International Intraocular Retinoblastoma Classification Group Research Articles

The Impact of Tumor Laterality (Unilateral vs. Bilateral) on Presentation and Management Outcome in Patients with Retinoblastoma.

Background: This study compares the outcomes of managing retinoblastoma between patients with unilateral and bilateral presentations. Methods: The study, conducted at the King Hussein Cancer Center in Amman, Jordan, retrospectively analyzed cases of retinoblastoma treated between March 2003 and December 2019. Evaluation criteria included clinical features, disease stage, treatment methods, and overall management outcomes. Results: The study comprised 697 eyes from 478 patients with retinoblastoma, with 52% being males. Bilateral disease was observed in 70% of patients, and a family history of retinoblastoma was more prevalent in cases with bilateral disease (20%) compared to those with unilateral disease (4%). Unilateral cases had a median age at diagnosis of 28 months, whereas bilateral cases were diagnosed at a median age of 6 months. Extra-ocular retinoblastoma was detected in 1% of eyes. According to the International Intraocular Retinoblastoma Classification (IIRC), 88% of unilateral cases presented with advanced disease (IIRC group D/E), compared to 46% in bilateral cases. Primary enucleation was performed in 29% of unilateral cases and 16% of bilateral cases (p-value 0.0007). Eye salvage rates were 31% in unilateral cases and 68% in bilateral cases (p-value < 0.0001). At 120 months of follow-up, 5% of patients died from secondary neoplasms or metastases, 81% were alive, and 14% were lost to follow-up. There was no significant difference in metastasis, secondary neoplasms, or mortality between patients with unilateral and bilateral retinoblastoma. Conclusions: This study highlights the nuanced differences in clinical characteristics and outcomes between unilateral and bilateral retinoblastoma, emphasizing the necessity of customized management and early detection strategies. It demonstrates that while bilateral retinoblastoma benefits from earlier detection and has a higher rate of eye salvage, there is no significant difference in metastasis or mortality rates when compared to unilateral cases. The critical roles of primary enucleation in advanced cases, along with effective communication and patient education, are also underscored to improve treatment adherence. Overall, these findings point to the importance of tailored approaches in optimizing outcomes for the diverse patient population affected by retinoblastoma.

Abstract 6717: Extracellular vesicles in diagnostic retinoblastoma aqueous humor correlate with disease stage and clinical outcome: a pilot study

Abstract Introduction: Retinoblastoma (RB), a pediatric retinal malignancy, is unique in that it cannot be biopsied, impeding biomarker discovery. Aqueous humor (AH) is an ocular fluid that is an established source of tumor information, serving as a surrogate liquid biopsy. Extracellular vesicles (EVs) are promising biomarker candidates, and were recently established in RB AH. EVs are membrane-enclosed secretory vesicles carrying bioactive molecular information, which can be phenotyped using validated tetraspanin protein markers. Currently, relationships between EVs and RB clinical features are unknown, but establishing such relationships is necessary to determine the utility of EVs as RB biomarkers. Methods: We quantified and phenotyped EVs in 37 AH samples from 18 RB eyes with varying International Intraocular Retinoblastoma Classification (IIRC) stages and explored clinical correlations. Samples were collected from 10 eyes at diagnosis (DX) and 27 eyes during treatment (Tx). By outcome, 6 DX eyes were enucleated and 4 were salvaged. DX samples were collected from one A, one B, six D and two E eyes by IIRC group. 10μL of unprocessed AH underwent Single Particle-Interferometric Reflectance Imaging Sensor (SP-IRIS) (Exoview R100) analysis for fluorescent-based particle count and immunophenotyping of tetraspanin expression (CD63/81/9). Counts were converted to percentages. Statistics were done with Mann-Whitney U, ANOVA, and Tukey’s tests. Results: Samples from DX eyes (n=10) contained a higher number of EVs than samples from Tx eyes (n=27) (1.68 x 107 ± 4.28 x 107 per mL vs. 2.10x 106 ± 1.33 x 106 per mL) by SP-IRIS analysis. By percentage, DX samples were enriched with CD63/81+ EVs (P&amp;lt;0.001) while Tx samples had more homogenous mono-CD63+ dominant EV populations (P=0.007). Enrichment of CD63/81+ EVs was significantly higher in enucleated AH (n=6) than salvaged AH (n=4) when compared by count (P=0.038) and marginally higher when compared by percentage (P=0.067). The CD9/81+ EV population percentage was significant in salvaged eyes (P=0.01). By IIRC, CD63/81+ EVs were most abundant in Group E eyes (n= 2) when compared to Group D eyes (n=6) by count (P&amp;lt;0.001), and when compared to Group A+B eyes (n=2) by count (P=0.01) and percentage (P=0.019). Group A+B eyes had a larger percentage of CD9/81+ EVs than did Group E eyes (P=0.043). Conclusions: EV quantity in RB AH decreases with treatment, and phenotypic expression profiles vary by treatment status and clinical outcome. TheCD63/81+ EV subpopulation is higher in eyes with advanced Group E disease and those requiring enucleation, while the CD9/81+ subpopulation is higher in eyes with less advanced Group A+B disease and those salvaged with treatment. Our data suggests that EV phenotypes correlate with RB clinical features, and further research into these subpopulations offers the prospect of establishing critical RB biomarkers. Citation Format: Sarah Pike, Chen-Ching Peng, Paolo Neviani, Jesse L. Berry, Liya Xu. Extracellular vesicles in diagnostic retinoblastoma aqueous humor correlate with disease stage and clinical outcome: a pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6717.

