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Kleber TJ, Sherry AD, Arifin AJ, Kupferman GS, Kouzy R, Abi Jaoude J, Lin TA, Beck EJ, Miller AM, Passy AH, McCaw ZR, Msaouel P, Ludmir EB. Justification, margin values, and analysis populations for oncologic noninferiority and equivalence trials: a meta-epidemiological study. J Natl Cancer Inst 2025; 117:898-906. [PMID: 39657246 PMCID: PMC12058270 DOI: 10.1093/jnci/djae318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 11/04/2024] [Accepted: 11/27/2024] [Indexed: 12/17/2024] Open
Abstract
BACKGROUND Noninferiority and equivalence trials evaluate whether an experimental therapy's effect on the primary endpoint is contained within an acceptable margin compared with standard of care. The reliability and impact of this conclusion, however, is largely dependent on the justification for this design, the choice of margin, and the analysis population used. METHODS A meta-epidemiological study was performed of phase 3 randomized noninferiority and equivalence oncologic trials registered at ClinicalTrials.gov. Data were extracted from each trial's registration page and primary manuscript. RESULTS We identified 65 noninferiority and 10 equivalence trials that collectively enrolled 61 632 patients. Of these, 61 (81%) trials demonstrated noninferiority or equivalence. A total of 65 (87%) trials were justified in the use of a noninferiority or equivalence design either because of an inherent advantage (53 trials), a statistically significant quality-of-life improvement (6 trials), or a statistically significant toxicity improvement (6 trials) of the interventional treatment relative to the control arm. Additionally, 69 (92.0%) trials reported a prespecified noninferiority or equivalence margin of which only 23 (33.3%) provided justification for this margin based on prior literature. For trials with time-to-event primary endpoints, the median noninferiority margin was a hazard ratio of 1.22 (range = 1.08-1.52). Investigators reported a per-protocol analysis for the primary endpoint in only 28 (37%) trials. CONCLUSIONS Although most published noninferiority and equivalence trials have clear justification for their design, few provide rationale for the chosen margin or report a per-protocol analysis. These findings underscore the need for rigorous standards in trial design and reporting.
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Affiliation(s)
- Troy J Kleber
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Alexander D Sherry
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Andrew J Arifin
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
- Division of Radiation Oncology, London Health Sciences Centre/Western University, London, Canada
| | - Gabrielle S Kupferman
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Ramez Kouzy
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Joseph Abi Jaoude
- Department of Radiation Oncology, Stanford University, Stanford, CA 94305, United States
| | - Timothy A Lin
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Esther J Beck
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Avital M Miller
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Adina H Passy
- Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Zachary R McCaw
- Insitro, South San Francisco, CA 94080, United States
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
| | - Pavlos Msaouel
- Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
- Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
| | - Ethan B Ludmir
- Department of Gastrointestinal Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
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Guo H, Miao L, Yu C. The efficacy of targeted therapy and/or immunotherapy with or without chemotherapy in patients with colorectal cancer: A network meta-analysis. Eur J Pharmacol 2025; 988:177219. [PMID: 39716565 DOI: 10.1016/j.ejphar.2024.177219] [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: 08/22/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer. METHODS A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS). RESULTS A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib + Binimetinib + Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy + Cetuximab + Dalotuzumab (Chemo-CET-DAL), Encorafenib + Cetuximab (ENC-CET), and Panitumumab + Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy + Bevacizumab + Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy + Bevacizumab, ENC-CET, Chemotherapy + Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET. CONCLUSIONS In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.
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Affiliation(s)
- Haoyan Guo
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China
| | - Longjie Miao
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, 518104, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chengdong Yu
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Alvares D, Mercier F. Bridging the gap between two-stage and joint models: The case of tumor growth inhibition and overall survival models. Stat Med 2024; 43:3280-3293. [PMID: 38831490 DOI: 10.1002/sim.10128] [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: 09/20/2023] [Revised: 04/03/2024] [Accepted: 05/20/2024] [Indexed: 06/05/2024]
Abstract
Many clinical trials generate both longitudinal biomarker and time-to-event data. We might be interested in their relationship, as in the case of tumor size and overall survival in oncology drug development. Many well-established methods exist for analyzing such data either sequentially (two-stage models) or simultaneously (joint models). Two-stage modeling (2stgM) has been challenged (i) for not acknowledging that biomarkers are endogenous covariable to the survival submodel and (ii) for not propagating the uncertainty of the longitudinal biomarker submodel to the survival submodel. On the other hand, joint modeling (JM), which properly circumvents both problems, has been criticized for being time-consuming, and difficult to use in practice. In this paper, we explore a third approach, referred to as a novel two-stage modeling (N2stgM). This strategy reduces the model complexity without compromising the parameter estimate accuracy. The three approaches (2stgM, JM, and N2stgM) are formulated, and a Bayesian framework is considered for their implementation. Both real and simulated data were used to analyze the performance of such approaches. In all scenarios, our proposal estimated the parameters approximately as JM but without being computationally expensive, while 2stgM produced biased results.
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Affiliation(s)
- Danilo Alvares
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - François Mercier
- Modeling and Simulation, Roche Innovation Center, Basel, Switzerland
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DeRidder LB, Hare KA, Lopes A, Jenkins J, Fitzgerald N, MacPherson E, Fabian N, Morimoto J, Chu JN, Kirtane AR, Madani W, Ishida K, Kuosmanen JLP, Zecharias N, Colangelo CM, Huang HW, Chilekwa M, Lal NB, Srinivasan SS, Hayward AM, Wolpin BM, Trumper D, Quast T, Rubinson DA, Langer R, Traverso G. Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing. MED 2024; 5:780-796.e10. [PMID: 38663403 DOI: 10.1016/j.medj.2024.03.020] [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: 10/27/2023] [Revised: 01/26/2024] [Accepted: 03/21/2024] [Indexed: 07/15/2024]
Abstract
BACKGROUND Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. METHODS We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). FINDINGS We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. CONCLUSIONS We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. FUNDING This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.
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Affiliation(s)
- Louis B DeRidder
- Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Kyle A Hare
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Aaron Lopes
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Josh Jenkins
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Nina Fitzgerald
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Emmeline MacPherson
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Niora Fabian
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Josh Morimoto
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Jacqueline N Chu
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Harvard Medical School, Boston, MA 02115, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Ameya R Kirtane
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Wiam Madani
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Keiko Ishida
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Johannes L P Kuosmanen
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Naomi Zecharias
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | | | - Hen-Wei Huang
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Makaya Chilekwa
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Nikhil B Lal
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; MIT Media Lab, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Shriya S Srinivasan
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Alison M Hayward
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Brian M Wolpin
- Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - David Trumper
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Troy Quast
- College of Public Health, University of South Florida, Tampa, FL 33612, USA
| | - Douglas A Rubinson
- Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Robert Langer
- Harvard-MIT Division of Health Science Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Giovanni Traverso
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Yuan Y, Zhou H, Liu S. Statistical and practical considerations in planning and conduct of dose-optimization trials. Clin Trials 2024; 21:273-286. [PMID: 38243399 PMCID: PMC11134987 DOI: 10.1177/17407745231207085] [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] [Indexed: 01/21/2024]
Abstract
The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In addition, practical considerations for selecting an appropriate design and planning and executing the trial are discussed. The article also presents freely available software tools that can be utilized for designing and implementing dose-optimization trials. The approaches and their implementation are illustrated through real-world examples.
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Affiliation(s)
- Ying Yuan
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Heng Zhou
- Biostatistics and Research Decision Sciences, Merck and Co., Inc, Rahway, NJ, USA
| | - Suyu Liu
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Jacobsen A, Siebler J, Grützmann R, Stürzl M, Naschberger E. Blood Vessel-Targeted Therapy in Colorectal Cancer: Current Strategies and Future Perspectives. Cancers (Basel) 2024; 16:890. [PMID: 38473252 DOI: 10.3390/cancers16050890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 02/06/2024] [Accepted: 02/10/2024] [Indexed: 03/14/2024] Open
Abstract
The vasculature is a key player and regulatory component in the multicellular microenvironment of solid tumors and, consequently, a therapeutic target. In colorectal carcinoma (CRC), antiangiogenic treatment was approved almost 20 years ago, but there are still no valid predictors of response. In addition, treatment resistance has become a problem. Vascular heterogeneity and plasticity due to species-, organ-, and milieu-dependent phenotypic and functional differences of blood vascular cells reduced the hope of being able to apply a standard approach of antiangiogenic therapy to all patients. In addition, the pathological vasculature in CRC is characterized by heterogeneous perfusion, impaired barrier function, immunosuppressive endothelial cell anergy, and metabolic competition-induced microenvironmental stress. Only recently, angiocrine proteins have been identified that are specifically released from vascular cells and can regulate tumor initiation and progression in an autocrine and paracrine manner. In this review, we summarize the history and current strategies for applying antiangiogenic treatment and discuss the associated challenges and opportunities, including normalizing the tumor vasculature, modulating milieu-dependent vascular heterogeneity, and targeting functions of angiocrine proteins. These new strategies could open perspectives for future vascular-targeted and patient-tailored therapy selection in CRC.
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Affiliation(s)
- Anne Jacobsen
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of General and Visceral Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Jürgen Siebler
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of Medicine 1-Gastroenterology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Robert Grützmann
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
- Department of General and Visceral Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Michael Stürzl
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
| | - Elisabeth Naschberger
- Division of Molecular and Experimental Surgery, Translational Research Center, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Kussmaulallee 12, D-91054 Erlangen, Germany
- Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), D-91054 Erlangen, Germany
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Chitkara A, Kaur N, Desai A, Mehta D, Anamika F, Sarkar S, Gowda N, Sethi P, Thawani R, Chen EY. Risks of hypertension and thromboembolism in patients receiving bevacizumab with chemotherapy for colorectal cancer: A systematic review and meta-analysis. Cancer Med 2023; 12:21579-21591. [PMID: 38069531 PMCID: PMC10757147 DOI: 10.1002/cam4.6662] [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: 05/22/2023] [Revised: 09/12/2023] [Accepted: 10/03/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Guidelines show that for metastatic colorectal cancer (mCRC), a combination of three-drug regimens, fluorouracil, leucovorin, and oxaliplatin and bevacizumab (BVZ), is one of the first-line standard therapies. BVZ is generally well tolerated; however, it is associated with infrequent, life-threatening side effects such as severe hypertension (HTN) (5%-18%), Grade ≥3 arterial thromboembolism (ATE) (2.6%), Grade ≥3 hemorrhagic events (1.2%-4.6%), and gastrointestinal perforation (0.3%-2.4%). This meta-analysis aims to evaluate the additive risk of BVZ-induced severe HTN and thromboembolism when BVZ is combined with a standard chemotherapy regime in patients with mCRC. METHODS Our search was conducted from January 29, 2022, to February 22, 2022, through databases of PubMed, clinicaltrial.gov, EMBASE, Web of Science, and Cochrane Library. Data analysis from randomized controlled trials (RCTs) and clinical trials was conducted using Review Manager V.5.4, comparing BVZ-chemotherapy to chemotherapy only, focusing on cardiovascular AE such as HTN and arterial and venous thromboembolism. RESULTS The analysis from 26 clinical trials and RCTs showed that the odds of HTN were about four times higher, and ATE subgroup analysis of 11 studies showed over two times higher odds of ATE in patients being treated with BVZ compared to the chemotherapy-only group. CONCLUSION BVZ, when added to the standard chemotherapy regimen for mCRC, was associated with higher odds of developing HTN and thromboembolism, specifically ATE, than the chemotherapy-only group. Our findings are significant as they provide vital information in analyzing the risk-benefit ratio of adding BVZ to the standard chemotherapy regime in patients with mCRC, especially in patients with vascular comorbidities.
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Affiliation(s)
- Akshit Chitkara
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Nirmaljot Kaur
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Aditya Desai
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Devanshi Mehta
- Loma Linda UniversityCalifornia in Internal MedicineCaliforniaUSA
| | - Fnu Anamika
- Internal MedicineHackensack Meridian Ocean UniversityBrickNew JerseyUSA
| | - Srawani Sarkar
- Research LabAlbert Einstein College of MedicineNew YorkNew YorkUSA
| | - Nandini Gowda
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Prabhdeep Sethi
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Rajat Thawani
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
| | - Emerson Y. Chen
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
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Jiang L, Yuan Y. Seamless phase II/III design: a useful strategy to reduce the sample size for dose optimization. J Natl Cancer Inst 2023; 115:1092-1098. [PMID: 37243720 PMCID: PMC10483325 DOI: 10.1093/jnci/djad103] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 05/02/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023] Open
Abstract
BACKGROUND The traditional more-is-better dose selection paradigm, originally developed for cytotoxic chemotherapeutics, can be problematic when applied to the development of novel molecularly targeted agents. Recognizing this issue, the US Food and Drug Administration initiated Project Optimus to reform the dose optimization and selection paradigm in oncology drug development, emphasizing the need for greater attention to benefit-risk considerations. METHODS We identify different types of phase II/III dose-optimization designs, classified according to trial objectives and endpoint types. Through computer simulations, we examine their operating characteristics and discuss the relevant statistical and design considerations for effective dose optimization. RESULTS Phase II/III dose-optimization designs are capable of controlling family-wise type I error rates and achieving appropriate statistical power with substantially smaller sample sizes than the conventional approach while also reducing the number of patients who experience toxicity. Depending on the design and scenario, the sample size savings range from 16.6% to 27.3%, with a mean savings of 22.1%. CONCLUSIONS Phase II/III dose-optimization designs offer an efficient way to reduce sample sizes for dose optimization and accelerate the development of targeted agents. However, because of interim dose selection, the phase II/III dose-optimization design presents logistical and operational challenges and requires careful planning and implementation to ensure trial integrity.
