21.2.1 History

A 9-month-old boy was found to have a white right eye on photographs and diagnosed with a unilateral retinoblastoma of the right orbit on ocular ultrasound and magnetic resonance imaging (MRI) scans. After an initial evaluation by an ophthalmologist and a pediatric oncology team, it was found that the tumor was not a candidate for more conservative methods of control (i.e., cryotherapy, thermotherapy, or plaque radiotherapy). The family elected to defer enucleation as an initial treatment.

Past medical history: Noncontributory.

Past surgical history: Noncontributory.

Family history: No history of retinoblastoma or other cancers within the family.

Social history: Noncontributory.

Examination: Well-developed, well-nourished child in no acute distress. Unremarkable neurological examination. Ocular examination demonstrates a large macular retinoblastoma (Fig. 21.1).

21.2.2 Clinical Course

After a thorough discussion with the multidisciphnary team and the patient’s family, the plan was made to proceed with IAC with melphalan (Fig. 21.2). Follow-up ophthalmological examinations after the first treatment demonstrated complete regression of the retinoblastoma (Fig. 21.3).

21.4.1 Endovascular Technique

Currently, this treatment is employed for retinoblastoma patients as primary treatment for unilateral or bilateral retinoblastoma, and as secondary treatment following failure from other treatments. Under general anesthesia, the site of cannula-tion in the femoral artery is prepped in a sterile fashion avoiding the use of cotton material in order to prevent foreign body microembolization.

A pediatric arterial sheath is placed at the femoral artery. Anticoagulation with heparin is utilized with activated clotting time (ACT), being 2 to 2.5 times the normal at all times. No guidewire is used in this procedure. Selectively, the internal carotid artery is catheterized with a greatly flexible Marathon Flow Directed MicroCatheter (Medtronic, Minneapolis, Minnesota, ev3, Covidien, USA). An internal carotid artery injection is then performed to visualize the cerebral vasculature and to select the best approach showing the takeoff of the ophthalmic artery from the internal carotid artery. Then, the same micro-catheter is guided all the way toward the origin of the ophthalmic artery. The ophthalmic artery is the first intracranial branch of the internal carotid artery. Using fluoroscopic guidance, the ostium of the ophthalmic artery of the affected eye is subsequently superselectively catheterized. Due to the angle of origin of the ophthalmic artery, this turn of the catheter tip is technically challenging and requires proficiency and expertise. ¹ Once the microcatheter is in stable position at the ostium of the ophthalmic artery, a superselective injection is formed to confirm the catheter positioning, to make sure that there is no reflux of contrast in the carotid artery and, if there is, to gauge the pressure of injection to avoid such a reflux.

Once the catheter positioning is confirmed, chemotherapy is delivered. The drugs are diluted in 30 mL of normal saline and are injected very slowly over 30 minutes at the rate 1 mL/min. The chemotherapy injection is pulsatile to avoid drug streaming (varying drug concentration due to laminar flow in arteries) and to deliver drug homogeneously. After the injection of each chemotherapeutic agent, an angiogram of the globe and brain is performed to rule out an embolic or hemorrhagic complication. The contrast is flushed with saline, and the microcatheter is then slowly withdrawn from the ophthalmic artery, the guide is removed, protamine is administered to reverse the heparin effect, and hemostasis is achieved at the femoral puncture site with 30 minutes of manual compression. The entire procedure (including time of injection of chemotherapy) takes 1 to 5 hours depending on the vascular anatomy of the patient. The child has to be on complete bed rest for 6 hours with a temporary cast in the leg to avoid bleeding from the femoral site. Oral aspirin is usually given in the dose of 1 to 3 mg/kg for 2 weeks to prevent vascular thrombosis, and topical atropine is given for 1 week.

Alternative catheterization technique in the event of failure to selectively catheterize ophthalmic artery includes ² :

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  Utilization of a 4 French (F-13-mra diameter) pediatric arterial sheath. Catheterization of the internal carotid artery with 4 French Berenstein II pediatric guide (Cordis Neurovascular, Miami Lakes, Florida). Then, the ophthalmic artery is superselectively catheterized with a microcatheter (Prowler 10) (Cordis Neurovascular, Miami Lakes, Florida) and a microwire (Synchro 10) (Boston Scientific, Natick, Massachusetts).

  
  
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  Catheterization of the ipsilateral middle meningeal artery, in 3 to 5% of the patients, the ophthalmic artery arises from the middle meningeal artery instead of the internal carotid artery. ³

  
  
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  Utilization of the Japanese technique which involves placement of a temporary balloon to occlude the internal carotid artery prior to delivery of chemotherapy. With this technique, the chemotherapy is infused much more rapidly because of the limitation of occlusion of the internal carotid artery. This technique likely results in more widespread delivery of the chemotherapy.

For bilateral cases, both eyes have been treated in the same session. After infusing chemotherapy in one eye, the catheter is retracted to the aorta and then advanced to the contralateral internal carotid artery and ophthalmic artery. Caution is advised to dose the chemotherapy to avoid cumulative toxicity. ⁴ Munier and coworkers cautioned against the use of this technique of bilateral IAC as there is risk of causing sight threatening vaso-occlusive complications, potentially in both eyes. ⁵

21.4.2 Medications

The pharmacological advantage of IAC is the first pass of the drug through the tumor circulation prior to reaching systemic circulation. Certain characteristics of medications that are advantageous for intra-arterial administration are high extraction fraction within target organ, high capillary permeability, and rapid systemic metabolism. ¹ The drug dosage is determined by the ocular size and not by the body weight. ⁶

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  Melphalan is a nitrogen mustard alkylating agent. In experimental studies, retinoblastoma cell lines were very sensitive to this drug, but it was not used systematically due to severe adverse effect profile. ⁷ In the IAC technique, the systemic absorption is minimal, and melphalan has become the primary chemotherapeutic agent. Melphalan is ideally suited for this technique because of its short half-life of 1.5 hours. ²

  
  
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  Topotecan belongs to the group of topoisomerases I inhibitor. Topotecan has shown effective activity against retinoblastoma in mouse models ⁸ and has been used systematically for metastatic retinoblastoma with other chemotherapeutic agents. ⁹

  
  
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  Carboplatin is an alkylating agent, is the primary drug of choice for systemic chemotherapy, and is also used as a periocular chemotherapeutic agent.

  
  
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  Methotrexate is an antimetabolite and has been used for the treatment of systemic retinoblastoma and pinealoblastoma.

  
  
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  Digoxin belongs to the class of cardenolides and has been in use for many years to treat congestive heart failure. Antczak and associates studied the effect of cardenolide ouabain in a xenograft model of retinoblastoma. In their experimental model, they found complete regression of the tumor in 14 days with no evidence of toxicity even at high doses. ¹⁰ Based on the preclinical study, Patel and coworkers reported the use of systemic and intra-arterial digoxin, but documented measurable, although incomplete, tumor regression with intraarterial digoxin. They suggested further clinical trials to evaluate the dosage and utility of digoxin in the management of retinoblastoma. ¹¹