Deirdre Weymann, Emanuel Krebs, Samantha Pollard, Melanie Mcphail, Ian Bosdet, Stephen Yip, Alison M Weppler, Aly Karsan, Helen Anderson, Tania Bubela, Michael R Law, Aaron Kesselheim, Dean A Regier
Background Targeted treatment or immunotherapy may yield increased, durable responses for melanoma patients. Whether patient-level benefits translate to population health is unknown. This study sought to estimate patient and population impacts of a cancer control policy that reimbursed multi-gene panel testing and pembrolizumab for metastatic melanoma in British Columbia, Canada. Methods This retrospective study examined a population-based cohort of 721 adults diagnosed with metastatic melanoma in British Columbia who received single or multi-gene testing between 2013 and 2018. We determined patient-level policy impacts using 11 genetic algorithm matching of policy-affected patients with historical controls, and Kaplan-Meier analysis and inverse probability of censoring weighted regression of two-year healthcare costs and survival times. For population-level effects, we applied interrupted time-series analysis on monthly health system expenditures and mortality rates, estimating ARIMA and generalized least squares Poisson regressions. Results Matched cohort analysis (ncontrol = 154, nintervention = 154) found mean cumulative patient-level cost increases of $53,963 (95% CI$35,641, $72,621; P < .001) and increased survival times of 111 days (95% CI: 44, 166; P < .001) over two years. Higher patient-level systemic therapy spending of $48,890 (95% CI: $31,110, $66,910; P < .001) drove overall cost differences. Population interrupted time-series analysis detected an immediate, sustained increase in mean monthly healthcare expenditures of $1,921 per patient (95% CI: $935, $2,908; P < .001). Higher overall spending did not coincide with population-level mortality changes. Conclusions The policy of reimbursing multi-gene testing and pembrolizumab produced patient survival improvements, but selectivity of response prevented population mortality improvement. Healthcare system costs significantly increased at both the patient- and population-levels.
{"title":"Patient and population impacts of multi-gene panel and pembrolizumab coverage in metastatic melanoma","authors":"Deirdre Weymann, Emanuel Krebs, Samantha Pollard, Melanie Mcphail, Ian Bosdet, Stephen Yip, Alison M Weppler, Aly Karsan, Helen Anderson, Tania Bubela, Michael R Law, Aaron Kesselheim, Dean A Regier","doi":"10.1093/jnci/djaf307","DOIUrl":"https://doi.org/10.1093/jnci/djaf307","url":null,"abstract":"Background Targeted treatment or immunotherapy may yield increased, durable responses for melanoma patients. Whether patient-level benefits translate to population health is unknown. This study sought to estimate patient and population impacts of a cancer control policy that reimbursed multi-gene panel testing and pembrolizumab for metastatic melanoma in British Columbia, Canada. Methods This retrospective study examined a population-based cohort of 721 adults diagnosed with metastatic melanoma in British Columbia who received single or multi-gene testing between 2013 and 2018. We determined patient-level policy impacts using 11 genetic algorithm matching of policy-affected patients with historical controls, and Kaplan-Meier analysis and inverse probability of censoring weighted regression of two-year healthcare costs and survival times. For population-level effects, we applied interrupted time-series analysis on monthly health system expenditures and mortality rates, estimating ARIMA and generalized least squares Poisson regressions. Results Matched cohort analysis (ncontrol = 154, nintervention = 154) found mean cumulative patient-level cost increases of $53,963 (95% CI$35,641, $72,621; P &lt; .001) and increased survival times of 111 days (95% CI: 44, 166; P &lt; .001) over two years. Higher patient-level systemic therapy spending of $48,890 (95% CI: $31,110, $66,910; P &lt; .001) drove overall cost differences. Population interrupted time-series analysis detected an immediate, sustained increase in mean monthly healthcare expenditures of $1,921 per patient (95% CI: $935, $2,908; P &lt; .001). Higher overall spending did not coincide with population-level mortality changes. Conclusions The policy of reimbursing multi-gene testing and pembrolizumab produced patient survival improvements, but selectivity of response prevented population mortality improvement. Healthcare system costs significantly increased at both the patient- and population-levels.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472707","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
De-escalation trials in oncology have received increased attention recently because there is a growing concern that patients with cancer are being overtreated—more patients (than would benefit) are being treated, earlier in the disease course, at a higher dose, for a longer duration, at a higher frequency. Thus, it is important to understand if less treatment allows us to achieve similar outcomes, a strategy referred to as de-escalation of treatment. However, one of the major concerns with such de-escalation strategies is the possibility of compromising treatment efficacy. While de-escalated treatment with lesser therapeutic burden is a worthwhile goal in itself because it leads to less physical, financial, and time toxicities, de-escalation cannot come at a substantial compromise of treatment efficacy. The commonest way to test whether such de-escalation strategies are safe and do not lead to unacceptable compromise in efficacy is through a non-inferiority design trial. Such trials require larger sample size, and thus, more funding and longer time to be completed. However, de-escalation trials do not necessarily need to be non-inferiority design. In this article, I make a case for using superiority design to test de-escalation strategies. This will avoid the limitations of non-inferiority design and make de-escalation strategies more efficient to test.
