Intraophthalmic Artery Chemotherapy Research Articles

Strabismus in retinoblastoma survivors with long-term follow-up

To report the long-term strabismus rate in salvaged retinoblastoma (Rb) patients and investigate possible risk factors leading to strabismus. The medical records of patients with Rb presenting at a single institution over a 9-year period were reviewed retrospectively with regard to ocular alignment outcomes after long-term follow-up. A total of 64 eyes of 42 patients (22 bilateral cases [52%]) were included, presenting with International Intraocular Retinoblastoma Classification (IIRC) in the worse eye as follows: group A (n=1), B (n=16), C (n=12), D (n=11), no Rb (n=2). Fifteen patients (36%) were initially referred because of family history of Rb. Mean age at presentation was 8.2months (range, 0.3-58.3months). Overall treatments included intravenous chemotherapy (62 eyes), intraophthalmic artery chemotherapy (10 eyes), brachytherapy (11 eyes), transpupillary thermotherapy (22 eyes), cryotherapy (47 eyes), and external beam radiotherapy (4 eyes). At final follow-up (mean, 93.7months), 69% of patients had strabismus, with exotropia being the most common type (n=18), followed by esotropia (n=8), and alternate exotropia/esotropia (n=3). On univariate analysis, the worse eye group IIRC and cTNMH, sporadic cases, strabismus, and foveal tumor at presentation were found to be significantly associated with strabismus at final follow-up (P≤0.043). On multivariate analysis, only foveal involvement was found to be significant (P<0.001). Strabismus, exotropia in particular, is a common adverse sequela following successful conservative treatment for Rb, with 69% of the present cohort having some type of deviation after long-term follow-up, for which foveal tumor at presentation was found to be a significant risk factor.

The management of retinoblastoma.

Retinoblastoma (Rb) is the most common primary intraocular malignancy of childhood, but an uncommon paediatric cancer, with a constant incidence worldwide of 1:15,000-1:20,000 live births. Despite its rarity, Rb has served as a cornerstone in the field of oncology in many of the aspects that comprise cancer management, including classification schemes, treatment modalities, genetic testing and screening. Until just over half a century ago, the major treatment for Rb was eye removal, and prognosis was poor with outcome fatal for most children. The dramatic evolution, in a short period of time across all fields of Rb management, as well as the development of specialized centres, better infrastructure and introduction of awareness campaigns, has resulted in nearly 100% survival in developed countries and allowed eye salvage in many of the cases. External beam radiotherapy was used as the main treatment choice for four decades, but replaced by chemotherapy at the turn of the century. Initially, and still in many centres, chemotherapy is administered intravenously, but recently is targeted directly into the eye by means of intra-ophthalmic artery and intravitreal chemotherapy. To date, a range of treatments is available to the Rb expert, including enucleation, but there is lack of consensus in a number of scenarios as to what to use and when. In such a rare cancer, treatment outcomes are reported usually via retrospective analyses, with few prospective randomized controlled trials. Classification schemes have also evolved following the introduction of new treatment modalities, but discrepancies exist among centres with respect to the preferred schema and its interpretation. Retinoblastoma management is a remarkable success story, but the future will require a collaborative effort in the form of multicentre randomized controlled trials in order to further improve the quality of care for this subset of young children with ocular cancer.

Giant retinal tear after intra-arterial chemotherapy for advanced unilateral retinoblastoma

BackgroundRetinoblastoma is considered the most common intraocular malignancy in childhood, comprising 4% of all pediatric cancers. Management of retinoblastoma has evolved over the past two decades and intra-ophthalmic artery chemotherapy has emerged as a new modality of globe-conserving treatment with excellent results. This treatment achieves effective tumor reduction by delivering localized chemotherapy, decreases enucleation rate, and minimizes systemic and local side effects.Case presentationWe report the case of an 8-year-old girl with a late presentation of an advanced unilateral retinoblastoma associated to diffuse exudative retinal detachment in the right eye, classified as group E by the International Classification of Retinoblastoma. The initial therapeutic proposal for the patient was five sessions of intra-ophthalmic artery chemotherapy (IAC) associated to large spot diode laser therapy. After undergoing four sessions of IAC, the fundus exam revealed a giant retinal tear associated to a total retinal detachment in the affected eye. The IAC treatment was concluded and enucleation was considered the best treatment option at that moment, since IAC was unable to control the tumor’s activity and the patient’s eye presented with a complex rhegmatogenous retinal detachment (RRD). However, family left for a second opinion and never returned.ConclusionsThe usage of IAC for retinoblastoma management may lead to important local complications. Despite rare, RRD secondary to IAC may occur. We postulate that the giant tear observed in this case was caused by the rapid tumor necrosis using this route of treatment.

