Common Sense Oncology: Equity, Value, and Outcomes That Matter.

While some recent drug treatments have been transformative for patients with cancer, many treatments offer small benefits despite high clinical toxicity, time toxicity and financial toxicity. Moreover, treatments that do provide substantial clinical benefits are not available to many patients globally due to issues with availability and affordability. The Common Sense Oncology's vision is that patients will have access to treatments that provide meaningful improvements in outcomes that matter, regardless of where they live. In recognition of the growing challenges in the field of oncology, Common Sense Oncology seeks to achieve this vision by improving evidence generation, evidence interpretation and evidence communication.

Cost and value of cancer medicines in a single-payer public health system in Ontario, Canada: a cross-sectional study.

BACKGROUND: The financial impact of cancer medicines on health systems is not well known. We describe temporal trends in expenditure on cancer medicines within the single-payer health system of Ontario, Canada, and the extent of clinical benefit these treatments offer. METHODS: In this cross-sectional study, we identified cancer medicines and expenditures from formularies and costing databases (the New Drug Funding Program, Ontario Drug Benefit Program, and The High-Cost Therapy Funding Program) during 10 consecutive years (April 1, 2012, to March 31, 2022) in Ontario, Canada. For intravenous medicines, we applied the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) to identify expenditures associated with substantial clinical benefit. We also identified treatments associated with improved overall survival or quality of life. FINDINGS: 69 intravenous and 98 oral or injectable medicines were funded during 2012-22. Annual expenditure on cancer medicines increased by approximately 15% per year during 2012-22; the increase was more rapid in the most recent 4 years. Total expenditure on cancer medicines in the 2021-22 financial year was CA$1·7 billion. Immune checkpoint inhibitors were the single biggest expense by class ($284 million), representing 17% of the entire cancer medicine annual budget. Drugs with the highest individual costs were lenalidomide ($178 million) and pembrolizumab ($163 million), each accounting for around 10% of the entire budget. 29 (76%) of 38 indications eligible for ESMO-MCBS scoring met the threshold for substantial clinical benefit. Eight (21%) indications had no randomised trial evidence of improved overall survival, and only four (11%) were associated with improved QOL. $346 million (67% of the expenditure on intravenous cancer medicines) was spent on drugs that improved median overall survival by more than 6 months, $82 million (16%) was spent on medicines with overall survival gains of 3-6 months, and $32 million (6%) was spent on medicines with overall survival gains of less than 3 months. $53 million (10%) was spent on medicines with no established improvement in overall survival. INTERPRETATION: Costs of cancer medicines to the Canadian health system are increasing rapidly. Most funded indications met thresholds for substantial clinical benefit and two-thirds of the expenditure were for medicines that improve survival by more than 6 months. Whether this cost trajectory can be maintained in a sustainable, equitable, high-quality health system is unclear. Efforts are needed to ensure the price of medicines with substantial benefit is affordable and funding of treatments with very modest benefit might need to be re-assessed, particularly when alternative supportive and palliative therapies are available. FUNDING: None.

Magnitude of effect and sample size justification in trials supporting anti-cancer drug approval by the US Food and Drug Administration.

Approval of drugs is based on randomized trials observing statistically significant superiority of an experimental agent over a standard. Statistical significance results from a combination of effect size and sampling, with larger effect size more likely to translate to population effectiveness. We assess sample size justification in trials supporting cancer drug approvals. We identified US FDA anti-cancer drug approvals for solid tumors from 2015 to 2019. We extracted data on study characteristics, statistical plan, accrual, and outcomes. Observed power (Pobs) was calculated based on completed study characteristics and observed hazard ratio (HRobs). Studies were considered over-sampled if Pobs > expected with HRobs similar or worse than expected or if Pobs was similar to expected with HRobs worse than expected. We explored associations with over-sampling using logistic regression. Of 75 drug approvals (reporting 94 endpoints), 21% (20/94) were over-sampled. Over-sampling was associated with immunotherapy (OR: 5.5; p = 0.04) and associated quantitatively but not statistically with targeted therapy (OR: 3.0), open-label trials (OR: 2.5), and melanoma (OR: 4.6) and lung cancer (OR: 2.17) relative to breast cancer. Most cancer drug approvals are supported by trials with justified sample sizes. Approximately 1 in 5 endpoints are over-sampled; benefit observed may not translate to clinically meaningful real-world outcomes.

Efficacy-effectiveness gaps in oncology: Looking beyond survival.

The efficacy-effectiveness (EE) gap describes the differences in survival seen in clinical trials and routine clinical practice, where patients in real-world practice often have inferior outcomes compared to trial populations. However, EE gaps may exist beyond survival outcomes, including gaps in quality of life, toxicity, cost-effectiveness, and patient time, and these EE gaps should also influence patient and clinician treatment decisions. Failure to clearly acknowledge these EE gaps may cause patients, clinicians, and health care systems to have unrealistic expectations of the benefits of therapy across a range of important clinical and economic domains. In this commentary, the authors review the evidence supporting the existence of EE gaps in quality of life, time toxicity, cost and toxicities, and urge for further research into this important topic.

Meta-analysis of sex and racial subgroup participation rates and differential treatment effects for trials in solid tumor malignancies leading to US Food and Drug Administration registration between 2010 and 2021.

BACKGROUND: The lack of sociodemographic diversity in clinical trials limits the generalizability of results. The authors examined participation rates and effect modification by sex and race in oncology trials. METHODS: The authors extracted outcome data stratified by sex and race for registration trials supporting US Food and Drug Administration (FDA) approval (2010-2021). Effect modification by race and sex was examined using quantitative and qualitative methods. A random-effects meta-analysis and pairwise comparison of progression-free survival (PFS) and overall survival (OS) outcomes was conducted by sex and race. RESULTS: Ninety-five trials with 123 end points and 54,365 patients provided information on sex. Trial patients were more often male (n = 35,482; 65% vs. 56% male patients in US Surveillance, Epidemiology, and End Results [SEER] data), although the proportion of male patients was similar after adjusting by tumor type (60% in FDA data vs. 58% in SEER data). There was no difference in pooled outcomes among male versus female patients (PFS: hazard ratio, 0.99; 95% confidence interval, 0.92-1.07; p = .89; OS: hazard ratio, 0.99; 95% confidence interval, 0.93-1.07; p = .90). In total, 111 trials including 74,217 patients provided information on race, and 68% of patients identified as White, compared with 72.3% in US SEER incidence data. Black patients were under-represented compared with US SEER incidence data, although ethnicity was poorly reported throughout the data set. In the authors' network meta-analysis by race, there were no statistically significant differences in PFS or OS outcomes. CONCLUSIONS: No significant differences in PFS or OS outcomes were identified when the analyses were stratified by sex or race. Certain racial minorities remain under-represented, and clearer reporting of race and ethnicity is needed. Representation of female patients in FDA trials is similar to that in SEER data after adjusting for tumor type.

Global Cancer Drug Development-A Report From the 2022 Accelerating Anticancer Agent Development and Validation Meeting.

Rapidly expanding systemic treatment options, combined with improved screening, diagnostic, surgical, and radiotherapy techniques, have led to improved survival outcomes for many cancers over time. However, these overall survival gains have disproportionately benefited patients in high-income countries, whereas patients in low- and middle-income countries (LMICs) continue to experience challenges in accessing timely and guideline concordant care. In September 2022, the Accelerating Anticancer Agent Development and Validation workshop was held, focusing on global cancer drug development. Panelists discussed key barriers such as the lack of diagnostic services and human resources, drug accessibility and affordability, lack of research infrastructure, and regulatory and authorization challenges, with a particular focus on Africa and Latin America. Potential opportunities to improve access and affordability were reviewed, such as the importance of prioritizing investments in diagnostics, investing health infrastructure and work force planning, coordinated drug procurement efforts and streamlined regulatory processing, incentivized pricing through regulatory change, and the importance of developing and promoting clinical trials that can answer relevant clinical questions for patients in LMICs. As a cancer community, we must continue to advocate for and work toward equitable access to high-quality interventions for patients, regardless of their geographical location.

Augmenting clinical trial economic analysis by linking cancer trial data to administrative data: current landscape and future opportunities.

BACKGROUND: Economic analyses based on clinical trial data are costly and time consuming, and alternative methods for performing economic analyses should be explored. OBJECTIVE AND METHODS: In this perspective, we examine the emerging role of administrative data for economic analyses in cancer. RESULTS: Compared with routinely collected clinical trial data, routinely collected administrative data have several strengths including high capture rates for healthcare encounters, less resource utilisation, low rates of misclassification, long follow-up periods and the opportunity to collect data points not traditionally captured in clinical trials. However, there are also limitations including the need for accurate data linkage across multiple databases and systems, the costs and time associated with data linkage, the potential time lag between trial data collection and the availability of administrative data, and limited data on quality of life, toxicity and indirect costs. In this perspective, we identify important barriers and potential solutions to performing economic analyses for oncology using administrative data, and outline strategies to increase research in this field. CONCLUSION: The use of routinely collected administrative data sets for economic analyses of clinical trials presents a unique opportunity that could complement and validate economic analyses based on trial-level data.

Differential treatment effect between younger and older adults for new cancer therapies in solid tumors supporting US Food and Drug Administration approval between 2010 and 2021.

BACKGROUND: Over one half of cancer diagnoses occur in patients aged 65 and older. The authors quantified how treatment effects differ between older and younger patients in oncology registration trials. METHODS: The authors performed a retrospective cohort study of registration trials supporting US Food and Drug Administration approval of cancer drugs (from January 2010 to December 2021). The primary outcome was differential treatment effect by age (younger than 65 years vs. 65 years or older) for progression-free survival and overall survival. Random effects meta-analysis and a pairwise comparison of outcomes by age group also were performed. RESULTS: Among 263 trials that met the inclusion criteria, 120 trials with 153 end points and 83,152 patients presented age-specific outcome data. Among the included randomized patients, 38% were aged 65 years and older compared with an incidence proportion of 55% in data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Studies evaluating prostate cancer had the highest representation of patients aged 65 years or older (73%), whereas breast cancer studies had the lowest (20%). There were no changes in the proportion of patients aged 65 years or older over time (p = .86). Only 7% of end points showed a statistically significant interaction between outcome and age group. In a pooled analysis, there was an association between treatment effect and age for progression-free survival that approached but did not meet significance (hazard ratio, 0.95; p = .06), and there was no difference for overall survival (hazard ratio, 0.97; p = .79). CONCLUSIONS: Older adults remain under-represented in oncology registration trials. Significant differences in outcomes by age group were uncommon in individual trials and pooled analyses. However, clinical trial participants differ from real-world patients older than 65 years, and increased enrollment and ongoing research into differential treatment effects by age are needed.

Global application of National Comprehensive Cancer Network resource-stratified guidelines for systemic treatment of colon cancer: a population-based, customisable model for cost, demand, and procurement.

BACKGROUND: Resource-stratified guidelines (RSGs) can inform systemic treatment decisions in the face of limited resources. The objective of this study was to develop a customisable modelling tool to predict the demand, cost, and drug procurement needs of delivering National Comprehensive Cancer Network (NCCN) RSG-based systemic treatment for colon cancer. METHODS: We developed decision trees for first-course systemic therapy for colon cancer based on the NCCN RSGs. Decision trees were merged with data from the Surveillance, Epidemiology, and End Results programme, the International Agency for Research on Cancer's GLOBOCAN 2020 national estimates for colon cancer incidence, country-level income data, and data on drug costs from Redbook (USA), the Pharmaceutical Benefits Scheme (Australia), and the Management Sciences for Health 2015 International Medical Products price guide to estimate global treatment needs and costs, and forecast drug procurement. Simulations and sensitivity analyses were used to explore the effect of scaling up services globally and the effect of alternative stage distributions on treatment demand and cost. We generated a customisable model, in which estimates can be tailored to local incidence, epidemiological, and costing data. FINDINGS: First-course systemic therapy is indicated in 608 314 (53·6%) of 1 135 864 colon cancer diagnoses in 2020. Indications for first-course systemic therapy are projected to rise to 926 653 in 2040; the indications in 2020 might be as high as 826 123 (72·7%), depending on stage distribution assumptions. Adhering to NCCN RSGs, patients with colon cancer in low-income and middle income countries (LMICs) would constitute 329 098 (54·1%) of 608 314 global systemic therapy demands, but only 10% of global expenditure on systemic therapies. The total cost of NCCN RSG-based first-course systemic therapy for colon cancer in 2020 would be between about US$4·2 and about $4·6 billion, depending on stage distribution. If all patients with colon cancer in 2020 were treated according to maximal resources, global expenditure on systemic therapy for colon cancer would rise to around $8·3 billion. INTERPRETATION: We have developed a customisable model that can be applied at global, national, and subnational levels to estimate systemic treatment needs, forecast drug procurement, and calculate expected drug costs on the basis of local data. This tool can be used to plan resource allocation for colon cancer globally. FUNDING: None.

Exploring immune interactions in triple negative breast cancer: IL-1ß inhibition and its therapeutic potential.

Triple negative breast cancer (TNBC) has poor prognosis when compared to other breast cancer subtypes. Despite pre-clinical data supporting an immune targeted approach for TNBCs, immunotherapy has failed to demonstrate the impressive responses seen in other solid tumor malignancies. Additional strategies to modify the tumor immune microenvironment and potentiate response to immunotherapy are needed. In this review, we summarise phase III data supporting the use of immunotherapy for TNBC. We discuss the role of IL-1ß in tumorigenesis and summarize pre-clinical data supporting IL-1ß inhibition as a potential therapeutic strategy in TNBC. Finally, we present current trials evaluating IL-1ß in breast cancer and other solid tumor malignancies and discuss future studies that may provide a strong scientific rationale for the combination of IL-1ß and immunotherapy in the neoadjuvant and metastatic setting for people with TNBC.

Scoping review protocol on the impact of antimicrobial resistance on cancer management and outcomes.

INTRODUCTION: Antimicrobial resistance (AMR) is a growing global public health concern and is becoming a significant challenge in the management of patients with cancer. Due to the immunosuppressive nature of cancer treatment, infection is a common complication and the necessary high usage of antibiotics increases the risk of AMR. Failure to adequately prevent and treat infection in patients with cancer as a result of AMR can increase the morbidity and mortality of the disease. The objective of this scoping review is to understand the relationship between AMR and cancer in order to develop effective antimicrobial stewardship in this patient population and minimise the detrimental effects of AMR on cancer outcomes. METHODS AND ANALYSIS: This scoping review will follow the Arksey and O'Malley methodology framework. An exploratory review of the literature on antibiotic resistance in cancer care will help to define the research questions (stage 1). A broad range of electronic databases (MEDLINE ALL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and Embase) and search terms will be used to retrieve relevant articles published between 2000 and 2021 (stage 2). Studies will be systematically selected based on the eligibility criteria by two independent reviewers (stage 3). The titles and abstracts will be appraised to determine whether articles meet the eligibility criteria. This will be followed by screening of the full texts and only relevant publications will be retrieved. Data will then be extracted, collated and charted (stage 4); and the summary of aggregated results will be presented (stage 5). ETHICS AND DISSEMINATION: As this scoping review will collect and synthesise data from publicly available sources, no ethics review is required. When data collection and summarisation is completed, results will be disseminated through peer-reviewed publication and the key findings of the review will be presented at relevant conferences.

Perceived guideline clarity impacts guideline-concordant care for breast cancer screening in women age 40-49.

BACKGROUND: Canadian and US Task Forces recommend against routine mammography screening for women age 40-49 at average breast cancer risk as harms outweigh benefits. Both suggest individualized decisions based on the relative value women place on potential screening benefits and harms. Population-based data reveal variation in primary care professionals (PCPs) mammography rates in this age group after adjusting for sociodemographic factors, highlighting the need to explore PCP screening perspectives and how this informs clinical behaviours. Results from this study will inform interventions that can improve guideline concordant breast screening for this age group. METHODS: Qualitative semi-structured interviews were performed with PCPs in Ontario, Canada. Interviews were structured using the theoretical domains framework (TDF) to explore determinants of breast cancer screening best-practice behaviours: (1) risk assessment; (2) discussion regarding benefits and harms; and (3) referral for screening. ANALYSIS: Interviews were transcribed and analyzed iteratively until saturation. Transcripts were coded deductively by behaviour and TDF domain. Data that did not fit within a TDF code were coded inductively. The research team met repeatedly to identify potential themes that influenced or were important consequences of the screening behaviours. The themes were tested against further data, disconfirming cases, and different PCP demographics. RESULTS: Eighteen physicians were interviewed. The theme of perceived guideline clarity (a lack of clarity on guideline-concordant practices) influenced all behaviours and moderated the extent to which the risk assessment and discussion occurred. Many were unaware of how risk-assessment factored into the guidelines and/or did not perceive that a shared-care discussion was guideline-concordant. Deferral to patient preference (screening referral without a complete discussion of benefits and harms) occurred when the PCPs had low knowledge regarding harms and/or if they experienced regret (TDF domain: emotion) resulting from prior clinical experiences. Older providers described patient's influence impacting their decisions and physicians trained outside Canada, practicing in higher-resourced areas, and female physicians described being influenced by beliefs about consequences of benefits of screening. CONCLUSION: Perceived guideline clarity is an important driver of physician behaviour. Improving guideline concordant care should start by clarifying the guideline itself. Thereafter, targeted strategies include building skills in identifying and overcoming emotional factors and communication skills important for evidence-based screening discussions.

