Socioeconomic status and retinoblastoma survival: Experience of a tertiary cancer center in Brazil.

BACKGROUND: Little is known about socioeconomic status (SES) and its effects in childhood cancer survival. This study aims to discuss the association between SES and survival of patients with retinoblastoma (RB) from a tertiary treatment center. PROCEDURE: A retrospective cohort study was conducted, including all patients with RB referred to the Brazilian National Institute of Cancer in Rio de Janeiro (January 2000-December 2016). RESULTS: Data from 160 patients were analyzed with mean age at diagnosis of 22.85 months (SD ± 14.29). Eighty-three patients (51.9%) had an interval to diagnosis equal to or longer than six months, and 13 children (8.1%) abandoned treatment. Five-year overall survival rate for all patients was 78.8% (95% CI, 72.4%-85.9%). In a multivariate model, patients whose fathers had more than nine years of study had a lower death risk. Patients from families having more than one child under five years had a 213% higher risk of death compared with those living with no other small child. Treatment abandonment also had a profound effect on death risk. CONCLUSION: Childhood cancer is notably important considering the potential years of life lost. RB has even more important elements, as the possibility of vision loss in cases with delayed diagnosis. Family characteristics seem to be highly related to RB survival, especially in low- and middle-income countries, where inequalities are still a public health issue. Strategies to improve survival should focus not only on large-scale settings such as improving national healthcare systems but also on more personalized actions that might help to mitigate disparities.

Global Retinoblastoma Treatment Outcomes: Association with National Income Level.

PURPOSE: To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels. DESIGN: International, multicenter, registry-based retrospective case series. PARTICIPANTS: Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents. METHODS: Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes. MAIN OUTCOME MEASURES: Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy). RESULTS: Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P < 0.001). Patients in UMICs and LMICs reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HICs, metastasis-related mortality was 10.3-fold higher for UMICs and 9.3-fold higher for LMICs, and the risk for local treatment failure was 2.2-fold and 1.6-fold higher, respectively (all P < 0.001). CONCLUSIONS: This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage.

Global Retinoblastoma Presentation and Analysis by National Income Level.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Establishment of a formal program for retinoblastoma: Feasibility of clinical coordination across borders and impact on outcome.

Retinoblastoma is an ocular tumor that occurs in young children, in either heritable or sporadic manner. The relative rarity of retinoblastoma, and the need for expensive equipment, anesthesia, and pediatric ophthalmologic expertise, are barriers for effective treatment in developing countries. Also, with an average age-adjusted incidence of two to five cases per million children, patient number limits development of local expertise in countries with small populations. Lebanon is a small country with a population of approximately 4.5 million. In 2012, a comprehensive retinoblastoma program was formalized at the Children's Cancer Institute (CCI) at the American University of Beirut Medical Center, and resources were allocated for efficient interdisciplinary coordination to attract patients from neighboring countries such as Syria and Iraq, where such specialized therapy is also lacking. Through this program, care was coordinated across hospitals and borders such that patients would receive scheduled chemotherapy at their institution, and monthly retinal examinations and focal laser therapy at the CCI in Lebanon. Our results show the feasibility of successful collaboration across borders, with excellent patient and physician adherence to treatment plans. This was accompanied by an increase in patient referrals, which enables continued expertise development. However, the majority of patients presented with advanced intraocular disease, necessitating enucleation in 90% of eyes in unilateral cases, and more than 50% of eyes in bilateral cases. Future efforts need to focus on expanding the program that reaches to additional hospitals in both countries, and promoting early diagnosis, for further improvement of globe salvage rates.

Racial, Ethnic, and Socioeconomic Disparities in Retinoblastoma Enucleation: A Population-Based Study, SEER 18 2000-2014.

