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Retinoblastoma if left untreated is almost invariably fatal, but prognosis improved markedly when surgeons in the late 19th century learned to enucleate eyes harbouring early retinoblastoma. Without compromising prognosis, management of retinoblastoma has since focused on the preservation of vision, evolving from surgical removal of the eye to radiotherapy and recently to systemic chemotherapy. Systemic chemotherapy (using the intravenous route) with or without focal consolidation therapy has not only been highly successful in retaining many eyes with visual function but has also avoided radiation-induced side effects. However, systemic chemotherapy by default exposes the entire body to significant doses of highly toxic drugs in order that only a minute fraction (<1% by weight) of the body can be treated. The potential late side effects of this massive overtreatment are still largely unknown.
This insight has driven the advent of periocular administration1 and more recently, selective intra-arterial administration of chemotherapeutic drugs.2 Superselective cannulation of the ophthalmic artery requires a trained interventionist and given that reports of significant side effects are now emerging,3 4 it may seem logical to bypass the ophthalmic artery and simply inject the drug(s) into the vitreous cavity.
We have learned from the many tens of thousands of intravitreal injections using antiangiogenic drugs, for example, for age-related macular degeneration, that side effects such as retinal detachment, vitreous haemorrhage and endophthalmitis are extremely rare.5 However, cancer treatment comes with an additional caveat as retinoblastoma is a poorly cohesive cancer and for many years there has been a widespread concern that a needle entering an eye with retinoblastoma may cause extraocular spread of tumour cells.6
Much of the concern about extraocular spread is based on the detection of tumour cells in needle tracks in a few eyes enucleated after diagnosis following fine-needle aspiration biopsy (FNAB).7 However, there are only a few documented cases of actual extraocular spread of retinoblastoma caused by FNAB.8 During FNAB, the negative pressure applied to dislodge tumour cells and aspirate them into the hollow needle is likely to increase the risk of displacing them into the needle tract. Also, significantly wider, typically 25–27-gauge (outer diameter approximately 0.51–0.41 mm) needles are used compared to the 30–32-gauge needles (outer diameter approximately 0.30–0.23 mm) employed for intravitreal chemotherapy injections. Nevertheless, intravitreal chemotherapy for retinoblastoma is a repetitive treatment and the risk of extraocular spread is likely to rise as the number of injections increases.
Intravitreal chemotherapy for retinoblastoma was introduced by Ericson and Rosengren in Gothenburg more than half a century ago.9 At the time it was (and still remains) a highly controversial treatment. Allegedly, Bengt Rosengren told Norman Ashton, then the doyen of European ophthalmic pathology, of their first attempt when they met at a conference. Perhaps he anticipated an encouraging remark, but Ashton is said to have looked him straight in the eye and responded, “Are you completely mad?”. One of the authors of this editorial (SS) reported on a series of three children, each with advanced retinoblastoma in an only eye, being treated with repeated intravitreal chemotherapy. This paper was rejected by no less than three journals (arguably because the technique was perceived as too dangerous to be shared with the ophthalmic community) before it was eventually published in this journal in 1995.10
Since then there have been a few published reports of a small number of patients treated on a compassionate basis or after vitreous seeding.11 12 More recently, at the biennial meeting of the International Society of Ocular Oncology in Buenos Aires in November 2011, Suzuki and Kaneko reported on 237 eyes of 227 patients treated with a staggering 896 intravitreal injections of melphalan. Only one of these eyes (0.4%) was judged to have extraocular spread caused by injection at a mean follow-up of 91 months.
This issue of the journal features three papers with detailed data from two case series of children with advanced intraocular retinoblastoma who were managed with intravitreal chemotherapy; one series used intravitreal carboplatin in two patients who failed systemic chemotherapy13 and the other series used 135 intravitreal injections of melphalan in 30 eyes of 30 children with most injections given for globe salvage after the onset of vitreous seeding.14 15 All of the injections in both series were given with a 32-gauge needle (outer needle diameter approximately 0.23 mm). Safety measures varied and included injecting subconjunctival carboplatin immediately before intraocular injection, guidance by high-frequency ultrasonography to avoid injection in an area of detectable vitreous seeding, hypotony to minimise reflux induced by anterior chamber paracentesis prior to intravitreal injection, and postinjection triple freeze–thaw cryotherapy at the site of intravitreal injection. Importantly, none of the children had extraocular tumour spread detected during the period of follow-up.
Until now, intravitreal chemotherapy has only been used for globe salvage in selected cases with advanced intraocular retinoblastoma. Complications including extraocular spread appear to be rare. As intravitreal chemotherapy requires less multidisciplinary expertise than either systemic chemotherapy or intra-arterial chemotherapy and also is inherently much less expensive, it would be tempting to speculate that intravitreal chemotherapy will be used more frequently for retinoblastoma in the future. However, we would caution against this technique being used in an unrestricted manner or away from a dedicated tertiary care setting as this may per se increase the likelihood of extraocular tumour spread.
Importantly, there are several alternative routes for intraocular drug delivery (currently under investigation) that do not require full penetration of the eye wall.16 17 Any one of these routes may play a role in the future management of retinoblastoma.
Even though the risk of extraocular dissemination of tumour cells may be small, we do not know which drug (or indeed combination of drugs), dosing or injection frequency to use. We do, however, encourage the diffusion of any new knowledge gained from this technique and appreciate that the authors of he reports in this issue have been willing to share their experience with the ophthalmic community.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
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