Beyond Clinical Trials: Understanding Neurotrophic Tropomyosin Receptor Kinase Inhibitor Challenges and Efficacy in Real-World Pediatric Oncology.

PURPOSE: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. PATIENTS AND METHODS: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. RESULTS: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. CONCLUSION: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.

Nonmetastatic Rhabdomyosarcoma in Children and Adolescents: Overall Results of the European Pediatric Soft Tissue Sarcoma Study Group RMS2005 Study.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The RMS2005 study included two phase III randomized trials for high-risk (HR) and observational trials for low (LR), standard (SR), and very high-risk (VHR) patients who have been partially reported. Herein, we present a comprehensive report of results achieved for the complete unselected nonmetastatic cohort and analyze the evolution of treatment in comparison with previous European protocols. After a median follow-up of 73.1 months, the 5-year event-free survival (EFS) and overall survival (OS) of the 1,733 patients enrolled were 70.7% (95% CI, 68.5 to 72.8) and 80.4% (95% CI, 78.4 to 82.3), respectively. The results by subgroup: LR (80 patients) EFS 93.7% (95% CI, 85.5 to 97.3), OS 96.7% (95% CI, 87.2 to 99.2); SR (652 patients) EFS 77.4% (95% CI, 73.9 to 80.5), OS 90.6% (95% CI, 87.9 to 92.7); HR (851 patients) EFS 67.3% (95% CI, 64.0 to 70.4), OS 76.7% (95% CI, 73.6 to 79.4); and VHR (150 patients) EFS 48.8% (95% CI, 40.4 to 56.7), OS 49.7% (95% CI, 40.8 to 57.9). The RMS2005 study demonstrated that 80% of children with localized rhabdomyosarcoma could be long-term survivors. The study has established the standard of care across the European pediatric Soft tissue sarcoma Study Group countries with the confirmation of a 22-week vincristine/actinomycin D regimen for LR patients, the reduction of the cumulative ifosfamide dose in the SR group, and for HR disease, the omission of doxorubicin and the addition of maintenance chemotherapy.

Pain Assessment in Pediatric Patients with Primary Bone Cancer in a Single Site Cohort / Avaliação da Dor em Pacientes Pediátricos com Câncer Ósseo Primário em uma Coorte de um Centro Único / Evaluación del Dolor en Pacientes Pediátricos con Cáncer Óseo Primario en una Cohorte de un Solo Centro

Introduction: Pain is the main symptom described in cancer patients. Objective: To assess pain classification and management in pediatric patients with primary bone cancer over time: admission, during treatment and follow-up, and to investigate factors associated with pain classification at the last assessment. Method: Retrospective cohort study of osteosarcoma and Ewing's sarcoma cases in individuals <19 years old treated at a single cancer referral site and followed up by a multidisciplinary team. The primary endpoint was pain score at the last assessment. Secondary outcome: evolution of pharmacological treatment. Results: 142 patients were included. The frequency of pain assessment increased during the study period from 53.5% at admission to 68.3% during treatment and 85.9% in follow-up. Of the patients who had pain assessed, 65.8% had pain at admission and 26.2% at the end of the study. There was an increase in the use of strong opioids and antidepressants. In the last evaluation, 56 patients (39.4%) were at the end-of-life and this was not associated with more pain (p=0.68). Meanwhile, those who had more pain used strong opioids (p=0.01) or steroids (p=0.03). Conclusion: Pain management during treatment resulted in increased use of strong opioids and antidepressants with pain reduction, revealing that pain control is possible. In the last assessment, end-of-life patients no longer had pain and patients with pain were the ones who used strong opioids and steroids at the most, showing the difficulty of pain control in some patients.

