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Xu DG, Tan J. Interplay of genetic and clinical factors in cancer-associated thrombosis: Deciphering the prothrombotic landscape of colorectal cancer. World J Gastroenterol 2025; 31:103901. [DOI: 10.3748/wjg.v31.i14.103901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/03/2025] [Accepted: 03/25/2025] [Indexed: 04/11/2025] Open
Abstract
Colorectal cancer (CRC), the third most prevalent cancer globally, exhibits a notable association with venous thromboembolism (VTE), significantly impacting patient morbidity and mortality. We delve into the complex pathogenesis of cancer-associated thrombosis (CAT) in CRC, highlighting the interplay of clinical risk factors and tumor-specific mechanisms. Our comprehensive review synthesizes the current understanding of CRC’s pro-thrombotic tendencies, examining both general clinical factors (e.g., age, gender, obesity, prior VTE history) and tumor-specific aspects (e.g., tumor location, stage, targeted therapies). Key findings illustrate how CRC cells themselves actively contribute to coagulation cascade activation through various procoagulant elements such as tissue factor, cancer procoagulant, and extracellular vesicles. We also explore how CRC influences host cells to adopt a procoagulant phenotype, thereby exacerbating thrombotic risks. This review underscores the role of genetic mutations in CRC (e.g.,KRAS, p53) in modulating coagulation-related protein expression and thrombosis risks. An in-depth understanding of the genetic landscape specific to CRC subtypes is essential for developing targeted anticoagulation strategies and could significantly advance thrombosis prevention while improving the overall management of patients with CRC. This highlights the urgent need for precision in addressing CAT within clinical settings.
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Affiliation(s)
- Duo-Gang Xu
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, China
| | - Jing Tan
- Department of General Surgery, Yan'an Hospital Affiliated to Kunming Medical University, Kunming 650051, Yunnan Province, China
- Key Laboratory of Tumor Immunological Prevention and Treatment of Yunnan Province, Kunming 650051, Yunnan Province, 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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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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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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Tan KF, In LLA, Vijayaraj Kumar P. Surface Functionalization of Gold Nanoparticles for Targeting the Tumor Microenvironment to Improve Antitumor Efficiency. ACS APPLIED BIO MATERIALS 2023; 6:2944-2981. [PMID: 37435615 DOI: 10.1021/acsabm.3c00202] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2023]
Abstract
Gold nanoparticles (AuNPs) have undergone significant research for their use in the treatment of cancer. Numerous researchers have established their potent antitumor properties, which have greatly impacted the treatment of cancer. AuNPs have been used in four primary anticancer treatment modalities, namely radiation, photothermal therapy, photodynamic therapy, and chemotherapy. However, the ability of AuNPs to destroy cancer is lacking and can even harm healthy cells without the right direction to transport them to the tumor microenvironment. Consequently, a suitable targeting technique is needed. Based on the distinct features of the human tumor microenvironment, this review discusses four different targeting strategies that target the four key features of the tumor microenvironment, including abnormal vasculature, overexpression of specific receptors, an acidic microenvironment, and a hypoxic microenvironment, to direct surface-functionalized AuNPs to the tumor microenvironment and increase antitumor efficacies. In addition, some current completed or ongoing clinical trials of AuNPs will also be discussed below to further reinforce the concept of using AuNPs in anticancer therapy.
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Affiliation(s)
- Kin Fai Tan
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, UCSI University, No. 1, Jalan Menara Gading, Taman Connaught, Cheras, Kuala Lumpur 56000, Malaysia
| | - Lionel Lian Aun In
- Department of Biotechnology, Faculty of Applied Sciences, UCSI University, Kuala Lumpur 56000, Malaysia
| | - Palanirajan Vijayaraj Kumar
- Department of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, UCSI University, No. 1, Jalan Menara Gading, Taman Connaught, Cheras, Kuala Lumpur 56000, Malaysia
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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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The Impact of Molecular Biology in the Seeding, Treatment Choices and Follow-Up of Colorectal Cancer Liver Metastases-A Narrative Review. Int J Mol Sci 2023; 24:ijms24021127. [PMID: 36674640 PMCID: PMC9863977 DOI: 10.3390/ijms24021127] [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: 12/03/2022] [Revised: 12/27/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
There is a clear association between the molecular profile of colorectal cancer liver metastases (CRCLM) and the degree to which aggressive progression of the disease impacts patient survival. However, much of our knowledge of the molecular behaviour of colorectal cancer cells comes from experimental studies with, as yet, limited application in clinical practice. In this article, we review the current advances in the understanding of the molecular behaviour of CRCLM and present possible future therapeutic applications. This review focuses on three important steps in CRCLM development, progression and treatment: (1) the dissemination of malignant cells from primary tumours and the seeding to metastatic sites; (2) the response to modern regimens of chemotherapy; and (3) the possibility of predicting early progression and recurrence patterns by molecular analysis in liquid biopsy.
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Brenner R, Amar-Farkash S, Klein-Brill A, Rosenberg-Katz K, Aran D. Comparative Analysis of First-Line FOLFOX Treatment With and Without Anti-VEGF Therapy in Metastatic Colorectal Carcinoma: A Real-World Data Study. Cancer Control 2023; 30:10732748231202470. [PMID: 37724508 PMCID: PMC10510351 DOI: 10.1177/10732748231202470] [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: 04/09/2023] [Revised: 08/21/2023] [Accepted: 08/28/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND FOLFOX (leucovorin calcium [folinic acid], fluorouracil, and oxaliplatin) combined with or without anti-VEGF therapy represents one of the primary first-line treatment options for metastatic colorectal carcinoma (mCRC). However, there is limited comparative data on the impact of anti-VEGF therapy on treatment effectiveness, survival outcomes, and tumor location. METHODS This retrospective, comparative study utilized data from the AIM Cancer Care Quality Program and commercially insured patients treated at medical oncology clinics in the US. We analyzed 1652 mCRC patients who received FOLFOX, of which 1015 (61.4%) were also treated with anti-VEGF therapy (VEGF cohort). RESULTS Patients in the VEGF cohort exhibited a higher frequency of lung (33% vs 23%; P < .001) and liver metastases (74% vs 62%; P < .001), underwent fewer liver surgeries prior to treatment (1.2% vs 3.6%; P = .002), and had a higher proportion of right-sided tumors (27% vs 18%; P = .001). Adjusted analysis revealed no significant difference in overall survival (OS) between patients treated with and without anti-VEGF (median survival: 25.4 vs 26.0 months; P = .4). FOLFOX-only treated patients experienced higher rates of post-treatment hospitalizations (22% vs 15%; P < .001). Notably, left-sided tumors treated with anti-VEGF showed a trend toward decreased OS (median survival: 26.8 vs 33 months; P = .09). CONCLUSION Our real-world data analysis suggests that the addition of anti-VEGF to FOLFOX offers limited and short-lived benefits in the context of mCRC and may provide differential survival benefit based on tumor sidedness.
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Affiliation(s)
- Ronen Brenner
- Department of Oncology, Edith Wolfson Medical Center, Holon, Israel
| | | | | | | | - Dvir Aran
- Carelon Digital Platforms, Tel Aviv, Israel
- Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel
- The Taub Faculty of Computer Science, Technion-Israel Institute of Technology, Haifa, Israel
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Jin H, Amonkar M, Aguiar-Ibáñez R, Thosar M, Chase M, Keeping S. Systematic literature review and network meta-analysis of pembrolizumab versus other interventions for previously untreated, unresectable or metastatic, microsatellite instability-high or mismatch repair-deficient colorectal cancer. Future Oncol 2022; 18:2155-2171. [PMID: 35332802 DOI: 10.2217/fon-2021-1633] [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: 11/21/2022] Open
Abstract
Aim: To compare pembrolizumab with competing interventions for previously untreated, unresectable or metastatic microsatellite instability-high or mismatch repair-deficient colorectal cancer. Method: Trials were identified via a systematic literature review and synthesized using a Bayesian network meta-analysis with time-varying hazard ratios (HRs). Results: Using intention-to-treat data, HRs for overall survival were generally in favor of pembrolizumab but not statistically significant; however, statistical significance was reached versus all comparators by month 16 when accounting for crossover. Estimated HRs for progression-free survival significantly favored pembrolizumab versus all comparators by month 12. Pembrolizumab was also superior to all comparators in terms of grade ≥3 adverse events. Conclusion: These analyses suggest that pembrolizumab is a highly efficacious and safe treatment in this population.
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Affiliation(s)
- He Jin
- PRECISIONheor, New York, NY 10165, USA
| | | | | | | | | | - Sam Keeping
- PRECISIONheor, Vancouver, BC, V6H 3Y4, Canada
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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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Colorectal Cancer: From Genetic Landscape to Targeted Therapy. JOURNAL OF ONCOLOGY 2021; 2021:9918116. [PMID: 34326875 PMCID: PMC8277501 DOI: 10.1155/2021/9918116] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 06/25/2021] [Indexed: 02/08/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer type and the second cause of death worldwide. The advancement in understanding molecular pathways involved in CRC has led to new classifications based on the molecular characteristics of each tumor and also improved CRC management through the integration of targeted therapy into clinical practice. In this review, we will present the main molecular pathways involved in CRC carcinogenesis, the molecular classifications. The anti-VEGF and anti-EGFR therapies currently used in CRC treatment and those under clinical investigation will also be outlined, as well as the mechanisms of primary and acquired resistance to anti-EGFR monoclonal antibodies (cetuximab and panitumumab). Targeted therapy has led to great improvement in the treatment of metastatic CRC. However, there has been variability in CRC treatment outcomes due to molecular heterogeneity in colorectal tumors, which underscores the need for identifying prognostic and predictive biomarkers for CRC-targeted drugs.
