Correlation of Technical and Adjunctive Factors with Quantitative Tumor Reduction in Children Undergoing Selective Ophthalmic Artery Infusion Chemotherapy for Retinoblastoma

DISCUSSION

To our knowledge, this is the first study that describes QTR and its derivative DTR, as metrics of SOAIC therapeutic efficacy. QTR uniquely enables one to measure the effect of individual treatments differentiated by technical factors (ie, CIT). In contrast, the ocular salvage rate is determined by the cumulative effect of multiple treatments with variations in technical factors that are difficult or impossible to control. Our focus on first-cycle SOAIC in previously untreated patients allowed us to eliminate confounding effects of prior treatment and isolate the impact of the neuroendovascular technique.

Our study reveals a correlation of IAV with satisfactory DTR. This correlation was significant for the aggregate population and a subgroup treated by SOAIC with <5 mg of single-agent melphalan (Fig 2). Furthermore, the average QTR was higher for first-cycle SOAIC performed with IAV (P < .01) in the latter subgroup. These associations eliminate doubt that the benefit of IAV was due to unequal distribution of differentially effective chemotherapeutics. Although IAV was associated with the late epoch, we found no correlation between DTR and epoch to suggest that the benefit of IAV was attributable to increasing experience of the operating team.

IAV enhancement of therapeutic efficacy could be related to augmentation of ocular perfusion, chemosensitization, or both. Verapamil has potent long-lasting vasodilator actions when administered by the arterial route.⁸ Because the tumoricidal effect is proportional to tumoral perfusion with chemotherapeutics, vasodilation in target tissue may enhance therapeutic efficacy. Laboratory and clinicopathologic studies have demonstrated that verapamil inhibits membrane-associated glycoproteins, conferring multidrug resistance to retinoblastoma cells and that expression of these glycoproteins by retinoblastoma is associated with treatment failure.^9⇓⇓-12 Biochemical studies show that these verapamil-sensitive glycoproteins actively export melphalan, rendering retinoblastoma cells resistant to the chemotherapeutic activity of melphalan.¹³ Owing to this mechanism, the chemosensitizing potency of verapamil is blunted at higher melphalan doses.^14,15 The results of our study are consistent with that paradigm (Fig 2).

The chemosensitizing tissue concentration of verapamil cannot be safely established by oral or intravenous routes, but the pharmacokinetics of superselective intra-arterial administration make it achievable. Others have leveraged intra-arterial administration strategies to commission the chemosensitizing properties of IAV.^16,17 Another property of verapamil underlies an anatomically specific advantage unique to the retina. Extensive research has demonstrated that verapamil is actively transported across the blood-retina barrier by retinal pigment epithelium proteins.^18,19 Thus, a combination of pharmacokinetic and molecular transport effects may enable chemosensitization with IAV during SOAIC.

In the current series, 2 of 25 children treated with IAV experienced hypotension. Both were infants younger than 12 months of age. Notably, some authors advise against intravenous verapamil administration in infants younger than 12 months of age due to a paucity of safety data.²⁰ Despite such recommendations, intravenous verapamil dosed at 100–200 µg per kilogram for 2 minutes remains the preferred treatment for some types of cardiac dysrhythmia in infants.²⁰ While most agree that the risk of verapamil toxicity is very high during the first 6 weeks of life, there is no evidence that the use of intravenous verapamil in older infants is unsafe.^20,21 The incidence of hypotension in this series is substantially lower than that reported in other series of SOAIC.²² In those series, IAV was not given, and procedural hypotension was related to autonomic reflexes associated with OA catheterization.²² It is possible that intraoperative hypotension in the current series was at least partially related to autonomic responses.

INA was not correlated with a therapeutic response in this study. INA has been used to limit perfusion of the sinonasal mucosa with chemotherapeutics during SOAIC. Theoretically, perfusion of the sinonasal mucosa through ethmoidal branches of the OA can cause a steal that reduces delivery of chemotherapeutics to the retina and may cause mucosal injury resulting in epistaxis.²³ Two infants receiving INA in the current study experienced procedure-related adverse events related to vasoconstriction (1 cerebral and 1 ophthalmic). Although OA spasm during SOAIC is primarily related to mechanical stimulation, the striking association of INA with increased FT in this study raises the possibility that INA may be a contributory factor and that off-target vasoconstriction caused by INA may interfere with OA catheterization. One patient in the current study demonstrated findings concerning for reversible cerebral vasoconstriction after administration of INA, which cannot be attributed to vessel instrumentation. Reversible cerebral vasoconstriction associated with concomitant administration of oxymetazoline and phenylephrine-containing eye drops during SOAIC has been reported in another patient.²⁴