Introdução: A dor é o principal sintoma descrito em pacientes com câncer. Objetivo: Avaliar a classificação e o manejo da dor em pacientes pediátricos com câncer ósseo primário ao longo do tempo: admissão, durante o tratamento e acompanhamento, e investigar fatores associados à classificação da dor na última avaliação. Método: Estudo de coorte retrospectivo de casos de osteossarcoma e sarcoma de Ewing em indivíduos <19 anos, atendidos em único centro de referência de câncer e acompanhados por equipe multidisciplinar. Desfecho primário: classificação da dor na última avaliação. Desfecho secundário: evolução do tratamento farmacológico. Resultados: Foram incluídos 142 pacientes. A frequência de avaliação da dor aumentou durante o período do estudo de 53,5% na admissão para 68,3% durante o tratamento, chegando a 85,9% no acompanhamento. Dos pacientes cuja dor foi avaliada, 65,8% tiveram dor no recrutamento e 26,2% ao final do estudo. Houve aumento no uso de opioides fortes e antidepressivos. Na última avaliação, 56 pacientes (39,4%) estavam no fim da vida sem associação com mais dor (p=0,68), enquanto os que apresentaram mais dor foram aqueles que usavam opioides fortes (p=0,01) ou esteroides (p=0,03). Conclusão: O manejo da dor durante o tratamento resultou em aumento do uso de opioides fortes e antidepressivos com redução da dor, revelando que o controle da dor é possível. Na última avaliação, os pacientes em fim de vida não apresentavam mais dor, e os pacientes com dor foram os que mais utilizaram opioides fortes e esteroides, evidenciando a dificuldade no controle da dor em alguns pacientes.

Introducción: El dolor es el principal síntoma descrito en pacientes oncológicos. Objetivo: Evaluar la clasificación y el manejo del dolor en pacientes pediátricos con cáncer óseo primario a lo largo del tiempo: registro, durante el tratamiento y seguimiento, e investigar los factores asociados entre la clasificación del dolor y última evaluación. Método: Estudio cohortes retrospectiva de casos de osteosarcoma y sarcoma de Ewing <19 años, tratados en único centro de referencia oncológica y seguidos por equipo multidisciplinar. Desenlace primario: calificación del dolor en la última evaluación. Desenlace secundario: evolución del tratamiento farmacológico. Resultados: Se incluyeron 142 pacientes. La frecuencia de evaluación del dolor aumentó durante el período de estudio del 53,5% al 68,3% y 85,9%. Los pacientes evaluados por dolor, el 65,8% tenía dolor al registro y 26,2% al final del estudio. Hubo aumento en el uso de opioides fuertes y antidepresivos. En la última evaluación, 56 pacientes (39,4%) estaban al final de su vida y esto no se asoció con más dolor (p=0,68), mientras que, quienes presentaron más dolor fueron quienes usaban opioides fuertes (p=0,01) o esteroides (p=0,03). Conclusión: Manejo del dolor durante el tratamiento resultó en un mayor uso de opioides fuertes y antidepresivos con reducción del dolor, revelando que es posible controlar el dolor. La última evaluación, pacientes al final de la vida ya no tenían dolor y pacientes con dolor eran los que más usaban opioides fuertes y esteroides, evidenciando la dificultad en el control del dolor en algunos pacientes.

Pediatric Emergency Care for Children and Adolescents with Cancer: Causes of Consultation and Factors Associated with Hospitalization / Atendimento de Emergência Pediátrica a Crianças e Adolescentes com Câncer: Causas de Consultas e Fatores associados à Internação / Atención de Emergencia Pediátrica al Niño y Adolescente con Cáncer: Causas de Consultas y Factores Asociados a la Hospitalización

Introduction: Pediatric emergency care is essential for adequate medical treatment of pediatric cancer-associated complications and for increasing the chances of cure. Objective: This study aimed to describe pediatric cancer-associated emergencies and outcomes, and to analyze the factors associated with hospitalization. Method: A retrospective observational cohort study was conducted including patients aged ≤19 years who attended the pediatric emergency of a general cancer hospital from April 17 to October 17, 2019. The variables analyzed were demographics, socioeconomic status, disease and treatment factors, reasons for seeking emergency care, and associated outcomes. Results: This study included 309 patients who required 994 emergency consultations, with a total of 766 reasons for seeking care. The median age was 4.86 years; 50.8% were female and 51.5% were white. The patients had solid tumors (49.8%), central nervous system tumors (27.5%), and hematological neoplasms (15.5%). Most of the patients were home discharged (72.2%) or to support houses (6.7%). Fever was the most frequent symptom (30.8%) and the most common reason for admission. 19.2% of the patients were admitted to the ward and 2.0% to the pediatric intensive care unit (2.0%). Only two of the 309 patients (0.6%) seeking care in the pediatric emergency died in the emergency room, and these patients were in end-of-life care. Conclusion: The availability of a pediatric emergency room with skilled professionals in supportive care of pediatric patients with cancer was essential for the management of disease and treatment-related complications

