Application of Multi-Criteria Decision Analysis (MCDA) to Prioritize Real-World Evidence Studies for Health Technology Management: Outcomes and Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration.

Multi-criteria decision analysis (MCDA) is a value assessment tool designed to help support complex decision-making by incorporating multiple factors and perspectives in a transparent, structured approach. We developed an MCDA rating tool, consisting of seven criteria evaluating the importance and feasibility of conducting potential real-world evidence (RWE) studies aimed at addressing uncertainties stemming from initial cancer drug funding recommendations. In collaboration with the Canadian Agency for Drugs and Technologies in Health's Provincial Advisory Group, a validation exercise was conducted to further evaluate the application of the rating tool using RWE proposals varying in complexity. Through this exercise, we aimed to gain insight into consensus building and deliberation processes and to identify efficiencies in the application of the rating tool. An experienced facilitator led a multidisciplinary committee, consisting of 11 Canadian experts, through consensus building, deliberation, and prioritization. A total of nine RWE proposals were evaluated and prioritized as low (n = 4), medium (n = 3), or high (n = 2) priority. Through an iterative process, efficiencies and recommendations to improve the rating tool and associated procedures were identified. The refined MCDA rating tool can help decision-makers prioritize important and feasible RWE studies for research and can enable the use of RWE for the life-cycle evaluation of cancer drugs.

COVID-related disruptions to colorectal cancer screening, diagnosis, and treatment could increase cancer Burden in Australia and Canada: A modelling study.

COVID-19 disrupted cancer control worldwide, impacting preventative screening, diagnoses, and treatment services. This modelling study estimates the impact of disruptions on colorectal cancer cases and deaths in Canada and Australia, informed by data on screening, diagnosis, and treatment procedures. Modelling was used to estimate short- and long-term effects on colorectal cancer incidence and mortality, including ongoing impact of patient backlogs. A hypothetical mitigation strategy was simulated, with diagnostic and treatment capacities increased by 5% from 2022 to address backlogs. Colorectal cancer screening dropped by 40% in Canada and 6.3% in Australia in 2020. Significant decreases to diagnostic and treatment procedures were also observed in Australia and Canada, which were estimated to lead to additional patient wait times. These changes would lead to an estimated increase of 255 colorectal cancer cases and 1,820 colorectal cancer deaths in Canada and 234 cases and 1,186 deaths in Australia over 2020-2030; a 1.9% and 2.4% increase in mortality, respectively, vs a scenario with no screening disruption or diagnostic/treatment delays. Diagnostic and treatment capacity mitigation would avert 789 and 350 deaths in Canada and Australia, respectively. COVID-related disruptions had a significant impact on colorectal cancer screening, diagnostic, and treatment procedures in Canada and Australia. Modelling demonstrates that downstream effects on disease burden could be substantial. However, backlogs can be managed and deaths averted with even small increases to diagnostic and treatment capacity. Careful management of resources can improve patient outcomes after any temporary disruption, and these results can inform targeted approaches early detection of cancers.

Creating a Multiply Imputed Value Set for the EQ-5D-5L in Canada: State-Level Misspecification Terms Are Needed to Characterize Parameter Uncertainty Correctly.

BACKGROUND: Parameter uncertainty in EQ-5D-5L value sets often exceeds the instrument's minimum important difference, yet this is routinely ignored. Multiple imputation (MI) accounts for parameter uncertainty in the value set; however, no valuation study has implemented this methodology. Our objective was to create a Canadian MI value set for the EQ-5D-5L, thus enabling users to account for parameter uncertainty in the value set. METHODS: Using the Canadian EQ-5D-5L valuation study (N = 1,073), we first refit the original model followed by models with state-level misspecification. Models were compared based on the adequacy of 95% credible interval (CrI) coverage for out-of-sample predictions. Using the best-fitting model, we took 100 draws from the posterior distribution to create 100 imputed value sets. We examined how much the standard error of the estimated mean health utilities increased after accounting for parameter uncertainty in the value set by using the MI and original value sets to score 2 data sets: 1) a sample of 1,208 individuals from the Canadian general public and 2) a sample of 401 women with breast cancer. RESULTS: The selected model with state-level misspecification outperformed the original model (95% CrI coverage: 94.2% v. 11.6%). We observed wider standard errors for the estimated mean utilities on using the MI value set for both the Canadian general public (MI: 0.0091; original: 0.0035) and patients with breast cancer (MI: 0.0169; original: 0.0066). DISCUSSION AND CONCLUSIONS: We provide 1) the first MI value sets for the EQ-5D-5L and 2) code to construct MI value sets while accounting for state-level model misspecification. Our study suggests that ignoring parameter uncertainty in value sets leads to falsely narrow SEs. HIGHLIGHTS: Value sets for health state utility instruments are estimated subject to parameter uncertainty; this parameter uncertainty may exceed the minimum important difference of the instrument, yet it is not fully captured using current methods.This study creates the first multiply imputed value set for a multiattribute utility instrument, the EQ-5D-5L, to fully capture this parameter uncertainty.We apply the multiply imputed value set to 2 data sets from 1) the Canadian general public and 2) women with invasive breast cancer.Scoring the EQ-5D-5L using a multiply imputed value set led to wider standard error estimates, suggesting that the current practice of ignoring parameter uncertainty in the value set leads to falsely low standard errors.Our work will be of interest to methodologists and developers of the EQ-5D-5L and users of the EQ-5D-5L, such as health economists, researchers, and policy makers.

