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Lecomte T, Giraudeau B, Phelip JM, Tournigand C, Ducreux M, Tougeron D, Lepage C, Mineur L, Laplaige P, Desgrippes R, Artru P, Borg C, Jary M, Bouché O, Metges JP, Guimbaud R, Aparicio T, Foubert F, Hautefeuille V, Muller M, Bouhier-Leporrier K, Darrius R, Lobet S, Monmousseau F, Bejan-Angoulvant T, Paintaud G, Ternant D. Bevacizumab-based chemotherapy adaptive to pharmacokinetic of bevacizumab in first-line treatment of patients with unresectable metastatic colorectal cancer: A double-blind, multicenter, randomized phase III trial study (PHARBEVACOL trial). Dig Liver Dis 2025; 57:624-630. [PMID: 40044552 DOI: 10.1016/j.dld.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 02/13/2025] [Indexed: 04/27/2025]
Abstract
Bevacizumab shows inter-individual pharmacokinetic variability, with an exposure-response relationship in metastatic colorectal cancer (mCRC) patients. This study explores whether a double dose of bevacizumab, compared to a standard dose, increases efficacy in mCRC patients treated with bevacizumab-based chemotherapy as first-line therapy and who have a low initial trough concentration of bevacizumab. PHARBEVACOL is a multicenter, randomized, double-blind, two-parallel group trial. All patients will receive first-line bi-weekly 5 mg/kg bevacizumab-based chemotherapy and those with low initial bevacizumab concentrations (≤15.5 mg/L) will be randomized to either continue the standard dose (5 mg/kg every 14 days) or receive a double dose (10 mg/kg every 14 days). The primary objective is to evaluate the effect of doubling dose on progression-free survival (PFS). During a screening phase, the first serum trough concentration will be measured on day 14, before the second infusion of bevacizumab. We hypothesize a 40 % PFS in the control group at 9 months versus 60 % in the study group, corresponding to a hazard ratio of 0.56. With 80 % power, a 5 % two-sided type I error, and a minimum 12-month follow-up, 116 patients need to be included. Since only 50 % of screened patients will be eligible for randomization, approximately 244 patients will be screened. Recruitment is scheduled to begin in February 2025.
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Affiliation(s)
- Thierry Lecomte
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Tours, Tours, France; INSERM UMR 1069, N2COx "Niche, Nutrition, Cancer and Oxidative Metabolism", Université de Tours, Tours, France.
| | | | - Jean-Marc Phelip
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU Saint Etienne, Saint Etienne, France
| | | | - Michel Ducreux
- Service d'Oncologie digestive, Institut Gustave Roussy, Villejuif, France
| | - David Tougeron
- Service d'Hépato-gastroentérologie, CHU de Poitiers, Poitiers, France
| | - Côme Lepage
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Dijon, Dijon, France
| | | | | | - Romain Desgrippes
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CH de Saint-Malo, Saint-Malo, France
| | | | - Christophe Borg
- Service d'Oncologie Médicale, CHU de Besançon, Besançon, France
| | - Marine Jary
- Service de chirurgie digestive, CHU Estaing, Clermont-Ferrand, France
| | - Olivier Bouché
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Reims, Reims, France
| | | | - Rosine Guimbaud
- Service d'oncologie médicale, CHU de Toulouse, Toulouse, France
| | - Thomas Aparicio
- Service d'Hépato-gastroentérologie et de cancérologie digestive, Hôpital Saint-Louis, AP-HP, Paris, France
| | - Fanny Foubert
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Nantes, Nantes, France
| | - Vincent Hautefeuille
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU d'Amiens, Amiens, France
| | - Marie Muller
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CHU de Nancy, Nancy, France
| | | | - Rémi Darrius
- Service d'Hépato-gastroentérologie et de cancérologie digestive, CH de Colmar, Colmar, France
| | - Sarah Lobet
- INSERM UMR 1069, N2COx "Niche, Nutrition, Cancer and Oxidative Metabolism", Université de Tours, Tours, France
| | | | - Théodora Bejan-Angoulvant
- Service de Pharmacologie Médicale, CHU de Tours, Tours, France; UMR 1327, ISCHEMIA, Membrane signalling and inflammation in reperfusion injuries, INSERM, Université de Tours, Tours, France; Plateforme Recherche, Centre Pilote de suivi Biologique des traitements par Anticorps, CHU de Tours, Tours, France
| | - Gilles Paintaud
- Service de Pharmacologie Médicale, CHU de Tours, Tours, France; UMR 1327, ISCHEMIA, Membrane signalling and inflammation in reperfusion injuries, INSERM, Université de Tours, Tours, France; Plateforme Recherche, Centre Pilote de suivi Biologique des traitements par Anticorps, CHU de Tours, Tours, France
| | - David Ternant
- Service de Pharmacologie Médicale, CHU de Tours, Tours, France; UMR 1327, ISCHEMIA, Membrane signalling and inflammation in reperfusion injuries, INSERM, Université de Tours, Tours, France; Plateforme Recherche, Centre Pilote de suivi Biologique des traitements par Anticorps, CHU de Tours, Tours, France
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Wang F, Chen G, Zhang Z, Yuan Y, Wang Y, Gao Y, Sheng W, Wang Z, Li X, Yuan X, Cai S, Ren L, Liu Y, Xu J, Zhang Y, Liang H, Wang X, Zhou A, Ying J, Li G, Cai M, Ji G, Li T, Wang J, Hu H, Nan K, Wang L, Zhang S, Li J, Xu R. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of colorectal cancer, 2024 update. Cancer Commun (Lond) 2025; 45:332-379. [PMID: 39739441 PMCID: PMC11947620 DOI: 10.1002/cac2.12639] [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: 11/27/2024] [Accepted: 12/02/2024] [Indexed: 01/02/2025] Open
Abstract
The 2024 updates of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for the diagnosis and treatment of colorectal cancer emphasize standardizing cancer treatment in China, highlighting the latest advancements in evidence-based medicine, healthcare resource access, and precision medicine in oncology. These updates address disparities in epidemiological trends, clinicopathological characteristics, tumor biology, treatment approaches, and drug selection for colorectal cancer patients across diverse regions and backgrounds. Key revisions include adjustments to evidence levels for intensive treatment strategies, updates to regimens for deficient mismatch repair (dMMR)/ microsatellite instability-high (MSI-H) patients, proficient mismatch repair (pMMR)/ microsatellite stability (MSS) patients who have failed standard therapies, and rectal cancer patients with low recurrence risk. Additionally, recommendations for digital rectal examination and DNA polymerase epsilon (POLE)/ DNA polymerase delta 1 (POLD1) gene mutation testing have been strengthened. The 2024 CSCO Guidelines are based on both Chinese and international clinical research, as well as expert consensus, ensuring their relevance and applicability in clinical practice, while maintaining a commitment to scientific rigor, impartiality, and timely updates.
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Affiliation(s)
- Feng Wang
- Department of Medical OncologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
| | - Gong Chen
- Department of Colorectal SurgerySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for CancerGuangzhouGuangdongP. R. China
| | - Zhen Zhang
- Department of Radiation OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Ying Yuan
- Department of Medical OncologyThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Yi Wang
- Department of RadiologyPeking University People's HospitalBeijingP. R. China
| | - Yuan‐Hong Gao
- Department of Radiation OncologySun Yat‐sen University Cancer Centre, The State Key Laboratory of Oncology in South ChinaGuangzhouGuangdongP. R. China
| | - Weiqi Sheng
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Zixian Wang
- Department of Medical OncologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
| | - Xinxiang Li
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Xianglin Yuan
- Department of OncologyTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Sanjun Cai
- Department of Colorectal SurgeryFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Li Ren
- Department of General SurgeryZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Yunpeng Liu
- Department of Medical OncologyThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Jianmin Xu
- Department of General SurgeryZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Yanqiao Zhang
- Department of OncologyHarbin Medical University Cancer HospitalHarbinHeilongjiangP. R. China
| | - Houjie Liang
- Department of OncologySouthwest HospitalThird Military Medical University (Army Medical University)ChongqingP. R. China
| | - Xicheng Wang
- Department of Gastrointestinal OncologyCancer Medical Center, Peking Union Medical College HospitalChinese Academy of Medical SciencesBeijingChina
| | - Aiping Zhou
- Department of Medical OncologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jianming Ying
- Department of PathologyChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Guichao Li
- Department of Radiation OncologyFudan University Shanghai Cancer CenterShanghaiP. R. China
| | - Muyan Cai
- Department of PathologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South ChinaGuangzhouGuangdongP. R. China
| | - Gang Ji
- Department of Gastrointestinal SurgeryXijing HospitalAir Force Military Medical UniversityXi'anShaanxiP. R. China
| | - Taiyuan Li
- Department of General SurgeryThe First Affiliated Hospital of Nanchang UniversityNanchangJiangxiP. R. China
| | - Jingyu Wang
- Department of RadiologyThe First Hospital of Jilin UniversityChangchunJilinP. R. China
| | - Hanguang Hu
- Department of Medical OncologyThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Kejun Nan
- Department of Medical OncologyThe First Affiliated Hospital of Xi'an Jiaotong UniversityXi'anShaanxiP. R. China
| | - Liuhong Wang
- Department of RadiologySecond Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Suzhan Zhang
- Department of Colorectal SurgeryThe Second Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangP. R. China
| | - Jin Li
- Department of Medical OncologyShanghai GoBroad Cancer HospitalChina Pharmaceutical UniversityShanghaiP. R. China
| | - Rui‐Hua Xu
- Department of Medical OncologySun Yat‐sen University Cancer Center, The State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat‐sen University, Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical SciencesGuangzhouGuangdongP. R. China
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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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Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [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: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
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Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Druzhkova I, Bylinskaya K, Plekhanov A, Kostyuk A, Kirillin M, Perekatova V, Khilov A, Orlova A, Polozova A, Komarova A, Lisitsa U, Sirotkina M, Shirmanova M, Turchin I. Effects of FOLFOX Chemotherapy on Tumor Oxygenation and Perfused Vasculature: An In Vivo Study by Optical Techniques. JOURNAL OF BIOPHOTONICS 2024. [DOI: 10.1002/jbio.202400339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/16/2024] [Indexed: 01/12/2025]
Abstract
ABSTRACTThe effects of cytotoxic chemotherapy on tumor vasculature and oxygenation are in the focus of modern investigations because vascular structure and distribution of oxygen influence tumor behavior and treatment response. The aim of our study was to monitor changes in the vascular component of colorectal tumor xenografts induced by a clinical combination of chemotherapy drugs FOLFOX in vivo using two complementary techniques: diffuse reflectance spectroscopy (DRS) and optical coherence tomography–based microangiography (OCT‐MA). These techniques revealed a slower decrease in tumor blood oxygenation in treated tumors as compared to untreated ones, faster suppression of tumor vasculature perfusion and increase in water content as a result of treatment, and decrease in total hemoglobin in untreated tumors. Immunohistochemical analysis of hypoxia‐inducible factor HIF‐2α detected tissue hypoxia as a consequence of inappropriate oxygen supply in the treated tumors. The obtained results show the prospects for monitoring of treatment efficacy using DRS and OCT‐MA.
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Affiliation(s)
- Irina Druzhkova
- Institute of Experimental Oncology and Biomedical Technologies Privolzhsky Research Medical University Nizhny Novgorod Russia
| | - Kseniya Bylinskaya
- Department for Radiophysical methods in medicine Institute of Applied Physics of Russian Academy of Sciences Nizhny Novgorod Russia
| | - Anton Plekhanov
- Institute of Experimental Oncology and Biomedical Technologies Privolzhsky Research Medical University Nizhny Novgorod Russia
| | - Alexey Kostyuk
- Department for Radiophysical methods in medicine Institute of Applied Physics of Russian Academy of Sciences Nizhny Novgorod Russia
| | - Mikhail Kirillin
- Department for Radiophysical methods in medicine Institute of Applied Physics of Russian Academy of Sciences Nizhny Novgorod Russia
| | - Valeriya Perekatova
- Department for Radiophysical methods in medicine Institute of Applied Physics of Russian Academy of Sciences Nizhny Novgorod Russia
| | - Aleksandr Khilov
- Department for Radiophysical methods in medicine Institute of Applied Physics of Russian Academy of Sciences Nizhny Novgorod Russia
| | - Anna Orlova
- Department for Radiophysical methods in medicine Institute of Applied Physics of Russian Academy of Sciences Nizhny Novgorod Russia
| | - Anastasiya Polozova
- Institute of Experimental Oncology and Biomedical Technologies Privolzhsky Research Medical University Nizhny Novgorod Russia
- Institute of Biology and Biomedicine Lobachevsky State University of Nizhny Novgorod Nizhny Novgorod Russia
| | - Anastasiya Komarova
- Institute of Experimental Oncology and Biomedical Technologies Privolzhsky Research Medical University Nizhny Novgorod Russia
- Institute of Biology and Biomedicine Lobachevsky State University of Nizhny Novgorod Nizhny Novgorod Russia
| | - Uliyana Lisitsa
- Institute of Experimental Oncology and Biomedical Technologies Privolzhsky Research Medical University Nizhny Novgorod Russia
| | - Marina Sirotkina
- Institute of Experimental Oncology and Biomedical Technologies Privolzhsky Research Medical University Nizhny Novgorod Russia
| | - Marina Shirmanova
- Institute of Experimental Oncology and Biomedical Technologies Privolzhsky Research Medical University Nizhny Novgorod Russia
| | - Ilya Turchin
- Department for Radiophysical methods in medicine Institute of Applied Physics of Russian Academy of Sciences Nizhny Novgorod Russia
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Keshavarzi F, Salari N, Jambarsang S, Mohammad Tabatabaei S, Shahsavari S, Fournier AJ. Overall survival with non-proportional hazards in first-line treatment for patients with metastatic colorectal cancer: Systematic review and network meta-analysis. Heliyon 2024; 10:e36464. [PMID: 39253267 PMCID: PMC11381762 DOI: 10.1016/j.heliyon.2024.e36464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 08/15/2024] [Accepted: 08/15/2024] [Indexed: 09/11/2024] Open
Abstract
This study aimed to identify the most effective first-line treatment for patients with metastatic colorectal cancer based on overall survival, identify the most commonly used treatment, and generate a meaningful ranking among all available treatments based on their relative effectiveness. Researchers used the ANOVA parametrization method to fit the second-order fractional polynomial network meta-analysis with a random-effect model. Using a non-proportional hazards network meta-analysis, 46 treatments were compared by considering a combination of direct and indirect evidence extracted from clinical trial studies. Included in the review were 46 trials involving 21350 patients. Between January 2000 and January 2023, researchers conducted a thorough search through Embase, PubMed/Medline, and Scopus. To undertake a secondary analysis of this data, we recreate individual patient data from published Kaplan-Meier (K-M) survival curves and assess the accuracy of that reconstruction. A random-effects model was used to evaluate the pooled overall survival and hazard ratio with a 95 percent confidence interval. The predicted survival curves for the network meta-analysis showed that GOLFIG and FOLFOX + Cetuximab treatments have higher survival, respectively. Our results provide moderate quality evidence and comparative effective estimates for various available first-line treatments for metastasis colorectal cancer based on network meta-analysis.