{"title":"De-escalation trials do not always need to be non-inferiority- A case for superiority design de-escalation trials in oncology","authors":"Bishal Gyawali","doi":"10.1093/jnci/djaf322","DOIUrl":"https://doi.org/10.1093/jnci/djaf322","url":null,"abstract":"De-escalation trials in oncology have received increased attention recently because there is a growing concern that patients with cancer are being overtreated—more patients (than would benefit) are being treated, earlier in the disease course, at a higher dose, for a longer duration, at a higher frequency. Thus, it is important to understand if less treatment allows us to achieve similar outcomes, a strategy referred to as de-escalation of treatment. However, one of the major concerns with such de-escalation strategies is the possibility of compromising treatment efficacy. While de-escalated treatment with lesser therapeutic burden is a worthwhile goal in itself because it leads to less physical, financial, and time toxicities, de-escalation cannot come at a substantial compromise of treatment efficacy. The commonest way to test whether such de-escalation strategies are safe and do not lead to unacceptable compromise in efficacy is through a non-inferiority design trial. Such trials require larger sample size, and thus, more funding and longer time to be completed. However, de-escalation trials do not necessarily need to be non-inferiority design. In this article, I make a case for using superiority design to test de-escalation strategies. This will avoid the limitations of non-inferiority design and make de-escalation strategies more efficient to test.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ting Zhang,Xing Hua,Chirayu Mohindroo,Xiaoyu Wang,Diptavo Dutta,Jia Liu,Shilpa Katta,Shengchao A Li,Jiahui Wang,Samuel O Antwi,Alan A Arslan,Laura E Beane Freeman,Paige M Bracci,Federico Canzian,Mengmeng Du,Steven Gallinger,Phyllis J Goodman,Verena Katzke,Charles Kooperberg,Loic Le Marchand,Rachel E Neale,Alpa V Patel,Sandra Perdomo,Xiao-Ou Shu,Kala Visvanathan,Stephen K Van Den Eeden,Emily White,Wei Zheng,Demetrius Albanes,Gabriella Andreotti,William R Bamlet,Paul Brennan,Julie E Buring,Stephen J Chanock,Yu Chen,Burcu Darst,Pietro Ferrari,Edward L Giovannucci,Michael Goggins,Christopher Haiman,Manal Hassan,Elizabeth A Holly,Rayjean J Hung,Miranda R Jones,Peter Kraft,Robert C Kurtz,Núria Malats,Steven C Moore,Kimmie Ng,Ann L Oberg,Irene Orlow,Ulrike Peters,Miquel Porta,Kari G Rabe,Nathaniel Rothman,Maria-José Sánchez,Howard D Sesso,Debra T Silverman,Melissa C Southey,Caroline Y Um,James Yarmolinsky,Herbert Yu,Chen Yuan,Jun Zhong,Brian M Wolpin,Harvey A Risch,Laufey T Amundadottir,Alison P Klein,Kai Yu,Haoyu Zhang,Rachael Z Stolzenberg-Solomon
BACKGROUNDThe associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood.METHODSWe investigated associations of genetic susceptibility to type 2 diabetes (T2D), eight T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242,283 cases, 1,569,734 controls), T1D (18,942 cases, 501,638 controls), and PDAC (10,244 cases and 360,535 controls) in individuals of European ancestry.RESULTSTwo-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI 1.05-1.15), particularly the T2D obesity (OR = 1.28; 95% CI 1.15-1.42) and lipodystrophy (OR = 1.25; 95% CI 1.03-1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI 0.99-1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions.CONCLUSIONSOur results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.
