From the Bascom Palmer Eye Institute (YP, HB, TGM, ACS, SKH, HAA), Department of Ophthalmology, Miami, Florida; the Department of Neurological Surgery (SQW, RM, MAA-S), University of Miami/Jackson Memorial Hospital, Miami, Florida; the Department of Pediatrics (CEF, JR), University of Miami Miller School of Medicine, Miami, Florida; and the Department of Radiation Oncology (AMM), University of Miami Sylvester Comprehensive Cancer Center, Miami, Florida.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Timothy G. Murray, MD, Bascom Palmer Eye Institute, P.O. Box 016880, Miami, FL 33101. E-mail: email@example.com
Retinoblastoma is the most common intraocular tumor in childhood, occurring in approximately 1 in 15,000 live births in the United States.1 Significant advances in treatment have resulted in increased survival rates and improved globe conservation. Nonetheless, 47% to 83% of patients with International Classification of Retinoblastoma (ICRB) Group D still respond poorly to traditional treatment modalities.2–4 Current treatment methods often consist of a multidisciplinary approach including laser, systemic and periocular chemotherapy, and radiation.5 In the most advanced cases, enucleation has usually been used as a definitive treatment option.6
Local periocular administration of carboplatin, a cisplatin analogue, is a therapy commonly used in combination with other treatment modalities for advanced retinoblastoma. Periocular drug delivery has been shown to enhance drug concentration within the eye and to minimize systemic toxicities.7–11 Complications following repeat carboplatin treatments, including fibrosis of orbital soft tissues, restriction of eye movements, optic nerve toxicity, and periorbital fat necrosis, have been well documented.12,13
However, the effect of periocular chemotherapy on orbital vasculature has not been described. We describe two patients who were treated with systemic chemotherapy and unilateral periocular carboplatin who later underwent intra-arterial chemotherapy secondary to tumor activity. Orbital angiography performed during the procedures enabled a rare evaluation of the preceding treatment effects on the ophthalmic and orbital vasculature.
A 3-year-old girl presented for evaluation of possible retinoblastoma. On examination, vision was central, steady, and maintained with a gaze preference for the right eye. Examination of the right eye was normal. In the left eye, dilated fundus examination revealed a large macular retinoblastoma tumor with extensive subretinal fluid and adjacent gross subretinal seeding (ICRB Group D, R-E Stage VB). The patient was treated with nine cycles of systemic chemotherapy that included carboplatin, etoposide, vincristine, and cyclosporine, as well as large spot (1.5 mm) diode laser. Laser therapy was delivered to the left eye with the 810-nm diode laser via the indirect ophthalmoscope (Oculight SLx; Iris Medical Instruments, Mountain View, CA). The patient underwent a follow-up examination under anesthesia every 3 to 4 weeks.
Following the ninth cycle of chemotherapy and laser, the tumor in the left eye continued to demonstrate persistent vascular activity. The patient was subsequently treated with two more laser treatments. After 11 laser treatments, a new tumor was detected abutting the optic nerve measuring approximately 6 × 5 × 2 mm in dimension. To salvage the left eye, three periocular carboplatin injections were then administered. At each treatment session, 20 mg of carboplatin in 2 mL (10 mg/mL) was delivered juxtasclerally and adjacent to the active tumor. The injections were given every 3 weeks and laser ablation therapy was continued with each injection. After the third periocular chemotherapy injection, the optic nerve head tumor continued to progress.
The patient then underwent intra-arterial chemotherapy under general anesthesia. Intra-arterial chemotherapy was provided 6 months following completion of systemic chemoreduction. This represented the clinical point when the tumor was clearly active and progressive. The details of this procedure have been described elsewhere.14 Selective injections of the left external and internal carotid arteries were performed, with special attention to the ophthalmic arteries. A straight 0.010-inch Marathon microcatheter (eV3, Inc., Irvine, CA) was maneuvered over a shaped 0.008-inch Mirage wire (eV3, Inc.) under roadmap guidance into the ostium of the left ophthalmic artery and a selective ophthalmic artery angiogram was performed. After evaluating the vascular anatomy, the catheter was flushed with normal saline.
