Complications of Intra-Arterial Chemotherapy (IAC) for Retinoblastoma: An Updated, Comprehensive Review

Introduction

Each year, approximately 8,000 children are diagnosed with retinoblastoma, making it the most prevalent intraocular malignancy in the pediatric population.^1,2 Although a tumor resembling retinoblastoma was first described in the medical literature by Petrus Pawius in 1597, most of the advancements in our understanding and treatment of the disease have occurred in the past 40 years.^3,4 The traditional treatment—enucleation of the affected eye, first proposed in 1809 by James Wardrop—has been supplemented with a growing armamentarium intended to cure retinoblastoma while also preserving the eye and any usable vision.⁴ Radiation therapy was pioneered as a treatment for retinoblastoma in the early twentieth century, but it has since faded in popularity. This is because of treatment side effects, including craniofacial deformities, cataracts, and optic neuropathy, as well as the demonstrated risk of secondary malignancies posed by radiotherapy to patients with hereditary retinoblastoma.^4,5,6

These undesirable side effects of radiation spurred treatment centers to move toward an approach characterized by systemic chemotherapy for intraocular retinoblastoma in the 1990s. Systemic chemotherapy, combined with adjuvant local consolidation therapies (including cryotherapy and photocoagulation), became the preferential management approach for most bilateral and select unilateral retinoblastomas.³ Shields and colleagues demonstrated the efficacy of chemoreduction and adjuvant therapies in controlling retinal tumors and preserving visual potential.⁷ However, systemic chemotherapy regimens can also cause significant systemic side effects, including hearing impairment, infertility, and development of secondary acute myelogenous leukemia (sAML).⁸

Concerns about the adverse effects of radiation and systemic chemotherapy prompted a search for therapies that might result in less systemic and ocular toxicity. Intra-arterial chemotherapy (IAC), with its potential benefit of high local target dose delivery combined with low systemic dose delivery, was first described as a treatment for retinoblastoma in 1958, when Reese and colleagues injected triethylene melamine into the internal carotid artery (ICA) of 31 patients with intraocular tumors.⁹ The method was refined in 2004 by Yamane and colleagues, who reported the use of a balloon catheter to more selectively infuse chemotherapy into the ophthalmic artery. The group treated 187 patients with 563 sessions of IAC and had a technical success rate of 97.5%.¹⁰ This approach, however, poses the risk of arterial dissection and thrombosis within the ICA, with subsequent intracranial embolization of thrombi.⁵

A team led by David Abramson and Pierre Gobin recognized the potential of IAC and developed “super-selective” ophthalmic artery infusion, utilizing interventional neuroradiologic techniques to cannulate the ophthalmic artery and directly infuse chemotherapy via the orbital arterial supply.^8,11 In the “super-selective” ophthalmic artery infusion technique, the patient is anesthetized, the femoral artery is punctured and a femoral arterial sheath placed, and anticoagulation is obtained using intravenous heparin. A catheter is navigated into the internal carotid artery ipsilateral to the tumor, and an arteriogram is performed to visualize the origin of the ophthalmic artery. A microcatheter is then introduced via the guide catheter and the ophthalmic artery is superselectively catheterized. After the microcatheter tip is situated within the ostium or proximal segment of the ophthalmic artery, a small amount of contrast is injected in order to verify that runoff is nearly exclusively into the ophthalmic artery, with at most minimal reflux into the ICA. The dose of chemotherapy is administered by slow, pulsatile hand injection over a range of 6–30 minutes. In cases where there is significant external carotid branch collateral reconstitution of the ophthalmic artery (typically from the middle meningeal artery, but potentially from the internal maxillary, accessory meningeal, or other arteries), these alternative routes could be employed instead, though this is infrequently the case. Following infusion, the catheters are withdrawn. Once anticoagulation has lapsed, the femoral sheath is removed, hemostasis is obtained in the femoral region with manual compression, and the patient is extubated. After 4 hours in the post-anesthesia care unit with the leg extended to lower the risk of bleeding from the puncture site, the patient is discharged the same day.^5,11

