Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

Indolent lymphoma care delivery and outcomes during the COVID-19 pandemic in Ontario, Canada.

The treatment pattern and outcomes in patients with indolent B-cell lymphoma treated during the coronavirus disease 2019 (COVID-19) pandemic period compared to the prepandemic period are unclear. This was a retrospective population-based study using administrative databases in Ontario, Canada (follow-up to 31 March 2022). The primary outcome was treatment pattern; secondary outcomes were death, toxicities, healthcare utilization (emergency department [ED] visit, hospitalization) and SARS-CoV-2 outcomes. Adjusted hazard ratios (aHR) from Cox proportional hazards models were used to estimate associations. We identified 4143 patients (1079 pandemic, 3064 prepandemic), with a median age of 69 years. In both time periods, bendamustine (B) + rituximab (BR) was the most frequently prescribed regimen. During the pandemic, fewer patients received R maintenance or completed the full 2-year course (aHR 0.81, 95% CI 0.71-0.92, p = 0.001). Patients treated during the pandemic had less healthcare utilization (ED visit aHR 0.77, 95% CI 0.68, 0.88, p < 0.0001; hospitalization aHR 0.81, 95% CI 0.70-0.94, p = 0.0067) and complications (infection aHR 0.69, 95% CI 0.57-0.82, p < 0.0001; febrile neutropenia aHR 0.66, 95% CI 0.47-0.94, p = 0.020), with no difference in death. Independent of vaccination, active rituximab use was associated with a higher risk of COVID-19 complications. Despite similar front-line regimen use, healthcare utilization and admissions for infection were less in the pandemic cohort.

A Prognostic Survival Model Incorporating Patient-Reported Outcomes for Transplant-Ineligible Patients With Multiple Myeloma.

Developing prognostic tools specifically for patients themselves represents an important step in empowering patients to engage in shared decision-making. Incorporating patient-reported outcomes may improve the accuracy of these prognostic tools. We conducted a retrospective population-based study of transplant-ineligible (TIE) patients with multiple myeloma (MM) diagnosed between January 2007 and December 2018. A multivariable Cox regression model was developed to predict the risk of death within 1-year period from the index date. We identified 2356 patients with TIE MM. The following factors were associated with an increased risk of death within 1 year: age > 80 (HR 1.11), history of heart failure (HR 1.52), "CRAB" at diagnosis (HR 1.61), distance to cancer center (HR 1.25), prior radiation (HR 1.48), no proteosome inhibitor/immunomodulatory therapy usage (HR 1.36), recent emergency department (HR 1.55) or hospitalization (HR 2.13), poor performance status (ECOG 3-4 HR 1.76), and increasing number of severe symptoms (HR 1.56). Model discrimination was high with C-statistic of 0.74, and calibration was very good. To our knowledge, this represents one of the first prognostic models developed in MM incorporating patient-reported outcomes. This survival prognostic tool may improve communication regarding prognosis and shared decision-making among older adults with MM and their health care providers.

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.

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.

Contact Days Associated With Cancer Treatments in the CCTG LY.12 Trial.

BACKGROUND: When cancer treatments have similar oncologic outcomes, the number of days with in-person healthcare contact (""contact days'') can help contextualize expected time use with each treatment. We assessed contact days in a completed randomized clinical trial. PATIENTS AND METHODS: We conducted a secondary analysis of the CCTG LY.12 RCT that evaluated 2-3 cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates and survival. We calculated patient-level "contact days" by analyzing trial forms. The study period was from assignment to progression or transplant. Days without healthcare contact were considered "home days''. We compared measures of contact days across arms. RESULTS: The study period was longer in the GDP arm (median 50, vs. 47 days, P = .007). Contact days were comparable in both arms (median 18 vs 19, P = 0.79), but home days were higher in the GDP arm (median 33 vs 28, P < .001). The proportion of contact days was lower in the GDP arm (34%, vs. 38%, P = .009). The GDP arm experienced more contact days related to planned outpatient chemotherapy (median, 10 vs. 8 days), but the DHAP arm experienced many more inpatient contact days (median, 11 vs. 0 days). CONCLUSIONS: Measures of time use, such as contact days, can be extracted from RCTs. In LY.12, despite comparable oncologic outcomes, GDP was associated with fewer contact days. Such information can guide decision-making for patients with hematological cancers, who already face significant healthcare contact.

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.

Primary care utilization for patients with newly diagnosed cancer during the COVID-19 pandemic: a population-based study.