PURPOSE: To determine the effect of race, ethnicity, and census tract-level composite socioeconomic status (SES) on retinoblastoma enucleation. This study augments Truong and associates, providing multivariate analyses combining sociodemographic and clinical characteristics with more accurate SES measures. We hypothesized that children from nonwhite, Hispanic, and lower socioeconomic backgrounds would have increased adjusted odds of enucleation. DESIGN: Retrospective cohort analysis. SETTING: Multicenter population-based study using the Surveillance, Epidemiology, and End Results (SEER) 18 Registries. STUDY POPULATION: Children aged 18 years and younger diagnosed with retinoblastoma between 2000 and 2014. Subjects were identified using International Classification of Diseases-Oncology (ICD-O) site and morphology codes. MAIN OUTCOME MEASURES: Enucleation odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Analysis of 959 retinoblastoma patients revealed that 70.8% were enucleated. Adjusted analyses showed associations between enucleation and Asian (OR 2.00, CI 1.08-3.71) or black (2.42, 1.41-4.16) race, Hispanic ethnicity (1.69, 1.16-2.46), and low SES (1.68, 1.09-2.58). Significantly increased enucleation risk was associated with older age at diagnosis (age 1-2 years 2.55, 1.80-3.61; >2 years 4.88, 2.57-9.25), unilateral disease (5.00, 3.45-7.14), and advanced stage (regional 4.71, 2.51-8.84; distant 3.15, 1.63-6.08). No interactions were observed between race, ethnicity, SES, and stage at diagnosis. Enucleation rates decreased over time across all racial, ethnic, and socioeconomic groups. CONCLUSIONS: Children from nonwhite, Hispanic, and lower socioeconomic backgrounds are more likely to receive enucleation. These associations are independent of stage of diagnosis, suggesting larger systemic disparities in retinoblastoma care. The origin of these differences requires further study and attention by clinicians and policy makers.

A stepwise strategy for rapid and cost-effective RB1 screening in Indian retinoblastoma patients.

India has the highest number of retinoblastoma (RB) patients among the developing countries owing to its increasing population. Of the patients with RB, about 40% have the heritable form of the disease, making genetic analysis of the RB1 gene an integral part of disease management. However, given the large size of the RB1 gene with its widely dispersed exons and no reported hotspots, genetic testing can be cumbersome. To overcome this problem, we have developed a rapid screening strategy by prioritizing the order of exons to be analyzed, based on the frequency of nonsense mutations, deletions and duplications reported in the RB1-Leiden Open Variation Database and published literature on Indian patients. Using this strategy for genetic analysis, mutations were identified in 76% of patients in half the actual time and one third of the cost. This reduction in time and cost will allow for better risk prediction for siblings and offspring, thereby facilitating genetic counseling for families, especially in developing countries.

Update on intra-arterial chemotherapy for retinoblastoma.

The tools for managing retinoblastoma have been increasing in the past decade. While globe-salvage still relies heavily on intravenous chemotherapy, tumors in advanced stage that failed chemotherapy are now referred for intra-arterial chemotherapy (IAC) to avoid enucleation. However, IAC still has many obstacles to overcome. We present an update on the indications, complications, limitations, success, and technical aspects of IAC. Given its safety and high efficacy, it is expected that IAC will replace conventional strategies and will become a first-line option even for tumors that are amenable for other strategies.

Direct costs for retinoblastoma treatment during the first year of comprehensive therapy in China.

PURPOSE: To evaluate the direct costs and analyze the potential cost-driving factors in the first year of retinoblastoma treatment in China. METHODS: Sixty-nine pediatric patients who received multidisciplinary treatment for retinoblastoma in three tertiary hospitals from 2006 to 2011 were included in this retrospective study. The direct costs, including costs for chemotherapy, focal therapy, anesthetic procedure, enucleation, fundus examination, hospitalization and outpatient appointment, transportation, and accommodation for family members, were obtained from medical records and interviews. RESULTS: The average direct costs for retinoblastoma treatment was U.S. $9,422 ± 3,709 per patient during the first year. Of this amount, chemotherapy-related expenses were $2,991 ± 3,083 (31.74%), transportation and accommodation expenses were $2,560 ± 1,348 (27.17%), general anesthetic procedure was $1,081 ± 2,711 (11.48%), and enucleation was $900 ± 1,015 (9.56%). The costs for intra-arterial chemotherapy ($1,224 ± 754) and chemotherapy drugs ($517 ± 134) were major components in chemotherapy-related expenses. The retinoblastoma clinical stage and family income positively correlated with the total direct costs (P = .0358 and .0185, respectively). CONCLUSION: Comprehensive treatment involving chemotherapy imposes an enormous economical burden on families affected by retinoblastoma in China.

Clinical presentation of retinoblastoma in a middle-income country.

The presenting features of retinoblastoma in developing countries and their correlation with disease stage and patient survival are poorly known and they may be useful as background information for planning early diagnosis initiatives. Therefore, we undertook a retrospective review of 508 patients (467 evaluable, 296 unilateral) treated in Argentina from 1988 to 2008. Patients presented at an older age than reported from high-income countries [mean age 24 mo (range, 0 to 165 mo), 31 mo for unilateral (range, 0 to 165 mo), and 13.3 mo (range, 0 to 62 mo) for bilateral disease]. Leukocoria was the most common presenting sign (n=402, 86%). Strabismus was the only complaint in 25 (5.3%) patients. Forty-two patients (9%) presented with an enlarged eyeball and 37 (7.9%) with a red eye. Retinoblastoma was diagnosed in 22 (4.7%) asymptomatic children. These patients and those with strabismus alone were significantly younger and had a significantly better survival. Children presenting with enlarged eyeballs were significantly older and had significantly lower survival. In multivariable analysis older age and presentation with enlarged eyeballs were independently associated to advanced stage and mortality (P<0.001). Retinoblastoma is diagnosed in later stages in our setting and presentation with eye enlargement and increasing age at diagnosis correlate with worse outcome.