In 1987, Inomata and colleagues tested 13 chemotherapeutic agents against colonies of retinoblastoma cells with a clonogenic assay and demonstrated that melphalan (L-phenylalanine mustard) was the most effective.¹² Melphalan remains the primary agent used in IAC. However, it has also been used in conjunction with carboplatin and topotecan, usually after previous single-agent IAC or intravenous chemotherapy has failed.¹³ While IAC has shown impressive results in improving globe salvage and visual potential in advanced intraocular retinoblastoma, there have been concerns about potential complications of the procedure.^14,15

In 2014, several of the authors systematically reviewed the literature to categorize the complications of IAC. After initially studying 117 original articles, 35 were selected for review. We broadly divided complications of IAC into ocular and extraocular categories, with extraocular findings also comprising systemic adverse effects. The most frequent ocular side effects reported include ophthalmic artery thrombosis, sectoral choroidal nonperfusion, and retinal and vitreous hemorrhages. In the periocular region, the most common adverse effects reported were madarosis and periocular erythema. Systemically, the most common finding was transient hemodynamic instability during the procedure.⁵

The aim of the present study is to update our 2014 findings with a systematic review of the types of complications of IAC reported in recent studies. At the time of our original paper, IAC was a relatively new technique. Since the original publication, IAC has continued to increase in popularity and has assumed a prominent role in the management of retinoblastoma, especially in advanced unilateral disease.¹⁶ 

Methods

We conducted a literature search in the PubMed database. Search terms included “intra-arterial chemotherapy,” “IAC,” “ophthalmic arterial chemotherapy,” and “ophthalmic artery chemotherapy” in order to maximize results. Inclusion criteria were original, English-language, publications reporting complications of IAC for retinoblastoma published from 2014 to 2020.

We categorized all reported complications as being systemic (ie, manifesting more broadly than a local effect in the orbital region, such as hemodynamic effects), extraocular/periocular (effects of IAC outside the eye, such as in the extraocular muscles, forehead, or other areas adjacent to the eye), or intraocular (effects inside the globe, either the anterior or posterior segments).

Results  

We identified 68 publications using PubMed, of which 29 did not meet inclusion criteria. Of the 39 that did meet inclusion, 33 articles were retrospective case series, 4 were prospective case series, and 2 were case reports.  

Systemic Complications

Several systemic adverse effects of varying severity have been reported after IAC (Table 1). Multiple authors reported the development of myelosuppression and fever after IAC, ^17-20 with 1 case of pancytopenia resulting in hospital admission.²¹ In a retrospective series of 62 patients treated with IAC, Hua and colleagues reported that 14 children (22%) experienced fever.¹⁷ Chen and colleagues described 1 patient who developed grade 3–4 neutropenia and required a red blood cell transfusion.²² Wang and colleagues reported 2 cases of serious myelosuppression with a significant decrease in neutrophils occurring within 1 week of IAC, both treated successfully with subcutaneous injection of granulocyte-stimulating factor.²⁰Another side effect reported by multiple authors was transient nausea and vomiting after IAC.^17-20,23-25 Finally, there were 3 reports of patients suffering anaphylactic shock as a result of the procedure.^23,26,27 No subsequent doses of IAC were discontinued, and all children in these cases recovered without further sequelae.