BACKGROUND: The COVID-19 pandemic greatly impacted primary care and cancer care. We studied how primary care utilization in Ontario, Canada changed for patients who were newly diagnosed with cancer just prior to the COVID-19 pandemic compared to those diagnosed in non-pandemic years. METHODS: This population-based, retrospective cohort study used linked healthcare databases to compare outcomes for patients with a new malignancy diagnosed within the year prior to the COVID-19 pandemic, between July 1 and September 30, 2019 (COVID-19 cohort) to those diagnosed in the same months in 2018 and 2017 (pre-pandemic cohort). We used Poisson regression models to compare rates of in-person and virtual visits to patients' usual primary care physician (PCP), emergency department (ED) visits, and hospitalizations, all reported per person-year of follow-up. RESULTS: In-person visits to usual PCPs decreased from 4.07/person-year in the pre-pandemic cohort to 2.58 in the COVID-19 cohort (p < 0.0001). Virtual visits to usual PCPs increased from 0.00 to 1.53 (p < 0.0001). Combined in-person and virtual visits to patients' usual PCPs was unchanged from 4.07 to 4.12 (p = 0.89). The rate of ED visits decreased from 0.99/person-year to 0.88 (p < 0.0001). Non-elective hospitalizations remained unchanged, from 0.49/person-year to 0.47 (p = 0.1675). CONCLUSION: There was a sizeable shift in primary care visits for cancer patients from in-person to virtual during the pandemic, although there was no resultant increase in hospitalizations. This suggests that early in the pandemic, virtual care allowed for continuity in utilization of primary care, though further studies are required to confirm this persisted later in the pandemic.

The impact of oral hypoglycemics and statins on outcomes in myelodysplastic syndromes.

Observational studies suggest an anti-neoplastic effect associated with statins, metformin, and dipeptidyl peptidase-4 inhibitors (DPP4i), while sulfonylureas may have a neutral or detrimental effect. We linked the Ontario subset of a prospective Canadian myelodysplastic syndromes (MDS) registry with provincial administrative databases. We assessed the impact of statin/oral hypoglycemic medication exposure on overall survival (OS) using Cox regression analysis, controlling for comorbidities and sociodemographic factors. Five hundred thirty-three patients aged ≥ 66 years were included: 49.3% used statins, 18.9% used metformin, 9.0% used sulfonylureas, and 6.4% used DPP4i. Three hundred ninety-five patients were lower-risk based on the International Prognostic Scoring System. On univariate analysis, we identified a marginal improvement in OS in the lower-risk group using DPP4i (HR 0.98, 95% CI 0.95-1.00, P = 0.05), while there was no impact on mortality for higher-risk DPP4i users (HR 1.03, CI 0.99-1.07, P = 0.21). There was no mortality difference for statins (HR 1.00, CI 1.00-1.01, P = 0.93), metformin (HR 1.00, CI 0.99-1.01, P = 0.81), or sulfonylureas (HR 1.00, CI 0.99-1.02, P = 0.43) in the entire cohort, as well as when stratified into lower/higher-risk groups. On multivariable analysis in the lower-risk group, there was no association between DPP4i and OS (HR 0.98, CI 0.95-1.00, P = 0.06). Prospective studies with larger cohorts of patients and longer follow-up are required to further study the impact of DPP4i in MDS.

Frailty in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma Receiving Curative-Intent Therapy: A Population-Based Study.

BACKGROUND: The objectives of this study were to determine whether frailty is associated with survival in a population-based sample of patients with diffuse large B-cell lymphoma (DLBCL) and to describe the healthcare utilization patterns of frail versus nonfrail patients during treatment. METHODS: A retrospective cohort study was conducted using population-based data in Ontario, Canada. Patients aged ≥66 years diagnosed between 2006 and 2017 with DLBCL or transformed follicular lymphoma who received first-line curative-intent chemoimmunotherapy were included. Frailty was defined using a modified version of a generalizable frailty index developed for use with Ontario administrative data. Cox regression was performed to examine the association between frailty and 1-year mortality. RESULTS: A total of 5,527 patients were included (median age, 75 years [interquartile range, 70-80 years]; 48% female), of whom 2,699 (49%) were classified as frail. Within 1 year of first-line treatment, 32% (n=868) of frail patients had died compared with 20% (n=553) of nonfrail patients (unadjusted hazard ratio, 1.8; 95% CI, 1.6-2.0; P<.0001). Frail patients had higher healthcare utilization during treatment, with most hospitalizations related to infection and/or lymphoma. In multivariable modeling controlling for age, inpatient diagnosis, number of chemoimmunotherapy cycles received, comorbidity burden, and healthcare utilization, frailty remained independently associated with 1-year mortality (adjusted hazard ratio, 1.5; 95% CI, 1.3-1.7; P<.0001). CONCLUSIONS: In a population-based sample of older adult patients with DLBCL receiving front-line curative-intent therapy, half were classified as frail, and their adjusted relative rate of death in the first year after starting treatment was 50% higher than that of nonfrail patients. Frailty seems to be associated with poor treatment tolerance and a higher likelihood of requiring acute hospital-based care.

