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Sharma R, Gulati A, Chopra K. Era of surrogate endpoints and accelerated approvals: a comprehensive review on applicability, uncertainties, and challenges from regulatory, payer, and patient perspectives. Eur J Clin Pharmacol 2025; 81:605-623. [PMID: 40080138 DOI: 10.1007/s00228-025-03822-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025]
Abstract
PURPOSE The regulatory landscape in rare diseases and oncology has evolved to address unmet medical needs by implementing expedited approval pathways. The US FDA's Accelerated Approval and the EMA's Conditional Marketing Authorization facilitate earlier patient access to therapies through reliance on surrogate endpoints derived from early-phase clinical trials. The review aims to provide a comprehensive review of the role and utilization of surrogate endpoints in accelerated drug approvals, highlighting their strengths, limitations, and the varying perspectives of stakeholders on their validity and utility. METHODS This article reviews existing literature and regulatory guidelines to assess the effectiveness and challenges associated with surrogate endpoints in expedited approval pathways. It also examines the post-approval commitment adherence required by regulatory bodies, exploring discrepancies among stakeholder perspectives. RESULTS Findings indicate that while surrogate endpoints enable faster market access, uncertainties remain regarding post-approval commitments and their consistency. Differences in stakeholder opinions also persist, reflecting varying levels of confidence in the validity and applicability of surrogate endpoints. CONCLUSION Surrogate endpoints play a crucial role in accelerating drug approvals in areas with high unmet needs, yet challenges around post-approval commitments and stakeholder acceptance suggest the need for enhanced regulatory clarity and ongoing assessment of surrogate endpoint validity.
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Affiliation(s)
- Rohini Sharma
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
| | - Anamika Gulati
- Centre for Studies in Science Policy, School of Social Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Kanwaljit Chopra
- University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India.
- Pharmacology Research Laboratory, UGC Centre of Advanced Studies, University Institute of Pharmaceutical Sciences (UIPS), Panjab University, Chandigarh, 160014, India.
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2
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Wroblewski TH, Ajmal E, Ononogbu-Uche F, Lerner DP, Bigdeli TB, Divers J, Barthélemy EJ. Molecular Biomarkers Associated with Traumatic Brain Injury Outcome in Individuals of Black Racial Identity or African Ancestry: A Narrative Review. World Neurosurg 2025; 194:123620. [PMID: 39732452 DOI: 10.1016/j.wneu.2024.123620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 12/11/2024] [Accepted: 12/19/2024] [Indexed: 12/30/2024]
Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide and a major global health concern. In the United States, individuals of Black or African American racial identity experience disproportionately higher rates of TBI and suffer from worse postinjury outcomes. Contemporary research agendas have largely overlooked or excluded Black populations, resulting in the continued marginalization of Black patient populations in TBI studies, thereby limiting the generalizability of ongoing research to patients in the United States and around the world. This review aims to highlight what is currently known, and identify knowledge gaps, in research on molecular biomarkers associated with TBI in Black populations. A PubMed literature search was conducted to identify studies that investigate molecular biomarkers associated with TBI outcomes that include participants of Black racial identity and those of African ancestry. Studies identified for this review investigate biomarkers associated with TBI outcomes through a lens that specifically examines race, ethnicity, or ancestry. Most studies focused on blood- or cerebrospinal fluid-derived protein biomarkers. Studies identified statistical variation in S100ß, ubiquitin C-terminal hydrolase-L1, amyloid-ß, and tau across participant race, either at baseline or following TBI. Additionally, several studies identified genetic polymorphisms associated with TBI outcomes related to apolipoprotein E, ANKK1, and COMT polymorphism and TBI outcome and identified allele frequency variation across population ancestry. The role of race and ancestry on biomarkers associated with TBI outcome remains indeterminate and subsequent work is still required to understand the implications for patients with TBI.
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Affiliation(s)
- Tadeusz H Wroblewski
- College of Medicine, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Global Neurosurgery Laboratory, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; MD-PhD Program, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Erum Ajmal
- College of Medicine, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Global Neurosurgery Laboratory, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Favour Ononogbu-Uche
- College of Medicine, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Global Neurosurgery Laboratory, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - David P Lerner
- Department of Neurology, One Brooklyn Health/Brookdale University Hospital and Medical Center, Brooklyn, New York, USA; Department of Neurology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA
| | - Tim B Bigdeli
- Department of Psychiatry and Behavioral Sciences, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Department of Epidemiology and Biostatistics, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; VA New York Harbor Healthcare System, Brooklyn, New York, USA
| | - Jasmin Divers
- Division of Health Services Research, Department of Foundations of Medicine, NYU Grossman Long Island School of Medicine, NYU Langone Health, New York, New York, USA
| | - Ernest J Barthélemy
- College of Medicine, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Global Neurosurgery Laboratory, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Department of Neurology, One Brooklyn Health/Brookdale University Hospital and Medical Center, Brooklyn, New York, USA; Department of Neurology, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Division of Neurosurgery, Department of Surgery, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Department of Community Health Sciences, School of Public Health, SUNY Downstate Health Sciences University, Brooklyn, New York, USA; Department of Surgery, One Brooklyn Health/Brookdale University Hospital and Medical Center, Brooklyn, New York, USA.
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Li P, Huang D. NSUN2-mediated RNA methylation: Molecular mechanisms and clinical relevance in cancer. Cell Signal 2024; 123:111375. [PMID: 39218271 DOI: 10.1016/j.cellsig.2024.111375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/26/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
Cancer remains a leading cause of morbidity and mortality worldwide, necessitating the ongoing investigation of molecular targets for improved diagnosis, prognosis, and therapy. Among these targets, RNA modifications, particularly N5-methylcytosine (m5C) in RNA, have emerged as critical regulators of gene expression and cellular functions. NOP2/Sun RNA methyltransferase family member 2 (NSUN2) is a key enzyme in m5C modification, significantly influencing various biological processes and tumorigenesis. NSUN2 methylates multiple RNA species, including transfer RNAs (tRNAs), messenger RNAs (mRNAs), and non-coding RNAs, impacting RNA stability, translation efficiency, and cellular stress responses. These modifications, in turn, affect cell proliferation, differentiation, and survival. In cancer, NSUN2 is frequently upregulated, associated with aggressive tumor phenotypes, poor prognosis, and therapy resistance. Its role in oncogenic signaling pathways further underscores its importance in cancer biology. This review offers a comprehensive overview of NSUN2's role in cancer, focusing on its involvement in RNA methylation and its implications for tumor initiation and progression. Additionally, we explore the potential of NSUN2 as a biomarker for cancer diagnosis and prognosis, and its promise as a therapeutic target.
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Affiliation(s)
- Penghui Li
- Department of gastrointestinal surgery, The First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang 471000, Henan, China.
| | - Di Huang
- Department of Child Health Care, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China
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García de Yébenes Prous MJ, Carmona Ortells L. Biomarkers: how to consolidate them in clinical practice. REUMATOLOGIA CLINICA 2024; 20:386-391. [PMID: 39004560 DOI: 10.1016/j.reumae.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/20/2024] [Indexed: 07/16/2024]
Abstract
An inadequate biomarker validation can affect many patients' diagnosis, treatment, and follow-up. Therefore, special interest should be placed on performing these analyses correctly so that biomarkers can be applicable to patients and evidence of their clinical usefulness can be generated. A methodological work on the concept of biomarkers is presented, as well as the difficulties associated with the methodological approach to their development, validation, and implementation in clinical practice.
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Barshilia D, Huang JJ, Komaram AC, Chen YC, Chen CD, Syu MY, Chao WC, Chau LK, Chang GE. Ultrasensitive and Rapid Detection of Procalcitonin via Waveguide-Enhanced Nanogold-Linked Immunosorbent Assay for Early Sepsis Diagnosis. NANO LETTERS 2024; 24:2596-2602. [PMID: 38251930 PMCID: PMC10906069 DOI: 10.1021/acs.nanolett.3c04762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2024]
Abstract
Sepsis, a life-threatening inflammatory response, demands economical, accurate, and rapid detection of biomarkers during the critical "golden hour" to reduce the patient mortality rate. Here, we demonstrate a cost-effective waveguide-enhanced nanogold-linked immunosorbent assay (WENLISA) based on nanoplasmonic waveguide biosensors for the rapid and sensitive detection of procalcitonin (PCT), a sepsis-related inflammatory biomarker. To enhance the limit of detection (LOD), we employed sandwich assays using immobilized capture antibodies and detection antibodies conjugated to gold nanoparticles to bind the target analyte, leading to a significant evanescent wave redistribution and strong nanoplasmonic absorption near the waveguide surface. Experimentally, we detected PCT for a wide linear response range of 0.1 pg/mL to 1 ng/mL with a record-low LOD of 48.7 fg/mL (3.74 fM) in 8 min. Furthermore, WENLISA has successfully identified PCT levels in the blood plasma of patients with sepsis and healthy individuals, offering a promising technology for early sepsis diagnosis.
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Affiliation(s)
- Devesh Barshilia
- Department of Mechanical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan
- Advanced Institute of Manufacturing with High-Tech Innovations (AIM-HI), National Chung Cheng University, Chiayi 621301, Taiwan
| | - Jhen-Jie Huang
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 621301, Taiwan
| | | | - Yi-Che Chen
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 621301, Taiwan
| | - Chun-Da Chen
- Department of Laboratory Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin 640, Taiwan
| | - Min-Yu Syu
- Department of Laboratory Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin 640, Taiwan
| | - Wen-Cheng Chao
- Department of Critical Care Medicine, Taichung Veterans General Hospital, Taichung 402202, Taiwan
| | - Lai-Kwan Chau
- Department of Chemistry and Biochemistry, National Chung Cheng University, Chiayi 621301, Taiwan
- Center for Nano Bio-Detection, National Chung Cheng University, Chiayi 621301, Taiwan
| | - Guo-En Chang
- Department of Mechanical Engineering, National Chung Cheng University, Chiayi 621301, Taiwan
- Advanced Institute of Manufacturing with High-Tech Innovations (AIM-HI), National Chung Cheng University, Chiayi 621301, Taiwan
- Center for Nano Bio-Detection, National Chung Cheng University, Chiayi 621301, Taiwan
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Jin Y, Ren H, Yue Q, Wu W, Liu C, Guo Y, Zhao P. Surrogacy of one-year survival for overall survival in advanced hepatocellular carcinoma. BMC Cancer 2024; 24:258. [PMID: 38395854 PMCID: PMC10893652 DOI: 10.1186/s12885-024-12000-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND The increasing number of sequential treatments complicates the evaluation of overall survival (OS) in clinical trials for hepatocellular carcinoma (HCC), therefore, reliable surrogate endpoints (SEs) are required. This study aimed to evaluate the surrogacy of progression-free survival (PFS) and one-year (1-yr) milestone survival for OS in HCC trials. METHODS We systematically searched databases for randomized clinical trials that evaluated systemic treatments for advanced HCC. Individual patient data were reconstructed to calculate the 1-yr survival rate. We adopted a two-stage meta-analytic validation model to evaluate the correlation between SEs and OS, and the correlation between treatment effects on SEs and OS. The hazard ratio (HR) was calculated to assess the treatment effects on PFS and OS, and the 1-yr survival ratio was calculated to evaluate the treatment effects on the 1-yr milestone survival. RESULTS Thirty-two HCC trials involving 13,808 patients were included. A weak correlation was detected between the median PFS and median OS (R2 = 0.32), whereas the correlation improved between PFS HR and OS HR (R2 = 0.58). We identified strong correlations between the 1-yr survival rate and median OS and between the 1-yr survival ratio and OS HR (R2 = 0.74 and 0.65, respectively). In subgroup analyses, PFS HR strongly correlated with OS HR in trials relevant to immune checkpoint inhibitors (ICIs). Although the correlation remained weak between PFS and OS even in trials with PFS HR ≤ 0.6, the 1-yr survival rate and 1-yr survival ratio were strong surrogates for median OS and OS HR, respectively (R2 = 0.77 and 0.75). CONCLUSIONS One-year milestone survival outperformed PFS as a SE for OS in HCC, indicating the application of 1-yr survival as a secondary endpoint. In particular, PFS HR was a potential SE for OS HR in the ICI trials.
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Affiliation(s)
- Yuzhi Jin
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University & National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China
| | - Hui Ren
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University & National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China
| | - Qianhua Yue
- Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610000, China
| | - Wei Wu
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University & National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China
| | - Chuan Liu
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University & National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China
| | - Yixuan Guo
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University & National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China
| | - Peng Zhao
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University & National Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, 310058, China.
- The First Affiliated Hospital, Zhejiang University School of Medicine & Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, 79 Qingchun Road, Hangzhou, China.
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Potter GE, Callier V, Shrestha B, Joshi S, Dwivedi A, Silva JC, Laurens MB, Follmann DA, Deye GA. Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials? Malar J 2023; 22:383. [PMID: 38115002 PMCID: PMC10729369 DOI: 10.1186/s12936-023-04802-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Accepted: 11/22/2023] [Indexed: 12/21/2023] Open
Abstract
BACKGROUND Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as VEHR = 1-hazard ratio or VERR = 1-risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: VEmolFOI, the vaccine-induced proportion reduction in incidence of new clones acquired over time, and VEC, the vaccine-induced proportion reduction in mean number of infecting clones per exposure. METHODS Power of VEmolFOI and VEC was compared to that of VEHR and VERR by simulations and analytic derivations, and the four VE methods were applied to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion. RESULTS In the trial of RTS,S vaccine, a significantly reduced number of clones at first infection was observed, but this was not the case in trials of PfSPZ Vaccine or primaquine, although the PfSPZ trial lacked power to show a reduction. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from VEC compared to VEHR for data like those from RTS,S, but VEC is less powerful than VEHR for trials in which the number of clones at first infection is not reduced. VEmolFOI was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate VEmolFOI. The primaquine VEmolFOI estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing VEmolFOI from improving power. CONCLUSIONS The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, these estimators are not recommended as primary endpoints for small trials unless supported by targeted data analysis. TRIAL REGISTRATIONS NCT00866619, NCT02663700, NCT02143934.