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Avallone A, Piccirillo MC, Nasti G, Rosati G, Carlomagno C, Di Gennaro E, Romano C, Tatangelo F, Granata V, Cassata A, Silvestro L, De Stefano A, Aloj L, Vicario V, Nappi A, Leone A, Bilancia D, Arenare L, Petrillo A, Lastoria S, Gallo C, Botti G, Delrio P, Izzo F, Perrone F, Budillon A. Effect of Bevacizumab in Combination With Standard Oxaliplatin-Based Regimens in Patients With Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA Netw Open 2021; 4:e2118475. [PMID: 34309665 PMCID: PMC8314140 DOI: 10.1001/jamanetworkopen.2021.18475] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
IMPORTANCE Although bevacizumab is a standard of care in combination treatments for metastatic colorectal cancer (mCRC), its clinical benefit has been limited. OBJECTIVE To determine whether sequential scheduling of bevacizumab administration in combination with chemotherapy improves treatment efficacy in patients with mCRC, in keeping with the tumor vascular normalization hypothesis. DESIGN, SETTING, AND PARTICIPANTS This open-label, randomized clinical phase 3 trial was conducted from May 8, 2012, to December 9, 2015, at 3 Italian centers. Patients aged 18 to 75 years with unresectable, previously untreated, or single line-treated mCRC were recruited. Follow-up was completed December 31, 2019, and data were analyzed from February 26 to July 24, 2020. INTERVENTIONS Patients received 12 biweekly cycles of standard oxaliplatin-based regimens (modified FOLFOX-6 [levo-folinic acid, fluorouracil, and oxaliplatin]/modified CAPOX [capecitabine and oxaliplatin]) plus bevacizumab administered either on the same day as chemotherapy (standard arm) or 4 days before chemotherapy (experimental arm). MAIN OUTCOMES AND MEASURES The primary end point was the objective response rate (ORR) measured with Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included progression-free survival, overall survival, safety, and quality of life (QOL). RESULTS Overall, 230 patients (136 men [59.1%]; median age, 62.3 [interquartile range, 53.3-67.6] years) were randomly assigned to the standard arm (n = 115) or the experimental arm (n = 115). The median duration of follow-up was 68.3 (95% CI, 61.0-70.0) months. No difference in ORR (57.4% [95% CI, 47.8%-66.6%] in the standard arm and 56.5% [95% CI, 47.0-65.7] in the experimental arm; P = .89) or progression-free survival (10.5 [95% CI, 9.1-12.3] months in the standard arm and 11.7 [95% CI, 9.9-12.9] months in the experimental arm; P = .15) was observed. However, the median overall survival was 29.8 (95% CI, 22.5-41.1) months in the experimental arm compared with 24.1 (95% CI, 18.6-29.8) months in the standard arm (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.99; P = .04). Moreover, the experimental arm was associated with a significant reduction in the rate of severe diarrhea (6 [5.3%] vs 19 [16.5%]; P = .006) and nausea (2 [1.8%] vs 8 [7.0%]; P = .05) and improved physical functioning (mean [SD] change from baseline, 0.65 [1.96] vs -7.41 [2.95] at 24 weeks; P = .02), and constipation scores (mean [SD] change from baseline, -17.2 [3.73] vs -0.62 [4.44]; P = .003). CONCLUSIONS AND RELEVANCE In this randomized clinical trial, sequential administration of bevacizumab plus chemotherapy did not improve ORR, the primary end point. However, the overall survival advantage, fewer adverse effects, and better health-related QOL associated with sequential bevacizumab administration might provide the basis for exploring antiangiogenic combination treatments with innovative perspectives. TRIAL REGISTRATION EudraCT Identifier: 2011-004997-27; ClinicalTrials.gov Identifier: NCT01718873.
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Affiliation(s)
- Antonio Avallone
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italy
| | - Maria C. Piccirillo
- Clinical Trials Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Guglielmo Nasti
- Innovative Therapy for Abdominal Metastases, IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Gerardo Rosati
- Medical Oncology Unit, S. Carlo Hospital, Potenza, Italy
| | - Chiara Carlomagno
- Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
| | - Elena Di Gennaro
- Experimental Pharmacology Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Carmela Romano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italy
| | - Fabiana Tatangelo
- Pathology Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Vincenza Granata
- Radiology Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Antonino Cassata
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italy
| | - Lucrezia Silvestro
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italy
| | - Alfonso De Stefano
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italy
| | - Luigi Aloj
- Nuclear Medicine Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
- currently affiliated with Department of Radiology, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
| | - Valeria Vicario
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italy
| | - Anna Nappi
- Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori–Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione G. Pascale, Napoli, Italy
| | - Alessandra Leone
- Experimental Pharmacology Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | | | - Laura Arenare
- Clinical Trials Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Antonella Petrillo
- Radiology Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Secondo Lastoria
- Nuclear Medicine Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Ciro Gallo
- Università della Campania Luigi Vanvitelli, Napoli, Italy
| | - Gerardo Botti
- Pathology Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Paolo Delrio
- Colorectal Oncological Surgery, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Francesco Izzo
- Colorectal Oncological Surgery, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
- Hepatobiliary Surgery Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Franco Perrone
- Clinical Trials Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, Italy
| | - Alfredo Budillon
- Experimental Pharmacology Unit, Istituto Nazionale Tumori–IRCCS, Fondazione G. Pascale, Napoli, 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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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: 24] [Impact Index Per Article: 6.0] [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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15
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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: 27] [Impact Index Per Article: 5.4] [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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16
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Rezvani H, Mortazavizadeh SM, Allahyari A, Nekuee A, Najafi SN, Vahidfar M, Ghadyani M, Khosravi A, Qarib S, Sadeghi A, Esfandbod M, Rajaeinejad M, Rezvani A, Hajiqolami A, Payandeh M, Shazad B, Anjidani N, Meskinimood S, Alikhasi A, Karbalaeian M, Salari S. Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial. Clin Ther 2020; 42:848-859. [PMID: 32334845 DOI: 10.1016/j.clinthera.2020.03.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 12/30/2019] [Accepted: 03/16/2020] [Indexed: 01/04/2023]
Abstract
PURPOSE The purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC). METHODS This Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m2 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements. FINDINGS A total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46-1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55-1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm. IMPLICATIONS The proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.
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Affiliation(s)
- Hamid Rezvani
- Department of Medical Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Abolghasem Allahyari
- Division of Hematology and Medical Oncology, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | | | | | - Mojtaba Ghadyani
- Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Adnan Khosravi
- Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siroos Qarib
- Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Mohsen Esfandbod
- Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | | | | | | | - Babak Shazad
- Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nassim Anjidani
- Head of Medical Department, OrchidPharmed Company, Tehran, Iran
| | - Shahab Meskinimood
- Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Afsaneh Alikhasi
- Department of Radiology, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Moein Karbalaeian
- Division of General Medicine of Medical School of Shaheed Sadoughi Medical School of Yazd University, Yazd, Iran
| | - Sina Salari
- Department of Medical Oncology, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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17
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Baek SK, Lee KT, Bae SB, Lee SC. Evaluating the recent developments in palliative chemotherapy for metastatic colorectal cancer. Korean J Intern Med 2019; 34:1188-1196. [PMID: 31346151 PMCID: PMC6823574 DOI: 10.3904/kjim.2019.071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 05/21/2019] [Indexed: 12/17/2022] Open
Abstract
The incidence of colorectal cancer (CRC) has increased. CRC is the third most common cancer and the fourth most common cause of cancer-related deaths in Korea. Palliative chemotherapy can be used to shrink tumors and ease symptoms caused by the cancer when cure is not possible. It is important to identify chemotherapeutic agents that can be used to effectively treat metastatic CRC (mCRC) and thus improve the survival and quality of life of patients with mCRC. This review aimed to evaluate the recent developments in palliative chemotherapy for mCRC and the biological or targeted agents used based on genetic alterations.
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Affiliation(s)
- Sun Kyung Baek
- Department of Internal Medicine, Kyung Hee University Hospital, Seoul, Korea
| | - Kyu Taek Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sang Byung Bae
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sang-Cheol Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
- Correspondence to Sang-Cheol Lee, M.D. Division of Hematology & Oncology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnamgu, Cheonan 31151, Korea Tel: +82-41-570-3803 Fax: +82-41-574-5762 E-mail:
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18
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Nanotechnology is an important strategy for combinational innovative chemo-immunotherapies against colorectal cancer. J Control Release 2019; 307:108-138. [DOI: 10.1016/j.jconrel.2019.06.017] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/12/2019] [Accepted: 06/16/2019] [Indexed: 12/15/2022]
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Matikas A, Souglakos J, Katsaounis P, Kotsakis A, Kouroupakis P, Pantazopoulos N, Kentepozidis N, Nikolaidi A, Messaritakis I, Tzovara I, Hatzidaki D, Prinarakis E, Georgoulias V. MINOAS: A Single-arm Translational Phase II Trial of FOLFIRI Plus Aflibercept as First-line Therapy in Unresectable, Metastatic Colorectal Cancer. Target Oncol 2019; 14:285-293. [DOI: 10.1007/s11523-019-00647-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Sandhu J, Lavingia V, Fakih M. Systemic treatment for metastatic colorectal cancer in the era of precision medicine. J Surg Oncol 2019; 119:564-582. [PMID: 30802315 DOI: 10.1002/jso.25421] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 02/10/2019] [Indexed: 01/05/2023]
Abstract
The treatment of metastatic colorectal cancer has evolved over the last two decades with the FDA approval of several cytotoxic, biological, and targeted agents. In this paper, we review the impact of sidedness, RAS, BRAF, HER-2, and other immune biomarkers on metastatic colorectal cancer treatment selection and sequencing in both the palliative and curative intent settings.