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Affiliation(s)
- Liyun Jiang
- Research Center of Biostatistics and Computational Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ying Yuan
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Maring JG, Eijsink JFH, Tichelaar FD, Veluwenkamp-Worawutputtapong P, Postma MJ, Touw DJ, de Groot JWB. Role of Patient-Reported Outcomes in Clinical Trials in Metastatic Colorectal Cancer: A Scoping Review. Cancers (Basel) 2023; 15:1135. [PMID: 36831478 PMCID: PMC9953919 DOI: 10.3390/cancers15041135] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 02/06/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
PURPOSE To perform a scoping review on the use of Patient-Reported Outcome Measures (PROMs) in randomized trials on systemic therapy in patients with metastatic colorectal cancer (mCRC) between 2010 and 2021. METHODS First, a search on clinicaltrials.gov was performed, looking for randomized trials in mCRC. The use of PROMs was analyzed quantitatively. Subsequently, we assessed the completeness of PROM reporting based on the CONSORT PRO extension in publications related to the selected trials acquired using Embase and PubMed. RESULTS A total of 46/176 trials were registered on clinicaltrials.gov used PROMs. All these trials used validated PROM instruments. The EORTC QLQ-C30 was most frequently used (37 times), followed by the EQ-5D (21 times) and the EORTC QLQ-CR29 (six times). A total of 56/176 registered trials were published. In 35% (n = 20), the results of the PROMs were available. Overall, 7/20 (35%) trials documented all items of the CONSORT PRO extension and quality of reporting according to the CONSORT PRO extension was higher than in the period 2004-2012. In 3/20 (15%) of the published trials, the results of PROMs were not discussed nor included in the positioning of the new treatment compared to the reference treatment. CONCLUSION When PROMs are used, the quality of reporting on patient-reported outcomes is improving, but this must continue in order to optimize the translation of trial results to individual patient values.
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Affiliation(s)
- Jan Gerard Maring
- Department of Clinical Pharmacy, Isala, NL 8025 AB Zwolle, The Netherlands
| | - Job F. H. Eijsink
- Department of Clinical Pharmacy, Isala, NL 8025 AB Zwolle, The Netherlands
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, NL 9713 GZ Groningen, The Netherlands
| | - Friso D. Tichelaar
- Department of Health Sciences, University Medical Centre Groningen, University of Groningen, NL 9713 GZ Groningen, The Netherlands
| | | | - Maarten J. Postma
- Department of Health Sciences, University Medical Centre Groningen, University of Groningen, NL 9713 GZ Groningen, The Netherlands
- Department of Economics, Econometrics & Finance, Faculty of Economics & Business, University of Groningen, NL 9713 GZ Groningen, The Netherlands
| | - Daan J. Touw
- Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, NL 9713 GZ Groningen, The Netherlands
- Department of Pharmaceutical Analysis, Groningen Research Institute of Pharmacy, University of Groningen, NL 9713 GZ Groningen, The Netherlands
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10
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He J, Liu Y, Liu C, Hu H, Sun L, Xu D, Li J, Wang J, Chen X, Lin R, Jiang Y, Zhang Y, Zhang W, Cheng Y, Wu X, Fang M, Li E, Xu Y, Chen Y, Li J, Cui Y, Pan Z, Zhang S, Yuan Y, Ding K. A Randomized Phase III Study of Anlotinib Versus Bevacizumab in Combination With CAPEOX as First-Line Therapy for RAS/BRAF Wild-Type Metastatic Colorectal Cancer: A Clinical Trial Protocol. Technol Cancer Res Treat 2023; 22:15330338231152350. [PMID: 36727222 PMCID: PMC9900663 DOI: 10.1177/15330338231152350] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 12/09/2022] [Accepted: 01/05/2023] [Indexed: 02/03/2023] Open
Abstract
Background: Chemotherapy combined with antivascular endothelial growth factor (VEGF) or anti-epidermal growth factor receptor monoclonal antibodies is the most promising approach to prolong survival and improve the quality of life of patients with unresectable metastatic colorectal cancer (mCRC). Anlotinib is an oral antiangiogenic tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, fibroblast growth factor receptors 1-4, and platelet-derived growth factor receptors a/β. Since anlotinib combined with oxaliplatin and capecitabine (CAPEOX) as a first-line treatment was previously shown to be effective and safe for patients with RAS/BRAF wild-type (WT) mCRC, we designed this randomized, open-label, parallel-group, non-inferiority, phase III study to evaluate the efficacy and safety of anlotinib plus CAPEOX versus bevacizumab plus CAPEOX in patients with RAS/BRAF WT mCRC. Methods/design: The primary inclusion criteria are Eastern Cooperative Oncology Group performance status 0/1, confirmed RAS/BRAF WT colorectal adenocarcinoma, and unresectable metastases assessed by a multidisciplinary team. The main exclusion criteria are as follows: high microsatellite instability or deficient mismatch repair status, resectable or potentially resectable metastases, and previous systemic therapy for mCRC. A total of 698 patients will be randomized into the anlotinib and bevacizumab groups in a 1:1 ratio. Patients will receive 4 to 8 cycles of induction therapy (CAPEOX plus anlotinib or bevacizumab), followed by maintenance treatment (capecitabine plus anlotinib or bevacizumab) until disease progression or unacceptable toxicity. Progression-free survival (PFS) assessed by an independent review committee is the primary endpoint, whereas investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, resection rate of liver metastases, quality of life, and safety are the secondary endpoints. Enrollment commenced in May 2021. Discussion: A prospective, randomized, phase III trial will provide a meaningful comparison of the efficacy and safety of anlotinib plus CAPEOX with standard treatment for patients with unresectable RAS/BRAF WT mCRC.
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Affiliation(s)
- Jinjie He
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention
and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Yue Liu
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention
and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Chengcheng Liu
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention
and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Hanguang Hu
- Medical Oncology, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Lifeng Sun
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention
and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Dong Xu
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention
and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Jun Li
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention
and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Junye Wang
- Affiliated
Hospital of Jining Medical University,
Jining, China
| | | | - Rongbo Lin
- Fujian
Provincial Cancer Hospital, Fuzhou,
China
| | - Yi Jiang
- Affiliated
Cancer Hospital of Shantou University Medical
College, Shantou, China
| | - Yanqiao Zhang
- Affiliated
Cancer Hospital of Harbin Medical
University, Harbin, China
| | | | | | - Xiaohong Wu
- Affiliated
Hospital of Jiangnan University, Wuxi,
China
| | - Mingzhi Fang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing
University of Chinese Medicine, Nanjing, China
| | - Enxiao Li
- The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an,
China
| | - Ye Xu
- Fudan
University Shanghai Cancer Center,
Shanghai, China
| | - Ye Chen
- The First
Affiliated Hospital of Henan University of Science and
Technology, Luoyang, China
| | - Jiayi Li
- The First
Affiliated Hospital of Xiamen University,
Xiamen, China
| | - Yanyan Cui
- Affiliated Hospital of Chifeng University, Chifeng, China
| | - Zhanyu Pan
- Tianjin
Medical University Cancer Institute and
Hospital, Tianjin, China
| | - Songnan Zhang
- Affiliated Hospital of Yanbian University, Yanbian, China
| | - Ying Yuan
- Medical Oncology, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
| | - Kefeng Ding
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention
and Intervention, Ministry of Education, The Second Affiliated Hospital of Zhejiang
University School of Medicine, Hangzhou,
China
- Cancer Center Zhejiang University, Zhejiang, China
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11
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The Association between Baseline Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Chemotherapy: A Systematic Review with Network Meta-Analysis. Cancers (Basel) 2022; 15:cancers15010284. [PMID: 36612290 PMCID: PMC9818995 DOI: 10.3390/cancers15010284] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/03/2023] Open
Abstract
(1) Although emerging evidence suggests that proton pump inhibitor (PPI)-induced dysbiosis negatively alters treatment response to immune checkpoint inhibitors (ICIs) in cancer patients, no study systematically investigates the association between PPIs, ICIs, and chemotherapy; (2) Cochrane Library, Embase, Medline, and PubMed were searched from inception to 20 May 2022, to identify relevant studies involving patients receiving ICIs or chemotherapy and reporting survival outcome between PPI users and non-users. Survival outcomes included overall survival (OS) and progression-free survival (PFS). Network meta-analyses were performed using random-effects models. p-scores, with a value between 0 and 1, were calculated to quantify the treatment ranking, with a higher score suggesting a higher probability of greater effectiveness. We also conducted pairwise meta-analyses of observational studies to complement our network meta-analysis; (3) We identified 62 studies involving 26,484 patients (PPI = 8834; non-PPI = 17,650), including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), melanoma, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and squamous cell carcinoma (SCC) of the neck and head. Eight post-hoc analyses from 18 randomized-controlled trials were included in our network, which demonstrated that, in advanced NSCLC and UC, patients under ICI treatment with concomitant PPI (p-score: 0.2016) are associated with both poorer OS (HR, 1.49; 95% CI, 1.37 to 1.67) and poorer PFS (HR, 1.41; 95% CI, 1.25 to 1.61) than those without PPIs (p-score: 1.000). Patients under ICI treatment with concomitant PPI also had poorer OS (HR, 1.18; 95% CI, 1.07 to 1.31) and poorer PFS (HR, 1.30; 95% CI, 1.14 to 1.48) in comparison with those receiving chemotherapy (p-score: 0.6664), implying that PPIs may compromise ICI's effectiveness, making it less effective than chemotherapy. Our pairwise meta-analyses also supported this association. Conversely, PPI has little effect on patients with advanced melanoma, RCC, HCC, and SCC of the neck and head who were treated with ICIs; (4) "PPI-induced dysbiosis" serves as a significant modifier of treatment response in both advanced NSCLC and UC that are treated with ICIs, compromising the effectiveness of ICIs to be less than that of chemotherapy. Thus, clinicians should avoid unnecessary PPI prescription in these patients. "PPI-induced dysbiosis", on the other hand, does not alter the treatment response to ICIs in advanced melanoma, RCC, HCC, and SCC of the head and neck.
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12
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Lin WY, Wang SS, Kang YN, Porpiglia AS, Chang Y, Huang CH, Bhimani R, Abdul-Lattif E, Azmat M, Wang TH, Lin YS, Chang YC, Chi KY. Do proton pump inhibitors affect the effectiveness of chemotherapy in colorectal cancer patients? A systematic review with meta-analysis. Front Pharmacol 2022; 13:1048980. [PMID: 36578549 PMCID: PMC9792119 DOI: 10.3389/fphar.2022.1048980] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/25/2022] [Indexed: 12/14/2022] Open
Abstract
Proton pump inhibitors (PPI), one of the most commonly prescribed medications, carry a myriad of adverse events. For colorectal cancer (CRC) patients, it still remains unclear whether the concurrent use of proton pump inhibitors (PPI) would negatively affect chemotherapy. PubMed, Medline, Embase, and Cochrane Library were searched from inception to 10 June 2022, to identify relevant studies involving CRC patients receiving chemotherapy and reporting comparative survival outcomes between PPI users and non-users. Meta-analyses were performed using random-effects models. We identified 16 studies involving 8,188 patients (PPI = 1,789; non-PPI = 6,329) receiving either capecitabine-based or fluorouracil-based regimens. The overall survival (HR, 1.02; 95% CI, 0.91 to 1.15; I2 = 0%) and progression-free survival (HR, 1.15; 95% CI, 0.98 to 1.35; I2 = 29%) were similar between PPI users and non-users in patients taking capecitabine-based regimens, with low statis-tical heterogeneity. Although the subgroup analysis indicated that early-stage cancer patients taking capecitabine monotherapy with concurrent PPI had a significantly higher disease progression rate (HR, 1.96; 95% CI, 1.21 to 3.16; I2 = 0%) than those who did not use PPIs, both groups had comparable all-cause mortality (HR, 1.31; 95% CI, 0.75 to 2.29; I2 = 0%). On the other hand, there was little difference in both OS and PFS in both early- and end-stage patients taking capecitabine combination therapy between PPI users and non-users. Conversely, the use of concomitant PPI in patients taking fluorouracil-based regimens contributed to a marginally significant higher all-cause mortality (HR, 1.18; 95% CI, 1.00 to 1.40; I2 = 74%), but with high statistical heterogeneity. In conclusion, PPI has little survival influence on CRC patients treated with capecitabine-based regimens, especially in patients taking capecitabine combination therapy. Thus, it should be safe for clinicians to prescribe PPI in these patients. Although patients treated with fluorouracil-based regimens with concomitant PPI trended toward higher all-cause mortality, results were subject to considerable heterogeneity. Systematic Review Registration: identifier https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022338161.
