Advanced Intraocular Retinoblastoma Research Articles

Evolving criteria for group E retinoblastoma: impact on outcomes

ObjectiveTo assess the impact of evolving criteria for group E retinoblastoma on ocular survival outcomes. DesignA retrospective observational study. MethodsSingle-institution consecutive case series of patients with advanced intraocular retinoblastoma (groups D and E) were classified based on International Intraocular Retinoblastoma Classification (IIRC) and International Classification of Retinoblastoma (ICRB) criteria. The main outcomes measured were ocular survival, frequency of histopathologic risk factors (HRF), and the need for adjuvant therapy. ResultsA total of 332 eyes of 298 patients were classified into group D (150, 45%) and E eyes (182, 55%) based on IIRC criteria. ICRB classification resulted in upstaging of 57 group D eyes (17%) to group E. Eyes that were upstaged to group E from D in the ICRB classification (E1) differed significantly, with a greater proportion undergoing primary enucleation (17 of 57, 30%) than those that were not (10 of 93, 11%) (p = 0.003). Similar significant differences were observed between group E2 and E3 eyes (p < 0.0001). Ocular survival according to Kaplan–Meier estimates at 12 months of 79%, 59%, 49%, and 1% differed significantly between all groups (ICRB D, E1, E2, and E3, respectively). ConclusionProposed new subgrouping of group E eyes into E1, E2, and E3 based on clinical criteria is based upon natural history of tumor progression and is predictive of ocular survival. Preservation of the existing lower boundaries for group E by ICRB and IIRC offers the possibility of reanalyzing existing published data.

Management of Intraocular Retinoblastoma: ICMR Consensus Guidelines.

Retinoblastoma (RB) is the most common childhood intraocular malignancy. Delayed presentation due to a lack of awareness and advanced intraocular tumors are a common scenario in low-middle income countries (LMICs). Remarkable treatment advances have been made in the past few decades allowing globe salvage in advanced intraocular RB (IORB) including systemic chemotherapy with focal consolidation and targeted treatments like intraarterial chemotherapy and intravitreal chemotherapy. However, a lack of availability and affordability limits the use of such advances in LMICs. External beam radiotherapy, despite risk of second cancers in RB with germline mutations, still remains useful for recalcitrant RB not responding to any other treatment. When choosing conservative treatment for advanced IORB, the cost and long duration of treatment, morbidity from multiple evaluation under anesthesias (EUAs), side effects of treatment and risk of treatment failure need to be taken into account and discussed with the parents. In this article, the authors discuss the ICMR consensus guidelines on the management of IORB.

Intra-arterial chemotherapy in refractory and advanced intraocular retinoblastoma.

To evaluate the efficacy of secondary and salvage intra-arterial chemotherapy (IAC) as a globe salvage treatment modality in advanced and refractory intraocular retinoblastoma. A retrospective chart review of advanced intraocular retinoblastoma (groups D and E International Classification of Retinoblastoma [ICRB] classification) patients refractory to intravenous chemotherapy (IVC) and undergoing IAC as the secondary and salvage treatment modality between December 2018 and June 2021 was carried out. All patients underwent the IAC procedure by super-selective ophthalmic artery catheterization and with triple-drug chemotherapeutic agents of melphalan, topotecan, and carboplatin. Data were collected about tumor regression, eye salvage, metastasis, and survival outcome at follow-up. Out of 13 patients, 12 patients received secondary IAC after being primarily treated with IVC and focal therapies and one patient received rescue IAC after recurrence following primary IAC. Mean number of IAC cycles administered was 2. Overall, globe salvage rate was 53.84%, with a mean follow-up of 17.53 months (range 6-37 months), three patients had enucleation for residual tumor or tumor recurrence. One patient developed metastasis post enucleation and two patients who were lost to follow-up after enucleation advice for residual tumor developed orbital tumor extension and eventually died of metastasis. Secondary triple-drug IAC following failure of IVC, along with other adjunct treatment modalities might a be a cost-effective option for eye salvage in advanced intraocular retinoblastoma patients who refuse enucleation, with a globe salvage rate of 53.84%. It can also be an effective approach to improve treatment compliance and can help in addressing the barrier of treatment refusal when enucleation is advised.

Twenty-Year Retrospective Study of Post-Enucleation Chemotherapy in High-Risk Patients with Unilateral Retinoblastoma.