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Affiliation(s)
- Jaideep Sandhu
- Department of Medical Oncology, City of Hope National Medical Center, Duarte, California
| | | | - Marwan Fakih
- Medical Oncology and Therapeutics Research, Briskin Center for Clinical Research, GI Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, California
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Baraniskin A, Buchberger B, Pox C, Graeven U, Holch JW, Schmiegel W, Heinemann V. Efficacy of bevacizumab in first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis. Eur J Cancer 2019; 106:37-44. [DOI: 10.1016/j.ejca.2018.10.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Accepted: 10/10/2018] [Indexed: 12/20/2022]
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Xu R, Xu C, Liu C, Cui C, Zhu J. Efficacy and safety of bevacizumab-based combination therapy for treatment of patients with metastatic colorectal cancer. Onco Targets Ther 2018; 11:8605-8621. [PMID: 30584320 PMCID: PMC6287670 DOI: 10.2147/ott.s171724] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Aim The use of bevacizumab in combination therapy is an emerging trend in metastatic colorectal cancer treatment. However, the clinical value of different combination types remains under debate. Thus, a meta-analysis of randomized controlled trials (RCTs) comparing bevacizumab-based combination therapy with monotherapy (therapy that uses one type of treatment, such as chemotherapy or surgery alone, to treat metastatic colorectal cancer) was performed, aiming to evaluate the safety and efficacy of bevacizumab-based combination therapy and to find a more beneficial combination. Methods We searched for clinical studies that evaluated bevacizumab-based combination therapy in metastatic colorectal cancer. We extracted data from these studies to evaluate the relative risk (RR) of overall response rate (ORR) and grade 3/4 treatment-related adverse events (AEs), HRs of overall survival (OS), and progression-free survival (PFS). Results Eight RCTs were identified (n=3,424). Treatments included combinations of bevacizumab and oxaliplatin, fluorouracil, and leucovorin (FOLFOX4), combinations of bevacizumab and capecitabine and oxaliplatin, combinations of bevacizumab and fluorouracil/leucovorin, combinations of bevacizumab and irinotecan, fluorouracil, and leucovorin (IFL), and combinations of bevacizumab and capecitabine. Bevacizumab-based combination therapy showed higher ORR (RR: 1.40; 95% CI: 1.10-1.78; P=0.005), PFS (HR: 0.64; 95% CI: 0.55-0.73; P=0.000), and OS (HR: 0.82; 95% CI: 0.73-0.92; P=0.001) values than monotherapy. However, higher grade 3/4 treatment-related AEs (RR: 1.27; 95% CI: 1.15-1.41; P=0.000) were observed in combination therapy than in monotherapy. Conclusion This meta-analysis showed that the addition of IFL to bevacizumab better benefits PFS and safety. Adding FOLFOX4 was associated with better ORR and OS. The efficacy and safety of an IFL-bevacizumab-FOLFOX4 combination should be given greater weight in future clinical trials, guidelines, and clinical practice.
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Affiliation(s)
- Ran Xu
- Medical School of Nantong University, Jiangsu 226001, China, .,Huai'an Key Laboratory of Gastrointestinal Cancer, Jiangsu 223001, China,
| | - Chen Xu
- Medical School of Nantong University, Jiangsu 226001, China,
| | - Chuntong Liu
- XuZhou Medical University, Jiangsu 221000, China
| | - Can Cui
- Macau University of Science and Technology, Macau 519020, China
| | - Jing Zhu
- Department of Oncology, The Affiliated Huaian NO 1 People's Hospital of Nanjing Medical University, Jiangsu 223001, China,
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da Silva WC, de Araujo VE, Lima EMEA, dos Santos JBR, Silva MRRD, Almeida PHRF, de Assis Acurcio F, Godman B, Kurdi A, Cherchiglia ML, Andrade EIG. Comparative Effectiveness and Safety of Monoclonal Antibodies (Bevacizumab, Cetuximab, and Panitumumab) in Combination with Chemotherapy for Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis. BioDrugs 2018; 32:585-606. [PMID: 30499082 PMCID: PMC6290722 DOI: 10.1007/s40259-018-0322-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The last decade has seen the increasing use of biological medicines in combination with chemotherapy containing 5-fluorouracil/oxaliplatin or irinotecan for the treatment of metastatic colorectal cancer (mCRC). These combinations have resulted in increased progression-free survival (PFS) in patients with mCRC; however, there are remaining concerns over the extent of their effect on overall survival (OS). Published studies to date suggest no major differences between the three currently available monoclonal antibodies (MoAbs); however, there are differences in costs. In addition, there is rising litigation in Brazil in order to access these medicines as they are currently not reimbursed. OBJECTIVE The aim was to investigate the comparative effectiveness and safety of three MoAbs (bevacizumab, cetuximab and panitumumab) associated with fluoropyrimidine-based chemotherapy regimens and compared to fluoropyrimidine-based chemotherapy alone in patients with mCRC, through an updated systematic review and meta-analysis of concurrent or non-concurrent observational cohort studies, to guide authorities and the judiciary. METHOD A systematic review and meta-analysis was performed based on cohort studies published in databases up to November 2017. Effectiveness measures included OS, PFS, post-progression survival (PPS), Response Evaluation Criteria In Solid Tumors (RECIST), response rate, metastasectomy and safety. The methodological quality of the studies was also evaluated. RESULTS A total of 21 observational cohort studies were included. There were statistically significant and clinically relevant benefits in patients treated with bevacizumab versus no bevacizumab mainly around OS, PFS, PPS and the metastasectomy rate, but not for the disease control rates. However, there was an increase in treatment-related toxicities and concerns with the heterogeneity of the studies. CONCLUSION The results pointed to an advantage in favor of bevacizumab for OS, PFS, PPS, and metastasectomy. Although this advantage may be considered clinically modest, bevacizumab represents a hope for increased survival and a chance of metastasectomy for patients with mCRC. However, there are serious adverse events associated with its use, especially severe hypertension and gastrointestinal perforation, that need to be considered.
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Affiliation(s)
- Wânia Cristina da Silva
- Postgraduate Program in Medicines and Pharmaceutical Services, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Vânia Eloisa de Araujo
- Postgraduate Program in Medicines and Pharmaceutical Services, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
- School of Dentistry, Pontifical Catholic University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Jessica Barreto Ribeiro dos Santos
- Postgraduate Program in Medicines and Pharmaceutical Services, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Michael Ruberson Ribeiro da Silva
- Postgraduate Program in Medicines and Pharmaceutical Services, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Francisco de Assis Acurcio
- Postgraduate Program in Medicines and Pharmaceutical Services, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
- Postgraduate Program in Public Health, School of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Brian Godman
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
- Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
- Health Economics Centre, University of Liverpool Management School, Liverpool, UK
- School of Pharmacy, Sefako Makgatho Health Sciences University, Garankuwa, Pretoria, South Africa
| | - Amanj Kurdi
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK
- Department of Pharmacology, College of Pharmacy, Hawler Medical University, Erbil, Iraq
| | - Mariângela Leal Cherchiglia
- Postgraduate Program in Medicines and Pharmaceutical Services, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
- Postgraduate Program in Public Health, School of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Eli Iola Gurgel Andrade
- Postgraduate Program in Medicines and Pharmaceutical Services, School of Pharmacy, Federal University of Minas Gerais, Belo Horizonte, Brazil
- Postgraduate Program in Public Health, School of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Brazil
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Pfeiffer P, Köhne CH, Qvortrup C. The changing face of treatment for metastatic colorectal cancer. Expert Rev Anticancer Ther 2018; 19:61-70. [PMID: 30381969 DOI: 10.1080/14737140.2019.1543593] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Introduction: Since late 1990's therapy of metastatic colorectal cancer (mCRC) patients has changed considerable, and the combination of doublet or triplet chemotherapy and a targeted agent are now routinely used. With the introduction of more intensified regimens, it has become even more important to identify patients that will benefit from and can tolerate therapy. Furthermore, the increasing understanding of the biology of mCRC has led to the discovery of new potential targets. Therefore, therapy of patients with mCRC has undergone considerable change from 'one strategy fits all' towards a more personalized therapy. Areas covered: We present an overview of the recent literature on approved systemic treatment of mCRC however with focus on how the treatment strategy has changed based on clinical and molecular parameters that presently are used routinely in the clinical situation. Expert commentary: The face of treatment of mCRC has changed from 'one strategy fits all' to a personalized approach in which both clinical, molecular parameters and the aim of therapy have to be taking into account when planning the optimal treatment strategy for the individual mCRC patient.
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Affiliation(s)
- Per Pfeiffer
- a Department of Oncology , Odense University Hospital , Odense C , Denmark
| | - Claus-Henning Köhne
- b University Campus Klinikum Oldenburg, Carl von Ossietzky University, North-West-German Cancer Center , Oldenburg , NS , Germany
| | - Camilla Qvortrup
- c Department of Oncology, Rigshospitalet , Copenhagen University , Copenhagen , Denmark
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25
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Morano F, Sclafani F. Duration of first-line treatment for metastatic colorectal cancer: Translating the available evidence into general recommendations for routine practice. Crit Rev Oncol Hematol 2018; 131:53-65. [PMID: 30293706 DOI: 10.1016/j.critrevonc.2018.08.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 07/22/2018] [Accepted: 08/22/2018] [Indexed: 12/13/2022] Open
Abstract
Over the last two decades the number of front-line regimens for metastatic colorectal cancer has progressively increased. Nevertheless, there is still no consensus on the optimal duration of treatment or the role of de-escalated/maintenance strategies after induction chemotherapy. In this article we provide an overview of the studies that addressed the duration of first-line systemic treatment with cytotoxic agents plus or minus targeted therapies highlighting caveats and limitations of the same. Also, we try to translate the available evidence into practical recommendations that can be used in everyday practice to inform treatment decisions. The main conclusion of our review article is that continuing induction treatment until progression may improve disease control but there is no evidence to suggest that adopting this practice can prolong survival. On the other hand, de-escalated treatment strategies offer an opportunity to reduce the burden of toxicity while maintaining satisfactory oncological outcomes.
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Affiliation(s)
- Federica Morano
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Sclafani
- The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom.