Isolated reports of neurological and cerebrovascular complications after IAC have also been described. Ammanuel and colleagues reported that a patient suffered a seizure 2 days after IAC, and magnetic resonance imaging (MRI) confirmed a small cerebral infarct. The patient subsequently recovered, with no neurological deficits.²⁸ In a retrospective series of 30 patients treated with IAC, Batu Oto and colleagues described 1 patient who suffered a stroke that was resolved with anti-platelet therapy.²⁹ Hahn and colleagues detailed a T2-hyperintense lesion noticed incidentally on MRI after a patient had received 5 cycles of IAC. The authors postulated that this finding was due to a focal ischemic lesion after cerebral angiography.³⁰ Radros and colleagues reported 2 cases of angiographically documented cerebral embolization during IAC, without evidence of neurological deficit or ischemic injury seen on MRI.²⁵ Finally, Sweid and colleagues reported 1 case of dissection of the internal carotid artery (ICA) caused by the microcatheter and another case of vasospasm of the ICA.²⁷

Vascular complications in the region of the arterial puncture have also been described by multiple authors. Radros and colleagues described the incidence of groin hematoma occurring in 2 patients, constituting 15% of their patient cohort.²⁵ In a retrospective series of 3.5 years of IAC experience in Malaysia, Liu and colleagues reported that 1 patient suffered from a femoral artery hemorrhage.³¹ In a retrospective series of 69 IAC patients by Stenzel and colleagues, 2.9% of all patients had serious femoral artery complications. One patient developed asymptomatic femoral artery occlusion after IAC, resulting in a high-grade stenosis after heparinization. Another patient had compartment syndrome, which was treated with surgical intervention. Other patients in the series had rebleeding in the groin, femoral artery dissection, and pseudoaneurysm formation.³² A final complication reported was blue toe syndrome, characterized by transient peripheral artery occlusion. Batu Oto and colleagues detailed 1 patient who presented with blue toe color and pain 1 day after IAC. The patient was treated with oral aspirin (40 mg/day) and low molecular weight heparin, and the condition resolved within 10 days.²⁹

Hemodynamic instability occurring during IAC is another potentially serious adverse effect.^20,24,33,34 In 2015, Kato and colleagues reported that 63 of 94 patients (67%) undergoing IAC at a major center had at least 1 serious respiratory compliance event, but that all patients recovered without lasting effects.³⁴ In 2018, Nghe and colleagues prospectively evaluated hemodynamic instability in a cohort of children undergoing IAC. They found that respiratory compliance events occurred in 20% of procedures, all within 2 minutes of the catheter entering the ophthalmic artery. All patients were successfully stabilized, with no lasting complications, as was true for all reports of this complication. They did not find a correlation between patients’ weight, age, passive smoking history, presence of asthma, or history of recent upper respiratory tract infection and the occurrence of severe compliance events.³³

None of the papers reviewed reported death as a complication of IAC.

Extraocular/Periocular Complications

Adverse effects of IAC have also been reported in the periocular region (Table 2). Many authors have reported the common occurrence of eyelid and forehead edema across cohorts, presumably from local effects of a high-dose chemotherapy agent perfusing the soft tissue.^{14,17-25,30,31,35-38} Wang and colleagues detailed eyelid edema occurring in 15 of 61 patients in their treated cohort,  a complication rate of 24.6%.²⁰ Others have reported rates of edema greater than 10% within their cohorts.^{14,17,18,20,21,23-25,30,31,39} These reactions are typically transient and resolve without treatment.^14,18,20 Another commonly reported adverse effect in the periocular region is ptosis (Figure 1).^{14,20,22-25,29,35,36,39-41} In a retrospective cohort of 67 patients who underwent IAC, Shields and colleagues reported blepharoptosis in 10 eyes, constituting 14% of the treated eyes. The ptosis resolved within 3 months.¹⁴ Additionally, forehead pigmentation and erythema is commonly seen after IAC (Figure 2) and has been described by multiple authors.^14,23,29,42 Tuncer and colleagues reported 3 patients (13.6%) in their series developing transient cutaneous forehead redness, which spontaneously resolved.²³ Quinn and colleagues described an unusual complication, with a patient displaying periorbital edema and a forehead burn. Instead of receiving the IAC infusion through the typical ophthalmic artery, the patient had been treated via the frontal branch of the superficial temporal artery (STA), with the forehead soft tissue branches of the STA manually occluded during chemotherapy injection. The patient developed a forehead burn and periorbital edema, perhaps due to melphalan-induced necrosis or due to compression-related ischemia during the 10-minute procedure. The patient underwent steroid treatment that resolved the periocular edema within 2–3 days and plastic surgery to repair the eschar.³⁶

Figure 1. Ptosis after intra-arterial chemotherapy.