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Affiliation(s)
- Gail E Potter
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
| | - Viviane Callier
- Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Biraj Shrestha
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Sudhaunshu Joshi
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Ankit Dwivedi
- Institute for Genomic Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Joana C Silva
- Institute for Genomic Sciences, University of Maryland School of Medicine, Baltimore, MD, USA
- Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Matthew B Laurens
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Dean A Follmann
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Gregory A Deye
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
- AstraZeneca PLC, Gaithersburg, MD, USA
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Zheng X, Zhang L, Wu L, Zhao J, Sun J, Fang Y, Zhou J, Chu Q, Shen Y, Yang Z, Chen L, Huang M, Lin X, Liu Z, Shen P, Wang Z, Wang X, Wang H, Han Z, Liu A, Zhang H, Ye F, Gao W, Wu F, Song Z, Chen S, Zhou C, Wang Q, Xu C, Huang D, Zheng X, Miao Q, Jiang K, Xu Y, Wu S, Wang H, Zhang Q, Yang S, Li Y, Chen S, Lin G. Baseline C-reactive protein predicts efficacy of the first-line immune checkpoint inhibitors plus chemotherapy in advanced lung squamous cell carcinoma: a retrospective, multicenter study. BMC Cancer 2023; 23:1244. [PMID: 38104105 PMCID: PMC10725584 DOI: 10.1186/s12885-023-11737-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 12/10/2023] [Indexed: 12/19/2023] Open
Abstract
AIMS To investigate the predictive value of baseline C-reactive protein (CRP) levels on the efficacy of chemotherapy plus immune checkpoint inhibitors (ICI) in patients with advanced lung squamous cell carcinoma (LSCC). MATERIALS AND METHODS In this retrospective multicenter study spanning from January 2016 to December 2020, advanced LSCC patients initially treated with chemotherapy or a combination of chemotherapy and ICI were categorized into normal and elevated CRP subgroups. The relationship between CRP levels and treatment outcomes was analyzed using multivariate Cox proportional hazards models and multivariate logistic regression, focusing primarily on the progression-free survival (PFS) endpoint, and secondarily on overall survival (OS) and objective response rate (ORR) endpoints. Survival curves were generated using the Kaplan-Meier method, with the log-rank test used for comparison between groups. RESULTS Of the 245 patients evaluated, the 105 who received a combination of chemotherapy and ICI with elevated baseline CRP levels exhibited a significant reduction in PFS (median 6.5 months vs. 11.8 months, HR, 1.78; 95% CI: 1.12-2.81; p = 0.013) compared to those with normal CRP levels. Elevated CRP was identified as an independent risk factor for poor PFS through multivariate-adjusted analysis. However, among the 140 patients receiving chemotherapy alone, baseline CRP levels did not significantly influence PFS. Furthermore, within the combination therapy group, there was a notable decrease in the ORR (51% vs. 71%, p = 0.035), coupled with a significantly shorter OS (median 20.9 months vs. 31.5 months, HR, 2.24; 95% CI: 1.13-4.44; p = 0.033). CONCLUSION In patients with advanced LSCC, elevated baseline CRP levels were identified as an independent predictive factor for the efficacy of combination therapy with chemotherapy and ICI, but not in chemotherapy alone. This suggests that CRP may be a valuable biomarker for guiding treatment strategies.
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Affiliation(s)
- Xinlong Zheng
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Longfeng Zhang
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Lin Wu
- The Second Department of Thoracic Oncology, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, China
| | - Jun Zhao
- Department of Thoracic Medical Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jianguo Sun
- Cancer Institute, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Yong Fang
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Zhejiang, China
| | - Jin Zhou
- School of Medicine, Sichuan Cancer Hospital and Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yihong Shen
- Department of Respiratory Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhenzhou Yang
- Department of Cancer Center, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Lijin Chen
- Department of Oncology, Affiliated Quanzhou First Hospital of Fujian Medical University, Quanzhou, China
| | - Meijuan Huang
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyan Lin
- Department of Oncology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Zhenhua Liu
- Department of Medical Oncology, Provincial Clinical College, Fujian Medical University, Fujian provincial hospital, Fuzhou, China
| | - Peng Shen
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhijie Wang
- Medical Oncology Department, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, China
| | - Xin Wang
- Department of Oncology, Zhongshan Hospital of Xiamen University, Xiamen, China
| | - Huijuan Wang
- Department of Respiratory Medicine, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhengbo Han
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Anwen Liu
- Department of Oncology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hongmei Zhang
- Department of Oncology, Xijing Hospital, Airforce Military Medical University, Xian, Shanxi, China
| | - Feng Ye
- Department of Medical Oncology, Cancer Hospital, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, China
| | - Wen Gao
- Department of Medical Oncology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China
| | - Fang Wu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhengbo Song
- Department of Clinical Trial, Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, Zhejiang, China
| | - Shengchi Chen
- Department of Oncology, Nanping First Hospital Affiliated to Fujian Medical University, Nanping, China
| | - Chenzhi Zhou
- Respiratory Medicine Department, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qian Wang
- Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Chunwei Xu
- Department of Respiratory Medicine, Affiliated Jinling Hospital, Medical School of Nanjing University Nanjing, Nanjing, Jiangsu, China
| | - Dingzhi Huang
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Xiaobin Zheng
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Qian Miao
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Kan Jiang
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yiquan Xu
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Shiwen Wu
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Haibo Wang
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Qiuyu Zhang
- Institute of Immunotherapy, Fujian Medical University, Fuzhou, China
| | - Shanshan Yang
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yujing Li
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Sihui Chen
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Gen Lin
- Department of Thoracic Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China.
- Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis, Fuzhou, China.
- Interdisciplinary Institute for Medical Engineering, Fuzhou University, Fuzhou, China.
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Azizi M, Shahgolzari M, Fathi-Karkan S, Ghasemi M, Samadian H. Multifunctional plant virus nanoparticles: An emerging strategy for therapy of cancer. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1872. [PMID: 36450366 DOI: 10.1002/wnan.1872] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/07/2022] [Accepted: 11/11/2022] [Indexed: 12/05/2022]
Abstract
Cancer therapy requires sophisticated treatment strategies to obtain the highest success. Nanotechnology is enabling, revolutionizing, and multidisciplinary concepts to improve conventional cancer treatment modalities. Nanomaterials have a central role in this scenario, explaining why various nanomaterials are currently being developed for cancer therapy. Viral nanoparticles (VNPs) have shown promising performance in cancer therapy due to their unique features. VNPs possess morphological homogeneity, ease of functionalization, biocompatibility, biodegradability, water solubility, and high absorption efficiency that are beneficial for cancer therapy applications. In the current review paper, we highlight state-of-the-art properties and potentials of plant viruses, strategies for multifunctional plant VNPs formulations, potential applications and challenges in VNPs-based cancer therapy, and finally practical solutions to bring potential cancer therapy one step closer to real applications. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.
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Affiliation(s)
- Mehdi Azizi
- Department of Tissue Engineering and Biomaterials, School of Advanced Medical Sciences and Technologies, Hamadan University of Medical Sciences, Hamadan, Iran
- Dental Implants Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mehdi Shahgolzari
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sonia Fathi-Karkan
- Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Advanced Sciences and Technologies in Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Maryam Ghasemi
- Renal Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Hadi Samadian
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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10
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Potter GE, Callier V, Shrestha B, Joshi S, Dwivedi A, Silva JC, Laurens MB, Follmann DA, Deye GA. Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials? RESEARCH SQUARE 2023:rs.3.rs-3370731. [PMID: 37790581 PMCID: PMC10543529 DOI: 10.21203/rs.3.rs-3370731/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/05/2023]
Abstract
Background Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as V E H R = 1 - hazard ratio or V E R R = 1 - risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: V E m o l F O I , the vaccine-induced proportion reduction in incidence of new clones acquired over time, and V E C , the vaccine-induced proportion reduction in mean number of infecting clones per exposure. Methods We used simulations and analytic derivations to compare power of these methods to V E H R and V E R R and applied them to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion. Results The RTS,S vaccine significantly reduced the number of clones at first infection, but PfSPZ vaccine and primaquine did not. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from V E C compared to V E H R for data like RTS,S, but V E C is less powerful than V E H R for vaccines which do not reduce the number of clones at first infection. V E m o l F O I was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate V E m o l F O I . The primaquine V E m o l F O I estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing V E m o l F O I from improving power. Conclusions The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, we recommend against these estimators as primary endpoints for small trials unless supported by targeted data analysis. Trial registrations NCT00866619, NCT02663700, NCT02143934.
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Affiliation(s)
- Gail E Potter
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health
| | - Viviane Callier
- Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research
| | | | | | - Ankit Dwivedi
- Institute for Genomic Sciences, University of Maryland School of Medicine
| | - Joana C Silva
- Institute for Genomic Sciences and Department of Microbiology & Immunology, University of Maryland School of Medicine
| | - Matthew B Laurens
- Center for Vaccine Development and Global Health, University of Maryland School of Medicine
| | - Dean A Follmann
- Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health
| | - Gregory A Deye
- Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health
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11
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Alderuccio JP, Kuker RA, Yang F, Moskowitz CH. Quantitative PET-based biomarkers in lymphoma: getting ready for primetime. Nat Rev Clin Oncol 2023; 20:640-657. [PMID: 37460635 DOI: 10.1038/s41571-023-00799-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 08/20/2023]
Abstract
The use of functional quantitative biomarkers extracted from routine PET-CT scans to characterize clinical responses in patients with lymphoma is gaining increased attention, and these biomarkers can outperform established clinical risk factors. Total metabolic tumour volume enables individualized estimation of survival outcomes in patients with lymphoma and has shown the potential to predict response to therapy suitable for risk-adapted treatment approaches in clinical trials. The deployment of machine learning tools in molecular imaging research can assist in recognizing complex patterns and, with image classification, in tumour identification and segmentation of data from PET-CT scans. Initial studies using fully automated approaches to calculate metabolic tumour volume and other PET-based biomarkers have demonstrated appropriate correlation with calculations from experts, warranting further testing in large-scale studies. The extraction of computer-based quantitative tumour characterization through radiomics can provide a comprehensive view of phenotypic heterogeneity that better captures the molecular and functional features of the disease. Additionally, radiomics can be integrated with genomic data to provide more accurate prognostic information. Further improvements in PET-based biomarkers are imminent, although their incorporation into clinical decision-making currently has methodological shortcomings that need to be addressed with confirmatory prospective validation in selected patient populations. In this Review, we discuss the current knowledge, challenges and opportunities in the integration of quantitative PET-based biomarkers in clinical trials and the routine management of patients with lymphoma.
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Affiliation(s)
- Juan Pablo Alderuccio
- Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
| | - Russ A Kuker
- Department of Radiology, Division of Nuclear Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Fei Yang
- Department of Radiation Oncology, Division of Medical Physics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Craig H Moskowitz
- Department of Medicine, Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
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12
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Merino M, Kasamon Y, Theoret M, Pazdur R, Kluetz P, Gormley N. Irreconcilable Differences: The Divorce Between Response Rates, Progression-Free Survival, and Overall Survival. J Clin Oncol 2023; 41:2706-2712. [PMID: 36930853 PMCID: PMC10414695 DOI: 10.1200/jco.23.00225] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 02/16/2023] [Accepted: 02/23/2023] [Indexed: 03/19/2023] Open
Affiliation(s)
- Margret Merino
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
| | - Yvette Kasamon
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
| | - Marc Theoret
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
- Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD
| | - Richard Pazdur
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
- Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD
| | - Paul Kluetz
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
- Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD
| | - Nicole Gormley
- Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
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13
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Kim DG, Lee JY, Ahn JH, Lee T, Eom M, Cho HS, Ku J. Quantitative ultrasound for non-invasive evaluation of subclinical rejection in renal transplantation. Eur Radiol 2023; 33:2367-2377. [PMID: 36422649 DOI: 10.1007/s00330-022-09260-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 09/25/2022] [Accepted: 10/19/2022] [Indexed: 11/25/2022]
Abstract
OBJECTIVES This study aimed to investigate the predictive efficacy of shear-wave elastography, superb microvascular imaging (SMI), and CEUS for allograft rejection in kidney transplants without graft dysfunction. METHODS From January 2021 to November 2021, 72 consecutive patients who underwent both allograft biopsy and ultrasound were evaluated. Blood test results were obtained within a week of the ultrasound examinations, which were performed before the protocol biopsy. Resistive index (RI), tissue viscoelasticity, vascular index, and quantitative CEUS parameters were measured. Patients were divided based on biopsy results into the rejection and non-rejection groups. RESULTS Among the 72 patients, 21 patients had pathological characteristics of acute rejection. RI of allograft was significantly higher in the rejection group (p = 0.007), compared to the non-rejection group. There were no significant between-group differences in vascular indices of SMI, mean elasticity, and mean viscosity. Meanwhile, among the parameters obtained by the time-intensity curve on CEUS, the cortical and medullary ratios of average contrast signal intensity, peak enhancement, wash-in area AUC, wash-in perfusion index, wash-out AUC, and wash-in and wash-out AUC were significantly different between the two groups (p < 0.05). In the receiver operating characteristic curve analysis for predicting allograft rejection, the AUC was 0.853 for the combination of six CEUS parameters, RI, and blood urea nitrogen. CONCLUSIONS Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for diagnosing subclinical allograft rejection. Furthermore, the combination of CEUS parameters, RI, and blood urea nitrogen may be helpful for the early detection of renal allograft rejection. KEY POINTS • Among non-invasive quantitative ultrasound measurements, CEUS parameters are the most useful for the diagnosis of subclinical allograft rejection. • On CEUS, the C/M ratios of MeanLin, PE, WiAUC, WiPI, WoAUC, and WiWoAUC are significantly lower in the rejection group; the combination of these showed reliable predictive performance for rejection. • The combination of CEUS parameters, RI, and BUN has a high predictive capability for subclinical allograft rejection.
