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1
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Xu C, Ren J, Liu C, Gai Y, Cheng X, Wang Y, Wang G. Comparative efficacy of cetuximab combined with FOLFOX or CAPEOX in first-line treatment of RAS/BRAF wild-type metastatic colorectal cancer: a multicenter case-control study. Anticancer Drugs 2025; 36:383-393. [PMID: 39903643 PMCID: PMC11969360 DOI: 10.1097/cad.0000000000001697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 01/03/2025] [Indexed: 02/06/2025]
Abstract
FOLFOX combined with cetuximab is a recommended first-line treatment regimen for RAS/BRAF wild-type metastatic colorectal cancer (mCRC). CAPEOX combined with cetuximab differs from the FOLFOX regimen by using oral capecitabine instead of continuous infusion of fluorouracil, offering greater convenience and cost-effectiveness with higher patient acceptance. However, the comparative efficacy of these two regimens remains debatable, necessitating further evidence to explore any differences in their efficacy. This study collected medical records of mCRC patients who were treated with CAPEOX or FOLFOX combined with cetuximab from 1 October 2021 to 16 October 2023 at Harbin Medical University Cancer Hospital and the First Hospital of Shanxi Medical University. Eligible patients were selected based on inclusion criteria and followed up through the hospital's follow-up system and telephone interviews. Kaplan-Meier survival analysis and Cox proportional hazards regression analysis were used to assess patients' progression-free survival (PFS) and overall survival (OS). A total of 71 eligible patients were enrolled in this study; 43 patients received CAPEOX combined with cetuximab (Group A, n = 43), and 28 patients received FOLFOX combined with cetuximab (Group B, n = 28). The two groups achieved similar median PFS (mPFS) and median OS (mOS), with mPFS of 18 months and 12 months, respectively ( P = 0.23), and mOS of 33 months and 20 months, respectively ( P = 0.21), with no statistically significant differences. The results of this study demonstrated that CAPEOX combined with cetuximab is an equally viable option for first-line treatment of RAS/BRAF wild-type mCRC as FOLFOX combined with cetuximab.
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Affiliation(s)
- Chang Xu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin
| | - Jing Ren
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin
| | - Changqing Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin
| | - Yi Gai
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin
| | - Xiangyu Cheng
- Shanxi Medical University
- Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University
| | - Yusheng Wang
- Department of Oncology Digestive, First Hospital of Shanxi Medical University, Taiyuan, China
| | - Guangyu Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin
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Cheng YC, Chen MY, Yadav VK, Pikatan NW, Fong IH, Kuo KT, Yeh CT, Tsai JT. Targeting FABP4/UCP2 axis to overcome cetuximab resistance in obesity-driven CRC with drug-tolerant persister cells. Transl Oncol 2025; 53:102274. [PMID: 39823981 PMCID: PMC11787020 DOI: 10.1016/j.tranon.2025.102274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 11/24/2024] [Accepted: 01/05/2025] [Indexed: 01/20/2025] Open
Abstract
Colorectal cancer (CRC) is closely linked to obesity, a condition that significantly impacts tumor progression and therapeutic resistance. Although cetuximab, an EGFR-targeting monoclonal antibody, is a cornerstone in metastatic CRC treatment, resistance often emerges, leading to poor outcomes. This study investigated the role of drug-tolerant persister (DTP) cells and their metabolic interactions within the tumor microenvironment (TME) in cetuximab resistance. Using patient-derived organoids and in vivo models, we identified the FABP4/UCP2 axis as a critical mediator of resistance. Organoids derived from cetuximab non-responders revealed upregulated FABP4 and UCP2 expression post-treatment. Coculture experiments with adipocytes showed that FABP4 and UCP2 promote lipid metabolic reprogramming, facilitating cancer cell survival in a dormant state. CRISPR/Cas9 mediated inhibition of FABP4 disrupted this metabolic interaction, sensitising resistant cells to cetuximab. In vivo, the FABP4 inhibitor BMS309403, either alone or in combination with cetuximab, significantly reduced tumor growth in resistant CRC models, highlighting its therapeutic potential. These findings establish the FABP4/UCP2 axis as a pivotal driver of cetuximab resistance in obesity-associated CRC and suggest that targeting this metabolic pathway could improve outcomes in DTP-resistant CRC patients.
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Affiliation(s)
- Yi-Chiao Cheng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114202, Taiwan
| | - Ming-Yao Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Vijesh Kumar Yadav
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Narpati Wesa Pikatan
- Division of Urology, Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia
| | - Iat-Hang Fong
- Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan
| | - Kuang-Tai Kuo
- Department of Surgery, Division of Thoracic Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 23561, Taiwan
| | - Chi-Tai Yeh
- Department of Medical Research & Education, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan; Continuing Education Program of Food Biotechnology Applications, College of Science and Engineering, National Taitung University, Taitung 95092, Taiwan.
| | - Jo-Ting Tsai
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Department of Radiology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan.
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Azeem M, Ur Rehman A, Rasheed S, Shahzad A, Javed MH, Jamil QA, Karuniawati H, Al-Tamimi SK. The impact of combining cetuximab with the traditional chemotherapy regimens on clinical effectiveness in metastatic colorectal cancer: a systematic review and meta-analysis. BMC Cancer 2025; 25:331. [PMID: 39994602 PMCID: PMC11849154 DOI: 10.1186/s12885-025-13515-3] [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: 08/02/2024] [Accepted: 01/14/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) poses a high rate of morbidity and mortality despite various treatment advances. Cetuximab, an anti-EGFR, has shown promising efficacy in improving outcomes when combined with chemotherapy. Understanding its efficacy is essential for optimizing treatment strategies in mCRC. This systematic review and meta-analysis aims to evaluate the effectiveness of combining cetuximab with chemotherapy in mCRC. METHODS PubMed and Google Scholar were systematically searched following the benchmarks indicated by PRISMA. The primary outcomes of the study were progression-free survival (PFS) and overall survival (OS). Statistical analyses were executed using Stata version 16. RESULTS The meta-analysis encompassed 25 studies involving 3788 mCRC patients. The median age spans from 18 to 77 years. The cetuximab plus chemotherapy exhibited a higher PFS and OS with a significant difference (PFS: HR = 0.79, 95% CI = 0.63-0.96, p < 0.01, I2 = 38% and OS: HR = 0.78, 95% CI = 0.60-0.91, p < 0.01, I2 = 47%) compared to the control group. Subgroup analysis based on randomized controlled trials demonstrated consistent treatment effects for PFS (HR = 0.77, 95% CI = 0.62-0.93) and OS (HR = 0.76, 95% CI = 0.61-0.88) in the cetuximab treatment group. CONCLUSIONS Combining cetuximab with chemotherapy offers a potential benefit in improving survival outcomes for metastatic colorectal cancer patients, as indicated by this study. These results suggest that cetuximab may be a valuable addition to mCRC treatment strategies, warranting further clinical investigation and integration into standard care.
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Affiliation(s)
- Marryam Azeem
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Anees Ur Rehman
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.
| | - Saba Rasheed
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Aleena Shahzad
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Muhammad Hamza Javed
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Qurratul Ain Jamil
- Department of Pharmacy Practice, Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur, Pakistan
| | - Hidayah Karuniawati
- Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Muhammadiyah Surakarta, Surakarta, Indonesia
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Zhang M, Fu Y, Xie T, Yang Z, Zhang D, Zhou R. Physical insights guided rational design of anti-EGFR antibody to reverse the acquired resistance. Int J Biol Macromol 2025:141304. [PMID: 39986495 DOI: 10.1016/j.ijbiomac.2025.141304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/24/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025]
Abstract
Cetuximab (Ctx), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) for colorectal cancer treatment, often faces diminished clinical efficacy due to acquired resistance driven by EGFR mutations. Here, we investigated the molecular mechanisms underlying this mutation-induced drug resistance and developed a mechanism-based strategy to restore the binding affinity of Ctx to EGFR mutants. Through molecular dynamics simulations and free energy perturbation calculations, we discovered that most resistant mutations primarily alter the electrostatic properties of the binding interface. Focusing on two key mutations, EGFR K489E and I491M, we rationally designed two Ctx variants-CtxD103R for EGFRK489E and CtxD103E_E105D for EGFRI491M-using electrostatic compensation and steric hindrance adjustment strategies. Surface plasmon resonance measurements verified that the two designed Ctx variants exhibit improved binding affinity to the corresponding EGFR mutants compared with wild-type Ctx. Additionally, western blot experiments using HEK-293 T cells showed that the designed CtxD103R effectively inhibits EGF-stimulated phosphorylation of EGFRK489E. Our findings highlight a rational design approach, empowered by interaction landscape at atomic detail, as a promising and cost-effective strategy to combat mutation-driven resistance in antibody therapies.
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Affiliation(s)
- Mingjiao Zhang
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yaqi Fu
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Teng Xie
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zaixing Yang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou 215123, China
| | - Dong Zhang
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Ruhong Zhou
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; Department of Chemistry, Columbia University, New York, NY 10027, United States.