Orbital angiography exhibited significantly attenuated orbital vasculature in the left eye compared to the right eye (Fig. 1). Both eyes demonstrated normal caliber ophthalmic arteries with significant extraorbital blood flow. The left eye (Fig. 1B) showed a small, sclerosed central retinal artery and a poor choroidal blush when compared to the right eye (Fig. 1A). The blood transit time was markedly decreased in the left eye (Fig 1B), requiring 7 seconds from injection to choroidal blush versus 1.5 seconds in the right eye (Fig. 1A). Normal orbital vasculature without delayed blood flow was seen on the right side (Fig. 1A).
Figure 1. Case 1. Lateral Angiogram of the Right (a) and Left (b) Ophthalmic Arteries 7 Seconds After Selective Injection Showing only a Thin Rim of Posterior Choroidal Blush in the Left Eye (b), Which Had Undergone Systemic and Periocular Chemotherapy, as Well as Laser Ablation, Compared to the Well-Developed Choroidal Blush in the Right Eye (a), Which Had only Undergone Systemic Chemotherapy. The Left Central Retinal Artery (b) Is of Significantly Smaller Caliber Compared to the More Robust Caliber of the Right Central Retinal Artery (a).
The chemotherapeutic agent, melphalan, was then prepared by diluting the desired dose (5 mg) in 30 cc of sterile normal saline and infused by micro-pulse injection over 30 minutes. Following the infusion, a follow-up carotid angiogram was performed to evaluate for any inadvertent thromboembolic changes.
A 5-month-old girl presented for evaluation of possible retinoblastoma. On examination, vision was central, steady, and maintained with a gaze preference for the left eye. Examination of the left eye was normal. In the right eye, dilated fundus photographs revealed a large, elevated macular retinoblastoma extending to the optic nerve. Gross vitreous and subretinal seeding were also detected (ICRB Group D, R-E Stage VB). Systemic evaluation demonstrated no evidence of metastatic tumor and the patient was treated with nine cycles of vincristine, carboplatin, etoposide, and cyclosporine and focal laser ablation. The patient underwent a follow-up examination under anesthesia every 3 to 4 weeks.
Following the ninth cycle of chemotherapy, a recurrence of multifocal subretinal seeding was detected in the right eye. The patient was subsequently treated with adjuvant periocular carboplatin chemotherapy injections (20 mg of carboplatin in 2 mL [10 mg/mL] delivered juxtasclerally adjacent to the active tumor) every 3 weeks and laser ablation therapy was continued with each injection. Examination of the left eye remained normal. Following three periocular carboplatin injections, the right eye continued to demonstrate persistent vitreous seeding, prompting further treatment with supraselective intra-arterial ophthalmic artery melphalan infusion (5 mg) in the same manner as described for case 1.
Orbital angiography exhibited significantly attenuated orbital vasculature in the right eye compared to the left eye (Fig. 2). The right eye showed a small, sclerosed central retinal artery and a poor choroidal blush (Fig. 2B). The blood transit time was markedly decreased in the right eye (Fig. 2B), requiring 9 seconds from injection to choroidal blush versus 2 seconds in the left eye (Fig. 2A). Additionally, the choroidal blush was not completed by 20 seconds, with the anterior choroid and iris never showing a normal vascular blush. The posterior ciliary arteries appeared tortuous with reduced caliber and stagnation of contrast dye. Multiple anomalous vessels were seen supplying the posterior choroid. Normal orbital vasculature was seen in the left eye without delayed blood flow (Fig. 2A).
Figure 2. Case 2. Lateral Angiogram of the Left (a) and Right (b) Ophthalmic Arteries 7 Seconds After Selective Injection Showing Virtually No Posterior Choroidal Blush in the Right Eye (b), Which Had Undergone Systemic and Periocular Chemotherapy, as Well as Laser Ablation, Compared to the Well-Developed Choroidal Blush in the Left Eye (a), Which Had only Undergone Systemic Chemotherapy. The Right Central Retinal Artery (b) Is of Significantly Smaller Caliber (b) Compared to the More Robust Caliber of the Left Central Retinal Artery (a).