Validating Restricted Mean Survival Time Estimates From Reconstructed Kaplan-Meier Data Against Original Trial Individual Patient Data From Trials Conducted by the Canadian Cancer Trials Group.

OBJECTIVES: The development of novel cancer therapies, including immuno-oncology agents, has increased interest in reconstructed individual patient data (IPD) based restricted mean survival time (RMST) analyses. Additionally, reconstructed IPD-based RMST is recommended in cost-effectiveness analyses when original trial IPD are not available. Nevertheless, recently concerns regarding potential bias of reconstructed-IPD RMST have been presented, because reconstructed-IPD RMSTs have not been validated and previous validation endpoints may not capture the entire Kaplan-Meier (KM) curve, especially the "tail." Our study aims to validate the recommended method of IPD reconstruction by comparing reconstructed IPD- and original trial IPD-based RMST. METHODS: Canadian Cancer Trials Group trials from 1990 to 2017 were included. Overall survival and progression-free survival IPD were reconstructed based on published KM curves using the Guyot method. Analysts were blinded to original trial IPD. RMST was calculated at 1 year and over the entire KM curve. Reconstructed-IPD and original trial-IPD (gold-standard) RMSTs were compared for accuracy and predictive error via mean deviation, mean absolute error (MAE), mean percentage bias, and Bland-Altman plots and across KM curve quality (vector traced or bitmapped). RESULTS: We identified 39 trials. The mean deviation, MAE, and mean percentage bias of RMST between the reconstructed IPD and original trial IPD were small. In particular, the mean deviation was -0.01 months and -0.04 months, MAE was 0.19 months and 0.24 months, and mean percentage bias was 0.82% and 0.84% in overall survival KM curves in control and experimental arms, respectively. Accuracy was generally not associated with KM curve quality. CONCLUSIONS: RMST derived from reconstructed IPD displayed excellent accuracy and predictive error compared with the gold standard. Reconstructed IPD could be used to calculate RMST in lieu of original trial IPD, to facilitate decision making for clinicians, researchers, and policy makers.

Association between diabetes and haematological malignancies: a population-based study.

AIMS/HYPOTHESIS: Contemporary data for the association of diabetes with haematological malignancies are lacking. We evaluated the risk of developing haematological malignancies and subsequent mortality in individuals with diabetes compared with those without diabetes. METHODS: We conducted a population-based observational study using healthcare databases from Ontario, Canada. All Ontario residents 30 years of age or older free of cancer and diabetes between 1 January 1996 and 31 December 2015 were eligible for inclusion. Using Cox regression analyses, we explored the association between diabetes and the risk and mortality of haematological malignancies (leukaemia, lymphoma, multiple myeloma). The impact of timing on associations was evaluated with analyses stratified by time since diabetes diagnosis (<3 months, 3 months to 1 year, ≥1 year). RESULTS: We identified 1,003,276 individuals with diabetes and age and sex matched these to 2,006,552 individuals without diabetes. Compared with individuals without diabetes, those with diabetes had a modest but significantly higher risk of a haematological malignancy (adjusted HR 1.10 [95% CI 1.08, 1.12] p < 0.0001). This association persisted across all time periods since diabetes diagnosis. Among those with haematological malignancies, diabetes was associated with a higher all-cause mortality (HR 1.36 [95% CI 1.31, 1.41] p < 0.0001) compared with no diabetes, as well as cause-specific mortality. CONCLUSIONS/INTERPRETATION: Diabetes is associated with a higher risk of haematological malignancies and is an independent risk factor of all-cause and cause-specific mortality. Greater efforts for lifestyle modification may not only reduce diabetes burden and its complications but may also potentially lower risk of malignancy and mortality. Graphical abstract.