Primary enucleation is a life-saving treatment for advanced intraocular retinoblastoma, particularly in patients with poor visual potential and functional contralateral eyes. This single-center study presents the treatment outcomes of patients with unilateral retinoblastoma who received primary enucleation and adjuvant chemotherapy with cyclophosphamide, vincristine, doxorubicin, and intrathecal methotrexate (CVDM) between 2000 and 2020. Twenty patients were enrolled in the study. The median age at diagnosis was 26 months (range, 1-45). Eighteen patients (90%) were in group E and two (10%) were in group D, according to the intraocular classification of retinoblastoma guidelines. Excluding one patient with an inadequate specimen, 19 patients (95%) had optic nerve involvement (ONI) at least up to the lamina cribrosa. Eight patients (40%) had choroidal invasion in addition to ONI. Two patients (10%) were surgical resection margin positive. The overall and event-free survival rates were 100% and 95%, respectively, for a median follow-up duration of 102.24 months (range 24.2-202.9). There were no relapses or deaths due to any cause, but one patient developed secondary rhabdomyosarcoma 99.6 months after chemotherapy. Treatment was well tolerated, with minimal hematotoxicity and hepatotoxicity. CVDM as a post-enucleation chemotherapy for advanced intraocular retinoblastoma has excellent outcomes with tolerable toxicity. However, in line with updated treatment trends, further risk stratification and lowering the treatment intensity should be considered. Continued long-term follow-up is required to further determine late effects.

The Role of Bone Marrow in Baseline Investigations for Advanced Intraocular Retinoblastoma

Objective: To assess the rationale for bone marrow biopsy/aspiration as a part of a routine systemic workup in advanced intraocular retinoblastoma (RB) in relation to high-risk histopathological post-enucleation features. Methods: A retrospective observational study was conducted at the Department of Pediatric Hematology and Oncology of the Children’s Hospital, Lahore, Pakistan. Data regarding demographics, clinical presentations, staging workup, and treatment strategies of all the newly diagnosed retinoblastoma cases registered at our centre from January 2018 to December 2019 were collected. Statistical analysis was performed using IBM SPSS statistics version 22. Results: Of the 61 patients, 41 (67%) showed unilateral disease, while bilateral and trilateral involvement was found in 17 (28%) and three (5%) cases, respectively. The mean age of presentation in our cohort was 25 months (median: 24 months; range: &lt;1–72 months). Amongst 81 eyes (61 patients), tumours were limited to an intraocular location in 54 eyes (46 patients). In this group, 42 eyes (38 patients) underwent enucleation. Adverse histopathology was found only in nine (23.68%) patients. None of the patients with the intraocular disease, with or without adverse histopathological features in enucleated eyes, were found to have bone marrow (BM) involvement. For 15 patients with extraocular disease, five (33%) patients were found to have bone marrow involvement based on initial investigations. Conclusion: Our study did not show any correlation between bone marrow positivity and advanced intraocular groups D/E RB. Therefore, BM evaluation can be avoided in this subset of patients with retinoblastoma at presentation, while stage III and IV patients (International Retinoblastoma Staging System IRSS) must be evaluated for metastasis. This will reduce the risks of biopsy to the patients and the burden on services. Keywords: Retinoblastoma, Bone Marrow Involvement, Intraocular disease.

Metastatic Death Based on Presenting Features and Treatment for Advanced Intraocular Retinoblastoma: A Multicenter Registry-Based Study