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Affiliation(s)
- Fatemeh Keshavarzi
- Department of Biostatistics, Faculty of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nader Salari
- Department of Biostatistics, Faculty of Health, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sara Jambarsang
- Department of Bio-Statistics and Epidemiology, Shahid Sadoughi University of Medical Science, Yazd, Iran
| | - Seyyed Mohammad Tabatabaei
- Department of Medical Informatics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodeh Shahsavari
- Department of Health Information Management, School of Allied Medical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
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Cohen R, Raeisi M, Chibaudel B, Shi Q, Yoshino T, Zalcberg JR, Adams R, Cremolini C, Van Cutsem E, Heinemann V, Tabernero J, Punt CJA, Arnold D, Hurwitz HI, Douillard JY, Venook AP, Saltz LB, Maughan TS, Kabbinavar F, Bokemeyer C, Grothey A, Mayer RJ, Kaplan R, Tebbutt NC, Randolph Hecht J, Giantonio BJ, Díaz-Rubio E, Sobrero AF, Peeters M, Koopman M, Goldberg RM, Andre T, de Gramont A. Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis. Eur J Cancer 2024; 207:114160. [PMID: 38896997 DOI: 10.1016/j.ejca.2024.114160] [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: 04/20/2024] [Revised: 05/27/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.
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Affiliation(s)
- Romain Cohen
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France
| | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Levallois-Perret, France
| | - Qian Shi
- Department of Quantitative Health Science, Mayo Clinic, Rochester, USA
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - John R Zalcberg
- Monash University School of Public Health and Preventive Medicine and Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom
| | - Chiara Cremolini
- Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy
| | - Eric Van Cutsem
- Department of Gastrointestinal and Liver Diseases, Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Volker Heinemann
- Department of Medical Oncology, LMU Hospital, University of Munich, Munich, Germany
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, Asklepios Klinik Altona, Hamburg, Germany
| | | | - Jean-Yves Douillard
- Medical Oncology Department, Integrated Centers for Oncology Nantes, Nantes, France
| | - Alan P Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | | | | | - Carsten Bokemeyer
- Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Niall C Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - J Randolph Hecht
- David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, USA
| | | | | | | | | | - Miriam Koopman
- University Medical Center Utrecht, Utrecht, the Netherlands
| | - Richard M Goldberg
- Department of Medicine, West Virginia University Cancer Institute, Morgantown, USA
| | - Thierry Andre
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France; ARCAD Foundation, Paris, France
| | - Aimery de Gramont
- ARCAD Foundation, Paris, France; Department of Medical Oncology, Franco-British Hospital, Levallois-Perret, France
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8
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Zhan Y, Cheng X, Mei P, Tan S, Feng W, Jiang H. Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials. BMC Cancer 2024; 24:893. [PMID: 39048944 PMCID: PMC11270896 DOI: 10.1186/s12885-024-12662-3] [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: 11/09/2023] [Accepted: 07/19/2024] [Indexed: 07/27/2024] Open
Abstract
OBJECTIVE To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis. METHODS The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens. RESULTS A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs. CONCLUSION In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.
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Affiliation(s)
- Yanrong Zhan
- Rudong People's Hospital / Affiliated Rudong Hospital of Xinglin College, Nantong University, Nantong, Jiangsu, 226400, China.
| | - Xianwen Cheng
- Ankang Hospital of Traditional Chinese Medicine, Ankang, Shaanxi, 725000, China
| | - Pingping Mei
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shufa Tan
- Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China
| | - Wenzhe Feng
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China.
| | - Hua Jiang
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China
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Lesan V, Olivier T, Prasad V. Progression-free survival estimates are shaped by specific censoring rules: Implications for PFS as an endpoint in cancer randomized trials. Eur J Cancer 2024; 202:114022. [PMID: 38547775 DOI: 10.1016/j.ejca.2024.114022] [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: 02/09/2024] [Revised: 03/09/2024] [Accepted: 03/12/2024] [Indexed: 04/21/2024]
Abstract
Kaplan-Meier analysis hinges on the assumption that patients who are censored- lost to follow-up, or only recently enrolled on the study- are no different, on average, than patients who are followed. As such, censoring these patients- omitting their future information and taking the average of those who were followed- should not dramatically change the overall estimate. Yet, in a recent clinical trial, two sets of censoring rules- one favored by trialists and one favored by the US Food and Drug Administration- were applied to a progression-free survival (PFS) estimate. In response, the PFS estimate changed dramatically, increasing the median in the experimental arm from 32 to 43 months, while the control arm was essentially unchanged. In this commentary, we explore the reasons why PFS changed so dramatically. We provide a broad overview of censoring in oncology clinical trials, and suggestions to ensure that PFS is a more reliable endpoint.
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Affiliation(s)
- Vadim Lesan
- Hematology and Oncology Department, Saarland University Hospital, Kirrberger Street 100, 66421, Homburg, Germany
| | - Timothée Olivier
- Oncology Service, Geneva University Hospital, 4 Gabrielle-Perret-Gentil Street, 1205, Geneva, Switzerland
| | - Vinay Prasad
- Department of Epidemiology and Biostatistics, University of California San Francisco, 550 16th St, 2nd Fl, San Francisco, CA 94158, USA.
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10
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Legoux JL, Faroux R, Barrière N, Le Malicot K, Tougeron D, Lorgis V, Guerin-Meyer V, Bourgeois V, Malka D, Aparicio T, Baconnier M, Lebrun-Ly V, Egreteau J, Khemissa Akouz F, Terme M, Lepage C, Boige V. First-Line LV5FU2 with or without Aflibercept in Patients with Non-Resectable Metastatic Colorectal Cancer: A Randomized Phase II Trial (PRODIGE 25-FFCD-FOLFA). Cancers (Basel) 2024; 16:1515. [PMID: 38672597 PMCID: PMC11049283 DOI: 10.3390/cancers16081515] [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: 03/27/2024] [Revised: 04/08/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Fluropyrimidine monotherapy is an option for some patients with inoperable metastatic colorectal cancer. Unlike bevacizumab, the addition of aflibercept, an antibody acting as an anti-angiogenic agent, has never been evaluated in this context. The aim of the study was to determine whether aflibercept could increase the efficacy of fluoropyrimidine monotherapy without increasing toxicity. This multicenter phase II non-comparative trial evaluated the addition of aflibercept to infusional 5-fluorouracil/folinic acid (LV5FU2 regimen) as first-line treatment in patients unfit to receive doublet cytotoxic chemotherapy. The primary endpoint was 6-month progression-free survival (PFS). The clinical hypotheses expected a PFS rate at 6 months of over 40% (60% expected). A total of 117 patients, with a median age of 81 years, were included: 59 in arm A (LV5FU2-aflibercept) and 58 in arm B (LV5FU2 alone). Six-month PFS was 54.7% in both arms (90% CI 42.5-66.5 in both). Median overall survival was 21.8 months (arm A) and 25.1 months (arm B). Overall toxicity was more common in arm A: grade ≥ 3 toxicity in 82% versus 58.2%. Given the 6-month PFS, the study can be considered positive. However, the toxicity of aflibercept in this population was high, and continuation of the trial into phase III is not envisaged.
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Affiliation(s)
- Jean-Louis Legoux
- Department of Hepato-Gastroenterology and Digestive Oncology, CHU d’Orléans, 14 avenue de l’Hôpital, CS 86709, 45067 Orleans CEDEX 2, France
| | - Roger Faroux
- Department of Hepato-Gastroenterology and Digestive Oncology, Centre Hospitalier Les Oudairies, Boulevard Stéphane Moreau, 85925 La Roche sur Yon, France;
| | - Nicolas Barrière
- Department of Hepato-Gastroenterology and Digestive Oncology, Hôpital Européen, 6 Rue Désirée Clary, CS 70356, 13331 Marseille CEDEX 03, France;
| | - Karine Le Malicot
- Fédération Francophone de Cancérologie Digestive (FFCD), EPICAD INSERM LNC-UMR 1231, Faculté de Médecine, University of Burgundy and Franche Comté, 7, Boulevard Jeanne d’Arc, 21079 Dijon, France;
| | - David Tougeron
- Department of Hepato-Gastroenterology, CHU de Poitiers, 2 Rue de la Miletrie, BP 577, 86021 Poitiers, France;
| | - Véronique Lorgis
- Department of Medical Oncology, Institut de Cancérologie de Bourgogne, GRReCC, 18 Cours Général de Gaulle, 21000 Dijon, France;
| | - Véronique Guerin-Meyer
- Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Boulevard Jacques Monod, 44805 Saint Herblain, France;
| | - Vincent Bourgeois
- Department of Hepato-Gastroenterology and Digestive Oncology, Centre Hospitalier Duchenne, Allée Jacques Monod-BP 609, 62321 Boulogne Sur Mer, France;
| | - David Malka
- Department of Cancer Medicine, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif CEDEX, France; (D.M.); (V.B.)
| | - Thomas Aparicio
- Department of Gastroenterology, Saint Louis Hospital, APHP, Université Paris Cité, Paris, 1 Avenue Claude Vellefaux, 75475 Paris, France;
| | - Matthieu Baconnier
- Department of Gastroenterology, Centre Hospitalier Annecy-Genevois, 1 Avenue de l’Hôpital, 74374 Pringy, France;
| | - Valérie Lebrun-Ly
- Department of Medical Oncology, CHU Dupuytren, 2 Avenue Martin Luther King, 87042 Limoges, France;
| | - Joëlle Egreteau
- Radiotherapy and Medical Oncology, Groupe Hospitalier Bretagne Sud, 5 Avenue de Choiseul, BP 12233, 56322 Lorient CEDEX, France;
| | - Faïza Khemissa Akouz
- Department of Hepato-Gastroenterology and Digestive Oncology, Saint Jean Hospital, 20 Avenue du Languedoc, BP 49954, 66046 Perpignan CEDEX 9, France;
| | - Magali Terme
- INSERM U970—PARCC (Paris Cardiovascular Research Center), European Georges Pompidou Hospital, Université Paris Descartes, Sorbonne Paris Cité, 56 rue Leblanc, 75015 Paris, France;
| | - Côme Lepage
- INSERM U866, Université de Bourgogne, 7 Boulevard Jeanne d’Arc, BP 27877, 21078 Dijon CEDEX, France;
| | - Valérie Boige
- Department of Cancer Medicine, Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif CEDEX, France; (D.M.); (V.B.)
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Cheung WY, Samimi S, Ma K, Knight GJ, Kassam S, Colwell B, Beaudoin A, Vincent MD, Trinkaus M, Filion A, Marquis K, Karachiwala H, Asmis T, Sideris L, Wani RJ, Ngan E, Inam N, Du Y, Nunez L, Eberg M, Alemayehu M, Meyer PF, Mancini J, Cirone Morris C. Real-World Safety and Effectiveness of a Bevacizumab Biosimilar (ABP 215) in Metastatic Colorectal Cancer Patients in Canada. Clin Colorectal Cancer 2024; 23:46-57.e4. [PMID: 38007297 DOI: 10.1016/j.clcc.2023.10.007] [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: 09/01/2023] [Revised: 10/17/2023] [Accepted: 10/23/2023] [Indexed: 11/27/2023]
Abstract
BACKGROUND ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.