Intravitreous Chemotherapy as Adjuvant Treatment for Vitreous Seeding in Retinoblastoma: A Philippine Tertiary Hospital Experience

Background. Intravitreal chemotherapy has been an effective addition in treating vitreous seeding in retinoblastoma. However, it was only in 2020 that it was used in the Philippines. There is no literature on its use in multiple Filipino retinoblastoma patients.Objectives. To describe the clinical course of the four patients who are the first to undergo intravitreal chemotherapy for vitreous seeding of retinoblastoma in the Philippine tertiary hospital.Methods. A case series of four eyes of four patients with retinoblastoma who underwent intravitreous injectionof melphalan and topotecan for vitreous seeding at the Department of Ophthalmology and Visual Sciences of aPhilippine tertiary hospital.Results. Two eyes, with International Intraocular Retinoblastoma Classification (IIRC) Group C with vitreous seeding, responded well to intravitreous melphalan and topotecan. One eye had recurrent vitreous seeding despite 10 intravitreal injections. One eye with IIRC Group E, did not respond to intravitreous chemotherapy and was eventually enucleated.This is the first case series on the local use of intravitreous chemotherapy in the country for vitreous seeding inretinoblastoma. The control of 50% achieved in this case series is lower than in other series due to longer treatment interval from poor follow-up and the presence of advanced disease.Conclusion. The use of intravitreous melphalan and topotecan can be an effective adjuvant for systemic chemotherapy in controlling vitreous seeding in eyes with IIRC Group C. It is not effective in controlling IIRC Group E disease.