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5
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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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6
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Zhang R, Su C, Jia Y, Xing M, Jin S, Zong H. Molecular mechanisms of HER2-targeted therapy and strategies to overcome the drug resistance in colorectal cancer. Biomed Pharmacother 2024; 179:117363. [PMID: 39236476 DOI: 10.1016/j.biopha.2024.117363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024] Open
Abstract
HER2 amplification is one of the mechanisms that induce drug resistance to anti-EGFR therapy in colorectal cancer. In recent years, data from several randomized clinical trials show that anti-HER2 therapies improved the prognosis of patients with HER2-positive colorectal cancer. These results indicate that HER2 is a promising therapeutic target in advanced colorectal cancer. Despite the anti-HER2 therapies including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates improving the outcomes, less than 30 % of the patients achieve objective response and eventually have drug resistance. It is necessary to explore the primary and secondary mechanisms for the resistance to anti-HER2 therapies, which will pave the way to overcome the drug resistance. Several studies have reported the potential mechanisms for the resistance to anti-HER2 therapies. In this review, we present a comprehensive overview of the recent advances in clinical research, mechanisms of treatment resistance, and strategies for reversing resistance in HER2-positive colorectal cancer patients.
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Affiliation(s)
- Rui Zhang
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Chang Su
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Yongliang Jia
- BGI College & Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China.
| | - Menglu Xing
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Shuiling Jin
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
| | - Hong Zong
- Department of Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
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7
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Zhan Y, Cheng X, Mei P, Tan S, Feng W, Jiang H. Safety of first-line systemic therapy in patients with metastatic colorectal cancer: a network meta-analysis of randomized controlled trials. BMC Cancer 2024; 24:893. [PMID: 39048944 PMCID: PMC11270896 DOI: 10.1186/s12885-024-12662-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 07/19/2024] [Indexed: 07/27/2024] Open
Abstract
OBJECTIVE To evaluate the safety of first-line systemic therapy for metastatic colorectal cancer through network meta-analysis. METHODS The literature from PubMed, Embase, Web of Science, and Cochrane Library databases was searched from the inception of the databases to August 15, 2023, and strict inclusion and exclusion criteria were applied to screen studies. The Cochrane Bias Risk Assessment Tool (RoB 2.0) was used to evaluate the quality of the included literature. Network meta-analysis was conducted using Stata 15.0 and R4.3.1 software to compare the incidence of adverse events (AEs) among different treatment regimens. RESULTS A total of 53 randomized controlled trials, involving 17,351 patients with metastatic colorectal cancer (mCRC), were ultimately included, encompassing 29 different therapeutic approaches. According to SUCRA rankings, the CAPOX regimen is most likely to rank first in terms of safety, while the FOLFOXIRI + panitumumab regimen is most likely to rank last. In terms of specific AEs, the CAPOX regimen, whether used alone or in combination with targeted drugs (bevacizumab and cetuximab), is associated with a reduced risk of neutropenia and febrile neutropenia, as well as an increased risk of thrombocytopenia and diarrhea. The FOLFOX regimen, with or without bevacizumab, is linked to an increased risk of neutropenia and peripheral sensory neuropathy. The FOLFIRI/CAPIRI + bevacizumab regimen is associated with a reduced risk of peripheral sensory neuropathy. S-1 and S-1 + oxaliplatin are well-tolerated in terms of gastrointestinal reactions. The FOLFOXIRI regimen, whether used alone or in combination with targeted drugs, is associated with various AEs. CONCLUSION In summary, the CAPOX regimen may be the safest option among the first-line systemic treatment regimens for mCRC patients, while the FOLFOXIRI + panitumumab regimen may be associated with a higher incidence of grade 3 or higher AEs.
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Affiliation(s)
- Yanrong Zhan
- Rudong People's Hospital / Affiliated Rudong Hospital of Xinglin College, Nantong University, Nantong, Jiangsu, 226400, China.
| | - Xianwen Cheng
- Ankang Hospital of Traditional Chinese Medicine, Ankang, Shaanxi, 725000, China
| | - Pingping Mei
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Shufa Tan
- Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China
| | - Wenzhe Feng
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China.
| | - Hua Jiang
- Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, 712000, China
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Zhou YW, Zhao X, Ni L, Cao P, Leng WB, Zhu Q, Gou HF, Zhang J, Li XF, Qiu M. Dynamic ctDNA-based analysis of drug-resistant gene alterations at RAS/BRAF wild-type metastatic colorectal cancer patients after cetuximab plus chemotherapy as the first-line treatment. Int Immunopharmacol 2024; 131:111887. [PMID: 38503018 DOI: 10.1016/j.intimp.2024.111887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 03/13/2024] [Accepted: 03/13/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND The purpose of this study was to explore the dynamic changes of genomic mutations and their correlations with the efficacy in metastatic colorectal cancer (mCRC) patients treated with cetuximab plus mFOLFOX as the first-line treatment. METHODS We included mCRC patients from January 2018 to October 2020 as a studied cohort which were treated with cetuximab plus mFOLFOX as first line therapy. Blood samples were collected for circulating tumor DNA (ctDNA) test at three timepoints: before the first-line therapy(baseline), at the time of first-line progression and at the time of second-line progression. Progression-free survival was considered as the primary endpoint while objective response rate and overall survival were determined as the secondary endpoints. RESULTS Totally 39 patients received first-line treatment, of which 25 patients entered the second-line treatment, while 10 patients entered the third-line treatment. The median follow-up time was 16.4 months (95 %CI, 14.8-19.3). Along the treatment from first-line progress disease (PD) to second-line PD, proportions of TP53 (12/18, 67 %), APC (10/18, 56 %), FBXW7 (3/18, 17 %), and AMER1 (2/18, 11 %) were gradually increased according to results of single nucleotide variation (SNV). CONCLUSIONS Resistant gene mutations caused by anti-EGFR drugs in RAS/BRAF wild-type mCRC patients can be observed by dynamic ctDNA analysis. TP53 and AMER1 mutations, tumor mutational burden (TMB) levels, and TP53/AMER1 co-mutation may predict the efficacy of the first-line cetuximab-contained treatment. Situations of genetic mutations were differentiated from first-line PD to second-line PD, which indicated that mutation detection may contribute to predict prognosis of mCRC patients.
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Affiliation(s)
- Yu-Wen Zhou
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Xin Zhao
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Ni
- Department of Oncology, Mianyang Central Hospital, Sichuan Province, China
| | - Peng Cao
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Bing Leng
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Zhu
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu 610041, Sichuan Province, China
| | - Hong-Feng Gou
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu 610041, Sichuan Province, China
| | - Jiao Zhang
- Genecast Biotechnology Co., Ltd., 88 Danshan Road, Xidong Chuangrong Building, Suite C, 1310-1318, Xishan District, Wuxi City, Jiangsu 214104, China
| | - Xiao-Fen Li
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, 37 Guoxue Xiang Street, Chengdu 610041, Sichuan Province, China
| | - Meng Qiu
- Department of Colorectal Cancer, West China Hospital, Sichuan University, Chengdu, China.
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9
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Shao Y, Hu J, Yao H, Jiang M, Song Z. Case report: Interstitial lung disease of XELOEX chemotherapy with cetuximab in advanced colon cancer induced. Medicine (Baltimore) 2023; 102:e36379. [PMID: 38115308 PMCID: PMC10727633 DOI: 10.1097/md.0000000000036379] [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: 09/14/2023] [Accepted: 11/09/2023] [Indexed: 12/21/2023] Open
Abstract
INTRODUCTION This paper presents a case of a Chinese patient with advanced colon cancer who developed drug-induced interstitial lung disease while undergoing treatment with cetuximab combined with XELOX. PATIENT CONCERNS A 75-year-old man with a history of colon cancer, had metastases in the liver, peritoneum, and lungs, which were initially treated with XELOX and cetuximab (0.4 g) in 2019. However, the lung metastases progressed, and the cetuximab dosage was adjusted to 0.9 g and then readjusted to 0.4 g. DIAGNOSIS In January 2021, computed tomography revealed developed interstitial lung disease, leading to the discontinuation of chemotherapy and cetuximab. INTERVENTIONS Receiving methylprednisolone pulse therapy. OUTCOMES The patient experienced respiratory failure and passed away. The Naranjo Algorithm Assessment score indicated a probable relationship between cetuximab and the adverse event. CONCLUSION This case highlights the need for regular pulmonary imaging examinations during cetuximab therapy, as drug-induced interstitial lung disease may be associated with the dose and duration of treatment.