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Affiliation(s)
- Deok-Gie Kim
- Department of Surgery, The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, Korea
| | - Jun Young Lee
- Transplantation Center, Wonju Severance Christian Hospital, Wonju, Korea.,Department of Nephrology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Center of Evidence Based Medicine, Institute of Convergence Science, Yonsei University, Seoul, Korea
| | - Jhii-Hyun Ahn
- Department of Radiology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea.
| | - Taesic Lee
- Division of Data Mining and Computational Biology, Institute of Global Health Care and Development, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Minseob Eom
- Department of Pathology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Hyun Seok Cho
- Department of Radiology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jihye Ku
- Department of Radiology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea
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14
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Roze S, Bertrand N, Eberst L, Borget I. Projecting overall survival in health-economic models: uncertainty and maturity of data. Curr Med Res Opin 2023; 39:367-374. [PMID: 36628431 DOI: 10.1080/03007995.2023.2167442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE As lifetime horizons are considered for economic evaluations, the Kaplan-Meier (KM) estimate is used to extrapolate survival in cases of immature overall survival (OS) data. This study estimated the error induced by the choice of distribution when extrapolating different levels of OS maturity. METHODS Fifteen phase 3 trials reporting KM estimates of OS where at least 70% maturity (i.e. 70% of the population had died during follow-up) were included and compared to artificially created truncated data (30 and 50% maturity). Individual patient-data were reproduced using the Guyot algorithm based on digitized KM curves. Parametric survival distributions were fit for each arm in each study, for each maturity level, using the same time horizon (equal to the maximum follow-up). For each KM curve, the best distribution was chosen based on visual inspection, Akaike/Bayesian information criteria, and external validity. Outcomes were measured as life expectancy in months (LM) and life months gained (LMG). RESULTS The Weibull (33%), log-logistic (32%) and log-normal (27%) were most often selected as the best fitting distribution. Compared to LM at full maturity, LM was overestimated in 23 and 40% of cases, at 30 and 50% maturity, respectively. Mean absolute error was 2.12months at 30% maturity, and decreased to 0.88months at 50% maturity. When comparing to mature data, the mean percentage of error in LMG was 126.4 and 62.4% at 30 and 50% maturity, respectively. CONCLUSION The extent of OS maturity increases the risk of error when projecting long-term life expectancy for economic models. Even marginal gains in OS maturity result in more accurate estimations and should be considered when developing models.
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Affiliation(s)
| | | | - Lauriane Eberst
- Medical Oncology Department, Institut de Cancerologie de Strasbourg Europe, Strasbourg, France
| | - Isabelle Borget
- Department of Biostatistics and Epidemiology, Gustave Roussy, Oncostat, U1018 Inserm, Paris-Saclay University, "Ligue Contre le Cancer" labeled team, Villejuif, France
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15
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Guidi L, Pellizzari G, Tarantino P, Valenza C, Curigliano G. Resistance to Antibody-Drug Conjugates Targeting HER2 in Breast Cancer: Molecular Landscape and Future Challenges. Cancers (Basel) 2023; 15:1130. [PMID: 36831473 PMCID: PMC9954056 DOI: 10.3390/cancers15041130] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/02/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
The treatment of HER2-positive metastatic breast cancer (mBC) with Trastuzumab emtansine (T-DM1) and Trastuzumab deruxtecan (T-DXd), two antibody-drug conjugates (ADCs) targeting HER2, is burdened by progression of disease related to the acquisition of mechanisms of resistance. Resistance to T-DM1 is caused by the decrease of HER2 expression, the alteration of intracellular trafficking, the impairment of lysosome functions, the drug expulsion through efflux pumps and the activation of alternative signal pathways. Instead, the decrease of HER2 expression and SLX4 loss of function mutations represent the first evidences of mechanisms of resistance to T-DXd, according to the results of DAISY trial. Several strategies are under evaluation to overcome resistances to anti-HER2 ADCs and improve clinical outcomes in patients progressing on these agents: combinations with tyrosine kinase inhibitors, statins, immune checkpoint inhibitors and synthetic DNA-damaging agents are emerging as promising approaches. Furthermore, novel anti-HER2 ADCs with innovative structures and mechanisms of action are in development, in the attempt to further improve the activity and tolerability of currently available agents.
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Affiliation(s)
- Lorenzo Guidi
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Gloria Pellizzari
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Paolo Tarantino
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Breast Oncology Program, Harvard Medical School, Boston, MA 02215, USA
| | - Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy
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16
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The scientific basis of combination therapy for chronic hepatitis B functional cure. Nat Rev Gastroenterol Hepatol 2023; 20:238-253. [PMID: 36631717 DOI: 10.1038/s41575-022-00724-5] [Citation(s) in RCA: 77] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2022] [Indexed: 01/13/2023]
Abstract
Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available.
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17
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Ciani O, Grigore B, Taylor RS. Development of a framework and decision tool for the evaluation of health technologies based on surrogate endpoint evidence. HEALTH ECONOMICS 2022; 31 Suppl 1:44-72. [PMID: 35608044 PMCID: PMC9546394 DOI: 10.1002/hec.4524] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/28/2021] [Accepted: 04/02/2022] [Indexed: 05/27/2023]
Abstract
In the drive toward faster patient access to treatments, health technology assessment (HTA) agencies and payers are increasingly faced with reliance on evidence based on surrogate endpoints, increasing decision uncertainty. Despite the development of a small number of evaluation frameworks, there remains no consensus on the detailed methodology for handling surrogate endpoints in HTA practice. This research overviews the methods and findings of four empirical studies undertaken as part of COMED (Pushing the Boundaries of Cost and Outcome Analysis of Medical Technologies) program work package 2 with the aim of analyzing international HTA practice of the handling and considerations around the use of surrogate endpoint evidence. We have synthesized the findings of these empirical studies, in context of wider contemporary body of methodological and policy-related literature on surrogate endpoints, to develop a web-based decision tool to support HTA agencies and payers when faced with surrogate endpoint evidence. Our decision tool is intended for use by HTA agencies and their decision-making committees together with the wider community of HTA stakeholders (including clinicians, patient groups, and healthcare manufacturers). Having developed this tool, we will monitor its use and we welcome feedback on its utility.
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Affiliation(s)
- Oriana Ciani
- Centre for Research on Health and Social Care ManagementSDA BocconiMilanLombardiaItaly
- Evidence Synthesis & Modelling for Health ImprovementCollege of Medicine and HealthUniversity of ExeterExeterDevonUK
| | - Bogdan Grigore
- Exeter Test GroupCollege of Medicine and HealthUniversity of ExeterExeterDevonUK
| | - Rod S. Taylor
- MRC/CSO Social and Public Health Sciences Unit & Robertson Centre for BiostatisticsInstitute of Health and Well BeingUniversity of GlasgowGlasgowScotlandUK
- College of Medicine and HealthUniversity of ExeterExeterDevonUK
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18
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Ho L, Xu Y, Zhang NL, Ho FF, Wu IXY, Chen S, Liu X, Wong CHL, Ching JYL, Cheong PK, Yeung WF, Wu JCY, Chung VCH. Quantification of prevalence, clinical characteristics, co-existence, and geographic variations of traditional Chinese medicine diagnostic patterns via latent tree analysis-based differentiation rules among functional dyspepsia patients. Chin Med 2022; 17:101. [PMID: 36038888 PMCID: PMC9425972 DOI: 10.1186/s13020-022-00656-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/15/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Traditional Chinese Medicine (TCM) treatment strategies are guided by pattern differentiation, as documented in the eleventh edition of the International Classification of Diseases (ICD). However, no standards for pattern differentiation are proposed to ensure inter-rater agreement. Without standardisation, research on associations between TCM diagnostic patterns, clinical features, and geographical characteristics is also not feasible. This diagnostic cross-sectional study aimed to (i) establish the pattern differentiation rules of functional dyspepsia (FD) using latent tree analysis (LTA); (ii) compare the prevalence of diagnostic patterns in Hong Kong and Hunan; (iii) discover the co-existence of diagnostic patterns; and (iv) reveal the associations between diagnostic patterns and FD common comorbidities. METHODS A total of 250 and 150 participants with FD consecutively sampled in Hong Kong and Hunan, respectively, completed a questionnaire on TCM clinical features. LTA was performed to reveal TCM diagnostic patterns of FD and derive relevant pattern differentiation rules. Multivariate regression analyses were performed to quantify correlations between different diagnostic patterns and between diagnostic patterns and clinical and geographical variables. RESULTS At least one TCM diagnostic pattern was differentiated in 70.7%, 73.6%, and 64.0% of the participants in the overall (n = 400), Hong Kong (n = 250), and Hunan (n = 150) samples, respectively, using the eight pattern differentiation rules derived. 52.7% to 59.6% of the participants were diagnosed with two or more diagnostic patterns. Cold-heat complex (59.8%) and spleen-stomach dampness-heat (77.1%) were the most prevalent diagnostic patterns in Hong Kong and Hunan, respectively. Spleen-stomach deficiency cold was highly likely to co-exist with spleen-stomach qi deficiency (adjusted odds ratio (AOR): 53.23; 95% confidence interval (CI): 21.77 to 130.16). Participants with severe anxiety tended to have liver qi invading the stomach (AOR: 1.20; 95% CI: 1.08 to 1.33). CONCLUSIONS Future updates of the ICD, textbooks, and guidelines should emphasise the importance of clinical and geographical variations in TCM diagnosis. Location-specific pattern differentiation rules should be derived from local data using LTA. In future, patients' pattern differentiation results, local prevalence of TCM diagnostic patterns, and corresponding TCM treatment choices should be accessible to practitioners on online clinical decision support systems to streamline service delivery.
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Affiliation(s)
- Leonard Ho
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Yulong Xu
- School of Information Technology, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Nevin L Zhang
- Department of Computer Science and Engineering, School of Engineering, The Hong Kong University of Science and Technology, Hong Kong, Hong Kong
| | - Fai Fai Ho
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Irene X Y Wu
- Xiangya School of Public Health, Central South University, 5/F, 238 Shang-Ma-Yuan-Ling Alley, Kai-Fu District, Changsha, Hunan, China.
| | - Shuijiao Chen
- Department of Gastroenterology, Xiangya Hospital, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer-Aided Diagnosis and Treatment for Digestive Disease, Changsha, Hunan, China
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Changsha, Hunan, China
- Hunan International Scientific and Technological Cooperation Base of Artificial Intelligence Computer-Aided Diagnosis and Treatment for Digestive Disease, Changsha, Hunan, China
| | - Charlene H L Wong
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Jessica Y L Ching
- Institute of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Pui Kuan Cheong
- Institute of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Wing Fai Yeung
- School of Nursing, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
| | - Justin C Y Wu
- Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Vincent C H Chung
- School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- The Jockey Club School of Public Health and Primary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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19
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Tremblay É, Gosselin C, Mai V, Lajoie AC, Kilo R, Weatherald J, Lacasse Y, Bonnet S, Lega JC, Provencher S. Assessment of Clinical Worsening End Points as a Surrogate for Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Circulation 2022; 146:597-612. [PMID: 35862151 DOI: 10.1161/circulationaha.121.058635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Clinical worsening (CW) is a composite end point commonly used in pulmonary arterial hypertension (PAH) trials. We aimed to assess the trial-level surrogacy of CW for mortality in PAH trials, and whether the various CW components were similar in terms of frequency of occurrence, treatment-related relative risk (RR) reduction, and importance to patients. METHODS We searched MEDLINE, Embase, and the Cochrane Library (January 1990 to December 2020) for trials evaluating the effects of PAH therapies on CW. The coefficient of determination between the RR for CW and mortality was assessed by regression analysis. The frequency of occurrence, RR reduction, and importance to patients of the CW components were assessed. RESULTS We included 35 independent cohorts (9450 patients). PAH therapies significantly reduced CW events (RR, 0.64 [95% CI, 0.55-0.73]), including PAH-related hospitalizations (RR, 0.61 [95% CI, 0.47-0.79]), treatment escalation (RR, 0.57 [95% CI, 0.38-0.84]) and symptomatic progression (RR, 0.58 [95% CI, 0.48-0.69]), and modestly reduced all-cause mortality when incorporating deaths occurring after a primary CW-defining event (RR, 0.860 [95% CI, 0.742-0.997]). However, the effects of PAH-specific therapies on CW only modestly correlated with their effects on mortality (R2trial, 0.35 [95% CI, 0.10-0.59]; P<0.0001), and the gradient in the treatment effect across component end points was large in the majority of trials. The weighted proportions of CW-defining events were hospitalization (33.5%) and symptomatic progression (32.3%), whereas death (6.7%), treatment escalation (5.6%), and transplantation/atrioseptostomy (0.2%) were infrequent. CW events were driven by the occurrence of events of major (49%) and mild-to-moderate (37%) importance to patients, with 14% of the events valued as critical. CONCLUSIONS PAH therapies significantly reduced CW events, but study-level CW is not a surrogate for mortality in PAH trials. Moreover, components of CW largely vary in frequency, response to therapy, and importance to patients and are thus not interchangeable. REGISTRATION URL: https://www.crd.york.ac.uk/PROSPERO; Unique identifier: CRD42020178949.