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Affiliation(s)
- Wan-Ying Lin
- Department of Family Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Shih-Syuan Wang
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yi-No Kang
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Andrea S. Porpiglia
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Yu Chang
- Section of Neurosurgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chin-Hsuan Huang
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Ronak Bhimani
- Department of Internal Medicine, Lower Bucks Hospital, Bristol, PA, United States
| | - Eahab Abdul-Lattif
- Department of Internal Medicine, Lower Bucks Hospital, Bristol, PA, United States
| | - Muneeba Azmat
- Department of Internal Medicine, Lower Bucks Hospital, Bristol, PA, United States
| | - Tsu-Hsien Wang
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yu-Shiuan Lin
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Yu-Cheng Chang
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
| | - Kuan-Yu Chi
- Department of Education, Center for Evidence-Based Medicine, Taipei Medical University Hospital, Taipei, Taiwan
- Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
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13
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Bekaii-Saab TS, Balser S, Lohmann R, Daoud H, Liedert B, Schliephake D. Phase IIIb study of the bevacizumab biosimilar candidate BI 695502 plus mFOLFOX6 in metastatic colorectal cancer. COLORECTAL CANCER 2022. [DOI: 10.2217/crc-2022-0002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Aim: This study assessed the safety, efficacy, pharmacokinetics and immunogenicity of the bevacizumab biosimilar candidate BI 695502 plus mFOLFOX6 in patients with metastatic colorectal cancer (mCRC). Materials & methods: Patients with untreated mCRC received BI 695502 and chemotherapy (oxaliplatin, leucovorin and 5-fluorouracil). Primary end point: proportion of patients with prespecified adverse events (AEs). Results: Of 123 patients enrolled and treated, 58.5% experienced prespecified AEs. Median progression-free survival was 10.5 months, median overall survival was 19.4 months, and objective response rate was 61.0%. There were no antidrug antibody or neutralizing antidrug antibody-positive samples post-baseline. Trough BI 695502 plasma concentrations increased until cycle 9 and stabilized thereafter. Conclusion: BI 695502 has an acceptable safety and efficacy profile in the treatment of mCRC. Trial Registration Number: NCT02776683 ( ClinicalTrials.gov ), 2015-003718-25 (EudraCT, European Clinical Trials Database https://www.clinicaltrialsregister.eu/ctr-search/search?query=2015-003718-25 ) Study name: Study 1302.3
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Affiliation(s)
- Tanios S Bekaii-Saab
- Mayo Clinic Cancer Center, Department of Internal Medicine, Mayo Clinic Hospital, 5777E. Mayo Blvd, Phoenix, AZ 85054, USA
| | - Sigrid Balser
- Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400 Biberach an der Riss, Germany
| | - Ragna Lohmann
- Boehringer Ingelheim International GmbH, Binger Str. 173, 55218 Ingelheim am Rhein, Germany
| | - Hasan Daoud
- Boehringer Ingelheim International GmbH, Binger Str. 173, 55218 Ingelheim am Rhein, Germany
| | - Bernd Liedert
- (Formerly at) Boehringer Ingelheim International GmbH, Binger Str. 173, 55218 Ingelheim am Rhein, Germany
| | - Dorothee Schliephake
- Boehringer Ingelheim International GmbH, Binger Str. 173, 55218 Ingelheim am Rhein, Germany
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14
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Chrabaszcz S, Rajeev R, Witmer HDD, Dhiman A, Klooster B, Gamblin TC, Banerjee A, Johnston FM, Turaga KK. A Systematic Review of Conversion to Resectability in Unresectable Metastatic Colorectal Cancer Chemotherapy Trials. Am J Clin Oncol 2022; 45:366-372. [PMID: 35838247 DOI: 10.1097/coc.0000000000000921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Metastasectomy in patients with metastatic colorectal cancer (mCRC) confers a significant survival benefit. We hypothesized that conversion to resectability (C2R) correlates with superior overall survival (OS) in patients with unresectable mCRC. METHODS A prospectively registered systematic review (PROSPERO CRD42015024104) of randomized clinical trials published after 2003 was conducted. Exposure of interest was C2R with a primary outcome of OS. Clinical trials were classified based on difference in C2R between study arms (<2%, 2% to 2.9%, ≥3%). Generalized estimating equations were used to measure associations while adjusting for multiple observations from the same trial. RESULTS Of 2902 studies reviewed, 30 satisfied selection criteria (n=13,618 patients). Median C2R was 7.3% (interquartile range [IQR]: 5% to 12.9%), with maximum C2R in the FOLFOX/FOLFIRI+cetuximab arm (28.6%). The median difference in C2R between 2 arms of the same study was 2.3% (IQR: 1.3% to 3.4%) with a maximum difference of 15.4% seen in FOLFOX/FOLFIRI+cetuximab versus FOLFOX/FOLFIRI. Median OS for the entire patient cohort was 20.7 months (IQR: 18.9 to 22.7 mo), with a between group difference of 1.3 months (IQR: -1.2 to 3.6 mo). The median survival difference between the 2 study arms with <2% C2R difference was 0.8 months versus 1.6 months with ≥3% C2R rates . Increasing C2R had an incremental dose-effect response on OS ( P =0.021), and higher response rates correlated with C2R rates ( P =0.003). CONCLUSIONS C2R occurs infrequently and variably in clinical trials enrolling patients with unresectable mCRC. Prioritization of chemotherapeutic agents that enhance C2R might improve OS of patients.
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Affiliation(s)
| | - Rahul Rajeev
- Department of Surgery, Virginia Commonwealth University, Richmond, VA
| | | | - Ankit Dhiman
- Department of Surgery, University of Chicago, Chicago, IL
| | | | | | | | | | - Kiran K Turaga
- Department of Surgery, University of Chicago, Chicago, IL
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15
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Liu Y, Xiao Q, He J, Hu H, Du J, Zhu Y, Chen J, Liu Z, Wang J, Sun L, Xu D, Li J, Liao X, Wang J, Cai Y, Cai C, Jin Z, Wang L, Yuan Y, Ding K. Phase II study of anlotinib in combination with oxaliplatin and capecitabine for patients with RAS/BRAF wild-type metastatic colorectal adenocarcinoma as the first-line therapy. BMC Med 2022; 20:155. [PMID: 35513832 PMCID: PMC9071922 DOI: 10.1186/s12916-022-02357-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 03/28/2022] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Anlotinib, an oral small molecule tyrosine kinase inhibitor targeting VEGFR 1/2/3, FGFR 1-4, PDGFR a/β, and c-kit, had demonstrated prolonged progression-free survival (PFS) in refractory metastatic colorectal cancer (mCRC). This multicenter, single-arm, phase II, exploratory study was conducted to evaluate the efficacy and safety of anlotinib combined with capecitabine and oxaliplatin as first-line treatment for unresectable RAS/BRAF wild-type mCRC. METHODS Patients aged 18-75 with RAS/BRAF wild-type unresectable mCRC, without prior systemic treatment, and ECOG performance status ≤1 were enrolled. Eligible patients received capecitabine (850 mg/m2, p.o., bid, on day 1-14 every 21 days), oxaliplatin (130 mg/m2, i.v., on day 1 every 21 days), and anlotinib (12 mg, p.o., qd, on days 1-14 every 21 days) as induction therapy. Following 6 cycles of therapy, patients who achieved response or stable disease received capecitabine and anlotinib as maintenance therapy until tumor progression. The primary endpoint was objective response rate (ORR) according to RECIST (version: 1.1), and the secondary endpoints were PFS, disease control rate (DCR), duration of response (DOR), and safety. RESULTS Between November 2019 and February 2021, 31 patients were enrolled. One patient was excluded for refusing treatment. The primary endpoint of ORR was 76.7% (95% CI, 57.7-90.1) with 1 patient achieving a complete response and 22 patients partial response. DCR was 93.3% (95% CI, 77.9-99.2). At a median follow-up of 14.1 months (95% CI, 9.9-18.3), median PFS was 11.3 months (95% CI, 7.1-14.1), and DOR was 7.9 months (95% CI, 5.5-12.7). Twenty-five (83.3%) patients experienced grade 3 or 4 treatment-emergent adverse events (TEAEs). No grade 5 TEAE was reported. The most common grade 3 or 4 TEAEs (>10%) were hypertension (15/30; 50%), neutrophil count decreased (8/30; 26.7%), and diarrhea (4/30; 13.3%). A total of 18 (60%) patients had TEAEs that resulted in dose reduction, interruptions, or delays. CONCLUSIONS Anlotinib combined with capecitabine and oxaliplatin showed considerable ORR, DCR, PFS, and DOR in the first-line therapy of mCRC with manageable toxicity profiles. TRIAL REGISTRATION ClinicalTrials.gov : NCT04080843.
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Affiliation(s)
- Yue Liu
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qian Xiao
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jinjie He
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Hanguang Hu
- Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jinlin Du
- Colorectal Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Yuping Zhu
- Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Jiaqi Chen
- Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhuo Liu
- Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Jianping Wang
- Colorectal Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Lifeng Sun
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dong Xu
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jun Li
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiujun Liao
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianwei Wang
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yibo Cai
- Colorectal Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Cheng Cai
- Colorectal Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Zhekang Jin
- Colorectal Surgery, Zhejiang University Jinhua Hospital, Jinhua, China
| | - Liuhong Wang
- Radiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ying Yuan
- Medical Oncology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Kefeng Ding
- Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Cancer Center Zhejiang University, Zhejiang, China.
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16
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Hubbard JM, Yin J, Schenk EL, Qin R, Reid J, Strand C, Fiskum J, Menefee M, Lin G, Doyle LA, Ivy P, Erlichman C, Adjei A, Haluska P, Costello BA. Phase I study of cediranib, an oral VEGFR inhibitor, in combination with selumetinib, an oral MEK inhibitor, in patients with advanced solid malignancies. Invest New Drugs 2022; 40:115-123. [PMID: 34515877 PMCID: PMC8766914 DOI: 10.1007/s10637-021-01175-6] [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: 08/16/2021] [Accepted: 08/30/2021] [Indexed: 12/14/2022]
Abstract
PURPOSE Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. METHODS Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. RESULTS Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. CONCLUSIONS Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.
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Affiliation(s)
- Joleen M. Hubbard
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Jun Yin
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - Erin L. Schenk
- Division of Medical Oncology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Rui Qin
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - Joel Reid
- Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, United States
| | - Carrie Strand
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | - Jack Fiskum
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, United States
| | | | - Grace Lin
- Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN 55905, United States
| | - L. Austin Doyle
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
| | - Percy Ivy
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States
| | - Charles Erlichman
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Alex Adjei
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
| | - Paul Haluska
- Bristol Myers Squibb, Lawrenceville, NJ 08648, United States
| | - Brian A. Costello
- Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, United States
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17
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Yao Y, Liu Z, Zhang H, Li J, Peng Z, Yu J, Cao B, Shen L. Serious Adverse Events Reporting in Phase III Randomized Clinical Trials of Colorectal Cancer Treatments: A Systematic Analysis. Front Pharmacol 2021; 12:754858. [PMID: 34867369 PMCID: PMC8636814 DOI: 10.3389/fphar.2021.754858] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 10/25/2021] [Indexed: 12/22/2022] Open
Abstract
Objective: The occurrence, development, and prognosis of serious adverse events (SAEs) associated with anticancer drugs in clinical trials have important guiding significance for real-world clinical applications. However, to date, there have been no studies investigating SAEs reporting in randomized clinical trials of colorectal cancer treatments. This article systematically reviewed the SAEs reporting of phase III randomized clinical trials of colorectal cancer treatments and analyzed the influencing factors. Methods: We reviewed all articles about phase III randomized clinical trials of colorectal cancer treatments published in the PubMed, Embase, Medline, and New England Journal of Medicine databases from January 1, 1993, to December 31, 2018, and searched the registration information of clinical trials via the internet sites such as "clinicaltrials.gov". We analyzed the correlation between the reported proportion (RP) of SAEs in the literature and nine elements, including the clinical trial sponsor and the publication time. Chi-square tests and binary logistic regression were used to identify the factors associated with improved SAEs reports. This study was registered on PROSPERO. Results: Of 1560 articles identified, 160 were eligible, with an RP of SAEs of 25.5% (41/160). In forty-one publications reporting SAEs, only 14.6% (6/41) described the pattern of SAEs in detail. In clinical trials sponsored by pharmaceutical companies, the RP of SAEs was significantly higher than that in those sponsored by investigators (57.6 versus 20.7%, p < 0.001). From 1993 to 2018, the RP of SAEs gradually increased (none (0/6) before 2000, 17.1% (12/70) from 2000 to 2009, and 34.5% (29/84) after 2009). The average RP of SAEs published in the New England Journal of Medicine (N Engl J Med), the Lancet, the Journal of the American Medical Association (JAMA), the Lancet Oncology (Lancet Oncol), and the Journal of Clinical Oncology (J Clin Oncol) was significantly higher than that published in other journals (31.9 versus 16.7%, p = 0.030). In the clinical trials referenced by clinical guidelines, the RP of SAEs was higher than that in non-referenced clinical trials (32.0 versus 15.9%, p = 0.023). Binary logistic regression analysis showed that pharmaceutical company sponsorship, new drug research, and sample size greater than 1000 were positive influencing factors for SAEs reporting. Conclusion: Although the RP of SAEs increased over time, SAEs reporting in clinical trials needs to be further improved. The performance, outcomes and prognosis of SAEs should be reported in detail to guide clinical practice in the real world.
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Affiliation(s)
- Yanhong Yao
- Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing, China.,Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhentao Liu
- Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing, China
| | - Hua Zhang
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jinyu Yu
- Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing, China
| | - Baoshan Cao
- Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
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18
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Kosugi C, Koda K, Denda T, Ishibashi K, Ishida H, Seike K, Sakata H, Yanagisawa S, Miyazaki A, Takayama W, Koike N, Shimizu H, Matsubara H. Multicenter phase II clinical study of the efficiency and safety of capecitabine plus intermittent oxaliplatin with bevacizumab as first-line therapy in patients with metastatic colorectal cancer (VOICE trial). Int J Colorectal Dis 2021; 36:2637-2647. [PMID: 34368890 DOI: 10.1007/s00384-021-03995-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/08/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE The aim of this phase II study was to evaluate the efficacy and safety of combination therapy with five-cycle CAPOX (capecitabine plus oxaliplatin) plus bevacizumab, followed by five-cycle maintenance therapy with capecitabine plus bevacizumab and reintroduction of CAPOX plus bevacizumab for five cycles, with a preplanned intermittent oxaliplatin strategy in metastatic colorectal cancer (mCRC). METHODS Patients with untreated mCRC were administered CAPOX (130 mg/m2 oxaliplatin on day 1, 2000 mg/m2/day capecitabine on days 1-14, every 21 days) + bevacizumab (7.5 mg/kg) every 3 weeks for five cycles, maintenance treatment without oxaliplatin for five cycles, and CAPOX + bevacizumab reintroduction for five cycles or upon tumor progression. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were the time to treatment failure (TTF), overall survival, response rate (RR), and safety. RESULTS Forty-seven patients who fulfilled the inclusion criteria were enrolled in the evaluation of efficacy and safety. Median PFS was 14.1 months (95% confidence interval [CI], 8.6-19.5), and median TTF was 12.3 months (95% CI, 10.3-14.3). The objective RRs were 51.1% (24/47) during induction therapy, 58.3% (21/36) during maintenance therapy, and 63.6% (14/22) during reintroduction therapy. The frequency of patients with neutropenia, diarrhea, peripheral sensory neuropathy, venous thromboembolism, or grade ≥ 3 allergic reactions was 2.1%. CONCLUSION CAPOX plus bevacizumab therapy with a preplanned intermittent oxaliplatin strategy consisting of brief five-cycle induction therapy, five-cycle maintenance therapy with capecitabine plus bevacizumab, and five-cycle reintroduction therapy consisting of CAPOX plus bevacizumab is safe and effective for mCRC patients. TRIAL REGISTRATION UMIN ID: 000,005,732, date of registration: June 7, 2011. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000006695.
