Maternal and childhood medical history and the risk of childhood brain tumours: a case-control study in Ontario, Canada.

BACKGROUND: Studies to date have yielded inconclusive results as to whether maternal medical history during pregnancy, and a child's early-life medical history contribute to the development of childhood brain tumours (CBTs). This study examined associations between maternal and childhood medical history and the risk of CBTs. METHODS: The Childhood Brain Tumour Epidemiology Study of Ontario (CBREO) examined children 0-15 years of age with newly diagnosed CBTs from 1997 to 2003. Multivariable logistic regression analysis determined associations for prenatal medications and childhood medical history, adjusted for child's demographics, and maternal education. Analyses were stratified by histology. A latency period analysis was conducted using 12- and 24-month lead times. RESULTS: Maternal intake of immunosuppressants during the prenatal period was significantly associated with glial tumours (OR 2.73, 95% CI 1.17-6.39). Childhood intake of anti-epileptics was significantly associated with CBTs overall, after accounting for 12-month (OR 8.51, 95% CI 3.35-21.63) and 24-month (OR 6.04, 95% CI 2.06-17.70) lead time before diagnosis. No associations for other medications were found. CONCLUSIONS: This study underscores the need to examine potential carcinogenic effects of the medication classes highlighted and of the indication of medication use. Despite possible reverse causality, increased CBT surveillance for children with epilepsy might be warranted.

Childhood head trauma and the risk of childhood brain tumours: A case-control study in Ontario, Canada.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population-based and hospital-based case-control study of children 0 to 15 years with newly diagnosed CBTs from 1997 to 2003 recruited across Ontario through paediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, or head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research.

The effect of average temperature on suicide rates in five urban California counties, 1999-⁠2019: an ecological time series analysis.

BACKGROUND: Suicide is among the top 10 leading causes of premature morality in the United States and its rates continue to increase. Thus, its prevention has become a salient public health responsibility. Risk factors of suicide transcend the individual and societal level as risk can increase based on climatic variables. The purpose of the present study is to evaluate the association between average temperature and suicide rates in the five most populous counties in California using mortality data from 1999 to 2019. METHODS: Monthly counts of death by suicide for the five counties of interest were obtained from CDC WONDER. Monthly average, maximum, and minimum temperature were obtained from nCLIMDIV for the same time period. We modelled the association of each temperature variable with suicide rate using negative binomial generalized additive models accounting for the county-specific annual trend and monthly seasonality. RESULTS: There were over 38,000 deaths by suicide in California's five most populous counties between 1999 and 2019. An increase in average temperature of 1 °C corresponded to a 0.82% increase in suicide rate (IRR = 1.0082 per °C; 95% CI = 1.0025-1.0140). Estimated coefficients for maximum temperature (IRR = 1.0069 per °C; 95% CI = 1.0021-1.0117) and minimum temperature (IRR = 1.0088 per °C; 95% CI = 1.0023-1.0153) were similar. CONCLUSION: This study adds to a growing body of evidence supporting a causal effect of elevated temperature on suicide. Further investigation into environmental causes of suicide, as well as the biological and societal contexts mediating these relationships, is critical for the development and implementation of new public health interventions to reduce the incidence of suicide, particularly in the face increasing temperatures due to climate change.

Are Surrogate Endpoints Unbiased Metrics in Clinical Benefit Scores of the ASCO Value Framework?