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26
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Xiao B, Wang W, Zhang D. Risk of bleeding associated with antiangiogenic monoclonal antibodies bevacizumab and ramucirumab: a meta-analysis of 85 randomized controlled trials. Onco Targets Ther 2018; 11:5059-5074. [PMID: 30174444 PMCID: PMC6110629 DOI: 10.2147/ott.s166151] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Aim Bevacizumab and ramucirumab are antiangiogenic monoclonal antibodies, which target vascular endothelial growth factor-A and vascular endothelial growth factor receptor-2, respectively, used in various cancers. Bleeding events have been described with these two agents. We conducted an up-to-date meta-analysis to determine the relative risk (RR) associated with the use of antiangiogenic monoclonal antibodies, bevacizumab and ramucirumab. Methods This meta-analysis of randomized controlled trials was performed after searching PubMed, American Society for Clinical Oncology Abstracts, European Society for Medical Oncology Abstracts, and the proceedings of major conferences for relevant clinical trials. RR and 95% CIs were calculated by random-effects or fixed-effects models for all-grade and high-grade bleeding events related to the angiogenesis inhibitors. Results Eighty-five randomized controlled trials were selected for the meta-analysis, covering 46,630 patients. The results showed that antiangiogenic monoclonal antibodies significantly increased the risk of all-grade (RR: 2.38, 95% CI: 2.09–2.71, p<0.00001) and high-grade (RR: 1.71, 95% CI: 1.48–1.97, p<0.00001) bleeding compared with control arms. In the subgroup analysis, bevacizumab significantly increased the risk of all-grade (RR: 2.73, 95% CI: 2.24–3.33, p<0.00001) and high-grade bleeding (RR: 1.98, 95% CI: 1.68–2.34, p<0.00001), but ramucirumab only increased the risk of all-grade bleeding (RR: 1.94, 95% CI: 1.76–2.13, p<0.00001) and no difference was observed for the risk of high-grade bleeding (RR: 1.04, 95% CI: 0.78–1.39, p=0.79) compared with the control group. For lung cancer patients, bevacizumab significantly increased the risk of all-grade (RR: 4.72, 95% CI: 1.99–11.19, p=0.0004) and high-grade pulmonary hemorrhage (RR: 3.97, 95% CI: 1.70–9.29, p=0.001), but no significant differences in the risk of all-grade (RR: 1.09, 95% CI: 0.76–1.57, p=0.64) and high-grade (RR: 1.22, 95% CI: 0.35–4.21, p=0.75) pulmonary hemorrhage were observed for ramucirumab. The increased risk of all-grade and high-grade bleeding was also observed in colorectal cancer or non-colorectal tumors and low-dose or high-dose angiogenesis inhibitors. Conclusion Antiangiogenic monoclonal antibodies are associated with a significant increase in the risk of all-grade and high-grade bleeding. Ramucirumab may be different from bevacizumab in terms of the risk of high-grade bleeding and the risk of all-grade and high-grade pulmonary hemorrhage in lung cancer patients.
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Affiliation(s)
- Bingkun Xiao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, Beijing, China
| | - Weilan Wang
- Department of Pharmacy, Chinese PLA General Hospital, Beijing, China,
| | - Dezhi Zhang
- Department of Pharmacy, The 264th Hospital of PLA, Taiyuan, Shanxi, China
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Rosen LS, Jacobs IA, Burkes RL. Bevacizumab in Colorectal Cancer: Current Role in Treatment and the Potential of Biosimilars. Target Oncol 2018; 12:599-610. [PMID: 28801849 PMCID: PMC5610666 DOI: 10.1007/s11523-017-0518-1] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Colorectal cancer (CRC) is a leading cause of tumor-related morbidity and mortality worldwide, with mortality most often attributable to metastatic disease. Bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor, has a significant role in the treatment of metastatic CRC (mCRC). However, patient access to bevacizumab may be limited in some regions or circumstances, owing to factors related to insurance coverage, reimbursement, patient out-of-pocket costs, or availability. As a result, outcomes for patients with mCRC may be worsened. Additionally, counterfeit bevacizumab has infiltrated legitimate supply chains, exposing patients to risk. Oncologists may also be affected detrimentally, since resolving access issues can be time-consuming and demoralizing. The imminent expiry of patents protecting bevacizumab provides other manufacturers with the opportunity to produce highly similar versions known as biosimilars. High-quality, safe, and effective biosimilars have the potential to expand access to bevacizumab. Most of the bevacizumab biosimilars currently in development are in clinical trials in patients with non-small-cell lung cancer, and future authorization for mCRC indications will, therefore, be based on extrapolation. This article reviews the current role of bevacizumab in the management of mCRC, the possible barriers associated with diminished access to bevacizumab, and the potential bevacizumab biosimilars in development. How biosimilars may impact the treatment of mCRC is also discussed.
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Affiliation(s)
- Lee S Rosen
- UCLA Division of Hematology-Oncology, 2020 Santa Monica Boulevard, Suite 600, Santa Monica, CA, 90404, USA
| | - Ira A Jacobs
- Pfizer Inc, 235 East 42nd Street, New York, NY, 10017-5755, USA.
| | - Ronald L Burkes
- Mount Sinai Hospital, Joseph and Wolf Lebovic Health Complex, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
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Vogel A, Kirstein MM. First-line molecular therapies in the treatment of metastatic colorectal cancer - a literature-based review of phases II and III trials. Innov Surg Sci 2018; 3:85-86. [PMID: 31579770 PMCID: PMC6604573 DOI: 10.1515/iss-2018-0012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 04/03/2018] [Indexed: 12/22/2022] Open
Abstract
Introduction: Metastatic colorectal cancer (mCRC) is one of the most common cancers and the second leading cause of cancer worldwide. With the improvement of systemic and operative therapies, median overall survival (mOS) reached 30 months or longer. Here, we will review the use of the anti-vascular endothelial growth factor (VEGF) and anti-epidermal growth factor receptor (EGFR) antibodies in combination with doublet and triplet chemotherapy in patients with borderline and primary unresectable mCRC. Methods: Phases II and III trials were included in investigating chemotherapy in the first-line in combination with an anti-VEGF(R) or anti-EGFR in a cohort of patients with mCRC. Results: The VEGF-antibody bevacizumab has improved progression-free survival (PFS) in several phase III trials in combination with a chemotherapy doublet. More recently, a higher efficacy has been demonstrated in combination with an intensified chemotherapy including 5-fluoropyrimidine (5-FU), oxaliplatin, and irinotecan within the phase III TRIBE study. Similarly, high resectability rates have been shown in the phase II Olivia trial for patients with liver-limited disease with an intensified chemotherapeutic regime. However, this increase in efficacy was accompanied by an increase in toxicity as well. The efficacy of the EGFR-antibodies cetuximab and panitumumab has been shown in several phase III trials, but their use is restricted to patients whose tumors are RAS wildtype (WT). The phase II trials, CELIM and PLANET, demonstrated a favorable long-term survival for patients with initially non-resectable colorectal liver metastases who respond to conversion therapy with EGFR-antibodies and undergo secondary resection. The CLGB and FIRE-3 trials delivered an inconsistent finding whether anti-VEGF or -EGFR treatment is the better option in the first-line setting. However, there is increasing evidence from post hoc analyses of prospective clinical trials that patients with left-sided tumors benefit from EGFR-directed combination therapy in terms of prolongation of OS and PFS compared with limited, if any, benefit for those with right-sided tumors. Conclusion: Both anti-VEGF- and anti-EGFR-directed therapies represent efficient treatment options for patients with mCRC in the first line. For patients with RAS WT, left-sided tumor anti-EGFR-based treatment is recommended. Intensified regimens can be offered initially to unresectable patients in order to achieve resectability at a price of higher toxicity.
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Affiliation(s)
- Arndt Vogel
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Martha M Kirstein
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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29
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Goey KKH, Mahmoud R, Sørbye H, Glimelius B, Köhne CH, Sargent DJ, Punt CJA, van Oijen MGH, Koopman M. Reporting of patient characteristics and stratification factors in phase 3 trials investigating first-line systemic treatment of metastatic colorectal cancer: A systematic review. Eur J Cancer 2018; 96:115-124. [PMID: 29729562 DOI: 10.1016/j.ejca.2018.03.026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2017] [Revised: 03/25/2018] [Accepted: 03/30/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Patient characteristics and stratification factors are important factors influencing trial outcomes. Uniform reporting on these parameters would facilitate cross-study comparisons and extrapolation of trial results to clinical practice. In 2007, standardisation on patient characteristics reporting and stratification in metastatic colorectal cancer (mCRC) trials was proposed. We investigated the reporting of prognostic factors and implementation of this proposal in mCRC trials published from 2005 to 2016. METHODS We searched PubMed and Embase (January 2005 - June 2016) for first-line phase 3 mCRC trials. Patient characteristics reporting and use of stratification factors were extracted and analysed for adherence to the proposal from 2007. RESULTS Sixty-seven trials (35,315 patients) were identified, reporting 48 different patient characteristics (median: 9 [range: 5-18] per study). Age, gender, performance status (PS), primary tumour site and adjuvant chemotherapy were frequently reported (87%-100%), in contrast to laboratory values, such as alkaline phosphatase, lactate dehydrogenase and white blood cell count (10%-25%). We identified 29 different stratification factors (median: 3 [range: 1-9] per study). The most common strata were PS and treatment centre (>60%). A median of 8/12 (range: 4-11) of the proposed parameters was reported. Although the percentage of studies reporting each factor slightly increased over time, there was no significant correlation between publication year and adherence to the proposal from 2007. CONCLUSIONS We observed persistent heterogeneity in the reporting of patient characteristics and use of stratification factors in first-line mCRC trials. The proposal from 2007 has not led to increased uniformity of patient characteristics reporting and use of stratification over time. There is an urgent need to address this issue to improve the interpretation of trial results.
