RESUMO
BACKGROUND: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. METHODS: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. RESULTS: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. CONCLUSIONS: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42016036802.
Assuntos
Neoplasias do Sistema Nervoso Central , Terapia com Prótons , Humanos , Terapia com Prótons/métodos , Terapia com Prótons/efeitos adversos , Neoplasias do Sistema Nervoso Central/radioterapia , Criança , Adolescente , Adulto Jovem , Resultado do Tratamento , AdultoRESUMO
In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.
Assuntos
COVID-19 , Humanos , SARS-CoV-2 , Pandemias , Consenso , OncologiaRESUMO
BACKGROUND: Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. METHODS: This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. FINDINGS: The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. INTERPRETATION: Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. FUNDING: None.
Assuntos
Antineoplásicos , Medicamentos Essenciais , Neoplasias , Adolescente , Criança , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Oncologia , Europa (Continente) , Medicamentos Essenciais/uso terapêutico , Antineoplásicos/uso terapêuticoRESUMO
BACKGROUND: Children with cancer are frequently immunocompromised. While children are generally thought to be at less risk of severe SARS-CoV-2 infection than adults, comprehensive population-based evidence for the risk in children with cancer is unavailable. We aimed to produce evidence of the incidence and outcomes from SARS-CoV-2 in children with cancer attending all hospitals treating this population across the UK. METHODS: Retrospective and prospective observational study of all children in the UK under 16 diagnosed with cancer through data collection from all hospitals providing cancer care to this population. Eligible patients tested positive for SARS-CoV-2 on reverse transcription polymerase chain reaction (RT-PCR). The primary end-point was death, discharge or end of active care for COVID-19 for those remaining in hospital. RESULTS: Between 12 March 2020 and 31 July 2020, 54 cases were identified: 15 (28%) were asymptomatic, 34 (63%) had mild infections and 5 (10%) moderate, severe or critical infections. No patients died and only three patients required intensive care support due to COVID-19. Estimated incidence of hospital identified SARS-CoV-2 infection in children with cancer under 16 was 3%. CONCLUSIONS: Children with cancer with SARS-CoV-2 infection do not appear at increased risk of severe infection compared to the general paediatric population. This is reassuring and supports the continued delivery of standard treatment.
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COVID-19/epidemiologia , Portador Sadio/epidemiologia , Neoplasias/virologia , SARS-CoV-2/genética , Adolescente , COVID-19/mortalidade , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Mortalidade , Neoplasias/mortalidade , Estudos Prospectivos , RNA Viral/genética , Estudos Retrospectivos , Índice de Gravidade de Doença , Reino Unido/epidemiologiaRESUMO
The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community.
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COVID-19/patologia , Disseminação de Informação/métodos , Bibliotecas Médicas , Neoplasias/patologia , Criança , Comorbidade , Recursos em Saúde , Humanos , Sistema de Registros , SARS-CoV-2RESUMO
The traditional cancer drug development pathway is increasingly being superseded by trials that address multiple clinical questions. These are collectively termed Complex Innovative Design (CID) trials. CID trials not only assess the safety and toxicity of novel anticancer medicines but also their efficacy in biomarker-selected patients, specific cancer cohorts or in combination with other agents. They can be adapted to include new cohorts and test additional agents within a single protocol. Whilst CID trials can speed up the traditional route to drug licencing, they can be challenging to design, conduct and interpret. The Experimental Cancer Medicine Centres (ECMC) network, funded by the National Institute for Health Research (NIHR), Cancer Research UK (CRUK) and the Health Boards of Wales, Northern Ireland and Scotland, formed a working group with relevant stakeholders from clinical trials units, the pharmaceutical industry, funding bodies, regulators and patients to identify the main challenges of CID trials. The working group generated ten consensus recommendations. These aim to improve the conduct, quality and acceptability of oncology CID trials in clinical research and, importantly, to expedite the process by which effective treatments can reach cancer patients.
Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto/métodos , Neoplasias/tratamento farmacológico , Projetos de Pesquisa , HumanosRESUMO
BACKGROUND: The European Neuroblastoma Study Group 5 (ENSG5) trial showed that time-intensive "rapid" induction chemotherapy (COJEC) was superior to "standard" 3-weekly chemotherapy for children with high-risk metastatic neuroblastoma. Long-term outcomes of the ENSG5 trial were analysed. PROCEDURE: Patients with metastatic neuroblastoma aged ≥12 months were randomly assigned to "standard" or "rapid" induction, receiving the same chemotherapy drugs and doses. Event-free survival (EFS) and overall survival (OS) were analysed and prognostic factors evaluated. Amongst patients surviving >5 years, a population of children with persistent metastatic disease after the end of treatment was identified and described. RESULTS: Ten-year EFS was 18.2% (95% confidence interval: 12.2-25.2) for the "standard" arm and 26.8% (19.5-34.7) for the "rapid" arm (hazard ratio [HR] 0.85, P = 0.28). Ten-year OS for the "standard" arm was 19.7% (13.4-26.8) and 28.3% (20.8-36.2) for the "rapid arm" (HR 0.83, P = 0.19). There was a trend for worse EFS and OS for patients having MYCN amplification (HR 1.37 and 1.40, respectively) and those with partial and mixed response to induction (HR 1.69 and 1.75 for EFS and 1.66 and 2.00 for OS, respectively). Among 69 patients who survived >5 years, six had persistent metastatic disease after the end of treatment. CONCLUSION: The benefit of the "rapid" induction regimen seems to be maintained in the long term, although the small number of survivors could justify the lack of statistical significance. MYCN amplification and poor metastatic response to induction could be associated with worse outcomes. A small group of patients with persistent metastatic disease that survived long term has been described.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neuroblastoma/tratamento farmacológico , Neuroblastoma/mortalidade , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Amplificação de Genes , Humanos , Quimioterapia de Indução , Lactente , Masculino , Proteína Proto-Oncogênica N-Myc/genética , Metástase Neoplásica , Neuroblastoma/genética , Neuroblastoma/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Surveillance magnetic resonance imaging (MRI) is routinely used to detect recurrence in children with high-grade central nervous system (CNS) tumors, although no consensus has been reached regarding its effectiveness and whether earlier detection is associated with improved patient outcomes. This review aimed to evaluate this practice and any associated benefits and harms. METHODS: Systematic searches for relevant studies were undertaken in a number of databases, including MEDLINE and EMBASE, from 1985 to August 2018. Study selection and data extraction was undertaken independently by two reviewers. Due to heterogeneity between studies, no pooling of data was undertaken. Reporting followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No comparative studies were identified. Three retrospective observational studies involving 306 patients were reviewed. All had high risk of bias by virtue of study design. Two studies reported outcomes by symptomatic status-both recurrence rates and overall survival for asymptomatic patients were comparable with those for clinically symptomatic patients. No quality-of-life outcomes were reported. CONCLUSION: There is a paucity of evidence to guide clinical practice as to the effectiveness of MRI surveillance in pediatric patients with high-grade CNS tumors. These studies do not clearly demonstrate benefit or harm for the practice. With more research needed, there is a role for researchers to build into future trials data collection on surveillance imaging to give more information for the assessment of imaging frequency and duration in asymptomatic patients. This is an important question not only to clinicians and patients and their families but also from a health service resource perspective.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Detecção Precoce de Câncer/métodos , Imageamento por Ressonância Magnética/métodos , Recidiva Local de Neoplasia/diagnóstico por imagem , Criança , Progressão da Doença , HumanosRESUMO
BACKGROUND: Magnetic resonance imaging (MRI) is routinely used as a surveillance tool to detect early asymptomatic tumour recurrence with a view to improving patient outcomes. This systematic review aimed to assess its utility in children with low-grade CNS tumours. METHODS: Using standard systematic review methods, twelve databases were searched up to January 2017. RESULTS: Seven retrospective case series studies (n = 370 patients) were included, with average follow-up ranging from 5.6 to 7 years. No randomised controlled trials (RCTs) were identified. Due to study heterogeneity only a descriptive synthesis could be undertaken. Imaging was most frequent in the first year post-surgery (with 2-4 scans) reducing to around half this frequency in year two and annually thereafter for the duration of follow-up. Diagnostic yield ranged from 0.25 to 2%. Recurrence rates ranged from 5 to 41%, with most recurrences asymptomatic (range 65-100%). Collectively, 56% of recurrences had occurred within the first year post-treatment (46% in the first 6-months), 68% by year two and 90% by year five. Following recurrence, 90% of patients underwent treatment changes, mainly repeat surgery (72%). Five-year OS ranged from 96 to 100%, while five-year recurrence-free survival ranged from 67 to 100%. None of the studies reported quality of life measures. CONCLUSION: This systematic review highlights the paucity of evidence currently available to assess the utility of MRI surveillance despite it being routine clinical practice and costly to patients, their families and healthcare systems. This needs to be evaluated within the context of an RCT.
Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Detecção Precoce de Câncer , Imageamento por Ressonância Magnética , Recidiva Local de Neoplasia/diagnóstico por imagem , Adolescente , Neoplasias do Sistema Nervoso Central/patologia , Criança , Pré-Escolar , Detecção Precoce de Câncer/métodos , Humanos , Lactente , Recém-Nascido , Gradação de Tumores , Adulto JovemRESUMO
New drugs are crucially needed for children with cancer. The European Paediatric Regulation facilitates paediatric class waivers for drugs developed for diseases only occurring in adults. In this Review, we retrospectively searched oncology drugs that were class waivered between June, 2012, and June, 2015. 147 oncology class waivers were confirmed for 89 drugs. Mechanisms of action were then assessed as potential paediatric therapeutic targets by both a literature search and an expert review. 48 (54%) of the 89 class-waivered drugs had a mechanisms of action warranting paediatric development. Two (2%) class-waivered drugs were considered not relevant and 16 (18%) required further data. In light of these results, we propose five initiatives: an aggregated database of paediatric biological tumour drug targets; molecular profiling of all paediatric tumours at diagnosis and relapse; a joint academic-pharmaceutical industry preclinical platform to help analyse the activity of new drugs (Innovative Therapy for Children with Cancer Paediatric Preclinical Proof-of-Concept Platform); paediatric strategy forums; and the suppression of article 11b of the European Paediatric Regulation, which allows product-specific waivers on the grounds that the associated condition does not occur in children. These initiatives and a mechanism of action-based approach to drug development will accelerate the delivery of new therapeutic drugs for front-line therapy for those children who have unmet medical needs.
Assuntos
Antineoplásicos/uso terapêutico , Legislação de Medicamentos , Neoplasias/tratamento farmacológico , Medicina de Precisão , Adolescente , Antineoplásicos/farmacologia , Produtos Biológicos/uso terapêutico , Criança , Pré-Escolar , Descoberta de Drogas/legislação & jurisprudência , Europa (Continente) , Humanos , Lactente , Recém-NascidoAssuntos
Antineoplásicos/uso terapêutico , Oncologia/legislação & jurisprudência , Neoplasias/tratamento farmacológico , Pediatria/legislação & jurisprudência , Formulação de Políticas , Idade de Início , Antineoplásicos/efeitos adversos , Europa (Continente) , Regulamentação Governamental , Necessidades e Demandas de Serviços de Saúde/legislação & jurisprudência , Humanos , Avaliação das Necessidades/legislação & jurisprudência , Neoplasias/epidemiologia , Segurança do Paciente/legislação & jurisprudênciaRESUMO
PURPOSE: There is an increasing need to evaluate innovative drugs for childhood cancer using combination strategies. Strong biological rationale and clinical experience suggest that multiple agents will be more efficacious than monotherapy for most diseases and may overcome resistance mechanisms and increase synergy. The process to evaluate these combination trials needs to maximize efficiency and should be agreed by all stakeholders. METHODS: After a review of existing combination trial methodologies, regulatory requirements, and current results, a consensus among stakeholders was achieved. RESULTS: Combinations of anticancer therapies should be developed on the basis of mechanism of action and robust preclinical evaluation, and may include data from adult clinical trials. The general principle for combination early-phase studies is that, when possible, clinical trials should be dose- and schedule-confirmatory rather than dose-exploratory, and every effort should be made to optimize doses early. Efficient early-phase combination trials should be seamless, including dose confirmation and randomized expansion. Dose evaluation designs for combinations depend on the extent of previous knowledge. If not previously evaluated, limited evaluation of monotherapy should be included in the same clinical trial as the combination. Randomized evaluation of a new agent plus standard therapy versus standard therapy is the most effective approach to isolate the effect and toxicity of the novel agent. Platform trials may be valuable in the evaluation of combination studies. Patient advocates and regulators should be engaged with investigators early in a proposed clinical development pathway and trial design must consider regulatory requirements. CONCLUSION: An optimized, agreed approach to the design and evaluation of early-phase pediatric combination trials will accelerate drug development and benefit all stakeholders, most importantly children and adolescents with cancer.
