A multi-institutional feasibility study of intra-arterial chemotherapy in children with retinoblastoma. A Children's Oncology Group study (COG ARET12P1).

BACKGROUND: Intra-arterial chemotherapy (IA) as a treatment to salvage the eye with advanced retinoblastoma is increasingly utilized based on successes reported by institutions around the world mainly through retrospective studies. OBJECTIVE: To study the feasibility of delivering melphalan directly into the ophthalmic artery in a multi-institutional prospective study in children with newly diagnosed unilateral group D retinoblastoma. METHODS: The Children's Oncology Group (COG) initiated study ARET12P1 in 2014 and was open to nine institutions. Eligible patients older than six months of age were enrolled. The feasibility of delivering three injections of melphalan into the ophthalmic artery every 28 days was assessed. RESULTS: Nine institutions participated in this trial. Fourteen patients were enrolled, two of whom were unevaluable for feasibility. Four patients experienced a feasibility failure. In two patients, the ophthalmic artery could not be accessed for the second IA injection, in one the artery could not be accessed for the first injection, and one patient experienced grade 4 hypotension during the procedure. CONCLUSION: Delivery of prescribed therapy within the context of this study did not meet the feasibility goals of the study with only a 67% feasibility success rate. These results should caution centers that plan to initiate this treatment and suggest investment in training to achieve technical expertise or referral to centers with expertise.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FINDINGS OF DEEP CAPILLARY PLEXUS MICROISCHEMIA AFTER INTRAVENOUS CHEMOTHERAPY FOR RETINOBLASTOMA.

PURPOSE: To study changes in the foveal microvascular anatomy using optical coherence tomography angiography (OCTA) after intravenous chemotherapy (IVC) for retinoblastoma (RB). METHODS: A retrospective comparative case-control series included 10 age-matched normal eyes with no documented ocular pathology (control), 10 fellow eyes of patients with unilateral RB treated with IVC (RB fellow), and 10 eyes with extramacular RB in patients with bilateral RB treated with IVC (RB tumor). All eyes were scanned using enhanced depth imaging optical coherence tomography and OCTA. Enhanced depth imaging optical coherence tomography measurements of central macular thickness and subfoveolar choroidal thickness as well as OCTA measurements of foveal avascular zone (FAZ) area in superficial (sFAZ) and deep (dFAZ) plexus and capillary density (CD) in the superficial (sCD) and deep (dCD) plexus were performed. Comparison among the three groups was conducted. RESULTS: Among the three cohorts (control, RB fellow, and RB tumor), there was no difference in mean age at measurement (12, 10, and 12 years) and mean interval between last IVC and OCTA (RB fellow and RB tumor) (9, 10 years). Optical coherence tomography and OCTA revealed no significant difference in central macular thickness (all P ≥ 0.161), choroidal thickness (all P ≥ 0.066), sFAZ (all P ≥ 0.618), dFAZ (all P ≥ 0.610), and sCD (all P ≥ 0.638) comparing controls versus RB fellow, controls versus RB tumor, and RB fellow versus RB tumor. By contrast, mean dCD was significantly greater in controls (52%), compared with both RB fellow (49%, P = 0.026) and RB tumor (48%, P = 0.028) groups, but no difference was found between RB fellow and RB tumor (49% vs. 48%, P = 0.515). LogMAR visual acuity showed no difference among the three groups (all P ≥ 0.150). CONCLUSION: At mean 10-year follow-up, slight reduction in dCD seems to occur after IVC for RB without alterations in central macular thickness, choroidal thickness, FAZ, or sCD and without visual compromise.

Diffuse Anterior Retinoblastoma with Globe Salvage and Visual Preservation in 3 Consecutive Cases.

PURPOSE: Diffuse anterior retinoblastoma is an exquisitely rare variant of retinoblastoma in which the tumor resides in the anterior segment of the eye, without apparent retinal involvement. Previously published cases have been managed with enucleation. We describe globe salvage and visual preservation in 3 consecutive cases using chemotherapy and radiotherapy. DESIGN: Retrospective case series. PARTICIPANTS: Three children with diffuse anterior retinoblastoma. METHODS: Plaque radiotherapy plus intravenous chemotherapy. MAIN OUTCOME MEASURES: Globe and vision preservation. RESULTS: The mean patient age at presentation elsewhere was 5.7 years (median, 7; range, 3-7 years). There were 2 white female patients and 1 African American male patient. The initial observation by parents/caregiver was reduced vision (n = 1), red eye (n = 1), or cloudy eye (n = 1), and the initial finding by physician was iris tumor (n = 2) or hyphema (n = 1). Referring diagnosis was iris melanoma (n = 1), infectious endotheliitis (n = 1), and possible tumor (nonspecified) (n = 1). At our evaluation, visual acuity was 20/50 to 20/60 (n = 2) and fix no follow (n = 1). In all cases, the opposite eye was normal. Mean intraocular pressure was 20 mm Hg (median, 16; range, 15-30 mmHg). Our examination revealed solid iris tumor (n = 3), ciliary body involvement (n = 2), and anterior chamber seeding (n = 3). In no case was there choroidal or retinal tumor, vitreous seed or subretinal seed, or extrascleral extension. Clear corneal fine-needle aspiration biopsy confirmed the diagnosis as retinoblastoma in each case. Treatment included plaque radiotherapy (n = 3) plus additional systemic chemotherapy (n = 2). At mean follow-up of 35 months (median, 34; range, 20-51 months), there has been no recurrence, extrascleral extension, enucleation, metastasis, or death. In all 3 cases, cataract surgery was necessary at a mean interval of 16 months after complete and stable regression of retinoblastoma. CONCLUSIONS: The rare diffuse anterior form of retinoblastoma can be managed with globe-salvaging alternatives and with visual preservation in selected cases.

