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Racovitan V, Goodman E, Cheung WY, Nichols AC, Caulley L, Wurzba S
Abstract:
Oral human papillomavirus (HPV) infection is a risk for oropharyngeal cancer (OPC), now the leading HPV-related cancer in males in Canada. P16 positivity is a marker of HPV positivity. Since 2015, all major Canadian cancer centers perform routine p16 tumor marker testing of OPCs to define their HPV status but recent data on the HPV-attributable fraction for OPC in Canada do not exist. A retrospective chart review was conducted of all squamous cell OPC cases in patients 18 years and older diagnosed from 2016 to 2020 in 4 major Canadian hospital-based regional oncology centers to determine the HPV attributable fraction for OPC in Canada using p16 as a surrogate marker for HPV. 1154 OPC cases were identified. Most patients (85.4%) were male; about one-third 26 (31.4%) had never smoked. Most OPC (80.6%) were P16 positive. p16 positivity was 27 associated with younger age (mean age p16+ 61.6 vs. p16- 66.5 years, p < 0.0001), male sex 28 (p16+ males 84.0% vs p16+ females 60.9%, p < 0.0001), lower tumor stage (Stage 1 p16+ 29 88.1% vs Stage 4 p16+ 69.4%, p < 0.001), and non-smoking (never smoked 92.3% vs past 30 smoker 82.8% vs current smoker 65.0%, p < 0.001). Logistic regression confirmed these 31 associations. This study, the largest cohort of Canadian patients with OPC yet reported, demonstrates the high attributable fraction for HPV-related OPC. HPV-related OPC was more likely in men, younger individuals, and never smokers. These findings highlight the burden of HPV-related OPC in Canada and support gender-neutral HPV vaccination as an important public health strategy to prevent head and neck cancer.
Daca-Álvarez M, Brunori A, Carbone A, Carbonell C, Tangen CM, Unger JM, Lucia MS, Oliva M, De Censi A, Brenner DR, Thompson IM, Balaguer F
Abstract:
Chemoprevention has emerged as a promising strategy to reduce cancer incidence by using pharmacologic agents that interrupt the carcinogenesis process. This review discusses emerging insights and recent advancements in chemoprevention, emphasizing novel approaches in several cancer types. Specifically, we examine breast cancer prevention, focusing on optimized endocrine therapy dosing to enhance adherence and minimize adverse effects while maintaining efficacy. Additionally, the potential of glucagon-like peptide-1 receptor agonists to mitigate obesity-related cancer risks is evaluated, highlighting their role in addressing an increasingly prevalent risk factor in the general population. The review further explores strategies targeting colorectal cancer (CRC), specifically in familial adenomatous polyposis, a hereditary CRC syndrome that exemplifies the complex interplay between chemoprevention, genetic risk, and patient management. In prostate cancer, we highlight the evidence supporting the use of 5-alpha reductase inhibitors, detailing their effectiveness in reducing cancer incidence as well as their safety profile. Across these areas, this review underscores the importance of precision medicine, advocating for personalized approaches that balance efficacy, safety, and quality-of-life considerations. Ultimately, advancing chemopreventive strategies through targeted research and clinical trials is essential for reducing cancer burden and improving patient outcomes.
Basmadjian RB, Xu Y, Quan ML, Lupichuk S, Cheung WY, Brenner DR
Abstract:
INTRODUCTION: Outcome prediction research in early-onset breast cancer (EoBC) is limited. This study evaluated the predictive performance of NHS PREDICT v2.1 and developed two prediction models for 5-year and 10-year all-cause mortality in a cohort of EoBC patients in Alberta, Canada. METHODS: Adults < 40 years diagnosed with invasive breast cancer in Alberta, Canada from 2004 to 2020 were included. Patient data were entered into PREDICT v2.1 and mortality estimates at 5 and 10 years were extracted. Two prediction models were developed for all-cause mortality: multivariable Cox regression with LASSO penalization (LASSO Cox) and random survival forests (RSF). Internal validation of the developed models was performed using nested tenfold cross-validation repeated 200 times. Model performance was assessed using receiver operator characteristic and calibration curves for mortality at 5 and 10 years. RESULTS: In total, 1827 patients with EoBC were eligible for inclusion. At 5 years, PREDICT had an area under the curve of 0.78 (95%CI 0.74-0.82) and overestimated mortality by 2.4% (95%CI 0.70-4.33) in the overall cohort. No differences in observed and predicted mortality by PREDICT were observed at 10 years. The LASSO Cox model showed better discrimination at 5 and 10 years than the RSF model, but both had poor calibration and underestimated mortality. CONCLUSION: PREDICT v2.1 tended to overestimate 5-year mortality in those with > 30% predicted risks and 10-year mortality in those with > 50% predicted risks for EoBC in Alberta, Canada. We did not identify additional models that would be clinically useful by applying machine learning. More follow-up data and emerging systemic treatment variables are required to study outcome prediction in modern cohorts.
Jimenez-Zepeda VH, Stephen MM, Chan H, Cheung WY
Abstract:
BACKGROUND: Proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) are important backbones in early line treatments for patients with multiple myeloma (MM). This study examined real-world treatment patterns, clinical outcomes and healthcare resource utilization (HCRU) of double-class exposed (DCE) patients with MM after prior PI and IMiD-based treatment. METHODS: DCE patients were identified using integrated administrative databases in the province of Alberta, Canada. DCE patients who commenced subsequent lines of therapy (LOT) between January 2012 and December 2022 were included. RESULTS: Among 831 DCE patients identified to have initiated subsequent LOT during the study period, median age was 68.0 years. IMiD (61%) was the most commonly used therapeutic class after progressing on double-class exposure, followed by PI (39%) and monoclonal antibodies (26%). Attrition rates after first subsequent LOT, defined as death before receiving the next LOT, was 27%, and attrition from second to third subsequent LOT was 30%. Median time to next treatment or death was 12.1 months (95% confidence interval: 10.3-14.1) and median overall survival was 34.4 months (30.3-40.2) from the start of the next subsequent LOT after double-class exposure. healthcare resource utilization (HCRU) during the first year of starting subsequent LOT was high, with a median of 1 ED visit, 1 inpatient admission, 30 clinic visits, 3 infusion appointments, 56 unique healthcare encounters. On average, patients spent 42.2 days on laboratory tests. CONCLUSION: Clinical outcomes among patients with MM initiating postdouble-class exposure treatments remain suboptimal, with high attrition rates and significant healthcare use, highlighting the need for therapies that reduce patient burden.
Chan KK, Takhar P, Evans WK, Mercer RE, Denburg A, Beca J, Muñoz C, Gavura S, Cheung WY, Hoch J, Craig E, de Oliveira C, Geirnaert M, Trudeau M, Ahuja T, Peacock S, Dai WF, Isaranuwatchai W, Bombard Y, Chambers C, Earle CC, Alvi R, Pechlivanoglou P, Tadrous M
Abstract:
OBJECTIVE: The Canadian Real-world Evidence for Value in Cancer (CanREValue) Collaboration was established in response to growing interest in using real-world evidence (RWE) to support health technology assessment (HTA). CanREValue has developed a framework to generate and use RWE to inform cancer drug funding decisions. DESIGN AND PARTICIPANTS: The RWE framework was developed using a multistage, multistakeholder approach. First, an environmental scan and qualitative study were conducted to understand the current state and key stakeholder perspectives on RWE. Next, five formal working groups (WGs) were established consisting of stakeholders with cancer drug funding expertise including clinicians, patients, methodologists, payers, regulatory decision-makers and data analysts. Through stakeholder consultations, including modified Delphi exercises and workshops, each WG developed specific framework components and identified facilitators and barriers that may impact the uptake of RWE. SETTING: The CanREValue Collaboration consisted of membership and participation from stakeholders and expertise from across Canada. Central research operations were managed from Toronto, Ontario, Canada. OUTCOMES: Development of an RWE framework reflective of the needs and perspectives of stakeholders directly involved and/or impacted by cancer drug funding decisions across Canada. RESULTS: Through an iterative process, a comprehensive RWE framework was developed that outlined the end-to-end processes necessary for the generation and use of RWE for HTA reassessment in Canada. The framework consists of four phases that uses various tools, templates and processes, which can be applied as a whole or in part. A diverse range of stakeholders and expertise is involved in the decision-making of each phase of the process: Phase I: identification, selection and prioritisation of RWE questions; phase II: initiating and planning the RWE study; phase III: conducting the RWE study and phase IV: conducting reassessment. CONCLUSIONS: As the cancer drug funding landscape continues to evolve, the need for RWE to support evidence-based policy reform, pricing and reallocation of funding from low to high value settings is crucial. We have developed a framework that is adaptable and responsive to the changing landscape. The tools, templates and processes within the framework can be applied by various stakeholder groups in whole or in part to support cancer drug funding decision-making in Canada and can be adapted for use in other jurisdictions.
Greystoke A, Daumont MJ, Rault C, Baltus H, Ding PQ, Emanuel G, Lucherini S, Vo L, Saglimbene VM, Ralphs E, Leal C, Schoemaker MJ, Katalinic A, Waldmann A, Cheung WY
Abstract:
BACKGROUND: Recent therapeutic advancements for non-metastatic non-small cell lung cancer (NSCLC) have increased the need for real-world baselines against which future changes in patient management and clinical outcomes can be compared. METHODS: Data on patient characteristics, initial treatment, and overall survival (OS) were derived from adult patients diagnosed with stage I-IIIC NSCLC (2010-2020) in a regional Canadian database (Oncology Outcomes [O2]), an English national registry (Cancer Analysis System [CAS]), and four regional German registries (VONKOdb) and retrospectively analyzed separately using analogous methodology. RESULTS: Data from 85,433 patients were analyzed. Stage at diagnosis varied, with proportions with stage I NSCLC ranging from 30.9% (VONKOdb) to 44.2% (O2) and with stage III disease from 36.9% (O2) to 48.5% (VONKOdb). Across the data sources, proportions receiving surgery ± other treatments were similar for stages I and II, but decreased through stages IIIA, IIIB, and IIIC (range, 24.7-42.7%, 4.6-21.8%, and 0.9-7.5%, respectively). Overall, 70.3-85.2% of patients received active treatment for NSCLC, with a trend toward lower proportions among those with stage III disease. Reached median OS tended to be longest in patients with resected stage I/II NSCLC (range, 28.8-128.0 months) and shortest in patients with stage IIIB/IIIC disease treated with systemic anticancer therapy (SACT) alone, radiotherapy alone, or SACT + palliative radiotherapy (range, 4.8-21.2 months). CONCLUSIONS: These data provide insights into treatment pathways and survival outcomes before the widespread use of immunotherapy-based and targeted therapies and will serve as an important baseline for future evaluations of emerging treatments for patients with non-metastatic NSCLC.
Ruan Y, Carbonell C, Brown K, Hilsden RJ, Brenner DR
Abstract:
BackgroundColorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related death worldwide. Colorectal adenomas (CRAs) are a crucial precursor for CRC and a target for preventive strategies. Recent network meta-analyses (NMAs) of randomized controlled trials (RCTs) suggest that chemopreventive agents (CPAs) are associated with reductions in CRC incidence. However, the quality of this evidence is low due to significant variability in the methods and types of studies assessed.PurposeOur study reviewed the efficacy and safety of CPAs on CRAs or CRCs evaluated in NMAs of RCTs and assessed the quality of all published NMAs on CPAs.Research DesignWe searched PubMed, Embase, and Cochrane Library for studies published from inception to July 29, 2024. We included all NMAs assessing the efficacy and safety of CPAs on CRC in both average-risk (general population) and high-risk (previous history of adenoma/CRC) populations. ResultsNine NMAs comparing 15 different interventions were included. Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) such as celecoxib were the most studied. Aspirin demonstrated efficacy against the development of any CRA and low-dose aspirin was consistently more protective than high-dose aspirin. However, the effect of aspirin against advanced CRA was not statistically significant. Concerns for long-term aspirin use included an increased risk of gastrointestinal bleeding and ulceration, but when evaluating all serious adverse events (SAEs), aspirin users did not have an increased risk compared to controls. Non-aspirin NSAIDs showed better efficacy against advanced CRA. However, the use of non-aspirin NSAIDs such as celecoxib was associated with significantly increased risk of SAEs, particularly cardiovascular disease events.ConclusionsConsidering the balance of efficacy and safety, low-dose aspirin is currently the best option for chemoprevention of CRA/CRC. Future research is needed to better characterize the patient subgroups that benefit most and to develop new, more effective CPAs.
Phillips WJ, Jackson A, Kidane B, Lim G, Navani V, Wheatley-Price P
Abstract:
The role of immunotherapy as systemic therapy for nonmetastatic non-small cell lung cancer (NSCLC) has evolved rapidly over the last decade. There are several well-conducted phase 3 clinical trials evaluating immunotherapy in the neoadjuvant, perioperative, adjuvant and nonoperative setting. In this narrative review, we summarize the data from these studies and discuss ongoing controversies in applying these data to clinical practice. These controversies relate to the value of the adjuvant component of perioperative immunotherapy, treatment of patients with PDL1 negative tumors, defining resectability, optimal use of operative versus nonoperative management, the role of stereotactic radiation therapy for very early lung cancers, and management of tumors with an oncogenic driver.
Wheatley-Price P, Navani V, Pabani A, Routy B, Snow S, Denault MH, Kim Y, Syed I, Devost N, Hui D, Qadeer RA, Arora P, Velummailum R, Springford A, McKibbon C, Ho C
Abstract:
BACKGROUND: Chemoradiotherapy (CRT) followed by durvalumab (CRT → durvalumab) is standard of care to treat patients with unresectable, stage III non-small cell lung cancer (NSCLC). The RELEVANCE study was designed to provide real-world effectiveness and safety data for CRT → durvalumab in Canadian settings. PATIENTS AND METHODS: RELEVANCE was a retrospective, observational, multicenter chart review that included adult patients with unresectable, stage III NSCLC treated with CRT alone or CRT → durvalumab at 5 Canadian cancer centers. Key outcomes included treatment patterns, adverse events of special interest (AESI), and overall survival (OS). RESULTS: 487 patients were included (144 CRT alone; 343 CRT → durvalumab). Median follow-up was 43.1 and 35.8 months for the CRT alone and CRT → durvalumab groups, respectively. The most frequently observed regimen included radiotherapy dose 54-66 Gy and radiosensitizing carboplatin. Median treatment duration was 1.5 months (CRT alone) and 13.4 months (CRT → durvalumab), and 47 % of patients completed a full course of durvalumab. Median OS and 3-year OS rate were 21.3 months and 32 % for CRT alone and 44.6 months and 56 % for CRT → durvalumab. Exploratory analysis by programmed cell death-ligand 1 (PD-L1) expression status of the CRT → durvalumab group noted 3-year OS rates of 69 %, 44 %, and 39 % in the PD-L1 ≥ 50 % (high), 1 %-49 % (intermediate), and < 1 % (negative) populations, respectively (32 %, 38 %, and 24 % for CRT alone, respectively). PD-L1 high expression was associated with lower risk of death vs. PD-L1 negative expression (P < 0.05). The most common AESI with CRT → durvalumab was pneumonitis. Median OS for patients who completed durvalumab was not reached and was 41.3 months among patients who discontinued durvalumab due to AEs. CONCLUSION: Results validate the treatment benefit and safety of the PACIFIC regimen in real-world Canadian settings. Among patients who received CRT → durvalumab, there was a correlation between increasing PD-L1 status and improved OS; however, shorter OS was observed in patients discontinuing durvalumab early due to AEs. TWITTER ABSTRACT: Real-world Canadian RELEVANCE study validates effectiveness and safety of durvalumab in patients with unresectable, stage III NSCLC.
Hutchinson JM, Ruan Y, Chia BJ, Brown CJ, Hilsden RJ, Loree JM, Brenner DR
Abstract:
IMPORTANCE: Cell-free DNA (cfDNA) testing is an emerging approach for colorectal cancer screening that has been approved in the US. The impact of cfDNA testing in the Canadian setting, assuming adherence mirroring prior real-world cfDNA work and assay performance from a Guardant Health study, is unknown. OBJECTIVE: To estimate how cfDNA screening impacts clinical and economic outcomes in Canada compared with existing screening approaches (fecal immunochemical testing [FIT] or colonoscopies). DESIGN, SETTING, AND PARTICIPANTS: The OncoSim-Colorectal model (version 3.6.5.7) was used to simulate participation, relative effectiveness, and cost of introduction of cfDNA tests every 3 years. A population of 32 million Canadians were simulated and examined for outcomes and costs between 2024 and 2092. EXPOSURES: Screening with colonoscopy, FIT, or cfDNA. MAIN OUTCOMES AND MEASURES: Screen-detected colorectal cancer cases, deaths, health-adjusted person-years, potential years of life lost, and cost of cancer screening and management were examined. RESULTS: Under higher participation, cfDNA detected 393 087 cases of colorectal cancer between 2024 and 2092 compared with 156 009 cases in the FIT scenario, and cfDNA reduced overall mortality by 121 383 deaths compared with current predictions with FIT. Linear regression models indicated that approximately 78% participation with 80% adherence or 69% participation with 100% adherence to cfDNA screening would be required to reduce deaths below the levels achieved by colonoscopy testing. Higher costs were associated with cfDNA testing, where each health-adjusted person-year had a cost of CAD $234.80 (US $164.06), and 0.025 deaths were averted per CAD $100 000 (US $69 874) additional dollars spent compared with FIT testing. When cfDNA testing was modeled with the same participation as FIT testing (43%), there was worse overall population impact (eg, greater number of deaths), emphasizing the importance of high participation for cfDNA testing to improve outcomes. CONCLUSIONS AND RELEVANCE: This study suggests that cfDNA testing could result in increased detection of colorectal cancer and reduced mortality if higher participation than reported in previous studies is achieved at the population level. Patient input on acceptance of blood-based vs stool-based screening may help inform real-world implementation.
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