Anti-VEGF Drug Effective for Treating ROP; Safety Issues Unresolved

HOUSTON – Treatment with intravitreal bevacizumab monotherapy showed significant benefit over conventional laser treatment in infants with stage 3+ retinopathy of prematurity, according to results of the BEAT-ROP clinical trial as reported in the Feb. 17 issue of the New England Journal of Medicine.

However, timing of treatment is critical, and significant questions remain about the safety of using intravitreal bevacizumab in this population and the appropriate dose of the drug, according to the researchers.

Results of the BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) trial further showed significant efficacy of bevacizumab treatment for zone I – but not zone II – disease.

Bevacizumab works by inhibiting vascular endothelial growth factor (VEGF), a key factor in the progression of ROP. The drug has been approved by the Food and Drug Administration for the treatment of metastatic colorectal and other cancers, but has been used off label to treat neovascular ocular disorders, such as age-related macular degeneration. The drug has not been approved by the FDA for the use in this study.

To study its emerging use in the treatment of ROP, Dr. Helen A. Mintz-Hittner of the University of Texas, Houston, and colleagues conducted a prospective, controlled, randomized, stratified, multicenter trial in which they compared the outcomes of intravitreal bevacizumab monotherapy and conventional laser therapy for stage 3+ ROP (N. Engl. J. Med. 2011;364:603-15).

The researchers enrolled 150 infants with a birth weight of 1,500 g or less and a gestational age of 30 weeks or less beginning at 4 weeks’ chronological age or 31 weeks’ postmenstrual age, whichever was later, between March 13, 2008, and Aug. 4, 2010. A total of 67 infants had zone I disease and 83 had zone II posterior disease. The researchers randomized 75 infants each to receive intravitreal bevacizumab monotherapy (0.625 mg in 0.025 mL of solution) and conventional laser therapy.

Seven infants (five with bevacizumab treatment and two with laser treatment) died before reaching 54 weeks’ postmenstrual age and without having reached the primary outcome. This 1.5-fold greater death rate with bevacizumab could not be evaluated as to significance because the trial was too small. For an assessment of mortality at 5% significance and 80% power, a sample size of 2,800 patients would have had to have been studied, according to the authors. Although the researchers observed no systemic or local toxic effects that were attributable to the administration of bevacizumab, they stated that "an assessment of local or systemic toxicity would have required an even larger sample."

The researchers evaluated the 143 surviving infants for recurrence at 54 weeks’ postmenstrual age, and had photos that were taken at 54 weeks assessed by six independent experts.

For zones I and II disease combined, ROP recurred in 6% of infants (4 of 70) who received intravitreal bevacizumab, significantly lower than the recurrence in 26% of infants (19 of 73) who received conventional laser therapy. The difference was even more significant for zone I disease alone: ROP recurred in 6% of infants (2 of 21) who received bevacizumab vs. 42% of infants (14 of 33) of infants who received conventional laser treatment. There was little significant treatment effect for zone II posterior disease alone, however, with recurrence in 12% of infants (5 of 40) in the laser group vs. 5% of the bevacizumab group.

Also, conventional laser therapy permanently destroyed vessels in the peripheral retina, whereas bevacizumab allowed continued vessel growth into the peripheral retina, the researchers found.

Nevertheless, they say, "safety is the primary reason for exercising caution when considering the use of intravitreal bevacizumab in the treatment of neonates. Both mortality and morbidity must be considered."

In addition, further research is necessary to determine an ideal dosage of bevacizumab for treating ROP, as well as the duration and frequency of follow-up and the management of recurrence.

In an editorial accompanying the article, Dr. James D. Reynolds of the Ross Eye Institute at the State University of New York at Buffalo favored the use of intravitreal bevacizumab (N. Engl. J. Med. 2011;364:677-8).

The results of the BEAT-ROP trial suggest that intravitreal bevacizumab monotherapy appears to be far safer and more effective than conventional laser for treating retinopathy of prematurity. These findings suggest that bevacizumab may represent a real breakthrough in treating this disease, he said.

Dr. Reynolds pointed out that intravitreal bevacizumab has numerous advantages, including simplicity of administration, a rapid effect, decreased loss of visual field compared with conventional laser treatment, and continued normal retinal vascularization.