Clinicopathological Presentation of Retinoblastoma in Ethiopia

Introduction: The presenting symptoms of retinoblastoma in Ethiopia, as well as their relationship to the stage of the disease, are poorly understood, but they could be important as background knowledge for creating early detection initiatives. This study aimed to describe the clinical and histopathological characteristics of retinoblastoma among Ethiopian patients. Methods: A hospital-based cross-sectional analysis of all children with newly diagnosed retinoblastoma during the study period of May 2015 to December 2019, inclusive, who presented to a tertiary referral center during were included. Demographic, clinical, and histological characteristics were collected and descriptive statistics were done using SPSS Version 20.0 software. Results: A total of 217 patients (unilateral 84.3%, bilateral 15.7%) were studied. The median age at presentation was 29 months (34 months vs. 19.5 months in unilateral and bilateral cases, respectively, p < 0.001). Among all patients, 57.8% were male. Leukocoria was the most common presenting sign (37.3%) and followed by fungating mass (31.8%). Tumors were extraocular in 40.1% of cases. From the intraocular cases, 73.3% were advanced International Intraocular Retinoblastoma Classification Group D or E disease. Sixty-two (54.4%) of the eyes had high-risk pathological features. The median lag time was significantly shorter for intraocular versus extraocular cases (5 months vs. 12 months, respectively, p < 0.001). Conclusion: Our results show that the majority of Ethiopian children with retinoblastoma have delayed presentation and late stage at diagnosis. This suggests that national health promotion campaigns to increase public knowledge on the presenting signs of retinoblastoma may be critical to achieving early diagnosis. Furthermore, the development of standard management guidelines informed by this study will be helpful in managing the complex and advanced cases currently observed.

Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma

Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies. To assess the association between genotype and phenotype in patients with RB. This single-center, retrospective cohort study, conducted from January 1, 2000, to September 30, 2017, enrolled 1404 consecutive ascertained patients with RB who consulted an oncogeneticist. All patients had their genotype and phenotype recorded. Statistical analysis was performed from July 1, 2018, to December 31, 2018. RB1 germline and somatic pathogenic variant types, family history, and disease presentation characteristics (ie, age at diagnosis, sex, laterality, and International Intraocular Retinoblastoma Classification group). Among 1404 patients with RB (734 [52.3%] female; mean [SD] age, 20.2 [21.2] months), 866 cases (61.7%) were unilateral and 538 cases (38.3%) were bilateral. Loss of function variants were found throughout the coding sequence, with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P < .001) after excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity); a novel low-penetrance region was identified in exon 24. Compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with an earlier mean (SD) age at diagnosis (12.3 [11.3] months among 457 patients vs 16.3 [13.2] months among 55 patients; difference, 4 months; 95% CI, 1.9-6.1 months; P = .01), more frequent bilateral involvement (84.2% among 452 patients vs 65.2% among 45 patients; difference, 18.9%; 95% CI, 14.5%-23.3%; P < .001), and more advanced International Intraocular Retinoblastoma Classification group (85.3% among 339 patients vs 73.9% among 34 patients; difference: 11.4%; 95% CI, 6.5%-16.3%; P = .047). Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%]; P = .008), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%]; P = .01). These results suggest that RB risk is associated with the germline pathogenic variant and with maintenance of RB protein and that there is a sex-linked mechanism for nongermline carriers.

Examinations under anaesthesia as a measure of disease burden in unilateral retinoblastoma: the London experience

BackgroundEarly diagnosis strategies and advances in retinoblastoma (Rb) management have resulted in nearly 100% survival. More attention should, therefore, be given to quality of life considerations. We aimed to quantify...

The Incidence of Binocular Visual Impairment and Blindness in Children with Bilateral Retinoblastoma

Purpose: The study aimed to assess the incidence of and risk factors leading to visual impairment and legal blindness in children with retinoblastoma. Procedures: This is a single-center, retrospective case series of all patients with bilateral retinoblastoma presenting from 2010 to 2014. Results: A total of 44 patients were included in the study. Visual impairment was present in 14 (38%) children, legal blindness was present in 7 (19%) children. Bilateral macular tumors (BMT) were associated with visual impairment (12 of 18 patients with BMT, 2 of 19 patients without BMT, p = 0.0006) and legal blindness (7 of 18 patients with BMT, 0 of 19 patients without BMT, p = 0.003).The International Intraocular Retinoblastoma Classification (IIRC) of the better eye also predicted visual impairment (16% in IIRC Group A–C, 75% in IIRC Group D, E, p = 0.004) and blindness (3% eye in IIRC Group A–C, 50% in Group D, E, p = 0.005). Various non-Snellen visual acuity measures were able to predict visual impairment in pre-verbal children, providing them with early assistance. Conclusions: The rates of visual impairment and blindness reported in this paper can be used to counsel families regarding the risk of binocular visual impairment. Early detection and support for visually impaired infants are essential as development can be affected by severe visual impairment.