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Affiliation(s)
- Kaitlyn K H Goey
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Remi Mahmoud
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Halfdan Sørbye
- Department of Oncology, Haukeland University Hospital, Bergen, Norway; Department of Clinical Science, Haukeland University Hospital, Bergen, Norway
| | - Bengt Glimelius
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Claus-Henning Köhne
- University Clinic for Internal Medicine, Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany
| | - Daniel J Sargent
- Division of Biomedical Statistics and Informatics, Mayo Clinic Cancer Center, Mayo Clinic, Rochester, MN, USA
| | - Cornelis J A Punt
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Martijn G H van Oijen
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
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Schirripa M, Zhang W, Yang D, Cao S, Okazaki S, Loupakis F, Berger MD, Ning Y, Miyamoto Y, Suenaga M, Alberti G, West JD, Lonardi S, Khoukaz T, Bergamo F, Battaglin F, Antoniotti C, Falcone A, Stintzing S, Heinemann V, Lenz HJ. NOS2 polymorphisms in prediction of benefit from first-line chemotherapy in metastatic colorectal cancer patients. PLoS One 2018. [PMID: 29522543 PMCID: PMC5844536 DOI: 10.1371/journal.pone.0193640] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background Macrophages play a crucial role in the interaction between tumor and immune system, and iNOS is known as a surrogate marker of M1 macrophages activation. The goal of the study was to investigate the role of iNOS polymorphisms as prognostic marker in mCRC patients. Materials and methods Functional significant polymorphisms in the promoter of INOS gene were analyzed by PCR-based and direct DNA sequencing in 4 cohorts of patients receiving bevacizumab based first-line chemotherapy: two evaluation cohorts (TRIBE ARM A and ARM B) and two validation cohorts (FIRE 3 arm A and MOMA). The relation of the SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test. Subgroup analyses according to RAS status were preplanned. Results In the exploratory cohort 1 (TRIBE A), patients with CCTTT any>13repeats (N = 57) showed improved median PFS compared with patients carrying the ≤13/≤13 repeats variant (N = 152) (HR, 0.64; 95%CI 0.44–0.92, p = 0.010). Similar results were shown adopting the >26repeats/≤26 repeats (HR, 0.56; 95%CI 0.36–0.87, p = 0.005). In RAS mutant, patient with any>13 repeats (N = 24) had improved PFS results compared with those carrying the ≤13/≤13 repeats variant (N = 81) (HR, 0.51; 95%CI 0.30–0.87, p = 30.009). Similar results were found adopting the >26 repeats/≤26 repeats cut off: (HR, 0.52; 95%CI 0.27–0.98, p = 0.035). These data were partially confirmed in the exploratory cohort 2 (TRIBE B): a better median PFS was observed in patients with >26 repeats vs ≤26 repeats (N = 205) patients. However, these data were not confirmed in the two validation cohorts. Conclusion We failed to replicate the exploratory findings in both validation sets. The CCTTT polymorphic region of the INOS gene does not predict outcome in mCRC receiving bevacizumab based first line chemotherapy. Further investigations are needed to reveal mechanisms between tumor, immune system and chemotherapy response.
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Affiliation(s)
- Marta Schirripa
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Wu Zhang
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Satoshi Okazaki
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Fotios Loupakis
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Martin D. Berger
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Yan Ning
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Yuji Miyamoto
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Mitsukuni Suenaga
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Giulia Alberti
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padua, Italy
| | - Jordan D. West
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Sara Lonardi
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Taline Khoukaz
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | - Francesca Bergamo
- Unit of Medical Oncology 1, Department of Clinical and Experimental Oncology, Istituto Oncologico Veneto, IRCCS, Padua, Italy
| | - Francesca Battaglin
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
| | | | - Alfredo Falcone
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
| | - Sebastian Stintzing
- Medical Oncology and Comprehensive Cancer Center University of Munich, Munich, Germany
| | - Volker Heinemann
- Medical Oncology and Comprehensive Cancer Center University of Munich, Munich, Germany
| | - Heinz-Josef Lenz
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California, United States of America
- * E-mail:
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Ba-Sang DZ, Long ZW, Teng H, Zhao XP, Qiu J, Li MS. A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer. Oncotarget 2018; 7:84468-84479. [PMID: 27806321 PMCID: PMC5356673 DOI: 10.18632/oncotarget.12994] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 10/02/2016] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). RESULTS Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. MATERIALS AND METHODS Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). CONCLUSIONS These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC.
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Affiliation(s)
- Dan-Zeng Ba-Sang
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Zi-Wen Long
- Department of Gastric Cancer and Soft-Tissue Sarcoma Surgery, Fudan university Shanghai Cancer Center, Shanghai 200032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Hao Teng
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Xu-Peng Zhao
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Jian Qiu
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Ming-Shan Li
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
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Gu Y, Yu H, Hao C, Martin TA, Hargest R, He J, Cheng S, Jiang WG. NHERF1 regulates the progression of colorectal cancer through the interplay with VEGFR2 pathway. Oncotarget 2018; 8:7753-7765. [PMID: 27999191 PMCID: PMC5352358 DOI: 10.18632/oncotarget.13949] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Accepted: 12/01/2016] [Indexed: 01/05/2023] Open
Abstract
The oncogenic role of ectopic expression of Na+/H+ exchanger regulatory factor 1 (NHERF1) was recently suggested in colorectal cancer, where it was implicated in playing a role in the tumor hypoxia microenvironment. Here we showed that a high level expression of NHERF1 was found in colorectal cancer tissues and that the expression of NHERF1 was positively correlated with VEGFR2 expression. The prognostic value of VEGFR2 expression in colorectal cancer relied on the expression of NHERF1. The up-regulation of NHERF1 induced by the exposure to hypoxia in colon cancer cells depended on the activation of VEGFR2 signaling. NHERF1 in turn inhibited the activation of VEGFR2 signaling which could be regulated by the interaction between NHERF1 and VEGFR2, resulting in the reduction of migration and invasion of colon cancer cells. These results suggest a dynamic interplay between NHERF1 and VEGFR2 signaling in colorectal cancer, which could explain the contribution of NHERF1 to the regulation of tumor cell responses to the hypoxia microenvironment.
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Affiliation(s)
- Yanan Gu
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China.,Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China
| | - Hefen Yu
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China.,Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China
| | - Chengcheng Hao
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China.,Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China
| | - Tracey A Martin
- Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China.,Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Rachel Hargest
- Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China.,Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Junqi He
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China.,Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China
| | - Shan Cheng
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China.,Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China
| | - Wen G Jiang
- Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing 100069, China.,Beijing Key Laboratory of Cancer & Metastasis Research, Capital Medical University, Beijing 100069, China.,Cardiff China Medical Research Collaborative, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
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Ulivi P, Marisi G, Passardi A. Relationship between hypoxia and response to antiangiogenic therapy in metastatic colorectal cancer. Oncotarget 2018; 7:46678-46691. [PMID: 27081084 PMCID: PMC5216829 DOI: 10.18632/oncotarget.8712] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2016] [Accepted: 03/31/2016] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer remains a major public health problem worldwide. Despite the introduction of antiangiogenic drugs for the treatment of metastatic disease, a large number of issues remains unresolved. In particular, studies on predictive biomarkers of response and pathways of resistance to these agents are lacking, making it difficult to accurately select candidates for treatment. Hypoxia is the prime driving force for tumor angiogenesis and a vicious cycle between hypoxia and angiogenesis can be observed in tumors. Anti-angiogenic drugs act inhibiting tumor vasculature and, as consequence, inducing hypoxia. However, hypoxia could, in turn, induce an increase of metastatic potential of cells and a series of phenomena that could induce drug resistance. In the present review biological mechanisms of hypoxia and its relation with angiogenesis, and resistance to antiangiogenic therapy will be discussed. Moreover, data from clinical trials on antiangiogenic drugs in metastatic colorectal cancer will be reviewed, and the role of hypoxia in monitoring the response to treatment will be analysed. Combination strategies using anti-angiogenic and hypoxia inhibiting drugs are also discussed as they constitute promising field of research.
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Affiliation(s)
- Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy
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Stragier E, Prenen H. Antiangiogenic therapies in colorectal cancer. MEMO-MAGAZINE OF EUROPEAN MEDICAL ONCOLOGY 2017. [DOI: 10.1007/s12254-017-0359-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Jang HJ, Kim BJ, Kim JH, Kim HS. The addition of bevacizumab in the first-line treatment for metastatic colorectal cancer: an updated meta-analysis of randomized trials. Oncotarget 2017; 8:73009-73016. [PMID: 29069844 PMCID: PMC5641187 DOI: 10.18632/oncotarget.20314] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/06/2017] [Indexed: 02/07/2023] Open
Abstract
Bevacizumab has shown survival benefits when added to chemotherapy in patients with metastatic colon cancer (mCRC). However, the efficacy of bevacizumab may depend on the accompanying chemotherapeutic regimen. We performed this meta-analysis to examine the impact of the choice of chemotherapy regimen on the survival benefits of bevacizumab in the first-line treatment for patients with mCRC. Electric databases were searched for eligible randomized trials. From 9 studies, 3,710 patients with mCRC were included in the meta-analysis of hazard ratios (HRs) for progression-free survival (PFS) or overall survival (OS). Compared with chemotherapy alone, the addition of bevacizumab to chemotherapy significantly prolonged PFS (HR = 0.66 [95% confidence interval (CI), 0.55-0.77], P < 0.0001) and OS (HR = 0.84 [95% CI, 0.77-0.92], P = 0.0001). In the subgroup analysis according to the chemotherapeutic regimens, bevacizumab showed both PFS (HR = 0.57 [95% CI, 0.41-0.77], P = 0.0004) and OS (HR = 0.79 [95% CI, 0.67-0.93], P = 0.004) advantages only in combination with irinotecan-based regimen. In conclusion, this meta-analysis confirms that the addition of bevacizumab to chemotherapy significantly prolongs PFS and OS in the first-line treatment for mCRC. The subgroup analyses suggest that irinotecan-based regimen may be a better partner of bevacizumab in terms of both PFS and OS.