However, the timing is critical, he added. If treatment is administered too early, it may interfere with necessary retinal vascularization. Treatment that occurs too late may accelerate the cicatricial phase of ROP, leading to early retinal detachment.

Also, intravitreal bevacizumab reaches the systemic circulation, which raises concern about untoward effects on an infant’s developing organs. Although there are no documented instances of this, a much larger sample size than that of this study is necessary to determine the statistical safety of the drug in premature infants. The dose of intravitreal bevacizumab is a fraction of the dose used for cancer treatment, and the amount of circulating bevacizumab is very small. "Bearing in mind the pharmacokinetics of bevacizumab, the extensive experience of adults taking this drug, and [the results of this study], it seems reasonable to assume that intravitreal bevacizumab is safe. However, continued vigilance will be important as use of the drug continues," Dr. Reynolds wrote.

"As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice in premature infants," Dr. Reynolds concluded.

The BEAT-ROP study was supported by grants from Research to Prevent Blindness, the U.S. National Eye Institute, and the Hermann Eye Fund as well as research funds from the Alfred W. Lasher III Professorship and a grant from the center for clinical and translational science at the University of Texas Health Science Center in Houston. Helen A. Mintz-Hittner, the corresponding author, receives honoraria from the Bascom Palmer Eye Institute and Clarity Medical Systems, as well as from testifying as an expert witness in a retinopathy of prematurity suit.

Dr. Reynolds received payment as an expert witness in trials concerning treatment of ROP from various legal firms and royalties for an up-to-date glaucoma chapter.

HOUSTON – Treatment with intravitreal bevacizumab monotherapy showed significant benefit over conventional laser treatment in infants with stage 3+ retinopathy of prematurity, according to results of the BEAT-ROP clinical trial as reported in the Feb. 17 issue of the New England Journal of Medicine.

However, timing of treatment is critical, and significant questions remain about the safety of using intravitreal bevacizumab in this population and the appropriate dose of the drug, according to the researchers.

Results of the BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) trial further showed significant efficacy of bevacizumab treatment for zone I – but not zone II – disease.

Bevacizumab works by inhibiting vascular endothelial growth factor (VEGF), a key factor in the progression of ROP. The drug has been approved by the Food and Drug Administration for the treatment of metastatic colorectal and other cancers, but has been used off label to treat neovascular ocular disorders, such as age-related macular degeneration. The drug has not been approved by the FDA for the use in this study.

To study its emerging use in the treatment of ROP, Dr. Helen A. Mintz-Hittner of the University of Texas, Houston, and colleagues conducted a prospective, controlled, randomized, stratified, multicenter trial in which they compared the outcomes of intravitreal bevacizumab monotherapy and conventional laser therapy for stage 3+ ROP (N. Engl. J. Med. 2011;364:603-15).

The researchers enrolled 150 infants with a birth weight of 1,500 g or less and a gestational age of 30 weeks or less beginning at 4 weeks’ chronological age or 31 weeks’ postmenstrual age, whichever was later, between March 13, 2008, and Aug. 4, 2010. A total of 67 infants had zone I disease and 83 had zone II posterior disease. The researchers randomized 75 infants each to receive intravitreal bevacizumab monotherapy (0.625 mg in 0.025 mL of solution) and conventional laser therapy.

Seven infants (five with bevacizumab treatment and two with laser treatment) died before reaching 54 weeks’ postmenstrual age and without having reached the primary outcome. This 1.5-fold greater death rate with bevacizumab could not be evaluated as to significance because the trial was too small. For an assessment of mortality at 5% significance and 80% power, a sample size of 2,800 patients would have had to have been studied, according to the authors. Although the researchers observed no systemic or local toxic effects that were attributable to the administration of bevacizumab, they stated that "an assessment of local or systemic toxicity would have required an even larger sample."

The researchers evaluated the 143 surviving infants for recurrence at 54 weeks’ postmenstrual age, and had photos that were taken at 54 weeks assessed by six independent experts.

For zones I and II disease combined, ROP recurred in 6% of infants (4 of 70) who received intravitreal bevacizumab, significantly lower than the recurrence in 26% of infants (19 of 73) who received conventional laser therapy. The difference was even more significant for zone I disease alone: ROP recurred in 6% of infants (2 of 21) who received bevacizumab vs. 42% of infants (14 of 33) of infants who received conventional laser treatment. There was little significant treatment effect for zone II posterior disease alone, however, with recurrence in 12% of infants (5 of 40) in the laser group vs. 5% of the bevacizumab group.