Purpose:To evaluate presenting features, tumor size, and treatment methods for risk of metastatic death due to advanced intraocular retinoblastoma (RB).Design:International, multicenter, registry-based retrospective case series.Participants:A total of 1841 patients with advanced RB.Methods:Advanced RB was defined by 8th edition American Joint Committee on Cancer (AJCC) categories cT2 and cT3 and new AJCC-Ophthalmic Oncology Task Force (OOTF) Size Groups (1: < 50% of globe volume, 2: > 50% but < 2/3, 3: > 2/3, and 4: diffuse infiltrating RB). Treatments were primary enucleation, systemic chemotherapy with secondary enucleation, and systemic chemotherapy with eye salvage.Main Outcome Measures:Metastatic death.Results:The 5-year Kaplan–Meier cumulative survival estimates by patient-level AJCC clinical subcategories were 98% for cT2a, 96% for cT2b, 88% for cT3a, 95% for cT3b, 92% for cT3c, 84% for cT3d, and 75% for cT3e RB. Survival estimates by treatment modality were 96% for primary enucleation, 89% for systemic chemotherapy and secondary enucleation, and 90% for systemic chemotherapy with eye salvage. Risk of metastatic mortality increased with increasing cT subcategory (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastatic mortality in categories cT3c (glaucoma, hazard ratio [HR], 4.9; P = 0.011), cT3d (intraocular hemorrhage, HR, 14.0; P < 0.001), and cT3e (orbital cellulitis, HR, 19.6; P < 0.001) than in category cT2a and with systemic chemotherapy with secondary enucleation (HR, 3.3; P < 0.001) and eye salvage (HR, 4.9; P < 0.001) than with primary enucleation. The 5-year Kaplan–Meier cumulative survival estimates by AJCC-OOTF Size Groups 1 to 4 were 99%, 96%, 94%, and 83%, respectively. Mortality from metastatic RB increased with increasing Size Group (P < 0.001). Cox proportional hazards regression analysis revealed that patients with Size Group 3 (HR, 10.0; P = 0.002) and 4 (HR, 41.1; P < 0.001) had a greater risk of metastatic mortality than Size Group 1.Conclusions:The AJCC-RB cT2 and cT3 subcategories and size-based AJCC-OOTF Groups 3 (> 2/3 globe volume) and 4 (diffuse infiltrating RB) provided a robust stratification of clinical risk for metastatic death in advanced intraocular RB. Primary enucleation offered the highest survival rates for patients with advanced intraocular RB.

High-risk Pathologic Features Based on Presenting Findings in Advanced Intraocular Retinoblastoma: A Multicenter, International Data-Sharing American Joint Committee on Cancer Study

Purpose:To determine the value of clinical features for advanced intraocular retinoblastoma as defined by the eighth edition of the American Joint Committee on Cancer (AJCC) cT3 category and AJCC Ophthalmic Oncology Task Force (OOTF) Size Groups to predict the high-risk pathologic features.Design:International, multicenter, registry-based retrospective case series.Participants:Eighteen ophthalmic oncology centers from 13 countries over 6 continents shared evaluations of 942 eyes enucleated as primary treatment for AJCC cT3 and, for comparison, cT2 retinoblastoma.Methods:International, multicenter, registry-based data were pooled from patients enrolled between 2001 and 2013. High-risk pathologic features were defined as AJCC categories pT3 and pT4. In addition, AJCC OOTF Size Groups were defined as follows: (1) less than half, (2) more than half but less than two thirds, (3) more than two thirds of globe volume involved, and (4) diffuse infiltrating retinoblastoma.Main Outcome Measures:Statistical risk of high-risk pathologic features corresponding to AJCC cT3 subcategories and AJCC OOTF Size Groups.Results:Of 942 retinoblastoma eyes treated by primary enucleation, 282 (30%) showed high-risk pathologic features. Both cT subcategories and AJCC OOTF Size Groups (P < 0.001 for both) were associated with high-risk pathologic features. On logistic regression analysis, cT3c (iris neovascularization with glaucoma), cT3d (intraocular hemorrhage), and cT3e (aseptic orbital cellulitis) were predictive factors for high-risk pathologic features when compared with cT2a with an odds ratio of 2.3 (P = 0.002), 2.5 (P = 0.002), and 3.3 (P = 0.019), respectively. Size Group 3 (more than two-thirds globe volume) and 4 (diffuse infiltrative retinoblastoma) were the best predictive factors with an odds ratio of 3.3 and 4.1 (P < 0.001 for both), respectively, for high-risk pathologic features when compared with Size Groups 1 (i.e., < 50% of globe volume).Conclusions:The AJCC retinoblastoma staging clinical cT3c–e subcategories (glaucoma, intraocular hemorrhage, and aseptic orbital cellulitis, respectively) as well as the AJCC OOTF Size Groups 3 (tumor more than two thirds of globe volume) and 4 (diffuse infiltrative retinoblastoma) both allowed stratification of clinical risk factors that can be used to predict the presence of high-risk pathologic features and thus facilitate treatment decisions.

Hematologic Complications Associated With Intra-arterial Chemotherapy for Retinoblastoma Treatment: A Single Institution Experience.