ECBO is used to optimize ocular hemodynamics during SOAIC because it ensures continuous anterograde OA flow throughout the entire period of chemotherapeutic administration, regardless of microcatheter injection pressure or the patient’s blood pressure.¹ The direction of OA flow during SOAIC is assessed by angiography and by subtracted fluoroscopic monitoring of contrast media injected through the treating microcatheter in a manner that simulates chemotherapy administration.¹ In children with well-developed external carotid artery-to-OA collaterals, OA flow may be frankly retrograde throughout the entire angiographic cycle. Alternatively, competitive retrograde inflow from external carotid artery collaterals may only be transiently revealed in the delayed phase of angiography as the angiographic injection pressure falls. Under these circumstances, all or some of the administered chemotherapeutic misses the tumor target and refluxes into the cerebral circulation. Another approach intended to overcome competitive flow from external carotid artery collaterals involves administration of chemotherapeutics through the dominant competing external carotid artery collateral, which is frequently the orbital branch of the ipsilateral middle meningeal artery. Advancing a microcatheter deep into such a collateral vessel often produces a pressure gradient that promotes blood flow in the collateral vessel to move toward the external carotid artery, away from the OA. Under these conditions, chemotherapeutic infusion is administered against the direction of arterial flow in the microcatheter-bearing collateral vessel. Moreover, external carotid artery anastomoses with the OA are often distal to the origin of the retinociliary trunk (parent vessel of the central retinal artery and posterior ciliary arteries). This anatomy makes a chemoinfusion administered through the external carotid artery branch countercurrent with blood flow entering the ostium of the OA origin from the internal carotid artery. In order for the chemotherapeutic to reach the retinal circulation under these circumstances, it must overcome a potentially stronger countercurrent flow from the internal carotid artery. As a result, administration of chemotherapy through external carotid artery collaterals trades one source of competitive countercurrent flow with alternative sources of countercurrent flow. We favor ECBO for the management of competitive countercurrent flow encountered during SOAIC because it completely suppresses all sources of countercurrent flow, without introducing new ones. Nonetheless, if the orbital branch of the middle meningeal artery is highly dominant and OA catheterization is challenging, administration of chemotherapy through the orbital branch of the middle meningeal artery may be preferable.

ECBO was not correlated with QTR or DTR in this study. However, because our practice was to perform ECBO in patients with intermittent or continuous OA flow reversal, selection bias likely masked the benefit. ECBO was associated with 11 minutes of additional FT in this study due to the need for fluoroscopy guidance during balloon catheter positioning, inflation, re-adjustment of the balloon during chemoinfusion, and deflation. This amount of added FT may not be significant, depending on the advantage provided by ECBO in any given case. Although there were no adverse events directly attributable to ECBO, our only 2 access site complications occurred in patients undergoing ECBO (Online Table 7). Notably, our method of ECBO relies on bifemoral arterial sheath placement, and patients undergoing ECBO were notably younger. These features raise the possibility that there is a tendency toward retrograde OA flow in younger patients because the ratio of extracranial vascular resistance to cerebrovascular resistance is elevated in early childhood. Indeed, transcranial Doppler studies provide indirect evidence of this.²⁵ It is also possible that age-related changes in OA anatomy may contribute to hemodynamic variations encountered in children. Perhaps expansion of the calvaria and bony orbit in early childhood cause physical displacement of OA anastomoses from corresponding external carotid artery feeders, resulting in developmental involution of anastomoses with maturation of the cranial skeleton. In any case, additional study is warranted to further investigate the safety and potential therapeutic advantage of ECBO.

As reported by others, our approach to SOAIC involves manual infusion of the total chemotherapy dose in a volume of 30 mL.^1,23 Although most operators strive to administer the infusion for 30 minutes, adjustment of infusion parameters is often necessary to prevent chemotherapeutic reflux into the internal carotid artery and maximally flood the anterograde target-tissue blood volume. Consequently, CIT varies. Although tumor killing during SOAIC is proportional to the duration of tumor chemotherapeutic exposure, higher average QTR and satisfactory DTR were associated with decreasing CIT in this study, albeit the associations were not statistically significant (Fig 3). It is possible that prolonged CIT with a fixed infusion volume diminishes the therapeutic potency by allowing chemotherapeutics entering the OA to be diluted by a larger volume of inflowing blood.

All except one of the ocular, neurovascular, and cardiovascular adverse events in this series were associated with prolonged FT, and these were predominantly in infants  younger than 12 months of age (Online Table 7). The findings emphasize that longer and technically more difficult cases are associated with a generalized increase in procedure-related risks and that infants  younger than 12 months of age are particularly at risk. In our study, satisfactory DTR correlated more closely with prolonged FT than brief FT. The results suggest that even children presenting with significant technical challenges realize the full therapeutic benefit of SOAIC. It is notable that the only procedure-related retinal hemorrhage in this series complicated an SOAIC treatment involving midsegment OA catheterization. In our approach to SOAIC, midsegment OA catheterization is generally avoided because we believe that it carries a higher risk of bronchospasm, bradycardia, hypotension, OA spasm, OA dissection, retinal hemorrhage, and retinal ischemia relative to ostial catheterization. Even in the absence of OA spasm, long-segment obturation of the OA by an indwelling microcatheter (as in midsegment catheterization) may create a “wedge dynamic” that pressurizes the retinal circulation during chemoinfusion (leading to retinal hemorrhage) or restricts retinal perfusion (leading to retinal ischemia). Furthermore, procedure-related OA microdissections or intramural hematomas created by excessive OA instrumentation may evolve into a stenosis that thwarts future treatment attempts.

One weakness of this study lies in the retrospective nature of data collection and analysis. Because the details of treatment were obtained by electronic medical record review rather than imaging review, the results are susceptible to documentation inaccuracies and omissions. Another weakness is that most patients received a mixture of different adjunctive therapies, making it difficult to isolate the effect of individual adjuncts. Furthermore, some potentially confounding variations of anatomy and technique (ostial-versus-midsegment OA catheterization) were not considered in our analysis.²⁶ Because midsegment OA catheterization is rarely performed in our practice, we do not think that variations in the OA catheterization technique contributed significantly to our results. Although only 1 case of midsegment catheterization was known to occur, our study methodology did not allow us to systematically classify cases according to catheterization technique. Investigation of the catheterization technique would have required analysis of OA angiograms rather than review of reports contained in the electronic medical record. Future studies should address the potential impact of the OA catherization technique. Although the current study suggests IAV enhancement of therapeutic efficacy, the study cohort is small and further study is necessary to determine whether the added therapeutic benefit outweighs the increased risks of drug-induced hypotension.