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Affiliation(s)
- Yanfei Shao
- Department of Pharmacy, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Jieru Hu
- Department of Pharmacy, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical College, Lishui, China
| | - Haibo Yao
- Gastrointestinal Surgery, Zhejiang Provincial People’s Hospital, Hangzhou, China
| | - Menglao Jiang
- Zhejiang Center of Drug and Cosmetics Evaluation, Hangzhou, China
| | - Zhouye Song
- Department of Pharmacy, Zhejiang Hospital, Hangzhou, China
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10
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Cheng X, Zhao F, Ke B, Chen D, Liu F. Harnessing Ferroptosis to Overcome Drug Resistance in Colorectal Cancer: Promising Therapeutic Approaches. Cancers (Basel) 2023; 15:5209. [PMID: 37958383 PMCID: PMC10649072 DOI: 10.3390/cancers15215209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 10/19/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023] Open
Abstract
Drug resistance remains a significant challenge in the treatment of colorectal cancer (CRC). In recent years, the emerging field of ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation, has offered new insights and potential therapeutic strategies for overcoming drug resistance in CRC. This review examines the role of ferroptosis in CRC and its impact on drug resistance. It highlights the distinctive features and advantages of ferroptosis compared to other cell death pathways, such as apoptosis and necrosis. Furthermore, the review discusses current research advances in the field, including novel treatment approaches that target ferroptosis. These approaches involve the use of ferroptosis inducers, interventions in iron metabolism and lipid peroxidation, and combination therapies to enhance the efficacy of ferroptosis. The review also explores the potential of immunotherapy in modulating ferroptosis as a therapeutic strategy. Additionally, it evaluates the strengths and limitations of targeting ferroptosis, such as its selectivity, low side effects, and potential to overcome resistance, as well as challenges related to treatment specificity and drug development. Looking to the future, this review discusses the prospects of ferroptosis-based therapies in CRC, emphasizing the importance of further research to elucidate the interaction between ferroptosis and drug resistance. It proposes future directions for more effective treatment strategies, including the development of new therapeutic approaches, combination therapies, and integration with emerging fields such as precision medicine. In conclusion, harnessing ferroptosis represents a promising avenue for overcoming drug resistance in CRC. Continued research efforts in this field are crucial for optimizing therapeutic outcomes and providing hope for CRC patients.
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Affiliation(s)
- Xiaofei Cheng
- Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; (B.K.); (D.C.)
| | - Feng Zhao
- Department of Radiation Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310030, China;
| | - Bingxin Ke
- Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; (B.K.); (D.C.)
| | - Dong Chen
- Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; (B.K.); (D.C.)
| | - Fanlong Liu
- Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; (B.K.); (D.C.)
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11
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Zekri J, Baghdadi MA, Ibrahim RB, Meliti A, Sobahy TM. Biweekly cetuximab in combination with capecitabine and oxaliplatin (XELOX) or irinotecan (XELIRI) in the first-line and second-line treatment of patients with RAS wild-type metastatic colorectal cancer. Ecancermedicalscience 2022; 16:1490. [PMID: 36819803 PMCID: PMC9934971 DOI: 10.3332/ecancer.2022.1490] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Indexed: 12/23/2022] Open
Abstract
Background Oral capecitabine in combination with intravenous oxaliplatin (XELOX) or irinotecan (XELIRI) are acceptable substitutions to fully intravenous regimens. Biweekly (as opposed to weekly) cetuximab is more convenient when combined with biweekly chemotherapy. Here, we report the tolerability and efficacy of biweekly cetuximab in combination with biweekly XELOX or XELIRI in patients with RAS wild-type metastatic colorectal cancer (RAS-WT mCRC). Methods Clinical data of consecutive patients with mCRC who received biweekly cetuximab (500 mg/m2) in combination with XELOX or XELIRI between January 2009 and May 2019 in the first- or second-line settings was extracted. Dosage of XEL (Capecitabine/XELODA) was 1,000 mg/m2 twice daily for 9 days, plus on day 1 oxaliplatin 85 mg/m2 or irinotecan 180 mg/m2. Treatment dose reduction and delay for ≥7 days was analysed as surrogates for toxicity. Extended RAS testing was performed in the context of this study for patients who received treatment based on limited KRAS-WT genotype. Results Sixty one patients with RAS-WT mCRC fulfilled the eligibility criteria. XELOX was administered to 26 (42.6%) and XELIRI to 35 (57.4%) of patients. For all patients in the first-line setting, the objective response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were 54%, 8 months and 25 months, respectively. The corresponding outcomes for the subgroup of patients who received first-line XELOX were 68%, 10 months and not reached, respectively. For all patients in the second-line setting, the ORR, PFS and OS were 50%, 7 months and 20 months, respectively. Chemotherapy components dose reduction and delays were observed in 18 (29.5%) and 25 (41%) patients, respectively. The corresponding frequencies for cetuximab were 3 (5%) and 31 (50.8%). Conclusion Biweekly cetuximab in combination with XELOX or XELIRI is tolerable and effective. The addition of cetuximab to capecitabine and oxaliplatin is associated with favourable outcome.
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Affiliation(s)
- Jamal Zekri
- College of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia,King Faisal Specialist Hospital & Research Centre (Jeddah), Jeddah 21499, Saudi Arabia
| | - Mohammed Abbas Baghdadi
- Research Centre, King Faisal Specialist Hospital & Research Centre (Jeddah), Jeddah 21499, Saudi Arabia
| | - Refaei Belal Ibrahim
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Al Azhar University, Cairo 11884, Egypt
| | - Abdelrazak Meliti
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Jeddah 21499, Saudi Arabia
| | - Turki M Sobahy
- Research Centre, King Faisal Specialist Hospital & Research Centre (Jeddah), Jeddah 21499, Saudi Arabia
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12
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Hoang T, Sohn DK, Kim BC, Cha Y, Kim J. Efficacy and Safety of Systemic Treatments Among Colorectal Cancer Patients: A Network Meta-Analysis of Randomized Controlled Trials. Front Oncol 2022; 11:756214. [PMID: 35223449 PMCID: PMC8864322 DOI: 10.3389/fonc.2021.756214] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 12/31/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Systemic treatments, namely, either monotherapy or combination therapy, are commonly administered to patients with advanced or metastatic colorectal cancer (CRC). This study aimed to provide the complete efficacy and safety profiles and ranking of systemic therapies for the treatment of unresectable advanced or metastatic CRC. METHODS We searched PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov from inception until June 30, 2021, and also the bibliographies of relevant studies. Randomized controlled trials comparing two or more treatments, namely, at least capecitabine, 5-fluorouracil, leucovorin, irinotecan, bevacizumab, cetuximab, oxaliplatin, or panitumumab were investigated. A network meta-analysis using the Bayesian approach was performed to compare the efficacy and safety of treatments. The surface under the cumulative ranking curve (SUCRA) was calculated for the probability of each treatment as the most effective. The overall response rate (ORR), disease control rate (DCR), overall survival (OS), progression-free survival (PFS), adverse events (AEs) grade ≥3, and serious adverse events (SAEs) were evaluated. RESULTS One hundred two publications with 36,147 participants were assigned to 39 different treatments. Among 11 treatments with full information on six outcomes, FOLFIRI/FOLFOX/FOLFOXIRI + bevacizumab significantly improved both the ORR and DCR, compared to FOLFIRI. Although FOLFOX and FOLFIRI/FOLFOX + cetuximab significantly prolonged both OS and PFS, treatments were comparable in terms of AEs grade ≥3 and SAEs. The top highest SUCRA values were observed in the FOLFOXIRI + panitumumab group for ORR (96%) and DCR (99%), FOLFIRI + bevacizumab + panitumumab group for OS (62%) and PFS (54%), and FOLFOXIRI + bevacizumab group for AEs grade ≥3 (59%) and SAEs (59%) outcomes. CONCLUSIONS These findings suggest an available range of systemic treatment therapies with different efficacy and safety profiles with patients. Further investigations of the side effects and mutation status are required to confirm our findings. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, identifier CRD42019127772.
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Affiliation(s)
- Tung Hoang
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, South Korea
| | - Dae Kyung Sohn
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea
| | - Byung Chang Kim
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea
| | - Yongjun Cha
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, South Korea
| | - Jeongseon Kim
- Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, Goyang, South Korea
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13
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Zhou J, Ji Q, Li Q. Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:328. [PMID: 34663410 PMCID: PMC8522158 DOI: 10.1186/s13046-021-02130-2] [Citation(s) in RCA: 123] [Impact Index Per Article: 30.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 08/22/2021] [Indexed: 12/28/2022]
Abstract
Cetuximab and panitumumab are monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) that are effective agents for metastatic colorectal cancer (mCRC). Cetuximab can prolong survival by 8.2 months in RAS wild-type (WT) mCRC patients. Unfortunately, resistance to targeted therapy impairs clinical use and efficiency. The mechanisms of resistance refer to intrinsic and extrinsic alterations of tumours. Multiple therapeutic strategies have been investigated extensively to overcome resistance to anti-EGFR mAbs. The intrinsic mechanisms include EGFR ligand overexpression, EGFR alteration, RAS/RAF/PI3K gene mutations, ERBB2/MET/IGF-1R activation, metabolic remodelling, microsatellite instability and autophagy. For intrinsic mechanisms, therapies mainly cover the following: new EGFR-targeted inhibitors, a combination of multitargeted inhibitors, and metabolic regulators. In addition, new cytotoxic drugs and small molecule compounds increase the efficiency of cetuximab. Extrinsic alterations mainly disrupt the tumour microenvironment, specifically immune cells, cancer-associated fibroblasts (CAFs) and angiogenesis. The directions include the modification or activation of immune cells and suppression of CAFs and anti-VEGFR agents. In this review, we focus on the mechanisms of resistance to anti-EGFR monoclonal antibodies (anti-EGFR mAbs) and discuss diverse approaches to reverse resistance to this therapy in hopes of identifying more mCRC treatment possibilities.