Long-term Visual Acuity, Strabismus, and Nystagmus Outcomes Following Multimodality Treatment in Group D Retinoblastoma Eyes

To analyze the long-term visual acuity, strabismus, and nystagmus outcomes in Group D retinoblastoma following multimodality treatments in a national retinoblastoma referral center. Retrospective interventional case series. A 13-year retrospective chart review of Group D eyes treated initially with intravenous chemotherapy (IVC) and followed up for at least 1 year from last treatment. Risk factors for final visual acuity (VA) were analyzed, and rate of strabismus and nystagmus at last follow-up visit were calculated. One hundred and four Group D eyes (92patients)presented to our center during the study period, of which 32 (27 patients) met the inclusion criteria. Following IVC (vincristine, etoposide, and carboplatin), adjuvant treatments included intraophthalmic artery chemotherapy in 5 (16%) eyes, plaque brachytherapy in 5 (16%), transpupillary thermotherapy (TTT) in 18 (56%), and cryotherapy in 24 (75%) eyes. On last examination, 64.41 ± 6.76months from presentation, mean final VA was 20/283 (logMAR equivalent of 1.15 ± 0.15). On univariate analysis, presentation age, foveal retinoblastoma (at initial examination), use of TTT, and tumor-foveola distance (at last visit) were found to be significant risk factors for worse VA (P < .026). On multivariate analysis, however, only TTT was found to be significant (P= .010). At last visit, 6 of 27 (22%) patients had nystagmus and 12 of 20 (60%) bilaterally salvaged patients had strabismus (n= 10 exotropia and n= 2 esotropia). After multimodality treatments initiated with IVC, 50% of salvaged Group D retinoblastoma eyes had <20/200 vision, with TTT being a risk factor for worse vision; 60% had strabismus; and 22% had nystagmus.

High-Risk Histopathology Features in Primary and Secondary Enucleated International Intraocular Retinoblastoma Classification Group D Eyes

To evaluate the rate and identify the risk factors for high-risk histopathologic features in group D retinoblastoma eyes enucleated as primary or secondary treatment. Retrospective analysis. A total of 64 enucleated group D eyes (62 patients), of which 40 (40 patients) were primary and 24 (22 patients) were secondary to other treatments. Clinicopathologic correlation of consecutive group D eyes enucleated from 2002 to 2014. High-risk histopathologic features were defined as the presence of anterior chamber seeds, iris infiltration, ciliary body/muscle infiltration, massive (≥3 mm) choroidal invasion, retrolaminar optic nerve invasion, or combined non-massive choroidal and prelaminar/laminar optic nerve invasion. High-risk histopathologic features, metastasis, and death. Of the 64 group D eyes, 37 (58%) were classified as cT2bN0M0H0, 24 (38%) were classified as cT2bN0M0H1, and 3 (5%) were classified as cT2aN0M0H1, according to the 8th edition cTNMH Retinoblastoma Staging. High-risk histopathologic features were detected in 10 eyes (16%) in the entire cohort, 5 eyes (13%) of the primary enucleated group (pT3aNxM0, n= 2 and pT3bNxM0, n= 3, 8th edition pTNM), and 5 eyes (21%) of the secondary enucleated group (pT2bNxM0, n= 2, pT3aNxM0, n= 2 and pT3cNxM0, n= 1). Absence ofvitreous seeds at presentation was the only predictive factor found for high-risk histopathologic features in the primary enucleation group (P= 0.042), whereas none were found in the secondary group (P ≥ 0.179). Invasion of the anterior structures (anterior chamber, iris, ciliary body/muscle) was detected significantly more after secondary enucleation (P= 0.048). All patients with high-risk histopathologic features were treated with adjuvant chemotherapy, and no metastases were recorded in a median follow-up time of 73.2 months (mean, 71.5; range,13.7-153.0). The choice of primary treatment for group D retinoblastoma should be carefully weighed, because according to this study, 13% of eyes harbor high-risk histopathologic features at presentation, with the absence of vitreous seeds being a potential risk factor. It is of special importance in group D eyes being considered for nonsystemic treatment, such as primary intraophthalmic artery chemotherapy. Secondary enucleated group D eyes with high-risk histopathologic features more commonly involved anterior structures, warranting meticulous clinical and histologic examinations for this subset of patients.