背景：以不同病理生理和遗传结构为特征的不同类型糖尿病与胰腺导管腺癌（PDAC）风险之间的关系尚不清楚。方法我们研究了2型糖尿病（T2D）、8种T2D机制簇、1型糖尿病（T1D）和年轻人成熟型糖尿病（MODY）的遗传易感性与PDAC风险的关系。我们使用全基因组关联研究（GWAS）对欧洲血统个体的T2D（242,283例，1,569,734例对照）、T1D（18,942例，501,638例对照）和PDAC（10,244例，360,535例对照）进行汇总统计。结果使用稳健调整谱评分（MR- raps）方法进行的两样本孟德尔随机化（MR）显示，基因预测的T2D与PDAC风险相关（OR = 1.10; 95% CI 1.05-1.15），尤其是T2D肥胖（OR = 1.28; 95% CI 1.15-1.42）和脂肪营养不良（OR = 1.25; 95% CI 1.03-1.51）。T1D与PDAC风险无关联（OR = 1.01; 95% CI 0.99-1.02）。使用基于摘要的自适应秩截断产物（sARTP）方法进行的途径/基因集分析显示，MODY基因集与PDAC风险之间存在显著相关性（P = 1.5 × 10-8），在排除20个已知的PDAC GWAS基因座（P = 7.6 × 10-4）后，该相关性仍然存在。在排除先前鉴定的GWAS位点区域后，HNF1A、FOXA3和HNF4A是贡献最大的基因。结论本遗传关联研究结果支持T2D，特别是肥胖和脂肪营养不良机制集群，以及MODY基因组易感区域在PDAC的病因中起作用。
{"title":"Different diabetes types and pancreatic ductal adenocarcinoma: a Mendelian randomization and pathway/gene-set analysis.","authors":"Ting Zhang,Xing Hua,Chirayu Mohindroo,Xiaoyu Wang,Diptavo Dutta,Jia Liu,Shilpa Katta,Shengchao A Li,Jiahui Wang,Samuel O Antwi,Alan A Arslan,Laura E Beane Freeman,Paige M Bracci,Federico Canzian,Mengmeng Du,Steven Gallinger,Phyllis J Goodman,Verena Katzke,Charles Kooperberg,Loic Le Marchand,Rachel E Neale,Alpa V Patel,Sandra Perdomo,Xiao-Ou Shu,Kala Visvanathan,Stephen K Van Den Eeden,Emily White,Wei Zheng,Demetrius Albanes,Gabriella Andreotti,William R Bamlet,Paul Brennan,Julie E Buring,Stephen J Chanock,Yu Chen,Burcu Darst,Pietro Ferrari,Edward L Giovannucci,Michael Goggins,Christopher Haiman,Manal Hassan,Elizabeth A Holly,Rayjean J Hung,Miranda R Jones,Peter Kraft,Robert C Kurtz,Núria Malats,Steven C Moore,Kimmie Ng,Ann L Oberg,Irene Orlow,Ulrike Peters,Miquel Porta,Kari G Rabe,Nathaniel Rothman,Maria-José Sánchez,Howard D Sesso,Debra T Silverman,Melissa C Southey,Caroline Y Um,James Yarmolinsky,Herbert Yu,Chen Yuan,Jun Zhong,Brian M Wolpin,Harvey A Risch,Laufey T Amundadottir,Alison P Klein,Kai Yu,Haoyu Zhang,Rachael Z Stolzenberg-Solomon","doi":"10.1093/jnci/djaf308","DOIUrl":"https://doi.org/10.1093/jnci/djaf308","url":null,"abstract":"BACKGROUNDThe associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood.METHODSWe investigated associations of genetic susceptibility to type 2 diabetes (T2D), eight T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242,283 cases, 1,569,734 controls), T1D (18,942 cases, 501,638 controls), and PDAC (10,244 cases and 360,535 controls) in individuals of European ancestry.RESULTSTwo-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI 1.05-1.15), particularly the T2D obesity (OR = 1.28; 95% CI 1.15-1.42) and lipodystrophy (OR = 1.25; 95% CI 1.03-1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI 0.99-1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10-8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10-4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions.CONCLUSIONSOur results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Mainou,Muatassem Alsadhan,Kalliopi Tsapa,Alissa Visram,Hira Mian,Rakesh Popat,Elias K Mai,Rajshekhar Chakraborty,Samer Al Hadidi,Meera Mohan,Aniko Szabo,Oliver Van Oekelen,Edward R Scheffer Cliff,Ghulam Rehman Mohyuddin
INTRODUCTIONAlthough myeloma represents a key success story in oncology, some drugs have failed to meet primary endpoints in randomized controlled trials (RCTs), despite promising early-phase activity. This analysis aimed to understand factors that increase the likelihood of meeting primary endpoints in myeloma RCTs.METHODSMyeloma RCTs published through October 2023 were identified using MEDLINE, PubMed, Embase, and the Cochrane Registry. Studies were classified as head-to-head (substituting one regimen for another) or add-on (adding one drug to existing regimen). Trials were considered successful if they achieved statistical significance for primary outcomes. Logistic regression identified predictors of meeting trial endpoints.RESULTSA total of 145 comparisons from 123 RCTs were included. Only two factors were independently associated with meeting primary endpoints in multivariate analysis. Higher median participant age was associated with lower odds of meeting the primary endpoint (OR per one-year increase, 0.90, 95% CI: 0.83-0.98). Overall survival (OS) was the primary endpoint in 20/145 comparisons, of which 3/20 met their endpoint. Selecting OS as primary endpoint was associated with reduced likelihood of success compared with progression-free survival by 94% (OR: 0.06, 95% CI: 0.01-0.23). Head-to-head design was not associated with lower success rates than add-on design (OR: 0.59; 95% CI: 0.22-1.62).CONCLUSIONTwo key factors predicted higher likelihood of meeting endpoints: younger patient age and primary endpoints other than overall survival. Although head-to-head design is considered riskier, it was not associated with decreased success. This analysis aims to better inform clinicians, industry, and regulators in myeloma drug development.