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Affiliation(s)
- Élodie Tremblay
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Camille Gosselin
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Vicky Mai
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Annie C Lajoie
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Roubi Kilo
- Pôle De Santé Publique, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, F-69310, Pierre-Bénite, France (R.K.)
| | - Jason Weatherald
- Department of Medicine, Division of Respiratory Medicine, Libin Cardiovascular Institute, University of Calgary, Canada (J.W.)
| | - Yves Lacasse
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Department of Medicine (Y.L., S.B., S.P.), Université Laval, Quebec City, Canada
| | - Sebastien Bonnet
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Department of Medicine (Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
| | - Jean-Christophe Lega
- Université de Lyon, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Centre national de la recherche scientifique, F-69100, Groupe d'Etude Multidisciplinaire des Maladies Thrombotiques, Department of Internal and Vascular Medicine, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, F-69310, Lyon, France (J.-C.L.)
| | - Steeve Provencher
- Institut Universitaire de Cardiologie et de Pneumologie de Québec Research Center (E.T., C.G., V.M., A.C.L., Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Department of Medicine (Y.L., S.B., S.P.), Université Laval, Quebec City, Canada.,Pulmonary Hypertension Research Group Quebec City, Canada (E.T., C.G., V.M., A.C.L., S.B., S.P.)
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20
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Implications of Oncology Trial Design and Uncertainties in Efficacy-Safety Data on Health Technology Assessments. Curr Oncol 2022; 29:5774-5791. [PMID: 36005193 PMCID: PMC9406873 DOI: 10.3390/curroncol29080455] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/10/2022] [Accepted: 08/11/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Advances in cancer medicines have resulted in tangible health impacts, but the magnitude of benefits of approved cancer medicines could vary greatly. Health Technology Assessment (HTA) is a multidisciplinary process used to inform resource allocation through a systematic value assessment of health technology. This paper reviews the challenges in conducting HTA for cancer medicines arising from oncology trial designs and uncertainties of safety-efficacy data. Methods: Multiple databases (PubMed, Scopus and Google Scholar) and grey literature (public health agencies and governmental reports) were searched to inform this policy narrative review. Results: A lack of robust efficacy-safety data from clinical trials and other relevant sources of evidence has made HTA for cancer medicines challenging. The approval of cancer medicines through expedited pathways has increased in recent years, in which surrogate endpoints or biomarkers for patient selection have been widely used. Using these surrogate endpoints has created uncertainties in translating surrogate measures into patient-centric clinically (survival and quality of life) and economically (cost-effectiveness and budget impact) meaningful outcomes, with potential effects on diverting scarce health resources to low-value or detrimental interventions. Potential solutions include policy harmonization between regulatory and HTA authorities, commitment to generating robust post-marketing efficacy-safety data, managing uncertainties through risk-sharing agreements, and using value frameworks. Conclusion: A lack of robust efficacy-safety data is a central problem for conducting HTA of cancer medicines, potentially resulting in misinformed resource allocation.
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21
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An efficient algorithm to assess multivariate surrogate endpoints in a causal inference framework. Comput Stat Data Anal 2022. [DOI: 10.1016/j.csda.2022.107494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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22
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Goldberg RM, Adams R, Buyse M, Eng C, Grothey A, André T, Sobrero AF, Lichtman SM, Benson AB, Punt CJA, Maughan T, Burzykowski T, Sommeijer D, Saad ED, Shi Q, Coart E, Chibaudel B, Koopman M, Schmoll HJ, Yoshino T, Taieb J, Tebbutt NC, Zalcberg J, Tabernero J, Van Cutsem E, Matheson A, de Gramont A. Clinical Trial Endpoints in Metastatic Cancer: Using Individual Participant Data to Inform Future Trials Methodology. J Natl Cancer Inst 2022; 114:819-828. [PMID: 34865086 PMCID: PMC9194619 DOI: 10.1093/jnci/djab218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/14/2021] [Accepted: 11/29/2021] [Indexed: 11/13/2022] Open
Abstract
Meta-analysis based on individual participant data (IPD) is a powerful methodology for synthesizing evidence by combining information drawn from multiple trials. Hitherto, its principal application has been in questions of clinical management, but an increasingly important use is in clarifying trials methodology, for instance in the selection of endpoints, as discussed in this review. In oncology, the Aide et Recherche en Cancérologie Digestive (ARCAD) Metastatic Colorectal Cancer Database is a leader in the use of IPD-based meta-analysis in methodological research. The ARCAD database contains IPD from more than 38 000 patients enrolled in 46 studies and continues to collect phase III trial data. Here, we review the principal findings of the ARCAD project in respect of endpoint selection and examine their implications for cancer trials. Analysis of the database has confirmed that progression-free survival (PFS) is no longer a valid surrogate endpoint predictive of overall survival in the first-line treatment of colorectal cancer. Nonetheless, PFS remains an endpoint of choice for most first-line trials in metastatic colorectal cancer and other solid tumors. Only substantial PFS effects are likely to translate into clinically meaningful benefits, and accordingly, we advocate an oncology research model designed to identify highly effective treatments in carefully defined patient groups. We also review the use of the ARCAD database in assessing clinical response including novel response metrics and prognostic markers. These studies demonstrate the value of IPD as a tool for methodological studies and provide a reference point for the expansion of this approach within clinical cancer research.
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Affiliation(s)
| | | | - Marc Buyse
- International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium
- Hasselt University, Hasselt, Belgium
| | - Cathy Eng
- Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Axel Grothey
- West Cancer Center and Research Institute, Germantown, TN, USA
| | | | | | | | - Al B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
| | | | - Tim Maughan
- Gray Institute of Radiation Oncology and Biology, University of Oxford, UK
| | - Tomasz Burzykowski
- International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium
- Hasselt University, Hasselt, Belgium
| | - Dirkje Sommeijer
- University of Amsterdam Academic Medical Centre and Flevohospital, Almere, the Netherlands
| | - Everardo D Saad
- International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium
- Dendrix Research, Sao Paulo, Brazil
| | | | - Elisabeth Coart
- International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium
| | | | | | | | | | - Julien Taieb
- Georges Pompidou European Hospital, Paris, France
| | | | - John Zalcberg
- Monash University, School of Public Health, Australia
| | - Josep Tabernero
- Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO), Barcelona, Spain
| | | | | | - Aimery de Gramont
- Hôpital Franco-Britannique, Paris, France
- Fondation ARCAD , Paris, France
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23
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Korn EL, Allegra CJ, Freidlin B. Clinical Benefit Scales and Trial Design: Some Statistical Issues. J Natl Cancer Inst 2022; 114:1222-1227. [PMID: 35583264 DOI: 10.1093/jnci/djac099] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/26/2022] [Accepted: 05/04/2022] [Indexed: 11/14/2022] Open
Abstract
Recently developed clinical-benefit outcome scales by the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO) allow standardized objective evaluation of outcomes of randomized clinical trials. However, incorporation of clinical-benefit outcome scales into trial designs highlights a number of statistical issues: the relationship between minimal clinical benefit and the target treatment-effect alternative used in the trial design, designing trials to assess long-term benefit, potential problems with using a trial endpoint that is not overall survival, and how to incorporate subgroup analyses into the trial design. Using the ESMO Magnitude of Clinical Benefit Scale as a basis for discussion, we review what these issues are and how they can guide the choice of trial-design target effects, appropriate endpoints, and pre-specified subgroup analyses to increase the chances that the resulting trial outcomes can be appropriately evaluated for clinical benefit.
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Affiliation(s)
- Edward L Korn
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - Carmen J Allegra
- Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA.,Division of Hematology and Oncology, Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Boris Freidlin
- Biometric Research Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
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24
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Hayashi-Mercado R, Pérez-Montaño C, Reyes-Sánchez J, Ramírez-Estudillo A. Findings of uncertain significance by optical coherence tomography (OCT) as prognostic factors in neovascular age-related macular degeneration (nAMD) treated with ranibizumab. Int J Retina Vitreous 2022; 8:29. [PMID: 35449032 PMCID: PMC9022246 DOI: 10.1186/s40942-022-00379-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/30/2022] [Indexed: 11/25/2022] Open
Abstract
Background Biomarkers hold great promise for personalized medicine as information gained from diagnostic or progression markers can be used to tailor treatment to the individual for highly effective intervention in the disease process. Methods The aim of this retrospective study was to evaluate the association between visual outcome and the presence of findings of uncertain significance by optical coherence tomography (OCT) pre and post loading dose in patients with neovascular age-related macular degeneration (nAMD) treated with ranibizumab. Results Univariate analysis revealed a higher letter gain in those with presence of onion sign (+ 5.6 ETDRS letters, p = 0.04) absence of prechoroidal cleft (+ 3.7 ETDRS letters, p = 0.04), intraretinal pseudocysts (+4.8 ETDRS letters, p = 0.002), subretinal pseudocysts (+ 4.6 ETDRS letters, p = 0.005) and choroidal caverns (+ 4.4 ETDRS, letters p = 0.0065). Conclusions The presence of prechoroidal cleft, intraretinal and subretinal pseudocysts and choroidal caverns were associated with lower visual gains. Moreover, we found that the onion sign is related as a biomarker of good prognostics. Trial registration Registration number: 2021R13B2. Date of registration: 01/05/2020
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Affiliation(s)
- Ricardo Hayashi-Mercado
- Retina and Vitreous Department, Fundación Hospital Nuestra Señora de La Luz, Ezequiel Montes 135, 06030, Mexico City, Mexico.
| | - Carla Pérez-Montaño
- Retina and Vitreous Department, Fundación Hospital Nuestra Señora de La Luz, Ezequiel Montes 135, 06030, Mexico City, Mexico
| | - Jaime Reyes-Sánchez
- Department of Population and Publica Health Sciences, Keck School of Medicine, University of Southern California, 1975 Zonal Ave, 90033, Los Angeles, CA, USA
| | - Abel Ramírez-Estudillo
- Retina and Vitreous Department, Fundación Hospital Nuestra Señora de La Luz, Ezequiel Montes 135, 06030, Mexico City, Mexico
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25
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Correlation between treatment effects on response rate and progression-free survival and overall survival in trials of targeted therapies in molecularly enriched populations. ESMO Open 2022; 7:100398. [PMID: 35183043 PMCID: PMC9058889 DOI: 10.1016/j.esmoop.2022.100398] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 01/06/2022] [Accepted: 01/18/2022] [Indexed: 11/29/2022] Open
Abstract
Background The number of randomized trials of agents targeting oncogene-addicted tumors has surged in the past 10 years. Using a meta-analysis, we explored whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in progression-free survival (PFS) or overall survival (OS) in populations with oncogene-addicted cancer. Patients and methods Using commercial text mining software I2E, we searched ClinicalTrials.gov and MEDLINE databases for randomized, phase III trials based on prospectively defined criteria, including (i) use of agents targeting EGFR activating mutations, ALK rearrangements, BRAF V600E or V600K mutations, and BCR-ABL fusion protein; (ii) molecularly enriched trial population or subpopulation; (iii) control arm only randomized to chemo/cytotoxic therapy. Correlative analyses were performed using ORR, OS, and PFS data from trials that met these criteria. Results A total of 62 trials were identified; 15 met all of the prespecified criteria. The ORR effect size (both the difference in ORR between arms and the log odds ratio) and log PFS hazard ratio were strongly correlated: –0.78 (P = 0.0007) for the ORR difference model; –0.74 (P = 0.0017) for the log odds ratio model. ORR effect size was positively correlated with the log OS hazard ratio, but more weakly: –0.67 (P = 0.013) for the ORR difference model and –0.58 (P = 0.036) for the log odds ratio model. Analysis of the treatment effects between OS and PFS found no correlation. Conclusions These analyses identified a strong correlation between treatment effects on ORR and PFS in randomized clinical trials investigating agents targeting oncogene-driven cancers. A weaker correlation was observed between ORR and OS. These meta-analysis results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.
Meta-analysis of trials comparing an agent targeting a primary oncogenic driver versus nontargeted therapy. Correlative analysis showed that ORR effect size and log PFS HR were strongly correlated. ORR effect size was positively correlated with the log OS HR ratio, but more weakly. Analysis of the treatment effects between OS and PFS found no correlation. Results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.
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26
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Marques-Magalhães Â, Cruz T, Costa ÂM, Estêvão D, Rios E, Canão PA, Velho S, Carneiro F, Oliveira MJ, Cardoso AP. Decellularized Colorectal Cancer Matrices as Bioactive Scaffolds for Studying Tumor-Stroma Interactions. Cancers (Basel) 2022; 14:cancers14020359. [PMID: 35053521 PMCID: PMC8773780 DOI: 10.3390/cancers14020359] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/02/2022] [Accepted: 01/06/2022] [Indexed: 12/12/2022] Open
Abstract
More than a physical structure providing support to tissues, the extracellular matrix (ECM) is a complex and dynamic network of macromolecules that modulates the behavior of both cancer cells and associated stromal cells of the tumor microenvironment (TME). Over the last few years, several efforts have been made to develop new models that accurately mimic the interconnections within the TME and specifically the biomechanical and biomolecular complexity of the tumor ECM. Particularly in colorectal cancer, the ECM is highly remodeled and disorganized and constitutes a key component that affects cancer hallmarks, such as cell differentiation, proliferation, angiogenesis, invasion and metastasis. Therefore, several scaffolds produced from natural and/or synthetic polymers and ceramics have been used in 3D biomimetic strategies for colorectal cancer research. Nevertheless, decellularized ECM from colorectal tumors is a unique model that offers the maintenance of native ECM architecture and molecular composition. This review will focus on innovative and advanced 3D-based models of decellularized ECM as high-throughput strategies in colorectal cancer research that potentially fill some of the gaps between in vitro 2D and in vivo models. Our aim is to highlight the need for strategies that accurately mimic the TME for precision medicine and for studying the pathophysiology of the disease.