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Affiliation(s)
| | - Setareh Samimi
- CIUSSS-du Nord-de-l'Île-de-Montréal, Montréal, QC, Canada
| | - Kim Ma
- CISSS de Laval, Laval, QC, Canada
| | | | - Shaqil Kassam
- Southlake Regional Health Centre, Newmarket, ON, Canada
| | - Bruce Colwell
- Nova Scotia Health Authority Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada
| | - Annie Beaudoin
- CIUSSS de I'Estrie - Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada
| | | | | | - Alain Filion
- CISSS de Chaudière-Appalaches, Lévis, QC, Canada
| | - Katerine Marquis
- CISSS du Bas-Saint-Laurent - Hôpital régional de Rimouski, Rimouski, QC, Canada
| | | | - Timothy Asmis
- The Ottawa Hospital Cancer Center, Ottawa, ON, Canada
| | - Lucas Sideris
- CIUSSS de l'Est-de-l'Île-de-Montréal - Hôpital Maisonneuve-Rosemont, Montréal, QC, Canada
| | | | | | - Naila Inam
- Amgen Canada Inc., Mississauga, ON, Canada
| | | | - Leyla Nunez
- IQVIA, Global Database Studies, Mölndal, Sweden
| | - Maria Eberg
- IQVIA Solutions Canada Inc., Kirkland, QC, Canada
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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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Song Y, Mao Q, Zhou M, Liu CJ, Kong L, Hu T. Effectiveness of bevacizumab in the treatment of metastatic colorectal cancer: a systematic review and meta-analysis. BMC Gastroenterol 2024; 24:58. [PMID: 38302922 PMCID: PMC10832121 DOI: 10.1186/s12876-024-03134-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 01/14/2024] [Indexed: 02/03/2024] Open
Abstract
OBJECTIVE To evaluate the benefit of bevacizumab under the comprehensive treatment strategy and its advantages over other drugs, so as to provide reference for the formulation of clinical plans. METHODS As of October 1, 2022, the randomized controlled clinical trials of bevacizumab in combination with metastatic colorectal cancer published in PubMed, Cochrane Library and Medline databases were searched. The odds ratio (OR) and its 95% confidence interval (CI) were used to evaluate the short-term disease control effect and long-term survival of the treatment strategy. RESULTS 21 RCTs (6665 patients; 3356 patients in the experimental group and 3309 patients in the control group; average age, 55-75 years) were treated with bevacizumab as the experimental group for metastatic colorectal cancer. BEV has stronger anti-tumor activity than the single treatment scheme (OR = 1.30, 95% CI: 1.11-1.52). And Benefits of the BEV group were 0.73 (0.55, 0.96), 1.26 (0.71, 2.24), 1.63 (0.92, 2.87) and 0.07 (0.02, 0.25) compared with CET, VAN, CED and PAN respectively. The disease control of BEV combined therapy was better (OR = 1.36, 95% CI: 1.04-1.78). The same as compared with cediranib (OR = 1.94, 95% CI: 1.06-3.55). However, the long-term prognosis of BEV, including the overall survival (HRs = 0.98, 95% CI: 0.84-1.15) and progression-free survival (HRs = 1.05,95% CI: 0.97-1.13) were not prolonged. The survival benefits of cetuximab and panitumumab were not reflected. CONCLUSION The addition of BEV can enhance the anti-tumor ability and disease control, while cetuximab and panitumumab may have stronger ability. However, it did not effectively improve the survival of patients. A more reasonable and effective treatment plan needs more clinical experimental support.
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Affiliation(s)
- Yu Song
- Department of Intensive Care Unit, the First Affiliated Hospital of Shandong Traditional Medical University, 250000, Jinan, China
| | - Qianqian Mao
- Department of Oncology, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, 210009, Nanjing, Jiangsu Province, China
| | - Manling Zhou
- Department of Oncology, Shenzhen Longhua District Central Hospital, Shenzhen, China
| | - Cheng-Jiang Liu
- Department of General Medicine, Affiliated Anqing First People's Hospital of Anhui Medical University, 246000, Anqing, AnHui, China.
| | - Li Kong
- Department of Intensive Care Unit, the First Affiliated Hospital of Shandong Traditional Medical University, 250000, Jinan, China.
| | - Ting Hu
- Department of General Practice, Anqing Municipal Hospital, 246000, Anqing, AnHui, China
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Yazdani A, Lenz HJ, Pillonetto G, Mendez-Giraldez R, Yazdani A, Sanof H, Hadi R, Samiei E, Venook AP, Ratain MJ, Rashid N, Vincent BG, Qu X, Wen Y, Kosorok M, Symmans WF, Shen JPYC, Lee MS, Kopetz S, Nixon AB, Bertagnolli MM, Perou CM, Innocenti F. Gene signatures derived from transcriptomic-causal networks stratified colorectal cancer patients for effective targeted therapy. RESEARCH SQUARE 2023:rs.3.rs-3673588. [PMID: 38168324 PMCID: PMC10760223 DOI: 10.21203/rs.3.rs-3673588/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Predictive and prognostic gene signatures derived from interconnectivity among genes can tailor clinical care to patients in cancer treatment. We identified gene interconnectivity as the transcriptomic-causal network by integrating germline genotyping and tumor RNA-seq data from 1,165 patients with metastatic colorectal cancer (CRC). The patients were enrolled in a clinical trial with randomized treatment, either cetuximab or bevacizumab in combination with chemotherapy. We linked the network to overall survival (OS) and detected novel biomarkers by controlling for confounding genes. Our data-driven approach discerned sets of genes, each set collectively stratify patients based on OS. Two signatures under the cetuximab treatment were related to wound healing and macrophages. The signature under the bevacizumab treatment was related to cytotoxicity and we replicated its effect on OS using an external cohort. We also showed that the genes influencing OS within the signatures are downregulated in CRC tumor vs. normal tissue using another external cohort. Furthermore, the corresponding proteins encoded by the genes within the signatures interact each other and are functionally related. In conclusion, this study identified a group of genes that collectively stratified patients based on OS and uncovered promising novel prognostic biomarkers for personalized treatment of CRC using transcriptomic causal networks.
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Affiliation(s)
- Akram Yazdani
- University of Texas Health Science center at Houston
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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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Kiyomi A, Koizumi F, Imai S, Yamana H, Horiguchi H, Fushimi K, Sugiura M. Bevacizumab-induced proteinuria and its association with antihypertensive drugs: A retrospective cohort study using a Japanese administrative database. PLoS One 2023; 18:e0289950. [PMID: 37561756 PMCID: PMC10414654 DOI: 10.1371/journal.pone.0289950] [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: 01/19/2023] [Accepted: 07/30/2023] [Indexed: 08/12/2023] Open
Abstract
Proteinuria is a major side-effect of the anti-tumor drug bevacizumab, although its incidence and risk factors in the real world are still unclear. Although renin-angiotensin-aldosterone system inhibitors are used clinically to prevent proteinuria, their efficacy remains unclear. The aim of the present study was to reveal the incidence and risk factors of bevacizumab-induced proteinuria and examine the effectiveness of antihypertensive drugs in preventing proteinuria. We conducted a retrospective cohort study using the National Hospital Organization Clinical Data Archives and Medical Information Analysis Databank. Hospitalized patients who received bevacizumab between January 1, 2016, and June 30, 2019, were included. The study outcome was proteinuria within 12 months of bevacizumab administration. Patient characteristics, laboratory tests, and medications were compared between patients with and without proteinuria using multivariable logistic regression analysis. Among the 2,458 patients, 27% developed proteinuria after bevacizumab administration. Nursing dependence (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.89-3.05; P<0.001) and systolic blood pressure ≥140 mmHg (OR, 1.44; 95% CI, 1.17-1.79; P<0.001) were identified as risk factors. Patients with an estimated glomerular filtration rate (eGFR) of 60-89, 45-59, and <45 mL/min/1.73 m2 had 29.7%, 76.8%, and 66.0% higher odds of proteinuria, respectively, than those with an eGFR ≥90 mL/min/1.73 m2. No significant relationship was observed between antihypertensive drugs and the occurrence of proteinuria. More patients may suffer from proteinuria after bevacizumab administration than previously reported. Nursing dependence and systolic blood pressure are predictive risk factors for bevacizumab-induced proteinuria. Patients at risk of proteinuria should be closely monitored.
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Affiliation(s)
- Anna Kiyomi
- Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Fukiko Koizumi
- Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Shinobu Imai
- Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
- Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, Tokyo, Japan
- Division of Pharmacoepidemiology, Department of Healthcare and Regulatory Sciences, School of Pharmacy, Showa University, Tokyo, Japan
| | - Hayato Yamana
- Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, Tokyo, Japan
- Data Science Center, Jichi Medical University, Tochigi, Japan
| | - Hiromasa Horiguchi
- Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, Tokyo, Japan
| | - Kiyohide Fushimi
- Department of Clinical Data Management and Research, Clinical Research Center, National Hospital Organization Headquarters, Tokyo, Japan
- Department of Health Policy and Informatics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Munetoshi Sugiura
- Department of Drug Safety and Risk Management, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
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Lau BC, Wu YF, No HJ, Ko RB, Devine MD, Das MS, Neal JW, Wakelee HA, Ramchandran K, Gensheimer MF, Diehn M, Chin AL, Loo BW, Vitzthum LK. Pulmonary Hemorrhage in Patients Treated With Thoracic Stereotactic Ablative Radiotherapy and Antiangiogenic Agents. J Thorac Oncol 2023; 18:922-930. [PMID: 37085030 DOI: 10.1016/j.jtho.2023.04.007] [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: 12/16/2022] [Revised: 04/07/2023] [Accepted: 04/12/2023] [Indexed: 04/23/2023]
Abstract
INTRODUCTION Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFis). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone. METHODS We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any-grade and grade 3 plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR plus VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone. RESULTS Treatment with VEGFi plus SABR was associated with higher rates of G3+ pulmonary hemorrhage compared with those treated with SABR alone for the overall cohort (3-y incidence: 7.9% versus 0.6%, p < 0.01) and those with central tumors (19.1% versus 3.3%, p = 0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% versus 45.0%, p = 0.044), but not central nonabutting tumors (0.0% versus 1.3%, p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi plus SABR compared with VEGFi alone (9.6% versus 1.3%, p = 0.04). CONCLUSIONS The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.
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Affiliation(s)
- Brianna C Lau
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Yufan F Wu
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Hyunsoo J No
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California
| | - Ryan B Ko
- Oakland University William Beaumont School of Medicine, Auburn Hills, Michigan
| | - Max D Devine
- University of Nebraska College of Medicine, Omaha, Nebraska
| | - Millie S Das
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California; Veteran Affairs (VA) Palo Alto Health Care System, Palo Alto, California
| | - Joel W Neal
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California
| | - Heather A Wakelee
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California
| | - Kavitha Ramchandran
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California
| | - Michael F Gensheimer
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California
| | - Maximilian Diehn
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California
| | - Alexander L Chin
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California
| | - Billy W Loo
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California
| | - Lucas K Vitzthum
- Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California; Stanford Cancer Institute, Stanford, California.
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18
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Cann CG, LaPelusa MB, Cimino SK, Eng C. Molecular and genetic targets within metastatic colorectal cancer and associated novel treatment advancements. Front Oncol 2023; 13:1176950. [PMID: 37409250 PMCID: PMC10319053 DOI: 10.3389/fonc.2023.1176950] [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: 03/01/2023] [Accepted: 05/30/2023] [Indexed: 07/07/2023] Open
Abstract
Colorectal cancer results in the deaths of hundreds of thousands of patients worldwide each year, with incidence expected to rise over the next two decades. In the metastatic setting, cytotoxic therapy options remain limited, which is reflected in the meager improvement of patient survival rates. Therefore, focus has turned to the identification of the mutational composition inherent to colorectal cancers and development of therapeutic targeted agents. Herein, we review the most up to date systemic treatment strategies for metastatic colorectal cancer based on the actionable molecular alterations and genetic profiles of colorectal malignancies.
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Affiliation(s)
- Christopher G. Cann
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Michael B. LaPelusa
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Sarah K. Cimino
- Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Cathy Eng
- Department of Medicine: Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, United States
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19
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Deng J, Zeng X, Hu W, Yue T, Luo Z, Zeng L, Li P, Chen J. Different doses of bevacizumab in combination with chemotherapy for advanced colorectal cancer: a meta-analysis and Bayesian analysis. Int J Colorectal Dis 2023; 38:164. [PMID: 37289304 DOI: 10.1007/s00384-023-04442-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/21/2023] [Indexed: 06/09/2023]
Abstract
OBJECTIVE The aim of the present study was to explore the incremental benefit of bevacizumab (Bev) in the treatment of advanced colorectal cancer (CRC) with different doses. METHODS A literature search of eight electronic databases (China National Knowledge Infrastructure, Wanfang databases, Chinese Biomedical Database, VIP medicine information, Cochrane Library, MEDLINE, PubMed, and EMBASE) was conducted from database creation to December 2022. Randomized controlled trials (RCTs) that compared Bev at various dosages + chemotherapy (CT) versus placebo (or blank control) + CT were selected. The overall survival (OS), progression-free survival (PFS), overall response rate (ORR; complete response [CR] + partial response [PR]), and grade ≥ 3 adverse events (AEs) were integrated first by pooled analysis. The likelihood of ideal dosage of Bev was then ranked using random effects within Bayesian analysis. RESULTS Twenty-six RCTs involving 18,261 patients met the inclusion criteria. OS increased significantly after using 5 mg (HR: 0.87, 95% CI 0.75 to 1.00) and 10 mg dosages of Bev (HR: 0.75, 95% CI 0.66 to 0.85) with CT, but statistical significance was not attained for the 7.5 mg dose (HR: 0.95, 95% CI 0.83 to 1.08). A significantly increased in PFS with doses of 5 mg (HR: 0.69, 95% CI 0.58 to 0.83), 7.5 mg (HR: 0.81, 95% CI 0.66 to 1.00), and 10 mg (HR: 0.60, 95% CI 0.53 to 0.68). ORR distinctly increased after 5 mg (RR: 1.34, 95% CI 1.15 to 1.55), 7.5 mg (RR: 1.25, 95% CI 1.05 to 1.50), and10 mg (RR: 2.27, 95% CI 1.82 to 2.84) doses were administered. Grade ≥ 3 AEs increased clearly in 5 mg (RR: 1.11, 95% CI 1.04 to 1.20) compared to 7.5 mg (RR: 1.05, 95% CI 0.82 to 1.35) and 10 mg (RR: 1.15, 95% CI 0.98 to 1.36). Bayesian analysis demonstrated that 10 mg Bev obtained the maximum time of OS (HR: 0.75, 95% CrI 0.58 to 0.97; probability rank = 0.05) indirectly compared to 5 mg and 7.5 mg Bev. Compared with 5 mg and 7.5 mg Bev, 10 mg Bev also holds the longest duration for PFS (HR: 0.59, 95% CrI 0.43 to 0.82; probability rank = 0.00). In terms of ORR, 10 mg Bev holds the maximum frequency (RR: 2.02, 95% CrI 1.52 to 2.66; probability rank = 0.98) in comparison to 5 mg and 7.5 mg Bev clearly. For grade ≥ 3 AEs, 10 mg Bev has the maximum incidence (RR: 1.15, 95% CrI 0.95 to 1.40, probability rank = 0.67) in comparison to other doses of Bev. CONCLUSION The study suggests that 10 mg dose Bev could be more effective in treating advanced CRC in efficacy, but 5 mg Bev could be more safer in terms of safety.
