Hemodynamic and Anatomic Variations Require an Adaptable Approach during Intra-Arterial Chemotherapy for Intraocular Retinoblastoma: Alternative Routes, Strategies, and Follow-Up

Discussion

IAC in the treatment of intraocular retinoblastoma is currently a widely accepted therapeutic strategy used in specialized centers. Theoretically, the technique of drug delivery into the OA to target the tumor is not difficult if the neurovascular interventionalist has been properly trained. Indeed, navigation of the ICA and catheterization of the OA are facilitated by the very small size of the currently available microcatheters. However, in a remarkable number of cases, the procedure is more difficult and laborious than expected and cannot proceed conventionally. In such cases, the neurovascular interventionalist is required to use a more adaptable approach to minimize technical failures and to maximize IAC efficacy.

Two technically challenging scenarios potentially undermining IAC success can be found with a certain frequency in the angiographic room. The first scenario is a troublesome and unstable catheterization of the OA ostium despite its visualization by selective angiography of the ICA. As previously reported,⁹ this situation is usually secondary to a too angulated origin of the OA from the ICA, which makes the catheterization unsteady. In such cases, resuming the balloon technique applied to the ICA has been suggested⁹ despite all its drawbacks (ie, the risk of evoking ischemic complications, dilution of the drugs in a volume of blood that is too large, the reduced time of drug perfusion). We have found that this technical problem can be overcome by just customizing the tip of the catheter; in particular, it is possible to bend it to the desired angulation to fit the anatomy of the patient. Thus, >16% of our patients have been regularly treated as scheduled without the necessity of performing the balloon-assisted occlusion of the ICA.

The second unfavorable scenario is when an adequate choroidal blush is unattainable even when OA catheterization is achieved. In this situation, the contrast medium flows back into the ICA instead of diffusing along the OA without any visible vasospam. Indeed, the reflux of contrast medium into the ICA is likely secondary to an inversion of the blood flow within the OA due to several possible anastomoses with the ECA, which may provide alternative pathways for the orbital blood supply.^12,15 In such cases, balloon occlusion of the ICA with drug infusion just below the block may not be as effective as the use of alternative routes through the ECA because the blood supply to the orbit comes just from the latter source. In children, the hemodynamic balance between the OA and the ECA may be subtle. This balance is verified by the number of eyes treated with a VP (17.2% of cases) and, when the pattern was FPEC, by the various anastomoses that, in some cases, have been used for drug delivery in the same children.

Actually, even when previous visualization of the OA has been successful, subsequent attempts to achieve an acceptable choroidal blush through the OA in the same child may fail due to momentary imbalances of the local hemodynamics in favor of the ECA, leading to an inversion of the flow. A series of unpredictable and possibly unknown factors, including vasospasm, are possibly at the basis of such phenomenona. The presence of the catheter itself into the OA origin has been suggested as a possible cause of hemodynamic disturbance leading to the activation of collateral circulations.¹⁰ Previous chemotherapy may even reduce the caliber of the OA,⁴ inducing the recruitment of blood via anastomoses with the ECA. At any rate, the presence of anastomoses between the OA and the ECA has been suspected as a variable that could negatively impact the effectiveness of the IAC.¹⁰ Far from it, we believe that the ECA and some of its branches represent potential alternative routes for IAC. In our and in others' experience,^9,16,17 some of these routes have already been used to deliver antitumoral drugs. Our study shows that 16.29% of procedures occurred via 1 of the many alternative pathways previously described and involving branches of the ECA.¹² This adaptable approach allowed us to increase the number of successful sessions of IAC. In particular, we calculated that 24.52% of eyes could have skipped at least 1 session of IAC if we had not looked for anastomotic pathways. In a retrospective review of 351 procedures of IAC, Klufas et al⁹ reported that 7.8% of IAC infusions occurred through the MMA and that in 4.7% of cases, they resumed the balloon-assisted occlusion of the ICA because a suitable anastomosis between the OA and MMA was not found.

By using other anastomotic pathways, we show that IAC can be successfully performed in a larger number of patients. Thus, a promising technique has been recently proposed to manage competitive backflow from ECA collaterals. Instead of searching and catheterizing the anastomoses between the ECA and the OA, anterograde redirection of the blood flow was achieved by balloon occlusion of the ECA.¹⁸ However, even this approach has drawbacks (puncture of both femoral arteries, 2 catheter-microcatheter systems within the same artery), and its efficacy/safety versus catheterization of the ECA branches still requires validation.

Although the use of the ECA and its branches for IAC has been previously reported,^9,16,17 its effectiveness and safety have never been demonstrated in comparison with regular IAC via the OA. Our retrospective study suggests that the use of branches of the ECA in selected cases is as effective as the direct injection into the OA in terms of ophthalmologic response (90.4% for PFO, 88.2% for VP, 77.8% for PFEC). Concerning the outcome, our results show that no statistically significant difference can be found when comparing the 3 groups. However, in light of the limited number of drug deliveries through branches of the ECA and the short follow-up, results have to be interpreted with caution and conclusions should be validated in a larger population and in a longer time perspective.

An even more adaptable approach for IAC can be applied in extremely selected cases. For instance, we artificially altered the orbital circulation, gluing some extraorbital vessels to reduce the volume of drug distribution or to create a more favorable intraorbital circulation to target the tumor. Although the desired goal was achieved and the choroidal blush was obtained, the number of cases was too low to allow a valid statistical evaluation on the efficacy of such procedures. We are aware that embolization of ECA branches is potentially dangerous even in very experienced hands because it can induce retinal or cranial nerve ischemia or stroke due to ICA reflux. However, in our case, embolizations have been performed by a skilled interventional neuroradiologist (S.B.) with experience in managing glue for arteriovenous malformations or fistulas even in the pediatric age group. In addition, this type of embolization is performed with a very small amount of glue for a proximal deafferentation.

Data concerning transient adverse events are in line with those described in other studies.^6,19⇓–21 Procedural complications, including embolic events, are rarely described in the literature,²¹ and this finding is consistent with our experience (0.4% of sessions). On the other hand, cardiac and respiratory reactions are commonly observed during this procedure. The pathophysiologic mechanism of these complications is currently unknown, likely involving an autonomic reflex.²² Most interesting, neither the cardiac and respiratory complications nor the embolic events ever occurred when patients were treated through the ECA; this finding suggests that this route of drug delivery, though more troublesome, should be considered safer than the OA cannulation.

Systemic adverse events, mainly pancytopenia, are also rare, probably due to the cumulative result from previous administration of systemic chemotherapy. Most local adverse events were transient and minor. Permanent local adverse events (chorioretinic atrophy and exotropia) were observed in 18.9% of eyes, a lower incidence compared with other reports.^3,23 Statistical analysis did not allow us to associate any adverse event with particular patterns of drug delivery. Concerns remain regarding the toxic effects of irradiation from repeat fluoroscopy in children with retinoblastoma. However, although the VP and PFEC showed higher exposure levels compared with the FPO, the overall irradiation was far lower than the toxic levels previously reported.⁸