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Affiliation(s)
- Hyun Joo Jang
- 1 Division of Gastroenterology, Department of Internal Medicine, Dongtan Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Hwasung 18450, Republic of Korea
| | - Bum Jun Kim
- 2 Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
- 3 Department of Internal Medicine, Korean Armed Forces Capital Hospital, The Armed Forces Medical Command, Sungnam 13574, Republic of Korea
| | - Jung Han Kim
- 2 Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
| | - Hyeong Su Kim
- 2 Division of Hemato-Oncology, Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul 07441, Republic of Korea
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A Novel Derivation Predicting Survival After Primary Tumor Resection in Stage IV Colorectal Cancer: Validation of a Prognostic Scoring Model and an Online Calculator to Provide Individualized Survival Estimation. Dis Colon Rectum 2017; 60:895-904. [PMID: 28796727 DOI: 10.1097/dcr.0000000000000821] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND A prognostic scoring model has been devised previously to predict survival following primary tumor resection in patients with metastatic colorectal cancer and unresectable metastases. This has yet to be validated. OBJECTIVE The main objectives of this study are to validate the proposed prognostic scoring model and create an interactive online calculator to estimate an individual's survival after primary tumor resection. DESIGN Clinical data and survival outcomes of patients were extracted from a prospectively maintained database. Patients were categorized into good, moderate, or poor survivor groups based on the previously proposed scoring algorithm. Discrimination was assessed and recalibration was performed, with the recalibrated model implemented as an interactive Web application to provide individualized survival probability. SETTINGS This study was conducted at a tertiary referral center. PATIENTS The study included 324 consecutive patients with metastatic colorectal carcinoma and unresectable metastases who underwent primary tumor resection between January 2008 and December 2013. MAIN OUTCOME MEASURES The primary outcome measured was overall survival. RESULTS Three hundred twenty-four patients were included in the study. Median survival in the good, moderate, and poor prognostic groups was 56.8, 25.7, and 19.9 months (log rank test, p = 0.003). The κ statistic was 0.638 and RD was 0.101. Significant differences in survival were found between the moderate and good prognostic groups (HR, 2.79; 95% CI, 1.51-5.15; p = 0.001) and between poor and good prognostic groups (HR, 4.12; 95% CI, 1.98-8.55; p < 0.001). The model was implemented as an interactive online calculator to provide individualized survival estimation after primary tumor resection (http://bit.ly/Stage4PrognosticScore). LIMITATIONS Selection bias and single-center data preclude the generalizability of the proposed model. Information regarding the severity or likelihood of developing symptoms from the primary tumor were also not accounted for in the prognostic scoring model proposed. CONCLUSIONS The prognostic scoring model provides good prognostic stratification of survival after primary tumor resection and may be a useful tool to predict survival after primary tumor resection. See Video Abstract at http://links.lww.com/DCR/A330.
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Strickler JH, Wu C, Bekaii-Saab T. Targeting BRAF in metastatic colorectal cancer: Maximizing molecular approaches. Cancer Treat Rev 2017; 60:109-119. [PMID: 28946014 DOI: 10.1016/j.ctrv.2017.08.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 08/08/2017] [Accepted: 08/11/2017] [Indexed: 02/07/2023]
Abstract
Oncogenic mutations in B-type Raf kinase (BRAF) occur in 7-10% of metastatic colorectal cancers (mCRC). Despite recent improvements in survival in the general population of patients with mCRC, patients with BRAF-mutant mCRC continue to have poor response to most systemic therapies, and prognosis remains poor. There is a substantial unmet need for novel therapeutic strategies to treat patients with BRAF-mutant mCRC. This review outlines the epidemiology, molecular pathogenesis, prognosis, and mechanisms of treatment resistance of BRAF-mutated CRC. Additionally, this review highlights novel therapeutic strategies aimed at enhancing response and improving outcomes.
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Affiliation(s)
- John H Strickler
- Duke University School of Medicine, 20 Duke Medicine Circle, Durham, NC 27710, USA
| | - Christina Wu
- Emory University, 1365-C Clifton Rd NE, Atlanta, GA 30322, USA
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Gouverneur A, Salvo F, Berdaï D, Moore N, Fourrier-Réglat A, Noize P. Inclusion of elderly or frail patients in randomized controlled trials of targeted therapies for the treatment of metastatic colorectal cancer: A systematic review. J Geriatr Oncol 2017; 9:15-23. [PMID: 28844343 DOI: 10.1016/j.jgo.2017.08.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/23/2017] [Accepted: 08/09/2017] [Indexed: 01/20/2023]
Abstract
Treatment of metastatic colorectal cancer (mCRC) has been modified since the launching of targeted therapies. Colorectal cancer (CRC) is common in elderly patients; their representation in randomized controlled trials (RCTs) is thus crucial. This study aimed to evaluate and quantify the inclusion of elderly/frail patients in RCTs of targeted therapies in mCRC. A systematic review using Medline, Scopus, Cochrane Database and ISI Web of Science was performed to identify all phase II/III RCTs of bevacizumab, cetuximab, panitumumab, regorafenib and aflibercept in mCRC until January 2015. Two reviewers independently performed studies selection, and data extraction. The protocol was registered in Prospero (CRD42015016163). Among 1,369, identified publications, 54 RCTs were selected. Nine RCTs (17%) excluded elderly patients; median age of the included population was <65years old in 50 RCTs (93%). Twenty RCTs (37%) excluded frail patients, and many RCTs excluded patients with uncontrolled hypertension or heart failure, patients treated with specific drugs (mainly anticoagulants), and patients with inadequate creatinine clearance. Elderly/frail patients are underrepresented in RCTs studying targeted therapies in mCRC, and those elderly patients included in RCTs do not reflect well the general elderly population with mCRC because of the exclusion criteria. RCTs results concerning targeted therapies can be inferred only to relatively healthy elderly subjects.
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Affiliation(s)
- Amandine Gouverneur
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France.
| | - Francesco Salvo
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Driss Berdaï
- CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Nicholas Moore
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Annie Fourrier-Réglat
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
| | - Pernelle Noize
- Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, F-33000 Bordeaux, France; CHU de Bordeaux, Pôle de santé publique, Service de Pharmacologie médicale, F-33000 Bordeaux, France
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Abstract
There have been remarkable advances in the treatment of metastatic colorectal cancer over the past 20 years, chiefly achieved by development of new active drugs and establishment of effective systemic therapy regimens. Multidisciplinary care of resectable liver disease with use of perioperative systemic therapy and superior liver resection has resulted in prolonged survival of select patients. Median overall survival has significantly improved with the modern multiagent regimens. This article reviews recent high-quality randomized clinical trials that were conducted to address optimal treatment of advanced and metastatic colorectal carcinoma, mainly focused on initially inoperable metastatic disease.
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40
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Corvigno S, Frödin M, Wisman GBA, Nijman HW, Van der Zee AG, Jirström K, Nodin B, Hrynchyk I, Edler D, Ragnhammar P, Johansson M, Dahlstrand H, Mezheyeuski A, Östman A. Multi-parametric profiling of renal cell, colorectal, and ovarian cancer identifies tumour-type-specific stroma phenotypes and a novel vascular biomarker. JOURNAL OF PATHOLOGY CLINICAL RESEARCH 2017; 3:214-224. [PMID: 28770105 PMCID: PMC5527322 DOI: 10.1002/cjp2.74] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 06/08/2017] [Indexed: 01/01/2023]
Abstract
A novel set of integrated procedures for quantification of fibroblast‐rich stroma and vascular characteristics has recently been presented allowing discovery of novel perivascular and stromal biomarkers in colorectal, renal cell, and ovarian cancer. In the present study, data obtained through these procedures from clinically well‐annotated collections of these three tumour types have been used to address two novel questions. First, data have been used to investigate if the three tumour types demonstrate significant differences regarding features such as vessel diameter, vessel density, and perivascular marker expression. Second, analyses of the cohorts have been used to explore the prognostic significance of a novel vascular metric, ‘vessel distance inter‐quartile range (IQR)’ that describes intra‐case heterogeneity regarding vessel distribution. The comparisons between the three tumour types demonstrated a set of significant differences. Vessel density of renal cell cancer was statistically significantly higher than in colorectal and ovarian cancer. Vessel diameter was statistically significantly higher in ovarian cancer. Concerning perivascular status, colorectal cancer displayed significantly higher levels of perivascular PDGFR‐β expression than the other two tumour types. Intra‐case heterogeneity of perivascular PDGFR‐β expression was also higher in colorectal cancer. Notably, these fibroblast‐dominated stroma phenotypes matched previously described experimental tumour stroma characteristics, which have been linked to differential sensitivity to anti‐VEGF drugs. High ‘vessel distance IQR’ was significantly associated with poor survival in both renal cell cancer and colorectal cancer. In renal cell cancer, this characteristic also acted as an independent prognostic marker according to multivariate analyses including standard clinico‐pathological characteristics. Explorative subset analyses indicated particularly strong prognostic significance of ‘vessel distance IQR’ in T stage 4 of this cancer type. Together, these analyses identified tumour‐type‐specific vascular‐stroma phenotypes of possible functional significance, and suggest ‘vessel distance IQR’ as a novel prognostic biomarker.