BACKGROUND: Clinical benefit scores (CBS) are key elements of the ASCO Value Framework (ASCO-VF) and are weighted based on a hierarchy of efficacy endpoints: hazard ratio for death (HR OS), median overall survival (mOS), HR for disease progression (HR PFS), median progression-free survival (mPFS), and response rate (RR). When HR OS is unavailable, the other endpoints serve as "surrogates" to calculate CBS. CBS are computed from PFS or RR in 39.6% of randomized controlled trials. This study examined whether surrogate-derived CBS offer unbiased scoring compared with HR OS-derived CBS. METHODS: Using the ASCO-VF, CBS for advanced disease settings were computed for randomized controlled trials of oncology drug approvals by the FDA, European Medicines Agency, and Health Canada in January 2006 through December 2017. Mean differences of surrogate-derived CBS minus HR OS-derived CBS assessed the tendency of surrogate-derived CBS to overestimate or underestimate clinical benefit. Spearman's correlation evaluated the association between surrogate- and HR OS-derived CBS. Mean absolute error assessed the average difference between surrogate-derived CBS relative to HR OS-derived CBS. RESULTS: CBS derived from mOS, HR PFS, mPFS, and RR overestimated HR OS-derived CBS in 58%, 68%, 77%, and 55% of pairs and overall by an average of 5.62 (n=90), 6.86 (n=110), 29.81 (n=101), and 3.58 (n=108), respectively. Correlation coefficients were 0.80 (95% CI, 0.70-0.86), 0.38 (0.20-0.53), 0.20 (0.00-0.38), and 0.01 (-0.18 to 0.19) for mOS-, HR PFS-, mPFS-, and RR-derived CBS, respectively, and mean absolute errors were 11.32, 12.34, 40.40, and 18.63, respectively. CONCLUSIONS: Based on the ASCO-VF algorithm, HR PFS-, mPFS-, and RR-derived CBS are suboptimal surrogates, because they were shown to be biased and poorly correlated to HR OS-derived CBS. Despite lower weighting than OS in the ASCO-VF algorithm, PFS still overestimated CBS. Simple rescaling of surrogate endpoints may not improve their validity within the ASCO-VF given their poor correlations with HR OS-derived CBS.

Do older and younger patients derive similar survival benefits from novel oncology drugs? A systematic review and meta-analysis.

Background: older patients are commonly believed to derive less benefit from cancer drugs, even if they fulfil clinical trial eligibility [Talarico et al. (2004, J Clin Oncol, 22(22):4626-31)]. We aim to examine if novel oncology drugs provide differential age-based treatment outcomes for patients on clinical trials. Methods: a systematic review of randomised control trials (RCTs) cited for clinical efficacy evidence in novel oncology drug approvals by the Food and Drug Administration, European Medicines Agency and Health Canada between 2006 and 2017 was conducted. Studies reporting age-based subgroup analyses for overall or progression-free survival (OS/PFS) were included. Hazard ratios (HRs) and confidence intervals (CIs) for age-based subgroups were extracted. Meta-analyses with random effects were conducted, examining patient subgroups <65 and ≥65 years separately and pooled HRs of studies primary endpoints (OS or PFS) compared to examine if differences existed between age-based subgroups. Sensitivity analyses were conducted for cancer type, primary endpoint and systemic treatment. Results: one-hundred-two RCTs, including 65,122 patients, met the inclusion criteria. One study reported age-based toxicity and none reported age-based quality of life (QOL) results. Pooled HRs [95% CIs] for patients <65 and ≥65 years were 0.61 [0.57-0.65] and 0.65 [0.61-0.70], respectively, with no difference between them (P = 0.14). Sensitivity analyses revealed similar results. Conclusion: our results suggest that older and young patients, who fulfil clinical trial eligibility, may derive similar relative survival benefits from novel oncology drugs. There is, however, a need to report age-based toxicity and QOL results to support patient discussions regarding the balance of treatment benefit and harm, to encourage informed decision-making.

One-Year Swallowing Outcomes in Patients Treated with Prophylactic Gabapentin During Radiation-Based Treatment for Oropharyngeal Cancer.

Recent investigations by our study team have demonstrated patients using gabapentin for pain management during chemoradiotherapy (CRT) do well maintaining swallowing during treatment with less need for narcotic pain medication, PEG dependence, weight loss, and short-term swallowing morbidity. The purpose of this investigation was to characterize the long-term swallowing function of these patients 1-year following treatment. Sequential patients receiving CRT for oropharyngeal cancer and concurrent gabapentin were evaluated 1-year following treatment for swallowing outcomes. Functional Oral Intake Scores (FOIS) were utilized to assess diet level. The MD Anderson Dysphagia Inventory (MDADI) was chosen to evaluate patient perception of swallowing function. Videofluoroscopic swallowing studies were completed approximately 1 year after treatment to assess physiologic outcomes as well as Penetration Aspiration Scores (PAS). Data from 26 consecutive participants were available for analysis. The majority of patients had advanced stage disease (Stage 3-4). No patients had a PEG tube 1-year following treatment, and the mean FOIS score was 6.83. Pharyngeal deficits were infrequent with reduced pharyngeal constriction and prominence/early closure of cricopharyngeus predominating. Mean PAS score was 1.5, indicating that the majority of patients had either no laryngeal penetration/aspiration, or transient penetration that was fully cleared. Mean MDADI score was 85.52, indicating that, in general, patients perceived their swallowing to be minimally impaired. Patients receiving gabapentin pain management as part of a comprehensive dysphagia prevention protocol during CRT have excellent long-term swallowing outcomes as reflected in diet levels, physiologic functioning, and patient-perceived quality of life.