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Affiliation(s)
- Ângela Marques-Magalhães
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- INEB-Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- ICBAS-School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
| | - Tânia Cruz
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- INEB-Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
| | - Ângela Margarida Costa
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- INEB-Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
| | - Diogo Estêvão
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- INEB-Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- ICBAS-School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
| | - Elisabete Rios
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- IPATIMUP-Institute of Pathology and Molecular Immunology, University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário São João, 4200-319 Porto, Portugal
| | - Pedro Amoroso Canão
- Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário São João, 4200-319 Porto, Portugal
| | - Sérgia Velho
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- IPATIMUP-Institute of Pathology and Molecular Immunology, University of Porto, 4200-135 Porto, Portugal
| | - Fátima Carneiro
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- IPATIMUP-Institute of Pathology and Molecular Immunology, University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário São João, 4200-319 Porto, Portugal
| | - Maria José Oliveira
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- INEB-Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- ICBAS-School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
- Department of Pathology, Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal;
| | - Ana Patrícia Cardoso
- i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal; (Â.M.-M.); (T.C.); (Â.M.C.); (D.E.); (E.R.); (S.V.); (F.C.); (M.J.O.)
- INEB-Institute of Biomedical Engineering, University of Porto, 4200-135 Porto, Portugal
- Correspondence: ; Tel.: +351-22-607-4900
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Raj CJ, Aishwarya CVS, Mounika KVSSN, Mishra B, Sumithra B, Vishal B, Mandal SK. Deciphering the Nexus Between Oxidative Stress and Spermatogenesis: A Compendious Overview. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1391:1-16. [PMID: 36472813 DOI: 10.1007/978-3-031-12966-7_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Oxidative stress (OS) and reactive oxygen species (ROS) are one of the main reasons for the multifactorial concern - male infertility. ROS are active components of cellular metabolism that are intrinsic to cellular functioning and are present at minimal and unreactive levels in normal cells. They are an integral component of the sperm developmental physiology, capacitation, and function. As said "anything in excess is poison," so is the case with ROS. These, when produced in excess to the antioxidants present in the seminal plasma, cause multiple malformations during the process of spermatogenesis such as lipid peroxidation, interfere with capacitation, sperm DNA fragmentation and damage to the membrane of the sperm which in turn reduces the motility of the sperm and its ability to fuse with the oocyte. Exposure of spermatozoa to oxidative stress is a major causative agent of male infertility. Thus, a delicate balance between the beneficial and detrimental effects of ROS for proper functions is of utter importance. In this chapter, the influence of ROS in OS which is a key player in male infertility along with the diagnosis, available treatment, and prevention of extensive ROS buildup within the spermatozoa are highlighted.
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Affiliation(s)
- Caleb Joel Raj
- Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad, Telangana, India
| | - C V S Aishwarya
- Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad, Telangana, India
| | - K V S S N Mounika
- Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad, Telangana, India
| | - Bishwambhar Mishra
- Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad, Telangana, India
| | - B Sumithra
- Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad, Telangana, India
| | - Bhushan Vishal
- School of Biological Sciences, Nanyang Technology University, Singapore, Singapore
| | - Sanjeeb Kumar Mandal
- Department of Biotechnology, Chaitanya Bharathi Institute of Technology, Hyderabad, Telangana, India.
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28
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Weir IR, Rider JR, Trinquart L. Counterfactual mediation analysis in the multistate model framework for surrogate and clinical time-to-event outcomes in randomized controlled trials. Pharm Stat 2022; 21:163-175. [PMID: 34346173 PMCID: PMC8776584 DOI: 10.1002/pst.2159] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 06/25/2021] [Accepted: 07/20/2021] [Indexed: 01/03/2023]
Abstract
In cancer randomized controlled trials, surrogate endpoints are frequently time-to-event endpoints, subject to the competing risk from the time-to-event clinical outcome. In this context, we introduce a counterfactual-based mediation analysis for a causal assessment of surrogacy. We use a multistate model for risk prediction to account for both direct transitions towards the clinical outcome and indirect transitions through the surrogate outcome. Within the counterfactual framework, we define natural direct and indirect effects with a causal interpretation. Based on these measures, we define the proportion of the treatment effect on the clinical outcome mediated by the surrogate outcome. We estimate the proportion for both the cumulative risk and restricted mean time lost. We illustrate our approach by using 18-year follow-up data from the SPCG-4 randomized trial of radical prostatectomy for prostate cancer. We assess time to metastasis as a surrogate outcome for prostate cancer-specific mortality.
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Affiliation(s)
- Isabelle R. Weir
- Department of Biostatistics, Boston University School of Public Health,Center for Biostatistics in AIDS Research in the Department of Biostatistics, Harvard T.H. Chan School of Public Health
| | | | - Ludovic Trinquart
- Department of Biostatistics, Boston University School of Public Health,Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA,Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA,Corresponding author: Ludovic Trinquart, 35 Kneeland St, Boston MA 02111;
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29
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Lux MP, Ciani O, Dunlop WCN, Ferris A, Friedlander M. The Impasse on Overall Survival in Oncology Reimbursement Decision-Making: How Can We Resolve This? Cancer Manag Res 2021; 13:8457-8471. [PMID: 34795526 PMCID: PMC8592394 DOI: 10.2147/cmar.s328058] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/27/2021] [Indexed: 11/23/2022] Open
Abstract
Mature overall survival (OS) data are often unavailable at the time of regulatory and reimbursement decisions for a new cancer treatment. For patients with early-stage cancers treated with potentially curative treatments, demonstrating an OS benefit may take years and may be confounded by subsequent lines of therapy or crossover to the investigational treatment. For patients with advanced-stage cancers, mature OS data may be available but difficult to interpret for similar reasons. There are strong opinions about approval and reimbursement in the absence of mature OS data, with concerns over delay in patient access set against concerns about uncertainty in long-term benefit. This position paper reflects our individual views as patient advocate, clinician or health economist on one aspect of this debate. We look at payer decisions in the absence of mature OS data, considering when and how non-OS trial outcomes could inform decision-making and how uncertainty can be addressed beyond the trial, supporting these views with evidence from the literature. We consider when it is reasonable for payers to expect or not expect mature OS data at the initial reimbursement decision (based on criteria such as cancer stage and treatment efficacy) acknowledging that there are settings in which mature OS data are expected. We propose flexible strategies for generating and appraising patient-relevant evidence, including context-relevant endpoints and quality of life measures, when survival rates are good and mature OS data are not expected. We note that fair reimbursement is important; this means valuing patient benefit as shown through prespecified endpoints and reappraising if there is ongoing uncertainty or failure to show a sustained benefit. We suggest that reimbursement systems continue to evolve to align with scientific advances, because innovation is only meaningful if readily accessible to patients. The proposed strategies have the potential to promote thorough assessment of potential benefit to patients and lead to timely access to effective medicines.
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Affiliation(s)
- Michael Patrick Lux
- Department of Gynecology and Obstetrics, Frauenklinik St. Louise Paderborn, St. Josefs-Krankenhaus Salzkotten, Frauen- und Kinderklinik St. Louise Paderborn, Paderborn, Germany
| | - Oriana Ciani
- Centre for Research on Health and Social Care Management, SDA Bocconi, Milan, Italy
| | | | | | - Michael Friedlander
- Prince of Wales Clinical School, University of New South Wales and Department of Medical Oncology, The Prince of Wales Hospital, Sydney, NSW, Australia
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30
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Bruix J, Chan SL, Galle PR, Rimassa L, Sangro B. Systemic treatment of hepatocellular carcinoma: An EASL position paper. J Hepatol 2021; 75:960-974. [PMID: 34256065 DOI: 10.1016/j.jhep.2021.07.004] [Citation(s) in RCA: 244] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/22/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022]
Abstract
The last 5 years have witnessed relevant advances in the systemic treatment of hepatocellular carcinoma. New data have emerged since the development of the EASL Clinical Practice Guidelines on the management of hepatocellular carcinoma in 2018. Drugs licensed in some countries now include 4 oral multi-tyrosine kinase inhibitors (sorafenib, lenvatinib, regorafenib and cabozantinib), 1 anti-angiogenic antibody (ramucirumab) and 4 immune checkpoint inhibitors, alone or in combination (atezolizumab in combination with bevacizumab, ipilimumab in combination with nivolumab, nivolumab and pembrolizumab in monotherapy). Prolonged survival in excess of 2 years can be expected in most patients with sensitive tumours and well-preserved liver function that renders them fit for sequential therapies. With different choices available in any given setting, the robustness of the evidence of efficacy and a correct matching of the safety profile of a given agent with patient characteristics and preferences are key in making sound therapeutic decisions. The recommendations in this document amend the previous EASL Clinical Practice Guidelines and aim to help clinicians provide the best possible care for patients today. In view of several ongoing and promising trials, further advances in systemic therapy of hepatocellular carcinoma are foreseen in the near future and these recommendations will have to be updated regularly.
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Affiliation(s)
- Jordi Bruix
- BCLC Group, Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBEREHD, Barcelona, Spain
| | - Stephen L Chan
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China
| | | | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Bruno Sangro
- Liver Unit and HPB Oncology Area, Clinica Universidad de Navarra-IDISNA and CIBEREHD, Pamplona, Spain.
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31
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Lengliné E, Peron J, Vanier A, Gueyffier F, Kouzan S, Dufour P, Guillot B, Blondon H, Clanet M, Cochat P, Degos F, Chevret S, Grande M, Putzolu J. Basket clinical trial design for targeted therapies for cancer: a French National Authority for Health statement for health technology assessment. Lancet Oncol 2021; 22:e430-e434. [PMID: 34592192 DOI: 10.1016/s1470-2045(21)00337-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 11/16/2022]
Abstract
During the past decade, health technology assessment bodies have faced new challenges in establishing the benefits of new drugs for individuals and health-care systems. A topic of increasing importance to the field of oncology is the so-called agnostic regulatory approval of targeted therapies for cancer (independent of tumour location and histology) granted on the basis of basket trials. Basket trials in oncology offer the advantage of simultaneously evaluating treatments for multiple tumours, even rare cancers, in a single clinical trial. To address the novel challenges introduced by these trials, an interdisciplinary panel was convened on behalf of the Transparency Committee of the French National Authority for Health to clarify an approach designed to guarantee a transparent, reproducible, and fair assessment of histology-agnostic treatments for reimbursement by the French National Health Insurance Fund. The requirements of this approach include the need for randomisation, clinically relevant endpoints, appropriate correction for multiple significance testing, characterisation of subgroup heterogeneity, and validation of underlying biomarker assays. A prospectively designated external control is encouraged when the implementation of a direct comparison is deemed infeasible. We also underline the importance of recording outcomes from basket trials in a registry for use as future external controls.
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Affiliation(s)
| | - Julien Peron
- Medical Oncology Department, Cancer Institute of the Hospices Civils of Lyon, Lyon, France
| | - Antoine Vanier
- Unit of Methodology Biostatistics and Data Management, INSERM CIC1415, University Hospital of Tours, Tours, France
| | - François Gueyffier
- UMR 5558 CNRS Lyon, Claude Bernard University Lyon 1, Lyon, France; Public Health Department, Lyon University Hospitals, Lyon, France
| | - Serge Kouzan
- Pulmonary Department, Centre Regional Hospital, Chambery, France
| | - Patrick Dufour
- Medical and Surgical Division of Digestive Pathology, Hautepierre Hospital, Louis Pasteur University, Strasbourg, France
| | - Bernard Guillot
- Dermatology Department, Saint Eloi University Hospital, Montpellier, France
| | - Hugues Blondon
- Department of Gastroenterology and Hepatology, Versailles Hospital, Le Chesnay, France
| | - Michel Clanet
- Pharmaceuticals Assessment Department, French National Authority for Health, Saint-Denis, France
| | - Pierre Cochat
- Pharmaceuticals Assessment Department, French National Authority for Health, Saint-Denis, France
| | - Françoise Degos
- Pharmaceuticals Assessment Department, French National Authority for Health, Saint-Denis, France
| | - Sylvie Chevret
- Biostatistics Department, Saint-Louis Hospital, Paris, France
| | - Mathilde Grande
- Pharmaceuticals Assessment Department, French National Authority for Health, Saint-Denis, France
| | - Jade Putzolu
- Pharmaceuticals Assessment Department, French National Authority for Health, Saint-Denis, France.
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Zhou J, Jiang X, Amy Xia H, Wei P, Hobbs BP. A survival mediation model with Bayesian model averaging. Stat Methods Med Res 2021; 30:2413-2427. [PMID: 34448657 DOI: 10.1177/09622802211037069] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Determining the extent to which a patient is benefiting from cancer therapy is challenging. Criteria for quantifying the extent of "tumor response" observed within a few cycles of treatment have been established for various types of solids as well as hematologic malignancies. These measures comprise the primary endpoints of phase II trials. Regulatory approvals of new cancer therapies, however, are usually contingent upon the demonstration of superior overall survival with randomized evidence acquired with a phase III trial comparing the novel therapy to an appropriate standard of care treatment. With nearly two-thirds of phase III oncology trials failing to achieve statistically significant results, researchers continue to refine and propose new surrogate endpoints. This article presents a Bayesian framework for studying relationships among treatment, patient subgroups, tumor response, and survival. Combining classical components of a mediation analysis with Bayesian model averaging, the methodology is robust to model misspecification among various possible relationships among the observable entities. A posterior inference is demonstrated via an application to a randomized controlled phase III trial in metastatic colorectal cancer. Moreover, the article details posterior predictive distributions of survival and statistical metrics for quantifying the extent of direct and indirect, or tumor response mediated treatment effects.