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Affiliation(s)
- Jing Zhou
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qing Ji
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Qi Li
- Department of Medical Oncology and Cancer Institute, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. .,Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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14
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Jung F, Guidolin K, Lee MHY, Lam-Tin-Cheung K, Zhao G, Doshi S, Chesney T, Englesakis M, Lukovic J, O’Kane G, Quereshy FA, Chadi SA. Interventions and Outcomes for Neoadjuvant Treatment of T4 Colon Cancer: A Scoping Review. Curr Oncol 2021; 28:2065-2078. [PMID: 34072615 PMCID: PMC8261638 DOI: 10.3390/curroncol28030191] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Revised: 05/13/2021] [Accepted: 05/24/2021] [Indexed: 01/27/2023] Open
Abstract
While adjuvant treatment of colon cancers that penetrate the serosa (T4) have been well-established, neoadjuvant strategies have yet to be formally evaluated. Our objective was to perform a scoping review of eligibility criteria, treatment regimens, and primary outcomes for neoadjuvant approaches to T4 colon cancer. A librarian-led, systematic search of MEDLINE, Embase, Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Primary research evaluating neoadjuvant treatment in T4 colon cancer were included. Screening and data abstraction were performed in duplicate; analyses were descriptive or thematic. A total of twenty studies were included, most of which were single-arm, single-center, and retrospective. The primary objectives of the literature to date has been to evaluate treatment feasibility, tumor response, disease-free survival, and overall survival in healthy patients. Conventional XELOX and FOLFOX chemotherapy were the most commonly administered interventions. Rationale for selecting a specific regimen and for treatment eligibility criteria were poorly documented across studies. The current literature on neoadjuvant strategies for T4 colon cancer is overrepresented by single-center, retrospective studies that evaluate treatment feasibility and efficacy in healthy patients. Future studies should prioritize evaluating clear selection criteria and rationale for specific neoadjuvant strategies. Validation of outcomes in multi-center, randomized trials for XELOX and FOLFOX have the most to contribute to the growing evidence for this poorly managed disease.
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Affiliation(s)
- Flora Jung
- Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (F.J.); (M.H.-Y.L.); (G.Z.)
| | - Keegan Guidolin
- Department of Surgery, University of Toronto, Toronto, ON M5T1P5, Canada; (K.G.); (K.L.-T.-C.); (S.D.); (T.C.); (F.A.Q.)
| | - Michael Ho-Yan Lee
- Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (F.J.); (M.H.-Y.L.); (G.Z.)
| | - Kimberley Lam-Tin-Cheung
- Department of Surgery, University of Toronto, Toronto, ON M5T1P5, Canada; (K.G.); (K.L.-T.-C.); (S.D.); (T.C.); (F.A.Q.)
| | - Grace Zhao
- Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (F.J.); (M.H.-Y.L.); (G.Z.)
| | - Sachin Doshi
- Department of Surgery, University of Toronto, Toronto, ON M5T1P5, Canada; (K.G.); (K.L.-T.-C.); (S.D.); (T.C.); (F.A.Q.)
| | - Tyler Chesney
- Department of Surgery, University of Toronto, Toronto, ON M5T1P5, Canada; (K.G.); (K.L.-T.-C.); (S.D.); (T.C.); (F.A.Q.)
- Department of Surgery, St. Michael’s Hospital, Toronto, ON M5B 1W8, Canada
| | - Marina Englesakis
- Library and Information Services, University Health Network, Toronto, ON M5G 2C4, Canada;
| | - Jelena Lukovic
- Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON M5G 2C1, Canada;
- Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada
| | - Grainne O’Kane
- Princess Margaret Cancer Centre, Division of Medical Oncology, Toronto, ON M5G 2C1, Canada
| | - Fayez A. Quereshy
- Department of Surgery, University of Toronto, Toronto, ON M5T1P5, Canada; (K.G.); (K.L.-T.-C.); (S.D.); (T.C.); (F.A.Q.)
- Princess Margaret Cancer Centre, Division of Surgical Oncology, University Health Network, Toronto, ON M5G 2C1, Canada
| | - Sami A. Chadi
- Department of Surgery, University of Toronto, Toronto, ON M5T1P5, Canada; (K.G.); (K.L.-T.-C.); (S.D.); (T.C.); (F.A.Q.)
- Princess Margaret Cancer Centre, Division of Surgical Oncology, University Health Network, Toronto, ON M5G 2C1, Canada
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15
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Deng X, Hou J, Deng Q, Zhong Z. Predictive value of clinical toxicities of chemotherapy with fluoropyrimidines and oxaliplatin in colorectal cancer by DPYD and GSTP1 gene polymorphisms. World J Surg Oncol 2020; 18:321. [PMID: 33280607 PMCID: PMC7720377 DOI: 10.1186/s12957-020-02103-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/30/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Fluoropyrimidines and platinum are still widely used for colorectal cancer (CRC) management. Several studies have reported that mutations of dihydropyrimidine dehydrogenase (DPYD) and glutathione S-transferase pi-1 (GSTP1) polymorphisms are related to chemotherapy-related adverse events. In the present study, we purposed to assess the impact of DPYD and GSTP1 variants on the toxicity of adjuvant chemotherapy risk among the Hakka population, minimize adverse events, and to maximize therapy outcome for individualized treatment. METHODS Genotyping was examined in 104 patients diagnosed with CRC cases and receiving fluoropyrimidine and platinum drug-based chemotherapy regimen by direct sequencing of DPYD and GSTP1 polymorphisms. Three DPYD variants including *2A, *5A, *9A, and GSTP1 c.313A>G were analyzed and clinical outcomes were assessed. RESULTS The data suggest that the incidence of DPYD*5A, DPYD*9A, and GSTP1 c.313A>G variants were 38.4%, 24%, and 32.7%, respectively. DPYD*2A variant was not found. A total of 23 patients (22.1%) suffered severe vomiting and 19 patients (18.3%) suffered severe anemia. DPYD*5A polymorphism was found significantly associated with grade 3/4 ulceration (p = 0.001). GSTP1 was determined to be an independent risk factor for severe vomiting and skin ulceration (p = 0.042 and p = 0.018, respectively). Patients with GSTP1 c. 313A>G mutant type contributed to a higher risk for grade severe toxicity compared with wild genotype (p = 0.027). Nevertheless, no significant difference was found between patients with DPYD*2A, *5A, and *9A for chemotherapeutic toxicity. CONCLUSIONS The results demonstrated that GSTP1 polymorphisms were useful predictors of severe events. Screening of single-nucleotide polymorphisms of GSTP1 in colorectal cancer patients before chemotherapy may help to realize personalized therapy.
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Affiliation(s)
- Xunwei Deng
- Department of Research Experimental Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, People's Republic of China
| | - Jingyuan Hou
- Department of Research Experimental Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, People's Republic of China
| | - Qiaoting Deng
- Department of Research Experimental Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, People's Republic of China
| | - Zhixiong Zhong
- Department of Research Experimental Center, Meizhou People's Hospital (Huangtang Hospital), Meizhou Hospital Affiliated to Sun Yat-Sen University, No. 63 Huangtang Road, Meijiang District, Meizhou, 514031, People's Republic of China.
- Guangdong Provincial Key Laboratory of Precision Medicine and Clinical Translational Research of Hakka Population, Meizhou, People's Republic of China.
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16
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Li R, Liang M, Liang X, Yang L, Su M, Lai KP. Chemotherapeutic Effectiveness of Combining Cetuximab for Metastatic Colorectal Cancer Treatment: A System Review and Meta-Analysis. Front Oncol 2020; 10:868. [PMID: 32547954 PMCID: PMC7270202 DOI: 10.3389/fonc.2020.00868] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 05/04/2020] [Indexed: 12/28/2022] Open
Abstract
This meta-analysis used the database including PubMed, Medline, Cochrane Library, CNKI, Chinese-Cqvip, and Wanfang for randomized controlled trials (RCTs) to investigate the clinical effectiveness for combining cetuximab treatment with chemotherapy for treating metastatic colorectal cancer (mCRC). A total of 12 RCTs involved 7,108 patients with mCRC were included. The patients received chemotherapy with (3,521 cases) or without cetuximab (3,587 cases). Outcomes were overall survival (OS), progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), odd ratio (OR), and risk ratio (HR). Our results showed that the chemotherapy alone group has shorter OS, PFS, and ORR than the chemotherapy plus cetuximab group, with significant differences (PFS:HR = 0.77, 95% CI = 0.72–0.82, P < 0.00001; OS:HR = 0.88, 95% CI = 0.79–0.99, P = 0.03; ORR:OR = 1.79, 95% CI = 1.30–2.47; P = 0.0003). Results of subgroup analysis showed that cetuximab treatment prolonged PFS and OS in KRAS wild-type patients, with statistically significant differences (PFS:HR = 0.79, 95% CI = 0.65–0.95, P = 0.01; OS:HR = 0.85, 95% CI = 0.74–0.98, P = 0.02). Combining cetuximab with chemotherapy, the PFS and OS of wild-type KRAS patients and the ORR of all patients were significantly improved.