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Affiliation(s)
- Jia Deng
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Xinglin Zeng
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenting Hu
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Tinghui Yue
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Zicheng Luo
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Lian Zeng
- College of Clinical Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Ping Li
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, Guiyang, 550001, China.
| | - Jiang Chen
- Colorectal and Anal Surgery, the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, No 71 Baoshan North Road, Guiyang, 550001, China.
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20
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Peeters M, Lipp HP, Park M, Yoon YC, Arnold D. SB8, an approved bevacizumab biosimilar based on totality of evidence: scientific justification of extrapolation. Future Oncol 2023; 19:427-450. [PMID: 36883661 DOI: 10.2217/fon-2022-1273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023] Open
Abstract
SB8 is a biosimilar of bevacizumab based on its similarity demonstrated by physicochemical, functional, non-clinical and clinical studies. Supported by the concept of extrapolation, SB8 was authorized and is used in a similar manner across all types of tumors as reference bevacizumab. Furthermore, SB8 offers convenience with prolonged stability compared with reference bevacizumab in diluted form. Although a biosimilar must demonstrate biosimilarity to a reference product with the 'totality of evidence' in a stringent regulatory process for marketing authorization, some concerns remain among healthcare practitioners, particularly about extrapolation. This review summarizes the concepts of the totality of evidence and extrapolation in biosimilar development and the role of bevacizumab biosimilars in the management of metastatic colorectal cancer as an extrapolated indication.
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Affiliation(s)
- Marc Peeters
- Antwerp University Hospital, 2650, Edegem, Belgium
| | | | - Minjeong Park
- Samsung Bioepis Co., Ltd, Incheon, 21987, Republic of Korea
| | - Ye Chan Yoon
- Samsung Bioepis Co., Ltd, Incheon, 21987, Republic of Korea
| | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, AK Klinik Altona, 22763, Hamburg, Germany
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21
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Stage IV Colorectal Cancer Management and Treatment. J Clin Med 2023; 12:jcm12052072. [PMID: 36902858 PMCID: PMC10004676 DOI: 10.3390/jcm12052072] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/02/2023] [Accepted: 03/04/2023] [Indexed: 03/08/2023] Open
Abstract
(1) Background: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related mortality worldwide. Up to 50% of patients with CRC develop metastatic CRC (mCRC). Surgical and systemic therapy advances can now offer significant survival advantages. Understanding the evolving treatment options is essential for decreasing mCRC mortality. We aim to summarize current evidence and guidelines regarding the management of mCRC to provide utility when making a treatment plan for the heterogenous spectrum of mCRC. (2) Methods: A comprehensive literature search of PubMed and current guidelines written by major cancer and surgical societies were reviewed. The references of the included studies were screened to identify additional studies that were incorporated as appropriate. (3) Results: The standard of care for mCRC primarily consists of surgical resection and systemic therapy. Complete resection of liver, lung, and peritoneal metastases is associated with better disease control and survival. Systemic therapy now includes chemotherapy, targeted therapy, and immunotherapy options that can be tailored by molecular profiling. Differences between colon and rectal metastasis management exist between major guidelines. (4) Conclusions: With the advances in surgical and systemic therapy, as well as a better understanding of tumor biology and the importance of molecular profiling, more patients can anticipate prolonged survival. We provide a summary of available evidence for the management of mCRC, highlighting the similarities and presenting the difference in available literature. Ultimately, a multidisciplinary evaluation of patients with mCRC is crucial to selecting the appropriate pathway.
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22
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Margalit O, Harmsen WS, Shacham-Shmueli E, Voss MM, Boursi B, Wagner AD, Cohen R, Olswold CL, Saltz LB, Goldstein DA, Hurwitz H, Tebbutt NC, Kabbinavar FF, Adams RA, Chibaudel B, Grothey A, Yoshino T, Zalcberg J, de Gramont A, Shi Q, Lenz HJ. Evaluating sex as a predictive marker for response to bevacizumab in metastatic colorectal carcinoma: Pooled analysis of 3,369 patients in the ARCAD database. Eur J Cancer 2023; 178:162-170. [PMID: 36446161 DOI: 10.1016/j.ejca.2022.10.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 10/21/2022] [Accepted: 10/23/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. METHODS Data from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000-2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. RESULTS Bevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74-1.20). CONCLUSIONS Our results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes.
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Affiliation(s)
- Ofer Margalit
- Sheba Medical Center, Ramat-Gan, Israel; Tel-Aviv University, Tel-Aviv, Israel.
| | - William S Harmsen
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA
| | | | - Molly M Voss
- Department of Quantitative Science Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Ben Boursi
- Sheba Medical Center, Ramat-Gan, Israel; Tel-Aviv University, Tel-Aviv, Israel
| | - Anna D Wagner
- Department of Oncology, Division of Medical Oncology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Romain Cohen
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA; Sorbonne University, Department of Medical Oncology, Saint-Antoine Hospital, AP-HP, F-75012 Paris, France; Sorbonne University, INSERM, Unité Mixte de Recherche Scientifique 938, Centre de Recherche Saint-Antoine, Equipe Instabilité des Microsatellites et Cancer, Equipe labellisée par la Ligue Nationale contre le Cancer, F-75012 Paris, France
| | - Curtis L Olswold
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA
| | | | | | | | - Niall C Tebbutt
- University of Melbourne, Australia; Austin Health, Heidelberg, Victoria, Australia
| | - Fairooz F Kabbinavar
- David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA
| | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | | | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Japan
| | - John Zalcberg
- Department of Medical Oncology, Alfred Health and School of Public Health, Monash University, Melbourne, Australia
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Qian Shi
- Department of Quantitative Science Research, Mayo Clinic, Rochester, MN, USA
| | - Heinz-Josef Lenz
- Department of Gastrointestinal Oncology, Keck School of Medicine at USC, Los Angeles, CA, USA
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23
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Kim S, Shin JK, Park Y, Huh JW, Kim HC, Yun SH, Lee WY, Cho YB. Bevacizumab increases the risk of anastomosis site leakage in metastatic colorectal cancer. Front Oncol 2022; 12:1018458. [PMID: 36353568 PMCID: PMC9639472 DOI: 10.3389/fonc.2022.1018458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/10/2022] [Indexed: 11/21/2022] Open
Abstract
Background Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor and is used in combination with first-line chemotherapy in the treatment of metastatic colorectal cancer. One of the side effects of bevacizumab is gastrointestinal perforation. This study was designed to identify the effect of bevacizumab in intestinal anastomosis site healing. Methods From January 2010 to December 2020, patients diagnosed with stage IV colorectal cancer treated with palliative chemotherapy or chemoradiotherapy followed by radical surgery were retrospectively reviewed. Clinical signs or symptoms and computed tomography were tools used for diagnosing anastomosis site leakage. The patients were divided into two groups, the bevacizumab group (n = 136) and the non-bevacizumab group (n = 124). Results Among the 260 patients 14 (5.4%) patients were diagnosed with anastomosis site leakage. In the bevacizumab group, 13 (9.6%) patients were diagnosed with anastomotic leakage. In the non-bevacizumab group, 1 (0.8%) patient was diagnosed with anastomotic leakage. Anastomosis site leakage was significantly higher in the bevacizumab treatment group (P < 0.001). In the bevacizumab group, period of drug discontinuation before surgery was factor associated with anastomosis site leakage in multivariable analysis (P = 0.031). Conclusion Stage IV colorectal patients treated with bevacizumab before radical surgery for primary cancer should be carefully observed of anastomosis site leakage after surgery, and the period of drug discontinuation before surgery should be longer than 5 weeks to avoid anastomosis site leakage.
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Affiliation(s)
- Seijong Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jung Kyong Shin
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yoonah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
- Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, South Korea
- Department of Biopharmaceutical Convergence, Sungkyunkwan University, Seoul, South Korea
- *Correspondence: Yong Beom Cho,
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24
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Taira K, Okazaki S, Akiyoshi K, Machida H, Ikeya T, Kimura A, Nakata A, Nadatani Y, Ohminami M, Fukunaga S, Otani K, Hosomi S, Tanaka F, Kamata N, Nagami Y, Fujiwara Y. Short bevacizumab infusion as an effective and safe treatment for colorectal cancer. Mol Clin Oncol 2022; 17:139. [PMID: 35949896 PMCID: PMC9353868 DOI: 10.3892/mco.2022.2572] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 07/12/2022] [Indexed: 11/30/2022] Open
Abstract
Bevacizumab is a humanized monoclonal antibody that contains <10% murine protein. To prevent infusion-related hypersensitivity reactions (HSRs), the initial bevacizumab infusion is delivered for 90 min, the second for 60 min and subsequent doses for 30 min. Several previous studies have shown that short bevacizumab infusions are safe and do not result in severe HSRs in patients with colorectal, lung, ovarian and brain cancer. However, the efficacy of short bevacizumab infusions for colorectal cancer management remains unclear. Therefore, to investigate this issue, a prospective multicenter study was conducted using 23 patients enrolled between June 2017 and March 2019. The initial infusion of bevacizumab was for 30 min followed by a second infusion rate of 0.5 mg/kg/min (5 mg/kg over 10 min and 7.5 mg/kg over 15 min. The primary endpoint was progression-free survival (PFS). The overall response and disease control rates were 57 and 87%, respectively. The median PFS time was 306 days (interquartile range, 204-743 days). No HSRs were noted. Adverse events associated with bevacizumab included grade 4 small intestinal perforation and grade 3 stroke in 1 patient each. These results suggest that a short bevacizumab infusion regime comprising an initial infusion for 30 min followed by a second infusion at 0.5 mg/kg/min is safe and efficacious for the management of colorectal cancer.
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Affiliation(s)
- Koichi Taira
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Shunsuke Okazaki
- Department of Clinical Oncology, Osaka City General Hospital, Osaka 534-0021, Japan
- Department of Medical Oncology, Nara Medical University Hospital, Nara 634-8521, Japan
| | - Kohei Akiyoshi
- Department of Clinical Oncology, Osaka City General Hospital, Osaka 534-0021, Japan
| | - Hirohisa Machida
- Department of Gastroenterology, Machida Gastrointestinal Hospital, Osaka 557-0001, Japan
| | - Tetsuro Ikeya
- Department of Surgery, Osaka Ekisaikai Hospital, Osaka 550-0022, Japan
| | - Akie Kimura
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Akinobu Nakata
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Yuji Nadatani
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Masaki Ohminami
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Shusei Fukunaga
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan
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Stahler A, Modest DP, Fischer von Weikersthal L, Kaiser F, Decker T, Held S, Graeven U, Schwaner I, Denzlinger C, Schenk M, Kurreck A, Heinrich K, Gießen-Jung C, Neumann J, Kirchner T, Jung A, Stintzing S, Heinemann V. First-line fluoropyrimidine plus bevacizumab followed by irinotecan-escalation versus initial fluoropyrimidine, irinotecan and bevacizumab in patients with metastatic colorectal cancer - Final survival and per-protocol analysis of the randomised XELAVIRI trial (AIO KRK 0110). Eur J Cancer 2022; 173:194-203. [PMID: 35940054 DOI: 10.1016/j.ejca.2022.06.019] [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: 04/05/2022] [Revised: 06/03/2022] [Accepted: 06/09/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND The randomised open-label phase III XELAVIRI trial failed to demonstrate non-inferiority of the sequential application of fluoropyrimidine plus bevacizumab followed by additional irinotecan at first progression (Arm A) versus initial combination of all agents (Arm B) for untreated metastatic colorectal cancer in the initial analysis of time-to-failure-of-strategy (TFS, 90% confidence boundary of 0.8). Here, we evaluate efficacy in the full analysis set (FAS), the per-protocol set, in addition to age-related and molecular subgroups. METHODS Median TFS, overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method and log-rank test. Cox regression models assessed hazard ratios (HRs) and confidence intervals (CIs) (TFS: 90%; OS, PFS: 95%). RESULTS Of 421 patients, 390 (92.6%), 391 (92.9%) and 357 (84.8%) events for TFS, OS and PFS were observed in the FAS with a median follow-up of 54.2 months (Arm A) versus 52.9 months (Arm B). Non-inferiority of sequential treatment for TFS was missed in the FAS (HR 0.93; 90% CI, 0.79-1.10; P = 0.482) and not shown in the per-protocol set (HR 0.93; 90% CI, 0.75-1.13, P = 0.433). Formal non-inferiority for TFS was observed for patients older than 70 years (HR 1.06; 90% CI, 0.80-1.41; P = 0.670) and patients with RAS mutant tumours (HR 1.12; 90% CI, 0.87-1.43; P = 0.465). In RAS/BRAF wild-type tumours, combination treatment was significantly superior to sequential therapy in all end-points. CONCLUSIONS In the overall population, XELAVIRI just missed to demonstrate the non-inferiority of sequential compared to combination therapy for TFS. However, the non-inferiority of sequential treatment was observed in elderly patients and RAS mutant tumours. TRIAL REGISTRATION Trial registration ID (clinicaltrials.gov) NCT01249638.