Effect of gabapentin on swallowing during and after chemoradiation for oropharyngeal squamous cell cancer.

The aim of this study was to examine the impact of gabapentin (neurontin) on swallowing and feeding tube use during chemoradiation (CRT) for oropharyngeal squamous cell carcinoma (OPSCC), and physiologic swallowing outcomes following completion of treatment. A total of 23 patients treated for OPSCC with concurrent CRT and prophylactically treated for pain using gabapentin were assessed. Historical controls were matched for T stage and primary site of disease. Timing of PEG use and removal were recorded. Video fluoroscopic swallowing studies were completed post-treatment to assess physiologic outcomes as well as penetration-aspiration scores (PAS). Functional oral intake scale (FOIS) scores were determined at the time of swallowing evaluation to assess diet level. Patients treated with gabapentin began using their PEG tubes later (3.7 vs. 2.29 weeks; P = 0.013) and had their PEG tubes removed earlier (7.29 vs. 32.56 weeks; P = 0.039) than the historical controls. A number of physiologic parameters were found to be less impacted in the gabapentin group, including oral bolus control (P = 0.01), epiglottic tilt (P = 0.0007), laryngeal elevation (P = 0.0017), and pharyngeal constriction (P = 0.002). PAS scores were significantly lower in the group treated with gabapentin (1.89 vs. 4; P = 0.0052). Patients receiving gabapentin had more advanced diet levels at the time of the initial swallowing study as evidenced by their FOIS scores (5.4 vs. 3.21; P = 0.0003). We conclude that patients using gabapentin for pain management during CRT appears to do well maintaining swallow function during treatment and have favorable post-treatment physiologic swallowing outcomes. Prospective evaluation is warranted.

Outcomes with non-small cell lung cancer and brain-only metastasis.

Background: We evaluated outcomes in non-small cell lung cancer (NSCLC) patients who presented with brain-only metastatic (BOM) disease overall and by EGFR/ALK mutation status. Methods: We analyzed clinico-demographic, treatment and survival data for all NSCLC patients who presented to our center between 2014 and 2016 with BOM as their first presentation of metastatic disease. Differences in overall survival (OS) were evaluated using log-rank tests for NSCLC wildtype (NSCLCwt) versus NSCLC with an ALK-rearrangement/EGFR-mutation (NSCLCmut+). Results: Of 109 patients with BOM, median age was 68 years; 51 % were female; 69 % Caucasian; 76 % ever-smoker; 76 % adenocarcinoma; and 25 % NSCLCmut+. While 41 patients (38 %) had subsequent brain-only progressive disease (PD), 22 (20 %) developed extracranial metastases. A higher proportion of NSCLCmut+ (vs -wt) subsequently progressed outside the brain (37 % vs 15 %, p = 0.03). Median time-to-first-extracranial-metastases was 8.5 (NSCLCmut+) vs 21.0 months (NSCLCwt; p = 0.23).With 17.7 months median follow-up, median-OS was 15.9 months [95%CI: 11.5-21.3; all patients]; 12.3 [7.4-18.4; NSCLCwt] and 38.9 [21.3-not reached (NR); NSCLCmut+] (p = 0.09). In 33 of 80 patients with de novo BOM, the primary tumor was treated with surgery or radiotherapy. In patients with NSCLCwt, there was no OS benefit associated with local lung tumor treatment (p = 0.68), whereas in NSCLCmut + pts, local lung tumor treatment correlated with greater OS (median-OS NR vs 21.5 months; p = 0.05). Conclusion: In patients with NSCLCwt with BOM, we observed a -predominant pattern of brain-only secondary progression, however patients with NSCLCmut + more often progressed extracranially. In patients with NSCLCmut+ and BOM, definitive primary tumor treatment correlated with improved survival.

Real-World Treatment Sequencing, Toxicities, Health Utilities, and Survival Outcomes in Patients with Advanced ALK-Rearranged Non-Small-Cell Lung Cancer.