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Affiliation(s)
- Rong Li
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Minqing Liang
- Department of Pharmacy, Guigang City People's Hospital, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang, China
| | - Xiao Liang
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Lu Yang
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Min Su
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China
| | - Keng Po Lai
- Guangxi Key Laboratory of Tumor Immunology and Microenvironmental Regulation, Guilin Medical University, Guilin, China.,Department of Chemistry, City University of Hong Kong, Hong Kong, China
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17
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The Role of Serum CEA and CA19-9 in Efficacy Evaluations and Progression-Free Survival Predictions for Patients Treated with Cetuximab Combined with FOLFOX4 or FOLFIRI as a First-Line Treatment for Advanced Colorectal Cancer. DISEASE MARKERS 2019; 2019:6812045. [PMID: 30805037 PMCID: PMC6360556 DOI: 10.1155/2019/6812045] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/21/2018] [Accepted: 11/01/2018] [Indexed: 12/21/2022]
Abstract
Background Previously, it was demonstrated that serum levels of tumor markers, CEA and CA19-9, correlated with chemotherapy. Consequently, it has been hypothesized that dynamic monitoring of changes in these markers may predict the shrinkage or growth of colorectal cancers. To test this hypothesis, we analyzed CEA and CA19-9 serum levels in patients with advanced colorectal cancer who received cetuximab in combination with chemotherapy. These levels were evaluated at various time points to identify their potential to serve as early efficacy predictors during treatment and early predictors of disease progression. Patients and Methods Measurements of tumor markers, CEA and CA 19-9, in patients with metastatic colorectal cancer (n = 73) who received cetuximab plus folinic acid, fluorouracil, and oxaliplatin or irinotecan (FOLFOX4/FOLFIRI) as a first-line treatment at our center were retrospectively analyzed. These levels were also compared with objective responses according to the World Health Organization criteria. Initially, 65 patients had elevated CEA levels (>5 ng/ml), and 59 patients had elevated levels of CA19-9 (>37 U/ml). A total of 172 cycles and 165 cycles of computed tomography/magnetic resonance imaging observations were available for review from these two patient groups. Results After completing three cycles of treatment, the best diagnosis of cetuximab resistance was achieved when CEA increased by 35% (efficacy, 83.33%; sensitivity, 75.41%) and when CA19-9 increased by 28% (efficacy, 80.00%; sensitivity, 84.31%). Next, the efficacy of cetuximab at the time of diagnosis (at the first imaging examination/after three cycles of treatment) was evaluated after the first cycle of chemotherapy. When CEA decreased by 60% from its baseline level, the best effective rate and sensitivity were observed (63.64% and 80.95%, respectively). Similarly, when CA19-9 was 45% lower than its baseline level, the best effective rate and sensitivity were observed (84.21% and 93.18%, respectively). To evaluate progression-free survival (PFS), levels of both CEA and CA19-9 were evaluated after the third cycle of chemotherapy. Increases of 35% and 28%, respectively, resulted in a shorter PFS period compared with the other patients (3.15 months vs. 9.10 months, respectively; P < 0.0001). Conversely, when the evaluation was performed after the first cycle of chemotherapy, patients exhibiting a 60% decrease in CEA and a 45% decrease in CA19-9 had a longer PFS period (11.13 months vs. 8.10 months, respectively; P = 0.0395). Conclusions CEA and CA19-9 are useful indicators of therapeutic curative effect from cetuximab combined with first-line chemotherapy. These markers also helped assess cetuximab resistance and served as early predictors of initial treatment effectiveness. Furthermore, a simultaneous increase or decrease in the levels of both indicators was consistent with the observed differences in PFS.
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18
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Papaxoinis G, Kotoula V, Giannoulatou E, Koliou GA, Karavasilis V, Lakis S, Koureas A, Bobos M, Chalaralambous E, Daskalaki E, Chatzopoulos K, Tsironis G, Pazarli E, Chrisafi S, Samantas E, Kaklamanos IG, Varthalitis I, Konstantara A, Syrigos KN, Pentheroudakis G, Pectasides D, Fountzilas G. Phase II study of panitumumab combined with capecitabine and oxaliplatin as first-line treatment in metastatic colorectal cancer patients: clinical results including extended tumor genotyping. Med Oncol 2018; 35:101. [PMID: 29855806 DOI: 10.1007/s12032-018-1160-1] [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] [Received: 05/14/2018] [Accepted: 05/27/2018] [Indexed: 12/12/2022]
Abstract
This clinical trial assessed the efficacy and toxicity of panitumumab combined with oxaliplatin and capecitabine as first-line treatment in KRAS exon 2 wild-type metastatic colorectal cancer (mCRC) patients. Patients with exon 2 KRAS wild-type mCRC received panitumumab 9 mg/Kg, oxaliplatin 130 mg/m2, and capecitabine 2000 mg/m2 repeated every 3 weeks. The primary endpoint was objective response rate (ORR, minimum 42 responses). We retrospectively assessed mutations in genes implicated in CRC with massively parallel sequencing; ERBB2 and EGFR amplification with fluorescence in situ hybridization, and tumor-infiltrating lymphocyte density. Among 78 patients enrolled, 45 (57.7%) completed 6 cycles. Most common grade 3-4 toxicities were skin rash (19.2%), diarrhea (18%), and neuropathy (6.4%). Among 5 (6.4%) potentially treatment-related deaths, 2 (2.6%) were characterized toxic. Objective response occurred in 43 (55.1%) of the patients (complete 6.4% and partial response 48.7%; stable 17.9% and progressive disease 7.7%), while 3.8% were non-evaluable and 15% discontinued their treatment early. Additional mutations in KRAS/NRAS/BRAF were found in 11/62 assessable (18%) tumors. After 51 months median follow-up, median progression-free (PFS) was 8.1 and overall survival 20.2 months, independently of KRAS/NRAS/BRAF or PI3K-pathway mutation status. Patients with TP53 mutations (n = 34; 55%), as well as those with left colon primary tumors (n = 66; 85%), had significantly better PFS, also confirmed in multivariate analysis. Although the clinical trial met its primary endpoint, according to the current standards, the efficacy and tolerability of the drug combination are considered insufficient. Extended genotyping yielded interesting results regarding the significance of TP53 mutations.ClinicalTrials.gov identifier: NCT01215539, Registration date: Sep 29, 2010.
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Affiliation(s)
- George Papaxoinis
- Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527, Athens, Greece.
| | - Vassiliki Kotoula
- Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.,Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Eleni Giannoulatou
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.,The University of New South Wales, Kensington, NSW, Australia
| | | | - Vasilios Karavasilis
- Department of Medical Oncology, Faculty of Medicine, School of Health Sciences, Papageorgiou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Sotirios Lakis
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Andreas Koureas
- Department of Radiology, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Mattheos Bobos
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Elpida Chalaralambous
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Emily Daskalaki
- Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kyriakos Chatzopoulos
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - George Tsironis
- Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
| | - Elisavet Pazarli
- Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Sofia Chrisafi
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Epaminontas Samantas
- Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece
| | - Ioannis G Kaklamanos
- Department of Surgery, School of Health Sciences, General Oncologic Hospital of Kifisia, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | - Konstantinos N Syrigos
- Oncology Unit GPP, Sotiria General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece
| | | | - Dimitrios Pectasides
- Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 11527, Athens, Greece
| | - George Fountzilas
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.,Aristotle University of Thessaloniki, Thessaloniki, Greece
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Bogach J, Levine O, Parpia S, Valencia M, Ruo L, Serrano P. Does the Addition of Biologic Agents to Chemotherapy in Patients with Unresectable Colorectal Cancer Metastases Result in a Higher Proportion of Patients Undergoing Resection? A Systematic Review and Meta-analysis. J Gastrointest Surg 2018; 22:523-528. [PMID: 29204907 DOI: 10.1007/s11605-017-3640-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 11/13/2017] [Indexed: 01/31/2023]
Abstract
BACKGROUND Surgical resection provides the best opportunity for cure for metastatic colorectal cancer. Whether addition of a biologic agent to chemotherapy improves the rate of conversion from unresectable to resectable disease remains uncertain. We carried out a systematic review of the literature and meta-analysis to define the impact of biologic agents on resection. METHODS We searched Medline, Embase, CENTRAL, and PubMed for randomized controlled trials published up until April 2017 comparing chemotherapy and biologics (intervention) vs. chemotherapy alone (control) in treatment-naïve patients with unresectable metastatic colorectal cancer. Study selection, data abstraction, risk of bias, and quality of evidence assessment were performed in duplicate. Random-effects meta-analysis was used to estimate the pooled odds ratio (OR) for resection rate and corresponding confidence interval (CI). RESULTS Nine studies, including a total of 4345 patients, were analyzed. Seven studies assessed epithelial growth factor receptor (EGFR)-directed monoclonal antibodies, and two used antiangiogenic agents. The addition of a biologic agent to chemotherapy was associated with higher resection rate (OR 1.47, 95% CI 1.07-2.02; resection rate 8.4 vs. 6.1%). Subgroup analysis based on mechanism of action of drugs showed benefit for resection rate only with EGFR-directed agents (OR 1.70, 95% CI 1.10-2.64). Heterogeneity among studies was low (I 2 = 34%). CONCLUSIONS The addition of biologic agents to systemic chemotherapy in patients with initially unresectable metastatic colorectal cancer improved resection rate. The optimal biologic agent for this outcome cannot yet be determined.