Also, conventional laser therapy permanently destroyed vessels in the peripheral retina, whereas bevacizumab allowed continued vessel growth into the peripheral retina, the researchers found.

Nevertheless, they say, "safety is the primary reason for exercising caution when considering the use of intravitreal bevacizumab in the treatment of neonates. Both mortality and morbidity must be considered."

In addition, further research is necessary to determine an ideal dosage of bevacizumab for treating ROP, as well as the duration and frequency of follow-up and the management of recurrence.

In an editorial accompanying the article, Dr. James D. Reynolds of the Ross Eye Institute at the State University of New York at Buffalo favored the use of intravitreal bevacizumab (N. Engl. J. Med. 2011;364:677-8).

The results of the BEAT-ROP trial suggest that intravitreal bevacizumab monotherapy appears to be far safer and more effective than conventional laser for treating retinopathy of prematurity. These findings suggest that bevacizumab may represent a real breakthrough in treating this disease, he said.

Dr. Reynolds pointed out that intravitreal bevacizumab has numerous advantages, including simplicity of administration, a rapid effect, decreased loss of visual field compared with conventional laser treatment, and continued normal retinal vascularization.

However, the timing is critical, he added. If treatment is administered too early, it may interfere with necessary retinal vascularization. Treatment that occurs too late may accelerate the cicatricial phase of ROP, leading to early retinal detachment.

Also, intravitreal bevacizumab reaches the systemic circulation, which raises concern about untoward effects on an infant’s developing organs. Although there are no documented instances of this, a much larger sample size than that of this study is necessary to determine the statistical safety of the drug in premature infants. The dose of intravitreal bevacizumab is a fraction of the dose used for cancer treatment, and the amount of circulating bevacizumab is very small. "Bearing in mind the pharmacokinetics of bevacizumab, the extensive experience of adults taking this drug, and [the results of this study], it seems reasonable to assume that intravitreal bevacizumab is safe. However, continued vigilance will be important as use of the drug continues," Dr. Reynolds wrote.

"As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice in premature infants," Dr. Reynolds concluded.

The BEAT-ROP study was supported by grants from Research to Prevent Blindness, the U.S. National Eye Institute, and the Hermann Eye Fund as well as research funds from the Alfred W. Lasher III Professorship and a grant from the center for clinical and translational science at the University of Texas Health Science Center in Houston. Helen A. Mintz-Hittner, the corresponding author, receives honoraria from the Bascom Palmer Eye Institute and Clarity Medical Systems, as well as from testifying as an expert witness in a retinopathy of prematurity suit.

Dr. Reynolds received payment as an expert witness in trials concerning treatment of ROP from various legal firms and royalties for an up-to-date glaucoma chapter.

HOUSTON – Treatment with intravitreal bevacizumab monotherapy showed significant benefit over conventional laser treatment in infants with stage 3+ retinopathy of prematurity, according to results of the BEAT-ROP clinical trial as reported in the Feb. 17 issue of the New England Journal of Medicine.

However, timing of treatment is critical, and significant questions remain about the safety of using intravitreal bevacizumab in this population and the appropriate dose of the drug, according to the researchers.

Results of the BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) trial further showed significant efficacy of bevacizumab treatment for zone I – but not zone II – disease.

Bevacizumab works by inhibiting vascular endothelial growth factor (VEGF), a key factor in the progression of ROP. The drug has been approved by the Food and Drug Administration for the treatment of metastatic colorectal and other cancers, but has been used off label to treat neovascular ocular disorders, such as age-related macular degeneration. The drug has not been approved by the FDA for the use in this study.

To study its emerging use in the treatment of ROP, Dr. Helen A. Mintz-Hittner of the University of Texas, Houston, and colleagues conducted a prospective, controlled, randomized, stratified, multicenter trial in which they compared the outcomes of intravitreal bevacizumab monotherapy and conventional laser therapy for stage 3+ ROP (N. Engl. J. Med. 2011;364:603-15).

The researchers enrolled 150 infants with a birth weight of 1,500 g or less and a gestational age of 30 weeks or less beginning at 4 weeks’ chronological age or 31 weeks’ postmenstrual age, whichever was later, between March 13, 2008, and Aug. 4, 2010. A total of 67 infants had zone I disease and 83 had zone II posterior disease. The researchers randomized 75 infants each to receive intravitreal bevacizumab monotherapy (0.625 mg in 0.025 mL of solution) and conventional laser therapy.