Sex-Based Analysis of Quality Indicators of End-of-Life Care in Gastrointestinal Malignancies.

Indices of aggressive or supportive end-of-life (EOL) care are used to evaluate health services quality. Disparities according to sex were previously described, with studies showing that male sex is associated with aggressive EOL care. This is a secondary analysis of 69,983 patients who died of a GI malignancy in Ontario between 2006 and 2018. Quality indices from the last 14-30 days of life and aggregate measures for aggressive and supportive EOL care were derived from administrative data. Hospitalizations, emergency department use, intensive care unit admissions, and receipt of chemotherapy were considered indices of aggressive care, while physician house call and palliative home care were considered indices of supportive care. Overall, a smaller proportion of females experienced aggressive care at EOL (14.3% vs. 19.0%, standardized difference = 0.13, where ≥0.1 is a meaningful difference). Over time, rates of aggressive care were stable, while rates of supportive care increased for both sexes. Logistic regression showed that younger females (ages 18-39) had increased odds of experiencing aggressive EOL care (OR 1.71, 95% CI 1.30-2.25), but there was no such association for males. Quality of EOL care varies according to sex, with a smaller proportion of females experiencing aggressive EOL care.

Comparative Effectiveness and Safety of Trastuzumab Biosimilars to Herceptin for Adjuvant Treatment of HER2+ Breast Cancer.

Background: Ontario publicly funds reference trastuzumab (Herceptin) and four biosimilar trastuzumab products for adjuvant treatment of HER2+ breast cancer. We assessed the real-world safety and effectiveness of biosimilar trastuzumab compared to Herceptin for adjuvant treatment of patients with HER2+ breast cancer. Methods: This was a population-based, retrospective study comparing the safety and effectiveness of biosimilar trastuzumab and Herceptin for neoadjuvant/adjuvant treatment of HER2+ breast cancer from 2016 to 2021. Treatment patients started biosimilar trastuzumab from November 2019 to June 2021; historical comparator patients started Herceptin from June 2016 to October 2019. Safety outcomes death within 30 days of last dose of trastuzumab, direct hospitalization, emergency department visit leading to hospitalization, early treatment discontinuation, and in-patient admission for congestive heart failure were measured using logistic/negative binomial regression. Overall survival (OS) was measured using Kaplan-Meier methods and Cox proportional hazards regression. Propensity score matching was applied. Results: From June 2016 to 2021, 5071 patients with breast cancer were treated with neoadjuvant/adjuvant trastuzumab. The rate of direct hospitalization (RR: 0.85, 95% CI: 0.74-0.98, p-value: 0.032) was significantly lower in biosimilar compared to Herceptin patients. OS (log-rank test p = 0.98) and risk of mortality (HR: 1.29, 95% CI: 0.72-2.30, p-value = 0.39) did not significantly differ between treatment groups. Conclusions: Biosimilar trastuzumab demonstrated similar safety and effectiveness to Herceptin. The findings can help improve confidence in and use of biosimilars and demonstrate the value of real-world evidence generation for supporting biosimilar implementations and reassessments.