Clinical presentation of retinoblastoma in Alexandria: A step toward earlier diagnosis

ObjectiveTo evaluate the clinical presentation of retinoblastoma in Alexandria, Egypt, correlate the timing of accurate diagnosis with the presence of advanced disease and identify causes of delayed presentation. MethodsRetrospective noncomparative single institution study reviews demographic and clinical data of all new children with retinoblastoma presenting to Alexandria Main University ocular oncology clinic (OOC) from January 2012 to June 2014. Diagnosis time was from initial parental complaint to retinoblastoma diagnosis and referral time was from retinoblastoma diagnosis to presentation to the Alexandria OCC. Delayed Diagnosis and referral were counted if >2weeks. Advanced presentation is defined as clinical TNMH (8th edition) staging of cT2 or cT3 (international intraocular retinoblastoma classification group D or E) in at least one eye or the presence of extra-ocular disease (cT4). ResultsSeventy eyes of 47 children were eligible: 52% unilateral, 7% with family history and 96% presented with leukocorea. Sixty-four percent of children had advanced intraocular disease and none had extra-ocular disease. Delayed presentation occurred in 58% of children and was significantly associated with advanced disease in both unilaterally and bilaterally affected children (p=0.003, 0.002 respectively). The delay in diagnosis was more in unilateral cases while the delay in referral was more in bilateral cases. The main cause of delayed presentation in unilateral retinoblastoma was misdiagnosis (30%) while parental shopping for second medical opinion (30%) was the main cause in bilateral children. ConclusionsDelayed diagnosis is a problem affecting retinoblastoma management. Better medical education and training, health education and earlier screening are recommended to achieve earlier diagnosis.

Optical Coherence Tomography–Guided Decisions in Retinoblastoma Management

Assess the role of handheld optical coherence tomography (OCT) in guiding management decisions during diagnosis, treatment, and follow-up of eyes affected by retinoblastoma. Retrospective, noncomparative, single-institution case series. All children newly diagnosed with retinoblastoma from January 2011 to December 2015 who had an OCT session during their active treatment at The Hospital for Sick Children (SickKids) in Toronto, Canada. The OCT sessions for fellow eyes of unilateral retinoblastoma without any suspicious lesion and those performed more than 6 months after the last treatment were excluded. Data collected included age at presentation, sex, family history, RB1 mutation status, 8th edition TNMH cancer staging and International Intraocular Retinoblastoma Classification (IIRC), and number of OCT sessions per eye. Details of each session were scored for indication-related details (informative or not) and assessed for guidance (directive or not), diagnosis (staging changed, new tumors found or excluded), treatment (modified, stopped, or modality shifted), or follow-up modified. Frequency of OCT-guided management decisions, stratified by indication and type of guidance (confirmatory vs. influential). Sixty-three eyes of 44 children had 339 OCT sessions over the course of clinical management (median number of OCT scans per eye, 5; range, 1-15). The age at presentation and presence of a heritable RB1 mutation significantly correlated with an increased number of OCT sessions. Indications included evaluation of post-treatment scar (55%) or fovea (16%), and posterior pole scanning for new tumors (11%). Of all sessions, 92% (312/339) were informative; 19 of 27 noninformative sessions had large, elevated lesions; of these, 14 of 19 were T2a or T2b (IIRC group C or D) eyes. In 94% (293/312) of the informative sessions, OCT directed treatment decisions (58%), diagnosis (16%), and follow-up (26%). Optical coherence tomography influenced and changed management from pre-OCT clinical plans in 15% of all OCT sessions and 17% of directive sessions. Optical coherence tomography improves the accuracy of clinical evaluation in retinoblastoma management.

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.