Figure 2. Forehead erythema in the V1 distribution immediately after intra-arterial chemotherapy.

Less common periocular side effects reported after IAC include transient cranial nerve palsies, extraocular muscle inflammation, and alopecia.^{14,24,38,39,41,43-45} Rojanaporn and colleagues reported 2 cases of strabismus arising from third cranial nerve palsy that developed after the second or third administration of IAC.⁴³ In a retrospective review of 9 patients who underwent IAC, Reddy and colleagues documented 1 case of transient sixth cranial nerve palsy, with -4 limitation of abduction after the third cycle of IAC. This same child also had nasal choroidal ischemia.⁴¹ Extraocular muscle inflammation was noticed on MRI in 5 out of 60 patients (8.3%) treated with IAC in a retrospective study by Chen and colleagues.⁴⁴ A rare extraocular complication reported by Shields and colleagues was the development of ipsilateral scalp alopecia, which resolved after 3 months.¹⁴

Intraocular Complications

A number of intraocular complications of IAC have been reported, ranging in severity and sometimes threatening the visual potential of the eye (Table 3). Multiple authors have detailed changes in the appearance and size of the globe as a complication of IAC.^25,38,44 Chen and colleagues conducted a retrospective study evaluating MRI changes in patients treated with IAC and found that 66.7% of 60 eyes treated were smaller than the contralateral eye after treatment. In that study, 2 eyes were enucleated due to atrophy of the globe after treatment with IAC.⁴⁴

Choroidal ischemia is another relatively commonly reported adverse effect of IAC that can be potentially vision-threatening.^{14,20,22,23,29,32,40,41,46} Choroidal ischemia has also been manifest as choroidal infarction, choroidal atrophy, chorioretinal atrophy, and choroidal occlusive vasculopathy.^20,21,47 Rates of choroidal ischemia ranged from 3.3%²⁰ to 37.5% in this literature survey.²³ Stathopoulos and colleagues conducted a large retrospective review of 206 eyes treated with IAC and found evidence of acute choroidal ischemia occurring in 35 of them (17%). Of the eyes with choroidal ischemia, 35% had diffuse atrophy, with complete atrophy involving the fovea. Choroidal atrophy was linked to negative visual outcomes, with a complete loss of vision occurring in 27% of involved eyes. Of particular note, in 60% of the eyes, choroidal ischemia occurred after the microcatheter tip was inserted distal to the ostium of the ophthalmic artery, suggesting that optimal microcatheter positioning involves the tip engaging with the ophthalmic ostium as minimally as is possible, while still directing injected drug toward the globe rather than into the internal carotid artery. In contrast, there was no relationship between the dose of chemotherapeutic agent and occurrence of ischemia.⁴⁷ Ancona-Lezama and colleagues reported a case of choroidal ischemia occurring after secondary IAC but sparing the watershed zone, suggesting the possibility of uneven drug distribution into the posterior ciliary arteries.⁴⁸