Targeted retinoblastoma management: when to use intravenous, intra-arterial, periocular, and intravitreal chemotherapy.

PURPOSE OF REVIEW: The management of retinoblastoma is complex and involves strategically chosen methods of enucleation, radiotherapy, chemotherapy, laser photocoagulation, thermotherapy, and cryotherapy. Chemotherapy has become the most common eye-sparing modality. There are four routes of delivery of chemotherapy for retinoblastoma, including intravenous, intra-arterial, periocular, and intravitreal techniques. The purpose of this review is to discuss the current rationale for each method and the anticipated outcomes. RECENT FINDINGS: The diagnosis of retinoblastoma should be clinically established prior to embarking on a chemotherapy protocol. There are over 25 conditions that can closely simulate retinoblastoma in a young child. In addition, enucleation is an acceptable method for management, particularly with advanced retinoblastoma. Intravenous chemotherapy is generally used for germline mutation (bilateral, familial) retinoblastoma with excellent tumor control for groups A, B, and C and intermediate control for group D eyes. Intra-arterial chemotherapy is used as primary therapy in selected cases for nongermline mutation (unilateral) retinoblastoma with excellent control, and also used as secondary therapy for recurrent solid retinoblastoma, subretinal seeds, and vitreous seeds. Periocular chemotherapy is employed to boost local chemotherapy dose in advanced bilateral groups D and E eyes or for localized recurrences. Intravitreal chemotherapy is used for recurrent vitreous seeds from retinoblastoma. Patients at high risk for metastases should receive intravenous chemotherapy. SUMMARY: Chemotherapy is effective for retinoblastoma and the targeted treatment route depends on the clinical features and anticipated outcomes.

Outcomes of Intravenous Chemotherapy (Chemoreduction) for Retinoblastoma Based on Patient Age in 964 Eyes of 554 Patients.

PURPOSE: To evaluate retinoblastoma control after intravenous chemotherapy (chemoreduction) by patient age at presentation. DESIGN: Retrospective case series. METHODS: This study included 964 eyes of 554 patients treated with chemoreduction at Ocular Oncology Service at Wills Eye Hospital. Patients received 6 monthly cycles of standard chemoreduction. Additional therapies for tumor control were performed as needed. RESULTS: Of 964 eyes, a comparison by age group (<6 months vs. 6-12 months vs. 13-24 months vs. >24 months) revealed more advanced age group with higher frequency of group E tumor (15% vs. 25% vs. 32% vs. 39%, P < 0.001). By treatment outcomes, complete tumor control was achieved with chemoreduction alone more often in less advanced age group (46% vs. 30% vs. 17% vs. 8%, P < 0.001). Additional treatment after chemoreduction was needed more often in more advanced age group with external beam radiotherapy (EBRT; 9% vs. 16% vs. 20% vs. 15%, P = 0.006) or enucleation (12% vs. 18% vs. 26% vs. 37%, P < 0.001). Over time (1994-1998 vs. 1999-2003 vs. 2004-2008 vs. 2009-2013 vs. 2014-2019), the paradigm for additional required treatment after chemoreduction shifted toward less EBRT (27% vs. 24% vs. 14% vs. 7% vs. 2%, P < 0.001) and more intra-arterial (0% vs. 0% vs. 1% vs. 25% vs. 48%, P < 0.001) and intravitreal (0% vs. 0% vs. 3% vs. 10% vs. 20%, P < 0.001) chemotherapy. CONCLUSIONS: Chemoreduction is a safe and effective treatment method for patients with retinoblastoma, demonstrating the best tumor control in the younger age groups.

Management of retinoblastoma in older children (>5 years) using intra-arterial chemotherapy: Comparison of outcomes to prechemotherapy and intravenous chemotherapy eras.