Introdução: O atendimento de emergência pediátrica é essencial para o tratamento adequado das complicações associadas ao câncer pediátrico e para aumentar as chances de cura. Objetivo: Descrever as emergências associadas ao câncer pediátrico e seus desfechos, e analisar os fatores associados à hospitalização. Método: Estudo de coorte observacional retrospectivo incluindo pacientes com idade ≤ 19 anos que foram atendidos na emergência pediátrica de um hospital oncológico geral no período de 17 de abril a 17 de outubro de 2019. As variáveis analisadas foram demográficas, socioeconômicas, fatores relacionados à doença e ao tratamento, razões para procurar atendimento de emergência e resultados associados. Resultados: Foram incluídos 309 pacientes que necessitaram de 994 consultas de emergência, totalizando 766 causas de atendimento. A idade mediana foi de 4,86 anos; 50,8% eram do sexo feminino e 51,5% afirmaram ser da raça branca. Os pacientes apresentavam tumores sólidos (49,8%), tumores do sistema nervoso central (27,5%) e neoplasias hematológicas (15,5%). A maioria dos pacientes foi liberada para a residência (72,2%) ou casa de apoio (6,7%). A febre foi o sintoma mais frequente (30,8%) e o motivo mais comum de admissão. Os pacientes foram internados em enfermaria (19,2%), ou em unidade de terapia intensiva pediátrica (2,0%). Somente dois dos 309 (0,6%) pacientes atendidos na emergência pediátrica morreram nesse setor, estando estes em cuidados de fim de vida. Conclusão: A disponibilidade de um departamento de emergência pediátrica com profissionais especializados e treinados em cuidados de suporte a pacientes pediátricos com câncer foi essencial para o manejo das complicações relacionadas à doença e ao tratamento

Introducción: La atención de emergencias pediátricas es fundamental para el adecuado tratamiento médico de las complicaciones asociadas al cáncer pediátrico y para aumentar las posibilidades de cura. Objetivo: Describir las emergencias asociadas al cáncer pediátrico y sus desenlaces, y analizar los factores asociados a la hospitalización. Método: Estudio de cohorte observacional retrospectivo que incluyó pacientes con edad ≤ 19 años que fueron atendidos en el servicio de emergencias pediátricas de un hospital general de oncología del 17 de abril al 17 de octubre de 2019. Las variables analizadas fueron demográficas, socioeconómicas, factores relacionados con la enfermedad y tratamiento, razones para buscar atención de emergencia y resultados asociados. Resultados: Se incluyeron 309 pacientes que requirieron 994 consultas de urgencia, totalizando 766 causas de atención. La mediana de edad fue de 4,86 años; el 50,8% eran mujeres y el 51,5% eran personas blancas. Los pacientes tenían tumores sólidos (49,8%), tumores del sistema nervioso central (27,5%) y neoplasias hematológicas (15,5%). La mayoría de los pacientes fueron dados de alta a su hogar (72,2%) o casa de apoyo (6,7%). La fiebre fue el síntoma más frecuente (30,8%) y el motivo de ingreso más frecuente. Los pacientes fueron admitidos en una sala (19,2%) o en una unidad de cuidados intensivos pediátricos (2,0%). Solo 2 de 309 (0,6%) pacientes atendidos en el servicio de emergencias pediátricas fallecieron en este sector, estando estos en cuidados al final de la vida. Conclusión: La disponibilidad de un servicio de emergencias pediátricas con profesionales especializados y capacitados en el cuidado de apoyo al paciente oncológico pediátrico fue fundamental para el manejo de las complicaciones relacionadas con la enfermedad y el tratamiento

Diverse mutational spectrum in the 13q14 chromosomal region in a Brazilian cohort of retinoblastoma.

Retinoblastoma is a rare childhood tumor caused by the inactivation of both copies of the RB1 gene. Early diagnosis and identification of heritable RB1 mutation carriers can improve the disease outcome and management via genetic counseling. We used the Multiplex Ligation-dependent Probe Amplification (MLPA) method to analyze the RB1 gene and flanking regions in blood samples from 159 retinoblastoma patients previously negative for RB1 point mutations via Sanger sequencing. We detected a wide spectrum of germline chromosomal alterations, ranging from partial loss or duplication of RB1 to large deletions spanning RB1 and adjacent genes. Mutations were validated via karyotyping, fluorescent in situ hybridization (FISH), SNP-arrays (Single Nucleotide Polymorphism-arrays) and/or quantitative relative real-time PCR. Patients with leukocoria as a presenting symptom showed reduced death rate (p = 0.013) and this sign occurred more frequently among carriers of two breakpoints within RB1 (p = 0.05). All unilateral cases presented both breakpoints outside of RB1 (p = 0.0075). Patients with one breakpoint within RB1 were diagnosed at earlier ages (p = 0.017). Our findings characterize the mutational spectrum of a Brazilian cohort of retinoblastoma patients and point to a possible relationship between the mutation breakpoint location and tumor outcome, contributing to a better prospect of the genotype/phenotype correlation and adding to the wide diversity of germline mutations involving RB1 and adjacent regions in retinoblastoma.