CAR T-cell Therapy for Diffuse Large B-cell Lymphoma in Canada: A Cost-Utility Analysis.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a novel cell therapy for treating non-Hodgkin lymphoma. The development of CAR T-cell therapy has transformed oncology treatment by offering a potential cure. However, due to the high cost of these therapies, and the large number of eligible patients, decision makers are faced with difficult funding decisions. Our objective was to assess the cost-effectiveness of tisagenlecleucel for adults with relapsed/refractory diffuse large B-cell lymphoma in Canada using updated survival data from the recent JULIET trial. METHODS: We developed an individual-simulated discrete event simulation model to assess the costs and quality-adjusted life-years (QALY) of tisagenlecleucel compared with salvage chemotherapy. Survival estimates were obtained from a published clinical trial and retrospective analysis. If patients remained progression free for 5 y, they were assumed to be in long-term remission. Costing and utility data were obtained from reports and published sources. A Canadian health care payer perspective was used, and outcomes were modeled over a lifetime horizon. Costs and outcomes were discounted at 1.5% annually, with costs reported in 2021 Canadian dollars. A probabilistic analysis was used, and model parameters were varied in 1-way sensitivity analyses and scenario analyses. RESULTS: After we incorporated the latest clinical evidence, tisagenlecleucel led to an additional cost of $503,417 and additional effectiveness of 2.48 QALYs, with an incremental cost-effectiveness ratio of $202,991 compared with salvage chemotherapy. At a willingness-to-pay threshold of $100,000/QALY, tisagenlecleucel had a 0% likelihood of being cost-effective. CONCLUSIONS: At the current drug price, tisagenlecleucel was not found to be a cost-effective option. These results heavily depend on assumptions regarding long-term survival and the price of CAR T. Real-world evidence is needed to reduce uncertainty. HIGHLIGHTS: For patients with diffuse large B-cell lymphoma who failed 2 or more lines of systemic therapy, CAR T was not found to be a cost-effective treatment option at a willingness-to-pay threshold of $100,000.These results heavily depend on the expected long-term survival. The uncertainty in the model may be improved using real-world evidence reported in the future.

Tissue mapping by cardiac magnetic resonance imaging for the prognostication of cardiac amyloidosis: A systematic review and meta-analysis.

BACKGROUND: Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV). METHODS: Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis. RESULTS: A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m2 vs 127 ± 37 g/m2, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I2 = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I2 = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I2 = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean). CONCLUSION: Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.

Machine Learning to Allocate Palliative Care Consultations During Cancer Treatment.

PURPOSE: For patients with advanced cancer, early consultations with palliative care (PC) specialists reduce costs, improve quality of life, and prolong survival. However, capacity limitations prevent all patients from receiving PC shortly after diagnosis. We evaluated whether a prognostic machine learning system could promote early PC, given existing capacity. METHODS: Using population-level administrative data in Ontario, Canada, we assembled a cohort of patients with incurable cancer who received palliative-intent systemic therapy between July 1, 2014, and December 30, 2019. We developed a machine learning system that predicted death within 1 year of each treatment using demographics, cancer characteristics, treatments, symptoms, laboratory values, and history of acute care admissions. We trained the system in patients who started treatment before July 1, 2017, and evaluated the potential impact of the system on PC in subsequent patients. RESULTS: Among 560,210 treatments received by 54,628 patients, death occurred within 1 year of 45.2% of treatments. The machine learning system recommended the same number of PC consultations observed with usual care at the 60.0% 1-year risk of death, with a first-alarm positive predictive value of 69.7% and an outcome-level sensitivity of 74.9%. Compared with usual care, system-guided care could increase early PC by 8.5% overall (95% CI, 7.5 to 9.5; P < .001) and by 15.3% (95% CI, 13.9 to 16.6; P < .001) among patients who live 6 months beyond their first treatment, without requiring more PC consultations in total or substantially increasing PC among patients with a prognosis exceeding 2 years. CONCLUSION: Prognostic machine learning systems could increase early PC despite existing resource constraints. These results demonstrate an urgent need to deploy and evaluate prognostic systems in real-time clinical practice to increase access to early PC.

Lymph node yield: Impact on oncologic outcomes in oral cavity cancer.

BACKGROUND: Lymph node metastases are associated with poor prognosis in oral cavity squamous cell carcinoma (OCSCC). In other cancers, clinical guidelines on the number of lymph nodes removed during primary surgery, lymph node yield (LNY), exist. Here, we evaluated the prognostic capacity of LNY on regional failure, locoregional recurrence, and disease-free survival (DFS) in patients with OCSCC treated by primary neck surgery. METHODS: This retrospective cohort study took place at Sunnybrook Health Sciences Centre in Toronto, Canada and involved a chart review of all adult patients with treatment-naive OCSCC undergoing primary neck dissection. For each outcome, we first used the maximally selected rank statistics and an optimism-corrected concordance to identify an optimal threshold of LNY. We then used a multivariable Cox proportional hazards model to assess the association between high LNY (>threshold) and each outcome. RESULTS: Among the 579 patients with OCSCC receiving primary neck dissection, 61.7% (n = 357) were male with a mean age of 62.9 years (standard deviation: 13.1) at cancer diagnosis. When adjusting for sociodemographic and clinical factors, LNY >15 was significantly associated with improved DFS (adjusted HR [aHR]: 0.73, 95% CI: 0.54-0.98), locoregional recurrence (aHR: 0.68, 95% CI: 0.49-0.95), and regional failure (aHR: 0.61, 95% CI: 0.39-0.93). CONCLUSIONS: Our study findings suggested high LNY to be a strong independent predictor of various patient-level quality of surgical care metrics. The optimal LNY we found (15) was lower than the conventionally recommended (18), which calls for further research to establish validity in practice.

