Evaluation of Treatment-Related Mortality Among Paediatric Cancer Deaths: a population based analysis.

BACKGROUND: Objectives were to describe the proportion of deaths due to treatment-related mortality (TRM) and to identify risk factors and probable causes of TRM among paediatric cancer deaths in a population-based cohort. METHODS: We included children with cancer ⩽18 years diagnosed and treated in Ontario who died between January 2003 and December 2012. Deaths were identified using a provincial registry, the Pediatric Oncology Group of Ontario Networked Information System. Probable causes of TRM were described. RESULTS: Among the 964 deaths identified, 821 were included. The median age at diagnosis was 6.6 years (range 0-18.8) and 51.8% had at least one relapse. Of the deaths examined, TRM occurred in 217/821 (26.4%) while 604/821 (73.6%) were due to progressive cancer. Deaths from TRM did not change over time. Using multiple regression, younger age, leukaemia diagnosis and absence of relapse were independently positively associated with TRM. The most common probable causes of TRM were respiratory, infection and haemorrhage. CONCLUSIONS: TRM was responsible for 26.4% of deaths in paediatric cancer. Underlying diagnosis, younger age and absence of relapse were associated with TRM and causes of TRM differed by diagnosis group. Future work should evaluate TRM rate and risk factors among newly diagnosed cancer patients

Dinutuximab beta for treating neuroblastoma: an evidence review group and decision support unit perspective of a NICE single technology appraisal

As part of its Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (EUSA Pharma) of dinutuximab beta (Qarziba®) to submit evidence of its clinical and cost effectiveness for treating neuroblastoma. The BMJ Technology Assessment Group (BMJ-TAG) was commissioned to act as the Evidence Review Group (ERG), reviewing the submission from the company. The Decision Support Unit (DSU) was commissioned to review additional evidence submitted by the company and to undertake further analyses. This article presents the critical review of the company’s submissions by the ERG and DSU, further analyses undertaken by the DSU, and the outcome of the NICE guidance. The clinical effectiveness for dinutuximab beta was derived from a phase III randomised controlled trial (RCT) that assessed the safety and efficacy of the addition of interleukin (IL)-2 to dinutuximab beta plus isotretinoin. This trial did not inform the relative effectiveness of dinutuximab beta versus isotretinoin alone, which was established practice in the UK for maintenance treatment. In the absence of direct evidence, the company initially conducted a naïve indirect treatment comparison against a historical control, and later performed a matching-adjusted indirect comparison (MAIC) against the isotretinoin arm of an RCT comparing dinutuximab alpha and isotretinoin. The company submitted a partitioned survival analysis model that calculated the incremental cost effectiveness of dinutuximab beta versus isotretinoin. The company’s original incremental cost-effectiveness ratio (ICER) was £22,338 per quality-adjusted life-year (QALY) gained. However, the ERG were concerned that the company’s ICER was not suitable for decision making, and thus carried out initial exploratory analysis as a first step to overcome the naïve estimation of treatment effectiveness in the model. The ERG’s analysis estimated an ICER of £111,858 per QALY gained. In their revised analysis incorporating the MAIC and other changes as requested by the appraisal committee, the company’s ICER was £24,661 per QALY gained. When the DSU incorporated longer-term isotretinoin data and made corrections to the model, the ICER increased to between £62,886 and £87,164 per QALY gained depending on the choice of survival model. A confidential Patient Access Scheme (PAS) decreased the ICERs. The ICERs with the PAS were over £40,000 per QALY gained, but the NICE committee additionally considered the patient population and its size, the disease severity, the potential for significant survival benefit and uncaptured health benefits, and recommended dinutuximab beta as a treatment option, subject to the company providing the agreed discount in the PAS

The contribution of CHEK2 to the TP53-negative Li-Fraumeni phenotype

Background: CHEK2 has previously been excluded as a major cause of Li-Fraumeni syndrome (LFS). One particular CHEK2 germline mutation, c.1100delC, has been shown to be associated with elevated breast cancer risk. The prevalence of CHEK21100delC differs between populations and has been found to be relatively high in the Netherlands. The question remains nevertheless whether CHEK2 germline mutations contribute to the Li-Fraumeni phenotype.Methods: We have screened 65 Dutch TP53-negative LFS/LFL candidate patients for CHEK2 germline mutations to determine their contribution to the LFS/LFL phenotype.Results: We identified six index patients with a CHEK2 sequence variant, four with the c.1100delC variant and two sequence variants of unknown significance, p.Phe328Ser and c.1096-?_1629+?del.Conclusion: Our data show that CHEK2 is not a major LFS susceptibility gene in the Dutch population. However, CHEK2 might be a factor contributing to individual tumour development in TP53-negative cancer-prone families

Evaluating the prevalence of diabetes mellitus subtypes in childhood cancer survivors: a systematic review protocol

