Scientific breakthroughs in paediatric ophthalmology could save lives and improve the prospects for generations to come.
Control for Recurrent Vitreous Retinoblastoma Seeding
New research indicates that intravitreal melphalan injections used to treat persistent or recurrent vitreous retinoblastoma seeding can successfully control tumours with minimal toxicity and complications.
Retinoblastoma is a rare cancer of the retina that accounts for about 3 per cent of all childhood cancers and can be hereditary or non-hereditary. It is usually diagnosed before a child reaches the age of three.
Left untreated, retinoblastoma can spread widely throughout the retina and the vitreous before making its way into the eye socket, the optic nerve and brain, then eventually into the bones and bone marrow.
intravitreal melphalan injections used to treat persistent or recurrent vitreous retinoblastoma seeding can successfully control tumours
Even following treatment for retinoblastoma, large tumors can detach from the retina and break into smaller tumors, called vitreous seeds. Recurrent or persistent vitreous seeds following treatment of retinoblastoma can be difficult to manage and often lead to enucleation.
A short term study published in JAMA Ophthalmology has described the technique and evaluated the efficacy and complications of intravitreal melphalan for vitreous seeding from retinoblastoma. The study, conducted at a tertiary referral center, involved 11 consecutive eyes of 11 patients with “viable persistent or recurrent vitreous seeds following treatment of retinoblastoma”.
All eyes received monthly intravitreal melphalan injections (20-30 µg) over a period of six months by transconjunctival pars plana route. Six patients received intravenous chemotherapy and five received intra-arterial chemotherapy. For all patients, triple-freeze cryotherapy was used at the site of the injection during needle withdrawal to prevent extraocular seeding.
The mean patient age at the time of commencing vitreous injections was 37 months and viable vitreous seeds involved 2 (n = 1), 3 (n = 4), or 4 (n = 6) quadrants. The patients received no more than six injections each, by which time the tumour had been controlled. Furthermore, at a mean of nine months’ follow-up, complete vitreous seed regression had been achieved and the globe had been salvaged in all 11 cases (100 per cent). There was no further vitreous seed development in any of the patients.
Carol L. Shields, MD; Fairooz P. Manjandavida, MD; Sruthi Arepalli, BA; Swathi Kaliki, MD; Sara E. Lally, MD; Jerry A. Shields, MD. Intravitreal Melphalan for Persistent or Recurrent Retinoblastoma Vitreous Seeds Preliminary Results. JAMA Ophthalmol. 2014;132(3):319-325. doi:10.1001/jamaophthalmol.2013.7666.
Intravitreal chemotherapy for retinoblastoma
There are several reports advocating the use of intravitreal chemotherapy for vitreous seeding in retinoblastoma, with good results. The main concern previously in this technique is the escape of the tumour cells from the injection site outside of the globe resulting in tumour metastasis. The use of the triple freeze technique at the time of needle withdrawal seems to be effective with no known reports of tumour spread so far. Another remaining question to be answered is, ‘is melphalan the best agent for this job?’
Bevacizumab Effective in Treating ROP
Researchers believe that a single injection of bevacizumab would be adequate to treat retinopathy of prematurity (ROP).
Retinopathy of prematurity is a neovascular retinal disorder that occurs primarily in infants of low birth weight (≤1250 g; mean, 700 g).
Thanks to good neonatal care and appropriate screening and treatment, in the developed world, only about one case in 820 infants causes blindness. However in developing countries, retinopathy of prematurity is a major cause of blindness, also affecting larger premature infants (birth weight ≤2000 g; mean, 1400 g).
Normal retinal development begins at 16 weeks gestation with retinal vascularisation on the internal retinal surface, which proceeds anteriorly from the optic nerve edge and reaches the edge of the temporal retina at 40 weeks gestation (term). In eyes with ROP, there is a disruption of the normal retinal development and abnormal neovascularisation consequently develops.
Zone I ROP and posterior Zone II, referring to ROP at the very posterior pole of the retina is the most difficult to treat and has a high incidence of recurrence that requires further treatment. ROP in this area also has a very high blinding rate. Left untreated, neovascularisation will progress to form fibrous bands that cause partial retinal detachment, and ultimately total retinal detachment.