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Affiliation(s)
- Jessica Bogach
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Oren Levine
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - Sameer Parpia
- Department of Oncology, McMaster University, Hamilton, ON, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
- Ontario Clinical Oncology Group, Juravinski Hospital, B3, Rm. 161, 711 Concession St., Hamilton, ON, L8V 1C3, Canada
| | - Marlie Valencia
- Department of Surgery, McMaster University, Hamilton, ON, Canada
| | - Leyo Ruo
- Department of Surgery, McMaster University, Hamilton, ON, Canada
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | - Pablo Serrano
- Department of Surgery, McMaster University, Hamilton, ON, Canada.
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
- Ontario Clinical Oncology Group, Juravinski Hospital, B3, Rm. 161, 711 Concession St., Hamilton, ON, L8V 1C3, Canada.
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Chen D, Li L, Zhang X, Gao G, Shen L, Hu J, Yang M, Liu B, Qian X. FOLFOX plus anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) is an effective first-line treatment for patients with RAS-wild left-sided metastatic colorectal cancer: A meta-analysis. Medicine (Baltimore) 2018; 97:e0097. [PMID: 29517682 PMCID: PMC5882422 DOI: 10.1097/md.0000000000010097] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The efficacy of oxaliplatin-based chemotherapy combined with anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) remains controversial in metastatic colorectal cancer (mCRC). This meta-analysis aims to estimate the effect of adding panitumumab or cetuximab to oxaliplatin-based chemotherapy in RAS wild type mCRC patients for the first-line treatment. The primary tumor location is also considered into this meta-analysis. METHODS RCT studies were identified by a search of MEDLINE, EMBASE, Cochrane library to October 2017, supplemented by manually retrieving ASCO, ESMO conference abstracts. The pooled hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS), and pooled odds ratios (OR) for the overall response rate (ORR) were calculated by Review Manager 5.3. RESULTS The results indicated that the addition of anti-EGFR mAbs to FOLFOX regimen in RAS wild-type mCRC patients for the first-line treatment resulted in considerable improvements in PFS (HR = 0.70; 95% confidence interval [CI]: 0.59-0.82; P < .0001), OS (HR = 0.79; 95%CI: 0.67-0.92; P = .003), and ORR (OR = 2.56; 95% CI: 1.77-3.70; P < .00001) compared with chemotherapy alone. However, in RAS/BRAF wild patients, no significant differences were observed when anti-EGFR mAb was added to FLOX or XELOX regimen compared with chemotherapy alone with regard to OS and PFS, whereas FOLFOX+anti-EGFR mAb showed a marked superior OS and PFS (OS, HR = 0.77; 95% CI: 0.61-0.98; P = .03; PFS, HR = 0.68; 95% CI: 0.57-0.82; P < .00001). A meta-analysis including TAILOR and PRIME study suggests that primary tumor location (PTL) predicted a survival benefit when adding the EGFR antibody to FOLFOX regimen in RAS-wild mCRC patients (OS, HR for left-sided: 0.71; 95% CI: 0.59-0.85; P = .0002 and HR for right-sided: 0.90; 95% CI: 0.65-1.25; P = .53). However, the HR for PFS and ORR still suggests a benefit from the addition of anti-EGFR mAb in right-sided mCRC patients. CONCLUSION So these results suggest anti-EGFR mAb and oxaliplatin are good partners in the FOLFOX regimen. The addition of EGFR antibody to FOLFOX markedly improved efficacy in RAS-wild patients with left-sided mCRC. In RAS/BRAF-wild patients, the efficacy is similar. For patients with right-sided tumor, a benefit showing a trendency in favor of anti-EGFR mAb can still seen. The molecular characteristics behind the tumor location need to be more explored urgently.
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Affiliation(s)
- Datian Chen
- Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University
- Department of Oncology, Haimen People's Hospital, Haimen
| | - Li Li
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Xiang Zhang
- Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University
| | - Guangyi Gao
- The Comprehensive Cancer Center, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lili Shen
- Department of Oncology, Haimen People's Hospital, Haimen
| | - Jing Hu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Mi Yang
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Baorui Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
| | - Xiaoping Qian
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University
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Wang J, Luo L, Wang D, Guo B, Li J, Yang Z, Tang D. Combination adjuvant chemotherapy with targeted drugs for treatment of colorectal cancer: A network meta-analysis. J Cell Biochem 2018; 119:1521-1537. [PMID: 28771807 DOI: 10.1002/jcb.26312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Accepted: 08/02/2017] [Indexed: 01/10/2023]
Abstract
Colorectal cancer (CRC) is one of the most fatal diseases in the world. The efficacy of present chemotherapy treatments are limited and the addition of targeted drugs have been put into practice. However, the preferred treatments among adjuvant chemotherapies still remain controversial and uncertain. To evaluate the efficacy of different adjuvant chemotherapies combined with or without targeted drugs to determine the optimal treatment for patients with CRC in clinical practice. PubMed and Embase were searched for eligible articles and only randomized controlled trials (RCTs) were included. R (Version 3.2.5) software was utilized to conduct the Bayesian network meta-analysis (NMA). Outcomes including overall survival (OS) and progression-free survival (PFS) were displayed using hazard ratios. And the rank probabilities of each treatment were evaluated using the surface under cumulative ranking curve. A total of 75 RCTs published after 1997 were included in the data analysis. Overall, FOLFIRI+ cetuximab was found to be the most effective treatment in terms of long-term survival and FOLFOX was the most effective pure chemotherapy treatment. The addition of targeted drugs will greatly improve the efficacy of chemotherapy. Targeted drug cetuximab combined with the chemotherapy regiment FOLFIRI is the preferable treatment for patients with CRC in clinical practice.
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Affiliation(s)
- Jinghui Wang
- Department of Oncological Hematology, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Li Luo
- Department of Oncological Hematology, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Dingxue Wang
- Department of Oncological Hematology, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Bin Guo
- Graduate College of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Jun Li
- College of Basic Medicine of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Zhu Yang
- Deanery of Guiyang College of TCM, Guiyang, Guizhou, China
| | - Dongxin Tang
- Department of Science and Education, First Affiliated Hospital of Guiyang College of TCM, Guiyang, Guizhou, China
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22
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Koch C, Schwing AM, Herrmann E, Borner M, Diaz-Rubio E, Dotan E, Feliu J, Okita N, Souglakos J, Arkenau HT, Porschen R, Koopman M, Punt CJA, de Gramont A, Tournigand C, Zeuzem S, Trojan J. Bevacizumab-based first-line chemotherapy in elderly patients with metastatic colorectal cancer: an individual patient data based meta-analysis. Oncotarget 2017. [PMID: 29535805 PMCID: PMC5828201 DOI: 10.18632/oncotarget.23475] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background The aim of this meta-analysis was to evaluate efficacy and safety of first-line chemotherapy with or without a monoclonal antibody in elderly patients (≥ 70 years) with metastatic colorectal cancer (mCRC), since they are frequently underrepresented in clinical trials. Results Individual data from 10 studies were included. From a total of 3271 patients, 604 patients (18%) were ≥ 70 years (median 73 years, range 70-88). Of these, 335 patients were treated with a bevacizumab-based first-line regimen and 265 were treated with chemotherapy only. The median PFS was 8.2 vs. 6.5 months and the median OS was 16.7 vs. 13.0 months in patients treated with and without bevacizumab, respectively. The safety profile of bevacizumab in combination with first-line chemotherapy did not differ from published clinical trials. Materials and Methods PubMed and Cochrane Library searches were performed on 29 April 2013 and studies published to this date were included. Authors were contacted to request progression-free survival (PFS), overall survival (OS) data, patient data on treatment regimens, age, sex and potential signs of toxicity in patients ≥ 70 years of age. Conclusions This meta-analysis suggests that the addition of bevacizumab to standard first-line chemotherapy improves clinical outcome in elderly patients with mCRC and is well tolerated.
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Affiliation(s)
- Christine Koch
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Anna M Schwing
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Eva Herrmann
- Institute of Biostatistics and Mathematical Modelling, Johann Wolfgang Goethe-University, Frankfurt, Germany
| | - Markus Borner
- Medical Oncology Institute, Inselspital, Bern, Switzerland
| | | | - Efrat Dotan
- Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jaime Feliu
- Department of Medical Oncology, La Paz University Hospital, CIBERONC, Madrid, Spain
| | | | - John Souglakos
- Department of Medical Oncology, University Hospital of Heraklion, University of Crete, Crete, Greece
| | | | | | - Miriam Koopman
- Department of Medical Oncology, University Medical Centre, Utrecht, The Netherlands
| | - Cornelis J A Punt
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | | | | | - Stefan Zeuzem
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
| | - Joerg Trojan
- Department of Gastroenterology, University Liver and Cancer Centre, Frankfurt, Germany
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23
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Risk of fatigue in cancer patients receiving anti-EGFR monoclonal antibodies: results from a systematic review and meta-analysis of randomized controlled trial. Int J Clin Oncol 2017; 23:389-399. [PMID: 29181651 DOI: 10.1007/s10147-017-1218-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 11/18/2017] [Indexed: 10/18/2022]
Abstract
BACKGROUND To evaluate the association between fatigue and anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR MAbs), we conducted the first meta-analysis to access the incidence and risk of fatigue associated with anti-EGFR MAbs. METHODS Electronic databases were searched for randomized controlled trials (RCTs) published up to February 2017. Eligible studies were selected according to PRISMA statement. Incidence rates, risk ratio (RRs), and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models. Outcomes of quality were summarized in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology. RESULTS Thirty-five RCTs (including 15,622 patients) were included; median follow-up ranged from 8.1 to 71.4 months, and the fatigue events were recorded and graded according to the Common Toxicity Criteria for Adverse Events version 2.0 or 3.0 in most of the included trials. For patients receiving anti-EGFR MAbs, the overall incidence of all-grade and high-grade fatigue was 54.1% and 10.5%, respectively. Compared with control, anti-EGFR MAbs significantly increased the risk of all-grade fatigue (RR 1.10, 95% CI, 1.05-1.14, moderate-quality evidence) and high-grade fatigue (RR 1.31, 95% CI, 1.19-1.45, moderate-quality evidence). No significant differences among subgroup analyses (anti-EGFR MAbs, tumor type, and median follow-up) on high-grade fatigue were observed. No evidence of publication bias was observed. CONCLUSION The present study suggested that anti-EGFR MAbs may increase the risk of fatigue in cancer patients.