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Affiliation(s)
- Jie Zhou
- Quantitative Health Sciences, 2569Cleveland Clinic, USA
| | - Xun Jiang
- 13498Center for Design and Analysis, Amgen, USA
| | | | - Peng Wei
- 4002The University of Texas MD Anderson Cancer Center, USA
| | - Brian P Hobbs
- Dell Medical School, 12330The University of Texas at Austin, USA
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33
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Kilo R, Laporte S, Arab R, Mainbourg S, Provencher S, Grenet G, Bertoletti L, Villeneuve L, Cucherat M, Lega JC. Meta-regression of randomized control trials with antithrombotics: weak correlation between net clinical benefit and all cause-mortality. Sci Rep 2021; 11:14728. [PMID: 34282198 PMCID: PMC8290002 DOI: 10.1038/s41598-021-94160-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/28/2021] [Indexed: 11/16/2022] Open
Abstract
This study aimed to explore the validity of the use of the net clinical benefit (NCB), i.e. the sum of major bleeding and thrombotic events, as a potential surrogate for all-cause mortality in clinical trials assessing antithrombotics. Published randomized controlled trials testing anticoagulants in the prevention or treatment of venous thromboembolism (VTE) and non-valvular atrial fibrillation (NVAF) were systematically reviewed. The validity of NCB as a surrogate endpoint was estimated by calculating the strength of correlation of determination (R2) and its 95% confidence interval (CI) between the relative risks of NCB and all-cause mortality. Amongst the 125 trials retrieved, the highest R2trial values were estimated for NVAF (R2trial = 0.41, 95% CI [0.03; 0.48]), and acute VTE (R2trial = 0.30, 95% CI [0.04; 0.84]). Conversely, the NCB did not correlate with all-cause mortality in prevention studies with medical (R2trial = 0.12, 95% CI [0.00; 0.36]), surgical (R2trial = 0.05, 95% CI [0.00; 0.23]), and cancer patients (R2trial = 0.006, 95% CI [0.00; 1.00]). A weak correlation between NCB and all cause-mortality was found in NVAF and acute VTE, whereas no correlation was observed in clinical situations where the mortality rate was low. Consequently, NCB should not be considered a surrogate outcome for all cause-mortality in anticoagulation trials.
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Affiliation(s)
- Roubi Kilo
- Hospices Civils de Lyon, Hôpital Lyon Sud, Service de Recherche Et D'Epidémiologie Cliniques, Lyon, France. .,Univ Lyon, Université Claude Bernard Lyon 1 - UMR CNRS 5558, Laboratoire de Biométrie Evolutive, Equipe Evaluation Et Modélisation Des Effets Thérapeutiques, Lyon, France. .,Pôle de Santé Publique, Hospices Civils de Lyon, Hôpital Lyon Sud, Chemin du Grand Revoyet, 69495, Pierre-Bénite, France.
| | - Silvy Laporte
- Unité De Recherche Clinique, Innovation, Pharmacologie, Hôpital Nord, CHU De Saint-Étienne, Saint-Etienne, France.,INSERM, UMR1059, Equipe Dysfonction Vasculaire Et Hémostase, Université Jean-Monnet, Saint-Etienne, France
| | - Rama Arab
- Univ Lyon, Université Claude Bernard Lyon 1 - UMR CNRS 5558, Laboratoire de Biométrie Evolutive, Equipe Evaluation Et Modélisation Des Effets Thérapeutiques, Lyon, France
| | - Sabine Mainbourg
- Service De Médecine Interne Et Vasculaire, Hospices Civils De Lyon, Hôpital Lyon Sud, Lyon, France.,Univ Lyon, Université Claude Bernard Lyon 1 - UMR CNRS 5558, Laboratoire de Biométrie Evolutive, Equipe Evaluation Et Modélisation Des Effets Thérapeutiques, Lyon, France
| | - Steeve Provencher
- Pneumologue, Centre De Recherche De L'institut Universitaire De Cardiologie Et De Pneumologie De Québec, Québec, Canada
| | - Guillaume Grenet
- Service Hospitalo Universitaire de PharmacoToxicologie, Pôle de Santé Publique, Hopsices Civils De Lyon, Lyon, France
| | - Laurent Bertoletti
- Service De Médecine Vasculaire Et Thérapeutique, Chu de Saint-Étienne, France.,INSERM, UMR1059, Equipe Dysfonction Vasculaire Et Hémostase, Université Jean-Monnet; INSERM, CIC-1408, CHU Saint-Etienne, 42055, Saint-Etienne, France
| | - Laurent Villeneuve
- Hospices Civils de Lyon, Hôpital Lyon Sud, Service de Recherche Et D'Epidémiologie Cliniques, 69495, Pierre-Bénite, France.,Université Lyon-1, EA 3738 CICLY, 69921, Oullins Cedex, Lyon, France
| | - Michel Cucherat
- Univ Lyon, Université Claude Bernard Lyon 1 - UMR CNRS 5558, Laboratoire de Biométrie Evolutive, Equipe Evaluation Et Modélisation Des Effets Thérapeutiques, Lyon, France
| | - Jean-Christophe Lega
- Service De Médecine Interne Et Vasculaire, Hospices Civils De Lyon, Hôpital Lyon Sud, Lyon, France.,Univ Lyon, Université Claude Bernard Lyon 1 - UMR CNRS 5558, Laboratoire de Biométrie Evolutive, Equipe Evaluation Et Modélisation Des Effets Thérapeutiques, Lyon, France
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34
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Grieve S, Ding K, Moore J, Finniss M, Ray A, Lees M, Hossain F, Murugesan A, Agar J, Acar C, Taylor J, Shepherd FA, Reiman T. Immunohistochemical validation study of 15-gene biomarker panel predictive of benefit from adjuvant chemotherapy in resected non-small-cell lung cancer: analysis of JBR.10. ESMO Open 2021; 5:S2059-7029(20)30069-7. [PMID: 32220948 PMCID: PMC7174014 DOI: 10.1136/esmoopen-2020-000679] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/11/2020] [Accepted: 02/12/2020] [Indexed: 12/18/2022] Open
Abstract
Objective There are no validated approaches to predict benefit from adjuvant chemotherapy for resected patients with non-small-cell lung cancer (NSCLC). The aim of this study was to translate a 15-gene mRNA expression profile published by Zhu et al, shown to be prognostic and predictive of benefit, into a readily applicable immunohistochemistry (IHC) panel. Methods For seven of the genes in the gene expression profile (GEP) for which suitable commercial antibodies were available, we semiquantitatively assessed the IHC expression and prognostic significance for 173 patients treated at the Saint John Regional Hospital (SJRH). Cut-offs for high and low expression were defined for each marker and applied to IHC scores from 291 of the 482 patients in JBR.10, including patients on both the adjuvant chemotherapy and observation arms. The prognostic and predictive value of these markers on overall survival (OS) or recurrence-free survival (RFS) was assessed by Cox regression models. Results In the SJRH cohort, in 62 patients with resected stage II–III NSCLC, the prognostic significance of IHC assays for four proteins were concordant with Zhu’s GEP results. Low FOSL2 (OS, HR=0.15; p=0.0001; RFS, HR=0.14; p<0.0001) and high STMN2 (RFS, HR=2.501; p=0.0197) were adverse prognostic factors. Low ATP1B1 and low TRIM14 expression trended toward worse OS and RFS. Validation of these markers with JBR.10 patients failed to show prognostic significance either individually or in combined risk classifications. Additionally, the interaction between these markers and chemotherapy treatment in predicting OS (FOSL2, p=0.52; STMN2 p=0.14; ATP1B1, p=0.33; TRIM14, p=0.81) or RFS (FOSL2, p=0.63; STMN2, p=0.12; ATP1B1, p=0.66; TRIM14, p=0.57) did not reach significance, individually or in combination panels. Conclusions Zhu’s GEP could not be translated into an IHC panel predictive of benefit from adjuvant chemotherapy. Future predictive biomarker analysis in the adjuvant NSCLC setting may need to focus on novel therapies.
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Affiliation(s)
- Stacy Grieve
- Department of Biology, University of New Brunswick Saint John, Saint John, New Brunswick, Canada
| | - Keyue Ding
- Canadian Cancer Trials Group, Kingston, Ontario, Canada
| | - Jonathan Moore
- Department of Medicine, Dalhousie University, Saint John, New Brunswick, Canada
| | - Mathew Finniss
- Department of Medicine, Dalhousie University, Saint John, New Brunswick, Canada
| | - Ayush Ray
- Department of Biology, University of New Brunswick Saint John, Saint John, New Brunswick, Canada
| | - Miranda Lees
- Department of Biology, University of New Brunswick Saint John, Saint John, New Brunswick, Canada
| | - Faisal Hossain
- Department of Biology, University of New Brunswick Saint John, Saint John, New Brunswick, Canada
| | - Alli Murugesan
- Department of Biology, University of New Brunswick Saint John, Saint John, New Brunswick, Canada.,Department of Medicine, Dalhousie University, Saint John, New Brunswick, Canada
| | - Jane Agar
- Department of Pathology, Saint John Regional Hospital, Saint John, New Brunswick, Canada
| | - Cenk Acar
- Department of Pathology, Saint John Regional Hospital, Saint John, New Brunswick, Canada
| | - James Taylor
- Canadian Cancer Trials Group, Kingston, Ontario, Canada
| | - Frances A Shepherd
- Department of Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Tony Reiman
- Department of Biology, University of New Brunswick Saint John, Saint John, New Brunswick, Canada .,Department of Medicine, Dalhousie University, Saint John, New Brunswick, Canada
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35
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Bruix J. Endpoints in clinical trials for liver cancer and their value in evidence-based clinical decision making: An unresolved Gordian knot. J Hepatol 2021; 74:1483-1488. [PMID: 33556420 DOI: 10.1016/j.jhep.2021.01.033] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/20/2022]
Abstract
The design and execution of clinical trials relies on strict definitions and criteria to avoid heterogeneous decisions by investigators at different sites. Ideally, definitions and decision making in clinical practice should mimic those implemented in trials, but this is not the case. Target populations are narrowly defined in trials, with the goal of evaluating activity and toxicity, and ultimately, demonstrating a survival benefit. In real-world practice, patients may not fit into the stringent inclusion/exclusion criteria of clinical trials. The evaluation of activity may also differ and the common policy to stop therapy upon progression may not be followed if progression is minor. Indeed, registration of progression may not reflect treatment failure or resistance. Parameters such as response according to RECIST criteria, time to progression and progression-free survival are not fully informative and cannot be assumed as a definitive surrogate for survival, which is the hardest endpoint in therapeutic cancer studies. This difference is because of the varying methods used to evaluate drug activity and tumour evolution, which ultimately dictates patient outcome. This expert opinion exposes the current discrepancies between research trials and clinical practice. Understanding the origin and limitations of such a conundrum should be the first step in refining the criteria that define drug activity, toxicity and treatment failure. Otherwise, evidence-based clinical practice and precision oncology will be an unattainable reality.
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Affiliation(s)
- Jordi Bruix
- BCLC Group, Liver Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBEREHD, Spain.
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36
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Gold ER. The fall of the innovation empire and its possible rise through open science. RESEARCH POLICY 2021; 50:104226. [PMID: 34083844 PMCID: PMC8024784 DOI: 10.1016/j.respol.2021.104226] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 01/26/2021] [Accepted: 02/28/2021] [Indexed: 12/13/2022]
Abstract
There is growing concern that the innovation system's ability to create wealth and attain social benefit is declining in effectiveness. This article explores the reasons for this decline and suggests a structure, the open science partnership, as one mechanism through which to slow down or reverse this decline. The article examines the empirical literature of the last century to document the decline. This literature suggests that the cost of research and innovation is increasing exponentially, that researcher productivity is declining, and, third, that these two phenomena have led to an overall flat or declining level of innovation productivity. The article then turns to three explanations for the decline - the growing complexity of science, a mismatch of incentives, and a balkanization of knowledge. Finally, the article explores the role that open science partnerships - public-private partnerships based on open access publications, open data and materials, and the avoidance of restrictive forms of intellectual property - can play in increasing the efficiency of the innovation system.
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Affiliation(s)
- E. Richard Gold
- McGill University, Faculty of Law and Faculty of Medicine, Canada
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37
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Vicente-Muñoz S, Lin P, Fan TWM, Lane AN. NMR Analysis of Carboxylate Isotopomers of 13C-Metabolites by Chemoselective Derivatization with 15N-Cholamine. Anal Chem 2021; 93:6629-6637. [PMID: 33880916 DOI: 10.1021/acs.analchem.0c04220] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
A substantial fraction of common metabolites contains carboxyl functional groups. Their 13C isotopomer analysis by nuclear magnetic resonance (NMR) is hampered by the low sensitivity of the 13C nucleus, the slow longitudinal relaxation for the lack of an attached proton, and the relatively low chemical shift dispersion of carboxylates. Chemoselective (CS) derivatization is a means of tagging compounds in a complex mixture via a specific functional group. 15N1-cholamine has been shown to be a useful CS agent for carboxylates, producing a peptide bond that can be detected via 15N-attached H with high sensitivity in heteronuclear single quantum coherence experiments. Here, we report an improved method of derivatization and show how 13C-enrichment at the carboxylate and/or the adjacent carbon can be determined via one- and two-bond coupling of the carbons adjacent to the cholamine 15N atom in the derivatives. We have applied this method for the determination of 13C isotopomer distribution in the extracts of A549 cell culture and liver tissue from a patient-derived xenograft mouse.