Metastatic Rhabdomyosarcoma: Results of the European Paediatric Soft Tissue Sarcoma Study Group MTS 2008 Study and Pooled Analysis With the Concurrent BERNIE Study.

PURPOSE: Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study. PATIENTS AND METHODS: In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible. RESULTS: MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% (P < .0001) and 3-year OS 60.0% versus 26.0% (P < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance. CONCLUSION: Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.

The do-not-resuscitate-like (DNRL) order, a medical directive for limiting life-sustaining treatment in the end-of-life care of children with cancer: experience of major cancer center in Brazil.

PURPOSE: In the last few decades, interest in palliative care and advance care planning has grown in Brazil and worldwide. Empirical studies are needed to reduce therapeutic obstinacy and medical futility in the end-of-life care of children with incurable cancer. The aim of this study was to investigate the effects of do-not-resuscitate-like (DNRL) orders on the quality of end-of-life care of children with incurable solid tumors at a cancer center in Brazil. METHODS: A retrospective observational cohort study of 181 pediatric patients with solid tumors followed at the Pediatric Oncology Department of the Brazilian National Cancer Institute, Rio de Janeiro, Brazil, who died due to disease progression from 2009 to 2013. Medical records were reviewed for indicators of quality of end-of-life care, including overtreatment, care planning, and care at death, in addition to documentation of the diagnosis of life-limiting illness and the presence of a DNRL order. Data were summarized using descriptive statistics. Univariate and multivariate logistic regression analyses were used to examine associations between demographics, disease, treatment, and indicators of end-of-life care with a DNRL order. RESULTS: A documented DNRL order was associated with lower odds of dying in the intensive care unit or emergency room (80%), dying within 30 days of endotracheal tube placement (80%), or cardiopulmonary resuscitation (CPR) administration at the time of death (96%). CONCLUSION: Placement of DNRL orders early in the disease process is critical in reducing futile treatment in pediatric patients with incurable cancer.

Epidemiological characteristics and survival outcomes of children with medulloblastoma treated at the National Cancer Institute (INCA) in Rio de Janeiro, Brazil.

BACKGROUND: Medulloblastoma (MB),the most common malignant brain tumor of childhood has survival outcomes exceeding 80% for standard-risk and 60% for high-risk patients in high-income countries (HICs). These results have not been replicated in low- and middle-income countries (LMICs), where 80% of children with cancer live. METHODS: This is a retrospective review of 114 children aged 3-18 years diagnosed with MB from 1997 to 2016 at National Cancer Institute (INCA). Sociodemographic, clinical, and treatment data were extracted from the medical records and summarized descriptively. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. RESULTS: The male-to-female ratio was 1.32 and the median age at diagnosis was 8.2 years. Headache (83%) and nausea/vomiting (78%) were the most common presenting symptoms. Five-year OS was 59.1% and PFS was 58.4%. The OS for standard-risk and high-risk patients was 69% and 53%, respectively. The median time to diagnosis interval was 50.5 days and the median time from surgery to radiation therapy initiation was 50.4 days. Patients who lived >40 km from INCA fared better (OS = 68.2% vs. 51.1%, p = .032). Almost 20% of families lived below the Brazilian minimum wage. Forty-five patients (35%) had metastatic disease at admission. Gross total resection was achieved in 57% of the patitents. CONCLUSIONS: Although there are considerable barriers to deliver effective MB treatment in countries like Brazil, the OS seen in the present study demonstrates that good outcomes are not only feasible but can and should be increased with appropriate interventions.

Malnutrition at diagnosis and throughout therapy in pediatric patients with solid tumors: A single-institution study in a developing country.