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Affiliation(s)
- Chihiro Kosugi
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba, 299-0111, Japan.
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba, 299-0111, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Keiichiro Ishibashi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama, Japan
| | - Kazuhiro Seike
- Department of Surgery, Odawara Municipal Hospital, Odawara, Kanagawa, Japan
| | - Haruhito Sakata
- Department of Surgery, Saisei Hospital, Hanamigawa, Chiba, Japan
| | - Shinji Yanagisawa
- Department of Surgery, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan
| | - Akinari Miyazaki
- Department of Surgery, Funabashi Municipal Medical Center, Funabashi, Chiba, Japan
| | - Wataru Takayama
- Department of Surgery, Chiba Prefectural Sawara Hospital, Sakura, Chiba, Japan
| | - Naoto Koike
- Department of Surgery, Seirei Sakura Citizen Hospital, Sakura, Chiba, Japan
| | - Hiroaki Shimizu
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba, 299-0111, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
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19
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Kichenadasse G, Miners JO, Mangoni AA, Karapetis CS, Hopkins AM, Sorich MJ. Proton Pump Inhibitors and Survival in Patients With Colorectal Cancer Receiving Fluoropyrimidine-Based Chemotherapy. J Natl Compr Canc Netw 2021; 19:1037-1044. [PMID: 33951613 DOI: 10.6004/jnccn.2020.7670] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 10/12/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Concomitant use of proton pump inhibitors (PPIs) may negatively affect the efficacy of anticancer drugs such as fluoropyrimidines in patients with colorectal cancer (CRC). The primary objective of this study was to assess whether there is an association between concomitant PPI use and survival outcomes in patients with CRC treated with a fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS A secondary analysis of 6 randomized controlled clinical trials in patients with advanced CRC was conducted using individual patient data through data-sharing platforms. The outcome measures were progression-free survival and overall survival in PPI users and nonusers. Subgroup analysis included the type of chemotherapy, capecitabine versus 5-FU, line of therapy, and addition of a vascular endothelial growth factor receptor inhibitor. Overall pooled hazard ratios (HRs) with 95% confidence intervals were calculated using a random effects model. RESULTS A total of 5,594 patients with advanced CRC across 6 trials and 11 trial arms were included; 902 patients were receiving a PPI at trial entry and initiation of chemotherapy. PPI use was significantly associated with worse overall survival (pooled HR, 1.20; 95% CI, 1.03-1.40; P=.02; I2 for heterogeneity = 69%) and progression-free survival (overall pooled HR, 1.20; 95% CI, 1.05-1.37; P=.009; I2 = 65%) after adjusting for clinical covariates. Furthermore, the association between concomitant PPI use and survival outcomes was similar across most treatment subgroups. CONCLUSIONS We speculate that alterations in the gut microbiome, altered immune milieu within the tumor, and interactions through transporters are potential mechanisms behind this association between PPI use and chemotherapy in patients with CRC, which warrant further study. Concomitant use of PPIs is associated with worse survival outcomes in patients with CRC treated with fluoropyrimidine-based chemotherapy. Clinicians should cautiously consider the concomitant use of PPIs in such patients.
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Affiliation(s)
- Ganessan Kichenadasse
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and.,2Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre/Flinders University, Bedford Park, South Australia, Australia
| | - John O Miners
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
| | - Arduino A Mangoni
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
| | - Christos S Karapetis
- 2Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre/Flinders University, Bedford Park, South Australia, Australia
| | - Ashley M Hopkins
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
| | - Michael J Sorich
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
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20
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Gulhati P, Yin J, Pederson L, Schmoll HJ, Hoff P, Douillard JY, Hecht JR, Tournigand C, Tebbut N, Chibaudel B, Gramont AD, Shi Q, Overman MJ. Threshold Change in CEA as a Predictor of Non-Progression to First-Line Systemic Therapy in Metastatic Colorectal Cancer Patients With Elevated CEA. J Natl Cancer Inst 2021; 112:1127-1136. [PMID: 32191317 DOI: 10.1093/jnci/djaa020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 12/17/2019] [Accepted: 01/28/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Carcinoembryonic antigen (CEA) levels are used in conjunction with imaging to monitor response to systemic therapy in metastatic colorectal cancer (mCRC). We sought to identify a threshold for CEA change from baseline to predict progressive disease (PD) in mCRC patients receiving first-line therapy. METHODS Patients from trials collected in the ARCAD database were included if baseline CEA was at least 10 ng/mL and repeat CEA was available within 14 days of first restaging scan. Optimal cutoffs for CEA change were identified by receiver operating characteristic analysis. Prediction performance of cutoffs was evaluated by sensitivity, specificity, and negative predictive value. Analyses were conducted by treatment class: chemotherapy alone, chemotherapy with anti-VEGF antibody, and chemotherapy with anti-EGFR antibody. RESULTS A total of 2643 mCRC patients treated with systemic therapy were included. Median percent change of CEA from baseline to first restaging for patients with complete response, partial response, or stable disease (non-PD) and PD was -53.1% and +23.6% for chemotherapy alone (n = 957) and -71.7% and -45.3% for chemotherapy with anti-VEGF antibody (n = 1355). The optimal area under the curve cutoff for differentiating PD from non-PD on first restaging was -7.5% for chemotherapy alone and -62.0% for chemotherapy with anti-VEGF antibody; chemotherapy alone, adjusted odds ratio = 6.51 (95% CI = 3.31 to 12.83, P < .001), chemotherapy with anti-VEGF antibody, adjusted odds ratio = 3.45 (95% CI = 1.93 to 6.18, P < .001). A 99% negative predictive value clinical cutoff for prediction of non-PD would avoid CT scan at first restaging in 21.0% of chemotherapy alone and 16.2% of chemotherapy with anti-VEGF antibody-treated patients. Among patients with stable disease on first restaging, those with decreased CEA from baseline had statistically significantly improved progression-free and overall survival. CONCLUSIONS Change in CEA from baseline to first restaging can accurately predict non-progression and correlates with long-term outcomes in patients receiving systemic chemotherapy.
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Affiliation(s)
- Pat Gulhati
- Department of Medical Oncology, Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ, USA
| | - Jun Yin
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Levi Pederson
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | | | - Paulo Hoff
- Centro de Oncologia de Brasilia do Sirio Libanes-Unidade Lago Sul, Sao Paulo, Brazil
| | - Jean-Yves Douillard
- Integrated Centres for Oncology, Department of Medical Oncology, St-Herblain, France
| | - J Randolph Hecht
- David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | | | - Niall Tebbut
- Department of Oncology, Olivia Newton John Cancer Research Institute, Heidelberg, VIC, Australia
| | | | | | - Qian Shi
- Department of Health Science Research, Mayo Clinic, Rochester, MN, USA
| | - Michael James Overman
- Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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21
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Webster-Clark M, Keil AP, Sanoff HK, Stürmer T, Westreich D, Lund JL. Introducing longitudinal cumulative dose to describe chemotherapy patterns over time: Case study of a colon cancer trial. Int J Cancer 2021; 149:394-402. [PMID: 33729546 DOI: 10.1002/ijc.33565] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/09/2021] [Accepted: 02/22/2021] [Indexed: 01/07/2023]
Abstract
Adjuvant chemotherapy regimens take months to complete. Despite this, studies evaluate chemotherapy adherence via measures assessed at the end of treatment (eg, number of patients missing any dose, relative dose intensity [RDI]). This approach ignores information like the timing of treatment delays. We propose longitudinal cumulative dose (LCD) to integrate impacts of dose reductions, missed doses and dose delays over time. We obtained data from the 2246 participants in the MOSAIC trial randomized to FOLFOX (all three agents) or 5-FU/LV (only 5-fluorouracil and leucovorin). We evaluated proportions of patients stopping treatment early and reducing, missing or delaying a dose in each arm for each chemotherapy agent at each cycle. We calculated LCD, the fraction of the final standard dose a participant reached by a given day, for each participant and each agent and compared it over time and at 24 weeks between treatment arms. Participants randomized to FOLFOX were more likely to stop treatment, reduce doses, miss doses or delay cycles; these differences increased over time. Median LCD for oxaliplatin in the FOLFOX arm at 24 weeks was 77%. The LCD for 5-fluorouracil differed between arms (FOLFOX arm median: 81%; 5-FU/LV arm median: 96%). Visualizing LCD highlighted the timing of deviations from standard administration in a way RDI could not, with major differences in 5-fluorouracil LCD across treatment arms beginning after the sixth dose. Further evaluation of LCD and its impacts on clinical outcomes may clarify mechanisms for heterogeneous patient outcomes.
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Affiliation(s)
- Michael Webster-Clark
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Alexander P Keil
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Hanna K Sanoff
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Til Stürmer
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Daniel Westreich
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jennifer L Lund
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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22
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Angiogenesis Inhibitors for Colorectal Cancer. A Review of the Clinical Data. Cancers (Basel) 2021; 13:cancers13051031. [PMID: 33804554 PMCID: PMC7957514 DOI: 10.3390/cancers13051031] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Accepted: 02/21/2021] [Indexed: 12/24/2022] Open
Abstract
Since the late 1990s, therapy for metastatic colorectal cancer (mCRC) has changed considerably, and the combination of doublet or triplet chemotherapy and a targeted agent are now routinely used. The targeting of angiogenesis, the development of new blood vessels, represents a key element in the overall treatment strategy. Since the approval in 2004 of the first anti-angiogenetic drug, multiple agents have been approved and others are currently under investigation. We present an overview of the recent literature on approved systemic treatment of mCRC, with a focus on anti-angiogenic drugs, and current treatment approaches, and elaborate on the future role of angiogenesis in colorectal cancer as seen from a clinical perspective. The treatment of mCRC, in general, has changed from "one strategy fits all" to a more personalized approach. This is, however, not entirely the case for anti-angiogenetic treatments, partly due to a lack of validated biomarkers. The anti-angiogenetic standard treatment at the present primarily includes monoclonal antibodies. The therapeutic field of angiogenesis, however, has received increased interest after the introduction of newer combinations. These approaches will likely change the current treatment strategy, once again, to the overall benefit of patients.
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23
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Bolhuis K, Kos M, van Oijen MGH, Swijnenburg RJ, Punt CJA. Conversion strategies with chemotherapy plus targeted agents for colorectal cancer liver-only metastases: A systematic review. Eur J Cancer 2020; 141:225-238. [PMID: 33189037 DOI: 10.1016/j.ejca.2020.09.037] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/07/2020] [Accepted: 09/27/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND There is no consensus on the optimal systemic conversion therapy in patients with unresectable colorectal cancer liver-only metastases (CRLM) to achieve a complete resection. Interpretation of trials is complicated by heterogeneity of patients caused by emerging prognostic and predictive characteristics, such as RAS/BRAF mutation status, lack of consensus on unresectability criteria and lack of data on clinical outcome of secondary resections. A systematic review was performed of characteristics of study populations and methodology of trials regarding patients with initially unresectable colorectal cancer liver-only metastases. METHODS Phase II/III randomised trials, published after 2008, regarding first-line systemic conversion therapy in patients or subgroups of patients with CRLM were included. Data on secondary resection outcomes were collected. RESULTS Overall, 20 trials were included for analysis: seven prospective trials in patients with unresectable CRLM and 13 trials in the overall population of unresectable metastatic colorectal cancer (mCRC) with retrospective subgroup analysis of CRLM patients. Fourteen trials did not provide unresectability criteria at baseline, and criteria differed among the remaining studies. Trials and study populations were heterogeneous in prognostic/predictive factors, use of primary end-points, and reporting on long-term clinical outcomes. R0-resection rates in CRLM patients varied between CRLM studies and mCRC studies, with rates of 22-57% and 11-38%, respectively. CONCLUSIONS Cross-study comparison of (subgroups of) studies regarding first-line systemic treatment in patients with unresectable CRLM is hampered by heterogeneity in study populations, trial designs, use of (K)RAS/BRAF mutational tumour status, and differences/absence of unresectability criteria. No optimal conversion systemic regimen can be selected from available data. Prospective studies with well-defined criteria of these issues are warranted.
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Affiliation(s)
- Karen Bolhuis
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands.
| | - Milan Kos
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | - Martijn G H van Oijen
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands
| | - Rutger-Jan Swijnenburg
- Amsterdam UMC, University of Amsterdam, Department of Surgery, Amsterdam, the Netherlands
| | - Cornelis J A Punt
- Amsterdam UMC, University of Amsterdam, Department of Medical Oncology, Amsterdam, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, the Netherlands
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24
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Komorowski AS, MacKay HJ, Pezo RC. Quality of adverse event reporting in phase III randomized controlled trials of breast and colorectal cancer: A systematic review. Cancer Med 2020; 9:5035-5050. [PMID: 32452660 PMCID: PMC7367648 DOI: 10.1002/cam4.3095] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 04/11/2020] [Accepted: 04/13/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Clinical trial reports often emphasize efficacy over harms, leading to misinterpretation of the risk-to-benefit ratio of new therapies. Clear and sufficiently detailed reporting of methods and results is especially important in the abstracts of trial reports, as readers often base their assessment of a trial on such information. In this study, we evaluated the quality of adverse event (AE) reporting and abstract quality in phase III randomized controlled trials (RCTs) of systemic therapies in breast and colorectal cancer. METHODS Medline, EMBASE, Cochrane Database of RCTs, and Cochrane Database of Systematic Reviews were searched from November 2005 to September 2018. Phase III RCTs evaluating systemic therapies in breast or colorectal cancer were included. Each article was independently reviewed by two investigators using a standardized data extraction form based on guidelines developed by the Consolidated Standards of Reporting Trials (CONSORT) group. Descriptive statistics, bivariate analysis, and multivariable linear regression were used to analyze data. All statistical tests were two-sided. RESULTS Of 166 RCTs identified, 99.4% reported harms in the manuscript body, and 59.6% reported harms in the abstract. Reporting was restricted to severe harms in 15.6% of RCTs. Statistical comparison of AE rates went unreported in 59.0% of studies. Information regarding AEs leading to dose reductions, treatment discontinuations, or study withdrawals went unreported in 59.3%, 18.7%, and 86.8% of studies, respectively. Recently published RCTs (P = .009) and those sponsored at least partially by for-profit companies (P = .003) had higher abstract quality scores. CONCLUSIONS Breast and colorectal cancer phase III RCTs inadequately report CONSORT-compliant AE data. Improved guideline adherence and abstract reporting is required to properly weigh benefits and harms of new oncologic therapies. SYSTEMATIC REVIEW REGISTRATION NUMBER CRD42019140673.