Impact on costs and outcomes of multi-gene panel testing for advanced solid malignancies: a cost-consequence analysis using linked administrative data.

Background: To date, economic analyses of tissue-based next generation sequencing genomic profiling (NGS) for advanced solid tumors have typically required models with assumptions, with little real-world evidence on overall survival (OS), clinical trial enrollment or end-of-life quality of care. Methods: Cost consequence analysis of NGS testing (555 or 161-gene panels) for advanced solid tumors through the OCTANE clinical trial (NCT02906943). This is a longitudinal, propensity score-matched retrospective cohort study in Ontario, Canada using linked administrative data. Patients enrolled in OCTANE at Princess Margaret Cancer Centre from August 2016 until March 2019 were matched with contemporary patients without large gene panel testing from across Ontario not enrolled in OCTANE. Patients were matched according to 19 patient, disease and treatment variables. Full 2-year follow-up data was available. Sensitivity analyses considered alternative matched cohorts. Main Outcomes were mean per capita costs (2019 Canadian dollars) from a public payer's perspective, OS, clinical trial enrollment and end-of-life quality metrics. Findings: There were 782 OCTANE patients with 782 matched controls. Variables were balanced after matching (standardized difference <0.10). There were higher mean health-care costs with OCTANE ($79,702 vs. $59,550), mainly due to outpatient and specialist visits. Publicly funded drug costs were less with OCTANE ($20,015 vs. $24,465). OCTANE enrollment was not associated with improved OS (restricted mean survival time [standard error]: 1.50 (±0.03) vs. 1.44 (±0.03) years, log-rank p = 0.153), varying by tumor type. In five tumor types with ≥35 OCTANE patients, OS was similar in three (breast, colon, uterus, all p > 0.40), and greater in two (ovary, biliary, both p < 0.05). OCTANE was associated with greater clinical trial enrollment (25.4% vs. 9.5%, p < 0.001) and better end-of-life quality due to less death in hospital (10.2% vs. 16.4%, p = 0.003). Results were robust in sensitivity analysis. Interpretation: We found an increase in healthcare costs associated with multi-gene panel testing for advanced cancer treatment. The impact on OS was not significant, but varied across tumor types. OCTANE was associated with greater trial enrollment, lower publicly funded drug costs and fewer in-hospital deaths suggesting important considerations in determining the value of NGS panel testing for advanced cancers. Funding: T.P H holds a research grant provided by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario (#IA-035 and P.HSR.158) and through funding of the Canadian Network for Learning Healthcare Systems and Cost-Effective 'Omics Innovation (CLEO) via Genome Canada (G05CHS).

Re-examining prophylactic cranial irradiation in small cell lung cancer: a systematic review and meta-analysis.

Background: Patients with small cell lung cancer (SCLC) are at high risk for brain metastases. Prophylactic cranial irradiation (PCI) is recommended in this population to reduce the incidence of brain metastases and prolong survival. We aimed to assesses the efficacy of PCI in this population in the era of routine brain imaging. To our knowledge, this is the first systematic review and meta-analysis to examine the use among patients who were radiographically confirmed not to have brain metastases after completion of first-line therapy. Methods: In this systematic review and meta-analysis, cohort studies and controlled trials reporting on the use of PCI for patients SCLC were identified in EMBASE, MEDLINE, CENTRAL, and grey literature sources. The literature search was conducted on November 12, 2023. Summary data were extracted. Random-effects meta-analyses pooled hazard ratios (HR) for the primary outcome of overall survival between PCI and no intervention groups. This study is registered with the Open Science Framework, DOI:10.17605/OSF.IO/BC359, and PROSPERO, CRD42021249466. Findings: Of 4318 identified records, 223 were eligible for inclusion. 109 reported on overall survival in formats amenable to meta-analysis; PCI was associated with longer survival in all patients with SCLC (HR 0.59; 95% CI, 0.55-0.63; p < 0.001; n = 56,770 patients), patients with limited stage disease (HR 0.60; 95% CI, 0.55-0.65; p < 0.001; n = 78 studies; n = 27,137 patients), and patients with extensive stage disease (HR 0.59; 95% CI, 0.51-0.70; p < 0.001; n = 28 studies; n = 26,467 patients). Between-study heterogeneity was significant when pooled amongst all studies (I2 = 73.6%; 95% CI 68.4%-77.9%). Subgroup analysis did not reveal sources of heterogeneity. In a subgroup analysis on studies that used magnetic resonance imaging to exclude presence of brain metastases at restaging among all patients, overall survival did not differ significantly between patients who did or did not receive PCI (HR 0.74; 95% CI, 0.52-1.05; p = 0.08; n = 9 studies; n = 1384 patients). Interpretation: Our findings suggested that administration of PCI is associated with a survival benefit, but not when considering studies that radiographically confirmed absence of brain metastases, suggesting that the survival benefit conferred by PCI might be therapeutic rather than prophylactic. Funding: No funding.