{"title":"Optimizing oncology drug development: systematic review of 22 years of myeloma randomized controlled trials.","authors":"Maria Mainou,Muatassem Alsadhan,Kalliopi Tsapa,Alissa Visram,Hira Mian,Rakesh Popat,Elias K Mai,Rajshekhar Chakraborty,Samer Al Hadidi,Meera Mohan,Aniko Szabo,Oliver Van Oekelen,Edward R Scheffer Cliff,Ghulam Rehman Mohyuddin","doi":"10.1093/jnci/djaf326","DOIUrl":"https://doi.org/10.1093/jnci/djaf326","url":null,"abstract":"INTRODUCTIONAlthough myeloma represents a key success story in oncology, some drugs have failed to meet primary endpoints in randomized controlled trials (RCTs), despite promising early-phase activity. This analysis aimed to understand factors that increase the likelihood of meeting primary endpoints in myeloma RCTs.METHODSMyeloma RCTs published through October 2023 were identified using MEDLINE, PubMed, Embase, and the Cochrane Registry. Studies were classified as head-to-head (substituting one regimen for another) or add-on (adding one drug to existing regimen). Trials were considered successful if they achieved statistical significance for primary outcomes. Logistic regression identified predictors of meeting trial endpoints.RESULTSA total of 145 comparisons from 123 RCTs were included. Only two factors were independently associated with meeting primary endpoints in multivariate analysis. Higher median participant age was associated with lower odds of meeting the primary endpoint (OR per one-year increase, 0.90, 95% CI: 0.83-0.98). Overall survival (OS) was the primary endpoint in 20/145 comparisons, of which 3/20 met their endpoint. Selecting OS as primary endpoint was associated with reduced likelihood of success compared with progression-free survival by 94% (OR: 0.06, 95% CI: 0.01-0.23). Head-to-head design was not associated with lower success rates than add-on design (OR: 0.59; 95% CI: 0.22-1.62).CONCLUSIONTwo key factors predicted higher likelihood of meeting endpoints: younger patient age and primary endpoints other than overall survival. Although head-to-head design is considered riskier, it was not associated with decreased success. This analysis aims to better inform clinicians, industry, and regulators in myeloma drug development.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"162 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145477507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rafael Emilio De Feria Cardet,Stephen Goodall,Tracey-Lea Laba,Marion Haas,Ian D Davis,Deborah J Street,Christopher J Sweeney,Richard De Abreu Lourenço
INTRODUCTIONThe use of surrogate outcomes to support treatment efficacy and cost-effectiveness in localised prostate cancer has the potential to shorten time to access for new medicines, but may be associated with greater uncertainty. We sought to understand how members of society might trade-off drug efficacy, safety, cost-effectiveness, and evidence strength when asked to consider funding new treatments for localised prostate cancer.METHODSA discrete choice experiment among the Australian general population was conducted. Treatment choices were described by: cost-effectiveness, Government cost, adverse events, patients expected to benefit from treatment, nature of benefits, completeness of data available, and the extent of follow-up. Responses were analysed using mixed logit and latent class models to assess heterogeneity.RESULTSThe survey was completed by 1,003 participants. Respondents favoured interventions that benefited a high proportion of patients (OR = 2.44 CI 95%=2.10, 2.69), were cost-effective (OR = 0.89 CI 95%= 0.82, 0.98), low cost to Government (OR = 0.75 CI 95%= 0.68, 0.82) and with long follow-up time (OR = 1.25 CI 95%= 1.12, 1.39). Respondents showed aversion to ongoing studies (OR = 0.81 CI 95%= 0.75, 0.88). Respondents were willing to accept less certain evidence if associated with a lower cost-effectiveness ratio (ICER). Latent class analysis revealed two subgroups with different preference patterns.CONCLUSIONSThe analysis found preference for interventions with maximum benefits while minimising costs. Respondents preferred studies with longer follow-up time for reimbursement decisions despite consequent treatment delays. Notably, respondents were willing to accept the uncertainty associated with surrogate outcomes-reflected through study length and completeness of evidence-provided the intervention demonstrated a favourable ICER.