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Affiliation(s)
- Adam S. Komorowski
- Division of Medical MicrobiologyMcMaster UniversityHamiltonONCanada
- Sunnybrook Research InstituteSunnybrook Health Sciences CentreTorontoONCanada
| | - Helen J. MacKay
- Division of Medical OncologySunnybrook Health Sciences CentreTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
| | - Rossanna C. Pezo
- Division of Medical OncologySunnybrook Health Sciences CentreTorontoONCanada
- Department of MedicineUniversity of TorontoTorontoONCanada
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25
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Abdel-Rahman O, Karachiwala H, Easaw JC. Outcomes of Patients With Advanced Gastrointestinal Cancer in Relationship to Opioid Use: Findings From Eight Clinical Trials. J Natl Compr Canc Netw 2020; 18:575-581. [PMID: 32380454 DOI: 10.6004/jnccn.2019.7382] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 11/26/2019] [Indexed: 11/17/2022]
Abstract
BACKGROUND This study assessed the patterns of opioid use among patients with advanced gastrointestinal cancers who were included in 8 clinical trials and evaluated the impact of opioid use on survival outcomes of included patients. METHODS Deidentified datasets from 8 clinical trials evaluating first-line systemic treatment of advanced gastrointestinal cancers were accessed from the Project Data Sphere platform (ClinicalTrial.gov identifiers: NCT01124786, NCT00844649, NCT00290966, NCT00678535, NCT00699374, NCT00272051, NCT00305188, and NCT00384176). These trials evaluated patients with pancreatic carcinoma, gastric carcinoma, hepatocellular carcinoma (HCC), and colorectal carcinoma. Multivariable logistic regression analysis was used to evaluate factors predicting the use of opioids. Kaplan-Meier survival estimates were used to compare survival outcomes in each disease entity among patients who did or did not receive opioid treatment. Multivariable Cox regression analysis was then used to further assess the impact of opioid use on survival outcomes in each disease entity. RESULTS A total of 3,441 participants were included in the current analysis. The following factors predicted a higher probability of opioid use within logistic regression analysis: younger age at diagnosis (odds ratio [OR], 0.990; 95% CI, 0.984-0.997; P=.004), nonwhite race (OR for white vs nonwhite, 0.749; 95% CI, 0.600-0.933; P=.010), higher ECOG score (OR for 1 vs 0, 1.751; 95% CI, 1.490-2.058; P<.001), and pancreatic primary site (OR for colorectal vs pancreatic, 0.241; 95% CI, 0.198-0.295; P<.001). Use of opioids was consistently associated with worse overall survival (OS) in Kaplan-Meier survival estimates of each disease entity (P=.008 for pancreatic cancer; P<.001 for gastric cancer, HCC, and colorectal cancer). In multivariable Cox regression analysis, opioid use was associated with worse OS among patients with pancreatic cancer (hazard ratio [HR], 1.245; 95% CI, 1.063-1.459; P=.007), gastric cancer (HR, 1.725; 95% CI, 1.403-2.122; P<.001), HCC (HR, 1.841; 95% CI, 1.480-2.290; P<.001), and colorectal cancer (HR, 1.651; 95% CI, 1.380-1.975; P<.001). CONCLUSIONS Study findings suggest that opioid use is consistently associated with worse OS among patients with different gastrointestinal cancers. Further studies are needed to understand the underlying mechanisms of this observation and its potential implications.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Hatim Karachiwala
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
| | - Jacob C Easaw
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
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Abdel-Rahman O, Spratlin J, Koski S. Vitamin and herbal supplements’ use among patients with advanced gastrointestinal cancers included in eight clinical trials. J Cancer Res Clin Oncol 2020; 146:2089-2097. [DOI: 10.1007/s00432-020-03201-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/24/2020] [Indexed: 12/28/2022]
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Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 2020; 5:22. [PMID: 32296018 PMCID: PMC7082344 DOI: 10.1038/s41392-020-0116-z] [Citation(s) in RCA: 1001] [Impact Index Per Article: 200.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/24/2019] [Accepted: 12/31/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.
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Affiliation(s)
- Yuan-Hong Xie
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
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Fan Q, Lv W, Xu Y, Dong Y, Xiang Z, Wang J. Selective Vascular Endothelial Growth Factor Receptor Inhibitors Provide Limited Benefits for Metastatic Colorectal Cancer: A Meta-Analysis. Curr Pharm Des 2020; 26:3171-3186. [PMID: 32067605 DOI: 10.2174/1381612826666200218095932] [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: 10/12/2019] [Accepted: 01/24/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) is one of the most common and deadly cancers worldwide. For most patients diagnosed with mCRC and managed with 5-fluorouracil (5-FU)/leucovorin plus oxaliplatin (FOLFOX), the median survival time is still less than 2 years. Small molecule selective vascular endothelial growth factor receptor (VEGFR) inhibitors have been demonstrated to have strong anti-tumour activity in various cancer models. OBJECTIVE To demonstrate the efficacy and safety of selective VEGFR inhibitors in the management of mCRC. METHODS A comprehensive search in PubMed, EMBASE, Web of Science, Ovid MEDLINE, Google Scholar, Springer and Cochrane Central databases was performed for randomized controlled trials (RCTs) focusing on the effect of selective VEGFR inhibitors on mCRC. The primary outcome measures were progression-free survival (PFS) rates, overall survival (OS) rates, complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rates (ORRs), disease control rates (DCRs) and adverse effect (AE) rates. The dates of the included studies ranged from the inception of the database to January 15, 2020. RESULTS Twenty-two RCTs were included. A total of 9362 patients met the inclusion criteria. Compared with placebo, selective VEGFR inhibitors significantly increased the PFS rate, SD, PR and DCR, reduced PD, caused more treatment-emergent adverse events (TEAEs), hypertension, hand-foot skin reaction, diarrhoea, fatigue, and thrombocytopaenia and increased aspartate aminotransferase(AST) concentration. There was no significant difference between selective VEGFR inhibitors and placebo regarding OS rate, CR, ORR, proteinuria, hyperbilirubinaemia or alkaline phosphatase(ALP) concentration. Additionally, compared with FOLFOX4+placebo, FOLFOX4+ selective VEGFR inhibitors, clearly reduced PD, and caused more 3-4 AEs, serious AEs, hypertension, hand-foot syndrome, diarrhoea, nausea, vomiting, decreased appetite, dehydration, fatigue, dizziness, neutropaenia and thrombocytopaenia. For PFS rate, OS rate, CR, PR, SD, ORR, abdominal pain, peripheral sensory neuropathy, asthaenia, anaemia and hypokalaemia rates, there was no significant difference between FOLFOX4+ selective VEGFR inhibitors and FOLFOX4+placebo. However, compared with FOLFOX4+bevacizumab, FOLFOX4+selective VEGFR inhibitors, led to increased hypertension, neutropaenia, fatigue, thrombocytopaenia and asthaenia. There is no clear difference between FOLFOX4+selective VEGFR inhibitors and FOLFOX4+ bevacizumab with regard to PFS rate, OS rate, CR, PR, SD, PD, ORR, diarrhoea, nausea, vomiting, peripheral neuropathy and abdominal pain rates. Selective VEGFR inhibitors+cetuximab increased PFS and PR and reduced PD compared to cetuximab, but there was no statistical difference between the two groups for OS and SD. CONCLUSION Compared with placebo or cetuximab, selective VEGFR inhibitors alone or combined with cetuximab seemed to be more efficacious for mCRC respectively; however, the effects were not better than FOLFOX4 alone or when combined with bevacizumab for mCRC. Additionally, selective VEGFR inhibitors were not as safe as placebo or FOLFOX4 alone or in combination with bevacizumab in mCRC.
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Affiliation(s)
- Qin Fan
- Shanxi Dayi Hospital, Taiyuan, China
| | - Wenhao Lv
- Changzhi Medical College, Shanxi, China
| | - Yuexin Xu
- Changzhi Medical College, Shanxi, China
| | - Yuan Dong
- Changzhi Medical College, Shanxi, China
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Pasquier J, Ghiabi P, Chouchane L, Razzouk K, Rafii S, Rafii A. Angiocrine endothelium: from physiology to cancer. J Transl Med 2020; 18:52. [PMID: 32014047 PMCID: PMC6998193 DOI: 10.1186/s12967-020-02244-9] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/28/2020] [Indexed: 02/08/2023] Open
Abstract
The concept of cancer as a cell-autonomous disease has been challenged by the wealth of knowledge gathered in the past decades on the importance of tumor microenvironment (TM) in cancer progression and metastasis. The significance of endothelial cells (ECs) in this scenario was initially attributed to their role in vasculogenesis and angiogenesis that is critical for tumor initiation and growth. Nevertheless, the identification of endothelial-derived angiocrine factors illustrated an alternative non-angiogenic function of ECs contributing to both physiological and pathological tissue development. Gene expression profiling studies have demonstrated distinctive expression patterns in tumor-associated endothelial cells that imply a bilateral crosstalk between tumor and its endothelium. Recently, some of the molecular determinants of this reciprocal interaction have been identified which are considered as potential targets for developing novel anti-angiocrine therapeutic strategies.
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Affiliation(s)
- Jennifer Pasquier
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France.
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar.
| | - Pegah Ghiabi
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Lotfi Chouchane
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, 10065, USA
- Laboratory of Genetic Medicine and Immunology, Weill Cornell Medicine-Qatar, Doha, Qatar
| | - Kais Razzouk
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France
| | - Shahin Rafii
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Arash Rafii
- Nice Breast Institute, 57 bld de la Californie, 06000, Nice, France
- Stem Cell & Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Doha, Qatar
- Department of Genetic Medicine, Weill Cornell Medicine, New York, NY, 10065, USA
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Abdel-Rahman O, Ghosh S, Walker J. Outcomes of metastatic colorectal cancer patients in relationship to prior and concurrent antibiotics use; individual patient data analysis of three clinical trials. Clin Transl Oncol 2020; 22:1651-1656. [PMID: 32008218 DOI: 10.1007/s12094-020-02301-1] [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: 01/03/2020] [Accepted: 01/09/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND Antibiotic use at the time of chemotherapy has been linked with inferior outcomes among a number of solid tumors. The current study aims at further assessing this observation among metastatic colorectal cancer patients treated with first-line systemic chemotherapy. METHODS This is a pooled analysis of three clinical trial datasets (NCT00384176; NCT00272051; NCT00305188) that were accessed from the Project Data Sphere platform. Kaplan-Meier survival estimates were used to evaluate the impact of antibiotic use on overall and progression-free survival and multivariable Cox regression models were employed to further assess this impact. RESULTS A total of 1446 patients were included in the current analysis. These include 108 patients who received antibiotics before the start of chemotherapy, 499 patients who received antibiotics after the start of chemotherapy, and 839 patients who did not receive antibiotics. Using Kaplan-Meier survival estimates, the use of antibiotics prior to the start of chemotherapy was associated with worse progression-free (P = 0.001) and overall survival (P < 0.001). Likewise, when multivariable Cox regression analyses were conducted, prior antibiotic use is associated with worse progression-free (HR for antibiotic use during chemotherapy versus antibiotic use prior to chemotherapy = 0.764; 95% CI 0.604-0.966; P = 0.024) and overall survival (HR for antibiotic use during chemotherapy versus antibiotic use prior to chemotherapy = 0.710; 95% CI 0.537-0.940; P = 0.017). CONCLUSION Antibiotic use before (but not following) the start of 5FU-based chemotherapy is associated with worse progression-free and overall survival among patients with metastatic colorectal cancer.
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Affiliation(s)
- O Abdel-Rahman
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T4G1Z2, Canada.
| | - S Ghosh
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T4G1Z2, Canada
| | - J Walker
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, T4G1Z2, Canada
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Lombardi P, Marandino L, De Luca E, Zichi C, Reale ML, Pignataro D, Di Stefano RF, Ghisoni E, Mariniello A, Trevisi E, Leone G, Muratori L, La Salvia A, Sonetto C, Leone F, Aglietta M, Novello S, Scagliotti GV, Perrone F, Di Maio M. Quality of life assessment and reporting in colorectal cancer: A systematic review of phase III trials published between 2012 and 2018. Crit Rev Oncol Hematol 2020; 146:102877. [PMID: 31981880 DOI: 10.1016/j.critrevonc.2020.102877] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 12/09/2019] [Accepted: 01/17/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND In this study, our aim was to describe quality of life (QoL) prevalence and heterogeneity in QoL reporting in colorectal cancer phase III trials. METHODS We included all phase III trials evaluating anticancer drugs in colorectal cancer patients published between 2012 and 2018 by 11 major journals. RESULTS Out of the 67 publications identified, in 41 (61.2 %) QoL was not listed among endpoints. Out of 26 primary publications of trials including QoL among endpoints, QoL results were not reported in 10 (38.5 %). Overall, no QoL data were available in 51/67 (76.1 %) primary publications. In particular, in the metastatic setting, QoL data were not available in 12/18 (66.7 %) trials with primary endpoint overall survival, and in 20/29 (69.0 %) trials with other primary endpoints. CONCLUSIONS QoL was absent in a high proportion of recently published phase III trials in colorectal cancer, even in trials of second or further lines, where attention to QoL should be particularly high.