Children treated with metronomic chemotherapy in a low-income country: METRO-MALI-01.

BACKGROUND: Metronomic chemotherapy (MC) is defined as the frequent administration of chemotherapy at doses below the maximal tolerated dose and with no prolonged drug-free break. As off-patent chemotherapeutic drugs can be used and given the low toxicity profile of this approach, MC seems to be well adapted to low-income countries. OBJECTIVE: The aim of this study was to assess the efficacy and safety of a vincristine/cyclophosphamide/methotrexate MC regimen given to children with refractory cancer of various tumor types. METHODS: This prospective, pilot, single-center study evaluated the use of MC with a first cycle consisting of weekly vincristine (1.5 mg/m) on days 1, 8, 15, and 22, daily cyclophosphamide (25 mg/m) on days 1 to 21, and twice weekly methotrexate (15 mg/m) on days 21 to 42, followed by a 1-week break. For the following cycles, vincristine was administered only at weeks 1 and 5 of the cycle. This treatment was proposed to children with refractory cancer following treatments with the standard protocols available in our institution and to patients who were not eligible for the protocol. Adverse events were determined through laboratory analyses and investigator observations. RESULTS: From November 2008 to December 2009, 12 children (median age, 3.7 y; range, 2 to 7 y) were included. The most frequent diagnoses were Wilms tumors (6) and retinoblastoma (5). No objective response was observed, but 7 patients experienced disease stabilization (58%) and continued their treatment for 15 to 24 weeks. After a median follow-up of 39 weeks, 6 patients (50%) were alive. Most importantly, in 3 patients (25%), disease remained stable for at least 6 months after completion of treatment. One grade 4 anemia was observed in 1 patient and 1 grade 4 nonfebrile neutropenia in 1 patient. No other grade 3 or 4 toxicities were noted. CONCLUSION: The MC regimen that we report here was well tolerated and was associated with disease stabilization. Most importantly, stabilization could be maintained for over 6 additional months after completion of treatment in 3 patients. The potential of MC in children and young adults in low-income countries warrants further studies.

Retinoblastoma: the challenges of management in Ibadan, Nigeria.

BACKGROUND: Retinoblastoma is a common highly malignant tumor of the eye. Late presentation leads to poor survival rate in many developing countries. OBJECTIVE: To identify problems associated with management of retinoblastoma. METHODS: A retrospective review of cases of retinoblastoma at the University College Hospital, Ibadan, between January 1992 and December 2007. RESULTS: A total of 32 eyes of 26 patients were studied. Sixteen were males and 10 were females. Minimum age at presentation was 4 months and maximum age was 60 months (mean 30.69+/-14.2 mo). Over 90% presented after 1 month of onset. Reasons for late diagnosis included late presentation for unknown reasons, missed diagnosis, and mismanagement in a previous hospital. Eleven of 26 patients defaulted to avoid removal of the eye, and treatment was only completed in 5 patients. Problems included financial constraint regarding investigations and procurement of drugs, as well as availability of the chemotherapy. CONCLUSIONS: Retinoblastoma is a problematic malignancy of childhood associated with management problems often related to difficulty with patients accepting removal of the affected eye and financial constraint for treatment.

Impact of an education program on late diagnosis of retinoblastoma in Honduras.

BACKGROUND: In developed countries, more than 90% of children with retinoblastoma present with limited-stage disease and are cured; however, in countries with limited resources, like Honduras, most patients present with advanced disease and cure rates are less than 50%. Early diagnosis is necessary to improve the survival of children with retinoblastoma in these countries. PROCEDURE: We describe the preliminary results of a retinoblastoma education program linked to a national vaccination campaign in Honduras. Posters and flyers were designed to be accessible to poorly educated readers, to convey the severity of retinoblastoma, and to provide contact information. Charts and an electronic database were reviewed to determine age at diagnosis, presenting signs and symptoms, date of diagnosis, and outcome. RESULTS: During the eight previous years (July 1995-June 2003), 73% of the 59 diagnosed cases of retinoblastoma were extraocular; in contrast, during the post-campaign period (June 2003-January 2005), only 35% of the 23 diagnosed cases showed extraocular spread (P = 0.002). More than one-third of patients in both time periods either refused therapy or abandoned treatment. CONCLUSION: This inexpensive approach is an effective first step toward improving survival of childhood retinoblastoma. Abandonment and refusal of therapy are continuing obstacles.