Nivolumab for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Retrospective Tertiary Centre's Real-World Experience.

Nivolumab, a PD-1 checkpoint inhibitor, was approved in Canada in 2017 for the treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) based on the phase 3 trial CHECKMATE-141. We aimed to examine the demographics and efficacy of nivolumab in a Canadian, real-world setting. A retrospective chart review was performed on patients who received nivolumab for R/M HNSCC from 2017 to 2020 at a high-volume cancer centre. Data were abstracted from 34 patients, based on physician notes and imaging reports. The median patient age at nivolumab initiation was 61, 24% were female, and 62% were current or former smokers. Prior to nivolumab, 44% of patients underwent surgery, 97% radiation, and 100% chemotherapy. Most (97%) therapies were for primary disease. Overall survival at 6 and 12 months following drug initiation was 38% and 23%, respectively. Progression-free survival at 6 and 12 months was 33% and 22%, respectively. Eighteen percent of patients experienced an immune-related adverse event, the most common of which was pneumonitis (3/8) and endocrine events (3/8). Seven out of eight of the immune adverse events were grade 1-2; 1/8 was grade 3. Nivolumab appears to have decreased survival rates in our single-centre Canadian population compared to CHECKMATE-141 and presented a manageable adverse event profile for R/M HNSCC.

Machine Learning-Based Early Warning Systems for Acute Care Utilization During Systemic Therapy for Cancer.

BACKGROUND: Emergency department visits and hospitalizations frequently occur during systemic therapy for cancer. We developed and evaluated a longitudinal warning system for acute care use. METHODS: Using a retrospective population-based cohort of patients who started intravenous systemic therapy for nonhematologic cancers between July 1, 2014, and June 30, 2020, we randomly separated patients into cohorts for model training, hyperparameter tuning and model selection, and system testing. Predictive features included static features, such as demographics, cancer type, and treatment regimens, and dynamic features, such as patient-reported symptoms and laboratory values. The longitudinal warning system predicted the probability of acute care utilization within 30 days after each treatment session. Machine learning systems were developed in the training and tuning cohorts and evaluated in the testing cohort. Sensitivity analyses considered feature importance, other acute care endpoints, and performance within subgroups. RESULTS: The cohort included 105,129 patients who received 1,216,385 treatment sessions. Acute care followed 182,444 (15.0%) treatments within 30 days. The ensemble model achieved an area under the receiver operating characteristic curve of 0.742 (95% CI, 0.739-0.745) and was well calibrated in the test cohort. Important predictive features included prior acute care use, treatment regimen, and laboratory tests. If the system was set to alarm approximately once every 15 treatments, 25.5% of acute care events would be preceded by an alarm, and 47.4% of patients would experience acute care after an alarm. The system underestimated risk for some treatment regimens and potentially underserved populations such as females and non-English speakers. CONCLUSIONS: Machine learning warning systems can detect patients at risk for acute care utilization, which can aid in preventive intervention and facilitate tailored treatment. Future research should address potential biases and prospectively evaluate impact after system deployment.

Changes in Health Care Costs, Survival, and Time Toxicity in the Era of Immunotherapy and Targeted Systemic Therapy for Melanoma.

