Cristina E. Fernandes

Supraselective intra-arterial chemotherapy: evaluation of treatment-related complications in advanced retinoblastoma.

Purpose: The purpose of this study is to report the complication profile and safety evaluation of supraselective intra-arterial melphalan chemotherapy in children undergoing treatment with advanced retinoblastoma. Methods: Twelve eyes of 10 children with advanced retinoblastoma (Reese-Ellsworth Group Vb or International Classification Group D) were treated with supraselective intra-ophthalmic artery infusion of melphalan. Eleven eyes of nine children had previously failed traditional management with systemic chemotherapy and laser ablation and underwent intra-ophthalmic artery infusion of melphalan as an alternative to enucleation. Serial ophthalmic examinations, retinal photography, and ultrasonographic imaging were used to evaluate treatment regime. Results: Ophthalmic artery cannulation was successfully performed in 12 eyes of 10 patients (total 16 times). Striking regression of tumor, subretinal and vitreous seeds were seen early in each case. No severe systemic side effects occurred. Grade III neutropenia was seen in one patient. No transfusions were required. Three patients developed a vitreous hemorrhage obscuring tumor visualization. One patient developed periocular edema associated with inferior rectus muscle inflammation per orbital MRI. This same patient had scattered intraretinal hemorrhages and peripapillary cotton wool spots consistent with a Purtscher’s-like retinopathy that resolved spontaneously. At the 6-month follow-up examination, nine eyes had no evidence of tumor progression, whereas three eyes were enucleated for tumor progression. In each enucleated case, viable tumor was identified on histopathologic examination. Conclusions: Ophthalmic intra-arterial infusion with melphalan is an excellent globe-conserving treatment option in advanced retinoblastoma cases with minimal systemic side effects. Local toxicities include microemboli to the retina and choroid (1/12, 8%), vitreous hemorrhage (3/12, 25%), and myositis (1/12, 8%). Enucleation remained a definitive treatment for tumor progression in 3 of 12 eyes in this small case series with limited follow-up. Further studies are necessary to establish the role of supraselective intra-arterial melphalan chemotherapy for children with retinoblastoma.

Current Update on Retinoblastoma

Treatment of retinoblastoma has undergone significant advancements over the past few decades, as globe-salvaging therapies with chemoreduction and focal consolidation are favored over external beam radiation and enucleation. With current chemotherapy protocols and focal laser, survival in the United States and other developed countries has now climbed to almost 100% with many children maintaining functional vision. However, in other continents such as Africa, survival rates drop significantly.1, 2 Additionally, children with advanced tumors often require enucleation. Novel therapeutic directions are actively being pursued for these advanced retinoblastoma tumors, as well as development of treatments that decrease associated risks of systemic chemotherapy. Additionally, there are a number of experimental adjuvant therapies that have been shown to be efficacious in animal models, and may be part of the future armamentarium of cancer treatment. Finally, novel imaging modalities are being developed that may aid in the diagnosis and management of retinoblastoma in the future. The following review discusses current updates on retinoblastoma.

Clinicopathologic review of enucleated eyes after intra-arterial chemotherapy with melphalan for advanced retinoblastoma.

change if the air had direct access to the venous circulatory system. The clinical situation is further complicated by a patent foramen ovale (which is present in 23%-45% of adults, based on autopsy studies). A patent foramen ovale allows trapped air to access the arterial circulatory system through the opening between the right and left atrium. This can result in air emboli throughout the systemic arterial circulatory system, causing cerebral, cardiac, and visceral infarction, as occurred in the second case. Treatment of VAE consists of immediately flooding the operative field with fluid to stop entry of the air. Additional measures would be at the discretion of the anesthesiologist and include increasing inspired oxygen, discontinuing nitrous oxide, if it is being used, inotropic support, and aspiration of air if a right atrial catheter has been placed. Although this complication is rare, ophthalmologists should be aware that it can occur during an air/fluid exchange, especially in the setting of significant trauma. During retinal cases, the anesthesiologist may not be fully aware of maneuvers happening within the eye, and the operating surgeon may be the first to recognize this problem if a patient becomes hemodynamically unstable after an air/fluid exchange is initiated. Promptly terminating the air infusion and returning the eye to a fluid filled state may help avoid systemic morbidity.