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Affiliation(s)
- Pasquale Lombardi
- Department of Oncology, University of Turin, Candiolo Cancer Institute - FPO- IRCCS, Candiolo, TO, Italy
| | - Laura Marandino
- Department of Oncology, University of Turin, Candiolo Cancer Institute - FPO- IRCCS, Candiolo, TO, Italy
| | - Emmanuele De Luca
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Torino, Italy
| | - Clizia Zichi
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Torino, Italy
| | - Maria Lucia Reale
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Daniele Pignataro
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Rosario F Di Stefano
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Eleonora Ghisoni
- Department of Oncology, University of Turin, Candiolo Cancer Institute - FPO- IRCCS, Candiolo, TO, Italy
| | - Annapaola Mariniello
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Elena Trevisi
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Gianmarco Leone
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Leonardo Muratori
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Anna La Salvia
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Cristina Sonetto
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Francesco Leone
- Department of Oncology, University of Turin, Candiolo Cancer Institute - FPO- IRCCS, Candiolo, TO, Italy
| | - Massimo Aglietta
- Department of Oncology, University of Turin, Candiolo Cancer Institute - FPO- IRCCS, Candiolo, TO, Italy
| | - Silvia Novello
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Giorgio V Scagliotti
- Department of Oncology, University of Turin, San Luigi Gonzaga Hospital, Orbassano, TO, Italy
| | - Francesco Perrone
- Clinical Trials Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale"-IRCCS, Napoli, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Torino, Italy.
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Yoshida Y, Kaneko M, Narukawa M. Magnitude of advantage in tumor response contributes to a better correlation between treatment effects on overall survival and progression-free survival: a literature-based meta-analysis of clinical trials in patients with metastatic colorectal cancer. Int J Clin Oncol 2020; 25:851-860. [PMID: 31950377 DOI: 10.1007/s10147-020-01619-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 01/07/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Although it is suggested that the endpoints originated from the concept of tumor shrinkage dynamics, such as early tumor shrinkage and depth of response, are strongly associated with overall survival (OS) in patients with metastatic colorectal cancer (mCRC), they are yet to be validated as a single surrogate endpoint of OS by themselves. This study aimed to investigate the impact of advantage in tumor response on the correlation between treatment effects on progression-free survival (PFS) and OS in mCRC patients. METHODS Based on an electronic search, we identified randomized controlled trials of first-line therapy for mCRC. The impact of advantage in objective response rate (ORR) on the correlation between treatment effects on PFS and OS was evaluated based on Spearman correlation coefficients (rs). RESULTS Forty-seven trials with a total of 24,018 patients were identified. The hazard ratio for PFS showed a relatively higher correlation with that for OS (rs = 0.63) when the trials were limited to those that demonstrated a larger difference in ORR, compared to the case for trials that demonstrated a smaller difference (rs = 0.32). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (targeted or non-targeted). CONCLUSIONS The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS benefit based on PFS in patients with mCRC. The accuracy of OS estimation in mCRC is expected to be improved by considering the degree of tumor shrinkage in conjunction with PFS.
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Affiliation(s)
- Yosuke Yoshida
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo, 108-8641, Japan. .,MSD K.K., a Subsidiary of Merck & Co., Inc, Kenilworth, NJ, USA.
| | - Masayuki Kaneko
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo, 108-8641, Japan
| | - Mamoru Narukawa
- Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Shirokane 5-9-1, Minato-ku, Tokyo, 108-8641, Japan
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Abdel-Rahman O. ECOG performance score 0 versus 1: impact on efficacy and safety of first-line 5-FU-based chemotherapy among patients with metastatic colorectal cancer included in five randomized trials. Int J Colorectal Dis 2019; 34:2143-2150. [PMID: 31732876 DOI: 10.1007/s00384-019-03430-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/10/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Within the context of metastatic colorectal cancer, patients with Eastern Cooperative Oncology Group (ECOG) performance score 0-1 are usually pooled together in clinical practice guidelines and clinical trials' reports. The current study aims to delineate potential differences in outcomes between metastatic colorectal cancer patients with ECOG score 0 versus 1 who are treated with currently accepted first-line fluorouracil (5FU)-based chemotherapy. METHODS The current study is based on a pooled dataset from five clinical trials of 5FU-based treatment for metastatic colorectal cancer (NCT00272051; NCT00115765; NCT00305188; NCT00364013; and NCT00384176). Patients with metastatic colorectal cancer and ECOG score of 0-1 were eligible for the current study. Multivariable logistic regression analysis was used to assess the relationship between ECOG performance status and the development of different toxicities. Kaplan-Meier survival estimates were used to clarify the impact of the ECOG score on overall and progression-free survivals. Multivariable Cox regression analysis was then used to evaluate the impact of ECOG score on overall and progression-free survivals. RESULTS A total of 3143 patients were included in the current analysis. Within multivariable logistic regression analysis, patients with an ECOG score of 0 have a lower probability of serious adverse events (OR 0.678; 95% CI 0.583-0.788; P < 0.001), fatal adverse events (OR 0.552; 95% CI 0.397-0.766; P < 0.001), high-grade anemia (OR 0.426; 95% CI 0.252-0.721; P = 0.001), and high-grade nausea/vomiting (OR 0.697; 95% CI 0.509-0.955; P = 0.024). Through Kaplan-Meier survival analysis, patients with an ECOG score of 0 have better overall and progression-free survivals (P < 0.001 for both endpoints). Median overall survival was 27.63 months among patients with an ECOG score of 0 versus 20.00 months among patients with an ECOG score of 1. Within multivariable Cox regression analysis, patients with ECOG score of 0 were associated with better overall and progression-free survivals (HR for overall survival 0.613; 95% CI 0.556-0.676; P < 0.001); (HR for progression-free survival 0.765; 95% CI 0.705-0.829; P < 0.001). CONCLUSION Compared with patients with ECOG score of 1, patients with ECOG score of 0 have better overall and progression-free survival, and less probability of serious and fatal adverse events. This distinction in outcomes should be noted when choosing appropriate therapeutic strategies and when designing/reporting the results of clinical trials.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T4G 1Z2, Canada.
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Abdel-Rahman O, Karachiwala H. Impact of age on toxicity and efficacy of 5-FU-based combination chemotherapy among patients with metastatic colorectal cancer; a pooled analysis of five randomized trials. Int J Colorectal Dis 2019; 34:1741-1747. [PMID: 31492988 DOI: 10.1007/s00384-019-03389-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/01/2019] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To assess the impact of age on toxicity and efficacy outcomes of metastatic colorectal cancer treated with 5FU-based combination chemotherapy. METHODS Project Data Sphere (PDS) platform has been accessed and de-identified datasets of the following clinical trials were downloaded (NCT00272051; NCT00305188; NCT00115765; NCT00364013; and NCT00384176). Multivariable logistic regression analysis was used to assess the impact of age (< 70 years versus ≥ 70 years) on the probability of different toxicities. Multivariable Cox regression analysis was additionally used to evaluate the impact of age (< 70 years versus ≥ 70 years) on overall and progression-free survival. RESULTS Among a total of 3223 patients included in the current analysis, 2488 patients were < 70 years; while 735 patients were ≥ 75 years at randomization. Older age was associated with a higher probability of serious adverse events (OR (odds ratio) 0.649; 95% CI 0.545-0.772; P < 0.001), fatal adverse events (OR 0.416; 95% CI 0.299-0.579; P < 0.001), all-grade diarrhea (OR 0.834; 95% CI 0.699-0.994, P = 0.043), high-grade diarrhea (OR 0.734; 95% CI 0.577-0.933, P = 0.012), high-grade stomatitis (OR 0.500, 95% CI 0.290-0.861, P = 0.012), high-grade thrombocytopenia (OR 0.578; 95% CI 0.359-0.930, P = 0.024), all-grade neutropenia (OR 0.690; 95% CI 0.578-0.824, P < 0.001), and high-grade neutropenia (OR 0.661; 95% CI 0.549-0.796, P < 0.001). In a multivariable Cox regression analysis for factors affecting overall survival, older age was associated with worse overall survival (hazard ratio for younger age versus older age 0.848; 95% CI 0.754-0.954, P = 0.006). On the hand, older age was not associated with worse progression-free survival (hazard ratio for younger age versus older age 0.933; 95% CI 0.843-1.032, P = 0.179). CONCLUSION Metastatic colorectal cancer patients ≥ 70 years of age who are treated with 5FU-based combination chemotherapy are more likely to have serious adverse events, fatal adverse events as well as worse overall survival compared to younger patients.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T4G1Z2, Canada.
| | - Hatim Karachiwala
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, T4G1Z2, Canada
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Burzykowski T, Coart E, Saad ED, Shi Q, Sommeijer DW, Bokemeyer C, Díaz-Rubio E, Douillard JY, Falcone A, Fuchs CS, Goldberg RM, Hecht JR, Hoff PM, Hurwitz H, Kabbinavar FF, Koopman M, Maughan TS, Punt CJA, Saltz L, Schmoll HJ, Seymour MT, Tebbutt NC, Tournigand C, Van Cutsem E, de Gramont A, Zalcberg JR, Buyse M. Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer. JAMA Netw Open 2019; 2:e1911750. [PMID: 31539075 PMCID: PMC6755539 DOI: 10.1001/jamanetworkopen.2019.11750] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Accepted: 07/28/2019] [Indexed: 12/25/2022] Open
Abstract
Importance Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). Objective To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. Design, Setting, and Participants Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti-epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. Main Outcomes and Measures Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size-weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. Results For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti-epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). Conclusions and Relevance In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer.
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Affiliation(s)
- Tomasz Burzykowski
- International Drug Development Institute, Louvain-la-Neuve, Belgium
- Hasselt University, Diepenbeek, Belgium
| | - Elisabeth Coart
- International Drug Development Institute, Louvain-la-Neuve, Belgium
| | - Everardo D. Saad
- International Drug Development Institute, Louvain-la-Neuve, Belgium
| | - Qian Shi
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Dirkje W. Sommeijer
- The University of Sydney, Camperdown, New South Wales, Australia
- Academic Medical Centre, Amsterdam, the Netherlands
- Flevohospital, Almere, the Netherlands
| | - Carsten Bokemeyer
- Department of Internal Medicine II and Clinic, University of Hamburg, Hamburg, Germany
| | - Eduardo Díaz-Rubio
- Hospital Clinico San Carlos and Centro de Investigación Biomédica en Red Cáncer, CIBERONC, Madrid, Spain
| | | | | | | | | | - J. Randolph Hecht
- David Geffen School of Medicine, University of California, Los Angeles
| | - Paulo M. Hoff
- Instituto de Câncer do Estado de São Paulo, São Paulo, Brazil
| | | | | | - Miriam Koopman
- Department of Medical Oncology, University Medical Centre Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Timothy S. Maughan
- Cancer Research UK and the Medical Research Council Oxford Institute for Radiation Oncology, Oxford, United Kingdom
| | - Cornelis J. A. Punt
- Amsterdam University Medical Centrum, Department of Medical Oncology, University of Amsterdam, Amsterdam, the Netherlands
| | - Leonard Saltz
- Memorial Sloan-Kettering Cancer Center, New York, New York
| | | | | | | | | | - Eric Van Cutsem
- Division of Digestive Oncology, University Hospitals Gasthuisberg Leuven, Leuven, Belgium
| | - Aimery de Gramont
- Katholieke Universiteit, Leuven, Belgium
- Franco-British Institute, Levallois-Perret, France
| | - John R. Zalcberg
- School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia
| | - Marc Buyse
- Hasselt University, Diepenbeek, Belgium
- International Drug Development Institute Inc, San Francisco, California
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Zhang Y, Zou JY, Wang Z, Wang Y. Fruquintinib: a novel antivascular endothelial growth factor receptor tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer. Cancer Manag Res 2019; 11:7787-7803. [PMID: 31496821 PMCID: PMC6701622 DOI: 10.2147/cmar.s215533] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 07/28/2019] [Indexed: 12/13/2022] Open
Abstract
Angiogenesis plays a critical role in the neoplastic growth, progression, and metastasis of colorectal cancer (CRC) in a process regulated by vascular endothelial growth factor (VEGF) family members and their receptors (VEGFR). Several small-molecule anti-VEGFR tyrosine kinase inhibitors (TKIs), such as regorafenib, famitinib, axitinib and apatinib, have been shown to be effective in treating metastatic colorectal cancer (mCRC). Fruquintinib (ELUNATE®) is a novel oral anti-VEGFR TKI, originated and developed by Hutchison MediPharma. Fruquintinib is a potent and highly selective small-molecule inhibitor of VEGFR-1, -2 and -3. In the Phase 3 FRESCO trial, fruquintinib improved both overall survival (OS) and progression-free survival (PFS) in patients with mCRC, compared with placebo. Fruquintinib also showed an acceptable safety and tolerability profile. Based on the data from this trial, fruquintinib was approved by the China Food and Drug Administration (CFDA) in 2018, for the treatment of patients with mCRC who had undergone at least two prior standard anticancer therapies. The existing clinical trials and future prospects of fruquintinib in mCRC will be discussed in this article. In addition, to better understand the role of fruquintinib in this setting, recent advances in other anti-VEGFR TKIs for mCRC treatment are also reviewed herein.