Retinoblastoma (RB) is the most common intraocular pediatric malignancy. Advancements in intra-arterial chemotherapy (IAC) for treatment of RB have resulted in dramatic improvement in eye salvage rates. Data regarding IAC outcomes and associated hematologic toxicities are limited. The objective of this retrospective study was to analyze baseline characteristics, efficacy, and hematologic complications associated with IAC treatment in children with RB at a single international referral institution. Ninety-five sessions of IAC were performed in 28 patients. Mean age at RB diagnosis was 12.5 months (SD, 9.2 mo). Fourteen patients had bilateral RB. IAC agents included melphalan, carboplatin, and topotecan. The most common regimens were triple-agent IAC and single-agent melphalan (66.3% and 15.8%, respectively). Median number of IAC sessions was 3 (mean: 3.39, range: 1 to 9). Eye salvage rate was 83.7% with an overall survival rate of 100% at a median follow-up of 29 months (mean: 29.8 mo, range: 1 to 63 mo). A total of 26 patients (92.9%) experienced at least 1 hematologic toxicity during their treatment course Prevalence of neutropenia, anemia, and thrombocytopenia were 89.3%, 85.7%, and 25%, respectively. While IAC is effective in salvaging most eyes with advanced intraocular RB, over half of patients experienced clinically significant neutropenia and anemia. Clinicians should be vigilant in monitoring patients for IAC-related complications.

Characterization of the Portuguese population diagnosed with retinoblastoma

The purpose of this study is to characterize demographically and genetically the Portuguese population with retinoblastoma; to report the clinical stage at presentation and its impact on survival and ocular preservation rate and, finally, to assess the incidence of retinoblastoma in Portugal. Retrospective observational study including children consecutively diagnosed with retinoblastoma at the Portuguese National Referral Center of Intraocular Tumors, between October 2015 and October 2020. Twenty-eight children were diagnosed with retinoblastoma at our center, 15 hereditary from which 12 presented with bilateral retinoblastoma and 3 were unilateral. The overall mean age at diagnosis was 13.6 ± 11.1 months with hereditary retinoblastomas diagnosed slightly earlier at 9.6 ± 6.3 months. A familial history of retinoblastoma was found in only 4 (14.3%) of the cases. A pathogenic mutation in the RB1 gene was found in 13 (46.4%) of the children. The most frequent sign at referral was leukocoria in 71.4% of patients. Considering the ICRB classification of the tumors, 84.6% of non-hereditable hereditary retinoblastomas were referred to our center in advanced stages. In the group of hereditable retinoblastomas 86.7% presented with one of the eyes with advanced intraocular retinoblastoma. Fourteen children had one eye enucleated due to retinoblastoma. No deaths were registered during the study period. Considering the incidence analysis, we registered a year-of-birth controlled incidence analysis of 4.04 per 100.000 living births (IC 95% 1.59–6.49). This is the first characterization of the Portuguese Population diagnosed with Retinoblastoma in the National Reference Center.

Xanthatin Selectively Targets Retinoblastoma by Inhibiting the PLK1-Mediated Cell Cycle.

PurposeRetinoblastoma is the most common primary intraocular malignant tumor in children. Although intra-arterial chemotherapy and conventional chemotherapy have become promising therapeutic approaches for advanced intraocular retinoblastoma, the side effects threaten health and are unavoidable, making the development of targeted therapy an urgent need. Therefore, we intended to find a potential drug for human retinoblastoma by screening an in-house compound library that included 89 purified and well-characterized natural products.MethodsWe screened a panel of 89 natural products in retinoblastoma cell lines to find the inhibitor. The inhibition of the identified inhibitor xanthatin on cell growth was detected through half-maximal inhibitory concentration (IC50), flow cytometry assay, and zebrafish model system. RNA-seq further selected the target gene PLK1.ResultsWe reported the discovery of xanthatin as an effective inhibitor of retinoblastoma. Mechanistically, xanthatin selectively inhibited the proliferation of retinoblastoma cells by inducing cell cycle arrest and promoting apoptosis. Interestingly, xanthatin targeted PLK1-mediated cell cycle progression. The efficacy of xanthatin was further confirmed in zebrafish models.ConclusionsCollectively, our data suggested that xanthatin significantly inhibited tumor growth in vitro and in vivo, and xanthatin could be a potential drug treatment for retinoblastoma.