In the late 1980s threshold disease ROP was treated with cryotherapy and in the 1990s, laser therapy was introduced. The problem with both these treatments is that for severe ROP (Zone I Disease), they respond successfully to treatment in at best 50 per cent of cases, and progression onwards to blindness due to treatment failure in Zone I disease is very high. Even if successfully treated, there is some loss of peripheral vision and high myopia is not uncommonly seen in these children.
Researchers now believe that ROP occurs in two distinct phases: phase one, when increased oxygen post-partum leads to the cessation of vessel growth and vascular obliteration; and phase two when there is relative ischaemia which leads to neovascularization. These two phases are mediated by various chemical factors, one of which being vascular endothelial growth factor (VEGF). This understanding has led to an improved strategy for disease management
The use of anti-VEGF agents, primarily intravitreal bevacizumab, is an emerging treatment for acute severe retinopathy of prematurity.
A BEAT-ROP (Bevacizumab Eliminates the Angiogenic Threat of Retinopathy of Prematurity) study published in The New England Journal of Medicine compared intravitreal bevacizumab (an anti-VEGF agent) monotherapy and conventional laser therapy to observe ocular outcomes among infants with stage 3+ retinopathy of prematurity who had zone I or II posterior disease.
The researchers enrolled 150 patients with stage 3+ retinopathy of prematurity; 67 with zone I ROP and 83 with zone II posterior ROP into a prospective, randomised, stratified, controlled, multicenter clinical trial. Approximately 50 per cent of each group was assigned to intravitreal bevacizumab therapy while the other 50 per cent was treated with conventional laser therapy.
According to the authors, this study suggests the recurrence rates of ROP when treated with conventional laser therapy would be up to 50 per cent for zone I disease and up to 20 per cent for zone II posterior disease. In contrast, recurrence rates after intravitreal bevacizumab monotherapy would be 10 per cent for zone I disease and 1 per cent for zone II posterior disease.
They wrote, “Our clinical study showed increased efficacy of intravitreal bevacizumab as compared with conventional laser therapy for stage 3+ retinopathy of prematurity when both zones I and II were considered (absolute difference in the risk of recurrence, 20 percentage points; 95 per cent CI, 9 to 32).
“Our sample was sufficiently large to show significant efficacy of intravitreal bevacizumab for zone I disease but not for zone II posterior disease.”
The authors noted the ease with which bevacizumab can be administered at the patient’s bedside compared to treating with conventional laser therapy that requires “special training, expensive equipment, endotracheal intubation, and a location designated for the use of lasers”. They said bevacizumab is an “inexpensive drug”.
However they noted that a larger study would be required to determine the safety of bevacizumab and the dosage required to treat the disease at different stages and levels of aggression.
Additionally they said ROP had recurred in two of 62 eyes in infants with zone I disease and four of 78 eyes in infants with zone II posterior disease following treatment with bevacizumab. “This serves as a warning to clinicians that careful follow-up is needed in infants treated with intravitreal bevacizumab, who cannot be considered to be successfully treated until there is completion of vascularization with no active disease or clinically significant tractional elements.”
Helen A. Mintz-Hittner, M.D., Kathleen A. Kennedy, M.D., M.P.H., and Alice Z. Chuang, Ph.D. Efficacy of Intravitreal Bevacizumab for Stage 3+ Retinopathy of Prematurity. The New England Journal of Medicine.
The use of anti-VEGF agents for retinal neovascularisation has been shown to be very effective in many adult eye diseases, such as age related macular degeneration, diabetic retinopathy etc. In theory, it should work well in ROP, given that VEGF is one of the agents mediating the progression of the disease. However, the biggest concern is still the long term safety of these agents in the developing child. The growth of most of the organs of the child – the brain, kidneys, reproductive system, heart, etc – are also vascular dependent, and hence subjected to the influence of VEGF. Anti-VEGF agents have been detected in the blood system after intravitreal injections in neonates. Would this cause a problem to the organogenesis of these children?
There are also reports of recurrent retinal complications/neovascularisation months or potentially years later in children who have received bevacizumab for ROP. These children need to be monitored for years.
The use of anti-VEGF agents for ROP is here to stay, but much more research needs to be done to prove its safety and efficacy.
Geoff Lam is a Clinical Associate Professor at University of Western Australia Centre for Ophthalmology and Visual Science and School of Paediatrics and Child Health, and Head of the Department of Ophthalmology at Princess Margaret Hospital for Children. A/Prof Lam has published on a range of areas related to paediatric ophthalmology, including a novel technique for paediatric cataract surgery, eye trauma in children and squint surgery.