Importance: Melanoma treatment has evolved during the past decade with the adoption of adjuvant and palliative immunotherapy and targeted therapies, with an unclear impact on health care costs and outcomes in routine practice. Objective: To examine changes in health care costs, overall survival (OS), and time toxicity associated with primary treatment of melanoma. Design, Setting, and Participants: This cohort study assessed a longitudinal, propensity score (PS)-matched, retrospective cohort of residents of Ontario, Canada, aged 20 years or older with stages II to IV cutaneous melanoma identified from the Ontario Cancer Registry from January 1, 2018, to March 31, 2019. A historical comparison cohort was identified from a population-based sample of invasive melanoma cases diagnosed from the Ontario Cancer Registry from January 1, 2007, to December 31, 2012. Data analysis was performed from October 17, 2022, to March 13, 2023. Exposures: Era of melanoma diagnosis (2007-2012 vs 2018-2019). Main Outcomes and Measures: The primary outcomes were mean per-capita health care and systemic therapy costs (Canadian dollars) during the first year after melanoma diagnosis, time toxicity (days with physical health care contact) within 1 year of initial treatment, and OS. Standardized differences were used to compare costs and time toxicity. Kaplan-Meier methods and Cox proportional hazards regression were used to compare OS among PS-matched cohorts. Results: A PS-matched cohort of 731 patients (mean [SD] age, 67.9 [14.8] years; 437 [59.8%] male) with melanoma from 2018 to 2019 and 731 patients (mean [SD] age, 67.9 [14.4] years; 440 [60.2%] male) from 2007 to 2012 were evaluated. The 2018 to 2019 patients had greater mean (SD) health care (including systemic therapy) costs compared with the 2007 to 2012 patients ($47 886 [$55 176] vs $33 347 [$31 576]), specifically for stage III ($67 108 [$57 226] vs $46 511 [$30 622]) and stage IV disease ($117 450 [$79 272] vs $47 739 [$37 652]). Mean (SD) systemic therapy costs were greater among 2018 to 2019 patients: stage II ($40 823 [$40 621] vs $10 309 [$12 176]), III ($55 699 [$41 181] vs $9764 [$12 771]), and IV disease ($79 358 [$50 442] vs $9318 [$14 986]). Overall survival was greater for the 2018 to 2019 cohort compared with the 2007 to 2012 cohort (3-year OS: 74.2% [95% CI, 70.8%-77.2%] vs 65.8% [95% CI, 62.2%-69.1%], hazard ratio, 0.72 [95% CI, 0.61-0.85]; P < .001). Time toxicity was similar between eras. Patients with stage IV disease spent more than 1 day per week (>52 days) with physical contact with the health care system by 2018 to 2019 (mean [SD], 58.7 [43.8] vs 44.2 [26.5] days; standardized difference, 0.40; P = .20). Conclusions and Relevance: This cohort study found greater health care costs in the treatment of stages II to IV melanoma and substantial time toxicity for patients with stage IV disease, with improvements in OS associated with the adoption of immunotherapy and targeted therapies. These health system-wide data highlight the trade-off with adoption of new therapies, for which there is a greater economic burden to the health care system and time burden to patients but an associated improvement in survival.

SARS-CoV-2 Infection, Hospitalization, and Mortality in Adults With and Without Cancer.

Importance: Patients with cancer are at increased risk of SARS-CoV-2-associated adverse outcomes. Objective: To determine the associations of tumor type with SARS-CoV-2 infection, hospitalization, intensive care unit (ICU) admission, and death. Design, Setting, and Participants: This retrospective, population-based cohort study included community-dwelling adults aged at least 18 years in Ontario, Canada, ICES-linked provincial health databases from January 1, 2020, to November 30, 2021. Data were analyzed from December 1, 2021, to November 1, 2022. Exposures: Cancer diagnosis. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, and secondary outcomes included all-cause 14-day hospitalization, 21-day ICU admission, and 28-day death following SARS-CoV-2 infection. Cox proportional hazards models were used to obtain adjusted hazard ratios (aHRs) and 95% CIs. Results: Of 11 732 108 people in the ICES-linked health databases, 279 287 had cancer (57.2% female; mean [SD] age, 65.9 [16.1] years) and 11 452 821 people did not have cancer (45.7% female; mean [SD] age, 65.9 [16.0] years). Overall, 464 574 individuals (4.1%) developed SARS-CoV-2 infection. Individuals with hematologic malignant neoplasms (33 901 individuals) were at increased risk of SARS-CoV-2 infection (aHR, 1.19; 95% CI, 1.13-1.25), 14-day hospitalization (aHR, 1.75; 95% CI, 1.57-1.96), and 28-day mortality (aHR, 2.03; 95% CI, 1.74-2.38) compared with the overall population, while individuals with solid tumors (245 386 individuals) were at lower risk of SARS-CoV-2 infection (aHR, 0.93; 95% CI, 0.91-0.95) but increased risk of 14-day hospitalization (aHR, 1.11; 95% CI, 1.05-1.18) and 28-day mortality (aHR, 1.31; 95% CI, 1.19-1.44). The 28-day mortality rate was high in hospitalized patients with hematologic malignant neoplasms (163 of 321 hospitalized patients [50.7%]) or solid tumors (486 of 1060 hospitalized patients [45.8%]). However, the risk of 21-day ICU admission in patients with hematologic malignant neoplasms (aHR, 1.14; 95% CI, 0.93-1.40) or solid tumors (aHR, 0.93; 95% CI, 0.82-1.05) was not significantly different from that among individuals without cancer. The SARS-CoV-2 infection risk decreased stepwise with increasing numbers of COVID-19 vaccine doses received (1 dose: aHR, 0.63; 95% CI, 0.62-0.63; 2 doses: aHR, 0.16; 95% CI, 0.16-0.16; 3 doses: aHR, 0.05; 95% CI, 0.04-0.06). Conclusions and Relevance: These findings highlight the importance of prioritization strategies regarding ICU access to reduce the mortality risk in increased-risk populations, such as patients with cancer.

Mortality among patients with diffuse large B-cell lymphoma and mental disorders: a population-based study.

BACKGROUND: Mental disorders have been reported in patients with diffuse large B-cell lymphoma (DLBCL), but studies examining their association with mortality are lacking. METHODS: We conducted a population-based study using linked administrative health-care databases from Ontario, Canada. All patients with DLBCL 18 years of age or older treated with rituximab-based therapy between January 1, 2005, and December 31, 2017, were identified and followed until March 1, 2020. Mental disorders were defined as either preexisting or postdiagnosis (after lymphoma treatment initiation). Cox proportional hazards models were used to estimate the adjusted hazard ratio (HR) between mental disorders and 1-year and all-cause mortality while controlling for covariates. RESULTS: We identified 10 299 patients with DLBCL. The median age of the cohort was 67 years; 46% of patients were female, and 28% had a preexisting mental disorder. At 1-year follow-up, 892 (9%) had a postdiagnosis mental disorder, and a total of 2008 (20%) patients died. Preexisting mental disorders were not associated with 1-year mortality (adjusted HR = 1.06, 95% confidence interval [CI] = 0.96 to 1.17, P = .25), but postdiagnosis disorders were (adjusted HR = 1.51, 95% CI = 1.26 to 1.82, P = .0001). During a median follow-up of 5.2 years, 2111 (22%) patients had a postdiagnosis mental disorder, and 4084 (40%) patients died. Both preexisting and postdiagnosis mental disorders were associated with worse all-cause mortality (preexisting adjusted HR = 1.12, 95% CI = 1.04 to 1.20, P = .0024; postdiagnosis adjusted HR = 1.63, 95% CI = 1.49 to 1.79, P < .0001). CONCLUSIONS: Patients with DLBCL and mental disorders had worse short-term and long-term mortality, particularly those with postdiagnosis mental disorders. Further studies are needed to examine mental health service utilization and factors mediating the relationship between mental disorders and inferior mortality.

Power and sample size calculation for incremental net benefit in cost effectiveness analyses with applications to trials conducted by the Canadian Cancer Trials Group.

BACKGROUND: Historically, a priori power and sample size calculations have not been routinely performed cost-effectiveness analyses (CEA), partly because the absence of published cost and effectiveness correlation and variance data, which are essential for power and sample size calculations. Importantly, the empirical correlation between cost and effectiveness has not been examined with respect to the estimation of value-for-money in clinical literature. Therefore, it is not well established if cost-effectiveness studies embedded within randomized-controlled-trials (RCTs) are under- or over-powered to detect changes in value-for-money. However, recently guidelines (such as those from ISPOR) and funding agencies have suggested sample size and power calculations should be considered in CEAs embedded in clinical trials. METHODS: We examined all RCTs conducted by the Canadian Cancer Trials Group with an embedded cost-effectiveness analysis. Variance and correlation of effectiveness and costs were derived from original-trial data. The incremental net benefit method was used to calculate the power of the cost-effectiveness analysis, with exploration of alternative correlation and willingness-to-pay values. RESULTS: We identified four trials for inclusion. We observed that a hypothetical scenario of correlation coefficient of zero between cost and effectiveness led to a conservative estimate of sample size. The cost-effectiveness analysis was under-powered to detect changes in value-for-money in two trials, at willingness-to-pay of $100,000. Based on our observations, we present six considerations for future economic evaluations, and an online program to help analysts include a priori sample size and power calculations in future clinical trials. CONCLUSION: The correlation between cost and effectiveness had a potentially meaningful impact on the power and variance of value-for-money estimates in the examined cost-effectiveness analyses. Therefore, the six considerations and online program, may facilitate a priori power calculations in embedded cost-effectiveness analyses in future clinical trials.