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Affiliation(s)
- Arndt Stahler
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany.
| | - Dominik P Modest
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | | | | | | | | | - Ingo Schwaner
- Onkologische Schwerpunktpraxis Kurfürstendamm, Berlin, Germany
| | | | - Michael Schenk
- Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
| | - Annika Kurreck
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, LMU Munich, Germany
| | | | - Jens Neumann
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Thomas Kirchner
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Andreas Jung
- Institute of Pathology, Faculty of Medicine, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sebastian Stintzing
- Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology, and Cancer Immunology, Charitéplatz 1, 10117 Berlin, Germany; Charité - Universitätsmedizin, German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Germany; LMU Munich, German Cancer Consortium (DKTK), Partner Site Munich, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Tilsed CM, Fisher SA, Nowak AK, Lake RA, Lesterhuis WJ. Cancer chemotherapy: insights into cellular and tumor microenvironmental mechanisms of action. Front Oncol 2022; 12:960317. [PMID: 35965519 PMCID: PMC9372369 DOI: 10.3389/fonc.2022.960317] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Accepted: 07/01/2022] [Indexed: 12/12/2022] Open
Abstract
Chemotherapy has historically been the mainstay of cancer treatment, but our understanding of what drives a successful therapeutic response remains limited. The diverse response of cancer patients to chemotherapy has been attributed principally to differences in the proliferation rate of the tumor cells, but there is actually very little experimental data supporting this hypothesis. Instead, other mechanisms at the cellular level and the composition of the tumor microenvironment appear to drive chemotherapy sensitivity. In particular, the immune system is a critical determinant of chemotherapy response with the depletion or knock-out of key immune cell populations or immunological mediators completely abrogating the benefits of chemotherapy in pre-clinical models. In this perspective, we review the literature regarding the known mechanisms of action of cytotoxic chemotherapy agents and the determinants of response to chemotherapy from the level of individual cells to the composition of the tumor microenvironment. We then summarize current work toward the development of dynamic biomarkers for response and propose a model for a chemotherapy sensitive tumor microenvironment.
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Affiliation(s)
- Caitlin M. Tilsed
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| | - Scott A. Fisher
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| | - Anna K. Nowak
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, Australia
- Medical School, University of Western Australia, Crawley, WA, Australia
- Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
| | - Richard A. Lake
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
| | - W. Joost Lesterhuis
- National Centre for Asbestos Related Diseases, Institute for Respiratory Health, Nedlands, WA, Australia
- School of Biomedical Sciences, University of Western Australia, Crawley, WA, Australia
- Telethon Kids Institute, University of Western Australia, West Perth, WA, Australia
- *Correspondence: W. Joost Lesterhuis,
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Efficacy of FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in 1st-line treatment of older patients with RAS wild-type metastatic colorectal cancer: an analysis of the randomised trial FIRE-3. Br J Cancer 2022; 127:836-843. [PMID: 35637412 PMCID: PMC9427779 DOI: 10.1038/s41416-022-01854-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 04/14/2022] [Accepted: 05/09/2022] [Indexed: 12/09/2022] Open
Abstract
Summary
Background
The evidence on the efficacy of anticancer therapy is limited in older patients with metastatic colorectal cancer (mCRC). This retrospective analysis of phase III FIRE-3 trial assesses the efficacy of FOLFIRI plus either cetuximab or bevacizumab according to the patients’ age and sidedness of primary tumour.
Methods
The study endpoints overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between younger (<65 years) and older (≥65 years) patients, followed by stratification according to primary tumour sidedness. ORR was compared using Fisher´s exact test, OS and PFS were estimated by the Kaplan–Meier method and compared using the log-rank test. Univariate Cox regression analyses assessed hazard ratios and 95% confidence intervals for OS and PFS.
Results
Overall, older patients with RAS WT tumours had a significantly shorter OS when compared to younger patients (25.9 months vs 29.3 months, HR 1.29; P = 0.02). Also the proportion of right-sided tumours was significantly greater in older patients (27.1% vs 17.9%; P = 0.029). Secondary resection rates were numerically higher in younger patients (25.4% vs. 17.6%, P = 0.068) than in older patients. This was primarily seen in the Cetuximab arm, where older patients underwent less likely resection (13.1% vs. 26%; P = 0.02). Older patients with left-sided tumours showed only a trend towards greater efficacy of cetuximab (HR 0.86; P = 0.38). In patients with right-sided primary tumours, older patients did not appear to benefit from cetuximab in contrast to younger patients (≥65 years: 16.6 months vs 23.6 months, HR 1.1; P = 0.87; <65 years: 21.9 months vs 16.4 months HR 1.5; P = 0.31).
Conclusions
In FIRE-3, OS was generally shorter in older patients in comparison to younger patients. This could be explained by the overrepresentation of right-sided tumours and a lower secondary resection rate in older patients. The efficacy of targeted therapy was dependent on tumour sidedness in older patients with RAS WT mCRC.
Clinical trial
FIRE-3 (NCT00433927).
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Qi W, Zhang Q. Identification and Validation of Immune Molecular Subtypes and Immune Landscape Based on Colon Cancer Cohort. Front Med (Lausanne) 2022; 9:827695. [PMID: 35602471 PMCID: PMC9121983 DOI: 10.3389/fmed.2022.827695] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Accepted: 03/11/2022] [Indexed: 12/15/2022] Open
Abstract
BackgroundThe incidence and mortality rates of colon adenocarcinoma (COAD), which is the fourth most diagnosed cancer worldwide, are high. A subset of patients with COAD has shown promising responses to immunotherapy. However, the percentage of patients with COAD benefiting from immunotherapy is unclear. Therefore, gaining a better understanding of the immune milieu of colon cancer could aid in the development of immunotherapy and suitable combination strategies.MethodsIn this study, gene expression profiles and clinical follow-up data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and molecular subtypes were identified using the ConsensusClusterPlus package in R. Univariate and multivariate Cox regression analyses were performed to evaluate the prognostic value of immune subtypes. The graph structure learning method was used to reduce the dimension to reveal the internal structure of the immune system. Weighted correlation network analysis (WGCNA) was performed to identify immune-related gene modules. Finally, western blotting was performed to verify the gene expression patterns in COAD samples.ResultsThe results showed that 424 COAD samples could be divided into three subtypes based on 1921 immune cell-related genes, with significant differences in prognosis between subtypes. Furthermore, immune-related genes could be divided into five functional modules, each with a different distribution pattern of immune subtypes. Immune subtypes and gene modules were highly reproducible across many data sets. There were significant differences in the distribution of immune checkpoints, molecular markers, and immune characteristics among immune subtypes. Four core genes, namely, CD2, FGL2, LAT2, and SLAMF1, with prognostic significance were identified by WGCNA and univariate Cox analysis.ConclusionOverall, this study provides a conceptual framework for understanding the tumor immune microenvironment of colon cancer.
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First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study. Br J Cancer 2022; 126:1548-1554. [PMID: 35440667 PMCID: PMC9130487 DOI: 10.1038/s41416-022-01737-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 01/21/2022] [Accepted: 02/02/2022] [Indexed: 11/08/2022] Open
Abstract
Background Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results. Methods TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS. Results At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings. Conclusions TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy. Clinical trial information NCT02743221 (clinicaltrials.gov)
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Rinaldi I, Winston K, Vincent LD, Wicaksono A, Wardoyo MP, Nurrobi YAS, Leoni J. Overall Survival and Progression-Free Survival Comparison of Bevacizumab Plus Chemotherapy Combination Regiment versus Chemotherapy Only Regiment in Previously Untreated Metastatic Colorectal Cancer: Systematic Review and Meta-Analysis. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.9375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Colorectal cancer is the third-most common cancer in the world, in which 15%–25% of patients already had metastatic colorectal cancer (mCRC) at the time of diagnosis. The overall survival (OS) of mCRC is poor with the use of chemotherapy.
AIM: This systematic review and meta-analysis aim to examine the outcomes of OS and progression-free survival (PFS) of adding bevacizumab to different chemotherapy regiments compared to chemotherapy regiments only in the treatment of untreated mCRC.
METHODS: Literature searching was done in databases such as PubMed, EBSCO, SCOPUS, and ScienceDirect. The primary outcome measured in this systematic review and meta-analysis was OS, while the secondary outcome was PFS. Hazard ratio (HR) was used as the main summary measure with 95% confidence interval (CI). Publication bias was measured using a funnel plot.
RESULTS: Literature searching resulted in 11 selected studies, 9 selected for meta-analysis. Addition of bevacizumab showed significant better results in OS (HR 0.83, CI 95% 0.74–0.93; p = 0.002; I2 = 29%) and PFS (HR 0.62, 95% CI 0.51–0.75; p < 0.0001, I2 = 78%).
CONCLUSION: The addition of bevacizumab to chemotherapy resulted in better OS and PFS in untreated mCRC. Further studies are needed to confirm PFS benefit from the combination of bevacizumab and chemotherapy due to significant heterogeneity.
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Temraz S, Nasr F, Kattan J, Abigerges D, Moukadem W, Farhat F, Maatouk L, Chahine G, Shamseddine A. A Non-Interventional Multicenter Study of First-Line Bevacizumab in Combination with Chemotherapy in Patients with Metastatic Colorectal Cancer in Lebanon. Biologics 2022; 16:7-15. [PMID: 35221671 PMCID: PMC8881008 DOI: 10.2147/btt.s340525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 12/23/2021] [Indexed: 11/30/2022]
Abstract
Purpose When combined with chemotherapy, bevacizumab improves progression-free survival (PFS) in metastatic colorectal cancer (mCRC). This observational trial was designed to assess the safety and efficacy of bevacizumab plus first-line chemotherapy in a real-world setting in Lebanon. Patients and Methods A non-interventionaL multicenter study of first-LIne AVastin® (bevacizumab) in combination with chEmotherapy in patients with metastatic colorectal cancer (LLIVE) is a multicenter, prospective, Lebanon-based, observational study that enrolled mCRC patients who received first-line bevacizumab plus chemotherapy combination. The primary end point of the study was PFS. Secondary endpoints comprised the overall response rate (ORR) and the safety and tolerability of bevacizumab. Results A total of 196 patients were enrolled between July 2010 and August 2013. The median duration of follow-up was 11 months. Median duration of bevacizumab treatment was 4 months with FOLFOX being the chiefly chemotherapy regimen used in the first-line setting (26%). Median PFS was 8.22 months (95% confidence interval (CI): 7.005–9.443). The ORR was 50.3% (complete response 7.5%, partial response 42.8%). The most common adverse event encountered was hypertension (28%) followed by epistaxis (4.8%), diarrhea (4%), anemia (4%) and headache (4%). Grade 3/4 adverse events occurred in 15.2% of patients. Conclusion The trial further substantiated the efficacy and safety of bevacizumab and chemotherapy in the first-line treatment of mCRC patients in Lebanon.
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Affiliation(s)
- Sally Temraz
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Fadi Nasr
- Department of Hematology and Oncology, Mount Lebanon Hospital, Beirut, Lebanon
| | - Joseph Kattan
- Department of Hematology and Oncology, Saint- Joseph University, Beirut, Lebanon
| | - Dany Abigerges
- Department of Hematology and Oncology, Middle East Institute of Health, Bsalim, Lebanon
| | - Walid Moukadem
- Department of Hematology and Oncology, Haykal Hospital, Tripoli, Lebanon
| | - Fadi Farhat
- Department of Hematology and Oncology, Hammoud Hospital University Medical Center, Saida, Lebanon
| | | | - Georges Chahine
- Department of Hematology and Oncology, Hôtel-Dieu de France University Hospital, Beirut, Lebanon
| | - Ali Shamseddine
- Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
- Correspondence: Ali Shamseddine, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon, Tel +961 1 374374, Fax +961 1 370814, Email
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Abstract
Most patients with colorectal cancer (CRC) were diagnosed in advanced stage and the prognosis is poor. Therefore, early detection and prevention of CRC are very important. As with other cancers, there is also the tertiary prevention for CRC. The primary prevention is etiological prevention, which is mainly the treatment of adenoma or inflammation for preventing the development into cancer. The secondary prevention is the early diagnosis and early treatment for avoiding progressing to advanced cancer. The tertiary prevention belongs to the broad category of prevention, mainly for advanced CRC, through surgical treatment and postoperative adjuvant chemotherapy, radiotherapy, targeted therapy, immunotherapy for preventing tumor recurrence or metastasis. This consensus is based on the recent domestic and international consensus guidelines and the latest progress of international researches in the past five years. This consensus opinion seminar was hosted by the Chinese Society of Gastroenterology and Cancer Collaboration Group of Chinese Society of Gastroenterology, and was organized by the Division of Gastroenterology and Hepatology & Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University. The consensus opinion contains 60 statement clauses, the standard and basis of the evidence-based medicine grade and voting grade of the statement strictly complied with the relevant international regulations and practice.
