (one in every 25 patients) may require a second injection. I explain to parents that it's like a cancer. It can come back and if it isn't treated in time, it can lead to blindness - so follow-up is very important."
The next steps in research, Mintz-Hittner said, will be to further evaluate the drug therapy's safety, refine the dosage and timing of follow-up and also study long-term visual function.
Mintz-Hittner led the research with Kathleen A. Kennedy, M.D., M.P.H., the Richard Warren Mithoff Professor in Neonatal/Perinatal Medicine at UTHealth; and Alice Z. Chuang, Ph.D., the Gibson and Martha Gayle Professor in the Department of Ophthalmology and Visual Science at UTHealth.
In addition to UTHealth and Children's Memorial Hermann Hospital, other hospitals in the Houston area that participated in the clinical trial included Memorial Hermann Southwest Hospital, Clear Lake Regional Medical Center, and St. Joseph Medical Center. Other Texas hospitals were Driscoll Children's Hospital in Corpus Christi; Baylor University Medical Center in Dallas; Del Sol Medical Center, Las Palmas Medical Center and R.E. Thomason Hospital in El Paso; and Cook Children's Medical Center in Fort Worth. Other trial sites were Huntington Memorial Hospital in Pasadena, Calif.; Presbyterian-St. Luke's Hospital and Rocky Mountain Hospital for Children in Denver, Colo.; Children's Hospital of Illinois and OSF St. Francis Medical Center in Peoria, IL; and Palmetto Health Baptist Hospital and Palmetto Health Richland Hospital in Columbia, S.C.
The study, titled "Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity," was supported by grants from Research to Prevent Blindness, the National Eye Institute, the Hermann Eye Fund, research funds from the Alfred W. Lasher III Professorship and a grant from UTHealth Center for Clinical and Translational Sciences-Clinical Research Center.
University of Texas Health Science Center at Houston
And, finally, the coverage by the Wall Street Journal, which discusses why Avastin was chosen rather than Lucentis.
Drug Shows Promise For Newborn Blindness Treating Babies With Avastin Surpassed a Usual Therapy
By JENNIFER CORBETT DOOREN
Wall Street Journal, FEBRUARY 17, 2011
An inexpensive drug therapy far surpassed a conventional laser procedure in fixing a leading cause of blindness in babies born prematurely, according to a new study.
The results of the study, to be published this week in the New England Journal of Medicine, were so significant that the 15 hospitals participating in the research have stopped using lasers in favor of the drug, Avastin, which is injected into the eyes of the affected newborns. Avastin, made by Roche Holding AG's Genentech unit, is designed to be used for treating cancer, and the company doesn't promote its use for any eye conditions.
Babies born before 30 weeks of gestation have immature eyes and are at high risk of developing a condition called retinopathy of prematurity that is caused by uncontrolled growth of blood vessels in the eye. The blood-vessel growth can lead to scarring and detachment of the retina, which causes blindness.
The study's lead researcher, Helen Mintz-Hittner, an ophthalmology professor at the University of Texas Health Science Center at Houston Medical School, says retinopathy of prematurity is traditionally treated with a laser procedure that requires general anesthesia. Some babies need several treatments over time, and in most cases peripheral vision can't be saved.
Dr. Mintz-Hittner estimates there are about 3,000 to 4,000 cases of retinopathy of prematurity in the U.S. each year. The numbers are increasing as more premature babies survive.
An injection of Avastin stopped blood-vessel growth. In many cases, the drug was able to successfully treat retinopathy in premature babies with just one treatment. Babies get a small amount of anesthetic to numb the eye before being injected.
Avastin was designed to help treat cancer by choking off blood vessels to tumors, and doctors have been using it to treat some eye conditions. Genentech also markets a drug called Lucentis that's similar to Avastin and is approved by the Food and Drug Administration to treat age-related macular degeneration, which is the leading cause of blindness in older adults.
Dr. Mintz-Hittner says such a small dose of Avastin is used for premature babies that it costs about $40 to treat both eyes. A comparable dose of Lucentis would be about $2,500, she says. Avastin also is preferable to Lucentis for retinopathy in infants because of the way it's designed. Avastin is considered a large-molecule drug, so it can't easily travel outside the eye area. Dr. Mintz-Hittner said a theoretical concern with Lucentis, which is a smaller molecule, is that it might travel to other parts of the body and impact necessary blood-vessel growth in babies.
A Genentech spokesman said there's limited safety information about uses of Avastin in treating eye diseases. "We don't support or promote the off-label use of Avastin," he said, noting that Avastin is not approved for use in the eye.
About 150 premature babies were enrolled in the Houston-led study from March 2008 through August 2010. Half were randomized to receive Avastin and the other half received laser treatment. Seven babies died of causes unrelated to the eye treatments. The remaining 143 babies were followed for several weeks after their initial treatments to see if the retinopathy returned.
Overall, retinopathy recurred in four infants treated with Avastin compared with 19 infants treated with the laser, which translates into a 20% reduction in the risk of recurrence. The results were even more significant for babies with a harder-to-treat form of the disease called zone 1, in which abnormal blood vessels form at the very back of the eye. Among infants with this form of the disease, the recurrence rate was 6% with Avastin compared with 42% for laser therapy.
James D. Reynolds, an ophthalmology professor at the University of Buffalo, wrote in an accompanying editorial that Avastin should be the treatment of choice for babies with zone 1 retinopathy of prematurity.
Bradley and Kelly Henry, who had two daughters born prematurely, saw first hand the outcomes of the different treatments. Their daughter Grace was born in 2004 at 24 weeks' gestation, weighing under two pounds. She was later diagnosed with retinopathy of prematurity and had several laser treatments under Dr. Mintz-Hittner's care. Grace's left eye eventually burst after she developed glaucoma, and it had to be replaced with a glass eye. She has enough vision in the right eye to attend regular school but is considered legally blind."It's hard to watch your daughter walk into a flagpole because she can't see," Ms. Henry says.
By the time the Houston-area family's other daughter, Evelyn, was born early last year at 26 weeks' gestation, the Avastin study was under way. Evelyn wasn't enrolled but was able to receive Avastin after she was diagnosed with retinopathy.
Ms. Henry says she remembers being "elated" that Evelyn was able to receive Avastin. "I knew what the effects of laser treatment were," she says. Evelyn, now 13 months old, had just one treatment with Avastin and so far appears to be developing normally, Ms. Henry and Dr. Mintz-Hittner say.
The oldest children in the Avastin study are now nearly 3-years old and appear to be developing normally, Dr. Mintz-Hittner says, adding that so far she hasn't seen any significant side-effects from the drug. She says doctors need to be careful not to administer Avastin too early before the abnormal blood vessels fully develop, nor too late after the blood-vessel growth causes the retina to detach.