BACKGROUND: Changesin nutritional status can constitute a risk factor for reduced tolerance and effectiveness of antineoplastic treatment. Knowledge of the nutritional status of pediatric patients is important for implementing interventions to improve outcomes. We aimed to evaluate nutritional status at diagnosis and throughout therapy in pediatric patients with solid tumors. OBJECTIVES: To study the prevalence of malnutrition at diagnosis, compare different assessment tools, and examine longitudinal changes in nutritional status during the treatment of pediatric patients with solid tumors in a Brazilian institution. METHODS: This prospective single-center study enrolled patients with solid tumors (age <19 years) from June 2017 to May 2018. Nutritional evaluations were performed at diagnosis and after 3 and 6 months of treatment. z-Scores for height for age (H/A) and body mass index for age (BMI/A) were calculated using the Anthro/AnthroPlus software and mid-upper arm circumference (MUAC) percentile was used for nutritional classification. RESULTS: The prevalence of nutritional status at diagnosis was 29.3% malnourished, 49.5% adequate, and 21.2% overweight/obese. Nutritional status improved during the first 3 months of treatment, with a reduction in the proportion of malnourished patients and an increased number of patients with adequate nutritional status. CONCLUSIONS: The two combined indices, BMI/A and MUAC, facilitated the diagnosis of a greater number of patients with solid tumors who had nutritional alterations. A high prevalence of malnutrition was present at diagnosis. Nutritional status improved in the first 3 months of treatment and could be related to the multidisciplinary institutional approach following the diagnosis.

Evaluation of risk stratification strategies in pediatric patients with febrile neutropenia

Abstract Objective To evaluate the performance of risk stratification protocols for febrile neutropenia specific to the pediatric population. Methods Retrospective study of a cohort of pediatric patients undergoing cancer treatment with episodes of neutropenia due to chemotherapy and fever, treated at the emergency department of a tertiary cancer hospital from January 2015 to June 2017. Patients who were bone marrow transplant recipients and patients with neutropenia due to causes other than chemotherapy were excluded. Six protocols were applied to all patients: Rackoff, Alexander, Santolaya, Rondinelli, Ammann 2003, and Ammann 2010. The following outcomes were assessed: microbiological infection, death, ICU admission, and need for more than two antibiotics. The performance of each protocol was analyzed for sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operator characteristic (ROC) curve. Results This study evaluated 199 episodes of febrile neutropenia in 118 patients. Microbiological infection was identified in 70 samples from 45 distinct episodes (22.6%), 30 patients used more than two antibiotics during treatment (15%), eight required ICU admission (4%), and one patient died (0.8%). Three protocols achieved high sensitivity indices and NPV regarding the outcomes of death and ICU admission: Alexander, Rackoff, and Ammann 2010; however, Rackoff showed higher sensitivity (0.82) and NPV (0.9) in relation to the microbiological infection outcome. Conclusion The Rackoff risk rating showed the best performance in relation to microbiological infection, death, and ICU admission, making it eligible for prospective evaluation.

Evaluation of risk stratification strategies in pediatric patients with febrile neutropenia.

OBJECTIVE: To evaluate the performance of risk stratification protocols for febrile neutropenia specific to the pediatric population. METHODS: Retrospective study of a cohort of pediatric patients undergoing cancer treatment with episodes of neutropenia due to chemotherapy and fever, treated at the emergency department of a tertiary cancer hospital from January 2015 to June 2017. Patients who were bone marrow transplant recipients and patients with neutropenia due to causes other than chemotherapy were excluded. Six protocols were applied to all patients: Rackoff, Alexander, Santolaya, Rondinelli, Ammann 2003, and Ammann 2010. The following outcomes were assessed: microbiological infection, death, ICU admission, and need for more than two antibiotics. The performance of each protocol was analyzed for sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operator characteristic (ROC) curve. RESULTS: This study evaluated 199 episodes of febrile neutropenia in 118 patients. Microbiological infection was identified in 70 samples from 45 distinct episodes (22.6%), 30 patients used more than two antibiotics during treatment (15%), eight required ICU admission (4%), and one patient died (0.8%). Three protocols achieved high sensitivity indices and NPV regarding the outcomes of death and ICU admission: Alexander, Rackoff, and Ammann 2010; however, Rackoff showed higher sensitivity (0.82) and NPV (0.9) in relation to the microbiological infection outcome. CONCLUSION: The Rackoff risk rating showed the best performance in relation to microbiological infection, death, and ICU admission, making it eligible for prospective evaluation.

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.

Incidence and risk factors of communication, swallowing, and orofacial myofunctional disorders in children and adolescents with cancer and benign neoplasms.