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Affiliation(s)
- Ying Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Jia-Yun Zou
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
| | - Ying Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, People's Republic of China
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Abdel-Rahman O. Effect of Body Mass Index on 5-FU-Based Chemotherapy Toxicity and Efficacy Among Patients With Metastatic Colorectal Cancer; A Pooled Analysis of 5 Randomized Trials. Clin Colorectal Cancer 2019; 18:e385-e393. [PMID: 31378656 DOI: 10.1016/j.clcc.2019.07.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Revised: 06/19/2019] [Accepted: 07/09/2019] [Indexed: 10/26/2022]
Abstract
INTRODUCTION We conducted this study to assess the effect of baseline body mass index (BMI) on the toxicity and efficacy of systemic chemotherapy among patients with metastatic colorectal cancer (CRC). PATIENTS AND METHODS This was a pooled analysis of 5 clinical trials (NCT00115765, NCT00364013, NCT00272051, NCT00305188, and NCT00384176), which were accessed from the Project Data Sphere (www.projectdatasphere.org) platform. Multivariable logistic regression analysis was used to assess the relationship between BMI and the probability of different toxicities. Kaplan-Meier survival estimates were used to assess the effect of BMI on overall and progression-free survival. Multivariable Cox regression analysis was additionally conducted to evaluate the effect of BMI on overall and progression-free survival. RESULTS A total of 3155 patients were included in the current analysis. Within multivariable logistic regression analysis, higher BMI was associated with higher probability of all-grade nausea and vomiting (odds ratio [OR], 1.025; 95% confidence interval [CI], 1.009-1.042; P = .002) and peripheral neuropathy (OR, 1.018; 95% CI, 1.001-1.034; P = .036; analysis restricted to oxaliplatin-treated patients). Lower BMI was associated with a higher probability of all-grade anemia (OR, 0.975; 95% CI, 0.956-0.995; P = .015), high-grade anemia (OR, 0.941; 95% CI, 0.890-0.994; P = .030), all-grade neutropenia (OR, 0.983; 95% CI, 0.968-0.999; P = .034), and high-grade neutropenia (OR, 0.962; 95% CI, 0.945-0.979; P < .001). Higher BMI also seemed to correlate with better overall survival in a multivariable Cox regression model (hazard ratio as a continuous variable: 0.977; 95% CI, 0.967-0.988; P < .001). CONCLUSION Lower BMI was associated with a higher risk of hematological toxicities (anemia and neutropenia) whereas higher BMI might be associated with a higher risk of nausea, vomiting, and peripheral neuropathy. Higher BMI also seemed to be associated with better overall survival among patients with metastatic CRC.
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Affiliation(s)
- Omar Abdel-Rahman
- Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada.
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Safety and Tolerability of Anti-Angiogenic Protein Kinase Inhibitors and Vascular-Disrupting Agents in Cancer: Focus on Gastrointestinal Malignancies. Drug Saf 2019; 42:159-179. [PMID: 30649744 DOI: 10.1007/s40264-018-0776-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Angiogenesis is an essential process for tumor growth and metastasis. Inhibition of angiogenesis as an anticancer strategy has shown significant results in a plethora of tumors. Anti-angiogenic agents are currently part of many standard-of-care options for several metastatic gastrointestinal cancers. Bevacizumab, aflibercept, ramucirumab, and regorafenib have significantly improved both progression-free and overall survival in different lines of treatment in metastatic colorectal cancer. Second-line ramucirumab and third-line apatinib are effective anti-angiogenic treatments for patients with metastatic gastric cancer. Unfortunately, the anti-angiogenic strategy has major practical limitations: resistance inevitably develops through redundancy of signaling pathways and selection for subclonal populations adapted for hypoxic conditions. Anti-angiogenic agents may be more effective in combination therapies, with not only cytotoxics but also other emerging compounds in the anti-angiogenic class or in the separate class of the so-called vascular-disrupting agents. This review aims to provide an overview of the approved and "under development" anti-angiogenic compounds as well as the vascular-disrupting agents in the treatment of gastrointestinal cancers, focusing on the actual body of knowledge available on therapy challenges, pharmacodynamic and pharmacokinetic mechanisms, safety profiles, promising predictive biomarkers, and future perspectives.
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Qin S, Li A, Yi M, Yu S, Zhang M, Wu K. Recent advances on anti-angiogenesis receptor tyrosine kinase inhibitors in cancer therapy. J Hematol Oncol 2019; 12:27. [PMID: 30866992 PMCID: PMC6417086 DOI: 10.1186/s13045-019-0718-5] [Citation(s) in RCA: 212] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 03/05/2019] [Indexed: 02/08/2023] Open
Abstract
Angiogenesis has always been the topic of major scientific interest in the field of malignant tumors. Nowadays, targeting angiogenesis has achieved success in various carcinomas by several mechanisms, including the use of anti-angiogenic small molecule receptor tyrosine kinase inhibitors (TKIs). The development of TKIs targeting pro-angiogenic receptors, mainly vascular endothelial growth factor receptor (VEGFR) family, have significantly improved the outcome of certain types of cancers, like renal cell carcinoma, hepatocellular carcinoma, and colorectal carcinoma. However, the general response rate is not very satisfactory. The particular toxicity profile and resistance to anti-angiogenic targeted agents are unavoidable, and no specific marker is available to screen responsive patients to TKIs for precision therapy. To date, about 11 anti-angiogenic TKIs with different binding capacities to angiogenic receptor tyrosine kinase have been approved for the treatment of patients with advanced cancers. This review presents all approved anti-angiogenic small molecule receptor TKIs so far with an emphasis on their indications and clinical efficacy. We also discuss the combination between TKIs and immune checkpoint blockade inhibitors based on the most recent exciting outcome in immunotherapy.
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Affiliation(s)
- Shuang Qin
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Anping Li
- Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Shengnan Yu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Mingsheng Zhang
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei, China. .,Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Abdel-Rahman O. 5-Fluorouracil-related Cardiotoxicity; Findings From Five Randomized Studies of 5-Fluorouracil-based Regimens in Metastatic Colorectal Cancer. Clin Colorectal Cancer 2019; 18:58-63. [DOI: 10.1016/j.clcc.2018.10.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 10/16/2018] [Accepted: 10/25/2018] [Indexed: 10/27/2022]
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Dzobo K, Senthebane DA, Thomford NE, Rowe A, Dandara C, Parker MI. Not Everyone Fits the Mold: Intratumor and Intertumor Heterogeneity and Innovative Cancer Drug Design and Development. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2019; 22:17-34. [PMID: 29356626 DOI: 10.1089/omi.2017.0174] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Disruptive innovations in medicine are game-changing in nature and bring about radical shifts in the way we understand human diseases, their treatment, and/or prevention. Yet, disruptive innovations in cancer drug design and development are still limited. Therapies that cure all cancer patients are in short supply or do not exist at all. Chief among the causes of this predicament is drug resistance, a mechanism that is much more dynamic than previously understood. Drug resistance has limited the initial success experienced with biomarker-guided targeted therapies as well. A major contributor to drug resistance is intratumor heterogeneity. For example, within solid tumors, there are distinct subclones of cancer cells, presenting profound complexity to cancer treatment. Well-known contributors to intratumor heterogeneity are genomic instability, the microenvironment, cellular genotype, cell plasticity, and stochastic processes. This expert review explains that for oncology drug design and development to be more innovative, we need to take into account intratumor heterogeneity. Initially thought to be the preserve of cancer cells, recent evidence points to the highly heterogeneous nature and diverse locations of stromal cells, such as cancer-associated fibroblasts (CAFs) and cancer-associated macrophages (CAMs). Distinct subpopulations of CAFs and CAMs are now known to be located immediately adjacent and distant from cancer cells, with different subpopulations exerting different effects on cancer cells. Disruptive innovation and precision medicine in clinical oncology do not have to be a distant reality, but can potentially be achieved by targeting these spatially separated and exclusive cancer cell subclones and CAF subtypes. Finally, we emphasize that disruptive innovations in drug discovery and development will likely come from drugs whose effect is not necessarily tumor shrinkage.
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Affiliation(s)
- Kevin Dzobo
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa .,2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Dimakatso Alice Senthebane
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa .,2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Nicholas Ekow Thomford
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - Arielle Rowe
- 1 International Centre for Genetic Engineering and Biotechnology (ICGEB) , Cape Town, South Africa
| | - Collet Dandara
- 3 Pharmacogenetics Research Group, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town , Cape Town, South Africa
| | - M Iqbal Parker
- 2 Division of Medical Biochemistry, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town , Cape Town, South Africa
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Chibaudel B, Bachet JB, André T, Auby D, Desramé J, Deplanque G, Lecaille C, Louvet C, Tournigand C, Lebrun-Ly V, Dauba J, Lledo G, Garcia ML, Dubreuil O, Hamed NB, Meurisse A, Larsen AK, Tijeras-Raballand A, Bonnetain F, De Gramont A. Efficacy of aflibercept with FOLFOX and maintenance with fluoropyrimidine as first‑line therapy for metastatic colorectal cancer: GERCOR VELVET phase II study. Int J Oncol 2019; 54:1433-1445. [PMID: 30720091 DOI: 10.3892/ijo.2019.4709] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 12/18/2018] [Indexed: 11/06/2022] Open
Abstract
Aflibercept in combination with 5‑fluorouracil (5‑FU)/irinotecan improves overall survival in the second‑line therapy of patients with metastatic colorectal cancer (mCRC). In this study, we evaluated the effects of aflibercept in first‑line therapy with FOLFOX followed by maintenance with fluoropyrimidine. VELVET was a prospective, single‑arm multicenter phase II study (completed). Patients with previously untreated, unresectable, evaluable or measurable mCRC, with an age ≥18 years, and an ECOG performance status of 0‑2 received 6 cycles of modified FOLFOX7 (5‑FU/folinic acid and oxaliplatin) with aflibercept at 4 mg/kg every 2 weeks followed by maintenance therapy with fluoropyrimidine with aflibercept until disease progression or limiting toxicity. The reintroduction of oxaliplatin was performed at first progression. The primary endpoint was progression‑free survival (PFS) at 6 months. From May, 2013 to May, 2014, 49 patients were included and 48 were evaluable for response. In total, 33 patients (67.4%) were alive without progression at 6 months. The Kaplan‑Meier survival 6‑month and 1‑year PFS rates were 79.1 and 36.1%, respectively, and the median PFS was 9.3 months (95% CI, 8.3‑12.5). The objective response rate was 59.2% (N=29/49). The most common (≥10%) grade 3‑4 adverse events were hypertension (23%), fatigue (15%), neutropenia (12%), neuropathy (12%) and stomatitis (10%). Three (6%) treatment‑related deaths occurred: One from stroke, one from pulmonary embolism and one from neutropenic sepsis. On the whole, this study demonstrates the efficacy of aflibercept in combination with an oxaliplatin‑based regimen in the first‑line therapy of patients with mCRC. A strict monitoring of blood pressure and immediate management of hypertension during therapy is mandatory.
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Affiliation(s)
- Benoist Chibaudel
- Department of Medical Oncology, Franco‑British Institute, 92300 Levallois‑Perret, France
| | - Jean-Baptiste Bachet
- Department of Gastroenterology, Sorbonne University, Pierre and Marie Curie University Paris 6, CH Universitaire Pitié‑Salpétrière, 75013 Paris, France
| | - Thierry André
- Department of Medical Oncology, Sorbonne University, Hospital Saint‑Antoine, 75012 Paris, France
| | - Dominique Auby
- Department of Medical Oncology, CH de Mont‑de‑Marsan, Hospital Layné, 40024 Mont‑de‑Marsan, France
| | - Jérôme Desramé
- Department of Gastroenterology, Private Hospital Jean Mermoz, 69008 Lyon, France
| | - Gaël Deplanque
- Department of Medical Oncology, Hospital Saint‑Joseph, 75014 Paris, France
| | - Cédric Lecaille
- Department of Medical Oncology, Polyclinic Bordeaux Nord, 33300 Bordeaux, France
| | - Christophe Louvet
- Department of Medical Oncology, Institut Mutualiste Montsouris, 75014 Paris, France
| | | | | | - Jérôme Dauba
- Department of Medical Oncology, CH de Mont‑de‑Marsan, Hospital Layné, 40024 Mont‑de‑Marsan, France
| | - Gérard Lledo
- Department of Gastroenterology, Private Hospital Jean Mermoz, 69008 Lyon, France
| | - Marie-Line Garcia
- Centre de Recherche Saint‑Antoine, INSERM U938, Hospital Saint‑Antoine, 75012 Paris, France
| | - Olivier Dubreuil
- Department of Gastroenterology, Hospital Pitié‑Salpétrière, 75013 Paris, France
| | - Nabil Baba Hamed
- Department of Medical Oncology, Hospital Saint‑Joseph, 75014 Paris, France
| | - Aurélia Meurisse
- Department of Biostatistics, CHU Besançon, 25030 Besançon, France
| | - Annette K Larsen
- Cancer Biology and Therapeutics, Centre de Recherche Saint‑Antoine, INSERM U938, Sorbonne Université Faculté de Médecine, 75012 Paris, France
| | | | - Franck Bonnetain
- Department of Biostatistics, CHU Besançon, 25030 Besançon, France
| | - Aimery De Gramont
- Department of Medical Oncology, Franco‑British Institute, 92300 Levallois‑Perret, France
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Reguera-Nuñez E, Xu P, Chow A, Man S, Hilberg F, Kerbel RS. Therapeutic impact of Nintedanib with paclitaxel and/or a PD-L1 antibody in preclinical models of orthotopic primary or metastatic triple negative breast cancer. J Exp Clin Cancer Res 2019; 38:16. [PMID: 30635009 PMCID: PMC6330500 DOI: 10.1186/s13046-018-0999-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 12/06/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Triple negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, in part because of the current lack of any approved molecularly targeted therapy. We evaluated various combinations of three different drugs: nintedanib, an antiangiogenic TKI targeting VEGF receptors, paclitaxel (PTX), or a PD-L1 antibody, using models of orthotopic primary or advanced metastatic TNBC involving a metastatic variant of the MDA-MB-231 human cell line (called LM2-4) in SCID mice and two mouse lines (EMT-6 and a drug-resistant variant, EMT-6/CDDP) in immunocompetent mice. These drugs were selected based on the following: PTX is approved for TNBC; nintedanib combined with docetaxel has shown phase III clinical trial success, albeit in NSCLC; VEGF can act as local immunosuppressive factor; and PD-L1 antibody plus taxane therapy was recently reported to have encouraging phase III trial benefit in TNBC. METHODS Statistical analyses were performed with ANOVA followed by Tukey's Multiple Comparison Test or with Kruskal-Wallis test followed by Dunn's Multiple Comparison Test. Survival curves were analyzed using a Log-rank (Mantel Cox) test. Differences were considered statistically significant when p values were < 0.05. RESULTS Toxicity analyses showed that nintedanib is well tolerated when administered 5-days ON 2-days OFF; PTX toxicity differed in mice, varied with cell lines used and may have influenced median survival in the metastatic EMT6/CDDP model; while toxicity of PD-L1 therapy depended on the cell lines and treatment settings tested. In the LM2-4 system, combining nintedanib with PTX enhanced overall antitumor efficacy in both primary and metastatic treatment settings. In immunocompetent mice, combining nintedanib or PTX with the PD-L1 antibody improved overall antitumor efficacy. Using the advanced metastatic EMT-6/CDDP model, optimal efficacy results were obtained using the triple combination. CONCLUSIONS These results suggest circumstances where nintedanib plus PTX may be potentially effective in treating TNBC, and nintedanib with PTX may improve PD-L1 therapy of metastatic TNBC.