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Riedesser JE, Ebert MP, Betge J. Precision medicine for metastatic colorectal cancer in clinical practice. Ther Adv Med Oncol 2022; 14:17588359211072703. [PMID: 35237350 PMCID: PMC8882813 DOI: 10.1177/17588359211072703] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/17/2021] [Indexed: 12/22/2022] Open
Abstract
Globally, metastatic colorectal cancer is one of the leading causes for cancer-related death. Treatment limited to conventional chemotherapeutics extended life for only a few months. However, advances in surgical approaches and medical treatment regimens have greatly increased survival, even leading to long-term remission in selected patients. Advances in multiomics analysis of tumors have built a foundation for molecular-targeted therapies. Furthermore, immunotherapies are on the edge of revolutionizing oncological practice. This review summarizes recent advances in the growing toolbox of personalized treatment for patients with metastatic colorectal cancer. We provide an overview of current multimodal therapy and explain novel immunotherapy and targeted therapy approaches in detail. We emphasize clinically relevant therapies, such as inhibitors of MAPK signaling, and give recommendations for clinical practice. Finally, we describe the potential predictive impact of molecular subtypes and provide an outlook on novel concepts, such as functional precision medicine.
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Affiliation(s)
- Julian E. Riedesser
- Junior Clinical Cooperation Unit Translational
Gastrointestinal Oncology and Preclinical Models, German Cancer Research
Center (DKFZ), Heidelberg, Germany
| | - Matthias P. Ebert
- Department of Medicine II, University Medical
Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim,
GermanyMannheim Cancer Center, University Medical Center Mannheim, Medical
Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Betge
- Junior Clinical Cooperation Unit Translational
Gastrointestinal Oncology and Preclinical Models, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg 69120, GermanyDKFZ-Hector
Cancer Institute at University Medical Center Mannheim, Mannheim,
Germany.Department of Medicine II, University Medical Center Mannheim,
Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyMannheim
Cancer Center, University Medical Center Mannheim, Medical Faculty Mannheim,
Heidelberg University, Mannheim, Germany
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Sahebnasagh A, Nabavi SM, Kashani HRK, Abdollahian S, Habtemariam S, Rezabakhsh A. Anti-VEGF agents: As appealing targets in the setting of COVID-19 treatment in critically ill patients. Int Immunopharmacol 2021; 101:108257. [PMID: 34673299 PMCID: PMC8519896 DOI: 10.1016/j.intimp.2021.108257] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/27/2021] [Accepted: 10/10/2021] [Indexed: 01/04/2023]
Abstract
Recently, the medications used for the severe form of the coronavirus disease-19 (COVID-19) therapy are of particular interest. In this sense, it has been supposed that anti-VEGF compounds would be good candidates in the face of "cytokine storm" and intussuscepted angiogenesis due to having an appreciable anti-inflammatory effect. Therefore, they can be subjected to therapeutic protocols to manage acute respiratory distress syndrome (ARDS). Since the compelling evidence emphasized that VEGFs contribute to the inflammatory process and play a mainstay role in disease pathogenesis, in this review, we aimed to highlight the VEGF's plausible participation in the cytokine storm exacerbation in COVID-19. Next, the recent clinical advances regarding the anti-VEGF medications, including humanized monoclonal antibody, immunosuppressant, a tyrosine kinase inhibitor, and a cytokine inhibitor, have been addressed in the setting of COVID-19 treatment in critically ill patients. Together, retrieving the increased level of VEGF subsets, as well as antagonizing VEGF related receptors, could be helpful for the treatment of COVID-19, especially in those suffering from ARDS.
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Affiliation(s)
- Adeleh Sahebnasagh
- Clinical Research Center, Department of Internal Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | | | - Safieh Abdollahian
- Department of Nanobiotechnology, New Technologies Research Group, Pasteur Institute, Tehran, Iran
| | - Solomon Habtemariam
- Pharmacognosy Research Laboratories & Herbal Analysis Services UK, University of Greenwich, Chatham-Maritime, Kent ME4 4TB, UK
| | - Aysa Rezabakhsh
- Cardiovascular Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Wang F, Dai G, Deng Y, Tang Y, Wang W, Niu Z, Bi F, Zhu L, Guo Z, Yan J, Hu B, Tao M, Yang S, Zhang S, Wen L, Xu R. Efficacy and safety of chemotherapy combined with bevacizumab in Chinese patients with metastatic colorectal cancer: A prospective, multicenter, observational, non-interventional phase IV trial. Chin J Cancer Res 2021; 33:490-499. [PMID: 34584374 PMCID: PMC8435824 DOI: 10.21147/j.issn.1000-9604.2021.04.06] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 08/09/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE Bevacizumab has an important and evolving role in improving outcomes in patients with metastatic colorectal cancer (mCRC) worldwide and was approved in China in 2010. However, there are limited real-world data on the efficacy and safety of chemotherapy regimens combined with bevacizumab in Chinese patients with mCRC. This observational, phase IV trial study aimed to obtain more experience on the efficacy and safety of bevacizumab combined with chemotherapy in Chinese mCRC patients. METHODS Between September 2013 and November 2016, patients with histologically confirmed mCRC were enrolled in a prospective, multicenter, observational, non-interventional phase IV trial at 26 centers across China. Eligible patients received different chemotherapeutic regimens combined with bevacizumab. The efficacy and safety data in the intention-to-treat study population were analyzed. RESULTS A total of 611 patients were included in the efficacy analysis. The median overall survival and median progression-free survival was 18.00 and 10.05 months, respectively. The objective response rate was 21.00% and disease control rate was 89.40%. In subgroup analyses, the survival differences were observed according to metastatic status, duration of treatment and elevation in blood pressure. A total of 613 patients were evaluable for safety assessments. And 569 (92.82%) patients reported at least one adverse event (AE), and 151 (24.63%) experienced grade 3 or higher AEs. The incidence of bevacizumab-associated AEs of special interest was reported in 31 (5.06%) patients with hypertension (n=12), abscesses and fistulae (n=7), bleeding (n=6), proteinuria (n=3), gastrointestinal perforation (n=2) and venous thrombotic events (n=1). CONCLUSIONS This observational phase IV trial broadens our experience and knowledge of bevacizumab in the Chinese population and provides a good indication of its overall efficacy and safety. Bevacizumab in combination with chemotherapy offers clinical benefits to Chinese patients with mCRC and has an acceptable and manageable safety profile.
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Affiliation(s)
- Fenghua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Guanghai Dai
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing 100853, China
| | - Yanhong Deng
- Department of Medical Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Yong Tang
- Department of Medical Oncology, Xinjiang Medical University Cancer Hospital, Urumqi 830000, China
| | - Wei Wang
- Department of Medical Oncology, Foshan First People’s Hospital, Foshan 528010, China
| | - Zuoxing Niu
- Department of Medical Oncology, Shandong Cancer Hospital, Jinan 250117, China
| | - Feng Bi
- Department of Medical Oncology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liangjun Zhu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing 210009, China
| | - Zengqing Guo
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou 350014, China
| | - Jin Yan
- Department of Surgical Oncology, Sichuan Cancer Hospital, Chengdu 610041, China
| | - Bing Hu
- Department of Medical Oncology, Anhui Provincial Hospital, Hefei 230001, China
| | - Min Tao
- Department of Medical Oncology, the First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Shujun Yang
- Department of Medical Oncology, Henan Cancer Hospital, Zhengzhou 450003, China
| | - Suzhan Zhang
- Department of Medical Oncology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| | - Lu Wen
- Department of Medical Oncology, Shanxi Provincial Cancer Hospital, Taiyuan 030009, China
| | - Ruihua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
- Ruihua Xu. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine. No. 651 Dongfeng East Road, Guangzhou 510060, China.
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Yin G, Zhao L. Risk of hypertension with anti-VEGF monoclonal antibodies in cancer patients: a systematic review and meta-analysis of 105 phase II/III randomized controlled trials. J Chemother 2021; 34:221-234. [PMID: 34229563 DOI: 10.1080/1120009x.2021.1947022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
We performed a meta-analysis to fully investigate the hypertension of anti-VEGF mAbs in cancer patients. Databases were searched for randomized controlled trials (RCTs) treated with anti-VEGF mAbs till January 2021. The relevant RCTs in cancer patients treated with anti-VEGF mAbs were retrieved and the systematic evaluation was conducted. One hundred and five RCTs and 65358 patients were included. Our study suggests that anti-VEGF mAbs significantly increased the risks of all-grade (RR, 3.22; 95%CI, 2.83-3.65; p < 0.00001; I2=71%) and high-grade (RR, 6.15; 95%CI, 5.58-6.78; p < 0.00001; I2=48%) hypertension in cancer patients. Those risks may be dependent on drug type. Icrucumab did not association with an increased risk of hypertension. The RR of hypertension did not vary significantly according to the type of cancer, line of therapy, and treatment duration. The available data suggested that the use of anti-VEGF mAbs were associated with a significantly increased risk of hypertension.
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Affiliation(s)
- Gang Yin
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China.,Engineering Research Center for Pharmaceuticals and Equipments of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of pharmacy, Chengdu University, Chengdu, Sichuan, P.R. China
| | - Ling Zhao
- Central Nervous System Drug Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, Sichuan, P.R. China
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Monteiro AR, Conde RS, Basto R, Sclafani F, Deleporte A, Hendlisz A, Dal Lago L. Targeted agents in older patients with gastrointestinal cancers - An overview. J Geriatr Oncol 2021; 12:1240-1252. [PMID: 34226158 DOI: 10.1016/j.jgo.2021.06.013] [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: 04/07/2021] [Revised: 06/12/2021] [Accepted: 06/25/2021] [Indexed: 12/24/2022]
Abstract
Targeted agents have been increasingly used in different malignancies and are associated with improved survival outcomes, including gastrointestinal cancers. Their use in the treatment of older patients is appealing given their favorable toxicity profile. In the last years, this subgroup of patients has been attracting increased interest given their representativeness and specific clinical needs. Nonetheless, the lack of data on efficacy and safety of standard treatments in older patients hinders proper evidence-based decision-making, leaving most therapeutic recommendations to be extrapolated from registration trials with low representation of older and frail patients. However, even if most decisions regarding the use of targeted agents in older patients with gastrointestinal cancer remain guided by subanalyses of large trials, data from recent older adult-specific trials are beginning to emerge, particularly in colorectal cancer. This review aims to summarize the existing evidence on treatment of older patients with gastrointestinal carcinomas (colon and rectum, stomach, esophagus, liver, and pancreas) with targeted agents (cetuximab, panitumumab, bevacizumab, ramucirumab, aflibercept, regorafenib, encorafenib, trastuzumab, sorafenib, lenvatinib, cabozantinib, erlotinib, olaparib), and place the evidence in a geriatric oncology perspective.
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Affiliation(s)
- Ana Raquel Monteiro
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Rita Saúde Conde
- Instituto Português de Oncologia de Lisboa Francisco Gentil, Department of Medical Oncology, Rua Professor Lima Basto, 1099-023 Lisboa, Portugal.
| | - Raquel Basto
- Instituto Português de Oncologia de Coimbra Francisco Gentil, Department of Medical Oncology, Av. Bissaya Barreto 98, 3000-075 Coimbra, Portugal.
| | - Francesco Sclafani
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Amélie Deleporte
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Alain Hendlisz
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
| | - Lissandra Dal Lago
- Institut Jules Bordet, Department of Medicine, Blvd de Waterloo 121, 1000 Brussels, Belgium.
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Yin J, Dawood S, Cohen R, Meyers J, Zalcberg J, Yoshino T, Seymour M, Maughan T, Saltz L, Van Cutsem E, Venook A, Schmoll HJ, Goldberg R, Hoff P, Hecht JR, Hurwitz H, Punt C, Diaz Rubio E, Koopman M, Cremolini C, Heinemann V, Tournigard C, Bokemeyer C, Fuchs C, Tebbutt N, Souglakos J, Doulliard JY, Kabbinavar F, Chibaudel B, de Gramont A, Shi Q, Grothey A, Adams R. Impact of geography on prognostic outcomes of 21,509 patients with metastatic colorectal cancer enrolled in clinical trials: an ARCAD database analysis. Ther Adv Med Oncol 2021; 13:17588359211020547. [PMID: 34262614 PMCID: PMC8252342 DOI: 10.1177/17588359211020547] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 05/05/2021] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Benchmarking international cancer survival differences is necessary to evaluate and improve healthcare systems. Our aim was to assess the potential regional differences in outcomes among patients with metastatic colorectal cancer (mCRC) participating in international randomized clinical trials (RCTs). DESIGN Countries were grouped into 11 regions according to the World Health Organization and the EUROCARE model. Meta-analyses based on individual patient data were used to synthesize data across studies and regions and to conduct comparisons for outcomes in a two-stage random-effects model after adjusting for age, sex, performance status, and time period. We used mCRC patients enrolled in the first-line RCTs from the ARCAD database, which provided enrolling country information. There were 21,509 patients in 27 RCTs included across the 11 regions. RESULTS Main outcomes were overall survival (OS) and progression-free survival (PFS). Compared with other regions, patients from the United Kingdom (UK) and Ireland were proportionaly over-represented, older, with higher performance status, more frequently male, and more commonly not treated with biological therapies. Cohorts from central Europe and the United States (USA) had significantly longer OS compared with those from UK and Ireland (p = 0.0034 and p < 0.001, respectively), with median difference of 3-4 months. The survival deficits in the UK and Ireland cohorts were, at most, 15% at 1 year. No evidence of a regional disparity was observed for PFS. Among those treated without biological therapies, patients from the UK and Ireland had shorter OS than central Europe patients (p < 0.001). CONCLUSIONS Significant international disparities in the OS of cohorts of mCRC patients enrolled in RCTs were found. Survival of mCRC patients included in RCTs was consistently lower in the UK and Ireland regions than in central Europe, southern Europe, and the USA, potentially attributed to greater overall population representation, delayed diagnosis, and reduced availability of therapies.