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24
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Pak LM, Kemeny NE, Capanu M, Chou JF, Boucher T, Cercek A, Balachandran VP, Kingham TP, Allen PJ, DeMatteo RP, Jarnagin WR, D'Angelica MI. Prospective phase II trial of combination hepatic artery infusion and systemic chemotherapy for unresectable colorectal liver metastases: Long term results and curative potential. J Surg Oncol 2017; 117:634-643. [PMID: 29165816 DOI: 10.1002/jso.24898] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 10/09/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND/OBJECTIVES Combination hepatic artery infusion (HAI) and systemic (SYS) chemotherapy for unresectable CRLM results in high tumor-response rates. This study represents an update of long-term survival and conversion to resectability in patients with unresectable CRLM treated with HAI and SYS chemotherapy in a phase II study. METHOD The primary endpoint was complete resection. Multivariate and landmark analysis assessed the effect of complete resection on progression-free (PFS) and overall survival (OS). RESULTS From 2007 to 2012, 64 patients with median of 13 tumors were enrolled; 67% had prior chemotherapy. 33 patients (52%) were converted to resection. Median follow-up among survivors was 81 months. Median PFS and OS were 13 and 38 months, respectively, with 5-year-OS of 36%. Chemotherapy-naïve patients had 5-year-OS of 51%. Conversion to resection was the only independent factor prognostic of improved PFS and OS. Nine of 64 patients (14%) are NED (five since initial resection, three after resection of recurrent disease, one from chemotherapy alone) at median follow-up of 86 months from treatment initiation, and 72 months from last operative intervention. CONCLUSION Combination HAI and SYS is an effective therapy for high-volume unresectable CRLM, resulting in a high rate of resection, long-term survival, and the potential for cure.
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Affiliation(s)
- Linda M Pak
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nancy E Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Marinela Capanu
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanne F Chou
- Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Taryn Boucher
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vinod P Balachandran
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - T Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter J Allen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael I D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
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25
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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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Chan DLH, Segelov E, Wong RS, Smith A, Herbertson RA, Li BT, Tebbutt N, Price T, Pavlakis N. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. THE COCHRANE DATABASE OF SYSTEMATIC REVIEWS 2017. [PMID: 28654140 DOI: 10.1002/14651858.cd007047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity. OBJECTIVES To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents.The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed. SELECTION CRITERIA We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and standard therapy to another EGFR inhibitor (or the same inhibitor with a different dosing regimen) and standard therapy, or 4) the combination of EGFR inhibitor (whether MAb or TKI), anti-angiogenic therapy, and standard therapy to anti-angiogenic therapy and standard therapy alone. DATA COLLECTION AND ANALYSIS We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Subgroup analyses were performed by Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) status - firstly by status of KRAS exon 2 testing (mutant or wild type) and also by status of extended KRAS/NRAS testing (any mutation present or wild type). MAIN RESULTS We identified 33 randomised controlled trials for analysis (15,025 participants), including trials of both EGFR MAb and EGFR TKI. Looking across studies, significant risk of bias was present, particularly with regard to the risk of selection bias (15/33 unclear risk, 1/33 high risk), performance bias (9/33 unclear risk, 9/33 high risk), and detection bias (7/33 unclear risk, 11/33 high risk).The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression-free survival (HR 0.70, 95% CI 0.60 to 0.82; high-quality evidence), overall survival (HR 0.88, 95% CI 0.80 to 0.98; high-quality evidence), and response rate (OR 2.41, 95% CI 1.70 to 3.41; high-quality evidence). We noted evidence of significant statistical heterogeneity in all three of these analyses (progression-free survival: I2 = 76%; overall survival: I2 = 40%; and response rate: I2 = 77%), likely due to pooling of studies investigating EGFR MAb use in different lines of therapy. Rates of overall grade 3 to 4 toxicity, diarrhoea, and rash were increased (moderate-quality evidence for all three outcomes), but there was no evidence for increased rates of neutropenia.For the extended RAS wild-type population (no mutations in KRAS or NRAS), addition of EGFR MAb improved progression-free survival (HR 0.60, 95% CI 0.48 to 0.75; moderate-quality evidence) and overall survival (HR 0.77, 95% CI 0.67 to 0.88; high-quality evidence). Response rate was also improved (OR 4.28, 95% CI 2.61 to 7.03; moderate-quality evidence). We noted significant statistical heterogeneity in the progression-free survival analysis (I2 = 61%), likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies.We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab, in progression-free survival (HR 1.02, 95% CI 0.93 to 1.12; high quality evidence) or overall survival (HR 0.84, 95% CI 0.70 to 1.01; moderate-quality evidence). We noted significant statistical heterogeneity in the overall survival analysis (I2 = 51%), likely due to the pooling of first-line and second-line studies.The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets (meta-analysis not performed). The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival (HR 1.04, 95% CI 0.83 to 1.29; very low quality evidence), overall survival (HR 1.00, 95% CI 0.69 to 1.47; low-quality evidence), or response rate (OR 1.20, 95% CI 0.67 to 2.12; very low-quality evidence) but increased toxicity (OR 2.57, 95% CI 1.45 to 4.57; low-quality evidence). We noted significant between-study heterogeneity in most analyses.Scant information on quality of life was reported in the identified studies. AUTHORS' CONCLUSIONS The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data.
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Affiliation(s)
- David Lok Hang Chan
- Department of Medical Oncology, Royal North Shore Hospital, St Leonards, New South Wales, Australia, 2065
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Chan DLH, Segelov E, Wong RSH, Smith A, Herbertson RA, Li BT, Tebbutt N, Price T, Pavlakis N. Epidermal growth factor receptor (EGFR) inhibitors for metastatic colorectal cancer. Cochrane Database Syst Rev 2017; 6:CD007047. [PMID: 28654140 PMCID: PMC6481896 DOI: 10.1002/14651858.cd007047.pub2] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) inhibitors prevent cell growth and have shown benefit in the treatment of metastatic colorectal cancer, whether used as single agents or in combination with chemotherapy. Clear benefit has been shown in trials of EGFR monoclonal antibodies (EGFR MAb) but not EGFR tyrosine kinase inhibitors (EGFR TKI). However, there is ongoing debate as to which patient populations gain maximum benefit from EGFR inhibition and where they should be used in the metastatic colorectal cancer treatment paradigm to maximise efficacy and minimise toxicity. OBJECTIVES To determine the efficacy, safety profile, and potential harms of EGFR inhibitors in the treatment of people with metastatic colorectal cancer when given alone, in combination with chemotherapy, or with other biological agents.The primary outcome of interest was progression-free survival; secondary outcomes included overall survival, tumour response rate, quality of life, and adverse events. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, Issue 9, 2016; Ovid MEDLINE (from 1950); and Ovid Embase (from 1974) on 9 September 2016; and ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) on 14 March 2017. We also searched proceedings from the major oncology conferences ESMO, ASCO, and ASCO GI from 2012 to December 2016. We further scanned reference lists from eligible publications and contacted corresponding authors for trials for further information where needed. SELECTION CRITERIA We included randomised controlled trials on participants with metastatic colorectal cancer comparing: 1) the combination of EGFR MAb and 'standard therapy' (whether chemotherapy or best supportive care) to standard therapy alone, 2) the combination of EGFR TKI and standard therapy to standard therapy alone, 3) the combination of EGFR inhibitor (whether MAb or TKI) and standard therapy to another EGFR inhibitor (or the same inhibitor with a different dosing regimen) and standard therapy, or 4) the combination of EGFR inhibitor (whether MAb or TKI), anti-angiogenic therapy, and standard therapy to anti-angiogenic therapy and standard therapy alone. DATA COLLECTION AND ANALYSIS We used standard methodological procedures defined by Cochrane. Summary statistics for the endpoints used hazard ratios (HR) with 95% confidence intervals (CI) for overall survival and progression-free survival, and odds ratios (OR) for response rate (RR) and toxicity. Subgroup analyses were performed by Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral (V-Ras) oncogene homolog (NRAS) status - firstly by status of KRAS exon 2 testing (mutant or wild type) and also by status of extended KRAS/NRAS