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Affiliation(s)
- Sara Corvigno
- Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
| | - Magnus Frödin
- Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
| | - G Bea A Wisman
- Department of Gynecologic OncologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Hans W Nijman
- Department of Gynecologic OncologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Ate Gj Van der Zee
- Department of Gynecologic OncologyUniversity of Groningen, University Medical Center GroningenGroningenThe Netherlands
| | - Karin Jirström
- Department of Clinical Sciences, Division of Oncology and PathologyLund UniversityLundSweden
| | - Björn Nodin
- Department of Clinical Sciences, Division of Oncology and PathologyLund UniversityLundSweden
| | - Ina Hrynchyk
- City Clinical Pathologoanatomic BureauMinskBelarus
| | - David Edler
- Department of Molecular Medicine and SurgeryKarolinska University Hospital SolnaStockholmSweden
| | - Peter Ragnhammar
- Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
| | - Martin Johansson
- Department of Laboratory MedicineSkånes UniversitetssjukhusMalmö
| | - Hanna Dahlstrand
- Department of Oncology-PathologyKarolinska InstitutetStockholmSweden.,Department of OncologyUppsala University HospitalUppsalaSweden
| | - Artur Mezheyeuski
- Department of Oncology-PathologyKarolinska InstitutetStockholmSweden.,Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
| | - Arne Östman
- Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
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Predicting Outcome and Therapy Response in mCRC Patients Using an Indirect Method for CTCs Detection by a Multigene Expression Panel: A Multicentric Prospective Validation Study. Int J Mol Sci 2017; 18:ijms18061265. [PMID: 28608814 PMCID: PMC5486087 DOI: 10.3390/ijms18061265] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 06/06/2017] [Accepted: 06/07/2017] [Indexed: 01/20/2023] Open
Abstract
Colorectal cancer (CRC) is one of the major causes of cancer-related deaths. Early detection of tumor relapse is crucial for determining the most appropriate therapeutic management. In clinical practice, computed tomography (CT) is routinely used, but small tumor changes are difficult to visualize, and reliable blood-based prognostic and monitoring biomarkers are urgently needed. The aim of this study was to prospectively validate a gene expression panel (composed of GAPDH, VIL1, CLU, TIMP1, TLN1, LOXL3 and ZEB2) for detecting circulating tumor cells (CTCs) as prognostic and predictive tool in blood samples from 94 metastatic CRC (mCRC) patients. Patients with higher gene panel expression before treatment had a reduced progression-free survival (PFS) and overall-survival (OS) rates compared with patients with low expression (p = 0.003 and p ≤ 0.001, respectively). Patients with increased expression of CTCs markers during treatment presented PFS and OS times of 8.95 and 11.74 months, respectively, compared with 14.41 and 24.7 for patients presenting decreased expression (PFS; p = 0.020; OS; p ≤ 0.001). Patients classified as non-responders by CTCs with treatment, but classified as responders by CT scan, showed significantly shorter survival times (PFS: 8.53 vs. 11.70; OS: 10.37 vs. 24.13; months). In conclusion, our CTCs detection panel demonstrated efficacy for early treatment response assessment in mCRC patients, and with increased reliability compared to CT scan.
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42
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Zhao T, Wang X, Xu T, Xu X, Liu Z. Bevacizumab significantly increases the risks of hypertension and proteinuria in cancer patients: A systematic review and comprehensive meta-analysis. Oncotarget 2017; 8:51492-51506. [PMID: 28881662 PMCID: PMC5584263 DOI: 10.18632/oncotarget.18190] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 02/20/2017] [Indexed: 01/18/2023] Open
Abstract
Published data regarding the overall risks and incidence of hypertension and proteinuria associated with bevacizumab were still unclear. To quantify the precise risks and incidence, we performed this comprehensive meta-analysis of 72 published clinical trials including 21902 cases and 20608 controls. The overall incidence, risk ratios (RRs), and 95% confidence intervals (95% CIs) were calculated using a fixed or random-effect model based on the heterogeneity. The incidence of all-grade and high-grade hypertension were 25.3% (95% CI: 21.5%−29.5%) and 8.2% (95% CI: 7%−9.8%) for patients treated with bevacizumab. And the incidence of all-grade and high-grade proteinuria were 18% (95% CI: 11.7%−26.6%) and 2.4% (95% CI: 1.8%−3.2%), respectively. Compared with controls, bevacizumab significantly increased the risks of all-grade (RR: 3.595, 95% CI: 2.952−4.378) and high-grade hypertension (RR: 5.173, 95% CI: 4.188−6.390). Obviously increased risks of all-grade (RR: 3.369, 95% CI: 2.492−4.556) and high-grade proteinuria (RR: 5.494, 95% CI: 3.991−7.564) were also observed. In the subgroup analysis, the risks of hypertension and proteinuria may significantly vary with bevacizumab dosage, cancer types and concomitant drugs. Whereas, no obvious difference were discovered when stratified based on phase of trials, age of patients, treatment line and duration. So, close monitor and effective management were highly recommended for the safe use of bevacizumab.
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Affiliation(s)
- Tingting Zhao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Xiaonan Wang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Tingting Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Xiaodong Xu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, 210002, China
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43
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Li W, Li X, Liu S, Yang W, Pan F, Yang XY, Du B, Qin L, Pan Y. Gold nanoparticles attenuate metastasis by tumor vasculature normalization and epithelial-mesenchymal transition inhibition. Int J Nanomedicine 2017; 12:3509-3520. [PMID: 28496326 PMCID: PMC5422535 DOI: 10.2147/ijn.s128802] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Angiogenesis is a process by which vessels are formed through preexisting ones, and this plays a key role in the progression of solid tumors. However, tumor vessels are influenced by excessive pro-angiogenic factors, resulting in deformed structures that facilitate the intravasation of tumor cells into the circulation and subsequent metastasis. Moreover, abnormal tumor vessels have low blood perfusion and thereby decreased oxygen infusion into tumors. This results in a hostile microenvironment that promotes epithelial-mesenchymal transition (EMT), a process in which epithelial cells lose their polarity and gain increased motility, which is associated with metastasis and invasion. Here, we demonstrate that gold nanoparticles (AuNPs) facilitate tumor vasculature normalization, increase blood perfusion and alleviate hypoxia in melanoma tumors. Additionally, AuNPs were observed to reverse EMT in tumors, accompanied by the alleviation of lung metastasis. These AuNPs inhibited the migration of B16F10 cells and reversed EMT in B16F10 cells, indicating that AuNPs could directly regulate EMT independent of improvements in hypoxia. Taken together, our data demonstrated that AuNPs could induce tumor vasculature normalization and reverse EMT, resulting in decreased melanoma tumor metastasis.
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Affiliation(s)
- Wei Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University
| | - Xin Li
- Department of General Surgery, The First Affiliated Hospital of Jinan University
| | - Shuhao Liu
- Department of General Surgery, The First Affiliated Hospital of Jinan University
| | - Wende Yang
- Department of General Surgery, The First Affiliated Hospital of Jinan University
| | - Fan Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University
| | - Xiao-Yan Yang
- Department of General Surgery, The First Affiliated Hospital of Jinan University.,Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University
| | - Bin Du
- Department of Pathology, The First Affiliated Hospital of Jinan University
| | - Li Qin
- Department of Histology, and Embryology, Medical School of Jinan University, Guangzhou, People's Republic of China
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University
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44
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The role of bevacizumab in solid tumours: A literature based meta-analysis of randomised trials. Eur J Cancer 2017; 75:245-258. [PMID: 28242502 DOI: 10.1016/j.ejca.2017.01.026] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 01/11/2017] [Accepted: 01/23/2017] [Indexed: 12/22/2022]
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45
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Abdel-Qadir H, Ethier JL, Lee DS, Thavendiranathan P, Amir E. Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy: A systematic review and meta-analysis. Cancer Treat Rev 2016; 53:120-127. [PMID: 28104567 DOI: 10.1016/j.ctrv.2016.12.002] [Citation(s) in RCA: 172] [Impact Index Per Article: 19.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 12/08/2016] [Accepted: 12/09/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND The cardiovascular risk of angiogenesis inhibitors is not well-quantified. We hypothesized that, compared to direct vascular endothelial growth factor (VEGF) inhibitors (anti-VEGF antibodies or decoy receptors), small molecule agents have higher risk due to their less specific mechanism. METHODS We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for phase III randomised controlled trials comparing angiogenesis inhibitor-based therapy to other systemic therapy. Outcomes evaluated were hypertension, severe hypertension, cardiac dysfunction, congestive heart failure, cardiac ischemia, arterial thromboembolism, venous thromboembolism, and fatal cardiovascular events. Data were pooled using Mantel-Haenszel random effects method to generate odds ratios (OR). RESULTS We identified 77 studies meeting inclusion criteria. Compared to routine care, angiogenesis inhibitors were associated with a higher risk of hypertension (OR 5.28 [4.53-6.15], number needed to harm [NNH] 6), severe hypertension (OR 5.59 [4.67-6.69], NNH 17), cardiac ischemia (OR 2.83 [1.72-4.65], NNH 85) and cardiac dysfunction (OR 1.35 [1.06-1.70], NNH 139). VEGF inhibitors were associated with an increased risk of arterial thromboembolism (OR 1.52 [1.17-1.98], NNH 141). No significant interaction was observed between the two drug subgroups for any outcomes. We identified no significant increase in the risk of the other outcomes evaluated. CONCLUSION Angiogenesis inhibitors increase the risk of hypertension, arterial thromboembolism, cardiac ischemia and cardiac dysfunction. There was no significant difference in cardiovascular risk between direct VEGF inhibitors and small molecule agents.