Supraselective injection of intraarterial melphalan as the primary treatment for late presentation unilateral multifocal stage VB retinoblastoma

Purpose: The purpose of this study was to report a case of a 7-year-old girl with unilateral, multifocal Reese Ellsworth Stage Vb retinoblastoma who was successfully treated using intraarterial chemotherapy infusion as the primary therapy. Methods: This is an interventional case report. A 7-year-old girl presented with advanced unilateral retinoblastoma. The patient received intraarterial melphalan infusion therapy as the primary treatment. Results: Complete tumor resolution was seen at 1 month after intraarterial melphalan infusion. Conclusion: This case of advanced retinoblastoma in a 7-year-old girl was successfully treated with intraarterial melphalan infusion alone. Treatment resulted in complete resolution of the tumor 1 month after treatment. In comparison with systemic chemotherapy, intraarterial melphalan infusion therapy may be a less toxic and more effective primary treatment option in the future management of advanced retinoblastoma.

Retinoblastoma treatment burden and economic cost: impact of age at diagnosis and selection of primary therapy.

Purpose To follow the treatment history of patients with retinoblastoma to identify the trends in the number of hospital visits over time and the direct cost of medical care as determined by age at diagnosis and selected primary treatment modality. Design An Institutional Review Board (IRB) approved consecutive retrospective case series. Materials and methods Records from the Bascom Palmer Eye Institute were reviewed to identify 115 eligible patients (176 eyes) with retinoblastoma who underwent treatment at the Ocular Oncology Service between 1995 and 2010 and were available for extended follow-up evaluation. Results Bilateral disease was present in 53% (N = 61) of all patients, and 79% (N = 90) of patients were diagnosed in the first six months of life. Chemotherapy was used to treat 75% (N = 86) of all patients and 95% (N = 36) of patients diagnosed in the first six months of life. 100% (N = 4) of patients presenting between the age of five and nine were enucleated. Per episode of care, the lowest-cost treatment strategy was enucleation, followed by focal laser therapy, systemic chemotherapy with planned enucleation, systemic chemotherapy, and lastly, intra-arterial melphalan chemotherapy. Conclusion Age at diagnosis is directly associated with the type of treatment chosen for retinoblastoma. The burden of retinoblastoma treatment on children and families is significant. The direct medical cost of intra-arterial chemotherapy per episode of care is comparable to systemic chemotherapy, but current strategies utilizing multiple planned episodes of intra-arterial chemotherapy are significantly more costly and may be associated with less systemic side effects and similar favorable outcomes. At the Bascom Palmer Eye Institute, intra-arterial chemotherapy has quickly become the treatment of choice for globe conserving therapy of retinoblastoma.

Bilateral orbital vasculature alterations after systemic chemotherapy and external beam radiation therapy treatment of advanced retinoblastoma: implications for intraarterial chemotherapy management.

PURPOSE The purpose of this study was to report significant alterations in orbital vasculature after combined systemic chemoreduction with consolidating external beam radiotherapy treatment in a case of advanced retinoblastoma and to discuss implications for intraarterial melphalan rescue chemotherapy. METHODS We studied the case of a 22-month-old child who had been treated recently with intraarterial melphalan perfusion after multimodal therapy for advanced intraocular retinoblastoma. RESULTS Orbital angiography of both eyes, performed before the intraarterial melphalan injection, documented an atypical attenuated orbital vasculature. The right ophthalmic artery angiogram showed loss of a normal dominant central retinal artery. Instead, multiple dysplastic angiogenic vessels from the ophthalmic artery were found to supply the retina. A single long ciliary artery was noted with collateral vessels supplying the anterior globe. The left ophthalmic artery angiogram showed a stenotic artery with minimal anterograde flow. CONCLUSION Orbital vasculature may be impacted by combined systemic chemotherapy and external beam radiation therapy. These changes need to be considered in the use of intraarterial melphalan for the treatment of patients with advanced retinoblastoma.

Ophthalmic vasculature alterations following systemic chemotherapy and periocular Carboplatin treatment of advanced retinoblastoma.