Lenticular changes in eyes with advanced intraocular retinoblastoma: A histopathological study of 48 enucleated eyes

ABSTRACT Purpose To evaluate the lenticular changes in advanced intraocular retinoblastoma (RB) and identify the risk factors for cataract in these eyes. Methods Retrospective analysis of 48 primary enucleations. Results All enucleated eyes were classified either as group D (n = 7; 15%) or group E (n = 41; 85%) tumors based on the International Classification of Intraocular Retinoblastoma. Of the 48 enucleated eyes with RB, cataract was noted clinically in only 5 (18%) cases, while histopathology revealed cataractous changes in 28 (58%) cases. Based on histopathology, the cataractous changes included anterior subcapsular cataract (n = 10; 36%), cortical cataract (n = 6; 21%), posterior subcapsular cataract (n = 10; 36%) and both anterior and posterior subcapsular cataract (n = 2; 7%). Based on multivariate logistic regression, only increased area of necrosis on histopathology was the significant (p = .009) factor predictive of cataractous changes in lens with an odds ratio of 1.08. Conclusion Eyes with advanced RB can harbor cataract in 58% cases, though most of these are subclinical. Clinically significant cataract may be evident in only 18% cases. Increased tumor necrosis is associated with the development of cataractous changes in RB cases.

Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG).

Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers.

Chemotherapy for Retinoblastoma: Impact of Intravitreal Chemotherapy.

Chemotherapy is now the primary treatment of retinoblastoma in eyes with visual potential or those that are considered not advanced for retinoblastoma. In addition to intravenous chemotherapy (IVC), drugs delivered via alternative routes such as intra-arterial and intravitreal administration have emerged as promising options for management of retinoblastoma. Various studies have shown excellent results in salvaging nearly 100% of groups A-C eyes; however, intra-arterial chemotherapy (IAC) seems to offer superior local control rates as compared with IVC for advanced intraocular retinoblastoma (groups D and E eyes). Intravitreal chemotherapy (IVitC), that delivers the highest concentration of drug in the vitreous cavity while minimizing systemic drug concentration, has emerged in recent years (2012) as an effective treatment for refractory or persistent vitreous seeding. The role of concomitant and subsequent therapies is an important consideration, particularly the use of IVitC in combination with IAC. As IVitC became acceptable during the era of IAC, most of the patients treated previously with IVC did not receive IVitC. Therefore, it is possible that some of the IVC failures could have been avoided with the use of IVitC. We provide our perspective of published data that seems to be skewed by evolving practice patterns that project enhanced efficacy of IAC when compared with historic control rates achieved with IVC. In absence of better-quality data or randomized controlled trials, it is hard to establish superiority of one treatment over the other.

Intravitreal melphalan hydrochloride vs propylene glycol-free melphalan for retinoblastoma vitreous seeds: Efficacy, toxicity and stability in rabbits models and patients