OBJECTIVES: This real-world analysis describes treatment patterns, sequencing and clinical effectiveness, toxicities, and health utility outcomes in advanced-stage, incurable ALK-positive NSCLC patients across five different ALK-TKIs. MATERIALS AND METHODS: Clinicodemographic, treatment, and toxicity data were collected retrospectively in patients with advanced-stage ALK-positive NSCLC at Princess Margaret Cancer Centre. Patient-reported symptoms, toxicities, and health utilities were collected prospectively. RESULTS: Of 148 ALK-positive NSCLC patients seen July 2009-May 2021, median age was 58.9 years; 84 (57%) were female; 112 (76%) never-smokers; 54 (47%) Asian and 40 (35%) white; 139 (94%) received at least one ALK-TKI: crizotinib (n = 74; 54%) and alectinib (n = 61; 44%) were administered mainly as first-line ALK-TKI, ceritinib, brigatinib and lorlatinib were administered primarily after previous ALK-TKI failure. Median overall survival (OS) was 54.0 months; 31 (21%) patients died within two years of advanced-stage diagnosis. Treatment modifications were observed in 35 (47%) patients with crizotinib, 19 (61%) with ceritinib, 41 (39%) with alectinib, 9 (41%) with brigatinib and 8 (30%) with lorlatinib. Prevalence of dose modifications and self-reported toxicities were higher with early versus later generation ALK-TKIs (P<.05). The presence of early treatment modification was not negatively associated with progression-free survival (PFS) and OS analyses. CONCLUSION: Serial ALK-TKI sequencing approaches are viable therapeutic options that can extend quality of life and quantity-of-life, though a fifth of patients died within two years. No best single sequencing approach could be determined. Clinically relevant toxicities occurred across all ALK-TKIs. Treatment modifications due to toxicity may not necessarily compromise outcomes, allowing multiple approaches to deal with ALK-TKI toxicities.

Treatment patterns and outcomes in early-stage ALK-rearranged non-small cell lung cancer.

INTRODUCTION: We evaluated the baseline demographics, treatment patterns, and outcomes of patients with ALK-rearranged early stage (Stage I-III) non-small cell lung cancer (NSCLC). We also evaluated the efficacy and toxicity of durvalumab consolidation treatment in patients with ALK-rearranged unresectable stage III disease. METHODS: Retrospective chart-review analysis of all patients with histologically confirmed stage I-III reflexively tested ALK-rearranged NSCLC managed with curative intent at two Canadian Centers. RESULTS: Of 48 patients, 19 (40%) were stage I, 5 (10%) were stage II and 24 (50%) were stage-III. Median progression-free survival (PFS) was 27.6 months overall (95%CI: 20.5-51.4) and 144.4 months in stage-I, 27.6 months in stage-II and 14.9 months in stage III patients. Of 20 patients with unresectable stage-III disease treated with chemoradiation (9 also received durvalumab consolidation), 18/90% have relapsed. Median PFS was 10.9 months (95%CI:5.9-22.5). A non-significant trend toward improved PFS was seen in patients receiving additional durvalumab compared to patients treated with chemoradiation alone (median PFS, 12.5 vs 5.9 months, p = 0.16). Toxicity-related treatment modifications on subsequent first ALK-TKI at time of metastatic disease were needed in three (33%) patients who had received chemoradiation alone and two (29%) patients with consolidation durvalumab; no relevant pulmonary or hepato-toxicity was observed overall. CONCLUSION: Treatment strategies and PFS of patients with Stage I-III ALK-rearranged NSCLC are similar to patients without molecular driver alterations. Durvalumab consolidation treatment appears generally safe in patients with unresectable stage III ALK-rearranged disease; however, the degree of benefit of such an approach remains unclear.

Real-world outcomes of FOLFIRINOX vs gemcitabine and nab-paclitaxel in advanced pancreatic cancer: A population-based propensity score-weighted analysis.

BACKGROUND: In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) have been publicly funded for first-line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real-world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC. METHODS: Patients receiving first-line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population-based databases. Overall survival (OS) was assessed using Kaplan-Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models. RESULTS: For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70-0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia-related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia-related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar. CONCLUSION: In the real world, FFX had longer OS, less frequent all-cause EDV and all-cause hospitalization, but more febrile neutropenia-related hospitalization compared to GnP.

Estimating hazard ratios from published Kaplan-Meier survival curves: A methods validation study.