使用替代结果来支持局部前列腺癌的治疗疗效和成本效益有可能缩短新药获得时间，但可能存在更大的不确定性。当被要求考虑资助局部前列腺癌的新疗法时，我们试图了解社会成员如何权衡药物疗效、安全性、成本效益和证据强度。方法对澳大利亚普通人群进行离散选择实验。对治疗选择的描述包括：成本效益、政府成本、不良事件、预期从治疗中获益的患者、获益的性质、可用数据的完整性和随访的程度。使用混合logit和潜在类别模型分析反应以评估异质性。结果共有1003名参与者完成了调查。受访者倾向于使患者受益比例高（OR = 2.44 CI 95%=2.10, 2.69）、成本效益高（OR = 0.89 CI 95%= 0.82, 0.98）、政府成本低（OR = 0.75 CI 95%= 0.68, 0.82）、随访时间长（OR = 1.25 CI 95%= 1.12, 1.39）的干预措施。受访者对正在进行的研究表现出厌恶（OR = 0.81 CI 95%= 0.75, 0.88）。如果与较低的成本效益比（ICER）相关，受访者愿意接受不太确定的证据。潜类分析显示两个亚组具有不同的偏好模式。结论分析发现患者倾向于效益最大化、成本最小化的干预措施。受访者倾向于有较长的随访时间的研究报销决定，尽管随之而来的治疗延误。值得注意的是，受访者愿意接受与替代结果相关的不确定性-通过研究长度和证据的完整性反映-如果干预显示出有利的ICER。
{"title":"What matters to society when making decisions about reimbursing drugs for prostate cancer: a discrete choice experiment.","authors":"Rafael Emilio De Feria Cardet,Stephen Goodall,Tracey-Lea Laba,Marion Haas,Ian D Davis,Deborah J Street,Christopher J Sweeney,Richard De Abreu Lourenço","doi":"10.1093/jnci/djaf315","DOIUrl":"https://doi.org/10.1093/jnci/djaf315","url":null,"abstract":"INTRODUCTIONThe use of surrogate outcomes to support treatment efficacy and cost-effectiveness in localised prostate cancer has the potential to shorten time to access for new medicines, but may be associated with greater uncertainty. We sought to understand how members of society might trade-off drug efficacy, safety, cost-effectiveness, and evidence strength when asked to consider funding new treatments for localised prostate cancer.METHODSA discrete choice experiment among the Australian general population was conducted. Treatment choices were described by: cost-effectiveness, Government cost, adverse events, patients expected to benefit from treatment, nature of benefits, completeness of data available, and the extent of follow-up. Responses were analysed using mixed logit and latent class models to assess heterogeneity.RESULTSThe survey was completed by 1,003 participants. Respondents favoured interventions that benefited a high proportion of patients (OR = 2.44 CI 95%=2.10, 2.69), were cost-effective (OR = 0.89 CI 95%= 0.82, 0.98), low cost to Government (OR = 0.75 CI 95%= 0.68, 0.82) and with long follow-up time (OR = 1.25 CI 95%= 1.12, 1.39). Respondents showed aversion to ongoing studies (OR = 0.81 CI 95%= 0.75, 0.88). Respondents were willing to accept less certain evidence if associated with a lower cost-effectiveness ratio (ICER). Latent class analysis revealed two subgroups with different preference patterns.CONCLUSIONSThe analysis found preference for interventions with maximum benefits while minimising costs. Respondents preferred studies with longer follow-up time for reimbursement decisions despite consequent treatment delays. Notably, respondents were willing to accept the uncertainty associated with surrogate outcomes-reflected through study length and completeness of evidence-provided the intervention demonstrated a favourable ICER.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"88 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Erin J Aiello Bowles,Kelli O'Connell,Jenna Bhimani,Grace B Gallagher,Victoria S Blinder,Rachael Burganowski Doud,Isaac J Ergas,Jennifer J Griggs,Narre Heon,Tatjana Kolevska,Yuriy Kotsurovskyy,Candyce H Kroenke,Cecile A Laurent,Raymond Liu,Kanichi G Nakata,Sonia Persaud,Donna R Rivera,Janise M Roh,Sara Tabatabai,Emily Valice,Peng Wang,Elisa V Bandera,Lawrence H Kushi,Elizabeth D Kantor
BACKGROUNDOlder women (>65 years) diagnosed with breast cancer may be at risk for chemotherapy dose reductions. We evaluated associations of age at diagnosis with two measures of chemotherapy dose reductions: first cycle dose proportion (FCDP) <90%, and average relative dose intensity (ARDI) <90%.METHODSFrom the Optimal Breast cancer Chemotherapy Dosing study, we included 10,166 women aged 18+ years treated with adjuvant chemotherapy for stage I-IIIA breast cancer at Kaiser Permanente Northern California (KPNC) and Washington (KPWA) between 2004-2019. We examined associations between age at diagnosis with FCDP < 90% (reflecting clinician intent at chemotherapy initiation) and ARDI < 90% (reflecting average dose across the chemotherapy course). We used generalized linear models of the Poisson family with a log-link function and robust standard errors to calculate prevalence ratios (PR) for FCDP < 90% and ARDI < 90% with 95% confidence intervals (CI) adjusted for patient and tumor characteristics, with and without adjusting for pre-existing comorbidities. All tests for statistical significance were 2-sided.RESULTSThe proportion of women with FCDP < 90% ranged from 2.9% among women aged 18-39 years to 18.6% among women aged 75+ years. Before adjusting for comorbidities, women aged 75+ years were more likely to have FCDP < 90% (PR: 4.88; 95%CI: 3.58, 6.66) and ARDI < 90% (PR: 1.91; 95%CI: 1.58, 2.32) versus women aged 40-49 years. Results were similar after adjusting for comorbidities as a composite comorbidity score or individual comorbidities.CONCLUSIONOlder age at diagnosis was strongly associated with chemotherapy dose reductions in this population-based cohort, particularly at chemotherapy initiation but also across the course of treatment.