Outcomes of patients with indolent lymphoma treated with bendamustine plus rituximab compared to rituximab plus CVP or CHOP chemoimmunotherapy in Ontario.

Bendamustine (B) with rituximab (R) has become the preferred regimen for patients with indolent lymphoma in Ontario, Canada, compared to R with cyclophosphamide, vincristine, prednisone (CVP) or cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). We conducted a propensity-matched retrospective cohort population-based study of patients treated with R-CVP/CHOP from 2005 to 2012 and patients treated with BR from 2013 to 2018. The primary outcome was 5-year overall survival (OS), and secondary outcomes included toxicities and healthcare utilization. The 5-year OS for patients treated with BR (n = 2023) and R-CVP/CHOP (n = 2023) was 80% and 75% respectively. Treatment with BR was associated with improved OS (HR 0.79, 95% CI 0.69-0.91). During the first 9 months, patients treated with BR versus R-CVP/CHOP had a higher number of admissions for infection (22% compared to 17%, p < 0.01) and a higher number of mean ED visits (mean 1.01 ± 1.68 visits vs. 0.85 ± 1.51 visits, p < 0.01). This trend persisted for 3 years. The adjusted 5-year OS for patients 75 years and older did not differ based on treatment regimen (55.5% for BR vs. 55.4% for R-CVP/CHOP). Our study supports the use of BR for patients with indolent lymphoma requiring treatment but suggests increased risk of certain toxicities warranting careful patient selection.

Risk-adjusted chemoradiation according to human papilloma viral status for anal cancer: a pilot study.

Background and purpose: HPV-associated or positive (HPV+) anal cancer patients may have better outcome compared to those with HPV negative (HPV-) disease. We report a planned interim analysis of a prospective registry study that tailors chemoradiation (CRT) for anal cancer according to HPV status. Materials and methods: HPV+ patients received de-escalated radiation doses of 45, 50.4 and 55.8 Gy, while HPV- received 50.4, 55.8 and 63 Gy for T1, T2 and T3/T4 disease respectively. Chemotherapy consisted of a single dose of mitomycin-C and oral capecitabine on days of RT. All patients were planned by VMAT following CT, PET/CT and MR simulation. This cohort (n = 24) had a minimum 24-month follow-up. Disease free survival (DFS) and local failure rates (LFR) were compared with 180 patients managed by standard CRT (2 cycles of mitomycin-C and 5-fluorouracil, radiation doses 50.4-63 Gy based on T-category) from 2011-2018. Propensity score comparison was performed using a retrospective to prospective 2 to 1 match based on tumor size and N-category. Results: In the HPV+ cohort (n = 20), there were 2 local failures. Two of 4 HPV- patients failed locally. The 30-month DFS and LFR were 79% and 17% respectively. Similar DFS and LFR were observed in the retrospective (80% and 15% respectively) and matched patients (76% and 16% respectively). No grade ≥3 neutropenia and febrile neutropenia were observed in the registry cohort whereas 19% and 14% respectively were seen in the retrospective patients. Conclusion: De-escalation of CRT for HPV+ anal cancer may result in decreased acute toxicities and similar cancer outcomes compared to standard CRT.

Fracture risk among patients with cancer compared to individuals without cancer: a population-based study.

BACKGROUND: Patients with cancer may be at increased risk of osteoporosis and fracture; however, gaps exist in the existing literature and the association between cancer and fracture requires further examination. METHODS: We conducted a population-based cohort study of Ontario patients with cancer (breast, prostate, lung, gastrointestinal, haematologic) diagnosed between January 2007 to December 2018 and 1:1 matched non-cancer controls. The primary outcome was incident fracture (end of follow-up December 2019). Multivariable Cox regression analysis was used to estimate the relative fracture risk with sensitivity analysis accounting for competing risk of death. RESULTS: Among 172,963 cancer patients with non-cancer controls, 70.6% of patients with cancer were <65 years old, 58% were female, and 9375 and 8141 fracture events were observed in the cancer and non-cancer group, respectively (median follow-up 6.5 years). Compared to non-cancer controls, patients with cancer had higher risk of fracture (adjusted HR [aHR] 1.10, 95% CI 1.07-1.14, p < 0.0001), which was also observed for both solid (aHR 1.09, 95% CI 1.05-1.13, p < 0.0001) and haematologic cancers (aHR 1.20, 95% CI 1.10-1.31, p < 0.0001). Sensitivity analysis accounting for competing risk of death did not change these findings. CONCLUSIONS: Our study indicates that patients with cancer are at modest risk of fractures compared to non-cancer controls.