PURPOSE: To describe the incidence and risk factors of communication, swallowing, and orofacial myofunctional disorders in a cohort of children and adolescents with cancer and benign neoplasms. METHODS: A prospective cohort study conducted with children aged ⩾ 2 years and adolescents of both genders admitted at the Pediatric Oncology Department of the Instituto Nacional de Câncer (INCA) between March 2014 and April 2015. Study participants were submitted to a Speech-Language Pathology (SLP) assessment at three different times: (T1) at hospital admission; (T2) six months after admission; (T3) one year after admission. RESULTS: One hundred and sixty individuals were evaluated. At the time of hospital admission, 68 individuals (42.5%) presented with some type of SLP disorder. After one year of follow-up, 22.8% of the patients had developed new impairments. The occurrence of new speech-language disorders had a statistically significant association with the tumor site. In the risk analysis for the development of speech-language disorders with respect to the primary tumor site, compared to other sites, the central nervous system (CNS) tumor group was 8.29 times more likely to present some new alterations, while the head and neck (HN) tumor group had a 10.36-fold higher risk. CONCLUSION: An incidence of 22.8% for communication, swallowing, and orofacial myofunctional disorders was observed. The development of these disorders was greater in individuals with tumors in the CNS and in the HN region.

Vinorelbine and continuous low-dose cyclophosphamide as maintenance chemotherapy in patients with high-risk rhabdomyosarcoma (RMS 2005): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: For more than three decades, standard treatment for rhabdomyosarcoma in Europe has included 6 months of chemotherapy. The European paediatric Soft tissue sarcoma Study Group (EpSSG) aimed to investigate whether prolonging treatment with maintenance chemotherapy would improve survival in patients with high-risk rhabdomyosarcoma. METHODS: RMS 2005 was a multicentre, open-label, randomised, controlled, phase 3 trial done at 102 hospitals in 14 countries. We included patients aged 6 months to 21 years with rhabdomyosarcoma who were considered to be at high risk of relapse: those with non-metastatic incompletely resected embryonal rhabdomyosarcoma occurring at unfavourable sites with unfavourable age (≥10 years) or tumour size (>5 cm), or both; those with any non-metastatic rhabdomyosarcoma with nodal involvement; and those with non-metastatic alveolar rhabdomyosarcoma but without nodal involvement. Patients in remission after standard treatment (nine cycles of ifosfamide, vincristine, dactinomycin with or without doxorubicin, and surgery or radiotherapy, or both) were randomly assigned (1:1) to stop treatment or continue maintenance chemotherapy (six cycles of intravenous vinorelbine 25 mg/m2 on days 1, 8, and 15, and daily oral cyclophosphamide 25 mg/m2, on days 1-28). Randomisation was done by use of a web-based system and was stratified (block size of four) by enrolling country and risk subgroup. Neither investigators nor patients were masked to treatment allocation. The primary outcome was disease-free survival in the intention-to-treat population. Secondary outcomes were overall survival and toxicity. This trial is registered with EudraCT, number 2005-000217-35, and ClinicalTrials.gov, number NCT00339118, and follow-up is ongoing. FINDINGS: Between April 20, 2006, and Dec 21, 2016, 371 patients were enrolled and randomly assigned to the two groups: 186 to stop treatment and 185 to receive maintenance chemotherapy. Median follow-up was 60·3 months (IQR 32·4-89·4). In the intention-to-treat population, 5-year disease-free survival was 77·6% (95% CI 70·6-83·2) with maintenance chemotherapy versus 69·8% (62·2-76·2) without maintenance chemotherapy (hazard ratio [HR] 0·68 [95% CI 0·45-1·02]; p=0·061), and 5-year overall survival was 86·5% (95% CI 80·2-90·9) with maintenance chemotherapy versus 73·7% (65·8-80·1) without (HR 0·52 [95% CI 0·32-0·86]; p=0·0097). Toxicity was manageable in patients who received maintenance chemotherapy: 136 (75%) of 181 patients had grade 3-4 leucopenia, 148 (82%) had grade 3-4 neutropenia, 19 (10%) had anaemia, two (1%) had thrombocytopenia, and 56 (31%) had an infection. One (1%) patient had a grade 4 non-haematological toxicity (neurotoxicity). Two treatment-related serious adverse events occurred: one case of inappropriate antidiuretic hormone secretion and one of a severe steppage gait with limb pain, both of which resolved. INTERPRETATION: Adding maintenance chemotherapy seems to improve survival for patients with high-risk rhabdomyosarcoma. This approach will be the new standard of care for patients with high-risk rhabdomyosarcoma in future EpSSG trials. FUNDING: Fondazione Città della Speranza, Association Léon Berard Enfant Cancéreux, Clinical Research Hospital Program (French Ministry of Health), and Cancer Research UK.