Shorter Diagnosis-to-Treatment Interval in Diffuse Large B-Cell Lymphoma is Associated With Inferior Overall Survival in a Large, Population-Based Registry.

BACKGROUND: Because of prolonged screening requirements, patient and time-dependent selection have been proposed as potential biases in clinical trials. The screening process may exclude patients with a need for emergent treatment (and a short period from diagnosis to treatment initiation [DTI]). We explored the impact of DTI on overall survival (OS) in a population-based cohort of patients with diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: Using population-based administrative databases in Ontario, Canada, we identified adults aged ≥18 years with DLBCL treated with rituximab-based chemotherapy for curative intent between January 2005 and December 2015. Cox regression and multivariable analyses were presented to evaluate the impact of time from DTI on OS, controlling for relevant covariates. RESULTS: We identified 9,441 patients with DLBCL in Ontario; median age was 66 years, 53.6% were male, median number of comorbidities (Johns Hopkins aggregated diagnosis groups) was 10 (interquartile range [IQR], 8-13), and median DTI was 37 days (IQR, 22-61). Between treatment initiation and study end, 43% of patients died (median OS, 1 year; IQR, 0.4-2.8 years). Shorter DTI was a significant predictor of mortality (P<.001). Compared with the shortest DTI period of 0-18 days, those who commenced therapy at 19-29 days (hazard ratio [HR], 0.75; 95% CI, 0.68-0.84), 30-41 days (HR, 0.70; 95% CI, 0.63-0.78), 42-57 days (HR, 0.52; 95% CI, 0.46-0.58), and 58-180 days (HR, 0.52; 95% CI, 0.47-0.58) had improved survival. Increasing age (HR, 1.03; 95% CI, 1.03-1.04), male sex (HR, 1.23; 95% CI, 1.14-1.32), and increasing number of comorbidities (HR, 1.12; 95% CI, 1.11-1.13) were associated with inferior survival. CONCLUSIONS: Among patients with DLBCL, shorter DTI was associated with inferior OS. Therefore, DTI may represent a surrogate marker for aggressive biology. Clinical trials with lengthy screening periods are likely creating a time-dependent patient selection bias.

Reassessing the Net Benefit of Cancer Drugs With Evolution of Evidence Using the ASCO Value Framework.

BACKGROUND: Regulatory approval of oncology drugs is often based on interim data or surrogate endpoints. However, clinically relevant data, such as long-term overall survival and quality of life (QoL), are often reported in subsequent publications. This study evaluated the ASCO-Value Framework (ASCO-VF) net health benefit (NHB) at the time of approval and over time as further evidence arose. METHODS: FDA-approved oncology drug indications from January 2006 to December 2016 were reviewed to identify clinical trials scorable using the ASCO-VF. Subsequent publications of clinical trials relevant for scoring were identified (until December 2019). Using ASCO-defined thresholds (≤40 for low and ≥45 for substantial benefit), we assessed changes in classification of benefit at 3 years postapproval. RESULTS: Fifty-five eligible indications were included. At FDA approval, 40.0% were substantial, 10.9% were intermediate, and 49.1% were low benefit. We then identified 90 subsequent publications relevant to scoring, including primary (28.9%) and secondary endpoint updates (47.8%), safety updates (31.1%), and QoL reporting (47.8%). There was a change from initial classification of benefit in 27.3% of trials (10.9% became substantial, 9.1% became low, and 7.3% became intermediate). These changes were mainly due to updated hazard ratios (36.4%), toxicities (56.4%), new tail-of-the-curve bonus (9.1%), palliation bonus (14.5%), or QoL bonus (18.2%). Overall, at 3 years postapproval, 40.0% were substantial, 9.1% were intermediate, and 50.9% were low benefit. CONCLUSIONS: Because there were changes in classification for more than one-quarter of indications, in either direction, reassessing the ASCO-VF NHB as more evidence becomes available may be beneficial to inform clinical shared decision-making. On average, there was no overall improvement in the ASCO-VF NHB with longer follow-up and evolution of evidence.

A descriptive cost-analysis of MYX.1/MCRN003, a phase 2 clinical trial evaluating high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone in relapsed and refractory multiple myeloma.

BACKGROUND: The prevalence of multiple myeloma is increasing and there is a need to evaluate escalating therapy costs (Canadian Cancer Statistics A, 2020). The MYX.1 phase II trial showed that high-dose weekly carfilzomib, cyclophosphamide, and dexamethasone (wKCD) is efficacious in relapsed and refractory disease. We conducted a descriptive cost analysis, from the perspective of the Canadian public healthcare system, using trial data. METHODS: The primary outcome was the mean total cost per patient. Resource utilization data were collected from all 75 trial patients over a trial time horizon. Costs are presented in Canadian dollars (2020). RESULTS: The cost of treatment was calculated from the time of patient (pt) enrollment until the second data lock. The mean total cost was $203 336.08/pt (range $17 891.27-$505 583.55) Canadian dollars (CAD, where 1 CAD = 0.67 Euro (EUR)) and $14 081.45/pt per cycle. The median number of cycles was 15. The predominant cost driver was the cost of chemotherapy accounting for an average of $179 332.78/pt or $12 419.17/pt per cycle. Carfilzomib acquisition accounted for the majority of chemotherapy costs - $162 471.65/pt or $11 251.50/pt per cycle. Fifty-six percent (56%) of patients had at least one hospitalization during the trial period with an average cost of $12 657.86 per hospitalization. Three patients developed thrombotic microangiopathy (TMA) with an average cost of $18 863.32/pt including the cost of hospitalizations and therapeutic plasma exchange. CONCLUSIONS: High-dose wKCD is an active triplet regimen for relapsed and refractory multiple myeloma (RRMM) associated with reduced total cost compared with twice-weekly carfilzomib-based regimens.

Minimization of resource utilization data collected within cost-effectiveness analyses conducted alongside Canadian Cancer Trials Group phase III trials.

BACKGROUND: Cost-effectiveness analyses embedded within randomized trials allow for evaluation of value alongside conventional efficacy outcomes; however, collection of resource utilization data can require considerable trial resources. METHODS: We re-analyzed the results from four phase III Canadian Cancer Trials Group trials that embedded cost-effectiveness analyses to determine the impact of minimizing potential cost categories on the incremental cost-effectiveness ratios. For each trial, we disaggregated total costs into component incremental cost categories and recalculated incremental cost-effectiveness ratios using (1) only the top 3 cost categories, (2) the top 5 cost categories, and (3) all cost components. Using individual trial-level data, confidence intervals for each incremental cost-effectiveness ratio simulation were generated by bootstrapping and descriptively presented with the original confidence intervals (and incremental cost-effectiveness ratios) from the publications. RESULTS: Drug acquisition costs represented the highest incremental cost category in three trials, while hospitalization costs represented the other consistent cost driver and the top incremental cost category in the fourth trial. Recalculated incremental cost-effectiveness ratios based on fewer cost components (top 3 and top 5) did not differ meaningfully from the original published results. Based on conventional willingness-to-pay thresholds (US$50,000-US$100,000 per quality-adjusted life-year), none of the re-analyses would have changed the original perception of whether the experimental therapies were considered cost-effective. CONCLUSIONS: These results suggest that the collection of resource utilization data within cancer trials could be narrowed. Omission of certain cost categories that have minimal impact on incremental cost-effectiveness ratio, such as routine laboratory investigations, could reduce the costs and undue burden associated with the collection of data required for cancer trial cost-effectiveness analyses.

Statin and cyclooxygenase-2 inhibitors improve survival in newly diagnosed diffuse large B-cell lymphoma: a large population-based study of 4913 subjects.

Preclinical data suggests anti-lymphoma potential for statins, metformin and cyclooxygenase-2 (COX-2) inhibitors. We performed a retrospective population-based study of all adults aged ≥66 years diagnosed with diffuse large B-cell lymphoma (DLBCL) or transformed lymphoma treated with a rituximab containing regimen, between 2005 and 2015 in Ontario, Canada. Using administrative databases, we assessed the impact of medication exposures, prior to chemo-immunotherapy, on lymphoma survival. Cox regression analyses, controlling for sociodemographic factors and comorbidities, examined the relationship between medication exposure and survival. In total, 4913 patients were treated with curative intent (median age 75 years, 51% male) and 52·2% died at a median of 1 year from treatment initiation (67% due to DLBCL). In the year prior to commencing treatment, 45·7% received statins, 16·3% metformin, and 25·0% a COX-2 inhibitor. Adjusting for confounders, exposure to statin and COX-2 inhibitors prior to chemo-immunotherapy independently conferred a survival advantage: statin exposure for 30 days (hazard ratio [HR] 0·97, 95% confidence interval [CI] 0·96-0·98), 180 days (HR 0·84, 95% CI 0·80-0·89) and 365 days (HR 0·71, 95% CI 0·63-0·79) and COX-2 inhibitor exposure for 30 days (HR 0·95, 95% CI 0·95-0·98), 180 days (HR 0·76, 95% CI 0·66-0·86) and 365 days (HR 0·57, 95% CI 0·43-0·74). Metformin had no significant impact. This population-based study found a dose-related survival benefit of exposure to statins and COX-2 inhibitors prior to chemo-immunotherapy for newly diagnosed DLBCL.

