From the Ocular Oncology Service (NN, CLS, CGB, JAS), Wills Eye Institute, and the Department of Neurological Surgery (PMJ, RHR), Thomas Jefferson University, Philadelphia, Pennsylvania.
Supported by the Retina Research Foundation of the Retina Society in Cape Town, South Africa (CLS), and the Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS).
The authors have no financial or proprietary interest in the materials presented herein.
Address reprint requests to Carol L. Shields, MD, Ocular Oncology Service, Suite 1440, Wills Eye Institute, 840 Walnut Street, Philadelphia, PA 19107. E-mail: firstname.lastname@example.org
Retinoblastoma is a curable cancer of childhood, sensitive to both radiotherapy and chemotherapy.1 Over the past 3 decades, there have been substantial advances in eye-sparing conservative treatment strategies.2–7 Intra-arterial chemotherapy is a novel treatment for eyes that have failed other therapies and in selected cases as primary treatment.2,4–6,8–12 Control is typically achieved with three or more intra-arterial chemotherapy sessions, each of which carries a potential risk for vascular compromise to the brain and eye. We present a case of complete regression of retinoblastoma following only two sessions of intra-arterial melphalan as primary therapy.
A 22-month-old girl was referred to the Oncology Service of Wills Eye Institute, Thomas Jefferson University for left leukocoria and esotropia. The child displayed intrauterine growth restriction and was born at 33 weeks by spontaneous vaginal delivery. She spent 4 weeks in neonatal intensive care without oxygen supplementation. She had mild gross motor and language delay. There was no family history of ocular cancer or blindness.
On ocular examination, visual acuity was fix and follow with both eyes. Intraocular pressures were normal in both eyes. The right eye was normal. The left eye displayed leukocoria from a large retinal mass in the macula, measuring 16 × 14 mm in basal dimensions and 6.5 mm in thickness (Figs. 1A to 1C). Subretinal fluid, blood, and tumor seeds surrounded the lesion. Ultrasonography in the left eye confirmed an acoustically solid dome-shaped retinal mass with calcification on B-scan and high internal reflectivity on A-scan. Fluorescein angiography demonstrated hyperfluorescence of the mass throughout all sequences, with vascular leakage in the late phase. These findings were consistent with the diagnosis of unilateral sporadic retinoblastoma, Group C. Genetic screening of the RB1 gene did not reveal a known mutation.
Figure 1. (A) Color Fundus Photograph Taken During Examination Under Anesthesia Showing a Large Retinal Mass, Overlying the Optic Disc and Fovea, Measuring 16 × 14 × 6.5 mm. Subretinal Fluid Surrounded the Lesion. (B) Fluorescein Angiogram Showing Prominent Tumor Vascularity with Hyperfluorescence. (C) B-Scan Ultrasonography Demonstrating an Acoustically Solid Dome-Shaped Retinal Mass with Areas of Calcification and Corresponding Posterior Shadowing. (D) At 1-Year Follow-Up, Color Fundus Photograph Showed Complete Tumor Regression to a 60% Calcified Scar Measuring 12 × 8 mm in Diameter and 1.4 mm in Thickness as Measure with Ultrasonography. (E) Fluorescein Angiogram at 1-Year Follow-Up, Showing Intact Retinal and Choroidal Perfusion Without Vascular Obstruction. (F) B-Scan Ultrasonogram at 1-Year Follow-Up Demonstrates a Flat Scar with Areas of Calcification and Corresponding Posterior Shadowing.
Institutional Review Board approval and parental consent were obtained for subsequent treatment. The patient was treated with two monthly doses of melphalan (5 mg/30 cc dilution) infused via microcatheter cannulation of the left ophthalmic artery under fluoroscopic neurointerventional guidance (Fig. 2). At 1 month following the first cycle, tumor regression to 37% of original thickness with moderate dystrophic calcification was noted. The subretinal fluid, blood, and seeds had resolved. Mild transient nausea for 2 days, eyelid edema for 1 week, left exotropia for 9 months, and decline in absolute neutrophil count to 850 cells/μL that recovered to 1,600 cells/μL within 1 month was noted immediately following treatment. During the same visit, the tumor scar was consolidated with transpupillary thermotherapy for 5 minutes at 400 to 600 mW power. At 1 month after the second cycle, the flat tumor scar was 22% of its original thickness with increased calcification. Transient nausea for 1 day and absolute neutrophil count decline to 380 cells/μL with recovery to 1,600 cells/μL within 1 month and 3,300 cells/μL by 2 months was recorded.
Figure 2. Sagittal View of Fluoroscopy During the Infusion Procedure, Showing the Microcatheter Within the Proximal Portion of the Left Ophthalmic Artery After Making a “U-turn” from the Internal Carotid Artery and Demonstrating the Left Ophthalmic Artery and Its Branches Supplying the Globe.
At 1-year follow-up, the fundus findings remained stable with a flat, 60% calcified scar measuring 12 × 8 mm at the base and 1.4 mm in depth, confirmed by ultrasonography. Retinal/choroidal perfusion was intact (Figs. 1D to 1F). Electroretinogram of the left eye showed improved amplitudes. Exotropia had resolved and amblyopia patching was tolerated for 2 hours daily.
The management of retinoblastoma has evolved substantially from enucleation and external beam radiotherapy to intravenous chemotherapy to newer methods of chemotherapy by intra-arterial perfusion. Children with retinoblastoma classified as groups A, B, and C demonstrate complete tumor control with intravenous chemotherapy (chemoreduction) in 90% or more of cases.3 The long-term results following intra-arterial chemotherapy are not yet known.