Seven infants (five with bevacizumab treatment and two with laser treatment) died before reaching 54 weeks’ postmenstrual age and without having reached the primary outcome. This 1.5-fold greater death rate with bevacizumab could not be evaluated as to significance because the trial was too small. For an assessment of mortality at 5% significance and 80% power, a sample size of 2,800 patients would have had to have been studied, according to the authors. Although the researchers observed no systemic or local toxic effects that were attributable to the administration of bevacizumab, they stated that "an assessment of local or systemic toxicity would have required an even larger sample."

The researchers evaluated the 143 surviving infants for recurrence at 54 weeks’ postmenstrual age, and had photos that were taken at 54 weeks assessed by six independent experts.

For zones I and II disease combined, ROP recurred in 6% of infants (4 of 70) who received intravitreal bevacizumab, significantly lower than the recurrence in 26% of infants (19 of 73) who received conventional laser therapy. The difference was even more significant for zone I disease alone: ROP recurred in 6% of infants (2 of 21) who received bevacizumab vs. 42% of infants (14 of 33) of infants who received conventional laser treatment. There was little significant treatment effect for zone II posterior disease alone, however, with recurrence in 12% of infants (5 of 40) in the laser group vs. 5% of the bevacizumab group.

Also, conventional laser therapy permanently destroyed vessels in the peripheral retina, whereas bevacizumab allowed continued vessel growth into the peripheral retina, the researchers found.

Nevertheless, they say, "safety is the primary reason for exercising caution when considering the use of intravitreal bevacizumab in the treatment of neonates. Both mortality and morbidity must be considered."

In addition, further research is necessary to determine an ideal dosage of bevacizumab for treating ROP, as well as the duration and frequency of follow-up and the management of recurrence.

In an editorial accompanying the article, Dr. James D. Reynolds of the Ross Eye Institute at the State University of New York at Buffalo favored the use of intravitreal bevacizumab (N. Engl. J. Med. 2011;364:677-8).

The results of the BEAT-ROP trial suggest that intravitreal bevacizumab monotherapy appears to be far safer and more effective than conventional laser for treating retinopathy of prematurity. These findings suggest that bevacizumab may represent a real breakthrough in treating this disease, he said.

Dr. Reynolds pointed out that intravitreal bevacizumab has numerous advantages, including simplicity of administration, a rapid effect, decreased loss of visual field compared with conventional laser treatment, and continued normal retinal vascularization.

However, the timing is critical, he added. If treatment is administered too early, it may interfere with necessary retinal vascularization. Treatment that occurs too late may accelerate the cicatricial phase of ROP, leading to early retinal detachment.

Also, intravitreal bevacizumab reaches the systemic circulation, which raises concern about untoward effects on an infant’s developing organs. Although there are no documented instances of this, a much larger sample size than that of this study is necessary to determine the statistical safety of the drug in premature infants. The dose of intravitreal bevacizumab is a fraction of the dose used for cancer treatment, and the amount of circulating bevacizumab is very small. "Bearing in mind the pharmacokinetics of bevacizumab, the extensive experience of adults taking this drug, and [the results of this study], it seems reasonable to assume that intravitreal bevacizumab is safe. However, continued vigilance will be important as use of the drug continues," Dr. Reynolds wrote.

"As our experience with bevacizumab grows, its indications and relative contraindications will be refined. In the meantime, intravitreal bevacizumab should become the treatment of choice in premature infants," Dr. Reynolds concluded.

The BEAT-ROP study was supported by grants from Research to Prevent Blindness, the U.S. National Eye Institute, and the Hermann Eye Fund as well as research funds from the Alfred W. Lasher III Professorship and a grant from the center for clinical and translational science at the University of Texas Health Science Center in Houston. Helen A. Mintz-Hittner, the corresponding author, receives honoraria from the Bascom Palmer Eye Institute and Clarity Medical Systems, as well as from testifying as an expert witness in a retinopathy of prematurity suit.

Dr. Reynolds received payment as an expert witness in trials concerning treatment of ROP from various legal firms and royalties for an up-to-date glaucoma chapter.