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Affiliation(s)
- Jun Yin
- Department of Health Sciences Research, Mayo Clinic, 200 First Street, SW Rochester, MN 55905, USA
| | - Shaheenah Dawood
- Mediclinic City Hospital: North Wing, Dubai Health Care City, Dubai UAE
| | - Romain Cohen
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Jeff Meyers
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - John Zalcberg
- School of Public Health and Preventative Medicine, Monash University, Melbourne, Australia
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan
| | | | - Tim Maughan
- CRUK/MRC Oxford Institute for Radiation Oncology, Oxford, UK
| | - Leonard Saltz
- Memory Sloan Kettering Cancer Center, New York, NY, USA
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | - Alan Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | - Richard Goldberg
- Department of Oncology, West Virginia University, Morgantown, WV, USA
| | - Paulo Hoff
- Centro de Oncologia de Brasilia do Sirio Libanes: Unidade Lago Sul, Siro Libanes, Brazil
| | - J. Randolph Hecht
- Ronald Reagan UCLA Medical Center, UCLS Medical Center, Santa Monica, CA, USA
| | | | - Cornelis Punt
- Department of Medical Oncology, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Volker Heinemann
- Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany
| | | | - Carsten Bokemeyer
- Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Niall Tebbutt
- Sydney Medical School, University of Sydney, Sydney, Australia
| | | | | | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Qian Shi
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | | | - Richard Adams
- Cardiff University and Velindre Cancer Center, Cardiff, UK
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Coccolini F, Improta M, Cicuttin E, Catena F, Sartelli M, Bova R, de’ Angelis N, Gitto S, Tartaglia D, Cremonini C, Ordonez C, Baiocchi GL, Chiarugi M. Surgical site infection prevention and management in immunocompromised patients: a systematic review of the literature. World J Emerg Surg 2021; 16:33. [PMID: 34112231 PMCID: PMC8194010 DOI: 10.1186/s13017-021-00375-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 05/26/2021] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Immunocompromised patients are at higher risk of surgical site infection and wound complications. However, optimal management in the perioperative period is not well established. Present systematic review aims to analyse existing strategies and interventions to prevent and manage surgical site infections and other wound complications in immunocompromised patients. METHODS A systematic review of the literature was conducted. RESULTS Literature review shows that partial skin closure is effective to reduce SSI in this population. There is not sufficient evidence to definitively suggest in favour of prophylactic negative pressure wound therapy. The use of mammalian target of rapamycin (mTOR) and calcineurin inhibitors (CNI) in transplanted patient needing ad emergent or undeferrable abdominal surgical procedure must be carefully and multidisciplinary evaluated. The role of antibiotic prophylaxis in transplanted patients needs to be assessed. CONCLUSION Strict adherence to SSI infection preventing bundles must be implemented worldwide especially in immunocompromised patients. Lastly, it is necessary to elaborate a more widely approved definition of immunocompromised state. Without such shared definition, it will be hard to elaborate the needed methodologically correct studies for this fragile population.
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Affiliation(s)
- Federico Coccolini
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Via Paradisa 1, 56100 Pisa, Italy
| | - Mario Improta
- General Surgery Department, Bologna University Hospital, Bologna, Italy
| | - Enrico Cicuttin
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Via Paradisa 1, 56100 Pisa, Italy
| | - Fausto Catena
- Emergency Surgery Department, Parma University Hospital, Parma, Italy
| | | | - Raffaele Bova
- General Surgery Department, Bologna University Hospital, Bologna, Italy
| | - Nicola de’ Angelis
- Unit of Digestive and Hepato-biliary-pancreatic Surgery, Henri Mondor Hospital, Créteil, France
- UPEC, University Paris Est, Créteil, France
| | - Stefano Gitto
- Department of Experimental and Clinical Medicine, Firenze University, Firenze, Italy
| | - Dario Tartaglia
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Via Paradisa 1, 56100 Pisa, Italy
| | - Camilla Cremonini
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Via Paradisa 1, 56100 Pisa, Italy
| | - Carlos Ordonez
- Department of Surgery, Fundación Valle del Lili, Cali, Colombia
| | - Gian Luca Baiocchi
- Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
| | - Massimo Chiarugi
- General, Emergency and Trauma Surgery Department, Pisa University Hospital, Via Paradisa 1, 56100 Pisa, Italy
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Kristin E, Endarti D, Khoe LC, Taroeno-Hariadi KW, Trijayanti C, Armansyah A, Sastroasmoro S. Economic Evaluation of Adding Bevacizumab to Chemotherapy for Metastatic Colorectal Cancer (mCRC) Patients in Indonesia. Asian Pac J Cancer Prev 2021; 22:1921-1926. [PMID: 34181352 PMCID: PMC8418847 DOI: 10.31557/apjcp.2021.22.6.1921] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/19/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVE Since 2016, bevacizumab has been widely used to treat metastatic colorectal cancer (mCRC) in Indonesia. Nevertheless, the high cost of bevacizumab has raised the question of whether the therapy is considered cost-effective and should be included in the national health insurance system. This study aimed to assess the cost-effectiveness of bevacizumab plus chemotherapy versus chemotherapy alone for the treatment of mCRC patients. METHODS A Markov model was applied using the perspective of the Indonesian healthcare system to assess cost-effectiveness. The health outcomes were expressed in terms of quality-adjusted life years (QALY) using the validated EuroQoL-5D-5L instrument. Data for medical costs were collected from hospital billings in four hospitals located in three different cities in Indonesia. Meanwhile, data for utility were obtained from interviewing 90 patients who came to the hospital. We compared those mCRC patients who received chemotherapy alone either with FOLFOX or FOLFIRI, versus patients who received the addition of bevacizumab. RESULTS With the perspective of societal, the incremental cost-effectiveness ratio (ICER) of adding bevacizumab was USD 49,312 per QALY gained using secondary data and USD 28,446 per QALY using real world data. CONCLUSION Using either a healthcare or societal perspective, the addition of bevacizumab for mCRC treatment was considered not cost-effective.
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Affiliation(s)
- Erna Kristin
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.
| | - Dwi Endarti
- Department of Pharmaceutics, Faculty of Pharmacy, Gadjah Mada University, Yogyakarta, Indonesia.
| | - Levina Chandra Khoe
- Department of Community Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
| | - Kartika Widayati Taroeno-Hariadi
- Department of Pharmacology and Therapy, Faculty of Medicine Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.
| | | | - Armansyah Armansyah
- Center of Financing and Health Insurance, Ministry of Health, Government of Indonesia, Indonesia.
| | - Sudigdo Sastroasmoro
- Department of Pediatrics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
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Dunn C, Hong W, Gibbs P, Ackland S, Sjoquist K, Tebbutt NC, Price T, Burge M. Personalizing First-Line Systemic Therapy in Metastatic Colorectal Cancer: Is There a Role for Initial Low-Intensity Therapy in 2021 and Beyond? A Perspective From Members of the Australasian Gastrointestinal Trials Group. Clin Colorectal Cancer 2021; 20:245-255. [PMID: 34103264 DOI: 10.1016/j.clcc.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/16/2021] [Accepted: 05/02/2021] [Indexed: 01/18/2023]
Abstract
Palliative chemotherapy is the cornerstone of treatment for the majority of patients with metastatic colorectal cancer, with the aim of increasing length and quality of life. Although guidelines outline the available treatment options in the first line, they provide limited guidance on choice and intensity of the chemotherapy backbone. Data from the TRIBE and TRIBE2 studies confirm a survival benefit with triplet FOLFOXIRI and bevacizumab, and this is a preferred option for younger patients with good performance status able to tolerate it. However, the relative benefit of a fluoropyrimidine doublet with oxaliplatin or irinotecan over single-agent fluoropyrimidine with or without a biologic is less certain; the available data demonstrate that single-agent fluoropyrimidine plus a biologic with planned sequencing of subsequent agents can produce similar overall survival outcomes with reduced toxicity. Our analysis of local real-world registry data suggests that this is an underutilized approach, particularly in younger and fitter patients. Established prognostic factors, including patient age, performance status, tumor sidedness, and biomarkers such as RAS/BRAF, are key in treatment selection; patients with left-sided RAS/BRAF wild-type disease or patients with low tumor bulk may be ideal for a less intensive regimen. Further studies are required to confirm the value of less-intensive regimens in the modern era, where the incorporation of biologic therapies has become routine and where non-chemotherapy options are emerging as viable options for molecularly defined patient subsets.
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Affiliation(s)
- Catherine Dunn
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
| | - Wei Hong
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia; Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
| | - Stephen Ackland
- Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Katrin Sjoquist
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia; Cancer Care Centre, St. George Hospital, Kogarah, New South Wales, Australia
| | - Niall C Tebbutt
- Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia; Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
| | - Matthew Burge
- Department of Medical Oncology, Royal Brisbane Hospital, Herston, Queensland, Australia
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Jagieła J, Bartnicki P, Rysz J. Nephrotoxicity as a Complication of Chemotherapy and Immunotherapy in the Treatment of Colorectal Cancer, Melanoma and Non-Small Cell Lung Cancer. Int J Mol Sci 2021; 22:ijms22094618. [PMID: 33924827 PMCID: PMC8125622 DOI: 10.3390/ijms22094618] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/18/2021] [Accepted: 04/22/2021] [Indexed: 12/12/2022] Open
Abstract
Acute kidney injury is a common complication of many medical procedures, including those used in cancer treatment. Both chemotherapy and immunotherapy may result in deterioration of kidney function, which may lead to an increase in mortality among patients with cancer. Antineoplastic agents can affect any element of the nephron, leading to the appearance of clinical symptoms such as proteinuria, hypertension, electrolyte disorders, glomerulonephritis, acute and chronic interstitial nephritis and acute kidney injury. The medical literature describing renal complications occurring during chemotherapeutic and immunotherapeutic treatment in neoplasms, such as colorectal cancer, non-small cell lung cancer and melanoma, was analysed. The immune system plays an important role in controlling the development of neoplasms and fighting them. Oncological treatment algorithms include immunotherapy as monotherapy, combined with chemotherapy or chemotherapy as monotherapy. In the treatment of the above-mentioned neoplasms immunotherapeutics are used, such as checkpoint inhibitors (CPI) (i.e., ipilimumab, pembrolizumab, nivolumab, atezolizumab), vascular endothelial growth factor (VEGF) inhibitors (i.e., bevacizumab, ramucirumab) and a variety of chemotherapeutic agents (irinotecan, capecitabine, oxaliplatin, gefitinib, erlotinib, gemcitabine, cisplatin, paclitaxel, carboplatin, doclitaxel, vinorelbine, topotecan, etoposide). In our article, we focused on the number and type of renal complications as well as on the time of their manifestation when using specific treatment regimens. Our analysis also includes case reports. We discussed treatment of immunological complications and adjustments of the dose of chemotherapeutic agents depending on the creatinine clearance. Analysing the data from the literature, when two immunotherapeutic agents are used together, the number of recorded renal complications increases. Bevacizumab and ramucirumab are the cause of the largest number of renal complications among the immunotherapeutic agents described above. Cisplatin is the best-described substance with the greatest nephrotoxic potential among the chemotherapeutic agents. Crucial for renal complications are also cancer stage, previous chemotherapy and other risk factors of AKI such as age, comorbidities and medications used. Due to the described complications during oncological treatment, including kidney damage, it seems necessary to elaborate standards of cooperation between oncologists and nephrologists both during and after treatment of a patient with cancer. Therefore, it is necessary to conduct further research and develop algorithms for management of a cancer patient, especially during such an intensive progress in oncology.
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Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor KK, Cohen S, Cooper HS, Deming D, Farkas L, Garrido-Laguna I, Grem JL, Gunn A, Hecht JR, Hoffe S, Hubbard J, Hunt S, Johung KL, Kirilcuk N, Krishnamurthi S, Messersmith WA, Meyerhardt J, Miller ED, Mulcahy MF, Nurkin S, Overman MJ, Parikh A, Patel H, Pedersen K, Saltz L, Schneider C, Shibata D, Skibber JM, Sofocleous CT, Stoffel EM, Stotsky-Himelfarb E, Willett CG, Gregory KM, Gurski LA. Colon Cancer, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021; 19:329-359. [PMID: 33724754 DOI: 10.6004/jnccn.2021.0012] [Citation(s) in RCA: 913] [Impact Index Per Article: 228.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation-positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org. Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.