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Affiliation(s)
- Sara Vicente-Muñoz
- Center for Environmental and Systems Biochemistry, Markey Cancer Center, and Dept. of Toxicology & Cancer Biology, University of Kentucky, 789 S. Limestone Street, Lexington, Kentucky 40536, United States
| | - Penghui Lin
- Center for Environmental and Systems Biochemistry, Markey Cancer Center, and Dept. of Toxicology & Cancer Biology, University of Kentucky, 789 S. Limestone Street, Lexington, Kentucky 40536, United States
| | - Teresa W-M Fan
- Center for Environmental and Systems Biochemistry, Markey Cancer Center, and Dept. of Toxicology & Cancer Biology, University of Kentucky, 789 S. Limestone Street, Lexington, Kentucky 40536, United States
| | - Andrew N Lane
- Center for Environmental and Systems Biochemistry, Markey Cancer Center, and Dept. of Toxicology & Cancer Biology, University of Kentucky, 789 S. Limestone Street, Lexington, Kentucky 40536, United States
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Advani D, Sharma S, Kumari S, Ambasta RK, Kumar P. Precision Oncology, Signaling and Anticancer Agents in Cancer Therapeutics. Anticancer Agents Med Chem 2021; 22:433-468. [PMID: 33687887 DOI: 10.2174/1871520621666210308101029] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 01/05/2021] [Accepted: 01/12/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND The global alliance for genomics and healthcare facilities provides innovational solutions to expedite research and clinical practices for complex and incurable health conditions. Precision oncology is an emerging field explicitly tailored to facilitate cancer diagnosis, prevention and treatment based on patients' genetic profile. Advancements in "omics" techniques, next-generation sequencing, artificial intelligence and clinical trial designs provide a platform for assessing the efficacy and safety of combination therapies and diagnostic procedures. METHOD Data were collected from Pubmed and Google scholar using keywords: "Precision medicine", "precision medicine and cancer", "anticancer agents in precision medicine" and reviewed comprehensively. RESULTS Personalized therapeutics including immunotherapy, cancer vaccines, serve as a groundbreaking solution for cancer treatment. Herein, we take a measurable view of precision therapies and novel diagnostic approaches targeting cancer treatment. The contemporary applications of precision medicine have also been described along with various hurdles identified in the successful establishment of precision therapeutics. CONCLUSION This review highlights the key breakthroughs related to immunotherapies, targeted anticancer agents, and target interventions related to cancer signaling mechanisms. The success story of this field in context to drug resistance, safety, patient survival and in improving quality of life is yet to be elucidated. We conclude that, in the near future, the field of individualized treatments may truly revolutionize the nature of cancer patient care.
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Affiliation(s)
- Dia Advani
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Sudhanshu Sharma
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Smita Kumari
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory Shahbad Daulatpur, Bawana Road, Delhi 110042. India
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Garcia JS, Swords RT, Roboz GJ, Jacoby MA, Garcia-Manero G, Hong WJ, Yang X, Zhou Y, Platzbecker U, Steensma DP, Wolff JE, Fenaux P. A systematic review of higher-risk myelodysplastic syndromes clinical trials to determine the benchmark of azacitidine and explore alternative endpoints for overall survival. Leuk Res 2021; 104:106555. [PMID: 33705966 DOI: 10.1016/j.leukres.2021.106555] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 12/29/2022]
Abstract
The hypomethylating agent azacitidine can prolong overall survival (OS) in patients with higher risk-myelodysplastic syndromes (HR-MDS) compared to conventional regimens. However, outcomes differ largely between studies, making it challenging to determine the contribution of novel therapies added to azacitidine. Further, a discrepancy is seen between complete (CR) or partial (PR) response rates and OS improvement with azacitidine, making it challenging to rely on earlier endpoints than OS. We conducted a systematic literature search and study-level systematic review of 237 clinical studies to better understand outcomes for HR-MDS patients treated with azacitidine. Pooled marrow CR was 9% (N = 2654; 95% CI: 6-13 %), CR rate was 17 % (N = 6943; 95% CI: 15-20 %), and median OS (mOS) was 18.6 months (N = 2820; 95% CI: 15.3-21.9). A weak correlation to mOS was detected with CR rate (207 patient cohorts, Pearson's r = 0.315; P < 0.0005), and a much stronger correlation with median progression-free survival (mPFS) (r=0.88, P = 3 × 10-14). Six-months progression-free survival rates correlated with 1-year OS rates but were only infrequently reported (N = 41 patient cohorts) therefore not allowing a robust recommendation for a surrogate to the established OS endpoint. Larger patient numbers and patient-level data appear necessary, especially for designing future clinical trials using azacitidine combinations.
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Affiliation(s)
| | | | - Gail J Roboz
- Weill Medical College of Cornell University and New York-Presbyterian Hospital, NY, NY, USA
| | - Meagan A Jacoby
- Washington University School of Medicine, St. Louis, MO, USA
| | | | | | | | | | | | | | | | - Pierre Fenaux
- Hôpital Saint-Louis, Assistance Publique - Hôpitaux de Paris, Université de Paris, Paris, France
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40
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Abstract
Objectives: CD43 can be useful in routine flow cytometry. We conducted a systematic review aiming to describe when CD43 is used by flow cytometry in malignant hematology and to determine its value in these settings. Methods: Systematic review of MEDLINE (search 'CD43' AND 'flow cytometry,' starting in 2010). Results: Twenty-one of 103 entries retrieved were included in this systematic review. CD43 is used in three settings: 1) in the classification of mature B cell lymphoproliferative disorders, 2) as part of a strategy to quantify residual disease in chronic lymphocytic leukemia (CLL) and 3) to help classify CD10-positive B cell populations. In this section, the published data is summarized, the clinical usefulness in each of these settings is evaluated and illustrative cases are shown. Conclusion: CD43 has a growing role in the diagnosis and management of B cell malignancies; it has become essential for the classification of B cell lymphoproliferative disorders and may be of help in the differential diagnosis of CD10-positive lymphomas by FC. It is also required for optimal quantification of CLL residual disease, which will soon be used to guide therapeutic decisions.
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Affiliation(s)
- Marc Sorigue
- Hematology Laboratory, ICO-Hospital Germans Trias I Pujol, Functional Cytomics- IJC, Universitat Autònoma De Barcelona , Badalona, Spain
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41
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Molecular and Functional Imaging in Central Nervous System Drug Development. Mol Imaging 2021. [DOI: 10.1016/b978-0-12-816386-3.00084-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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Alvarez-Cardona JA, Zhang KW, Mitchell JD, Zaha VG, Fisch MJ, Lenihan DJ. Cardiac Biomarkers During Cancer Therapy: Practical Applications for Cardio-Oncology. JACC: CARDIOONCOLOGY 2020; 2:791-794. [PMID: 34396295 PMCID: PMC8352269 DOI: 10.1016/j.jaccao.2020.08.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/19/2020] [Accepted: 08/21/2020] [Indexed: 01/16/2023]
Key Words
- BNP, B-type natriuretic peptide
- CV, cardiovascular
- ECG, electrocardiography
- EMBx, endomyocardial biopsy
- GLS, global longitudinal strain
- HF, heart failure
- HFpEF, heart failure with preserved ejection fraction
- LGE, late gadolinium enhancement
- LV, left ventricular
- LVEF, left ventricular ejection fraction
- NP, natriuretic peptide
- NT-proBNP, N-terminal pro–B-type natriuretic peptide
- TTE, transthoracic echocardiography
- amyloidosis
- anthracyclines
- biomarkers
- cMRI, cardiac magnetic resonance imaging
- cardiotoxicity
- chemotherapy
- detection
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Affiliation(s)
- Jose A. Alvarez-Cardona
- Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Kathleen W. Zhang
- Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Joshua D. Mitchell
- Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Vlad G. Zaha
- Division of Cardiology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center and Advanced Imaging Research Center, University of Texas Southwestern, Dallas, Texas, USA
| | - Michael J. Fisch
- Department of General Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Daniel J. Lenihan
- Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri, USA
- Address for correspondence: Dr. Daniel J Lenihan, Cardio-Oncology Center of Excellence, Cardiovascular Division, Washington University in St. Louis, 660 South Euclid Avenue, Campus Box 8086, St. Louis, Missouri 63110. @ICOSociety
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Zhu Y, Yu X, Thamphiwatana SD, Zheng Y, Pang Z. Nanomedicines modulating tumor immunosuppressive cells to enhance cancer immunotherapy. Acta Pharm Sin B 2020; 10:2054-2074. [PMID: 33304779 PMCID: PMC7714985 DOI: 10.1016/j.apsb.2020.08.010] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/18/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer immunotherapy has veered the paradigm of cancer treatment. Despite recent advances in immunotherapy for improved antitumor efficacy, the complicated tumor microenvironment (TME) is highly immunosuppressive, yielding both astounding and unsatisfactory clinical successes. In this regard, clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME. Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME. The immunosuppressive TME may even dampen the efficacy of antitumor immunity. Recently, some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment (TIME) for robust immunotherapeutic responses. In this review, we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy, especially those unique classes associated with the immunosuppressive effect. The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation. After introducing the various strategies, we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.
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Affiliation(s)
- Yuefei Zhu
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
- Key Laboratory of Smart Drug Delivery, School of Pharmacy, Fudan University, Ministry of Education, Shanghai 201203, China
| | - Xiangrong Yu
- Department of Medical Imaging, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai 519000, China
| | - Soracha D. Thamphiwatana
- Department of Biomedical Engineering, Faculty of Engineering, Mahidol University, Nakhon Pathom 73170, Thailand
| | - Ying Zheng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
| | - Zhiqing Pang
- Key Laboratory of Smart Drug Delivery, School of Pharmacy, Fudan University, Ministry of Education, Shanghai 201203, China
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Grigore B, Ciani O, Dams F, Federici C, de Groot S, Möllenkamp M, Rabbe S, Shatrov K, Zemplenyi A, Taylor RS. Surrogate Endpoints in Health Technology Assessment: An International Review of Methodological Guidelines. PHARMACOECONOMICS 2020; 38:1055-1070. [PMID: 32572825 DOI: 10.1007/s40273-020-00935-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
In the drive towards faster patient access to treatments, health technology assessment (HTA) agencies are increasingly faced with reliance on evidence from surrogate endpoints, leading to increased decision uncertainty. This study undertook an updated survey of methodological guidance for using surrogate endpoints across international HTA agencies. We reviewed HTA and economic evaluation methods guidance from European, Australian and Canadian HTA agencies. We considered how guidelines addressed the methods for handling surrogate endpoints, including (1) level of evidence, (2) methods of validation, and (3) thresholds of acceptability. Across the 73 HTA agencies surveyed, 29 (40%) had methodological guidelines that made specific reference to consideration of surrogate outcomes. Of the 45 methods documents analysed, the majority [27 (60%)] were non-technology specific, 15 (33%) focused on pharmaceuticals and three (7%) on medical devices. The principles of the European network for Health Technology Assessment (EUnetHTA) guidelines published in 2015 on the handling of surrogate endpoints appear to have been adopted by many European HTA agencies, i.e. preference for final patient-relevant outcomes and reliance on surrogate endpoints with biological plausibility and epidemiological evidence of the association between the surrogate and final endpoint. Only a small number of HTA agencies (UK National Institute for Care and Excellence; the German Institute for Medical Documentation and Information and Institute for Quality and Efficiency in Health Care; the Australian Pharmaceutical Benefits Advisory Committee; and the Canadian Agency for Drugs and Technologies in Health) have developed more detailed prescriptive criteria for the acceptance of surrogate endpoints, e.g. meta-analyses of randomised controlled trials showing strong association between the treatment effect on the surrogate and final outcomes. As the decision uncertainty associated with reliance on surrogate endpoints carries a risk to patients and society, there is a need for HTA agencies to develop more detailed methodological guidance for consistent selection and evaluation of health technologies that lack definitive final patient-relevant outcome evidence at the time of the assessment.
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Affiliation(s)
- Bogdan Grigore
- Evidence Synthesis and Modelling for Health Improvement, College of Medicine and Health, Institute of Health Research, University of Exeter, Exeter, UK.