{"title":"Associations between age and chemotherapy dose reductions in women with stage I-IIIA breast cancer.","authors":"Erin J Aiello Bowles,Kelli O'Connell,Jenna Bhimani,Grace B Gallagher,Victoria S Blinder,Rachael Burganowski Doud,Isaac J Ergas,Jennifer J Griggs,Narre Heon,Tatjana Kolevska,Yuriy Kotsurovskyy,Candyce H Kroenke,Cecile A Laurent,Raymond Liu,Kanichi G Nakata,Sonia Persaud,Donna R Rivera,Janise M Roh,Sara Tabatabai,Emily Valice,Peng Wang,Elisa V Bandera,Lawrence H Kushi,Elizabeth D Kantor","doi":"10.1093/jnci/djaf314","DOIUrl":"https://doi.org/10.1093/jnci/djaf314","url":null,"abstract":"BACKGROUNDOlder women (>65 years) diagnosed with breast cancer may be at risk for chemotherapy dose reductions. We evaluated associations of age at diagnosis with two measures of chemotherapy dose reductions: first cycle dose proportion (FCDP) <90%, and average relative dose intensity (ARDI) <90%.METHODSFrom the Optimal Breast cancer Chemotherapy Dosing study, we included 10,166 women aged 18+ years treated with adjuvant chemotherapy for stage I-IIIA breast cancer at Kaiser Permanente Northern California (KPNC) and Washington (KPWA) between 2004-2019. We examined associations between age at diagnosis with FCDP < 90% (reflecting clinician intent at chemotherapy initiation) and ARDI < 90% (reflecting average dose across the chemotherapy course). We used generalized linear models of the Poisson family with a log-link function and robust standard errors to calculate prevalence ratios (PR) for FCDP < 90% and ARDI < 90% with 95% confidence intervals (CI) adjusted for patient and tumor characteristics, with and without adjusting for pre-existing comorbidities. All tests for statistical significance were 2-sided.RESULTSThe proportion of women with FCDP < 90% ranged from 2.9% among women aged 18-39 years to 18.6% among women aged 75+ years. Before adjusting for comorbidities, women aged 75+ years were more likely to have FCDP < 90% (PR: 4.88; 95%CI: 3.58, 6.66) and ARDI < 90% (PR: 1.91; 95%CI: 1.58, 2.32) versus women aged 40-49 years. Results were similar after adjusting for comorbidities as a composite comorbidity score or individual comorbidities.CONCLUSIONOlder age at diagnosis was strongly associated with chemotherapy dose reductions in this population-based cohort, particularly at chemotherapy initiation but also across the course of treatment.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joshua B Rager,Pianpian Cao,Rodney A Hayward,Rafael Meza,Hormuzd A Katki,Jeremy B Sussman,Tanner J Caverly
BACKGROUNDThere is little guidance on how to personalize recommendations for lung cancer screening (LCS) that accounts for the variation in expected net benefit from LCS. We sought to explore the individual and population implications of identifying net benefit thresholds where LCS could be encouraged, discouraged, or offered as an option through neutral shared decision making due to being highly preference sensitive.METHODSUsing a simulated US population of 40-80yos who have ever smoked, we used microsimulation to estimate individualized quality-adjusted life years saved with LCS. We then identified two net benefit thresholds for LCS that account for a range of patient preferences and scientific uncertainties and compared this approach to current United States Preventive Services Task Force (USPSTF) guidelines.RESULTSOur simulated population included 59 million. 15 million are USPSTF eligible and of those, 52% (8 million) maintain net benefit even after accounting for unfavorable preferences about screening. 3% (450,000) of the USPSTF population is considered low-net-benefit (routinely discourage) and 45% (7 million) are in an intermediate gray area where net benefit is dependent upon patient preferences about LCS (offer neutral SDM). 2.5 million ever-smoking adults are high-net-benefit but excluded by current USPSTF criteria. 20.5 million ever-smoking U.S. adults are intermediate-net-benefit but are currently excluded by USPSTF criteria.CONCLUSIONWe estimate that half of the USPSTF LCS-eligible population is in a high net-benefit group where LCS could be routinely encouraged. Current LCS eligibility criteria likely exclude many ever-smokers who are high-net-benefit and many more with intermediate net benefit.