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Affiliation(s)
- Elaine Reguera-Nuñez
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario Canada
- Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave, room S-217, Toronto, Ontario M4N 3M5 Canada
| | - Ping Xu
- Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave, room S-217, Toronto, Ontario M4N 3M5 Canada
| | - Annabelle Chow
- Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave, room S-217, Toronto, Ontario M4N 3M5 Canada
| | - Shan Man
- Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave, room S-217, Toronto, Ontario M4N 3M5 Canada
| | | | - Robert S. Kerbel
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario Canada
- Biological Sciences Platform, Sunnybrook Research Institute, 2075 Bayview Ave, room S-217, Toronto, Ontario M4N 3M5 Canada
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Webster-Clark MA, Sanoff HK, Stürmer T, Peacock Hinton S, Lund JL. Diagnostic Assessment of Assumptions for External Validity: An Example Using Data in Metastatic Colorectal Cancer. Epidemiology 2019; 30:103-111. [PMID: 30252687 PMCID: PMC6269648 DOI: 10.1097/ede.0000000000000926] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Methods developed to estimate intervention effects in external target populations assume that all important effect measure modifiers have been identified and appropriately modeled. Propensity score-based diagnostics can be used to assess the plausibility of these assumptions for weighting methods. METHODS We demonstrate the use of these diagnostics when assessing the transportability of treatment effects from the standard of care for metastatic colorectal cancer control arm in a phase III trial (HORIZON III) to a target population of 1,942 Medicare beneficiaries age 65+ years. RESULTS In an unadjusted comparison, control arm participants had lower mortality compared with target population patients treated with the standard of care therapy (trial vs. target hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.58, 0.89). Applying inverse odds of sampling weights attenuated the trial versus target HR (weighted HR = 0.96, 95% CI = 0.73, 1.26). However, whether unadjusted or weighted, hazards did not appear proportional. At 6 months of follow-up, mortality was lower in the weighted trial population than the target population (weighted trial vs. target risk difference [RD] = -0.07, 95% CI = -0.13, -0.01), but not at 12 months (weighted RD = 0.00, 95% CI = -0.09, 0.09). CONCLUSION These diagnostics suggest that direct transport of treatment effects from HORIZON III to the Medicare population is not valid. However, the proposed sampling model might allow valid transport of the treatment effects on longer-term mortality from HORIZON III to the Medicare population treated in clinical practice. See video abstract at, http://links.lww.com/EDE/B435.
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Affiliation(s)
| | - Hanna K Sanoff
- Department of Medicine, University of North Carolina, Chapel Hill, NC
| | - Til Stürmer
- From the Department of Epidemiology, University of North Carolina, Chapel Hill, NC
| | | | - Jennifer L Lund
- From the Department of Epidemiology, University of North Carolina, Chapel Hill, NC
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Abdel-Rahman O. Impact of Sex on Chemotherapy Toxicity and Efficacy Among Patients With Metastatic Colorectal Cancer: Pooled Analysis of 5 Randomized Trials. Clin Colorectal Cancer 2018; 18:110-115.e2. [PMID: 30679026 DOI: 10.1016/j.clcc.2018.12.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Accepted: 12/24/2018] [Indexed: 12/28/2022]
Abstract
PURPOSE To evaluate the impact of sex on toxicity and efficacy outcomes among patients with metastatic colorectal cancer receiving first-line 5-fluorouracil-based regimens. PATIENTS AND METHODS A pooled analysis of data sets from 5 clinical trials (NCT00115765, NCT00364013, NCT00272051, NCT00305188, NCT00384176) was performed. Kaplan-Meier analysis and log-rank testing were used to assess the differences in overall and progression-free survival between male and female subjects. Chi-square testing was used to examine the differences in the incidence of different toxicities between male and female subjects. Multivariate logistic regression analysis (adjusted for age, body mass index, Eastern Cooperative Oncology Group performance status, race, bevacizumab-containing treatment, and panitumumab-containing treatment) was further utilized to assess the impact of gender on different toxicities. Most of the patients were treated with FOLFOX (folinic acid, fluorouracil, and oxaliplatin)-based regimens. RESULTS A total of 3223 participants were included in the pooled cohort, among which were 1925 male and 1298 female subjects. Kaplan-Meier survival analysis and log-rank testing were utilized to compare overall and progression-free survival outcomes between male and female subjects. For both end points, there was no difference between male and female subjects (P = .884; P = .647, respectively). Comparing female to male subjects, female subjects were more likely to experience alopecia (20% vs. 8.6%; P < .001), all-grade diarrhea (60.3% vs. 56.7%; P = .039), all-grade nausea and vomiting (68.7% vs. 56.6%; P < .001), high-grade nausea and vomiting (7.1% vs. 4.5%; P = .002), all-grade anemia (19.6% vs. 14.2%; P < .001), all-grade neutropenia (51.1% vs. 36.6%; P < .001), and high-grade neutropenia (37.1% vs. 24.1%; P < .001). These differences were further confirmed in multivariate logistic regression analyses. CONCLUSION Female subjects with metastatic colorectal cancer receiving first-line chemotherapy demonstrated higher rates of a number of toxicities (essentially hematologic and gastrointestinal in nature). Additional studies into the differential effect of systemic therapy on female versus male subjects are needed.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt; Department of Oncology, University of Calgary, Tom Baker Cancer Centre, Calgary, Alberta, Canada.
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Giuliani J, Bonetti A. First-line therapies in metastatic colorectal cancer: integrating clinical benefit with the costs of drugs. Int J Colorectal Dis 2018; 33:1505-1516. [PMID: 30196427 DOI: 10.1007/s00384-018-3158-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/29/2018] [Indexed: 02/04/2023]
Abstract
PURPOSE In light of the relevant expenses of pharmacological interventions, it might be interesting to make a balance between the cost of the new drugs administered and the added value represented by the improvement in progression free survival (PFS) in first-line for metastatic colorectal cancer CRC (mCRC). METHODS Phase III randomized controlled trials (RCTs) that compared at least two first-line chemotherapy regimens for mCRC patients were evaluated. Differences in PFS between the different arms were compared with the pharmacological costs (at the pharmacy of our hospital). The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) was applied to the above RCTs. RESULTS Overall 28 phase III RCTs, including 19,958 patients, were analyzed. The FOLFOX resulted the least expensive (56 € per month of PFS gained) while the addition of irinotecan to FOLFOX (FOLFOXIRI) increased only marginally the costs (90 € per month of PFS gained). Treatments including the monoclonal antibodies showed a cost per month of PFS gained of 2823 € (FOLFIRI with cetuximab in KRAS wild-type patients and liver-only metastases), of € 15,822 (FOLFOX with panitumumab in KRAS wild type), and of 13,383 € (FOLFOX with bevacizumab). According to the ESMO-MCBS, the treatments including an EGFR-inhibitor (cetuximab or panitumumab) were associated with a score of 4, while the inclusion of bevacizumab reached a score of 3. CONCLUSIONS Our data demonstrate a huge difference in cost per month of PFS gained in modern first-line treatments in mCRC.
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Affiliation(s)
- Jacopo Giuliani
- Department of Oncology, Mater Salutis Hospital-Az. ULSS 9 Scaligera, Via Gianella 1-37045, Legnago, VR, Italy.
| | - Andrea Bonetti
- Department of Oncology, Mater Salutis Hospital-Az. ULSS 9 Scaligera, Via Gianella 1-37045, Legnago, VR, Italy
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Chakedis J, Beal EW, Sun S, Galo J, Chafitz A, Davidson G, Reardon J, Dillhoff M, Pawlik TM, Abdel-Misih S, Bloomston M, Schmidt CR. Implementation and early outcomes for a surgeon-directed hepatic arterial infusion pump program for colorectal liver metastases. J Surg Oncol 2018; 118:1065-1073. [DOI: 10.1002/jso.25249] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 09/04/2018] [Indexed: 12/13/2022]
Affiliation(s)
- Jeffery Chakedis
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Eliza W. Beal
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Steven Sun
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Jason Galo
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Aaron Chafitz
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Gail Davidson
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Joshua Reardon
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Mary Dillhoff
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Timothy M. Pawlik
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | - Sherif Abdel-Misih
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
| | | | - Carl R. Schmidt
- Division of Surgical Oncology, Department of Surgery; The Ohio State University Wexner Medical Center, Arthur G. James Cancer Hospital and Solove Research Institute; Columbus Ohio
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Wang XS, Ding XZ, Li XC, He Y, Kong DJ, Zhang L, Hu XC, Yang JQ, Zhao MQ, Gao SG, Lin TY, Li Y. A highly integrated precision nanomedicine strategy to target esophageal squamous cell cancer molecularly and physically. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2018; 14:2103-2114. [PMID: 30047470 PMCID: PMC6648684 DOI: 10.1016/j.nano.2018.06.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/31/2018] [Accepted: 06/13/2018] [Indexed: 01/02/2023]
Abstract
The prognosis of esophageal squamous cell carcinoma is poor. We hereby presented a highly integrated and clinically relevant precision nanomedicine strategy to target ESCC molecularly and physically for significant improvement of the treatment efficacy. We firstly identified PI3K overexpression in patient samples and its relation to poor patient survival. With our highly versatile tumor-targeted drug delivery platform (DCM), we were able to load a potent but toxic docetaxel (DTX) and a PI3K inhibitor (AZD8186) with favorable physical properties. The combination of the DTX-DCM and AZD8186-DCM showed a highly efficacious and synergistic anti-tumor effect and decreased hematotoxicity. A pro-apoptotic protein, Bax was significantly upregulated in ESCC cells treated with combination therapy compared to that with monotherapy. This study utilized a highly integrated precision nano-medicine strategy that combines the identification of cancer molecular target from human patients, precision drug delivery and effective combination therapy for the development of better ESCC treatment.
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Affiliation(s)
- Xin-Shuai Wang
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Xue-Zhen Ding
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Xiao-Cen Li
- Department of Biochemistry & Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA
| | - Yixuan He
- Department of Biochemistry & Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA
| | - De-Jiu Kong
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Li Zhang
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Xiao-Chen Hu
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Jun-Qiang Yang
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - Meng-Qi Zhao
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China
| | - She-Gan Gao
- Henan Key Laboratory of Cancer Epigenetics; Cancer hospital, The First Affiliated Hospital, College of Clinical Medicine, Medical College of Henan University of Science and Technology, Luoyang, China.
| | - Tzu-Yin Lin
- Department of Internal Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
| | - Yuanpei Li
- Department of Biochemistry & Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
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Goey KKH, Mahmoud R, Sørbye H, Glimelius B, Köhne CH, Sargent DJ, Punt CJA, van Oijen MGH, Koopman M. Reporting of patient characteristics and stratification factors in phase 3 trials investigating first-line systemic treatment of metastatic colorectal cancer: A systematic review. Eur J Cancer 2018; 96:115-124. [PMID: 29729562 DOI: 10.1016/j.ejca.2018.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 03/25/2018] [Accepted: 03/30/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Patient characteristics and stratification factors are important factors influencing trial outcomes. Uniform reporting on these parameters would facilitate cross-study comparisons and extrapolation of trial results to clinical practice. In 2007, standardisation on patient characteristics reporting and stratification in metastatic colorectal cancer (mCRC) trials was proposed. We investigated the reporting of prognostic factors and implementation of this proposal in mCRC trials published from 2005 to 2016. METHODS We searched PubMed and Embase (January 2005 - June 2016) for first-line phase 3 mCRC trials. Patient characteristics reporting and use of stratification factors were extracted and analysed for adherence to the proposal from 2007. RESULTS Sixty-seven trials (35,315 patients) were identified, reporting 48 different patient characteristics (median: 9 [range: 5-18] per study). Age, gender, performance status (PS), primary tumour site and adjuvant chemotherapy were frequently reported (87%-100%), in contrast to laboratory values, such as alkaline phosphatase, lactate dehydrogenase and white blood cell count (10%-25%). We identified 29 different stratification factors (median: 3 [range: 1-9] per study). The most common strata were PS and treatment centre (>60%). A median of 8/12 (range: 4-11) of the proposed parameters was reported. Although the percentage of studies reporting each factor slightly increased over time, there was no significant correlation between publication year and adherence to the proposal from 2007. CONCLUSIONS We observed persistent heterogeneity in the reporting of patient characteristics and use of stratification factors in first-line mCRC trials. The proposal from 2007 has not led to increased uniformity of patient characteristics reporting and use of stratification over time. There is an urgent need to address this issue to improve the interpretation of trial results.
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Affiliation(s)
- Kaitlyn K H Goey
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Remi Mahmoud
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Halfdan Sørbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, Haukeland University Hospital, Bergen, Norway
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Claus-Henning Köhne
- University Clinic for Internal Medicine, Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany
| | - Daniel J Sargent
- Division of Biomedical Statistics and Informatics, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Cornelis J A Punt
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Martijn G H van Oijen
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
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Ba-Sang DZ, Long ZW, Teng H, Zhao XP, Qiu J, Li MS. A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer. Oncotarget 2018; 7:84468-84479. [PMID: 27806321 PMCID: PMC5356673 DOI: 10.18632/oncotarget.12994] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 10/02/2016] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). RESULTS Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. MATERIALS AND METHODS Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). CONCLUSIONS These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC.
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Affiliation(s)
- Dan-Zeng Ba-Sang
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Zi-Wen Long
- Department of Gastric Cancer and Soft-Tissue Sarcoma Surgery, Fudan university Shanghai Cancer Center, Shanghai 200032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Hao Teng
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Xu-Peng Zhao
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Jian Qiu
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Ming-Shan Li
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
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