Purpose: Intra-arterial chemotherapy (IAC) has emerged as an effective treatment for retinoblastoma (RB) however, little information exists regarding its use in older patients (>5 years). In the present study, we evaluate the use of IAC (2008-2018) for RB in older patients and compare the outcomes to those in the prechemotherapy (<1994) and intravenous chemotherapy (IVC) (1994-2007) eras. Methods: A retrospective analysis of all patients older than 5 years treated with IAC for RB from 2008-2018. Comparisons were made to 26 active RB cases in older children treated in the prechemotherapy era and to 12 active RB cases treated in the IVC era. Results: There were 13 eyes with RB in 13 older patients treated in the IAC era. The median patient age was 6.8 years. Tumor response was achieved in all 13 eyes at a median interval of 1.1 months from first IAC. Globe salvage was achieved in eight eyes with five eyes requiring enucleation. At 14 months, median follow-up after IAC, there was no metastasis or death. Compared to the prechemotherapy era, those in the IAC era demonstrated significant reduction in need for enucleation (P < 0.001) and EBRT or enucleation (P < 0.001). Compared to the IVC era, there was significant reduction in need for EBRT (P = 0.02) and EBRT or enucleation (P = 0.03) and similar avoidance of metastasis (P > 0.99) and death (P > 0.99). Conclusion: Older patients with RB managed in the IAC era demonstrated reduced need for EBRT or enucleation compared to those managed in the IVC or prechemotherapy eras, with no instance of metastasis or death.

Unilateral Retinoblastoma Managed With Intravenous Chemotherapy Versus Intra-Arterial Chemotherapy. Outcomes Based on the International Classification of Retinoblastoma.

PURPOSE: The objective of this study was to compare outcomes after intravenous chemotherapy (IVC) versus intra-arterial chemotherapy (IAC) for unilateral retinoblastoma. DESIGN: A retrospective comparative interventional case series. METHODS: Patients with unilateral retinoblastoma managed with either IVC using vincristine, etoposide, and carboplatin or IAC using melphalan with or without topotecan with a minimum of 1-year follow-up were compared. The primary outcome measure was globe salvage. RESULTS: Of 91 patients with unilateral retinoblastoma, IVC was employed in 42 (46%) cases and IAC in 49 (54%). By comparison (IVC vs IAC), patients in the IAC group had greater mean tumor diameter (14 vs 18 mm, P < 0.001) and thickness (7 vs 10 mm, P = 0.001), greater percentage with active vitreous seeds (29% vs 55%, P = 0.01), and greater total retinal detachment (10% vs 43%, P < 0.001). There were no cases of group A in either treatment arm. Globe salvage was not significantly different in groups B, C, or E, but there was significantly improved globe salvage with IAC for group D (48% vs 91%, P = 0.004). Control was significantly better with IAC for solid tumor (62% vs 92%, P = 0.002), subretinal seeds (31% vs 86%, P = 0.006), and vitreous seeds (25% vs 74%, P = 0.006). There were no patients with pinealoblastoma, second cancer, metastasis, or death in either group. CONCLUSIONS: For unilateral retinoblastoma, IAC provided significantly superior globe salvage compared with IVC for group D eyes. In addition, IAC provided significantly superior control for solid tumor, subretinal seeds, and vitreous seeds.

Continuing challenges in the management of retinoblastoma with chemotherapy.

The management of retinoblastoma has gradually changed over the past 10 years. Over 95% of children with retinoblastoma in the United States are cured with modern techniques. The challenge remains, however, in maintaining the eye and vision. There is a trend away from enucleation and external beam radiotherapy toward focal conservative treatments involving primary chemoreduction in conjunction with thermotherapy and cryotherapy. This is related to earlier detection of the disease, recognition of more effective chemotherapeutic agents, more focused local treatment modalities, and, most importantly, knowledge of the long-term risks of external beam radiotherapy. Enucleation is still preferable for retinoblastoma that fills most of the eye, especially when the disease is unilateral or when there is concern for tumor invasion into the optic nerve, choroid, or orbit. The orbital integrated implant is placed after enucleation and provides acceptable prosthesis motility and appearance. External beam radiotherapy is still vital for treating advanced retinoblastoma, especially when there is diffuse vitreous or subretinal seeding after failure of other methods and preservation of vision is a priority. The most important recent advance in the management of retinoblastoma is the use of intravenous chemotherapy for tumor reduction, a technique of neoadjuvant chemotherapy termed "chemoreduction." This is followed by tumor consolidation with focal measures such as thermotherapy, cryotherapy, and plaque radiotherapy. This strategy provides reduced tumor volume and often permits consolidation with methods other than radiotherapy. It appears that vision can be preserved in some cases with these methods, avoiding some of the local complications like radiation cataract or macular edema that have been found with radiotherapy techniques. External beam radiotherapy and enucleation can now be avoided in most cases of Reese-Ellsworth groups I (minimal disease) through IV (moderate disease) retinoblastoma. The most advanced stage of retinoblastoma, Reese-Ellsworth group V, continues to provide the greatest difficulty for management, and external beam radiotherapy and enucleation are often employed in addition to chemoreduction to save the child's life. A collaborative prospective study in North America is currently under way to further study the benefits and risks of chemoreduction for minimal, moderate, and advanced retinoblastoma.