From the Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, Pennsylvania.
Supported by Eye Tumor Research Foundation, Philadelphia, Pennsylvania (CLS).
The authors have no proprietary or financial interest in the materials presented herein.
Address correspondence to Carol L. Shields, MD, Ocular Oncology Service, 840 Walnut Street, Suite 1440, Philadelphia, PA 19107. E-mail: firstname.lastname@example.org
Retinoblastoma is a rare retinal tumor caused by mutation in the RB1 tumor suppressor gene.1 The management of retinoblastoma is complex and varies with patient and tumor features including tumor stage and related seeding. For patients with unilateral sporadic retinoblastoma, treatment with targeted drug delivery by intra-arterial chemotherapy can offer an alternative to traditional systemic chemotherapy or enucleation. In most cases, this regimen requires three to six cycles of one or more agents for adequate tumor control. In this report, we describe successful control of group D retinoblastoma with minimal exposure of only two cycles of single-agent intra-arterial chemotherapy.
A 4-month-old male infant presented with leukocoria and left esotropia. Family history was negative for retinoblastoma. Ocular examination disclosed visual acuity of fix and follow with each eye. The right eye was unremarkable. The left eye showed leukocoria and 60 prism diopters of esotropia. Funduscopy of the left eye revealed a solitary white retinal tumor measuring 20 mm in basal dimension and with associated serous retinal detachment and diffuse sub-retinal seeds. There were no vitreous seeds (Fig. A). Ultrasonography demonstrated a partially calcified intraocular mass of 9.5-mm thickness (Fig. B). These findings were consistent with unilateral sporadic retinoblastoma in the left eye. The tumor was classified as International Classification of Retinoblastoma group D in the left eye.
Figure. A 4-month-old male infant with (A) group D retinoblastoma measuring 20 mm in basal dimension and (B) 9.5 mm thick on B-scan ultrasonography. After one cycle of intra-arterial chemotherapy, (C) tumor base regressed to 10 mm and (D) measured 4.2 mm thick on B-scan ultrasonography. After two cycles of intra-arterial chemotherapy, (E) tumor base regressed to 8 mm and (F) measured 4.2 mm thick on B-scan ultrasonography.
Due to the unilateral, solitary, sporadic occurrence of retinoblastoma, and in an effort to avoid systemic toxicities of intravenous chemotherapy and long-term implications of enucleation, intra-arterial chemotherapy was advised. Three cycles of intra-arterial chemotherapy with melphalan 5 mg in 30 cc were planned. Using microcatheter technique, the medication was slowly pulsed into the ophthalmic artery of the left eye over 30 minutes and the technique was repeated in 1 month. After two cycles of intra-arterial chemotherapy, the tumor was completely reduced to a calcified scar with 60% reduction in basal dimension and 56% reduction in thickness, measuring 8 mm in basal diameter and 4.2 mm in thickness (Figs. C and D). The tumor displayed type 3 regression pattern with 90% calcification. All subretinal seeds were calcified and inactive, and retinal detachment was completely resolved.
Due to excellent tumor response, the third cycle of intra-arterial chemotherapy was withheld. At 1 year of follow-up post-treatment, the patient continues to do well with complete tumor regression and without recurrence of tumor or seeds (Figs. E and F).
Retinoblastoma is a curable cancer if detected and treated while still confined within the retina, subretinal space, or vitreous cavity.2 The most popular and widely used classification systems for retinoblastoma include the Reese–Ellsworth Classification (Table 1) and the more modern International Classification of Retinoblastoma (Table 2).3–5 Although enucleation remains a powerful treatment for retinoblastoma, effort to preserve the eye and visual acuity is made whenever possible.
Table 1: Reese–Ellsworth Classification of Retinoblastoma
Table 2: International Classification of Retinoblastoma
The most effective non-enucleation methods for treatment of retinoblastoma include systemic intravenous chemotherapy (chemoreduction), intra-arterial chemotherapy, plaque radiotherapy, and external beam radiotherapy.2 External beam radiothrapy can effectively control mild, moderate, and occasionally advanced retinoblastoma, but carries the risk for adverse effects such as dry eye, cataract, retinopathy, papillopathy, hemorrhage, and secondary cancers.6 Chemoreduction can similarly control mild, moderate and occasionally advanced retinoblastoma, but with rare risks of hearing loss, renal toxicity, and induction of leukemia.7 In a comprehensive review of 249 eyes with retinoblastoma managed with chemoreduction, treatment success was achieved in 100% of eyes in group A eyes, 93% in group B, 90% in group C, and 47% in group D.8
Intra-arterial chemotherapy allows for direct application of a chemotherapeutic agent to the eye by cannulation of the ophthalmic artery, maximizing the concentration of chemotherapy to the cancer while minimizing systemic exposure.9 Gobin et al. reviewed 95 eyes (based on Reese–Ellsworth Classification, 8 eyes of groups I to III, 4 group IV, 10 group Va, and 73 group Vb) treated with intra-arterial chemotherapy as primary treatment and demonstrated that intra-arterial chemotherapy is a safe and effective treatment for retinoblastoma, with 81.7% event-free survival of all eyes and 80.5% event free survival of group V eyes at 2 years.10 In a study of 12 eyes treated with primary intra-arterial chemotherapy, Shields et al. reported eye preservation in 67% (n = 8), including 100% of group C and D eyes (n = 2, 4), and 33% of group E eyes (n = 6).11 These numbers, although small, represent a comparable success rate when compared to intravenous chemotherapy (chemoreduction) as listed above.8