The use of intravitreal chemotherapy has revolutionized the treatment of advanced intraocular retinoblastoma, as intravitreal melphalan has enabled difficult-to-treat vitreous tumor seeds to be controlled, leading to many more eyes being saved. However, melphalan hydrochloride (MH) degrades rapidly in solution, increasing logistical complexity with respect to time between medication preparation and administration for intravitreal administration under anesthesia for retinoblastoma. A new propylene glycol-free melphalan (PGFM) formulation has greater stability and could therefore improve access and adoption of intravitreal chemotherapy, allowing more children to retain their eye(s). We compared the efficacy and toxicity of both formulations, using our rabbit xenograft model and clinical patient experience. Three weekly 12.5 μg intravitreal injections of MH or PGFM (right eye), and saline (left eye), were administered to immunosuppressed rabbits harboring human WERI-Rb1 vitreous seed xenografts. Residual live cells were quantified directly, and viability determined by TUNEL staining. Vitreous seeds were reduced 91% by PGFM (p = 0.009), and 88% by MH (p = 0.004; PGFM vs. MH: p = 0.68). All residual cells were TUNEL-positive (non-viable). In separate experiments to assess toxicity, three weekly 12.5 μg injections of MH, PGFM, or saline were administered to non-tumor-bearing rabbits. Serial electroretinography, optical coherence tomography (OCT) and OCT-angiography were performed. PGFM and MH both caused equivalent reductions in electroretinography amplitudes, and loss of retinal microvasculature on OCT-angiography. The pattern of retinal degeneration observed on histopathology suggested that segmental retinal toxicity associated with all melphalan formulations was due to a vitreous concentration gradient-effect. Efficacy and toxicity were assessed for PGFM given immediately (within 1 h of reconstitution) vs. 4 h after reconstitution. Immediate- and delayed-administration of PGFM showed equivalent efficacy and toxicity. In addition, we evaluated efficacy and toxicity in patients (205 eyes) with retinoblastoma vitreous seeds, who were treated with a total of 833 intravitreal injections of either MH or PGFM as standard of care. Of these, we analyzed 118 MH and 131 PGFM monotherapy injections in whom serial ERG measurements were available to model retinal toxicity. Both MH and PGFM caused reductions in electroretinography amplitudes, but with no statistical difference between formulations. Comparing those patient eyes treated exclusively with PGFM versus those treated exclusively with MH, efficacy for tumor control and globe salvage was equivalent (PGFM vs. MH: 96.2% vs. 93.8%, p = 0.56), but PGFM-treated eyes received fewer injections than MH-treated eyes (average 3.2 ± 1.9 vs. 6.4 ± 2.1 injections, p < 0.0001). Taken together, these rabbit experiments and our clinical experience in retinoblastoma patients demonstrate that MH and PGFM have equivalent efficacy and toxicity. PGFM was more stable, with no decreased efficacy or increased toxicity even 4 h after reconstitution. We therefore now use PGFM over traditional MH for our patients for intravitreal treatment of retinoblastoma.

Cell-free DNA profiling in retinoblastoma patients with advanced intraocular disease: An MSKCC experience.

PurposeThe enucleation rate for retinoblastoma has dropped from over 95% to under 10% in the past 10 years as a result of improvements in therapy. This reduces access to tumor tissue for molecular profiling, especially in unilateral retinoblastoma, and hinders the confirmation of somatic RB1 mutations necessary for genetic counseling. Plasma cell‐free DNA (cfDNA) has provided a platform for noninvasive molecular profiling in cancer, but its applicability in low tumor burden retinoblastoma has not been shown. We analyzed cfDNA collected from 10 patients with available tumor tissue to determine whether sufficient tumorderived cfDNA is shed in plasma from retinoblastoma tumors to enable noninvasive RB1 mutation detection.MethodsTumor tissue was collected from eye enucleations in 10 patients diagnosed with advanced intra‐ocular unilateral retinoblastoma, three of which went on to develop metastatic disease. Tumor RB1 mutation status was determined using an FDA‐cleared tumor sequencing assay, MSK‐IMPACT. Plasma samples were collected before eye enucleation and analyzed with a customized panel targeting all exons of RB1.ResultsTumor‐guided genotyping detected 10 of the 13 expected somatic RB1 mutations in plasma cfDNA in 8 of 10 patients (average variant allele frequency 3.78%). Without referring to RB1 status in the tumor, de novo mutation calling identified 7 of the 13 expected RB1 mutations (in 6 of 10 patients) with high confidence.ConclusionPlasma cfDNA can detect somatic RB1 mutations in patients with unilateral retinoblastoma. Since intraocular biopsies are avoided in these patients because of concern about spreading tumor, cfDNA can potentially offer a noninvasive platform to guide clinical decisions about treatment, follow‐up schemes, and risk of metastasis.

Impact of Systemic Chemotherapy and Delayed Enucleation on Survival of Children with Advanced Intraocular Retinoblastoma