Cost-Effectiveness of Proton Versus Photon Therapy in Pediatric Medulloblastoma Treatment: A Patient Volume-Based Analysis.

BACKGROUND: Proton radiation therapy offers advantages over photon therapy, assisting with severe side effect avoidance. Pediatric patients with medulloblastoma have demonstrated benefit from this technology in recently published cohort studies. OBJECTIVES: To compare the costs and benefits between proton and photon therapy in treating pediatric medulloblastoma. METHODS: The model was built with a lifetime horizon from the Brazilian health system perspective using a 3% discount rate. A microsimulation model was developed after a literature search, comparing scenarios of equipment life span and number of patients treated per year (50, 100, and 150 patients with 10, 25, and 20 years of equipment life span). The baseline parameters were 50 patients treated annually and 20 years of equipment life span. RESULTS: The quality-adjusted life-year gain was 2.71, and the average incremental cost-effectiveness ratio was $34 590.54 per quality-adjusted life-year. For the willingness-to-pay threshold of 1 gross domestic product per capita, it was observed that the incorporation of the technology would be cost-effective if more than 150 patients were treated per year. The weight of the equipment life span and other variables was limited when it varied in the sensitivity analysis, without significant changes to the model results. CONCLUSIONS: Proton therapy is not cost-effective for pediatric medulloblastoma treatment from the Brazilian health system perspective. The investment is not worth when considering the number of potential patients and the country dimensions.

Health-related quality of life of Brazilian children and adolescents with benign and malignant solid tumours: A prospective cohort study during the first year after hospital admission.

INTRODUCTION: This study aims to assess the impact of paediatric benign and malignant solid tumours and its treatment on the health-related quality of life of children and adolescents who were followed up in a Reference Center in Pediatric Oncology in Rio de Janeiro. METHODS: It is a prospective cohort study. Quality of life assessment was performed using the PedsQL™ 4.0 Generic Core Scales and PedsQL™ 3.0 Cancer Module protocols three times: during hospital admission (T1), 6 months after admission (T2) and 1 year after admission (T3). RESULTS: We evaluated 132 patients, 59 men and 73 women, aged 2-17 years. In PedsQL™4.0, the Emotional Functioning scale was the one with the worst scores, while the scores on the Social Functioning scale was the best. In PedsQL™ 3.0, the worst domains were Procedural Anxiety and Worry. Patients with malignant bone tumours had the worst health-related quality of life. The group who received only surgery had better results. Total scores of PedsQL™4.0 and PedsQL™ 3.0 improved between T1 and T3. CONCLUSION: Children and adolescents with malignant and benign neoplasms undergo changes in quality of life as a result of the disease and treatment, but an improvement has been observed over time.

Preventing treatment abandonment for children with solid tumors: A single-center experience in Brazil.

BACKGROUND: High rates of treatment abandonment have been considered one of the major limitations to achieving high cure rates of childhood cancer in developing countries. The aims of this study were to report the prevalence and factors associated with treatment abandonment for children diagnosed with solid tumors in one reference center in Brazil and to describe effective strategies to prevent it. PROCEDURES: A retrospective review was conducted using data from 1139 children (0-18 years) treated for solid tumors at the Brazilian National Cancer Institute, during the period between January 2012 and December 2017. Treatment abandonment was defined as recommended by the International Society of Pediatric Oncology. The impact of implementing a patient-tracking system was evaluated. Descriptive statistics were used to analyze patient characteristics. Chi-square test was used for statistical analysis, with the significance level <0.05. RESULTS: Of 1139 patients, 1.66% refused or abandoned treatment. Although from 2012 to 2013 there was an increase in the abandonment rate, it then decreased by 63.8% from 2013 to 2017 (2.5% to 0.9%). In the multivariate model, only retinoblastoma diagnosis was associated with abandonment (odds ratio = 5.0; 95% confidence interval, 1.2-20.4; P = 0.025). In our cohort, abandonment rates were not associated with increased death. CONCLUSION: Monitoring missed appointments, and early interventions to address issues associated with providing resources to help families during treatment were effective in achieving very low abandonment rates.

Time to diagnosis of retinoblastoma in Latin America: A systematic review.