Targeting Notch-Driven Cytokine Secretion: Novel Therapies for Triple Negative Breast Cancer.

Compared with other breast cancer subtypes, triple negative breast cancer (TNBC) is an aggressive malignancy with a high recurrence rate and reduced overall survival. Immune checkpoint inhibition (ICI) has shown modest results in this subgroup, highlighting the need for improved targeted therapeutic options. Notch is a defining feature of TNBC and drives the expression of interleukin-1 beta (IL1ß) and C-C motif chemokine ligand 2 (CCL2). These cytokines are involved in the recruitment of tumor-associated macrophages (TAMs) to the tumor, resulting in immune evasion and tumor progression. Targeting Notch, IL1ß or CCL2 may reduce TAM recruitment and resistance to ICI, illuminating the potential of combination immunotherapy in TNBC.

Three-year disease-free survival in randomized trials of neoadjuvant chemotherapy and HER2-targeted therapy in breast cancer: A meta-analysis.

BACKGROUND: Outcomes for breast cancer patients with residual disease (RD) after neoadjuvant chemotherapy (NACT) and HER2-targeted therapy may be better than anticipated leading to a smaller absolute benefit of adjuvant trastuzumab emtansine (T-DM1). Therefore, accurate estimates of 3-year disease-free survival (DFS) can aid in treatment planning. METHODS: We reviewed randomized trials of NACT and HER2-targeted therapy in breast cancer (excluding T-DM1) and calculated mean 3-year DFS weighted by study sample size. Meta-regression comprising linear regression weighted by sample size (mixed-effects) was performed to explore associations between 3-year DFS and year of accrual and trial-level patient, disease, and treatment factors. Data were reported quantitatively irrespective of statistical significance. RESULTS: Eleven studies (N = 3581) were included in the primary analysis. The mean 3-year DFS for patients with RD was 79.7% (95% CI 77.4-80.9). This was higher for trials completing accrual after 2010 [83% (95% CI 79.3-86.3)] and for those receiving dual HER2 targeted therapy [83.4% (95% CI 79.2-87.7]. Better outcomes for ER positivity, later accrual and dual Her-2 targeted therapy were confirmed in meta-regression. Negative quantitative significance was observed for larger clinical tumor size and nodal involvement. CONCLUSIONS: The 3-year DFS for patients with RD has improved over time possibly due to dual HER2 targeted therapy. This will reduce the absolute benefit of adjuvant T-DM1 in this group of patients.

Determinants of guideline-concordant breast cancer screening by family physicians for women aged 40-49 years: a qualitative analysis.

BACKGROUND: Although the current Canadian Task Force on Preventive Health Care guideline recommends that physicians should inform women aged 40-49 years of the potential benefits and harms of screening mammography to support individualized decisions, previous reports of variation in clinical practice at the physician level suggest a lack of guideline-concordant care. We explored determinants (barriers and facilitators) of guideline-concordant care by family physicians regarding screening mammography in this age group. METHODS: We conducted qualitative semi-structured interviews by phone with family physicians in the Greater Toronto Area from January to November 2020. We structured interviews using the Theoretical Domains Framework to explore determinants (barriers and facilitators) of 5 physician screening behaviours, namely risk assessment, discussion regarding benefits and harms, decision or referral for mammography, referral for genetic counselling and referral to high-risk screening programs. Two independent researchers iteratively analyzed interview transcripts and deductively coded for each behaviour by domain to identify key behavioural determinants until saturation was reached. RESULTS: We interviewed 18 physicians (mean age 48 yr, 72% self-identified as women). Risk assessment was influenced by physicians' knowledge of risk factors, skills to synthesize risk and beliefs about utility. Physicians had beliefs in their capabilities to have informed patient-centred discussions, but insufficient knowledge regarding the harms of screening. The decision or referral for mammography was affected by emotions related to past patient outcomes, social influences of patients and radiology departments, and knowledge and beliefs about consequences (benefits and harms of screening). Referrals for genetic counselling and to high-risk screening programs were facilitated by their availability and by the knowledge and skills to complete forms. Lack of knowledge regarding which patients qualify and beliefs about consequences were barriers to referral. INTERPRETATION: Insufficient knowledge and skills for performance of risk assessment, combined with a tendency to overestimate benefits of screening relative to harms affected provision of guideline-concordant care. These may be effective targets for future interventions to improve guideline-concordant care.