OBJECTIVE: Various statistical methods have been developed to estimate hazard ratios (HRs) from published Kaplan-Meier (KM) curves for the purpose of performing meta-analyses. The objective of this study was to determine the reliability, accuracy, and precision of four commonly used methods by Guyot, Williamson, Parmar, and Hoyle and Henley. DESIGN: Pivotal randomized controlled trials (RCTs) in oncology were identified from the pan-Canadian Oncology Drug Review (pCODR) database (primary analysis) and the Food and Drug Administration's (FDA) drug approvals page (secondary analysis) between January 2012 and May 2016. Two reviewers independently reconstructed HRs using each method on KM curves extracted from each trial and compared them with reported HRs (gold standard). Bland-Altman plots and summary statistics were calculated to assess accuracy and precision of these methods. Interrater reliability was assessed using intraclass correlation coefficient (ICC). These four methods were also applied to KM curves of different structures (ie, flat versus steep curves). RESULTS: A total of 118 KM curves (55 RCTs) and 77 KM curves (46 RCTs) were extracted from pCODR and FDA, respectively. In the primary analysis, the Guyot method was the most accurate with the lowest mean error (0.0094; 95% CI, -0.0012-0.020). All four methods had excellent interrater reliability. The Guyot method showed the smallest bias and greatest precision on the Bland-Altman plots. The Guyot method was consistently superior in both the secondary and all sensitivity analyses. CONCLUSION: In the absence of reported HRs, we recommend that researchers consider the Guyot method to reconstruct HRs from KM curves when performing aggregate data meta-analyses.

Assessment of Whether the American Society of Clinical Oncology's Value Framework and the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale Measure Absolute or Relative Clinical Survival Benefit: An Analysis of Randomized Clinical Trials.

IMPORTANCE: The American Society of Clinical Oncology (ASCO) and the European Society for Medical Oncology (ESMO) have independently published value frameworks. To date, whether the clinical benefit scoring algorithms from these framework were intended to measure absolute or relative survival benefit remains unclear. OBJECTIVE: To empirically examine the measurement characteristics of these frameworks by comparing their survival efficacy components (ASCO clinical benefit score [CBS] and ESMO preliminary magnitude of clinical benefit grade [PMCBG]) with established measures of absolute (median survival difference and restricted mean survival time [RMST] difference) and relative (hazard ratios [HRs]) survival benefit. DATA SOURCES: The US Food and Drug Administration (FDA)'s Hematology and Oncology Approvals and Safety Notifications database was retrospectively reviewed to identify phase 3 randomized controlled trials (RCTs) cited for clinical efficacy evidence in oncology drug approvals from January 1, 2006, through December 31, 2017. STUDY SELECTION: Two reviewers searched the database for initial trials cited for approval. Phase 3 trials with overall survival, progression-free survival, and/or time to progression as their primary or coprimary end points were included. Notifications for noncancer indications or presenting label changes and trials that did not report HRs for the required end points and/or did not publish survival curves with number-at-risk data were excluded. Of 269 notifications initially identified, 107 met the selection criteria. DATA EXTRACTION AND SYNTHESIS: Sensitivity analyses were conducted by calculating the scores using (1) the framework-defined end point, including tail-of-curve bonus points (ASCO) or long-term plateau adjustments (ESMO) (framework-defined end point plus tail-of-curve bonus), (2) overall survival data only, and (3) progression-free survival data only. For primary and sensitivity analyses, Spearman correlation coefficients were calculated to examine the relationships between (1) ASCO-CBS or ESMO-PMCBG and RMST difference, (2) ASCO-CBS or ESMO-PMCBG and median survival difference, and (3) ASCO-CBS or ESMO-PMCBG and HR. Data were analyzed from January 7 through April 30, 2018. MAIN OUTCOMES AND MEASURES: In the primary analysis, ASCO-CBSs and ESMO-PMCBGs were calculated for the included trials using the framework-defined end point. RESULTS: Compared with measures of absolute survival benefit, ESMO-PMCBGs showed low to moderate correlations with RMST difference (ρ = 0.44) and moderate to high correlations with median survival difference (ρ = 0.64). ASCO-CBSs showed low to moderate correlations with both measures of absolute benefit (ρ = 0.43 for RMST difference; ρ = 0.44 for median survival). Compared with a relative measure of survival (HRs), ESMO-PMCBGs showed a low correlation (ρ = 0.47) and ASCO-CBSs showed a higher correlation (ρ = 0.76). CONCLUSIONS AND RELEVANCE: Neither framework consistently performed as an absolute measure of survival benefit. The incorporation of a direct measure of absolute clinical benefit, such as RMST difference, into the survival efficacy components of their algorithms should be considered.