| | - Oriana Ciani
- Evidence Synthesis and Modelling for Health Improvement, College of Medicine and Health, Institute of Health Research, University of Exeter, Exeter, UK
- Center for Research on Health and Social Care Management, SDA Bocconi, Milan, Italy
| | - Florian Dams
- KPM Center for Public Management, University of Bern, Bern, Switzerland
| | - Carlo Federici
- Center for Research on Health and Social Care Management, SDA Bocconi, Milan, Italy
| | - Saskia de Groot
- Institute for Medical Technology Assessment, Erasmus School of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, The Netherlands
| | - Meilin Möllenkamp
- Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany
| | - Stefan Rabbe
- Hamburg Center for Health Economics, Universität Hamburg, Hamburg, Germany
| | - Kosta Shatrov
- KPM Center for Public Management, University of Bern, Bern, Switzerland
| | - Antal Zemplenyi
- Syreon Research Institute, Budapest, Hungary
- Division of Pharmacoeconomics, Faculty of Pharmacy, University of Pécs, Pécs, Hungary
| | - Rod S Taylor
- Evidence Synthesis and Modelling for Health Improvement, College of Medicine and Health, Institute of Health Research, University of Exeter, Exeter, UK
- MRC/CSO Social and Public Health Sciences Unit and Robertson Centre for Biostatistics, Institute of Health and Well Being, University of Glasgow, Glasgow, Scotland
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45
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Taylor RS, Walker S, Ciani O, Warren F, Smart NA, Piepoli M, Davos CH. Exercise-based cardiac rehabilitation for chronic heart failure: the EXTRAMATCH II individual participant data meta-analysis. Health Technol Assess 2020; 23:1-98. [PMID: 31140973 DOI: 10.3310/hta23250] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Current national and international guidelines on the management of heart failure (HF) recommend exercise-based cardiac rehabilitation (ExCR), but do not differentiate this recommendation according to patient subgroups. OBJECTIVES (1) To obtain definitive estimates of the impact of ExCR interventions compared with no exercise intervention (control) on mortality, hospitalisation, exercise capacity and health-related quality of life (HRQoL) in HF patients; (2) to determine the differential (subgroup) effects of ExCR in HF patients according to their age, sex, left ventricular ejection fraction, HF aetiology, New York Heart Association class and baseline exercise capacity; and (3) to assess whether or not the change in exercise capacity mediates for the impact of the ExCR on final outcomes (mortality, hospitalisation and HRQoL), and determine if this is an acceptable surrogate end point. DESIGN This was an individual participant data (IPD) meta-analysis. SETTING An international literature review. PARTICIPANTS HF patients in randomised controlled trials (RCTs) of ExCR. INTERVENTIONS ExCR for at least 3 weeks compared with a no-exercise control, with 6 months' follow-up. MAIN OUTCOME MEASURES All-cause and HF-specific mortality, all-cause and HF-specific hospitalisation, exercise capacity and HRQoL. DATA SOURCES IPD from eligible RCTs. REVIEW METHODS RCTs from the Exercise Training Meta-Analysis of Trials for Chronic Heart Failure (ExTraMATCH/ExTraMATCH II) IPD meta-analysis and a 2014 Cochrane systematic review of ExCR (Taylor RS, Sagar VA, Davies EJ, Briscoe S, Coats AJ, Dalal H, et al. Exercise-based rehabilitation for heart failure. Cochrane Database Syst Rev 2014;4:CD003331). RESULTS Out of the 23 eligible RCTs (4398 patients), 19 RCTs (3990 patients) contributed data to this IPD meta-analysis. There was a wide variation in exercise programme prescriptions across included studies. Compared with control, there was no statistically significant difference in pooled time-to-event estimates in favour of ExCR, although confidence intervals (CIs) were wide: all-cause mortality had a hazard ratio (HR) of 0.83 (95% CI 0.67 to 1.04); HF-related mortality had a HR of 0.84 (95% CI 0.49 to 1.46); all-cause hospitalisation had a HR of 0.90 (95% CI 0.76 to 1.06); and HF-related hospitalisation had a HR of 0.98 (95% CI 0.72 to 1.35). There was a statistically significant difference in favour of ExCR for exercise capacity and HRQoL. Compared with the control, improvements were seen in the 6-minute walk test (6MWT) (mean 21.0 m, 95% CI 1.57 to 40.4 m) and Minnesota Living with Heart Failure Questionnaire score (mean -5.94, 95% CI -1.0 to -10.9; lower scores indicate improved HRQoL) at 12 months' follow-up. No strong evidence for differential intervention effects across patient characteristics was found for any outcomes. Moderate to good levels of correlation (R 2 trial > 50% and p > 0.50) between peak oxygen uptake (VO2peak) or the 6MWT with mortality and HRQoL were seen. The estimated surrogate threshold effect was an increase of 1.6 to 4.6 ml/kg/minute for VO2peak. LIMITATIONS There was a lack of consistency in how included RCTs defined and collected the outcomes: it was not possible to obtain IPD from all includable trials for all outcomes and patient-level data on exercise adherence was not sought. CONCLUSIONS In comparison with the no-exercise control, participation in ExCR improved the exercise and HRQoL in HF patients, but appeared to have no effect on their mortality or hospitalisation. No strong evidence was found of differential intervention effects of ExCR across patient characteristics. VO2peak and 6MWT may be suitable surrogate end points for the treatment effect of ExCR on mortality and HRQoL in HF. Future studies should aim to achieve a consensus on the definition of outcomes and promote reporting of a core set of HF data. The research team also seeks to extend current policies to encourage study authors to allow access to RCT data for the purpose of meta-analysis. STUDY REGISTRATION This study is registered as PROSPERO CRD42014007170. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Rod S Taylor
- Institute of Health Research, University of Exeter Medical School, Exeter, UK.,Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Sarah Walker
- Institute of Health Research, University of Exeter Medical School, Exeter, UK
| | - Oriana Ciani
- Institute of Health Research, University of Exeter Medical School, Exeter, UK.,Centre for Research on Health and Social Care Management, Bocconi University, Milan, Italy
| | - Fiona Warren
- Institute of Health Research, University of Exeter Medical School, Exeter, UK
| | - Neil A Smart
- School of Science and Technology, University of New England, Armidale, NSW, Australia
| | - Massimo Piepoli
- Heart Failure Unit, Cardiology, Guglielmo da Saliceto Hospital, Piacenza, Italy
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Sorigue M, Cañamero E, Sancho JM. Precision medicine in follicular lymphoma: Focus on predictive biomarkers. Hematol Oncol 2020; 38:625-639. [PMID: 32700331 DOI: 10.1002/hon.2781] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 07/16/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023]
Abstract
Current care for patients with follicular lymphoma (FL) offers most of them long-term survival. Improving it further will require careful patient selection. This review focuses on predictive biomarkers (ie, those whose outcome correlations depend on the treatment strategy) in FL, because awareness of what patient subsets benefit most or least from each therapy will help in this task. The first part of this review aims to summarize what biomarkers are predictive in FL, the magnitude of the effect and the quality of the evidence. We find predictive biomarkers in the setting of (a) indication of active treatment, (b) front-line induction (use of anthracyline-based regimens, CHOP vs bendamustine, addition of rituximab), (c) post-(front-line)induction (rituximab maintenance, radioimmunotherapy), and (d) relapse (hematopoietic stem cell transplant) and targeted agents. The second part of this review discusses the challenges of precision medicine in FL, including (a) cost, (b) clinical relevance considerations, and (c) difficulties over the broad implementation of biomarkers. We then provide our view on what biomarkers may become used in the next few years. We conclude by underscoring the importance of assessing the potential predictiveness of available biomarkers to improve patient care but also that there is a long road ahead before reaching their broad implementation due to remaining scientific, technological, and economic hurdles.
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Affiliation(s)
- Marc Sorigue
- Department of Hematology, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Eloi Cañamero
- Department of Hematology, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain
| | - Juan-Manuel Sancho
- Department of Hematology, ICO-Hospital Germans Trias i Pujol, Institut de Recerca Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain
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47
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Wu Z, Guymer RH. Can the Onset of Atrophic Age-Related Macular Degeneration Be an Acceptable Endpoint for Preventative Trials? Ophthalmologica 2020; 243:399-403. [PMID: 32805732 DOI: 10.1159/000510887] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/13/2020] [Indexed: 11/19/2022]
Abstract
The slowly progressive nature of age-related macular degeneration (AMD) means that establishing the efficacy of novel preventative treatments aiming to slow progression of disease, remains challenging, and where earlier endpoints are needed to improve their feasibility. This review examines whether the onset of atrophic AMD, as seen as anatomical signs on optical coherence tomography termed nascent geographic atrophy, could act as a useful surrogate endpoint for early intervention trials.
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Affiliation(s)
- Zhichao Wu
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia, .,Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia,
| | - Robyn H Guymer
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Victoria, Australia.,Ophthalmology, Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia
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48
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Stoppe C, Wendt S, Mehta NM, Compher C, Preiser JC, Heyland DK, Kristof AS. Biomarkers in critical care nutrition. Crit Care 2020; 24:499. [PMID: 32787899 PMCID: PMC7425162 DOI: 10.1186/s13054-020-03208-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/27/2020] [Indexed: 02/07/2023] Open
Abstract
The goal of nutrition support is to provide the substrates required to match the bioenergetic needs of the patient and promote the net synthesis of macromolecules required for the preservation of lean mass, organ function, and immunity. Contemporary observational studies have exposed the pervasive undernutrition of critically ill patients and its association with adverse clinical outcomes. The intuitive hypothesis is that optimization of nutrition delivery should improve ICU clinical outcomes. It is therefore surprising that multiple large randomized controlled trials have failed to demonstrate the clinical benefit of restoring or maximizing nutrient intake. This may be in part due to the absence of biological markers that identify patients who are most likely to benefit from nutrition interventions and that monitor the effects of nutrition support. Here, we discuss the need for practical risk stratification tools in critical care nutrition, a proposed rationale for targeted biomarker development, and potential approaches that can be adopted for biomarker identification and validation in the field.
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Affiliation(s)
- Christian Stoppe
- 3CARE—Cardiovascular Critical Care & Anesthesia Evaluation and Research, Aachen, Germany
- Department of Anesthesiology, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
| | - Sebastian Wendt
- 3CARE—Cardiovascular Critical Care & Anesthesia Evaluation and Research, Aachen, Germany
| | - Nilesh M. Mehta
- Department of Anesthesiology, Critical Care and Pain Medicine, Division of Critical Care Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, MA USA
| | - Charlene Compher
- Department of Biobehavioral Health Science, University of Pennsylvania and Clinical Nutrition Support Service, Hospital of the University of Pennsylvania, Philadelphia, PA USA
| | - Jean-Charles Preiser
- Erasme University Hospital, Université Libre de Bruxelles, 808 route de Lennik, B-1070 Brussels, Belgium
| | - Daren K. Heyland
- Department of Critical Care Medicine, Queen’s University, Angada 4, Kingston, ON K7L 2V7 Canada
- Clinical Evaluation Research Unit, Kingston General Hospital, Angada 4, Kingston, ON K7L 2V7 Canada
| | - Arnold S. Kristof
- Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program, Faculty of Medicine, Departments of Medicine and Critical Care, Research Institute of the McGill University Health Centre, 1001 Décarie Blvd., EM3.2219, Montreal, QC H4A 3J1 Canada
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49
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Huang M, O’Shaughnessy J, Zhao J, Haiderali A, Cortes J, Ramsey S, Briggs A, Karantza V, Aktan G, Qi CZ, Gu C, Xie J, Yuan M, Cook J, Untch M, Schmid P, Fasching PA. Evaluation of Pathologic Complete Response as a Surrogate for Long-Term Survival Outcomes in Triple-Negative Breast Cancer. J Natl Compr Canc Netw 2020; 18:1096-1104. [DOI: 10.6004/jnccn.2020.7550] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 02/18/2020] [Indexed: 11/17/2022]
Abstract
Background: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC. Methods: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs. Results: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS (P=.003), with a coefficient of determination of 0.68 (95% CI, 0.41–0.95). There was a weaker association between pCR and OS (P=.18), with a coefficient of determination of 0.24 (95% CI, 0.01–0.77). Consistent results were found in the exploratory analysis and sensitivity analyses. Conclusions: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.
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Affiliation(s)
- Min Huang
- 1Merck & Co., Inc., Kenilworth, New Jersey
| | - Joyce O’Shaughnessy
- 2Baylor University Medical Center, Texas Oncology, and U.S. Oncology, Dallas, Texas
| | - Jing Zhao
- 1Merck & Co., Inc., Kenilworth, New Jersey
| | | | - Javier Cortes
- 3IOB Institute of Oncology, Quironsalud Group, Madrid and Barcelona, Spain
- 4Vall d’Hebron Institute of Oncology, Barcelona, Spain
| | - Scott Ramsey
- 5Fred Hutchinson Cancer Research Center, and University of Washington, Seattle, Washington
| | - Andrew Briggs
- 6London School of Hygiene and Tropical Medicine, London, United Kingdom
| | | | | | | | - Chenyang Gu
- 8Analysis Group, Inc., Los Angeles, California
| | - Jipan Xie
- 8Analysis Group, Inc., Los Angeles, California
| | - Muhan Yuan
- 7Analysis Group, Inc., Boston, Massachusetts
| | - John Cook
- 9Complete HEOR Solutions, North Wales, Pennsylvania
| | - Michael Untch
- 10Department of Gynecology, Helios Klinikum Berlin-Buch, Berlin, Germany
| | - Peter Schmid
- 11Barts Cancer Institute, Queen Mary University of London, London, United Kingdom; and
| | - Peter A. Fasching
- 12Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
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50
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Fokas E, Glynne-Jones R, Appelt A, Beets-Tan R, Beets G, Haustermans K, Marijnen C, Minsky BD, Ludmir E, Quirke P, Sebag-Montefiore D, Garcia-Aguilar J, Gambacorta MA, Valentini V, Buyse M, Rödel C. Outcome measures in multimodal rectal cancer trials. Lancet Oncol 2020; 21:e252-e264. [PMID: 32359501 DOI: 10.1016/s1470-2045(20)30024-3] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 01/08/2020] [Accepted: 01/09/2020] [Indexed: 12/14/2022]
Abstract
There is a large variability regarding the definition and choice of primary endpoints in phase 2 and phase 3 multimodal rectal cancer trials, resulting in inconsistency and difficulty of data interpretation. Also, surrogate properties of early and intermediate endpoints have not been systematically assessed. We provide a comprehensive review of clinical and surrogate endpoints used in trials for non-metastatic rectal cancer. The applicability, advantages, and disadvantages of these endpoints are summarised, with recommendations on clinical endpoints for the different phase trials, including limited surgery or non-operative management for organ preservation. We discuss how early and intermediate endpoints, including patient-reported outcomes and involvement of patients in decision making, can be used to guide trial design and facilitate consistency in reporting trial results in rectal cancer.
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Affiliation(s)
- Emmanouil Fokas
- Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany; Frankfurt Cancer Institute, Frankfurt Germany.
| | | | - Ane Appelt
- Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Regina Beets-Tan
- Department of Radiology, The Netherlands Cancer Institute, Amsterdam, Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Geerard Beets
- Department of Surgery, The Netherlands Cancer Institute, Amsterdam, Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, Netherlands
| | - Karin Haustermans
- Department of Radiation Oncology, University Hospital Leuven, Leuven, Belgium
| | - Corrie Marijnen
- Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Bruce D Minsky
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ethan Ludmir
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Phil Quirke
- Division of Pathology and Data Analytics, School of Medicine, Leeds University, Leeds, UK
| | | | - Julio Garcia-Aguilar
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Antonietta Gambacorta
- Department of Radiation Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Vincenzo Valentini
- Department of Radiation Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Marc Buyse
- Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Diepenbeek, Belgium; International Drug Development Institute, San Francisco, CA, USA
| | - Claus Rödel
- Department of Radiotherapy and Oncology, University of Frankfurt, Frankfurt, Germany; German Cancer Consortium, German Cancer Research Center, Heidelberg, Germany; Frankfurt Cancer Institute, Frankfurt Germany
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