Radiotherapy prioritization in 143 national cancer control plans: Correlation with radiotherapy machine availability, geography and income level.

BACKGROUND: In 2015, the Global Task Force on Radiotherapy for Cancer Control (GTFRCC) called for 80% of National Cancer Control Plans (NCCP) to include radiotherapy by 2020. As part of the ongoing ESTRO Global Impact of Radiotherapy in Oncology (GIRO) project, we assessed whether inclusion of radiotherapy in NCCPs correlates with radiotherapy machine availability, national income, and geographic region. METHODS: A previously validated checklist was used to determine whether radiotherapy was included in each country's NCCP. We applied the CCORE optimal radiotherapy utilisation model to the GLOBOCAN 2020 data to estimate the demand for radiotherapy and compared this to the International Atomic Energy Agency (IAEA) Directory of Radiotherapy Centres (DIRAC) supply data, stratifying by income level and world region. World regions were defined according to the IAEA. FINDINGS: Complete data (including GLOBOCAN 2020, DIRAC and NCCP) was available for 143 countries. Over half (55%, n = 79) included a radiotherapy-specific checklist item within the plan. Countries which included radiotherapy services planning in their NCCP had a higher median number of machines (1.68 vs 0.75 machines/1000 patients needing radiotherapy, p < 0.001). There was significant regional and income-level heterogeneity in the inclusion of radiotherapy-related items in NCCPs. Low-income and Asia-Pacific countries were least likely to include radiation oncology services planning in their NCCP (p = 0.06 and p = 0.003, respectively). Few countries in the Asia-Pacific (18.6%) had a plan to develop or maintain radiation services, compared to 57% of countries in Europe. INTERPRETATION: Only 55% of current NCCPs included any information regarding radiotherapy, below the GTFRCC's target of 80%. Prioritisation of radiotherapy in NCCPs was correlated with radiotherapy machine availability. There was regional and income-level heterogeneity regarding the inclusion of specific radiotherapy checklist items in the NCCPs. Ongoing efforts are needed to promote the inclusion of radiotherapy in future iterations of NCCPs in order to improve global access to radiation treatment. FUNDING: No direct funding was used in this research.

Regional Variations in Clinical Trial Outcomes in Oncology.

BACKGROUND: It is unknown how often regional differences in oncology trials are observed. Based on our study findings, we quantified regional variation in registration studies in oncology and developed a question guide to help clinicians evaluate regional differences. METHODS: Using FDA archives, we identified registration studies in solid tumor malignancies from 2010 to 2020. We extracted the baseline study characteristics and participating countries and determined whether the primary publication reported a regional subgroup analysis. For studies presenting outcomes stratified by region, we extracted the stratified hazard ratios (HRs) and extracted or calculated the test for heterogeneity. We performed a random effects meta-analysis and a pairwise comparison to determine whether outcomes differed between high-income versus mixed-income regions. RESULTS: We included 147 studies in our final analysis. Studies supporting FDA drug approval have become increasingly multinational over time (ß = 0.5; P=.04). The median proportion of countries from high-income groups was 81.2% (range, 44%-100%), with no participation from low-income countries in our cohort. Regional subgroup analysis was presented for 78 studies (53%). Regional heterogeneity was found in 17.8% (8/45) and 18% (8/44) of studies presenting an overall survival (OS) and progression-free survival endpoint, respectively. After grouping regions by income level, we found no difference in OS outcomes in high-income regions compared with mixed-income regions (n=20; HR, 0.95; 95% CI, 0.84-1.07). To determine whether regional variation is genuine, clinicians should evaluate the data according to the following 5 questions: (1) Are the regional groupings logical? (2) Is the regional difference on an absolute or relative scale? (3) Is the regional difference consistent and plausible? (4) Is the regional difference statistically significant? (5) Is there a clinical explanation? CONCLUSIONS: As registration studies in oncology become increasingly international, regional variations in trial outcomes may be detected. The question guide herein will help clinicians determine whether regional variations are likely to be clinically meaningful or statistical anomalies.