A comparative analysis of IDH-mutant glioma in pediatric, young adult, and older adult patients.

BACKGROUND: The frequency and significance of IDH mutations in glioma across age groups is incompletely understood. We performed a multi-center retrospective age-stratified comparison of patients with IDH-mutant gliomas to identify age-specific differences in clinico-genomic features, treatments, and outcomes. METHODS: Clinical, histologic, and sequencing data from patients with IDH-mutant, grade 2-4 gliomas, were collected from collaborating institutions between 2013-2019. Patients were categorized as pediatric (<19y), YA (19-39y) or older adult (≥40y). Clinical presentation, treatment, histologic, and molecular features were compared across age categories using Fisher's exact test or analysis-of-variance. Cox proportional-hazards regression was used to determine association of age and other covariates with overall (OS) and progression-free survival (PFS). RESULTS: We identified a cohort of 379 patients (204 YA) with IDH-mutant glioma with clinical data. There were 155 (41%) oligodendrogliomas and 224 (59%) astrocytomas. YA showed significantly shorter PFS and shorter median time-to-malignant transformation (MT) compared to pediatric and adult groups, but no significant OS difference. Adjusting for pathology type, extent of resection, and upfront therapy in multivariable analysis, the YA group was independently prognostic of shorter PFS than pediatric and adult groups. Among astrocytomas, CDK4/6 copy number amplifications were associated with both shorter PFS and shorter OS. Among oligodendrogliomas, PIK3CA and CDKN2A/2B alterations were associated with shorter OS. CONCLUSIONS: IDH-mutant glioma YA patients had significantly shorter PFS and time to MT but did not differ in OS compared to pediatric and adult groups. Treatment approach varied significantly by patient age and warrant further study as addressable age-associated outcome drivers.

Two-stage subgroup-specific time-to-event (2S-Sub-TITE): An adaptive two-stage time-to-toxicity design for subgroup-specific dose finding in phase I oncology trials.

For phase I trials, the subgroup-specific time-to-event (Sub-TITE) design identifies the maximum tolerated dose (MTD) separately in 2+ heterogeneous patient subgroups. Sub-TITE allows borrowing strength and dynamic clustering across subgroups from the trial's start, but delaying the initiation of borrowing and clustering may improve trial accuracy. We propose the 2-stage Sub-TITE (2S-Sub-TITE) design in which the trial starts by estimating separate models per subgroup, and then initiates the Sub-TITE design at some pre-specified point of patient accrual. We evaluate the operating characteristics of the 2S-Sub-TITE design using simulations. Nine configurations of the 2S-Sub-TITE design (varying in timing of initiation of borrowing/clustering and prior probability of subgroup heterogeneity, p_hetero) and three control methods were compared across 1000 randomly-generated true toxicity probability scenarios. Effects of priors, sample size, escalation rules, target toxicity probability, accrual rate, and number of subgroups were evaluated. Metrics included: proportion of correct selection (PCS) of the true MTD, and average number of toxicities incurred. Among the 5 2S-Sub-TITE configurations (out of 9 total) with the highest PCS (45%) when the subgroup heterogeneity assumption is correct (all of which out-perform the control methods by 2%-6%), the configuration which enables borrowing and clustering allowance with p_hetero = 0.7 starting at 75% patient accrual best minimizes toxicities as well as losses in accuracy if the heterogeneity assumption is incorrect. For trials with high confidence in subgroup heterogeneity, the 2S-Sub-TITE configuration enabling borrowing/clustering with p_hetero = 0.7 starting at 75% patient accrual exhibits superior dose-finding accuracy compared to existing methods.

Early parental knowledge of late effect risks in children with cancer.

BACKGROUND/OBJECTIVES: Despite the pervasiveness of late effects in childhood cancer survivors, many parents feel inadequately informed about their child's risks. We assessed early parental knowledge of risks of late effects and predictors of increased knowledge. DESIGN/METHODS: Parents of children receiving cancer treatment at Dana-Farber/Boston Children's Cancer and Blood Disorders Center were surveyed about their knowledge of their child's likelihood of eight late effects. Individual risk for each late effect (yes/no) was assessed using the Children's Oncology Group's Long-Term Follow-Up Guidelines v5 as a reference. Descriptive statistics were used to summarize knowledge scores; ordinal logistic regression was used to identify predictors of higher knowledge. RESULTS: Of 96 parent participants, 11 (11.46%) correctly identified all of their child's risks for the eight late effects. Five of eight was the median number of correctly identified late effect risks. Among 21 parents whose children were at risk for ototoxicity, 95% correctly identified this risk. Conversely, parents of at-risk children were less knowledgeable about risks of secondary malignancy (63% correct identification, of N = 94 at risk), cardiac toxicity (61%; N = 71), neurocognitive impairment (56%; N = 63), and infertility (28%; N = 61). Ordinal logistic regression analysis identified no significant differences in parental knowledge of late effect risks by any factors evaluated. CONCLUSIONS: Gaps in parental knowledge of potential late effects of childhood cancer treatment emerge early in a child's care, and parents are more knowledgeable about some late effects, such as ototoxicity, than others, such as infertility. As no child- or parent-specific factors were associated with increased knowledge of late effect risks, interventions must be applied broadly.

Race, ethnicity, and goal-concordance of end-of-life palliative care in pediatric oncology.

BACKGROUND: Racial and ethnic minority children with cancer disproportionately receive intensive care at the end of life (EOL). It is not known whether these differences are goal-concordant or disparities. The authors sought to explore patterns of pediatric palliative care (PPC) and health care utilization in pediatric oncology patients receiving subspecialty palliative care at the end-of-life (last 6 months) and to examine goal-concordance of location of death in a subset of these patients. METHODS: This was a retrospective cohort study of pediatric oncology patients receiving subspecialty palliative care at a single large tertiary care center who died between January 2013 and March 2017. RESULTS: A total of 115 patients including 71 White, non-Hispanic patients and 44 non-White patients (including 12 Black patients and 21 Hispanic patients) were included in the analytic cohort. There were no significant differences in oncologic diagnosis, cause of death, or health care utilization in the last 6 months of life. White and non-White patients had similar PPC utilization including time from initial consult to death and median number of PPC encounters. Non-White patients were significantly more likely to die in the hospital compared to White patients (68% vs 46%, P = .03). Analysis of a subcohort with documented preferences (n = 45) revealed that 91% of White patients and 93% of non-White patients died in their preferred location of death. CONCLUSIONS: Although non-White children with cancer were more likely to die in the hospital, this difference was goal-concordant in our cohort. Subspecialty PPC access may contribute to the achievement of goal-concordant EOL care.