The first reports of intra-arterial chemotherapy (IAC), also known as superselective artery chemotherapy or chemosurgery, were published in the 1950s and 1960s for inoperable intracranial, head and neck, and genitourinary cancers. During the last 20 years, IAC has revolutionized the way oncologists manage select solid tumors, predominantly because it allows targeted therapeutic doses of chemotherapeutic agents without the expected toxic effects associated with conventional systemic delivery.^1-3 Intra-arterial chemotherapy is currently being used for multiple solid tumors, including hepatocellular carcinoma, pancreatic cancer, osteosarcoma, and glioblastoma multiforme. However, ocular oncologists use primary IAC more than any other specialty in medicine, mainly because of retinoblastoma.² Intra-arterial chemotherapy has also been used in the treatment of other ocular malignancies, including adenoid cystic carcinoma and unresectable orbital tumors.^4-6 The following article will review the history, surgical technique, pharmacotherapy, contraindications, adverse effects, and outcomes of IAC for retinoblastoma.

HISTORICAL PERSPECTIVE

Despite no substantial double-blind randomized controlled trial for retinoblastoma, primary treatment has evolved over the last 50 years from enucleation to external beam radiotherapy to chemotherapy (intravenous and IAC). The introduction of modern IAC in the treatment of retinoblastoma is credited to the work of Kaneko et al from Japan. In 1987, Inomata and Kaneko found via clonogenic assay that melphalan was superior to other established chemotherapeutic agents.⁷ However, the systemic therapeutic dose of melphalan for retinoblastoma was limited due to severe myelosuppression. To circumnavigate toxicity concerns, Yamane et al pioneered an endovascular technique to deliver melphalan at therapeutic doses directly to the ophthalmic artery circulation with minimal systemic toxicity. Their initial publication described balloon occlusion of the internal carotid artery distal to the ophthalmic artery. This allowed rapid (4 minutes) infusion of melphalan, minimizing cerebral ischemia, into the ophthalmic artery and other proximal arterial branches with a technical success rate of 97.5%.⁸ This remarkable achievement paved the way for Gobin et al to hone the technique using direct catheterization of the ophthalmic artery.⁹ After publication of the initial outcomes by Gobin et al, a worldwide interest in IAC has followed. Currently, IAC is used in some centers as primary, secondary, tandem, and rescue therapy in retinoblastoma treatment.

INTRA-ARTERIAL CHEMOTHERAPY TECHNIQUE

An experienced neurointerventional radiologist or endovascular neurosurgeon typically performs IAC for retinoblastoma under general anesthesia. The procedure can be performed in the outpatient or inpatient settings. Intravenous heparin is used for anticoagulation prior to the start of the procedure. Topical phenylephrine and intranasal vasoconstrictors may be used along the distribution of the supratrochlear artery to minimize chemotherapy delivery to the forehead and nose. The Seldinger technique is then used to access the ipsilateral femoral artery with a 4-French pediatric arterial sheath. Using fluoroscopy, the catheter is then guided to the ostium of the ophthalmic artery. Angiography is then performed to confirm the correct location and a patent ophthalmic artery vasculature, as well as to minimize any significant inadvertent reflux of dye into the cerebral circulation (Figure 1). Chemotherapeutic agents are then diluted in normal saline and manually injected slowly over 20-30 minutes in pulsatile fashion. After conclusion of the infusion, a repeat angiogram is performed to document a patent arterial flow and exclude a thromboembolic adverse event. If tandem IAC is performed, the catheter is then retracted to the level of the aorta and redirected to the contralateral internal carotid artery. It is important to note that the use of a guidewire should be avoided to minimize trauma to the ophthalmic artery. If the ophthalmic artery becomes sclerotic after multiple cycles or if it cannot be identified, the middle meningeal artery, a branch of the external carotid artery, may provide an alternative access to the ophthalmic artery.

After completion of the procedure, topical corticosteroids and oral aspirin (1-2 mg/kg body weight) may be prescribed to minimize forehead erythema and thrombotic events. Follow-up blood work 1 week after the procedure is typically performed to evaluate myelotoxicity that may occur in 10% to 20% of patients when the maximal systemic dose of melphalan is used (0.5 mg/kg).

PHARMACOTHERAPY

The initial study by Yamane et al used melphalan monotherapy during IAC mainly because the data from the clonogenic assay showed superior tumoricidal effects.⁸ Most recently, many centers are using melphalan, carboplatin, and topotecan triple therapy to reduce therapeutic resistance and increase the tumoricidal effects at different points in the cell cycle (Table 1).¹⁰

Melphalan, an alkylating agent, is the most important agent used during IAC, and it should be the first drug infused during the procedure in case vasospasm develops during IAC infusion. Systemic doses equal to or less than 0.5 mg/kg may cause mild neutropenia in approximately 15% of patients.¹¹ However, higher doses may cause severe myelosuppression that may require supportive care including recurrent blood transfusion.¹ Therefore, attention to dosing in children who weigh less than 15 kg is imperative. Children with bilateral retinoblastoma who are undergoing tandem therapy are particularly important and may not be able to receive melphalan in both eyes at every session. The typical dose of melphalan ranges from 3 mg to 7.5 mg depending on age, weight, and surface area.

Topotecan, a topoisomerase 1 inhibitor and camptothecin analog, works by destabilizing the S phase of the cell cycle and producing potentially lethal double-strand DNA breaks when encountered by the DNA replication machinery. Topotecan has less local tissue toxicity when compared to melphalan and carboplatin. Due to the limited toxicity to healthy tissues, it has gained popularity as adjuvant intravitreal and periocular chemotherapy. The recommended dosage is 0.3 mg to 2.0 mg.