Socioeconomic impact of modern multidisciplinary management of retinoblastoma.

OBJECTIVE: Our objective for this study was to examine the impact of the modern management of intraocular retinoblastoma on the patient and the family. METHODS: This study comprises a retrospective, noncomparative case series of 25 consecutive patients with multifocal, intraocular retinoblastoma that was treated with primary systemic chemotherapy. Medical charts were reviewed, and the following data were extracted: patients' age and gender, laterality of disease, and Reese-Ellsworth classification of each eye as well as the number of central venous lines placed, cycles of chemotherapy received, outpatient appointments, examinations under anesthesia, focal therapies administered, computed tomography/MRI, radiation treatments, anesthetic procedures administered, and miles traveled. RESULTS: Twenty patients with bilateral and 5 with unilateral intraocular retinoblastoma (median age: 9.3 months) had 895 outpatient appointments and underwent 698 examinations under anesthesia with 230 focal therapies, 347 days of radiotherapy, 226 computed tomography scans/MRIs, and 38 central venous line placements. A total of 1272 anesthetic procedures (median: 50) were performed with no major complication. In all, patients traveled 822312 miles (median: 22214 miles) to receive their care. The median follow-up was 82 months. CONCLUSIONS: Successful retinoblastoma management requires close surveillance, aggressive consolidation, and numerous anesthetic procedures, all of which the patients and the families must endure. There is a significant impact on the patient, the family, and hospital resources.

Critical factors in the performance and cost of two-dimensional gene scanning: RB1 as a model.

Two-dimensional (2-D) gene scanning (TDGS) is a method for mutation detection based on the electrophoretic separation of PCR-amplified DNA fragments according to size and base pair sequence. The use of denaturing gradient gel electrophoresis (DGGE) as the second separation step provides virtually 100% sensitivity, while the 2-D format allows the inspection of multiple gene fragments simultaneously. Analysis of many exons in parallel is greatly facilitated by extensive PCR multiplexing based on preamplification by long-distance PCR. Recently, TDGS has been applied to detect mutations in the retinoblastoma tumor suppressor gene RB1. Using RB1 as a model, we have now analyzed each step of the protocol, presenting overall improvements and a detailed cost analysis, where the total cost of the assay is found to be about $40 (US). An overall picture of TDGS cost-performance, as compared to direct sequencing, is provided as a function of the number of target fragments.

Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma.

To compare costs of molecular and conventional screening of retinoblastoma relatives, we evaluated the direct health care costs. With variables set at the most likely values (baseline), the expected cost (in 1994 Canadian dollars) of conventional screening was $31,430 for a prototype family consisting of seven at-risk relatives (three clinic exams and eight examinations under anaesthetic over the first 3 years of life for each relative). For the molecular strategy that involves looking for the RB1 gene mutation in the proband, testing the relatives for that mutation, and clinical follow-up similar to conventional strategy for relatives with mutation, the expected cost was $8,674, using baseline variables. Sensitivity analysis over the range of values for each variable revealed a significant saving of health care dollars by the molecular route, indicating the benefit of redirecting economic resources to molecular diagnosis in retinoblastoma.

Repercusiones socioeconómicas en el diagnóstico tardío del retinoblastoma / The influence of the social and economical status in the late retinoblastoma dignosis

Con el fin de determinar la repercusión del nivel socioeconómico en el diagnóstico tardío del retinoblastoma, se evaluaron 55 casos, tratados en el Hospital Infantil de México "Federico Gómez", durante cinco años (Enero de 1985 a Diciembre de 1989). De los 55 casos, el mínimo del edad de presentación fue de 30 meses, el 60 por ciento de procedencia foránea, con un estado avanzado de desnutrición en el 67 por ciento de los casos. Se clasificó un 40 por ciento en estadio IV de los cuales un 33 por ciento presentó daño en sistema nerviso central y un 38.6 por ciento daño en médula ósea. Los síntomas predominantes fueron Leucoria 92 por ciento, disminución de agudeza visual 74 por ciento, proptosis 64 por ciento. El 85 por ciento de los pacientes procedía del nivel socioeconómico bajo y ésta es la causa principal de diagnóstico tardío y abandono de tratamiento.