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Affiliation(s)
- Husam Abdel-Qadir
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Women's College Hospital, Toronto, Ontario, Canada.
| | - Josee-Lyne Ethier
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Douglas S Lee
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre and Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada
| | - Paaladinesh Thavendiranathan
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre and Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada
| | - Eitan Amir
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada; Princess Margaret Cancer Centre, Toronto, Ontario, Canada
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Chen K, Gong Y, Zhang Q, Shen Y, Zhou T. Efficacy and safety of addition of bevacizumab to FOLFIRI or irinotecan/bolus 5-FU/LV (IFL) in patients with metastatic colorectal cancer: A meta-analysis. Medicine (Baltimore) 2016; 95:e5221. [PMID: 27861344 PMCID: PMC5120901 DOI: 10.1097/md.0000000000005221] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Revised: 09/08/2016] [Accepted: 10/04/2016] [Indexed: 12/15/2022] Open
Abstract
Recent studies have paid much attention on the safety of bevacizumab as adjuvant chemotherapy for metastatic colorectal cancer. The aim of this meta-analysis was to study the efficacy and safety of bevacizumab in combination with irinotecan, bolus followed by infusional 5-fluorouracil, and leucovorin (FOLFIRI) and, irinotecan, bolus fluorouracil, leucovorin (IFL) for patients with metastatic colorectal cancer (mCRC).An electronic search of related trials was conducted from PubMed, EMBASE, Cochrane Library databases. Risk ratio (RRs) and its 95% confidence intervals (95% CIs) were calculated by using either DerSimonian-Laird method or Mantel-Haenszel method according to the heterogeneity of included articles. The risk of mortality, therapeutic efficacy, and adverse effect were meta-analyzed.In total, 6 RCTs including 2165 participants (1109 in the treatment group, 1056 in the control group) were included in this meta-analysis. Compared with FOLFIRI-panitumumab/cetuximab, the bevacizumab addition significantly reduced the complete response (CR) rate (RR [95%CI] = 0.31[0.11, 0.89], P = 0.03) and the risk of grade 3/4 adverse event (RR [95%CI] = 0.89[0.80, 0.98], P = 0.01). Compared with FOLFIRI and IFL alone, the addition of bevacizumb significantly increased the partial response (PR) and objective response (OR) rates. Compared with IFL alone, the addition of bevacizumb significantly reduced the mortality risk of PFS (RR [95%CI] = 0.53[0.42, 0.66], P < 0.00001) and OS (RR[95%CI] = 0.70[0.60, 0.82], P < 0.00001), but increased the risk of adverse events (RR[95%CI] = 1.14[1.06, 1.21], P = 0.0002).Combination chemotherapy of bevacizumab plus FOLFIRI or IFL had a relative high efficacy and acceptable safety for treatment of mCRC.
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Analysis of Clinical End Points of Randomised Trials Including Bevacizumab and Chemotherapy versus Chemotherapy as First-line Treatment of Metastatic Colorectal Cancer. Clin Oncol (R Coll Radiol) 2016; 28:e155-64. [DOI: 10.1016/j.clon.2016.05.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2015] [Revised: 03/14/2016] [Accepted: 03/15/2016] [Indexed: 01/18/2023]
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Ilic I, Jankovic S, Ilic M. Bevacizumab Combined with Chemotherapy Improves Survival for Patients with Metastatic Colorectal Cancer: Evidence from Meta Analysis. PLoS One 2016; 11:e0161912. [PMID: 27579775 PMCID: PMC5006969 DOI: 10.1371/journal.pone.0161912] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 08/15/2016] [Indexed: 01/31/2023] Open
Abstract
Background Colorectal cancer is one of the leading causes of cancer deaths in both sexes in the world. Improvement of existing therapy modalities and implementing new ones in order to improve survival of patients with colorectal cancer represents a great challenge for medicine. The aim of this paper was to assess the impact that adding bevacizumab to chemotherapy has on survival in patients with metastatic colorectal cancer, compared to the use of chemotherapy alone. Methods Hazard ratios (HRs) with their 95% confidence intervals (CI) were determined from the studies and pooled. Two-sided p values were reported and considered to indicate statistical significance if less than 0.05. Results A total of 12 studies that meet the inclusion criteria were identified in the literature search, 3 phase II studies and 9 phase III studies. Based on the random effects meta-analysis, a statistically significant improvement was identified for both overall survival (HR = 0.84; 95% CI: 0.74–0.94; p = 0.003) and progression free survival (HR = 0.64; 95% CI: 0.55–0.73; p<0.00001) in patients with metastatic colorectal cancer when bevacizumab was added to chemotherapy, compared to chemotherapy treatment alone. Conclusion The findings of this meta analysis confirm the benefit of adding bevacizumab to chemotherapy in terms of survival and progression free survival, but the magnitude of this effect is not consistent throughout the included studies. This suggests the need for further research of interaction of bevacizumab with chemotherapeutic agents as well as recognition of patients’ characteristics important for the treatment selection criteria.
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Affiliation(s)
- Irena Ilic
- Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
- * E-mail:
| | - Slobodan Jankovic
- Department of Pharmacology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Milena Ilic
- Department of Epidemiology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
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Botrel TEA, Clark LGDO, Paladini L, Clark OAC. Efficacy and safety of bevacizumab plus chemotherapy compared to chemotherapy alone in previously untreated advanced or metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer 2016; 16:677. [PMID: 27558497 PMCID: PMC4997727 DOI: 10.1186/s12885-016-2734-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 06/30/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of neoplasm-related death in the United States. Several studies analyzed the efficacy of bevacizumab combined with different chemotherapy regimens consisting on drugs such as 5-FU, capecitabine, irinotecan and oxaliplatin. This systematic review aims to evaluate the effectiveness and safety of chemotherapy plus bevacizumab versus chemotherapy alone in patients with previously untreated advanced or metastatic colorectal cancer (mCRC). METHODS Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoints were overall survival and progression-free survival. Data extracted from the studies were combined by using hazard ratio (HR) or risk ratio (RR) with their corresponding 95 % confidence intervals (95 % CI). RESULTS The final analysis included 9 trials comprising 3,914 patients. Patients who received the combined treatment (chemotherapy + bevacizumab) had higher response rates (RR = 0.89; 95 % CI: 0.82 to 0.96; p = 0.003) with heterogeneity, higher progression-free survival (HR = 0.69; 95 % CI: 0.63 to 0.75; p < 0.00001) and also higher overall survival rates (HR = 0.87; 95 % CI: 0.80 to 0.95; p = 0.002) with moderate heterogeneity. Regarding adverse events and severe toxicities (grade ≥ 3), the group receiving the combined therapy had higher rates of hypertension (RR = 3.56 95 % CI: 2.58 to 4.92; p < 0.00001), proteinuria (RR = 1.89; 95 % CI: 1.26 to 2.84; p = 0.002), gastrointestinal perforation (RR = 3.63; 95 % CI: 1.31 to 10.09; p = 0.01), any thromboembolic events (RR = 1.44; 95 % CI: 1.20 to 1.73; p = 0.0001), and bleeding (RR = 1.81; 95 % CI: 1.22 to 2.67; p = 0.003). CONCLUSION The combination of chemotherapy with bevacizumab increased the response rate, progression-free survival and overall survival of patients with mCRC without prior chemotherapy. The results of progression-free survival (PFS) and overall survival (OS) were comparatively higher in those subgroups of patients receiving bolus 5-FU or capecitabine-based chemotherapy plus bevacizumab, when compared to patients treated with infusional %-FU plus bevacizumab (no difference in PFS and OS). Regarding the type of cytotoxic scheme, regimens containing irinotecan and fluoropyrimidine monotherapy showed superior efficacy results when combined to bevacizumab.
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Affiliation(s)
- Tobias Engel Ayer Botrel
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123.
- CIOP - Centro Integrado de Oncologia e Pesquisa, Rua Santo Antônio 200, sala 301, Poços de Caldas, Minas Gerais, Brazil, 37701-036.
| | - Luciana Gontijo de Oliveira Clark
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123
| | - Luciano Paladini
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123
| | - Otávio Augusto C Clark
- Evidencias - A Kantar Health Company, Av. José de Souza Campos, 550 - 7°. andar (salas 71 e 72), Nova Campinas, Campinas, São Paulo, Brazil, 13092-123
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Zhu X, Tian X, Yu C, Hong J, Fang J, Chen H. Increased risk of hemorrhage in metastatic colorectal cancer patients treated with bevacizumab: An updated meta-analysis of 12 randomized controlled trials. Medicine (Baltimore) 2016; 95:e4232. [PMID: 27559943 PMCID: PMC5400309 DOI: 10.1097/md.0000000000004232] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND As an important antivascular endothelial growth factor monoclonal antibody, bevacizumab has been administrated for the treatment of cancer patients. Hemorrhage, one of the common adverse events of angiogenesis inhibitors, sometimes is also fatal and life-threatening. We aimed at determining the incidence and risk of hemorrhage associated with bevacizumab in patients with metastatic colorectal cancer (mCRC). METHODS We searched PubMed, EMBASE, and the Web of Science databases for relevant randomized controlled trials (RCTs). The overall incidence, overall relative risk (RR), and 95% confidence interval (CI) were calculated by using a random-effects or fixed-effects model based on the heterogeneity of selected trials. RESULTS A total of 10,555 mCRC patients from 12 RCTs were included in our study. The overall incidence of hemorrhage was 5.8% (95% CI 3.9%-7.8%). Bevacizumab significantly increased the overall risk of hemorrhage with an RR of 1.96 (95% CI 1.27-3.02). The RR of all-grade hemorrhage was 2.39 (95% CI 1.09-5.24) and 1.41 (95% CI 1.01-1.97) for high-grade hemorrhage. The risk of hemorrhage associated with bevacizumab was dose-dependent with an RR of 1.73 (95% CI 1.15-2.61) for 2.5 mg/kg/wk and 4.67 (95% CI 2.36-9.23) for 5 mg/kg/wk. More importantly, the RR of hemorrhage for treatment duration (<= 6 months and > 6 months) based on subgroup analysis was 4.13 (95% CI 2.58-6.61) and 1.43 (95% CI 0.96-2.14), respectively. CONCLUSION The addition of bevacizumab to concurrent antineoplastic in patients with mCRC significantly increased the risk of hemorrhage. The dose of bevacizumab may contribute to the risk of hemorrhage. And the 1st 6 months of treatment may be a crucial period when hemorrhagic events occur.
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Affiliation(s)
| | | | | | | | | | - Haoyan Chen
- State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, China
- Correspondence: Haoyan Chen, State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, 145 Middle Shandong Road, Shanghai 200001, China (e-mail: )
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