Assuntos
Antineoplásicos , Neoplasias , Adulto , Criança , Adolescente , Humanos , Antineoplásicos/efeitos adversos , Neoplasias/tratamento farmacológico , Desenvolvimento de MedicamentosRESUMO
The European Society for Paediatric Oncology (SIOPE) Radiation Oncology Working Group presents the QUARTET Project: a centralised quality assurance programme designed to standardise care and improve the quality of radiotherapy and imaging for international clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infrastructure and experience of the European Organisation for Research and Treatment of Cancer to deliver radiotherapy quality assurance programmes for large, prospective, international clinical trials. QUARTET-affiliated trials include children and adolescents with brain tumours, neuroblastoma, sarcomas including rhabdomyosarcoma, and renal tumours including Wilms' tumour. With nine prospective clinical trials and two retrospective studies within the active portfolio in March 2022, QUARTET will collect one of the largest repositories of paediatric radiotherapy and imaging data, support the clinical assessment of radiotherapy, and evaluate the role and benefit of radiotherapy quality assurance for this cohort of patients within the context of clinical trials.
Assuntos
Neoplasias Renais , Radioterapia (Especialidade) , Tumor de Wilms , Adolescente , Criança , Europa (Continente) , Humanos , Neoplasias Renais/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Tumor de Wilms/tratamento farmacológicoRESUMO
Clofarabine is a second-generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine-based chemotherapy regimes were effective and well-tolerated in this heavily pre-treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics.
Assuntos
Nucleotídeos de Adenina/uso terapêutico , Antineoplásicos/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Criança , Pré-Escolar , Clofarabina , Avaliação de Medicamentos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Recidiva , Resultado do TratamentoRESUMO
Optimization of therapy for childhood acute lymphoblastic leukemia (ALL) requires a greater understanding of the cells that proliferate to maintain this malignancy because a significant number of cases relapse, resulting from failure to eradicate the disease. Putative ALL stem cells may be resistant to therapy and subsequent relapses may arise from these cells. We investigated expression of CD133, CD19, and CD38 in pediatric B-ALL. Cytogenetic and molecular analyses demonstrated that karyotypically aberrant cells were present in both CD133(+)/CD19(+) and CD133(+)/CD19(-) subfractions, as were most of the antigen receptor gene rearrangements. However, ALL cells capable of long-term proliferation in vitro and in vivo were derived from the CD133(+)/CD19(-) subfraction. Moreover, these CD133(+)/CD19(-) cells could self-renew to engraft serial nonobese diabetic-severe combined immunodeficient recipients and differentiate in vivo to produce leukemias with similar immunophenotypes and karyotypes to the diagnostic samples. Furthermore, these CD133(+)/CD19(-) ALL cells were more resistant to treatment with dexamethasone and vincristine, key components in childhood ALL therapy, than the bulk leukemia population. Similar results were obtained using cells sorted for CD133 and CD38, with only the CD133(+)/CD38(-) subfraction demonstrating xenograft repopulating capacity. These data suggest that leukemia-initiating cells in childhood B-ALL have a primitive CD133(+)/CD19(-) and CD38(-) phenotype.
Assuntos
Antígenos CD/metabolismo , Glicoproteínas/metabolismo , Células-Tronco Neoplásicas/metabolismo , Peptídeos/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Antígeno AC133 , ADP-Ribosil Ciclase 1/metabolismo , Adolescente , Animais , Antígenos CD19/metabolismo , Proliferação de Células , Criança , Pré-Escolar , Rearranjo Gênico do Linfócito T/fisiologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
The COVID-19 pandemic has considerably changed health services for children with cancer worldwide by creating barriers throughout the care continuum. Reports available at this time suggest that asymptomatic and mild upper and lower respiratory tract syndromes are the most common presentation of COVID-19 in children with cancer. Nonetheless, severe cases of COVID-19 and deaths secondary to the infection have been reported. In addition to the direct effects of the severe acute respiratory syndrome coronavirus 2, children with cancer have suffered from the collateral consequences of the pandemic, including decreased access to diagnosis and cancer-directed therapy. The COVID-19 pandemic has presented unprecedented challenges to safe and effective care of children with cancer, including their enrollment in therapeutic clinical trials. Data from the Children's Oncology Group and Cancer Research U.K. Clinical Trials Unit show variability in the enrollment of children with cancer in clinical trials during the COVID-19 pandemic. However, the overall effects on outcomes for children with cancer undergoing care during the pandemic remain largely unknown. In this article, we review the current knowledge about the direct and collateral effects of the COVID-19 pandemic, including on clinical trial enrollment and operations.
Assuntos
COVID-19/epidemiologia , Atenção à Saúde , Neoplasias/diagnóstico , Neoplasias/terapia , Criança , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Neoplasias/epidemiologia , SARS-CoV-2 , Reino Unido/epidemiologiaRESUMO
One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials.