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Niraparib was recently funded in Canada for the maintenance treatment of ovarian cancer following platinum-based chemotherapy. However, the drug’s safety profile in the real world remains uncertain. We conducted a cohort study to describe the patient population using niraparib and the proportion that experienced adverse events between June 2019 and December 2022 in four Canadian provinces (Ontario, Alberta, British Columbia [BC], and Quebec). We used administrative data and electronic medical records from Ontario Health, Alberta Health Services, and BC Cancer, and registry data from Exactis Innovation. We summarized baseline characteristics using descriptive statistics and reported safety outcomes using cumulative incidence. We identified 514 patients receiving niraparib. Mean age was 67 years and most were initiated on a daily dose of 100 or 200 mg/day. Grade 3/4 anemia, neutropenia, and thrombocytopenia occurred in 11–16% of the cohort. In Ontario, the three-month cumulative incidence of grade 3/4 thrombocytopenia was 11.6% (95% CI, 8.3–15.4%), neutropenia was 7.1% (95% CI, 4.6–10.4%), and anemia was 11.3% (95% CI, 8.0–15.2%). Cumulative incidences in the remaining provinces were similar. Initial daily dose and proportions of hematological adverse events were low in the real world and may be related to cautious prescribing and close monitoring by clinicians.

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.

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.

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.

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.

Abstract 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.

Abstract Background Little is known about the association between the COVID‐19 pandemic and early survival among newly diagnosed cancer patients. Methods This retrospective population‐based cohort study used linked administrative datasets from Ontario, Canada. Adults (≥18 years) who received a cancer diagnosis between March 15 and December 31, 2020, were included in a pandemic cohort, while those diagnosed during the same dates in 2018/2019 were included in a pre‐pandemic cohort. All patients were followed for one full year after the date of diagnosis. Cox proportional hazards regression models were used to assess survival in relation to the pandemic, patient characteristics at diagnosis, and the modality of first cancer treatment as a time‐varying covariate. Interaction terms were explored to measure the pandemic association with survival for each cancer type. Results Among 179,746 patients, 53,387 (29.7%) were in the pandemic cohort and 37,741 (21.0%) died over the first post‐diagnosis year. No association between the pandemic and survival was found when adjusting for patient characteristics at diagnosis (HR 0.99 [95% CI 0.96–1.01]), while marginally better survival was found for the pandemic cohort when the modality of treatment was additionally considered (HR 0.97 [95% CI 0.95–0.99]). When examining each cancer type, only a new melanoma diagnosis was associated with a worse survival in the pandemic cohort (HR 1.25 [95% CI 1.05–1.49]). Conclusions Among patients able to receive a cancer diagnosis during the pandemic, one‐year overall survival was not different than those diagnosed in the previous 2 years. This study highlights the complex nature of the COVID‐19 pandemic impact on cancer care.

Abstract Background The efficacy‐effectiveness gap between randomized trial and real‐world evidence regarding the clinical benefit of ipilimumab for metastatic melanoma (MM) has been well characterized by previous literature, consistent with initial concerns raised by health technology assessment agencies (HTAs). As these differences can significantly impact cost‐effectiveness, it is critical to assess the real‐world cost‐effectiveness of second‐line ipilimumab versus non‐ipilimumab treatments for MM. Methods This was a population‐based retrospective cohort study of patients who received second‐line non‐ipilimumab therapies between 2008 and 2012 versus ipilimumab treatment between 2012 and 2015 (after public reimbursement) for MM in Ontario. Using a 5‐year time horizon, censor‐adjusted and discounted (1.5%) costs (from the public payer's perspective in Canadian dollars) and effectiveness were used to calculate incremental cost‐effectiveness ratios (ICERs) in life‐years gained (LYGs) and quality‐adjusted life years (QALYs), with bootstrapping to capture uncertainty. Varying the discount rate and reducing the price of ipilimumab were done as sensitivity analyses. Results In total, 329 MM were identified (Treated: 189; Controls: 140). Ipilimumab was associated with an incremental effectiveness of 0.59 LYG, incremental cost of $91,233, and ICER of $153,778/LYG. ICERs were not sensitive to discounting rate. Adjusting for quality of life using utility weights resulted in an ICER of $225,885/QALY, confirming the original HTA estimate prior to public reimbursement. Reducing the price of ipilimumab by 100% resulted in an ICER of $111,728/QALY. Conclusion Despite its clinical benefit, ipilimumab as second‐line monotherapy for MM patients is not cost‐effective in the real world as projected by HTA under conventional willingness‐to‐pay thresholds.

The Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration developed an MCDA rating tool to assess and prioritize potential post-market real-world evidence (RWE) questions/uncertainties emerging from public drug funding decisions in Canada. In collaboration with a group of multidisciplinary stakeholders from across Canada, the rating tool was developed following a three-step process: (1) selection of criteria to assess the importance and feasibility of an RWE question; (2) development of rating scales, application of weights and calculating aggregate scores; and (3) validation testing. An initial MCDA rating tool was developed, composed of seven criteria, divided into two groups. Group A criteria assess the importance of an RWE question by examining the (1) drug’s perceived clinical benefit, (2) magnitude of uncertainty identified, and (3) relevance of the uncertainty to decision-makers. Group B criteria assess the feasibility of conducting an RWE analysis including the (1) feasibility of identifying a comparator, (2) ability to identify cases, (3) availability of comprehensive data, and (4) availability of necessary expertise and methodology. Future directions include partnering with the Canadian Agency for Drugs and Technology in Health’s Provincial Advisory Group for further tool refinement and to gain insight into incorporating the tool into drug funding deliberations.

Abstract Background Little is known about the COVID‐19 pandemic impact on the provision of diagnostic imaging and physician visits at cancer diagnosis. Methods We used administrative databases from Ontario, Canada, to identify MRI/CT/ultrasound scans and in‐person/virtual physician visits conducted with cancer patients within 91 days around the date of diagnosis in 2016–2020. In separate segmented regression procedures, we assessed the trends in weekly volume of these services per thousand cancer patients in prepandemic (June 26, 2016 to March 14, 2020), the change in mean volume at the start of the pandemic, and the additional change in weekly volume during the pandemic (March 15, 2020, to September 26, 2020). Results Totally, 403,561 cancer patients were included. On March 15, 2020 (COVID‐19 arrived), mean scan volume decreased by 12.3% (95% CI: 6.4%–17.9%) where ultrasound decreased the most by 31.8% (95% CI: 23.9%–37.0%). Afterward, the volume of all scans increased further by 1.6% per week (95% CI: 1.3%–2.0%), where ultrasound increased the fastest by 2.4% (95% CI: 1.8%–2.9%). Mean in‐person visits dropped by 47.4% when COVID‐19 started (95% CI: 41.6%–52.6%) while virtual visits rose by 55.15‐fold (95% CI: 4927%‐6173%). In the pandemic (until September 26, 2020), in‐person visits increased each week by 2.6% (95% CI: 2.0%–3.2%), but no change was observed for virtual visits (p ‐value = 0.10). Conclusions Provision of diagnostic imaging and virtual visits at cancer diagnosis has been increasing since the start of COVID‐19 and has exceeded prepandemic utilization levels. Future work should monitor the impact of these shifts on quality of delivered care.

Due to the ramping down of cancer surgery in early pandemic, many newly diagnosed patients received other treatments first. We aimed to quantify the pandemic-related shift in rate of surgery following chemotherapy. This is a retrospective population-based cohort study involving adults diagnosed with cancer between 3 January 2016 and 7 November 2020 in Ontario, Canada who received chemotherapy as first treatment within 6-months of diagnosis. Competing-risks regression models with interaction effects were used to quantify the association between COVID-19 period (receiving a cancer diagnosis before or on/after 15 March 2020) and receipt of surgical reSection 9-months after first chemotherapy. Among 51,653 patients, 8.5% (n = 19,558) of them ultimately underwent surgery 9-months after chemotherapy initiation. Receipt of surgery was higher during the pandemic than before (sHR 1.07, 95% CI 1.02–1.13). Material deprivation was independently associated with lower receipt of surgery (least vs. most deprived quintile: sHR 1.11, 95% CI 1.04–1.17), but did not change with the pandemic. The surgical rate increase was most pronounced for breast cancer (sHR 1.13, 95% CI 1.06–1.20). These pandemic-related shifts in cancer treatment requires further evaluations to understand the long-term consequences. Persistent material deprivation-related inequity in cancer surgical access needs to be addressed.

The Canadian Real-world Evidence for Value in Cancer Drugs (CanREValue) Collaboration established the Engagement Working Group (WG) to ensure that all key stakeholders had an opportunity to provide input into the development and implementation of the CanREValue Real-World Evidence (RWE) Framework. Two consultations were held in 2021 to solicit patient perspectives on key policy and data access issues identified in the interim policy and data WG reports. Over 30 individuals, representing patients, caregivers, advocacy leaders, and individuals engaged in patient research were invited to participate. The consultations provided important feedback and valuable lessons in patient engagement. Patient leaders actively shaped the process and content of the consultation. Breakout groups facilitated by patient advocacy leaders gave the opportunity for open and thoughtful contributions from all participants. Important recommendations were made: the RWE framework should not impede access to new drugs; it should be used to support conditional approvals; patient relevant endpoints should be captured in provincial datasets; access to data to conduct RWE should be improved; and privacy issues must be considered. The manuscript documents the CanREValue experience of engaging patients in a consultative process and the useful contributions that can be achieved when the processes to engage are guided by patients themselves.

Background and purposeHPV-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 methodsHPV+ 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.ResultsIn 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.ConclusionDe-escalation of CRT for HPV+ anal cancer may result in decreased acute toxicities and similar cancer outcomes compared to standard CRT.

Emergency department (ED) use is a concern for surgery patients, physicians and health administrators particularly during a pandemic. The objective of this study was to assess the impact of the pandemic on ED use following cancer-directed surgeries. This is a retrospective cohort study of patients undergoing cancer-directed surgeries comparing ED use from 7 January 2018 to 14 March 2020 (pre-pandemic) and 15 March 2020 to 27 June 2020 (pandemic) in Ontario, Canada. Logistic regression models were used to (1) determine the association between pandemic vs. pre-pandemic periods and the odds of an ED visit within 30 days after discharge from hospital for surgery and (2) to assess the odds of an ED visit being of high acuity (level 1 and 2 as per the Canadian Triage and Acuity Scale). Of our cohort of 499,008 cancer-directed surgeries, 468,879 occurred during the pre-pandemic period and 30,129 occurred during the pandemic period. Even though there was a substantial decrease in the general population ED rates, after covariate adjustment, there was no significant decrease in ED use among surgical patients (OR 1.002, 95% CI 0.957–1.048). However, the adjusted odds of an ED visit being of high acuity was 23% higher among surgeries occurring during the pandemic (OR 1.23, 95% CI 1.14–1.33). Although ED visits in the general population decreased substantially during the pandemic, the rate of ED visits did not decrease among those receiving cancer-directed surgery. Moreover, those presenting in the ED post-operatively during the pandemic had significantly higher levels of acuity.

Canadian provinces routinely collect patient-level data for administrative purposes. These real-world data (RWD) can be used to generate real-world evidence (RWE) to inform clinical care and healthcare policy. The CanREValue Collaboration is developing a framework for the use of RWE in cancer drug funding decisions. A Data Working Group (WG) was established to identify data assets across Canada for generating RWE of oncology drugs. The mapping exercise was conducted using an iterative scan with informant surveys and teleconference. Data experts from ten provinces convened for a total of three teleconferences and two in-person meetings from March 2018 to September 2019. Following each meeting, surveys were developed and shared with the data experts which focused on identifying databases and data elements, as well as a feasibility assessment of conducting RWE studies using existing data elements and resources. Survey responses were compiled into an interim data report, which was used for public stakeholder consultation. The feedback from the public consultation was used to update the interim data report. We found that databases required to conduct real-world studies are often held by multiple different data custodians. Ninety-seven databases were identified across Canada. Provinces held on average 9 distinct databases (range: 8–11). An Essential RWD Table was compiled that contains data elements that are necessary, at a minimal, to conduct an RWE study. An Expanded RWD Table that contains a more comprehensive list of potentially relevant data elements was also compiled and the availabilities of these data elements were mapped. While most provinces have data on patient demographics (e.g., age, sex) and cancer-related variables (e.g., morphology, topography), the availability and linkability of data on cancer treatment, clinical characteristics (e.g., morphology and topography), and drug costs vary among provinces. Based on current resources, data availability, and access processes, data experts in most provinces noted that more than 12 months would be required to complete an RWE study. The CanREValue Collaboration’s Data WG identified key data holdings, access considerations, as well as gaps in oncology treatment-specific data. This data catalogue can be used to facilitate future oncology-specific RWE analyses across Canada.

Abstract Background We examined if oncology drug indications with high clinical benefit, as measured by the American Society of Clinical Oncology Value Framework (ASCO‐VF) and European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO‐MCBS), received public reimbursement status faster than those with lower clinical benefit from the time of pan‐Canadian Oncology Drug Review (pCODR) recommendation. Methods Oncology drug indications submitted to pCODR between July 2011 and October 2018 were examined. Included indications had a regulatory approval date, completed the pCODR review process, received a positive pCODR recommendation, and been funded by at least one province. Trials cited for clinical efficacy were used to determine the clinical benefit (per ASCO‐VF and ESMO‐MCBS) of drug indications. Results Eighty‐four indications were identified, yielding 65 ASCO‐VF and 50 ESMO‐MCBS scores. The mean ASCO‐VF and ESMO‐MCBS scores were 44.9 (SD = 21.1) and 3.3 (SD = 1.0), respectively. The mean time to provincial reimbursement from pCODR recommendation was 13.2 months (SD = 9.3 months). Higher ASCO‐VF and ESMO‐MCBS scores had low correlation with shorter time to reimbursement, (ρ = −0.21) and (ρ = 0.24), respectively. In the multivariable analyses, ASCO‐VF (p = 0.40) and ESMO‐MCBS (p = 0.31) scores were not significantly associated with time to reimbursement. Province and year of pCODR recommendation were associated with time to reimbursement in both ASCO and ESMO models. Conclusions Oncology drug indications with higher clinical benefit do not appear to be reimbursed faster than those with low clinical benefit. This suggests the need to prioritize oncology drug indications based on clinical benefit to ensure quicker access to oncology drugs with the greatest benefits.

Abstract Introduction Extrapolation of time-to-event data from clinical trials is commonly used in decision models for health technology assessment (HTA). The objective of this study was to assess performance of standard parametric survival analysis techniques for extrapolation of time-to-event data for a single event from clinical trials with limited data due to small samples or short follow-up. Methods Simulated populations with 50,000 individuals were generated with an exponential hazard rate for the event of interest. A scenario consisted of 5000 repetitions with six sample size groups (30–500 patients) artificially censored after every 10% of events observed. Goodness-of-fit statistics (AIC, BIC) were used to determine the best-fitting among standard parametric distributions (exponential, Weibull, log-normal, log-logistic, generalized gamma, Gompertz). Median survival, one-year survival probability, time horizon (1% survival time, or 99th percentile of survival distribution) and restricted mean survival time (RMST) were compared to population values to assess coverage and error (e.g., mean absolute percentage error). Results The true exponential distribution was correctly identified using goodness-of-fit according to BIC more frequently compared to AIC (average 92% vs 68%). Under-coverage and large errors were observed for all outcomes when distributions were specified by AIC and for time horizon and RMST with BIC. Error in point estimates were found to be strongly associated with sample size and completeness of follow-up. Small samples produced larger average error, even with complete follow-up, than large samples with short follow-up. Correctly specifying the event distribution reduced magnitude of error in larger samples but not in smaller samples. Conclusions Limited clinical data from small samples, or short follow-up of large samples, produce large error in estimates relevant to HTA regardless of whether the correct distribution is specified. The associated uncertainty in estimated parameters may not capture the true population values. Decision models that base lifetime time horizon on the model’s extrapolated output are not likely to reliably estimate mean survival or its uncertainty. For data with an exponential event distribution, BIC more reliably identified the true distribution than AIC. These findings have important implications for health decision modelling and HTA of novel therapies seeking approval with limited evidence.

The CanREValue Collaboration established the Reassessment & Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework.

Recently, there has been increased consideration of real-world data (RWD) and real-world evidence (RWE) in regulatory and health technology assessment (HTA) decision-making. Due to challenges in identifying high-quality and relevant RWD sources, researchers and regulatory/HTA bodies may turn to RWD generated in locales outside of the locale of interest (referred to as “transferring RWD”). We therefore performed a review of stakeholder guidance as well as selected case studies to identify themes for researchers to consider when transferring RWD from one jurisdiction to another. Our review highlighted that there is limited consensus on defining decision-grade, transferred RWD; certain stakeholders have issued relevant guidance, but the recommendations are high-level and additional effort is needed to generate comprehensive guidance. Additionally, the case studies revealed that RWD transferability has not been a consistent concern for regulatory/HTA bodies and that more focus has been put on the evaluation of internal validity. To help develop transferability best practices (alongside internal validity best practices), we suggest that researchers address the following considerations in their justification for transferring RWD: treatment pathways, nature of the healthcare system, incidence/prevalence of indication, and patient demographics. We also recommend that RWD transferability should garner more attention as the use of imported RWD could open doors to high-quality data sources and potentially reduce methodological issues that often arise in the use of local RWD; we thus hope this review provides a foundation for further dialogue around the suitability and utility of transferred RWD in the regulatory/HTA decision-making space.

The Canadian Real-world Evidence for Value in Cancer Drugs (CanREValue) Collaboration was established to develop a framework for generating and using real-world evidence (RWE) to inform the reassessment of cancer drugs following initial health technology assessment (HTA). The Reassessment and Uptake Working Group (RWG) is one of the five established CanREValue Working Groups. The RWG aims to develop considerations for incorporating RWE for HTA reassessment and strategies for using RWE to reassess drug funding decisions. Between February 2018 and December 2019, the RWG attended four teleconferences (with follow-up surveys) and two in-person meetings to discuss recommendations for the development of a reassessment process and potential barriers and facilitators. Modified Delphi methods were used to gather input. A draft report of recommendations (to December 2018) was shared for public consultation (December 2019 to January 2020). Initial considerations for developing a reassessment process were proposed. Specifically, reassessment can be initiated by diverse stakeholders, including decision makers from public drug plans or industry stakeholders. The reassessment process should be modelled after existing deliberation and recommendation frameworks used by HTA agencies. Proposed reassessment outcome categories include maintaining status quo, revisiting funding criteria, renegotiating price, or disinvesting. Overall, these initial considerations will serve as the basis for future advancements by the Collaboration.

Abstract Introduction While no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC. Methods A Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations. Results In the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib. Conclusions Available data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.

Precision medicine in oncology poses unique challenges to the generation of clinical and economic evidence used for cost-effectiveness analyses that can inform health technology assessment. The conduct of randomized controlled trials for biomarker-specific therapies targeted towards small populations has limitations in regard to feasibility, timeliness, and cost. These limitations result in associated challenges for groups involved in the generation of economic evidence to inform treatment-related decision making, including the Committee of Economic Analysis (CEA) at the Canadian Cancer Trials Group (CCTG). We provide a high-level description and vision about the new paradigm of clinical trial design, generation of economic evidence, and novel approaches to economic evaluations necessary in the space of precision medicine in oncology in Canada. The CEA’s previous approach to precision medicine, including master protocol designs and single-arm studies, is reviewed. Methods and approaches currently under consideration by the CEA and national collaborators, such as the role of real-world and clinical trial evidence in enabling life-cycle assessment of therapies, are explored. Finally, future initiatives being planned in the space of precision medicine at CCTG, such as the incorporation of correlative studies to identify and test high-performing biomarkers in trials, are discussed.

Purpose: To describe the trajectory of physical symptoms among cancer decedents who were receiving home care in the six months before death. Patients and Methods: An observational cohort study of cancer decedents in Ontario, Canada, who received home care services between 2007 and 2014. To be included, decedents had to use at least one home care service in the last six months of life. Outcomes were the presence of pain and several other physical symptoms at each week before death. Results: Our cohort included 27,295 cancer decedents (30,368 assessments). Forty-seven percent were female and 56% were age 75 years or older. The prevalence of all physical symptoms increased as one approached death, particularly in the last month of life. In the last weeks of life, 69% of patients reported having moderate–severe pain; however, only 20% reported that the pain was not controlled. Loss of appetite (63%), shortness of breath (59%), high health instability (50%), and self-reported poor health (44%) were also highly prevalent in the last week of life. Multivariate regression showed that caregiver distress, high health instability, social decline, uncontrolled pain, and signs of depression all worsened the odds of having a physical symptom in the last 3 months of life. Conclusion: In this large home care cancer cohort, trajectories of physical symptoms worsened close to death. While presence of moderate–severe pain was common, it was also reported as mostly controlled. Covariates, such as caregiver distress and social decline, were associated with having more physical symptoms at end of life.

The COVID-19 pandemic has a significant impact on cancer patients and the delivery of cancer care. To allow clinicians to adapt treatment plans for patients, Ontario Health (Cancer Care Ontario) issued a series of interim funding measures for the province’s New Drug Funding Program (NDFP), which covers the cost of most hospital-delivered cancer drugs. To assess the utility of the measures and the need for their continuation, we conducted an online survey of Ontario oncology clinicians. The survey was open 3–25 September 2020 and generated 105 responses. Between April and June 2020, 46% of respondents changed treatment plans for more than 25% of their cancer patients due to the pandemic. Clinicians report broad use of interim funding measures. The most frequently reported strategies used were treatment breaks for stable patients (62%), extending dosing intervals (59%), and deferring routine imaging (56%). Most clinicians anticipate continuing to use these interim funding measures in the coming months. The survey showed that adapting cancer drug funding policies has supported clinical care in Ontario during the pandemic.

Background: To determine the magnitude of difference between manufacturer-submitted and pan-Canadian Oncology Drug Review (pCODR) calculated incremental cost-effectiveness ratios (ICERs), incremental cost (ΔC), and incremental effectiveness (ΔE); to examine whether there is a significant difference in the proportion of ICERs deemed cost-effective; to evaluate trends in the ICERs over time; and to identify methodological issues in manufacturer-submitted economic models. Methods: Economic guidance reports for all drug indications submitted from July 2011–November 2018 were extracted from the pCODR database. Cumulative distribution plots were constructed to compare the manufacturer-submitted economic values with both the pCODR lower- and upper-reanalyzed estimates. The proportion of drug reviews considered cost-effective at varying willingness-to-pay (WTP) thresholds by the manufacturer and pCODR were calculated. Manufacturer changes in ICERs over time from 2012 to 2018 were determined. Recurring methodological issues with manufacturer submissions were tallied. Results: There were 73 unique indications that were included. Manufacturer-submitted ICERs were consistently lower than pCODR estimates for most indications. Manufacturer-submitted ICERs were generally more cost-effective over a range of WTP thresholds. From 2012 to 2018, manufacturer and economic guidance panel (EGP) lower limit reanalyzed ICERs did not change significantly over time. However, EGP upper limit re-analyses did show decreasing cost-effectiveness (increasing ICERs). The two most common issues identified in the manufacturer-submitted models were related to survival time horizon and utility estimates. Conclusions: Manufacturers tend to overestimate the cost-effectiveness of their therapies when submitting economic models to pCODR. Although certain methodological issues are still common in manufacturer-submitted models, revision rates are high for most issues raised by pCODR.

Abstract Introduction For patients with diffuse large B‐cell lymphoma (DLBCL), standard‐care is rituximab administered with CHOP or CHOP‐like chemotherapy (R‐CHOP). However, the effectiveness and safety of R‐CHOP among DLBCL patients with human immunodeficiency virus (HIV) infection is less clear, as HIV+ patients were omitted from most clinical trials and population‐level data from unselected patients are limited. R‐CHOP was funded for HIV‐associated DLBCL patients with CD4 >50/mm3 in Ontario in February 2015. Methods Patients with a new diagnosis of DLBCL were identified from the Ontario Cancer Registry between April 2010 and March 2018. HIV diagnosis and chemotherapy regimen were ascertained using administrative databases at Ontario Health. The effect of rituximab and HIV on overall survival was assessed in the HIV+ subgroup (R‐CHOP vs CHOP) and in the R‐CHOP subgroup (HIV+ vs HIV−). Results Among HIV+ patients, receipt of R‐CHOP was associated with a fivefold improvement in overall survival (hazard ratio [HR] 0.29 (0.13‐0.66) compared with CHOP), after adjustment. Among patients who received R‐CHOP (n = 6106), older age, male sex, lower neighborhood income, and higher comorbidity were associated with worse overall survival, after adjustment (P

Abstract Socioeconomic status (SES) has led to treatment and survival disparities; however, limited data exist for non‐small cell lung cancer (NSCLC). This study investigates the impact of SES on NSCLC diagnostic imaging, treatment, and overall survival (OS), and describes temporal disparity trends. The Ontario Cancer Registry was used to identify NSCLC patients diagnosed between 2007 and 2016. Through linkage to administrative datasets, patients’ demographics, imaging, treatment, and survival were obtained. Based on median household neighborhood income, the Ontario population was divided into five income quintiles (Q1‐Q5; Q1 = lowest income). Multivariable regressions assessed SES association with OS, imaging, treatment receipt, and treatment delay, and their interaction with year of diagnosis to understand temporal trends. Endpoints were adjusted for demographics, stage and comorbidities, along with treatments and imaging for OS. A total of 50 542 patients were identified. Higher SES patients (Q5 vs. Q1) showed improved 5‐year OS (hazard ratio, 0.89; 95% confidence interval [CI], 0.87‐0.92; P .05) despite widening income inequality.

Abstract 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.

Abstract Objectives Value‐based pricing of oncology drugs provides a best estimate for the price of a drug, as it relates to the benefits it provides for individual patients. To date, the impact of value‐based pricing to reference cost‐effectiveness thresholds (λ) on individual and population‐level health benefits remains uncharacterized. The current study examined the potential benefits of value‐based pricing by quantifying the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at manufacturer‐submitted price without value‐based pricing. Methods Pan‐Canadian Oncology Drug Review (pCODR) submissions were reviewed to identify eligible drug indications from which final economic guidance panel reports were reviewed for incremental costs (ΔC) and quality‐adjusted life‐years (ΔQALY) from manufacturer‐submitted, pCODR lower‐limit (pCODR‐LL) and upper‐limit (pCODR‐UL) re‐analyzed estimates. Annual number of cases in Ontario for each drug indication was obtained from population databases. Annual QALY gain per drug indication was determined by (ΔQALY × cases). Population QALY gain/loss in the absence of value‐based pricing to reference λ was estimated by the INHB: (INHB = [ΔQALY − (ΔC/λ)] × cases). Results In total, 34 drug indications (4629 cases) were identified. Annual gain in QALYs for the funded drug indications using manufacturer, pCODR‐LL, and pCODR‐UL estimates was 1851, 1617, and 1301, respectively. At a λ $100 000/QALY, funding in the absence of value‐based pricing resulted in loss of 2311, 2519, and 2604 QALYs. This would result in a provincial net annual loss of 460, 902, and 1303 QALYs. Conclusions Despite an annual gain in QALY per funded drug indication, a net loss in QALY for the province, in the absence of value‐based pricing, was demonstrated. Supportive evidence exists for value‐based pricing toward the promotion of health benefits for the greater population.

Background. Real-world evidence can be a valuable tool when clinical trial data are incomplete or uncertain. Bevacizumab was adopted as first-line therapy for metastatic colorectal cancer (mCRC) based on significant survival improvements in initial clinical trials; however, survival benefit diminished in subsequent analyses. Consequently, there is uncertainty surrounding the cost-effectiveness of bevacizumab therapy achieved in practice. Objective. To assess real-world cost-effectiveness of first-line bevacizumab with irinotecan-based chemotherapy versus irinotecan-based chemotherapy alone for mCRC in British Columbia (BC), Saskatchewan, and Ontario, Canada. Methods. Using provincial cancer registries and linked administrative databases, we identified mCRC patients who initiated publicly funded irinotecan-based chemotherapy, with or without bevacizumab, in 2000 to 2015. We compared bevacizumab-treated patients to historical controls (treated before bevacizumab funding) and contemporaneous controls (receiving chemotherapy without bevacizumab), using inverse-probability-of-treatment weighting with propensity scores to balance baseline covariates. We calculated incremental cost-effectiveness ratios (ICER) using 5-year cost and survival adjusted for censoring, with bootstrapping to characterize uncertainty. We also conducted one-way sensitivity analysis for key drivers of cost-effectiveness. Results. The cohorts included 12,112 (Ontario), 1,161 (Saskatchewan), and 2,977 (BC) patients. Bevacizumab significantly increased treatment costs, with mean ICERs between $78,000 and $84,000/LYG (life-year gained) in the contemporaneous comparisons and $75,000 and $101,000/LYG in the historical comparisons. Reducing the cost of bevacizumab by 50% brought ICERs in all comparisons below $61,000/LYG. Limitations. Residual confounding in observational data may bias results, while the use of original list prices overestimates current bevacizumab cost. Conclusion. The addition of bevacizumab to irinotecan-based chemotherapy extended survival for mCRC patients but at significant cost. At original list prices bevacizumab can only be considered cost-effective with certainty at a willingness-to-pay threshold over $100,000/LYG, but price reductions or discounts have a significant impact on cost-effectiveness.