Sondra Song Jie Chen,1,2 Ajantha Nadarajah,1,2 Laura Banfield,3 Adam Fleming,1,4 Lehana Thabane,5–8 Carol Portwine,1,4 M Constantine Samaan1–2,51Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada; 2Division of Pediatric Endocrinology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 3Health Sciences Library, McMaster University, Hamilton, Ontario, Canada; 4Division of Pediatric Hematology/Oncology, McMaster Children’s Hospital, Hamilton, Ontario, Canada; 5Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada; 6Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada; 7Centre for Evaluation of Medicines, St Joseph’s Health Care, Hamilton, Ontario, Canada; 8Biostatistics Unit, St Joseph’s Healthcare, Hamilton, Ontario, CanadaObjectives: The number of children who survive cancer is reaching new record levels, thanks to improved management strategies. However, this population is predisposed to chronic health conditions including cardiovascular disease and type 2 diabetes, yet the full scale of these diagnoses in this population is unclear. This protocol describes the conduct of a systematic review to report on the prevalence of diabetes mellitus (DM) subtypes in childhood cancer survivors.Methods: Searches will be conducted in MEDLINE, Embase, CINAHL, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials. We will also search gray literature in Theses A&I, ProQuest Dissertations, and Web of Science as well as clinicaltrials.gov. Screening search results and data abstraction will be done independently by two reviewers. We will conduct a meta-analysis if two studies have similar designs, populations, methods, and outcome measures reported.Results: The findings of this systematic review will provide insights into the scale of diabetes in childhood cancer survivors to allow the prioritization of subpopulations that need specific interventions to screen, prevent, and treat DM. This will likely lead to improved outcomes in childhood cancer survivors.Keywords: systematic review protocol, childhood cancer, cancer survivorship, diabetes mellitus, type 1 diabetes mellitus, type 2 diabetes mellitu

Refinement of the symptom screening in pediatrics tool (SSPedi).

BACKGROUND: Objective was to evaluate and refine a new instrument for paediatric cancer symptom screening named the Symptom Screening in Pediatrics Tool (SSPedi). METHODS: Respondents were children 8-18 years of age undergoing active cancer treatment and

Adolescents with acute lymphoblastic leukemia treated at pediatric versus adult hospitals

Background: The objective was to compare 5-year overall survival (OS) between adolescent and young adult (AYA) patients (age 15-19) with acute lymphoblastic leukemia (ALL) treated at a pediatric versus an adult center.Patients and methods: This was a population-based analysis using administrative data of Ontario ALL AYA patients diagnosed between 1986-2009. We calculated predicted survival proportions (PSPs) and 95% confidence intervals (CI). We also surveyed sites to determine whether pediatric or adult-based protocols were used in each period.Results: Overall, 290 patients between 15-19 years of age were diagnosed with ALL during the study period; 144 patients (49.7%) were treated at an adult center. When adjusted for gender, age, income quintile and time period, AYA patients treated at a pediatric center did not have a significantly different PSP (0.65, 95% CI: 0.56-0.75) in comparison to those treated at an adult center (0.62, 95% CI 0.52-0.73; P = 0.87). Most AYA patients treated at adult centers received pediatric protocols in the recent periods.Conclusions: Using population-based data, AYA ALL patients had similar outcomes whether treated at a pediatric or an adult center. Early introduction of aggressive treatment protocols in adult centers may have negated differences in outcomes among AYA patients by site of care

Value of FDG-PET/CT Examinations in Different Cancers of Children, Focusing on Lymphomas

The aim of the study was to assess sensitivity and specificity of FDG-PET/CT in different forms of childhood cancer. We retrospectively evaluated the results dedicated of 162 FDG-PET/CT examinations of 86 children treated with: Hodgkin lymphoma (HL; n = 31), non-Hodgkin lymphoma (NHL; n = 30) and other high grade solid tumors (n = 25). Patients were admitted and treated in two departments of pediatric hematology and oncology in Hungary. FDG-PET/CT was performed for staging (n = 25) and for posttreatment evaluation (n = 137). Imaging was performed in three FDG-PET/CT Laboratories, using dedicated PET/CT scanners. False positive results were defined as resolution or absence of disease progression over at least 1 year on FDG-PET/CT scans without any intervention. In some cases histopathological evaluation of suspicious lesions was performed. Fals negative results were defined as negative FDG-PET/CT results in case of active malignancy. Positive predictive values (PPV) and negative predictive values (NPV) were calculated. NPV was 100 %. The highest PPV was observed in high grade solid tumors (81 %), followed by HL (65 %) and NHL (61 %). There was a major difference of PPV in different histological types of HL (50 % in HL of mixed-cellularity subtype, 90 % in nodular sclerosing, and 100 % in lymphocyte-rich and lymphocyte depleted HL). We treated one patient with nodular lymphocyte predominant HL, who had 5 false positive FDG-PET/CT results. PPV of T- and B-lineage NHL were similar (60 % and 62 %, respectively). We observed an interesting difference of PPV in different stages of HL and NHL. In HL PPV was higher in early than in advanced disease forms: 66 % in stage II HL and 60 % in stage III HL, whereas there was an inverse relationship between PPV and disease stages in NHL 0 % in stage I and II patients, 67 % in stage III and 100 % in stage IV patients. PPV was lower in males (54 %) than in females (65 %). PPV were 64 % vs. 58 % in patients under vs. over 10 years of age. Negative FDG-PET/CT results during follow-up reliably predict the absence of malignancy. Positive FDG-PET/CT scan results in general have a low PPV. The relatively high PPV in patients with histologically proven high grade solid tumors, advanced stages of NHL and with nodular sclerosing, lymphocyte-rich and lymphocyte depleted subtypes of HL warrant a confirmation by biopsy, whereas the watch-and-wait approach can be used in other forms of childhood cancer patients with a positive FDG-PET/CT result in course of follow-up examinations