Minimal Disseminated Disease in Nonmetastatic Retinoblastoma With High-Risk Pathologic Features and Association With Disease-Free Survival

Fatal metastatic relapse may occur in children with retinoblastoma and high-risk pathologic features (HRPFs). Minimal dissemination (MD) may be an additional tool for risk estimation. The use of cone-rod homeobox (CRX) transcription factor messenger RNA for MD evaluation in metastatic retinoblastoma was previously reported, but no data in nonmetastatic cases with HRPFs are available. To evaluate whether MD is detectable in patients with nonmetastatic retinoblastoma and to assess its prognostic effect on disease-free survival (DFS). This single-institution cohort study of patients with nonmetastatic retinoblastoma and HRPFs used prospectively defined inclusion criteria and a sampling strategy to procure bone marrow (BM) and cerebrospinal fluid (CSF) samples from May 1, 2007, through October 31, 2013. Median follow-up was 38 months (range, 8-89 months). Survival analysis was closed in December 2015, and no further updates were made after that point. The study evaluated CRX messenger RNA by quantitative polymerase chain reaction in BM and CSF at diagnosis and follow-up. In 14 patients, GD2 synthase was used instead of CRX for CSF evaluation. Patients were treated under uniform guidelines. Metastatic relapse. The study included 96 children (median age at study inclusion, 26 months; range, 1-168 months; 46 male [47.9%]; 50 female [52.1%]) with nonmetastatic retinoblastoma and HRPFs (isolated massive choroidal invasion in 14, postlaminar optic nerve invasion in 51 [26 with concomitant massive choroidal and 13 with scleral invasion], 12 with scleral invasion without postlaminar optic nerve invasion, and 7 with tumor at the resection margin of the optic nerve) were evaluated at the time of primary or secondary enucleation. Minimal dissemination was detected in 9 patients (7 BM samples and 2 CSF samples) and was associated with extension beyond the resection margin of the optic nerve and scleral involvement, but only the former was independently associated (adjusted odds ratio, 57.0; 95% CI, 4.8-678.2; P = .001). In addition, MD occurred in 8 of the 43 International Intraocular Retinoblastoma Classification group E eyes with glaucoma (18.6%) and in 8 of 80 (10%) and 1 of 16 children (6.3%) who underwent primary or secondary enucleation, respectively. Children with MD had a 3-year DFS of 0.78 compared with 0.98 in those without MD (95% CI for the difference in DFS, 0.17-0.23; P = .004). These findings identified a high-risk population of children with retinoblastoma and HRPFs with MD. Because the number of events was small, these results, which suggest that children with International Intraocular Retinoblastoma Classification group E retinoblastoma and glaucoma have a higher risk of MD at diagnosis, should not be considered definitive at this time.

Does Pre-Enucleation Chemotherapy Lead to Increased Risk of Metastasis in Advanced Retinoblastoma?

TO THE EDITOR: We read the article by Zhao et al with interest. The authors have addressed an important question in an era where chemotherapy has become the mainstay of treatment in advanced retinoblastoma. The ocular salvage rates by chemotherapy in advanced retinoblastoma, International Intraocular Retinoblastoma Classification group D and E eyes, range between 37% and 47%. The concern about masking of high-risk histopathologic factors is apt especially with the advent of super-selective chemotherapy in retinoblastoma. We understand the limitations posed by a retrospective study. However, we would like to bring to the fore a few issues of concern. First is the lack of a protocol-based treatment in the series presented. The authors have acknowledged that the “pre-enucleation chemotherapy regimen was given at doses lower than therapeutic doses previously published.” The postenucleation treatment regimen in several patients was not based on pTNM risk and therefore inadequate adjuvant therapy was administered. We believe that this deficit in treatment may have affected disease-specific survival as an outcome in this study. Second, we beg to differ with the authors in their comment that primary enucleation would have prevented the spread of retinoblastoma in the four patients who developed metastasis. We suspect that extraocular disease may have been present in these patients at presentation. Despite the authors’ claim that extraocular retinoblastoma was excluded by imaging studies, the possibility of microscopic invasion remains. Even if primary enucleation had been done, the histopathologic risk stage would have remained at pT4b, necessitating aggressive adjuvant therapy. It might be agreed though, that had the patients undergone primary enucleation, time would have been gained in identifying the high risk factors earlier. Third, the shorter follow-up seen in the pre-enucleation chemotherapy group is implied by the authors to result from a lower risk perception leading to decreased surveillance. We feel however, that other unknown factors may have been responsible for the shorter follow-up in this group. The rationale behind chemoreduction is to downstage the tumor. Despite the deaths described in the article in the pre-enucleation chemotherapy group, a large majority (93%) of children did not develop metastasis. Of the four children who went on to die of metastasis, downstaging was noted only in one child while the rest showed a high pTNM stage after enucleation.