Population-Based Analysis Of The Use Of Radium-223 For Bone-Metastatic Castration-Resistant Prostate Cancer In Ontario, And Of Factors Associated With Treatment Completion And Outcome.

INTRODUCTION: Radium-223 (Ra223) prolongs the survival and improves the quality of life of men with metastatic, castration-resistant prostate cancer (mCRPC) to bones. However, compared to other mCRPC therapies, using Ra223 comes with its unique challenges. Hence, we aimed to identify Ra223 utilization patterns under real-world conditions, as well as factors predicting treatment completion and outcome. METHODS: In this retrospective chart analysis, 198 mCRPC patients were identified that had received Ra223 outside of clinical trials or access programs from January 2015 to October 2016 at four cancer centres in Ontario. The main outcomes studied were Ra223 completion rate, reasons for early treatment discontinuation, overall survival, and survival differences in patients completing Ra223 therapy versus patients receiving <6 cycles of Ra223. In addition, patient and disease characteristics were analysed to identify predictors of treatment completion and survival. RESULTS: In this cohort of patients mostly pretreated with abiraterone and/or enzalutamide (92.4%), almost half of which had also received docetaxel (48.5%), the Ra223 completion rate was 46.5%, and the actuarial median survival was 13.3 months. The main reason for early Ra223 discontinuation was disease progression, and Ra223 non-completion was associated with poorer outcome (median survival 8.1 months [6.0-12.2] versus 18.7 months [15.3-22.3] in men completing Ra223, p<0.0001). Lymph node metastases and a high baseline prostate-specific antigen (PSA) were independent predictors of early treatment discontinuation. Multivariable Cox proportional hazards models revealed early Ra223 discontinuation, baseline anemia, high PSA, prior skeletal-related events, visceral metastases, and being referred to another centre for Ra223 therapy as predictors of worse outcome. CONCLUSION: Despite a lower completion rate than observed under clinical trial conditions, the real-world results achieved with Ra223 are encouraging. If prospectively validated, predictive patient and disease characteristics identified in our cohort might become instrumental to identify mCRPC patients likely to complete and to most benefit from Ra223 therapy.

Reliability of Oncology Value Framework Outputs: Concordance Between Independent Research Groups.

Research groups are increasingly utilizing value frameworks, but little is known of their reliability. To assess framework concordance and interrater reliability between two major value frameworks currently in use, we identified all previously published datasets containing both scores from the American Society of Clinical Oncology Value Framework (ASCO-VF) and grades from the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). The intraclass correlation coefficient (ICC) was used to assess interrater reliability. Four eligible studies contained drugs evaluated by both value frameworks, resulting in a dataset of 39 grades/scores for discrete drug indications. ICC was 0.82 (95% confidence interval = 0.70 to 0.90) for ASCO-VF and 0.88 (95% confidence interval = 0.80 to 0.93) for ESMO-MCBS. Absolute concordance was found to be 5% for ASCO-VF and 44% for ESMO-MCBS, increasing to 74% and 80% when deviations within 20 points and 1 grade were considered, respectively. Interrater reliability of ASCO-VF and ESMO-MCBS is, therefore, near perfect, while absolute concordance is poor. This has implications when considering framework outputs in drug funding or treatment decision making.

Examining Trends in Cost and Clinical Benefit of Novel Anticancer Drugs Over Time.

PURPOSE: The purpose of this study was to determine if clinical benefits of novel anticancer drugs, measured by the ASCO Value Framework and European Society of Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale, have increased over time in parallel with increasing costs. METHODS: Anticancer drugs from phase III randomized controlled trials cited for clinical efficacy evidence in drug approvals between January 2006 to December 2015 were identified and scored using both frameworks. For each drug, the monthly price and incremental anticancer drug costs were calculated. Relationships between cost and year of approval were examined using generalized linear regressions models. Ordinary least square models were used to evaluate relationships between ASCO and ESMO scores and year of approval. Spearman correlation coefficients between costs and clinical benefit scores were calculated. RESULTS: In total, 42 randomized controlled trials were included. Both monthly prices and incremental anticancer drug costs were significantly associated with year of approval and showed an average annual increase of 9% and 21%, respectively. The predicted mean incremental anticancer drug cost increased from $30,447 in 2006 to $161,141 in 2015 (greater than five-fold increase). Both ASCO and ESMO scores were not statistically associated with year of approval or correlated with monthly prices or incremental anticancer drug costs. CONCLUSION: Over the past decade, costs of novel oncology drugs have increased, while clinical benefits of these medications have not experienced a proportional positive change. The incremental anticancer drug costs have increased at a much greater rate than monthly prices, indicating that the increase in anticancer drug costs may be higher than commonly reported.