Despite satisfactory tumor control, systemic chemotherapy, whether intravenous or intra-arterial, carries risks. With regard to intravenous chemoreduction, the most common toxicities are bone marrow suppression with transient cytopenias (89%) only rarely requiring packed red blood cell transfusion or granulocyte colony-stimulating factor, fever and neutropenia (28%), and documented bacterial infection (9%).13 There is also a rare but feared association of etoposide with secondary acute myelogenous leukemia.14
In the late 1980s, a new approach to retinoblastoma therapy was being explored by a Japanese team led by Kaneko. They pioneered the use of internal carotid artery catheterization for chemotherapy delivery into the ophthalmic artery with balloon impedance of distal flow.6 More recently, improvements in cannulation technique directly into the ophthalmic artery from reports in the United States have confirmed the powerful potential of this therapy for tumor control, with minimal systemic toxicity.2,5,8–12 Shields et al. delineated angiographically the difficulty of this intravascular technique.10 Abramson et al. disclosed their 3-year experience with this technique and identified that “combination therapy” was necessary for consolidation of more advanced disease even though only 1 of 28 eyes required enucleation.5 Reported side effects have been mild or transient, and include decrease in white blood cell count, eyelid edema, blepharoptosis, forehead hyperemia, and loss of cilia.4,5 However, the ophthalmology community is not ready to dismiss the potential serious risks of hemorrhage, thrombosis, embolism, and stroke, as well as retinal and ophthalmic arterial occlusion.
In our pilot study of 11 patients treated with intra-arterial chemotherapy, vitreous seeds were the main source of incomplete regression and recurrence.4 Technique-wise, there can be difficulty navigating the sharp “U-turn” from the internal carotid into the ophthalmic artery, especially with infants younger than 6 months.10 Thus, older children manifesting retinoblastoma with minimal vitreous seeds might be best suited to benefit from this therapy. In our case, dramatic tumor regression after only two chemotherapy infusions was achieved with lasting control at 1 year. This new therapy offers hope for globe preservation, minimizing systemic chemotherapy risks for the patient. However, as written in a recent editorial, this technique is relatively new and long-term risks remain unknown.4
- Shields JA, Shields CL. Management of retinoblastoma. In: Shields JA, Shields CL. Intraocular Tumors: An Atlas and Textbook, 2nd ed. Philadelphia: Lippincott, Williams and Wilkins; 2008:334–351.
- Shields CL, Shields JA. Retinoblastoma management: advances in enucleation, intravenous chemoreduction, and intra-arterial chemotherapy. Curr Opin Ophthalmol. 2010;21:203–212. doi:10.1097/ICU.0b013e328338676a [CrossRef]
- Shields CL, Mashayekhi A, Au AK, et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology. 2006;113:2276–2280. doi:10.1016/j.ophtha.2006.06.018 [CrossRef]
- Shields CL, Shields JA. Intra-arterial chemotherapy for retinoblastoma: the beginning of a long journey. Clin Experiment Ophthalmol. 2010;38:638–643. doi:10.1111/j.1442-9071.2010.02297.x [CrossRef]
- Abramson DH, Dunkel IJ, Brodie SE, Marr B, Gobin YP. Superselective ophthalmic artery chemotherapy as primary treatment for retinoblastoma (chemosurgery). Ophthalmology. 2010;117:1623–1629. doi:10.1016/j.ophtha.2009.12.030 [CrossRef]
- Kaneko A. Japanese contributions to ocular oncology. Int J Clin Oncol. 1999;4:321–326. doi:10.1007/s101470050078 [CrossRef]
- Shields CL, De Potter P, Himelstein BP, Shields JA, Meadows AT, Maris JM. Chemoreduction in the initial management of intraocular retinoblastoma. Arch Ophthalmol. 1996;114:1330–1338.
- Yamane T, Kaneko A, Mohri M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J Clin Oncol. 2004;9:69–73. doi:10.1007/s10147-004-0392-6 [CrossRef]
- Abramson DH, Dunkel IJ, Brodie SE, Kim JW, Gobin YP. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma: initial results. Ophthalmology. 2008;115:1398–1404. doi:10.1016/j.ophtha.2007.12.014 [CrossRef]
- Shields CL, Ramasubramanian AM, Rosenwasser RM, Shields JA. Superselective catheterization of the ophthalmic artery for intra-arterial chemotherapy for retinoblastoma. Retina. 2009;29:1207–1209.
- Brodie S, Gobin YP, Dunkel I, Kim J, Abramson D. Persistence of retinal function after selective ophthalmic artery chemotherapy infusion for retinoblastoma. Doc Ophthalmol. 2009;119:13–22. doi:10.1007/s10633-008-9164-3 [CrossRef]
- Aziz HA, Boutrid H, Murray TG, et al. Supraselective injection of intraarterial melphalan as the primary treatment for late presentation unilateral multifocal stage Vb retinoblastoma. Retina. 2010;30(4 suppl):S63–S65. doi:10.1097/IAE.0b013e3181cbda0f [CrossRef]
- Friedman DL, Himelstein B, Shields CL, et al. Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma. J Clin Oncol. 2000;18:12–17.
- Gombos DS, Hungerford J, Abramson DH, et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor?Ophthalmology. 2007;114:1378–1383. doi:10.1016/j.ophtha.2007.03.074 [CrossRef]