Periocular Topotecan for Intraocular Retinoblastoma

To review the effectiveness and toxicity of periocular topotecan hydrochloride in fibrin sealant (Tisseel) for the control of intraocular retinoblastoma. Retrospective medical record review of visually threatening or recurrent intraocular retinoblastoma treated with periocular topotecan. Eight children (10 eyes) received 1 to 4 injections of periocular topotecan in fibrin sealant, without or with concomitant laser and/or single freeze-thaw prechemotherapy cryotherapy. Median dose was 0.18 mg/kg (3.72 mg/m(2)). The 6 children who responded to treatment had small discrete tumors (8 International Intraocular Retinoblastoma Classification group A or B eyes). Of these, prior primary treatment for 3 children (3 eyes) was laser; for 1 child (2 eyes), systemic chemotherapy with focal laser; and for 2 children (3 eyes), periocular topotecan. In 4 children (4 eyes), tumor regression was sufficient for effective focal therapy, but in 2 children (4 eyes), long-term control required systemic chemotherapy. The 2 children who did not respond each had an International Intraocular Retinoblastoma Classification group D eye treated primarily with systemic chemotherapy, focal laser, and cryotherapy and recurrent disease that was not controlled by periocular topotecan; both eyes were eventually enucleated. No ocular and minimal hematological toxic effects were observed. At 11 months' median follow-up after topotecan treatment (18 months since diagnosis), all 8 group A and B eyes were retained with ongoing focal therapy required in only 1 group B eye; the 2 group D eyes were enucleated. Periocular topotecan in fibrin sealant can achieve volume reduction of small and recurrent retinoblastoma sufficient to allow successful focal therapy.

Retinoblastoma CSF Metastasis Cured By Multimodality Chemotherapy Without Radiation

Objective: Cerebrospinal fluid (CSF) metastasis is the most difficult type of retinoblastoma metastasis to cure, even with bone marrow transplant. Most metastatic retinoblastoma cells express P-glycoprotein causing multidrug resistance (MDR). P-glycoprotein-rich blood vessels form blood-brain and blood-eye barriers, inhibit drug entry into central nervous system (CNS) and eyes. High-dose craniospinal radiation is too morbid for treatment of young children. To cure CSF metastasis without radiation, we designed an intensive multimodality chemotherapy regimen. Method: After left eye enucleation, a 4-month-old boy with bilateral International Intraocular Retinoblastoma Classification Group E eyes and CSF metastasis was treated with 7-cycle high-dose carboplatin and etoposide, standard-dose vincristine, and high-dose/short-infusion cyclosporine to inhibit P-glycoprotein. Intraventricular drugs, non-substrate of P-glycoprotein (cytarabine), or less susceptible to MDR (topotecan), contributed to treatment of the metastasis. On achieving complete response, he was consolidated with supralethal-dosage carboplatin, etoposide, and cyclophosphamide, and his bone marrow rescued with autologous cord blood stem cells. Results: Following 1-cycle systemic chemotherapy and 2-dose intraventricular chemotherapy, the CSF metastasis cleared. The right eye tumor regressed completely. The patient remains in remission 8.3 years after diagnosis and 7.8 years post-transplant. Conclusion: Intensive multimodality chemotherapy can cure CSF metastasis in retinoblastoma without incurring extreme morbidity from craniospinal radiation.