Other vascular complications—including retinal vasculopathy, choroidal occlusions, ophthalmic artery occlusions, and retinal vein or artery occlusions—can occur along with choroidal ischemia or separately and have been widely described.^{14,17,18,21,22,29,31,32,35,40-45,47,49} Stathopoulos and colleagues documented 35 patients with acute choroidal ischemia. Four of those patients developed concurrent vascular complications; 2 patients had central retinal artery occlusion (CRAO), 1 patient had mixed central retinal artery and vein occlusion, and 1 patient had mixed central retinal artery and branch vein occlusion.⁴⁷ In a large retrospective study of 166 eyes treated with either primary (first-line therapy) or secondary (salvage therapy) IAC, Ancona-Lezama and colleagues found several different vascular toxicities, including retinal vasculature attenuation, peripheral pruning, branch retinal artery occlusion, central retinal artery occlusion, macular ischemia, optic disk pallor, retinal pigment epithelium (RPE) atrophy, and CRAO. The most common vascular complications in this series were CRAO (7% of eyes) and RPE atrophy (4% of eyes). There was no significant difference in vascular events between the cohorts treated with primary and those treated with secondary IAC.⁴⁶ Optic nerve infarction as a result of these vascular complications may occur (Figure 3). In a histopathological review of 23 enucleated eyes with retinoblastoma treated with IAC by Biewald and colleagues, 13 eyes (56.5%) displayed signs of toxic vasculopathies. CRAO occurred in 3 eyes, severe perivascular inflammation in 3 eyes, and choroidal ischemia in 7 eyes. One patient developed a severe vascular reaction, with acute retinal necrosis accompanied by proliferative retinopathy and vitreous hemorrhage, necessitating enucleation.⁴⁵ Finally, ophthalmic artery vasospasm after IAC has also been described.^{14,22,27,35,50}

Figure 3. At diagnosis of three peripheral tumors located at 7:00, 12:00 and 1:00 (not pictured here), the posterior pole of the left eye (A) appeared unremarkable. After the third intra-arterial chemotherapy delivery, the child returned to the emergency department with acute loss of vision within 2 days but an unremarkable posterior segment. Vascular compromise of the ophthalmic artery or its posterior ciliary branches was suspected due to treatment. The optic nerve and inferior temporal retina atrophied (B) over several weeks.

A number of researchers have also reported posterior segment and retinal complications after IAC. Vitreous hemorrhage has been detailed in many reports.^{14,17-19,21-24,29,30,32,39,40,42-44,46,49} Although vitreous hemorrhage itself is not a serious complication and usually resolves over time, it is significant in retinoblastoma patients because it may impact disease surveillance. Rates of reported vitreous hemorrhage range from 3.6%³⁹ to 41.2%.²¹ In 1 study, Ong and colleagues reported vitreous hemorrhage in 7 of 17 eyes treated with IAC. Three of the patients had accompanying neovascular glaucoma, and 5 eyes were enucleated. Hemorrhage in 1 patient resolved gradually.²¹ Vitreous hemorrhage and opacity were also demonstrated on MRI in patients treated with IAC. Chen and colleagues reported vitreous hemorrhage in 4 of 60 patients (6.7%). Contrast-enhanced T1 imaging can be particularly useful in identifying tumor characteristics and progression if vitreous hemorrhage occurs.⁴⁴

Another complication identified by multiple authors was retinal detachment, with rates ranging from 1.4%³² to 57%.⁴⁴ In a comparative study of IAC and intravenous chemotherapy as a first-line treatment, Munier and colleagues found similar rates of secondary retinal detachment developing in each cohort. Nine of 25 eyes in patients who received IAC experienced a detached retina, with 5 total, 3 partial, and 1 peritumoral detachment.²⁴ Batu Oto and colleagues detailed 1 patient with group C retinoblastoma and retinal detachment after IAC, which was successfully treated with scleral buckling.²⁹ Furthermore, Potic and colleagues conducted a retrospective study analyzing 30 eyes with advanced retinoblastoma (ICRB group D to group E) and the development of rhegmatogenous retinal detachment after IAC. Before IAC treatment, 11 of 30 eyes had preexisting retinal detachment and 19 eyes had none. After treatment with IAC, 16 of the 19 eyes with no retinal detachment developed the condition (9 total, 6 subtotal, and 1 localized). The average time between the beginning of the retinal detachment and the treatment with IAC was 41 months.⁵¹ Ventura and colleagues presented a case report of an 8-year-old girl with group E unilateral retinoblastoma who developed a giant retinal tear and rhegmatogenous retinal detachment after IAC. The rapid necrosis of tumors after treatment with IAC can cause secondary retinal detachments as tractional force is applied by the shrinking tumor to the retina.⁵² Another retinal complication seen after IAC is subretinal hemorrhage.^{17,18,20,26,40,44,46,49} In one report, Hua and colleagues detailed subretinal hemorrhage in 11% of children treated with IAC.¹⁷

Several less common intraocular side effects have also been reported in the IAC literature. Cataract formation following treatment with IAC was first reported by Suesskind and colleagues in 2014. In their case report, a diffuse dense cataract developed after the fifth cycle of IAC, which made funduscopy impossible. They postulated that the cataract formed due to chemotherapeutic toxicity or cumulative radiation exposure. Ultimately, tumor factors and the inability to visualize the retina forced enucleation of the eye.⁵³ Other reports have mentioned cataract, with Rishi and colleagues documenting Grade 2 posterior subcapsular cataract in 2 of 15 eyes treated in a retrospective review of 4 years of IAC experience in India.^19,24,42,44 Another adverse effect reported by some authors was bulbar conjunctival congestion.^17,18,21,31 In a retrospective review of 107 eyes in patients who underwent IAC, Chen and colleagues detailed 32 cases of conjunctival congestion (29.9%).¹⁸ Other rarer side effects found included papilledema,^25,39 iris atrophy,⁴² neovascularization,²⁴ and retinal pigment epithelium hyperpigmentation.³⁵

Discussion

IAC has become a leading primary and secondary treatment for retinoblastoma, with impressive results in salvaging eyes with advanced intraocular retinoblastoma.^14,16,39,54 IAC cures retinoblastoma and spares patients’ eyes that would otherwise have undergone enucleation. We anticipate that IAC will be leveraged increasingly as a primary treatment for group E and select bilateral retinoblastomas, representing a paradigm shift in the treatment for this disease.¹⁶ Much of the excitement surrounding IAC comes from its relatively favorable safety profile when compared with traditional retinoblastoma treatments, including external-beam radiotherapy and intravenous chemotherapy. Our systematic review was intended to highlight treatment-related adverse effects of varying severity.

In the articles we reviewed, no deaths, secondary cancers, or lasting neurological complications were associated with IAC. The most common systemic and extraocular adverse effects were transient. In the short term, fever, nausea, and periprocedure hemodynamic instability were common. The dramatically differing rates of hemodynamic instability between healthcare centers remain unexplained, but the phenomenon is universally transient in all reports. As long as the anesthesia teams treating patients undergoing IAC are prepared for the possibility of this adverse event, there should be little concern for long-term morbidity. Eyelid edema, forehead redness, and ptosis were also relatively common but resolved within weeks or months. However, reports of potentially irreversible complications, such as choroidal ischemia, were not uncommon. Such side effects, which can lead to permanent visual loss and blindness, are particularly important to consider in an eye with good visual potential.

Some complications of IAC can be attributed to technique error, while others are likely a consequence of toxicity from the chemotherapeutic agents. Some complications, including puncture site adverse effects (such as blue toe syndrome), are results of technical mishaps related to cerebral angiography in infants and very young children.⁵⁵ Ammanuel and colleagues reported fewer complications after revising safety protocols for IAC to use smaller sheaths, no guide catheter, and faster administration of chemotherapy.²⁸ As Stathopoulos and colleagues demonstrated, the incidence of choroidal ischemia and other retinal vascular events is linked to the position of the catheter in the ophthalmic artery. Technique, not chemotherapy dosage, correlated with instances of choroidal ischemia.⁴⁷ However, Reddy and colleagues argued that dosage may be as important as technique in reducing visual loss and severe complications after IAC, with fewer adverse effects occurring when age-adjusted doses of melphalan are used.⁴¹ In a rabbit model comparing ocular and systemic adverse events after intra-arterial instillation of saline versus melphalan versus carboplatin at various doses, high-dose melphalan and carboplatin were found to be associated with histological and ERG-related retinal morbidity, whereas standard-dose melphalan and infusion of saline were not.⁵⁶