Diagnosis and management of secondary epipapillary retinoblastoma

BackgroundReports on retinoblastoma relapse at the optic nerve head (ONH) are anecdotal and include only treatments by external beam radiotherapy (EBRT) or enucleation. We aimed to describe such cases, termed...

Primary intravenous chemotherapy for group D retinoblastoma: a 13-year retrospective analysis

BackgroundEye salvage rate for group D retinoblastoma using intravenous chemotherapy (IVC) as a primary modality is <50%. To report on 13 years' experience with the use of primary IVC for...

Anterior Segment Seeding in Eyes With Retinoblastoma Failing to Respond to Intraophthalmic Artery Chemotherapy.

Anterior chamber seeding following intraophthalmic artery chemotherapy is rarely reported. To describe clinicopathologic observations in eyes in which intraophthalmic artery chemotherapy for retinoblastoma failed and to report anterior chamber involvement. A retrospective case series of 12 enucleated eyes (11 patients) with retinoblastoma refractory to intraophthalmic artery chemotherapy between March 1, 2010, and October 31, 2013, at University College London Institute of Ophthalmology and the Retinoblastoma Service, Royal London Hospital. Data analysis was conducted from June 1, 2014, to March 1, 2015. The International Classification of Retinoblastoma groups were B in 1 eye (8%), C in 4 eyes (33%), and D in 7 eyes (58%). Systemic chemotherapy with vincristine sulfate, etoposide, and carboplatin had failed in 10 patients (91%) and 6 eyes (50%) received additional local treatments. In 6 eyes (50%) anterior chamber invasion was clinically detectable. On histopathologic examination, 4 eyes (33%) had no viable retinal tumor; the remainder had poorly differentiated tumor (6 eyes [50%]) or moderately differentiated tumor (2 eyes [17%]). Anterior segment involvement occurred in the ciliary body and/or ciliary muscle (7 eyes [58%]), iris (6 eyes [50%]), and cornea (4 eyes [33%]). Intraophthalmic artery chemotherapy can fail in eyes with retinoblastoma. In contrast to previous reports on outcomes following intraophthalmic artery chemotherapy, our series shows involvement of the anterior segment of the eye, including the ciliary body, iris, and cornea. Careful case selection and follow-up are advised.

Enophthalmos and Choroidal Atrophy after Intraophthalmic Artery Chemotherapy for Retinoblastoma

Superselective intraophthalmic artery chemotherapy (SSIOAC) has come to the forefront in the treatment of retinoblastoma. We have presented the histopathologic and radiologic findings of a retinoblastoma patient who subsequently developed enophthalmos, choroidal ischemia, iris atrophy, and scleritis as delayed toxicities of SSIOAC.

Outcome of retinoblastoma following limited sessions of intra-arterial chemotherapy in iran.

Background:The management of retinoblastoma remains a challenge to the multidisciplinary team, particularly as treatment affects not only visual outcomes, but also ocular retention and morbidity. Management of retinoblastoma has evolved over the past two decades.Objectives:To report the result of intra-ophthalmic artery chemotherapy (IAC) for the treatment of refractory and advanced retinoblastoma tumors.Patients and Methods:All patients who had failed to respond adequately to previous treatments and six naive patients with advanced retinoblastoma, receiving IAC between 2009 and 2012, were included in this institutional interventional case series. The patients received 1-2 treatments of IAC given 4-8 weeks apart. Complete response was defined as regressed tumor and complete disappearance of seeding clinically and partial response was defined as partial regression of the tumor with live parts of the tumor and/or lessening of seeds, but not complete disappearance of them clinically.Results:A total of 24 eyes of 24 patients were treated with IAC during the study period. The mean age at the time of IAC was 38.9 months (14-120 months), and the mean follow-up was 16.8 months (3-36 months) after IAC. Tumor control was achieved in 14 eyes (58.3%). Type 3 (combined fleshy and calcified remnants) was the most common type of regression (37.5%). Complications included vitreous hemorrhage in nine eyes (37.5%), arterial occlusion in two (8.3%), cyclitic membrane possibly secondary to ischemia and tractional retinal detachment in one patient (4.2%), chorioretinal atrophy in three (12.5%) patients, and neovascular glaucoma in one eye (4.2%). In eight (33.3%) patients, no complication happened. Globe salvage was achieved in 62.5% of the cases. The success rate for naive patients was 84%. Sixty-seven percent of the cases received transpupillary thermotherapy and cryotherapy before IAC.Conclusions:Intra-ophthalmic artery melphalan is an effective treatment for advanced cases of retinoblastoma, with a reasonable level of success. In the short follow up period of this study, it appears that the primary cases showed better results in the control of tumor.