The purpose of this study was to report significant alterations in orbital vasculature following combined systemic chemoreduction/laser ablation and periocular carboplatin treatment and to discuss treatment implications in two cases of advanced retinoblastoma. Assessment of orbital and ophthalmic vasculature was done following nine cycles of systemic chemotherapy. Intra-arterial chemotherapy was provided 6 months following completion of systemic chemoreduction, when the tumor was clearly active and progressive. Orbital angiography of both eyes, performed prior to the intra-arterial melphalan injection, documented sclerosis of the ophthalmic artery vasculature with delayed transit time, decreased choroidal blush, and anomalous vessels in the eye receiving periocular carboplatin injections. The orbital vasculature in the contralateral eye was not affected. Orbital and ophthalmic vascular alterations may occur with the use of combined systemic chemotherapy and periocular carboplatin. Systemic chemotherapy and focal transpupillary laser tumor ablation, alone, did not appear to impact the orbital and ophthalmic vascular supply. Impaired vascular supply may have significant influence on the impact of the efficacy of standard and future experimental therapeutic options.

Supraselective intra-arterial chemotherapy

Purpose: The purpose of this study is to report the complication profile and safety evaluation of supraselective intra-arterial melphalan chemotherapy in children undergoing treatment with advanced retinoblastoma. Methods: Twelve eyes of 10 children with advanced retinoblastoma (Reese-Ellsworth Group Vb or International Classification Group D) were treated with supraselective intra-ophthalmic artery infusion of melphalan. Eleven eyes of nine children had previously failed traditional management with systemic chemotherapy and laser ablation and underwent intra-ophthalmic artery infusion of melphalan as an alternative to enucleation. Serial ophthalmic examinations, retinal photography, and ultrasonographic imaging were used to evaluate treatment regime. Results: Ophthalmic artery cannulation was successfully performed in 12 eyes of 10 patients (total 16 times). Striking regression of tumor, subretinal and vitreous seeds were seen early in each case. No severe systemic side effects occurred. Grade III neutropenia was seen in one patient. No transfusions were required. Three patients developed a vitreous hemorrhage obscuring tumor visualization. One patient developed periocular edema associated with inferior rectus muscle inflammation per orbital MRI. This same patient had scattered intraretinal hemorrhages and peripapillary cotton wool spots consistent with a Purtscher’s-like retinopathy that resolved spontaneously. At the 6-month follow-up examination, nine eyes had no evidence of tumor progression, whereas three eyes were enucleated for tumor progression. In each enucleated case, viable tumor was identified on histopathologic examination. Conclusions: Ophthalmic intra-arterial infusion with melphalan is an excellent globe-conserving treatment option in advanced retinoblastoma cases with minimal systemic side effects. Local toxicities include microemboli to the retina and choroid (1/12, 8%), vitreous hemorrhage (3/12, 25%), and myositis (1/12, 8%). Enucleation remained a definitive treatment for tumor progression in 3 of 12 eyes in this small case series with limited follow-up. Further studies are necessary to establish the role of supraselective intra-arterial melphalan chemotherapy for children with retinoblastoma.

Required reduction in dose of chemotherapy for retinoblastoma due to down syndrome-associated chemosensitivity

PURPOSE To report a case of a boy with bilateral germinal retinoblastoma and Down syndrome who was successfully treated despite a predilection toward chemotoxicity associated with Down syndrome. METHODS A 3-month-old boy presenting with germinal retinoblastoma and Down syndrome was treated with diode laser and systemic carboplatin and low-dose vincristine, with gradual dose escalation. Etoposide and cyclosporine were later added for a greater tumor response. After cyclosporine was added, the patient was hospitalized due to vincristine toxicity. The vincristine dose was further lowered, and periocular carboplatin injections were given to establish control of intraocular disease. RESULTS The tumors regressed after 11 sessions of laser and chemotherapy. Because of residual vitreous seeding in the right eye, a series of two periocular carboplatin injections were given. Six more laser sessions were applied to the tumors. There is no evidence of active retinoblastoma after 11 months of follow-up. CONCLUSION Because of increased chemosensitivity in patients with Down syndrome, it is important to reduce systemic drug dosages and consider augmenting local therapy in retinoblastoma cases.