Do patients with reduced or excellent performance status derive the same clinical benefit from novel systemic cancer therapies? A systematic review and meta-analysis.

BACKGROUND: Whether patients with excellent and reduced performance status (PS) derive different net clinical benefit from novel anticancer systemic therapies on clinical trials is unclear. MATERIALS AND METHODS: A systematic review was conducted of randomised controlled trials (RCTs) cited for drug approvals between 2006 and August 2015 by the Food and Drug Administration, the European Medicines Agency and Health Canada. Included studies had overall survival (OS) and/or progression-free survival (PFS) primary endpoints. Meta-analyses of OS/PFS based on PS dichotomised into excellent and reduced subgroups were performed using random effects. RESULTS: The systematic review identified 110 RCTs, with none reporting PS subgroup analyses for toxicity and 66 (60%) for efficacy. For these 66 RCTs involving 44 511 patients, pooled HRs for excellent and reduced groups were 0.65 (95% CI 0.61 to 0.70) and 0.67 (95% CI 0.62 to 0.72), respectively, with no difference between the two groups (p=0.68). Sensitivity analyses based on drug or cancer type and type of endpoints (OS or PFS) demonstrated similar results. CONCLUSIONS: No decrease in relative efficacy from novel systemic therapy was found for patients with reduced PS when compared with patients with excellent PS for the range which were included in modern RCTs. Reporting of PS subgroup analyses of toxicities and more inclusion of patients with borderline low PS in RCTs should be considered for a more comprehensive understanding of the net clinical benefits of contemporary systemic therapies in patients across the spectrum of different PS.

Do the American Society of Clinical Oncology Value Framework and the European Society of Medical Oncology Magnitude of Clinical Benefit Scale Measure the Same Construct of Clinical Benefit?

Purpose Whether the ASCO Value Framework and the European Society for Medical Oncology (ESMO) Magnitude of Clinical Benefit Scale (MCBS) measure similar constructs of clinical benefit is unclear. It is also unclear how they relate to quality-adjusted life-years (QALYs) and funding recommendations in the United Kingdom and Canada. Methods Randomized clinical trials of oncology drug approvals by the US Food and Drug Administration, European Medicines Agency, and Health Canada between 2006 and August 2015 were identified and scored using the ASCO version 1 (v1) framework, ASCO version 2 (v2) framework, and ESMO-MCBS by at least two independent reviewers. Spearman correlation coefficients were calculated to assess construct (between frameworks) and criterion validity (against QALYs from the National Institute for Health and Care Excellence [NICE] and the pan-Canadian Oncology Drug Review [pCODR]). Associations between scores and NICE/pCODR recommendations were examined. Inter-rater reliability was assessed using intraclass correlation coefficients. Results From 109 included randomized clinical trials, 108 ASCOv1, 111 ASCOv2, and 83 ESMO scores were determined. Correlation coefficients for ASCOv1 versus ESMO, ASCOv2 versus ESMO, and ASCOv1 versus ASCOv2 were 0.36 (95% CI, 0.15 to 0.54), 0.17 (95% CI, -0.06 to 0.37), and 0.50 (95% CI, 0.35 to 0.63), respectively. Compared with NICE QALYs, correlation coefficients were 0.45 (ASCOv1), 0.53 (ASCOv2), and 0.46 (ESMO); with pCODR QALYs, coefficients were 0.19 (ASCOv1), 0.20 (ASCOv2), and 0.36 (ESMO). None of the frameworks were significantly associated with NICE/pCODR recommendations. Inter-rater reliability was good for all frameworks. Conclusion The weak-to-moderate correlations of the ASCO frameworks with the ESMO-MCBS, as well as their correlations with QALYs and with NICE/pCODR funding recommendations, suggest different constructs of clinical benefit measured. Construct convergent validity with the ESMO-MCBS did not increase with the updated ASCO framework.