Primary enucleation is a well-established method to achieve cure for advanced intraocular retinoblastoma. Recent treatment advances have induced a trend toward trial eye salvage using chemotherapy or other modalities. We investigated how pre-enucleation/postenucleation systemic chemotherapy and the resulting delayed enucleation affect patient survival after failed trial eye salvage. Multicenter, retrospective cohort study. Children with Group D and E retinoblastoma primarily or secondarily enucleated at 29 Chinese treatment centers. Data reviewed included clinical staging, time from diagnosis to enucleation, numbers of cycles of carboplatin, etoposide/teniposide and vincristine chemotherapy, disease-specific survival (DSS), histopathology, and follow-up. Primary outcome was DSS. Secondary outcome was histopathology of enucleated eyes. Primarily enucleated eyes had significantly shorter delay from diagnosis to enucleation than eyes treated with pre-enucleation chemotherapy (P < 0.001). Delay between diagnosis and enucleation >3.5 months (Group D) and >2 months (Group E) decreased survival (Group D: P= 0.018; Group E: P= 0.017). Compared with primarily enucleated children, children with 1 to 3 cycles of pre-enucleation chemotherapy for Group E eyes had no significant difference in survival (P= 0.74), but those who received ≥4 cycles had worse survival (P= 0.025). After pre-enucleation chemotherapy, more children with Group E (but not Group D) eyes had high-risk histopathology (pT3/pT4) (Group D: P= 0.076; Group E: P < 0.001) and worse survival than those primarily enucleated (P< 0.001). Postenucleation chemotherapy improved survival of children with high-risk histopathology (pT3/pT4) (P = 0.001) but did not change survival of children with low-risk histopathology (pT1/pT2) (P= 0.52). We observed that pre-enucleation chemotherapy offered no survival benefit and timely enucleation minimized risk of metastatic death. Postenucleation chemotherapy improved survival of children with high-risk histopathology but was not useful for those with low-risk histopathology. These findings facilitate informed discussion on the risks and benefits of delayed enucleation, the use of systemic chemotherapy for trial salvage of eyes with advanced intraocular retinoblastoma, and the specific children who benefit from postenucleation chemotherapy.

Unilateral unifocal advanced intraocular retinoblastoma: is reasonable to adopt intra‐arterial chemotherapy as single therapeutic choice?

AbstractPurposeTo report the outcome of 30 naive unilateral unifocal retinoblastoma cases treated with intra‐arterial chemotherapy alone.MethodsFrom 2008 to 2019, 192 eyes affected with retinoblastoma have been treated with intra‐arterial chemotherapy (IAC). 100 out of 192 (52%) eyes were naive advanced unilateral unifocal retinoblastoma (Group B‐E). 30 out of 100 (30%) received intra‐arterial chemotherapy alone. All patients underwent genetic testing at diagnosis. MR was performed at diagnosis, during treatment (when necessary), 3 months after last infusion and annually to evaluate eyeball growth.ResultsTumor control and globe salvage was achieved in 100% of the reported cases (follow‐up ranged from 11 years to 9 months). New tumors or relapse have not been detected. No further local or systemic therapies were necessary. Procedure complications and local and systemic effects are reported. No intraocular or orbital tumor recurrence or metastatic disease have been observed observed.ConclusionsThe outcome will be correlated to genetic analysis, doses and drugs used (alone or in combination) and number of infusions received.

Delayed Enucleation With Neoadjuvant Chemotherapy in Advanced Intraocular Unilateral Retinoblastoma: AHOPCA II, a Prospective, Multi-Institutional Protocol in Central America.

PURPOSETreatment abandonment because of enucleation refusal is a limitation of improving outcomes for children with retinoblastoma in countries with limited resources. Furthermore, many children present with buphthalmos and a high risk of globe rupture during enucleation. To address these unique circumstances, the AHOPCA II protocol introduced neoadjuvant chemotherapy with delayed enucleation.PATIENTS AND METHODSPatients with advanced unilateral intraocular disease (International Retinoblastoma Staging System [IRSS] stage I) were considered for upfront enucleation. Those with diffuse invasion of the choroid, postlaminar optic nerve, and/or anterior chamber invasion received six cycles of adjuvant chemotherapy (vincristine, carboplatin, and etoposide). Patients with buphthalmos and those with a perceived risk for enucleation refusal and/or abandonment were given two to three cycles of chemotherapy before scheduled enucleation followed by adjuvant chemotherapy to complete six cycles, regardless of pathology.RESULTSA total of 161 patients had unilateral IRSS stage I disease; 102 underwent upfront enucleation, and 59 had delayed enucleation. The estimated 5-year abandonment-sensitive event-free and overall survival rates for the group were 0.81 ± 0.03 and 0.86 ± 0.03, respectively. The 5-year estimated abandonment-sensitive event-free survival rates for patients undergoing upfront and delayed enucleation were 0.89 ± 0.03 and 0.68 ± 0.06, respectively (P = .001). Compared with AHOPCA I, abandonment for patients with IRSS stage I retinoblastoma decreased from 16% to 4%.CONCLUSIONAHOPCA describes the results of advanced intraocular retinoblastoma treated with neoadjuvant chemotherapy. In eyes with buphthalmos and patients with risk of abandonment, neoadjuvant chemotherapy can be effective when followed by enucleation and adjuvant chemotherapy. Our study suggests that this approach can save patients with buphthalmos from ocular rupture and might reduce refusal of enucleation and abandonment.