Quantifying the Survival Benefits of Oncology Drugs With a Focus on Immunotherapy Using Restricted Mean Survival Time.

BACKGROUND: Restricted mean survival time (RMST) overcomes limitations of current measures of survival benefits because it directly captures information of the entire area under Kaplan-Meier survival curves. Using RMST difference (absolute survival benefit) and RMST ratio (relative survival benefit), we quantified the magnitude of survival benefits of recent oncology drugs and compared immunotherapies with nonimmunotherapies. METHODS: Kaplan-Meier curves were extracted from phase II/III randomized controlled trials used by the FDA for oncology drug approvals from January 2011 through November 2017 with overall survival (OS) or progression-free survival (PFS) as primary endpoints. RMST differences, ratios, and their 95% confidence intervals were meta-analyzed to estimate absolute and relative survival benefits of contemporary oncology drugs and to compare immunotherapies with nonimmunotherapies. Meta-regression was conducted to adjust for potential confounders. RESULTS: Ninety-four trials with a total of 51,639 patients were included. Overall absolute survival benefits (RMST differences) were 1.55 months for OS (95% CI, 1.32-1.77) and 2.99 months for PFS (95% CI, 2.65-3.33). Overall relative survival benefits (RMST ratios) were 1.11 for OS (95% CI, 1.09-1.13) and 1.42 for PFS (95% CI, 1.36-1.48). Immunotherapy absolute PFS benefit was less than that of nonimmunotherapy (1.56 vs 3.23 months), whereas immunotherapy absolute OS benefit was larger than that of nonimmunotherapy by 0.59 months (2.02 vs 1.43 months). Adjusted OS RMST difference was 0.91 months greater for immunotherapy than for nonimmunotherapy after adjusting for confounders. CONCLUSIONS: Absolute survival benefits of recent oncology drugs are modest. Survival benefits of immunotherapies are not dramatically superior to those of nonimmunotherapies. Routine reporting and use of RMST may help patients, physicians, and payers make more informed and responsible decisions regarding the care of patients with cancer.

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.

Chinese and South Asian ethnicity, immigration status, and clinical cancer outcomes in the Ontario Cancer System.

BACKGROUND: In the United States, certain minority groups have been shown to have inferior cancer outcomes compared with the white majority population. However, to the authors' knowledge, the majority of research has not separated ethnicity from immigration status. The objective of the current study was to determine the impact of ethnicity, independent of immigration status, on cancer outcomes in Chinese and South Asian populations in Ontario, Canada. METHODS: The authors conducted a population-based retrospective cohort study using administrative databases in Ontario, Canada. Incident cancer cases were captured in Canadian-born Chinese and South Asian individuals, Chinese and South Asian immigrants, and the general Ontario reference population (non-Chinese/non-South Asian and non-immigrant) between 2000 and 2012. Subjects were followed until death (all-cause and cancer-specific), and Cox proportional hazard models were used to estimate the impact of Chinese and South Asian ethnicity on cancer outcomes after adjusting for explanatory variables. RESULTS: A total of 423,678 cancer cases were identified; at total of 6631 cases were identified in Canadian-born Chinese individuals and 2752 cases in Canadian-born South Asian individuals. After adjustment, the rate of all-cause mortality was lower for Canadian-born Chinese (hazard ratio [HR], 0.829; 95% confidence interval [95% CI], 0.795-0.865), Canadian-born South Asian (HR, 0.856; 95% CI, 0.797-0.919), and Chinese immigrant (recent immigrant: HR, 0.661 [95% CI, 0.610-0.716] and non-recent immigrant: HR, 0.853 [95% CI, 0.803-0.906]) populations compared with the general Ontario population. A similar effect was found for cancer-specific mortality. CONCLUSIONS: Chinese and South Asian ethnic groups appear to have lower cancer mortalities compared with the general Ontario population. After removing the well-documented protective effect of immigration, Chinese and South Asian ethnicities were found to be associated with a cancer survival advantage in Ontario, Canada. Cancer 2018;124:1473-82. © 2018 American Cancer Society.