Trigeminocardiac Reflex after Direct Infusion of Chemotherapy into the Ophthalmic Artery for Retinoblastoma

Introduction: Direct intra-ophthalmic artery infusion of chemotherapy has emerged as a front-line treatment modality for both early and advanced forms of retinoblastoma. The procedure has become common practice for neurointerventionalists at institutions with major ophthalmology centers. We present a case series of patients who manifest an autonomic reaction of acute hypoxemia, hypocapnia, hypotension, and bronchospasm consistent with trigeminocardiac reflex. We report our experience with this reaction, which is commonly seen during pediatric strabismus surgery but until now, rarely seen in the neuroangiography suite. Methods: We retrospectively reviewed our 5-year experience with intra-ophthalmic artery chemotherapy infusion for retinoblastoma. Procedure notes, anesthetic records, patient characteristics, and chemotherapeutic agents used were reviewed. Results: Over a 5-year period, 199 treatment sessions were performed in 49 patients. Twenty-eight TCR events were observed in 18 patients. Twenty-seven of these were quickly terminated following interruption of chemotherapy infusion, ventilatory support, and administration of pressor agents. In one case the procedure was aborted due to the prolonged duration of the reflex. There were no permanent sequelae. Conclusions: We found an appreciable incidence of trigeminocardiac reflex to intra-ophthalmic artery infusion of chemotherapy in patients with retinoblastoma. Both interventionalists and anesthesiologists should be aware of this potential event and be prepared to provide immediate resuscitative measures.

Superselective Intraophthalmic Artery Chemotherapy in a Nonhuman Primate Model

We describe the histopathologic findings in a nonhuman primate (NHP) model of superselective intraophthalmic artery chemotherapy (SSIOAC), detailing ocular and orbital vascular adverse effects. To further document, using comprehensive ocular and orbital histopathology, previously reported toxic effects observed with real-time ophthalmoscopy during SSIOAC in a NHP model. Comparative interventional case series. Preclinical trial approved under the guidelines of the Institutional Animal Care and Utilization committee. Six adult male rhesus macaques (Macacca mulatta). The right eye of each NHP was treated with 3 cycles of SSIOAC using either melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Both eyes in each animal were enucleated 6 hours after the final procedure, before euthanasia and formalin perfusion of the NHP; we then performed orbital dissection of the arterial vasculature and optic nerves. Histopathologic examination of the eyes, optic nerves, and orbital vessels of the 6 treated NHPs. We found leukostasis with retinal arteriole occlusion in all treated eyes. Retinal endothelial cells stained positive for 2 inflammatory markers, intercellular adhesion molecule 1 and interleukin 8. Transmission electron microscopy revealed occlusion of the retinal vessels with ultrastructural changes in the endothelial cells and surrounding pericytes. Additional findings included nerve fiber layer infarcts, central retinal artery thrombosis, hypertrophy and occlusion of choroidal arteries with disruption of the internal elastic lamina, patchy choroidal inflammation, and birefringent intravascular foreign bodies. Orbital findings included ophthalmic artery and central retinal artery wall dissection, fracturing of the internal elastic lamina, intimal hyperplasia, and eyelid vessel damage. Optic nerves displayed hemorrhage, leukostasis, and foreign body crystallization. Control eyes, optic nerves, and orbital vessels were normal. Histopathologic examination of our nonhuman primate model for SSIOAC revealed significant toxic effects in the ocular and orbital vasculature. These findings substantiate previous observations with real-time retinal imaging and parallel reported vascular toxic effects in children with retinoblastoma treated with SSIOAC.