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Affiliation(s)
- Al B Benson
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | - Alan P Venook
- 2UCSF Helen Diller Family Comprehensive Cancer Center
| | | | | | | | | | - Stacey Cohen
- 6Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Linda Farkas
- 9UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | | | | | | | - Steven Hunt
- 16Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | | | - Smitha Krishnamurthi
- 19Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | | | - Eric D Miller
- 22The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Mary F Mulcahy
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | - Katrina Pedersen
- 16Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
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García-Alfonso P, Díaz-Rubio E, Abad A, Carrato A, Massutí B, Ortiz-Morales MJ, Manzano Mozo JL, Muñoz A, Durán G, Sastre J, Safont MJ, Ferreiro R, Rivera F, González E, Valladares-Ayerbes M, Grávalos C, Alonso-Orduña V, Viéitez JM, Yubero A, Aranda E. First-Line Biological Agents Plus Chemotherapy in Older Patients with Metastatic Colorectal Cancer: A Retrospective Pooled Analysis. Drugs Aging 2021; 38:219-231. [PMID: 33615402 PMCID: PMC7914239 DOI: 10.1007/s40266-021-00834-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2021] [Indexed: 01/13/2023]
Abstract
BACKGROUND Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited. OBJECTIVE This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. METHODS This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. RESULTS In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%). CONCLUSIONS Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.
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Affiliation(s)
- Pilar García-Alfonso
- Servicio de Oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
| | - Eduardo Díaz-Rubio
- CIBERONC, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clinico San Carlos (IdISSC), Madrid, Spain
| | - Albert Abad
- ICO, Hospital Germans Trias i Pujol, Badalona, Spain
- IOR Hospital Universitario Dexeus, Barcelona, Spain
| | - Alfredo Carrato
- IRYCIS, CIBERONC, Hospital Universitario Ramón y Cajal, Alcalá University, Madrid, Spain
| | | | - María José Ortiz-Morales
- IMIBIC, CIBERONC, Reina Sofía Hospital, Instituto de Salud Carlos III, University of Córdoba, Córdoba, Spain
| | | | - Andrés Muñoz
- Servicio de Oncología, Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Gema Durán
- Hospital Universitario Regional y Virgen de la Victoria, Malaga, Spain
| | - Javier Sastre
- CIBERONC, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clinico San Carlos (IdISSC), Madrid, Spain
| | | | - Reyes Ferreiro
- IRYCIS, CIBERONC, Hospital Universitario Ramón y Cajal, Alcalá University, Madrid, Spain
| | - Fernando Rivera
- Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | | | - Manuel Valladares-Ayerbes
- Instituto de Investigación Biomédica (INIBIC), Complejo Hospitalario Universitario A Coruña, A Coruña, Spain
| | | | - Vicente Alonso-Orduña
- Instituto de Investigación Sanitaria de Aragón (IISA), Hospital Universitario Miguel Servet, Zaragoza, Spain
| | | | - Alfonso Yubero
- Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - Enrique Aranda
- IMIBIC, CIBERONC, Reina Sofía Hospital, Instituto de Salud Carlos III, University of Córdoba, Córdoba, Spain
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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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Optimal duration of therapy in the first line treatment of metastatic colorectal cancer: single center experience. VOJNOSANIT PREGL 2021. [DOI: 10.2298/vsp200924053j] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Background / Aim. FOLFOX (5fluorouracil, folinic acid, oxaliplatin)/CapOx
(capecitabine, oxaliplatin) plus bevacizumab and FOLFIRI (5 fluorouracil,
folinic acid, irinotecan) plus bevacizumab are a standard treatment options
for a first line treatment of metastatic colorectal carcinoma (mCRC). The
aim of this study was to compare overall response rate (ORR),
progression-free survival (PFS) and overall survival (OS) in the groups of
patients with mCRC who were treated in the first line with FOLFIRI/bev
versus FOLFOX/bev. At the same time, it was compared the safety profile in
observed groups of patients and investigated optimal treatment duration and
characteristics of patients who had the best treatment outcomes. Methods. In
a retrospective-prospective study, patients with mCRC were treated with a
chemotherapy protocols for the first line in combination with bevacizumab
(FOLFOX/bev, respectively, FOLFIRI/bev). Treatment efficacy was evaluated on
the basis of overall response rate (ORR), progression-free survival (PFS)
and overall survival (OS), and the safety of treatment was evaluated by
monitoring adverse drug reactions. Results. ORR was 70% in the FOLFIRI/bev
group and 50% in the FOLFOX/bev group. Median PFS for FOLFIRI/bev (n = 30)
and for FOLFOX/bev (n = 30) was 15.6 months and 12.1 months respectively
(HR, 0.85; 95% confidence interval (CI) 0.47-1.53; P = 0.5591). Median OS
for FOLFIRI/bev and for FOLFOX/bev was 24.7 months and 19.9 months
respectively (HR, 0.67; 95% confidence interval (CI) 0.37-1.23; P = 0.1552).
In both patient groups, the patients who received more than 9 cycles of
induction therapy had better treatment response in comparison with patients
who received less than 9 cycles of therapy. In FOLFOX/bev group PFS was 16.9
versus 9.7 months and OS was 22.1 versus 17.6 months respectively. In
FOLFIRI/bev group PFS was 9 months for patients who received less than 9
cycles of therapy versus 18.8 months for patients who received more than 9
cycles, OS was 18.0 versus 27.7 respectively. The adverse drug reactions
grade 3 and 4 were 7% in the FOLFIRI/bev group versus 27% in the FOLFOX/bev
group. Conclusion. Patients who received FOLFIRI/bev had better ORR (70 %
versus 50 %), PFS (15.6 versus 12.1 months) and OS (24.7 versus 19.9
months). In both patient groups, better treatment response had the patients
who received induction therapy for 4-6 months (more than 9 cycles of
therapy).
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Tuca A, Gallego R, Ghanem I, Gil-Raga M, Feliu J. Chemotherapy and Targeted Agents in the Treatment of Elderly Patients with Metastatic Colorectal Cancer. J Clin Med 2020; 9:E4015. [PMID: 33322567 PMCID: PMC7764481 DOI: 10.3390/jcm9124015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/04/2020] [Accepted: 12/07/2020] [Indexed: 12/20/2022] Open
Abstract
Colorectal cancer (CRC) is one of the main causes of cancer death in the elderly. The older patients constitute a heterogeneous group in terms of functional status, comorbidities, and aging-related conditions. Therefore, therapeutic decisions need to be individualized. Additionally, a higher toxicity risk comes from the fact that pharmacokinetics and pharmacodynamics of the drugs as well as the tissue tolerance can be altered with aging. Although the chemotherapy efficacy in metastatic colorectal cancer (mCRC) is similar for older and young patients, more toxicity is presented in the elderly. While the mono-chemotherapy provides the same benefit for young and older patients, doublets front-line chemotherapy improves progression-free survival (PFS) but not overall survival (OS) in the elderly. Furthermore, the benefit of the addition of bevacizumab to chemotherapy in older patients has been shown in several clinical trials, while the clinical data for the benefit of anti-epidermal growth factor antibodies are scarcer. Immunocheckpoint inhibitors could be an appropriate option for patients with microsatellite instability (MSI) tumors. A prior geriatric assessment is required before deciding the type of treatment in order to offer the best therapeutic option.
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Affiliation(s)
- Albert Tuca
- Department of Medical Oncology, Hospital Clinic, 08036 Barcelona, Spain;
| | - Rosa Gallego
- Department of Medical Oncology, General Hospital of Granollers, 08402 Granollers, Spain;
| | - Ismael Ghanem
- Department of Medical Oncology, Hospital Universitario La Paz, CIBERONC, 28046 Madrid, Spain;
| | - Mireia Gil-Raga
- Department of Medical Oncology, University General Hospital of Valencia, CIBERONC, 46014 Valencia, Spain;
| | - Jaime Feliu
- Department of Medical Oncology, Hospital Universitario La Paz, CIBERONC, 28046 Madrid, Spain;
- Cátedra UAM-AMGEN, 28049 Madrid, Spain
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Aggressive surgery could overcome the extent of initial peritoneal dissemination for advanced ovarian, fallopian tube, and peritoneal carcinoma. Sci Rep 2020; 10:21307. [PMID: 33277564 PMCID: PMC7718231 DOI: 10.1038/s41598-020-78296-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 11/20/2020] [Indexed: 12/27/2022] Open
Abstract
We examined whether the extent of initial peritoneal dissemination affected the prognosis of patients with advanced ovarian, fallopian tube, and peritoneal carcinoma when initially disseminated lesions > 1 cm in diameter were removed, regardless of the timing of aggressive cytoreductive surgery. The extent of peritoneal dissemination was assessed by the peritoneal cancer index (PCI) at initial laparotomy in 186 consecutive patients with stage IIIC/IV. Sixty patients underwent primary debulking surgery and 109 patients underwent neoadjuvant chemotherapy followed by interval debulking surgery. Seventeen patients could not undergo debulking surgery because of disease progression during neoadjuvant chemotherapy. The median initial PCI were 17. Upper abdominal surgery and bowel resection were performed in 149 (80%) and 171 patients (92%), respectively. Residual disease ≤ 1 cm after surgery was achieved in 164 patients (89%). The initial PCI was not significantly associated with progression-free survival (PFS; p = 0.13) and overall survival (OS; p = 0.09). No residual disease and a high-complexity surgery significantly prolonged PFS (p < 0.01 and p = 0.02, respectively) and OS (p < 0.01 and p ≤ 0.01, respectively). The extent of initial peritoneal dissemination did not affect the prognosis when initially disseminated lesions > 1 cm were resected.
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Aparicio J, Esposito F, Serrano S, Falco E, Escudero P, Ruiz-Casado A, Manzano H, Fernandez-Montes A. Metastatic Colorectal Cancer. First Line Therapy for Unresectable Disease. J Clin Med 2020; 9:E3889. [PMID: 33265959 PMCID: PMC7761096 DOI: 10.3390/jcm9123889] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 01/09/2023] Open
Abstract
Colorectal cancer (CRC) is a commonly diagnosed malignancy. The prognosis of patients with unresectable, metastatic colorectal cancer (mCRC) is dismal and medical treatment is mainly palliative in nature. Although chemotherapy remains the backbone of treatment, the landscape is changing with the understanding of its heterogeneity and molecular biology. First-line therapy relies on a combination of chemotherapy and targeted therapies, according to clinical patient characteristics and tumor molecular profile. Here we review current evidence from randomized clinical trials for using chemotherapy doublets or triplets, and for the addition of bevacizumab or anti-epidermal growth factor receptor (EGFR) agents. Novel therapies developed for small, selected populations are also discussed.
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Affiliation(s)
- Jorge Aparicio
- Department of Medical Oncology, Hospital Universitario y Politecnico La Fe, E-46007 Valencia, Spain
| | - Francis Esposito
- Department of Medical Oncology, Hospital Clinic, E-08041 Barcelona, Spain;
| | - Sara Serrano
- Department of Medical Oncology, Hospital Universitario Sant Joan de Reus, E-43204 Reus, Spain;
| | - Esther Falco
- Department of Medical Oncology, Hospital Son Llatzer, E-07004 Palma de Mallorca, Spain;
| | - Pilar Escudero
- Department of Medical Oncology, Hospital Clínico Universitario Lozano Blesa, E-50002 Zaragoza, Spain;
| | - Ana Ruiz-Casado
- Department of Medical Oncology, Hospital Universitario Puerta de Hierro, E-28220 Madrid, Spain;
| | - Hermini Manzano
- Department of Medical Oncology, Hospital Quirón Salud Palmaplanas, E-07004 Palma de Mallorca, Spain;
| | - Ana Fernandez-Montes
- Department of Medical Oncology, Complejo Hospitalario de Orense, E-32001 Orense, Spain;
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Phase II randomized trial of capecitabine with bevacizumab and external beam radiation therapy as preoperative treatment for patients with resectable locally advanced rectal adenocarcinoma: long term results. BMC Cancer 2020; 20:1164. [PMID: 33246428 PMCID: PMC7694337 DOI: 10.1186/s12885-020-07661-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 11/18/2020] [Indexed: 12/19/2022] Open
Abstract
Background Preoperative chemoradiotherapy with capecitabine is considered as a standard of care for locally advanced rectal cancer. The “Tratamiento de Tumores Digestivos” group (TTD) previously reported in a randomized Ph II study that the addition of Bevacizumab to capecitabine-RT conferred no differences in the pre-defined efficacy endpoint (pathological complete response). We present the follow-up results of progression-free survival, distant relapse-free survival, and overall survival data at 3 and 5 years. Methods Patients (pts) were randomized to receive 5 weeks of radiotherapy (45 Gy/25 fractions) with concurrent Capecitabine 825 mg/m2 twice daily, 5 days per week with (arm A) or without (arm b) bevacizumab (5 mg/kg once every 2 weeks). Results In our study, the addition of bevacizumab to capecitabine and radiotherapy in the neoadjuvant setting shows no differences in pathological complete response (15.9% vs 10.9%), distant relapse-free survival (81.0 vs 80.4 and 76.2% vs 78.2% at 3 and 5 years respectively), disease-free survival (75% vs 71.7 and 68.1% vs 69.57% at 3 and 5 years respectively) nor overall survival at 5-years of follow-up (81.8% vs 86.9%). Conclusions the addition of bevacizumab to capecitabine plus radiotherapy does not confer statistically significant advantages neither in distant relapse-free survival nor in disease-free survival nor in Overall Survival in the short or long term. Trial registration EudraCT number: 2009–010192-24. Clinicaltrials.gov number: NCT01043484. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07661-z.
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