Intra-arterial chemotherapy as primary or secondary treatment for infants diagnosed with advanced retinoblastoma before 3\u2009months of age

BackgroundTo evaluate the safety and efficacy of intra-arterial chemotherapy (IAC) for the primary or secondary treatment of infants diagnosed with advanced retinoblastoma before 3 months of age.MethodsThis single-center retrospective study included 39 infants (42 eyes) aged ≤3 months who were diagnosed with unilateral or bilateral advanced intraocular retinoblastoma (group D and E eyes) and received IAC as primary or secondary treatment between June 2012 and February 2017. Based on each patient’s therapeutic history and response to chemotherapeutic drugs, melphalan, topotecan, and/or carboplatin were used for IAC. The main outcomes included the technical success rate for IAC, survival rates, and adverse events.ResultsIn total, 29 and 13 eyes received IAC as primary and secondary treatments, respectively. Catheterization was successful in 136 of 137 procedures. All eyes in the secondary IAC group had previously received intravenous chemotherapy. The mean number of IAC sessions for each eye was 3 (range, 2–6). The 2-year ocular survival rates were 80.7% (95% confidence interval [CI], 58.9–91.7) in the primary IAC group and 91.7% (95% CI, 53.9–98.8) in the secondary IAC group. During the follow-up period, 1 patient with unilateral disease (group E) developed extraocular disease and died. The 2-year recurrence-free survival rates in the primary and secondary IAC groups were 71.9% (95% CI, 49.4–85.7) and 75.0% (95% CI, 40.8–91.2), respectively. During each catheterization procedure, the main complications included eyelid erythema (2.4%), fundus hemorrhage (11.9%), myelosuppression (7.7%), transient vomiting and hair loss (2.6%), and transient pancytopenia (2.6%). Prolonged complications included phthisis bulbi (19.0%), vision loss (19.0%), poor vision (9.5%), and cataract (2.4%). There was no case of stroke, neurological impairment, secondary malignant tumor, or metastasis.ConclusionsOur findings suggest that IAC, whether primary or secondary, is effective and fairly safe for the management of advanced retinoblastoma in infants aged < 3 months. However, adverse events related to intra-arterial injection and the visual outcomes cannot be neglected and require further investigation.

Bilateral advanced (group D or E) intraocular retinoblastoma: outcomes in 72 Asian Indian patients.

To study the clinical presentation, treatment, and outcomes of patients with bilateral advanced intraocular retinoblastoma. Retrospective case series of 72 patients. The mean age at presentation was 19 months. Leukocoria (n = 49, 68%) was the most common presenting complaint. The tumors were classified as groups D (n = 60, 42%) or E (n = 84, 58%) based on the Philadelphia version of International Classification of Retinoblastoma (ICRB); groups D (n = 84, 58%) or E (n = 60, 42%) based on Children's Hospital Los Angeles version of International Classification of Intraocular Retinoblastoma (ICIoR); T2 (n = 116, 81%) or T3 (n = 28, 19%) based on 8th edition American Joint Committee Classification (AJCC). Systemic chemotherapy (n = 138, 96%) was the most common primary treatment modality. The chance of globe salvage was higher for group D based on ICRB (83%; odds ratio (OR) 7.73; 95% confidence interval (CI) 3.45-17.33) or ICIoR (81%; OR 12.75; 95% CI 5.74-28.34) and T2b (73%; OR 5.19; 95% CI 2.51-10.73) based on AJCC. Over a mean follow-up period of 59 months, tumor recurrence was noted in 42 (29%) eyes and globe salvage was achieved in 83 (58%) eyes. Of the 50 eyes where vision was recorded, vision of 20/200 or better was achieved in 24 (48%) eyes. There were events of leukemia (n = 1, 1%), pinealoblastoma (n = 1, 1%), systemic metastasis (n = 3, 4%), and death (n = 4, 6%) during the follow-up period. Multimodality treatment allows globe salvage (58%) and vision salvage (48%) in eyes with advanced group D and E intraocular retinoblastoma.