{"title":"Personalizing lung cancer screening recommendations for heterogenous populations: a microsimulation study.","authors":"Joshua B Rager,Pianpian Cao,Rodney A Hayward,Rafael Meza,Hormuzd A Katki,Jeremy B Sussman,Tanner J Caverly","doi":"10.1093/jnci/djaf316","DOIUrl":"https://doi.org/10.1093/jnci/djaf316","url":null,"abstract":"BACKGROUNDThere is little guidance on how to personalize recommendations for lung cancer screening (LCS) that accounts for the variation in expected net benefit from LCS. We sought to explore the individual and population implications of identifying net benefit thresholds where LCS could be encouraged, discouraged, or offered as an option through neutral shared decision making due to being highly preference sensitive.METHODSUsing a simulated US population of 40-80yos who have ever smoked, we used microsimulation to estimate individualized quality-adjusted life years saved with LCS. We then identified two net benefit thresholds for LCS that account for a range of patient preferences and scientific uncertainties and compared this approach to current United States Preventive Services Task Force (USPSTF) guidelines.RESULTSOur simulated population included 59 million. 15 million are USPSTF eligible and of those, 52% (8 million) maintain net benefit even after accounting for unfavorable preferences about screening. 3% (450,000) of the USPSTF population is considered low-net-benefit (routinely discourage) and 45% (7 million) are in an intermediate gray area where net benefit is dependent upon patient preferences about LCS (offer neutral SDM). 2.5 million ever-smoking adults are high-net-benefit but excluded by current USPSTF criteria. 20.5 million ever-smoking U.S. adults are intermediate-net-benefit but are currently excluded by USPSTF criteria.CONCLUSIONWe estimate that half of the USPSTF LCS-eligible population is in a high net-benefit group where LCS could be routinely encouraged. Current LCS eligibility criteria likely exclude many ever-smokers who are high-net-benefit and many more with intermediate net benefit.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Philip E Castle,Brian Befano,Marianne Hyer,Li C Cheung,Thomas Lorey,Nancy Poitras,Nicolas Wentzensen
BACKGROUNDWe demonstrated that cervical cancer risk following any screening result is lower if there is a known prior negative screening history versus an unknown screening history. We extended these findings to look at how screening performs following repeatedly screening negative.METHODSApproximately 1.7 million women aged 30-64 years underwent triennial human papillomavirus (HPV) and cytology co-testing from 2003 to 2021. We modeled 5-year risks of cervical intraepithelial neoplasia grade 3 or more severe diagnoses (CIN3+) and invasive cervical cancer for the initial co-test and then successive rounds following negative co-testing. A logistic-Weibull prevalence-incidence model was used to model risks.RESULTSHPV test positivity was greater than cytology positivity for only the first co-test and both decreased with each screening round. Diagnostic yields of CIN3+ and cancer declined with each round of screening so that the first screen yielded 8-fold more CIN3+ and invasive cancer than the 5th screen following 4 consecutive negative co-tests. Five-year risks of CIN3+ for positive and negative HPV and cytology results, individually or combined, decreased considerably after the first screen with smaller decreases in each subsequent round. For cancer, we noticed a considerable decrease with the first screen only. Five-year CIN3+ risks were greater for positive HPV or cytology results with a longer antecedent screening interval and younger age at screening (ptrend<0.001).CONCLUSION(S)Triennial screening that includes HPV testing becomes inefficient after a single, and more so after multiple, negative screens. These data support the use of longer screening intervals, especially following negative screen(s).