Carboplatin, an alkylating agent and second-generation platinum compound, has been part of the treatment of retinoblastoma for decades because it is part of the classical 3-drug intravenous regimen (carboplatin, etoposide, and vincristin). Carboplatin was developed to provide similar effects to cisplatin with fewer side effects, particularly nephrotoxicity and ototoxicity. When performing tandem IAC, one eye may receive melphalan monotherapy and the other carboplatin and topotecan to minimize cumulative toxicity if weight precludes higher doses. The recommended dosage is 15 mg to 40 mg.

TREATMENT PROTOCOL

To date, no universal protocol exists. However, most centers utilize the maximal dose of melphalan tolerable based on the patient’s weight and height as well as the surface area and extent of the disease. The most widely accepted IAC treatment cycle interval is 4 weeks. The number of IAC sessions varies based on tumor classification and treatment center. In our hands, many unilateral group B/C tumors may respond well to 3 cycles. However, group D/E tumors and bilateral cases may require additional cycles. We utilize melphalan, carboplatin, and topotecan triple therapy in all unilateral cases. In bilateral cases we may need to alternate agents (eg, melphalan monotherapy to the right eye and carboplatin and topotecan combination to the left eye) every month due to systemic toxicity concerns. All patients also undergo monthly examinations under anesthesia and 810 nm large diode laser transpupillary thermotherapy to all active tumors.

CONTRAINDICATIONS

The most important contraindications for IAC are poor visualization of the tumor or suspected extraocular extension. Eyes with neovascular glaucoma, intraocular hemorrhage, orbital inflammation, prephthisical components, optic nerve extension, or extrascleral extension should avoid IAC. Because IAC is local, there is risk of systemic micrometastasis in advanced intraocular disease. Patients with extraocular extension require systemic chemotherapy, external beam radiation, and/or bone marrow transplant.

ADVERSE EVENTS

The most important breakthrough associated to IAC for retinoblastoma was increased tumoricidal effects without the systemic morbidity associated with intravenous chemotherapy. However, mild to moderate myelosuppression may develop starting 7 to 10 days after treatment. Blood transfusion are rare but may be needed in less than 1% of cases. Spasm of the ophthalmic artery is the most common reason leading to aborting the procedure. Strokes and cerebral ischemia are rare but serious potential complications.

The most common ocular side effects include periorbital edema, orbital inflammation, and forehead hyperemia.^2,12-15 Topical phenylephrine and intranasal vasoconstrictors can minimize these local self-limiting events. Third and sixth nerve palsies, ptosis, and focal madarosis have also been reported. The risk of severe visual loss and blindness due to vascular events increases with the number of cycles.¹² A recent study found the total incidence of ophthalmic artery thrombosis was 11.1% (23/208).¹² Other risks include optic neuropathy, ischemic and occlusive chorioretinopathy, central retinal artery occlusion, vitreous hemorrhage, and retinal detachment.^13,14

CLINICAL OUTCOMES

One of the initial IAC studies performed by Gobin et al reported 95 eyes with retinoblastoma. Catheterizations were successful in 98.5% (255 of 259 infusions) of cases. The mean number of infusions was 3.1 (median 3, range 2-7).⁹ For group RE V eyes, Kaplan-Meier estimates of ocular event-free survival at 2 years was 66.5% for all eyes, 80.5% for eyes that received IAC as a primary treatment, and 51.5% for eyes that previously received intravenous chemotherapy and/or external beam radiotherapy. Median follow-up was 13 months (range 1-29 months). Two children developed metastatic disease. None of the RE I-IV eyes required enucleation, but 19 of 83 RE V eyes were enucleated. The study concluded that IAC was safe and effective for the treatment of retinoblastoma.

Large studies have validated that eyes with virtually all group B and C tumors can undergo globe salvage with IAC and focal laser consolidation (Figures 2 and 3). The most important benefits are apparent in group D and E eyes.^11,16-18 Shields et al compared IAC (n=49) to intravenous chemotherapy (n=42) treated eyes with unilateral retinoblastoma. Eye salvage rate was significantly higher (91%) in group D eyes with IAC, compared with the intravenous chemotherapy group (48%).¹⁶ Another study by Munier et al comparing IAC to intravenous chemotherapy in group D eyes showed 100% globe salvage with IAC and 60% with intravenous chemotherapy.¹⁷ Peterson et al also reported similar outcomes in advanced retinoblastoma.¹¹

Most recently, a single-center study that evaluated 341 eyes treated with 1,292 consecutive infusions of IAC as primary or secondary therapy for retinoblastoma found 5-year overall globe salvage to be 76%, including 100% for groups B and C, 86% for group D, and 55% for group E.¹⁸ When IAC was used as secondary therapy, overall 5-year globe salvage was 71%. Younger patients had a higher rate of globe salvage. There were no patients with metastatic disease or death after 5 years of follow-up.

CONCLUSION

Retinoblastoma continues to represent a diagnostic and therapeutic challenge. Intra-arterial chemotherapy has created a paradigm shift, particularly in advanced retinoblastoma. These developments in retinoblastoma chemotherapy delivery have shifted attention to individualized treatment focused on preserving visual and anatomic function.¹⁹ Understanding the technique, dosing strategies, and potential adverse effects is critical to having optimal outcomes. Economic and technological hurdles may continue to limit availability of IAC in developing countries.²⁰ However, future studies will evaluate long-term systemic, globe, and visual outcomes associated with IAC. RP

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