Retinoblastoma (RB) is the most common intraocular tumor of childhood. In low income countries, Time to diagnosis (TTD: interval between first symptom and diagnosis) has been associated with extraocular disease, metastasis and mortality. However, the relationship between TTD and prognosis is complex and not simply a linear correlation, particularly if TTD is <6 months. This systematic review aims to identify studies reporting TTD of retinoblastoma in Latin America, highlighting factors affecting TTD, alongside proposals and initiatives to obtain shorter intervals. The review also aims to discuss the methodology linked to cancer pathways studies. The study respected PRISMA recommendations, was registered on Prospero, an international database for systematic review registries under number CRD42017076777. MEDLINE/PUBMED, LILACS and SCIELO databases were searched. Studies from Latin America and the Caribbean, published between 1997 and 2017, reporting TTD and age at diagnosis of patients with retinoblastoma were selected. Nine studies were selected, concerning 1560 patients from Argentina, Brazil, Chile, Honduras, Mexico and Peru. The median TTD ranged from 3 to 5 months and the median age at diagnosis ranged from 16.5 to 22.2 months. A prolonged TTD was observed and was associated to damaging results on retinoblastoma outcomes, particularly increasing extraocular disease, and mortality rates. Methodological heterogeneity was observed and reiterates the importance of standardization of TTD studies, allowing more reliable comparisons and greater knowledge about retinoblastoma pathways before diagnosis. Reports on successful initiatives against delayed diagnosis were scarce, emphasizing a need for further studies.

Dental and craniofacial alterations in long-term survivors of childhood head and neck rhabdomyosarcoma.

OBJECTIVE: Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma that affects children. Treatment involves chemoradiotherapy. This study aimed at evaluating the long-term alterations to teeth and cranial bones in children, teenagers, and young adults after oncologic treatment. STUDY DESIGN: We conducted a cross-sectional study of patients undergoing treatment for head and neck RMS between 1988 and 2011. We evaluated demographic, clinical, and treatment data and performed panoramic radiography, cephalometry, and photography. RESULTS: We evaluated 27 long-term survivors, most of whom had been treated between ages 0 to 5 years (51.9%). The total radiation dose applied was 50.4 Gy, and the chemotherapy combination included vincristine, actinomycin D, and cyclophosphamide in 51.9% of the cases. We observed 603 dental alterations, among which 377 (62.7%) occurred in patients ages 0 to 5 years, and root shortening was the most frequent alteration observed (24.2%). With regard to facial bones, 74% of the patients had some level of facial asymmetry, 70.4% had reduced facial depth, 48.4% had mandibles of short size, and 77.8% had reduced facial height. CONCLUSIONS: Children submitted to RMS treatment involving chemotherapy and radiotherapy displayed significant dental and craniofacial alterations, especially when treatment occurred between ages 0 and 5 years.

Fusion status in patients with lymph node-positive (N1) alveolar rhabdomyosarcoma is a powerful predictor of prognosis: Experience of the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

BACKGROUND: Alveolar rhabdomyosarcoma (aRMS) with lymph node involvement (N1 classification) accounts for up to 10% of all cases of RMS. The prognosis is poor, and is comparable to that of distant metastatic disease. In the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS2005 protocol, patients with a histologic diagnosis of aRMS/N1 received intensified chemotherapy with systematic locoregional treatment. METHODS: Patients with aRMS/N1 were enrolled prospectively after primary surgery/biopsy and fusion status was assessed in tumor samples. All patients received 9 cycles of induction chemotherapy and 6 months of maintenance therapy. Local treatment included radiotherapy to the primary site and lymph nodes with or without secondary surgical resection. RESULTS: A total of 103 patients were enrolled. The clinical characteristics of the patients were predominantly unfavorable: 90% had macroscopic residual disease after initial surgery/biopsy, 63% had locally invasive tumors, 77% had a tumor measuring >5 cm, and 81% had disease at unfavorable sites. Fusion genes involving forkhead box protein O1 (FOXO1) were detected in 56 of 84 patients. Events occurred in 52 patients: 43 developed disease recurrence, 7 had disease that was refractory to treatment, and 2 patients developed second neoplasms. On univariate analysis, unfavorable disease site, tumor invasiveness, Intergroup Rhabdomyosarcoma Study group III, and fusion-positive status correlated with worse prognosis. The 5-year event-free survival rate of patients with fusion-positive tumors was 43% compared with 74% in patients with fusion-negative tumors (P = .01). On multivariate analysis, fusion positivity and tumor invasiveness proved to be unfavorable prognostic markers. CONCLUSIONS: Fusion status and tumor invasiveness appear to have a strong impact on prognosis in patients with aRMS/N1. Fusion status will be used to stratify these patients in the next EpSSG RMS study, and treatment will be intensified in patients with fusion-positive tumors. Cancer 2018. © 2018 American Cancer Society.