The advantages of local intra-arterial delivery of chemotherapy are important and include minimal exposure to chemotherapy and few treatment sessions for complete control. However, this should be balanced against the complications, the most serious of which is ophthalmic or brain ischemic event. In a detailed study of 17 children with retinoblastoma treated with intra-arterial chemotherapy, Shields et al. described adverse effects of therapy including mild, transient findings of eyelid edema (n = 13), blepharoptosis (n = 10), and orbital congestion (n = 12), all of which resolved by 2 to 3 months post-treatment.12 More serious effects included acute vascular insult (n = 4) to the ophthalmic, retinal, or choroidal vessels.12 Short-term or long-term damage to these vessels could result in regional or generalized ocular ischemia and eventual loss of visual acuity. Although the pathogenesis remains unknown, vascular injury is thought to be the result of chemotherapy precipitation within the vessels and/or direct toxicity of the chemotherapy to the endothelial lining.12 To reduce these complications, the technique of cannulation and diluted chemotherapy injection is critical. Additionally, as few chemotherapy cycles as possible is preferred. Most children receive three or more cycles for complete control. Those who receive fewer than three cycles are termed “minimal exposure” intra-arterial chemotherapy. Minimal exposure (one or two cycles) intra-arterial chemotherapy can be sufficient for less advanced select group C or D retinoblastoma, but are not likely sufficient for more advanced group E eyes.13
We have described a case of group D unilateral sporadic retinoblastoma treated with only two intra-arterial chemotherapy cycles using melphalan, which resulted in complete and stable tumor regression, resolution of retinal detachment, and, most importantly, salvage of the life, eye, and vision.
- Shields CL. Pearls and forget-me-nots in the management of retinoblastoma. Retina Today. 2008;5:41–47.
- 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]
- Reese AB, Ellsworth RM. The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol. 1963;67:164–172.
- Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmol Clin North Am. 2005;18:41–53. doi:10.1016/j.ohc.2004.11.003 [CrossRef]
- Shields CL, Shields JA. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol. 2006;17:228–234. doi:10.1097/01.icu.0000193079.55240.18 [CrossRef]
- Abramson DH, Beaverson KL, Chang ST, Dunkel IJ, McCormick B. Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol. 2004;122:1316–1323. doi:10.1001/archopht.122.9.1316 [CrossRef]
- Rizzuti AE, Dunkel IJ, Abramson DH. The adverse events of chemotherapy for retinoblastoma: what are they? Do we know?Arch Ophthalmol. 2008;126:862–865. doi:10.1001/archopht.126.6.862 [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]
- 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. Ophthalmology. 2008;115:1398–1404. doi:10.1016/j.ophtha.2007.12.014 [CrossRef]
- Gobin YP, Dunkel IJ, Marr BP, Brodie SE, Abramson DH. Intraarterial chemotherapy for the management of retinoblastoma. Arch Ophthalmol. 2011;129:732–737. doi:10.1001/archophthalmol.2011.5 [CrossRef]
- Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no. 1, control of retinal tumors, subretinal seeds, and vitreous seeds [published online ahead of print June 13, 2011]. Arch Ophthalmol. 2011;129:1399–1406. doi:10.1001/archophthalmol.2011.150 [CrossRef]
- Shields CL, Bianciotto CG, Jabbour P, et al. Intra-arterial chemotherapy for retinoblastoma: report no. 2, treatment complications [published online ahead of print June 13, 2011]. Arch Ophthalmol. 2011;129-1407–1415.
- Shields CL, Kaliki S, Shah SU, et al. Minimal exposure (one or two cycles) of intra-arterial chemotherapy in the management of retinoblastoma. Ophthalmology. 2011;119:188–192. doi:10.1016/j.ophtha.2011.06.036 [CrossRef]
Reese–Ellsworth Classification of Retinoblastoma
|1||(a) Solitary tumor, < 4 disk diameters in size, at or behind equator; (b) Multiple tumors, all < 4 disk diameters in size, all at or behind equator|
|2||(a) Solitary tumor 4 to 10 disk diameters in size, at or behind equator; (b) Multiple tumors all 4 to 10 disk diameters in size, behind equator|
|3||(a) Any lesion anterior to the equator; (b) Solitary tumors > 10 disk diameters in size, behind equator|
|4||(a) Multiple tumors, some > 10 disk diameters in size; (b) Any lesion extending anterior to the ora serrata|
|5||(a) Massive tumor involving over half of retina; (b) Vitreous seeding|
International Classification of Retinoblastoma
|A||Small tumor (< 3 mm)|
|B||Larger tumor (> 3 mm), macular location (< 3 mm from fovea); juxtapapillary location (< 1.5 mm from disk); subretinal fluid|
|C||Focal seeding (< 3 mm from tumor)|
|D||Diffuse seeding (> 3 mm from tumor)|
|E||Extensive tumor; neovascular glaucoma; intraocular hemorrhage; invasion of optic nerve, choroid, sclera, orbit, anterior chamber|