{"title":"Impact of repeatedly screening negative on cervical cancer risk.","authors":"Philip E Castle,Brian Befano,Marianne Hyer,Li C Cheung,Thomas Lorey,Nancy Poitras,Nicolas Wentzensen","doi":"10.1093/jnci/djaf317","DOIUrl":"https://doi.org/10.1093/jnci/djaf317","url":null,"abstract":"BACKGROUNDWe demonstrated that cervical cancer risk following any screening result is lower if there is a known prior negative screening history versus an unknown screening history. We extended these findings to look at how screening performs following repeatedly screening negative.METHODSApproximately 1.7 million women aged 30-64 years underwent triennial human papillomavirus (HPV) and cytology co-testing from 2003 to 2021. We modeled 5-year risks of cervical intraepithelial neoplasia grade 3 or more severe diagnoses (CIN3+) and invasive cervical cancer for the initial co-test and then successive rounds following negative co-testing. A logistic-Weibull prevalence-incidence model was used to model risks.RESULTSHPV test positivity was greater than cytology positivity for only the first co-test and both decreased with each screening round. Diagnostic yields of CIN3+ and cancer declined with each round of screening so that the first screen yielded 8-fold more CIN3+ and invasive cancer than the 5th screen following 4 consecutive negative co-tests. Five-year risks of CIN3+ for positive and negative HPV and cytology results, individually or combined, decreased considerably after the first screen with smaller decreases in each subsequent round. For cancer, we noticed a considerable decrease with the first screen only. Five-year CIN3+ risks were greater for positive HPV or cytology results with a longer antecedent screening interval and younger age at screening (ptrend<0.001).CONCLUSION(S)Triennial screening that includes HPV testing becomes inefficient after a single, and more so after multiple, negative screens. These data support the use of longer screening intervals, especially following negative screen(s).","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"166 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145433809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yingya Zhao, Marina S Nogueira, Ginger L Milne, Yu-Tang Gao, Qiuyin Cai, Qing Lan, Haoyang Yi, Nathaniel Rothman, Xiao-Ou Shu, Wei Zheng, Qingxia Chen, Gong Yang
Background Experimental models indicate that oxidative stress (OxS) may shift from promoting to suppressing tumor development as cancer progresses. Methods We conducted a nested case-control study within two Shanghai cohorts for primary analysis and one U.S. cohort for replication. Over a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident colorectal cancer (CRC) cases were identified and matched to one control each. In the U.S. cohort, 251 incident CRC cases were matched to two controls each. Systemic OxS was assessed using urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) via UPLC-MS/MS. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated. Results After adjusting for selected covariates, an inversion association between OxS markers and CRC risk was observed in the Shanghai cohorts and independently replicated in the U.S. cohort. This inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years following enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating a 3-fold difference in risk, with P for overall association < .001. A similar pattern was observed for 8-oxo-Guo. No significant associations were found for CRC diagnosed beyond 5 years of enrollment. Conclusion This novel finding of a time-dependent inverse relationship between systemic OxS and CRC risk, if further confirmed, may prompt a reevaluation of redox-based chemoprevention strategies.
{"title":"Time-dependent relationship between urinary biomarkers of nucleic acid oxidation and colorectal cancer risk","authors":"Yingya Zhao, Marina S Nogueira, Ginger L Milne, Yu-Tang Gao, Qiuyin Cai, Qing Lan, Haoyang Yi, Nathaniel Rothman, Xiao-Ou Shu, Wei Zheng, Qingxia Chen, Gong Yang","doi":"10.1093/jnci/djaf312","DOIUrl":"https://doi.org/10.1093/jnci/djaf312","url":null,"abstract":"Background Experimental models indicate that oxidative stress (OxS) may shift from promoting to suppressing tumor development as cancer progresses. Methods We conducted a nested case-control study within two Shanghai cohorts for primary analysis and one U.S. cohort for replication. Over a median follow-up of 15.1 years in the Shanghai cohorts, 1938 incident colorectal cancer (CRC) cases were identified and matched to one control each. In the U.S. cohort, 251 incident CRC cases were matched to two controls each. Systemic OxS was assessed using urinary markers of DNA oxidation (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxo-dG]) and RNA oxidation (7,8-dihydro-8-oxo-guanosine [8-oxo-Guo]) via UPLC-MS/MS. Multivariable-adjusted odds ratios (ORs) for CRC risk were calculated. Results After adjusting for selected covariates, an inversion association between OxS markers and CRC risk was observed in the Shanghai cohorts and independently replicated in the U.S. cohort. This inverse association was time-dependent, manifesting only for CRC cases diagnosed within 5 years following enrollment. ORs (95% CI) for CRC at the 10th and 90th percentiles of 8-oxo-dG levels, relative to the median, were 1.87 (1.39 to 2.53) and 0.48 (0.37 to 0.63), respectively, demonstrating a 3-fold difference in risk, with P for overall association &lt; .001. A similar pattern was observed for 8-oxo-Guo. No significant associations were found for CRC diagnosed beyond 5 years of enrollment. Conclusion This novel finding of a time-dependent inverse relationship between systemic OxS and CRC risk, if further confirmed, may prompt a reevaluation of redox-based chemoprevention strategies.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Milit S Patel,Miranda B Lam,Erin Jay G Feliciano,Edward Christopher Dee
{"title":"Beyond the foundation: building on Medicaid expansion to achieve cancer equity.","authors":"Milit S Patel,Miranda B Lam,Erin Jay G Feliciano,Edward Christopher Dee","doi":"10.1093/jnci/djaf274","DOIUrl":"https://doi.org/10.1093/jnci/djaf274","url":null,"abstract":"","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145381076","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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