Abstract Background The soaring costs of anti‐cancer drugs pose a threat to the sustainability of cancer care. The pricing strategy chosen by manufacturers can impact the costs of oral anti‐cancer drugs during dose modifications, but this issue remains under‐recognized in the literature. In general, with the flat pricing strategy, there is a single fixed price for each tablet regardless of dosage strength, whereas with linear pricing, the price of each tablet increases with its dose. We hypothesize that flat pricing will have increased drug costs compared to linear pricing during dose reductions since the cost remains fixed despite decreased dose requirements. This practice may have significant financial implications considering the high costs, extensive utilization, and frequent occurence of dose reductions with anti‐cancer drugs. Methods Oral anti‐cancer drugs reviewed by the pan‐Canadian Oncology Drug Review program between 2011 and 2018 were identified. The cost per mg and cost per 28‐day cycle were calculated for dose levels −2 to +2. The percent change in cost per mg and cost per cycle during dose modifications from the standard dose were calculated. We conducted Mann‐Whitney U and Fisher‐exact tests to compare the association between drug costs during dose reductions and pricing strategy. Results In this study, 30 oral anti‐cancer drugs for use in 41 indications were analyzed; 44% of drugs used linear pricing and 56% used flat pricing. Dose reductions increased the mean cost per mg for drugs with linear pricing by 14.7% (range: 0%‐50%) at dose level −1 and 17.2% (range: 0%‐50%) at dose level −2 and flat pricing by 60.8% (range: 19%‐100%) at dose level −1 and 99.1% (range: 0%‐300%) at dose level −2. The cost per mg was significantly increased in drugs using flat pricing compared to linear pricing when dose reduction to either level ‐1 (P = 0.010) or level ‐2 (P = 0.006) occurred. The mean cost per cycle was decreased for drugs using linear pricing by 20.9% (range: −40% to 0%) at dose level −1 and 48.7% (range: −60% to −25%) at dose level −2 and flat pricing by 0.8% (range −6% to 0%) at dose level −1 and 11.0% (range: −50% to 100%) at dose level −2. The cost per cycle was significantly decreased in drugs with linear pricing compared to flat pricing when the standard dose is reduced to either dose level ‐1 (P = 0.005) or dose level ‐2 (P = 0.026). Conclusions Overall, flat pricing had significantly greater costs compared to linear pricing during dose reductions of anti‐cancer drugs. While there is a general expectation that the cost of drugs should decrease with dose reduction, drugs with flat pricing were generally found to have increased cost per mg and no change in the cost per cycle. The resultant increased spending on drug acquisition (despite purchasing lower doses) lead to financial wastage, which has significant implications on cost‐effectiveness considerations and budgets. Future economic evaluations should take into consideration the hidden costs associated with dose reductions of flat priced drugs.

Abstract Background The cost of new anticancer drugs is rising. We aimed to assess the clinical benefit and price of anti‐cancer drugs approved by the US Food and Drug Administration (FDA) for advanced gastrointestinal cancers. Methods Drugs approved between 2006 and 2017 for advanced GI malignancies were identified from FDA.gov, and their updated supporting trial data were searched. Incremental clinical benefit was quantified by using ESMO Magnitude of Clinical Benefit Scale version 1.1 (grade 0‐5) and ASCO Value Framework version 2 (score range −20 to 180). Higher scores indicate larger net benefit, and substantial benefit was defined as score 4 or 5 by the European Society for Medical Oncology (ESMO). The Micromedex REDBOOK was used to estimate the monthly average wholesale price (AWP) and total drug price (TDP) over the median treatment duration per patient. Clinical benefit, AWP and TDP of each drug class were assessed. Results In total, 16 GI cancer drugs received FDA approval for 24 indications, including five monoclonal antibodies (mAbs), five oral targeted therapies (TT), two immunotherapeutics (IO), three cytotoxic chemotherapies (CT), and one recombinant fusion protein (aflibercept). Most supporting trials (82%) reported overall survival benefit of less than 3 months and no significant improvement in quality of life. Only five agents (including one TT and one IO) with 21% the of approved indications met the ESMO's threshold of substantial clinical benefit. Median incremental benefit scores of TT and IO were comparable to other drug classes. However their median TDP was much higher at $153 402 and $98 208, respectively, compared to $30 330 USD per patient for CT. The estimated TDP did not correlate with clinical benefit scores. Conclusion Most FDA–approved gastrointestinal cancer drugs do not meet the ESMO threshold of substantial clinical benefit. TT and IO are estimated to carry significant drug costs, and further cost analysis of these drugs is urgently needed.

Abstract Background Chemotherapy is associated with a significant risk of toxicity, which often peaks between ambulatory visits to the cancer centre. Remote symptom management support is a tool to optimize self-management and healthcare utilization, including emergency department visits and hospitalizations (ED+H) during chemotherapy. We performed a single-arm pilot study to evaluate the feasibility, acceptability, and potential impact of a telephone symptom management intervention on healthcare utilization during chemotherapy for early stage breast cancer (EBC). Methods Women starting adjuvant or neoadjuvant chemotherapy for EBC at two cancer centres in Ontario, Canada, received standardized, nurse-led calls to assess common toxicities at two time points following each chemotherapy administration. Feasibility outcomes included patient enrollment, retention, RN adherence to delivering calls per the study schedule, and resource use associated with calls; acceptability was evaluated based on patient and provider feedback. Impact on acute care utilization was evaluated post hoc by linking individual patient records to provincial data holdings to examine ED+H patterns among participating patients compared to contemporaneous controls. Results Between September 2013 and December 2014, 77 women were enrolled (mean age 55 years). Most commonly used regimens were AC-paclitaxel (58%) and FEC-docetaxel (16%); 78% of patients received primary granulocyte colony-stimulating factor prophylaxis. 83.8% of calls were delivered per schedule; mean call duration was 9 min. The intervention was well received by both patients and clinicians. Comparison of ED+H rates among study participants versus controls showed that there were fewer ED visits in intervention patients [incidence rate ratio (IRR) (95% CI) = 0.54 (0.36, 0.81)] but no difference in the rate of hospitalizations [IRR (95% CI) = 1.02 (0.59, 1.77)]. Main implementation challenges included identifying eligible patients, fitting the calls into existing clinical responsibilities, and effective communication to the patient’s clinical team. Conclusions Telephone-based pro-active toxicity management during chemotherapy is feasible, perceived as valuable by clinicians and patients, and may be associated with lower rates of acute care use. However, attention must be paid to workflow issues for scalability. Larger scale evaluation of this approach is in progress.