Validating a Nonhuman Primate Model of Super-Selective Intraophthalmic Artery Chemotherapy: Comparing Ophthalmic Artery Diameters

Superselective intraophthalmic artery chemotherapy (SSIOAC) is being used for treatment of retinoblastoma; however, the hemodynamic consequences and toxicities are not fully known. We developed a nonhuman primate (NHP) model of SSIOAC and reported our clinical observations. For validation, we compared ophthalmic artery (OA) diameters between NHPs and children (<6 years). Endovascular cannulation of the right OA was performed three times each in six adult male Rhesus macaques. Angiographic OA images were obtained and measured, and postmortem OAs were histologically sectioned and measured. Retrospectively, computed tomography (CT) and magnetic resonance (MR) angiography images of the head in children and adolescents (as an adult reference) were used to measure the OA luminal diameter at its origin. The median angiographic diameter of treated NHP OA origins (n = 6) was 1.06 mm (range 0.94-1.56). Histologic measurements (8 of 12 NHP OAs) gave a median diameter of 1.09 mm (range 0.95-1.41). In 98 children (from 169 consecutive CT and MR angiography studies; median age 1.01 years, range 0.01-5.74), 186 OAs were measurable at the origin (median luminal diameter 1.28 mm, range 0.82-2.00; P = 0.16 for the angiographic NHP diameters versus pediatric cohort). Angiographic measurements of 34 OAs (of 20 consecutive studies of adolescents; median age 16.55 years, range 14.40-18.18) gave a median luminal diameter of 1.45 mm (origin, range 1.13-1.66; P < 0.0001, adolescent versus pediatric). Measurements of the OA luminal diameter at its origin were similar between our NHP and pediatric cohort, validating our NHP model for testing both the hemodynamic consequences and toxicities of SSIOAC.

Real-time Ophthalmoscopic Findings of Intraophthalmic Artery Chemotherapy in Retinoblastoma

Real-time Ophthalmoscopic Findings of Intraophthalmic Artery Chemotherapy in Retinoblastoma

Intra-Ophthalmic Artery Chemotherapy Triggers Vascular Toxicity through Endothelial Cell Inflammation and Leukostasis

Purpose. Super-selective intra-ophthalmic artery chemotherapy (SSIOAC) is an eye-targeted drug-delivery strategy to treat retinoblastoma, the most prevalent primary ocular malignancy in children. Unfortunately, recent clinical reports associate adverse vascular toxicities with SSIOAC using melphalan, the most commonly used chemotherapeutic. Methods. To explore reasons for the unexpected vascular toxicities, we examined the effects of melphalan, as well as carboplatin (another chemotherapeutic used with retinoblastoma), in vitro using primary human retinal endothelial cells, and in vivo using a non-human primate model, which allowed us to monitor the retina in real time during SSIOAC. Results. Both melphalan and carboplatin triggered human retinal endothelial cell migration, proliferation, apoptosis, and increased expression of adhesion proteins intracellullar adhesion molecule-1 [ICAM-1] and soluble chemotactic factors (IL-8). Melphalan increased monocytic adhesion to human retinal endothelial cells. Consistent with these in vitro findings, histopathology showed vessel wall endothelial cell changes, leukostasis, and vessel occlusion. Conclusions. These results reflect a direct interaction of chemotherapeutic drugs with both the vascular endothelium and monocytes. The vascular toxicity may be related to the pH, the pulsatile delivery, or the chemotherapeutic drugs used. Our long-term goal is to determine if changes in the drug of choice and/or delivery procedures will decrease vascular toxicity and lead to better eye-targeted treatment strategies.

Real-Time Ophthalmoscopic Findings of Superselective Intraophthalmic Artery Chemotherapy in a Nonhuman Primate Model

To report real-time ophthalmoscopic findings during superselective intraophthalmic artery chemotherapy (SSIOAC) in a nonhuman primate model. Six adult male Rhesus macaques (Macacca mulatta) were randomly assigned to 1 of 2 treatment cohorts: melphalan (5 mg/30 mL) or carboplatin (30 mg/30 mL). Each animal underwent 3 separate SSIOAC procedures at 3-week intervals. Digital retinal images were obtained during each infusion. Intravenous fluorescein angiography was performed immediately after each procedure. All SSIOAC procedures were successfully completed. Toxicities were equally distributed between drug cohorts. Systemic toxicities included mild bone marrow suppression in all animals and anorexia in 1. One animal had greater than 50% narrowing of the treated ophthalmic artery after its second infusion. All 18 procedures (100%) resulted in pulsatile optic nerve and choroid blanching, retinal artery narrowing, and retinal edema. Of the 18 procedures, retinal artery sheathing was found during 17 (94%), and retinal artery precipitates were seen in 10 (56%); choroidal hypoperfusion was seen by fluorescein angiogram in 18 (100%). Real-time ophthalmic investigations are useful and, in our nonhuman primate model, indicate prevalent, acute ocular vascular toxicities during SSIOAC. Real-time retinal imaging is feasible in a nonhuman primate model of SSIOAC. Application to SSIOAC in children may shed insight into reported vascular toxicities.