Periocular administration of carboplatin is often combined with other treatments for advanced retinoblastoma. Focal, periocular delivery of carboplatin enhances drug concentration within the eye and significantly decreases systemic toxicities.7–11 The current case series demonstrates the effect of periocular carboplatin on ophthalmic vasculature. Both patients in this series demonstrated significantly attenuated ophthalmic and orbital vasculature in the anterior and posterior orbit of the eye that had previously undergone periocular treatment. Previous observations have shown diffuse orbital exposure from juxtascleral injection of carboplatin (unpublished observation). The vascular alterations found in the current series when compared to fellow contralateral eyes included reduced vessel caliber, decreased flow and arterial transit time, and poor choroidal blush. Vascular sclerosis has been previously found in patients with non-ocular malignancies following treatment with systemic carboplatin.12,13,15–17 The ophthalmic literature has documented clinical and histopathologic evidence of marked orbital inflammation, severe restriction in ocular motility (secondary to presumed fibrotic muscular change), periorbital fat necrosis, and ischemic necrosis and atrophy of the optic nerve (histopathologic studies) following periocular carboplatin injection.12,13,17
In the current cases, the affected eyes did not present with tumors larger than ICRB Group D, R-E Stage VB, inflammatory necrosis, or other factors that could have affected the outcome.
The orbital angiographies obtained prior to treatment of the fellow eye in each case displayed normal orbital vasculature. Although these eyes were exposed to systemic chemotherapy, they did not undergo laser ablation therapy or periocular carboplatin. The findings in this series are consistent with our hypothesis that alterations in ophthalmic and orbital vasculature are likely caused by a synergistic effect of combination therapy with systemic chemotherapy and periocular carboplatin but not by systemic chemotherapy alone. The current observations also correspond with our previous case report that presented vascular abnormalities following combined systemic chemotherapy and external beam radiation-induced vasculopathy.18 These results suggest that systemic chemotherapy combined with either consolidating external beam radiotherapy18 or periocular carboplatin chemotherapy (ie, current report) may significantly impact orbital vasculature. As a result, these findings may be important when considering doses for intra-arterial melphalan in patients with advanced stage retinoblastoma.
In a recent histopathologic observation,19 we have reported four cases of eyes undergoing enucleation after treatment with supraselective ophthalmic artery melphalan treatment. Vascular alteration in the caliber of the reviewed extraocular vasculature was noted only in eyes that had received either external beam radiation therapy or periocular carboplatin chemotherapy. We believe that the mechanism of the orbital vascular alteration may be both direct effects of the carboplatin chemotherapy delivered in high concentration into a small confined tissue space such as the orbit and secondary inflammatory alterations that indirectly compromised orbital vasculature.
Finally, our findings also suggest that a decrease in ophthalmic perfusion may contribute to advanced progression of intraocular disease. Abnormal vasculature that impedes blood flow impairs oxygen and drug delivery, potentially resulting in resistance to radiotherapy and chemotherapy.
To our knowledge, these findings have never been reported and have important implications for the future treatment of advanced retinoblastoma with modalities that rely on the ophthalmic blood supply. For example, intra-arterial chemotherapy may be associated with incomplete tumor due to the reduced penetration of drug into the ocular tissues secondary to the alterations of ophthalmic vasculature from previous therapies. In the future, clinicians considering systemic or intra-arterial therapy after prior treatment with systemic and periocular chemotherapy should be cognizant of potential treatment-related alterations in ophthalmic vasculature that may impact the effectiveness of these treatments.
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- Hayden BC, Jockovich ME, Murray TG, et al. Pharmacokinetics of systemic versus focal carboplatin chemotherapy in the rabbit eye: possible implication in the treatment of retinoblastoma. Invest Ophthalmol Vis Sci. 2004;45:3644–3649. doi:10.1167/iovs.04-0228 [CrossRef]
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