Abstract Background Esophageal adenocarcinoma (EAC) incidence is increasing rapidly. Esophageal cancer has the second lowest 5-year survival rate of people diagnosed with cancer in Canada. Given the poor survival and the potential for further increases in incidence, phase-specific cost estimates constitute an important input for economic evaluation of prevention, screening, and treatment interventions. The study aims to estimate phase-specific net direct medical costs of care attributable to EAC, costs stratified by cancer stage and treatment, and predictors of total net costs of care for EAC. Methods A population-based retrospective cohort study was conducted using Ontario Cancer Registry-linked administrative health data from 2003 to 2011. The mean net costs of EAC care per 30 patient-days (2016 CAD) were estimated from the payer perspective using phase of care approach and generalized estimating equations. Predictors of net cost by phase of care were based on a generalized estimating equations model with a logarithmic link and gamma distribution adjusting for sociodemographic and clinical factors. Results The mean net costs of EAC care per 30 patient-days were $1016 (95% CI, $955–$1078) in the initial phase, $669 (95% CI, $594–$743) in the continuing care phase, and $8678 (95% CI, $8217–$9139) in the terminal phase. Overall, stage IV at diagnosis and surgery plus radiotherapy for EAC incurred the highest cost, particularly in the terminal phase. Strong predictors of higher net costs were receipt of chemotherapy plus radiotherapy, surgery plus chemotherapy, radiotherapy alone, surgery alone, and chemotherapy alone in the initial and continuing care phases, stage III-IV disease and patients diagnosed with EAC later in a calendar year (2007–2011) in the initial and terminal phases, comorbidity in the continuing care phase, and older age at diagnosis (70–74 years), and geographic region in the terminal phase. Conclusions Costs of care vary by phase of care, stage at diagnosis, and type of treatment for EAC. These cost estimates provide information to guide future resource allocation decisions, and clinical and policy interventions to reduce the burden of EAC.

Abstract Background There are limited data on the effects of trastuzumab on the right ventricle (RV). Therefore, we sought to evaluate the temporal changes in right ventricular (RV) structure and function as measured by cardiovascular magnetic resonance (CMR), and their relationship with left ventricular (LV) structure and function in breast cancer patients treated with trastuzumab. Methods Prospective, longitudinal, observational study involving 41 women with HER2+ breast cancer who underwent serial CMR at baseline, 6, 12, and 18 months after initiation of trastuzumab. A single blinded observer measured RV parameters on de-identified CMRs in a random order. Linear mixed models were used to investigate temporal changes in RV parameters. Results Of the 41 women (age 52 ± 11 years), only one patient experienced trastuzumab-induced cardiotoxicity. Compared to baseline, there were small but significant increases in the RV end-diastolic volume at 6 months (p = 0.002) and RV end-systolic volume at 6 and 12 months (p

Abstract Objective To review the available evidence and make recommendations regarding use of systemically administered drugs in combination or in sequence with radiation (RT) and/or surgery for cure and/or organ preservation in patients with locally advanced nonmetastatic (Stage III to IVB) squamous cell carcinoma of the head and neck (LASCCHN). Method Recognizing the Meta-analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) group reports have de facto guided practice since 2000, we searched for systematic reviews in the MEDLINE, EMBASE and Cochrane Database of Systematic Reviews published from January 2000 to February 2015 in reference to 4 research questions. A search was also conducted for randomized trials (RCTs) up to February 2015 not included in the meta-analyses. Result The MACH-NC reports, 5 additional meta-analyses, and 30 RCTs not included by MACH-NC were identified. For chemotherapy, MACH-NC findings showing improved overall survival with concomitant chemoRT did not require modification. High-dose cisplatin was most commonly studied. We confirmed this benefit with cisplatin monotherapy in patients treated with with postoperative concurrent chemoRT. Other than cetuximab, no targeted agents and radiosensitizers studied in RCTs were shown effective. TPF induction chemotherapy was superior to PF for tumor response and larynx preservation but not survival. Larynx preservation was reported with both CRT and induction chemotherapy approaches. Conclusion ChemoRT with cisplatin at least 40 mg/m2 per week given as radical or postoperative adjuvant remains a standard treatment approach for LASCCHN that improves overall survival but increases toxicity. 5-FU plus platinum is supported by less data but may be a reasonable alternative for patients unsuitable for cisplatin. Of note, stratification of outcomes by HPV-status was not available but outcomes for oropharynx cancer appeared similar to other subsites in chemoRT RCTs. No RCTs have yet demonstrated superiority or non-inferiority of cetuximab-RT to CRT. In view of this, cetuximab-RT is suggested only for patients not candidates for CRT. Taxane-based triplet induction chemotherapy is superior to doublets for rapid tumour downsizing and for larynx preservation, but does not improve overall survival and should be used with primary G-CSF prophylaxis. Further investigation of induction approaches for larynx preservation may be warranted.