Compounding efforts to identify the complications’ contributing factors, there is wide heterogeneity of technique between centers, each element of which can have a major impact on adverse events. These include the approach to groin puncture; caliber, shape, and characteristics of the specific microcatheters used; the placement of the microcatheter relative to the ophthalmic artery ostium; the instillation of chemotherapy via the ophthalmic versus external carotid branch collaterals to the ophthalmic circulation; the length of time over which the chemotherapy is injected (which in turn affects the dwell time of the microcatheter within the ophthalmic artery); and the chemotherapeutic regimen used. Further studies are needed to establish the mechanisms of IAC-related adverse effects and tailor techniques to mitigate them. Moving forward with IAC, it is important to consider both complications related to technique and those related to the inherent toxicities of chemotherapeutic drugs and dosages.

The connection between technique and adverse effects suggests a “learning curve” in IAC administration, with procedure-related complications decreasing as experience increases.^16,41,57 In a comparative study of complications between the “early IAC era” (2009–2011) and the “recent era,” Dalvin and colleagues found a significantly reduced burden of adverse effects in more recent procedures. Ophthalmic vascular events decreased from 59% per eye from 2009–2011 to 9% per eye in recent times. Although not statistically significant, vitreous hemorrhage decreased from 9% to 2%, and no vascular events occurred after IAC in 72 consecutive procedures from 2016–2017.⁴⁹ More broadly, the vast majority of neurointerventionalists treat adult patients (and occasionally teenagers) nearly exclusively, with infant patients being extraordinarily rare exceptions. Thus, performing IAC safely in the young patient cohort for whom retinoblastoma manifests requires significant alteration of and attention to pediatric neurointerventional techniques. In this regard, we would focus particularly on the large cohort report of Hoffman and colleagues (Complications of cerebral angiography in children younger than 3 years of age. J Neurosurgery Pediatrics 2014, 13:414), from the Cornell group that pioneered IAC. Of the reported 309 procedures, 292 were performed specifically for intra-arterial chemotherapy, and the mean age of the patients was 14.4 months. There were 0 neurological complications, 1 groin hematoma, and 1 transient femoral artery occlusion, an apt example of the low morbidity achievable by experienced pediatric oncologists.

On a related note, potential adverse effects of IAC that may not manifest for years are those related to radiation exposure from this fluoroscopically guided technique. Such exposure is of concern for any young pediatric patient but particularly for those with Rb gene mutations. Several experienced groups have recently reported the radiation dose of their patient cohort in conjunction with details of their technique,^58-60 and 1 recent report⁵⁰ compared the radiation doses from 5 distinct neurointerventional protocols, demonstrating >90% dose reduction through technique optimization by the same practitioners. As with other technique-related adverse events, neurointerventionalists with significant pediatric experience are more highly attuned to radiation exposure minimization in their patients than are adult-only practitioners.⁶¹ These results accentuate the importance of experience when performing IAC.

Limitations of this review include a focus on complications reported in the literature, most of which are detected during or shortly after IAC. Also, most reports did not provide information about long-term complications. It is unknown whether recurrence rates or patterns may be different in IAC-treated eyes, compared with those given systemic treatment or radiation treatment, necessitating close follow-up of these patients. When eyes with advanced disease are treated with IAC, there is some concern about lack of effective systemic treatment if there is already choroidal or post-laminal involvement, posing a risk of (untreated) metastatic disease, which can lead to death. Metastatic disease and failure rates for globe salvage were beyond the scope of this review. Finally, more studies are needed to further elucidate the causes of IAC adverse effect, potentially allowing for technique modification to increase safety.

As experience worldwide with IAC increases, we anticipate a continuing increase in number of treating centers, and hopefully a decrease in procedure-related adverse effects. The role of IAC in retinoblastoma management will expand across the world, and continued attention must be directed at understanding and reducing complications without compromising efficacy.

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