testing (any mutation present or wild type). MAIN RESULTS We identified 33 randomised controlled trials for analysis (15,025 participants), including trials of both EGFR MAb and EGFR TKI. Looking across studies, significant risk of bias was present, particularly with regard to the risk of selection bias (15/33 unclear risk, 1/33 high risk), performance bias (9/33 unclear risk, 9/33 high risk), and detection bias (7/33 unclear risk, 11/33 high risk).The addition of EGFR MAb to standard therapy in the KRAS exon 2 wild-type population improves progression-free survival (HR 0.70, 95% CI 0.60 to 0.82; high-quality evidence), overall survival (HR 0.88, 95% CI 0.80 to 0.98; high-quality evidence), and response rate (OR 2.41, 95% CI 1.70 to 3.41; high-quality evidence). We noted evidence of significant statistical heterogeneity in all three of these analyses (progression-free survival: I2 = 76%; overall survival: I2 = 40%; and response rate: I2 = 77%), likely due to pooling of studies investigating EGFR MAb use in different lines of therapy. Rates of overall grade 3 to 4 toxicity, diarrhoea, and rash were increased (moderate-quality evidence for all three outcomes), but there was no evidence for increased rates of neutropenia.For the extended RAS wild-type population (no mutations in KRAS or NRAS), addition of EGFR MAb improved progression-free survival (HR 0.60, 95% CI 0.48 to 0.75; moderate-quality evidence) and overall survival (HR 0.77, 95% CI 0.67 to 0.88; high-quality evidence). Response rate was also improved (OR 4.28, 95% CI 2.61 to 7.03; moderate-quality evidence). We noted significant statistical heterogeneity in the progression-free survival analysis (I2 = 61%), likely due to the pooling of studies combining EGFR MAb with chemotherapy with monotherapy studies.We observed no evidence of a statistically significant difference when EGFR MAb was compared to bevacizumab, in progression-free survival (HR 1.02, 95% CI 0.93 to 1.12; high quality evidence) or overall survival (HR 0.84, 95% CI 0.70 to 1.01; moderate-quality evidence). We noted significant statistical heterogeneity in the overall survival analysis (I2 = 51%), likely due to the pooling of first-line and second-line studies.The addition of EGFR TKI to standard therapy in molecularly unselected participants did not show benefit in limited data sets (meta-analysis not performed). The addition of EGFR MAb to bevacizumab plus chemotherapy in people with KRAS exon 2 wild-type metastatic colorectal cancer did not improve progression-free survival (HR 1.04, 95% CI 0.83 to 1.29; very low quality evidence), overall survival (HR 1.00, 95% CI 0.69 to 1.47; low-quality evidence), or response rate (OR 1.20, 95% CI 0.67 to 2.12; very low-quality evidence) but increased toxicity (OR 2.57, 95% CI 1.45 to 4.57; low-quality evidence). We noted significant between-study heterogeneity in most analyses.Scant information on quality of life was reported in the identified studies. AUTHORS' CONCLUSIONS The addition of EGFR MAb to either chemotherapy or best supportive care improves progression-free survival (moderate- to high-quality evidence), overall survival (high-quality evidence), and tumour response rate (moderate- to high-quality evidence), but may increase toxicity in people with KRAS exon 2 wild-type or extended RAS wild-type metastatic colorectal cancer (moderate-quality evidence). The addition of EGFR TKI to standard therapy does not improve clinical outcomes. EGFR MAb combined with bevacizumab is of no clinical value (very low-quality evidence). Future studies should focus on optimal sequencing and predictive biomarkers and collect quality of life data.
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Affiliation(s)
- David Lok Hang Chan
- Royal North Shore HospitalDepartment of Medical OncologySt LeonardsNew South WalesAustralia2065
| | - Eva Segelov
- Monash University and Monash HealthDepartment of OncologyLvl 7, MHTP building, Monash Health 240 Clayton RdClaytonVictoriaAustralia3168
| | - Rachel SH Wong
- University of SydneyDepartment of MedicineSydneyNSWAustralia2006
| | - Annabel Smith
- University of New South WalesDepartment of MedicineSydneyNSWAustralia2052
| | - Rebecca A Herbertson
- Ludwig Institute for Cancer ResearchMelbourne Centre for Clinical SciencesAustin Hospital HSB1145‐163 Studley RoadHeidelbergVictoriaAustralia3084
| | - Bob T. Li
- Memorial Sloan Kettering Cancer CenterThoracic Oncology and Early Drug Development Service1275 York AvenueNew YorkNYUSA10065
| | - Niall Tebbutt
- Olivia Newton‐John Cancer Wellness and Research Centre, Austin HospitalOlivia Newton‐John Cancer Research Institute145‐163 Studley RdHeidelbergVictoriaAustralia3084
| | - Timothy Price
- Olivia Newton‐John Cancer Wellness & Research Centre, Austin HospitalOlivia Newton‐John Cancer Research Institute, Level 5145‐163 Studley RdHeidelbergVictoriaAustralia3084
| | - Nick Pavlakis
- Royal North Shore HospitalDepartment of Medical OncologySt LeonardsNew South WalesAustralia2065
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Giuliani J, Bonetti A. The Pharmacological Costs of Complete Liver Resections in Unselected Advanced Colorectal Cancer Patients: Focus on Targeted Agents. A Review of Randomized Clinical Trials. J Gastrointest Cancer 2017; 47:341-350. [PMID: 27488729 DOI: 10.1007/s12029-016-9862-0] [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] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to evaluate the pharmacological costs of conversion chemotherapy with targeted biological agents in an unselected population of advanced colorectal cancer (CRC) patients in order to achieve an R0 liver resection. METHODS Full reports and updates of randomized clinical trials (RCTs) that compared at least two front-line therapy regimens with targeted biological agents for advanced CRC patients were selected. The present evaluation was restricted to randomized phase II and III trials. The costs of drugs are at the Pharmacy Hospital and are expressed in euros (€). RESULTS Our study began with the evaluation of 683 abstracts. Forty-eight trials were considered appropriate for further analysis. A more in-depth evaluation looking for the trials reporting the liver resection rates following conversion chemotherapy brought to the exclusion of other 37 trials, leaving 11 randomized trials (three phase II trials, including 522 patients and eight phase III trials, including 7191 patients). The pharmacological costs of conversion therapy increased with the substitution of prolonged infusion 5-Fluorouracil by capecitabine and, to a much higher extent, with the introduction of biologicals. CONCLUSIONS Two key issues are presented in this review. First, the pharmacological costs of commonly used front line regimens based on the targeted biological agents for the treatment of advanced CRC are highly variable. Second, the performance of the published schemes, in terms of resection rates, depends on patient's selection, tumor characteristics, and on the type of the scheme.
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Affiliation(s)
- Jacopo Giuliani
- Department of Medical Oncology, Mater Salutis Hospital, AULSS 21 della Regione Veneto, Legnago, VR, Italy. .,Department of Medical Oncology, ASL 21 della Regione Veneto, Via Gianella 1, 37045, Legnago, VR, Italy.
| | - Andrea Bonetti
- Department of Medical Oncology, Mater Salutis Hospital, AULSS 21 della Regione Veneto, Legnago, VR, Italy.,Department of Medical Oncology, ASL 21 della Regione Veneto, Via Gianella 1, 37045, Legnago, VR, Italy
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Ohashi Y, Kumagai K, Miyata Y, Matsubara R, Kitaura K, Suzuki S, Hamada Y, Suzuki R. Overexpression of ErbB4 is an independent marker for lymph node metastasis in Japanese patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2016; 122:313-21. [DOI: 10.1016/j.oooo.2016.04.017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 04/23/2016] [Accepted: 04/28/2016] [Indexed: 11/30/2022]
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Hazama S, Maeda H, Iwamoto S, Kim HM, Takemoto H, Kobayashi K, Sakamoto J, Nagata N, Oba K, Mishima H. A Phase II Study of XELOX and Cetuximab as First-Line Therapy in Patients With KRAS Wild Type Metastatic Colorectal Cancer (FLEET2 Study). Clin Colorectal Cancer 2016; 15:329-336. [PMID: 27507128 DOI: 10.1016/j.clcc.2016.07.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 06/23/2016] [Accepted: 07/05/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Despite the comparable clinical benefit of XELOX (capecitabine with oxaliplatin) and FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), the value of XELOX treatment in combination with cetuximab for metastatic colorectal cancer (mCRC) remains largely unknown. PATIENTS AND METHODS In this clinical trial we evaluated the efficacy and safety of weekly/biweekly cetuximab administration combined with biweekly XELOX in patients with previously untreated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild type mCRC. The primary end point was response rate (RR) with confirmation, and the secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), dose intensity, and the safety of the protocol treatment. RESULTS Forty patients who fulfilled the inclusion criteria participated in this study. The median treatment cycle number was 8 and the median dose intensities were 218 mg/m2/wk for cetuximab, 34 mg/m2/wk for oxaliplatin, and 821 mg/m2/d for capecitabine. One patient showed complete response and partial response was observed in 19 patients, giving an overall RR of 50% (95% confidence interval [CI], 33.8%-66.2%). Stable disease was obtained in 13 patients, resulting in a DCR of 82.5% (95% CI, 67.2%-92.7%). The PFS was 6.5 months (95% CI, 3.5-9.6 months), and the OS was 24.3 months (95% CI, 14.9-33.7 months). The safety profile revealed the common Grade 3/4 adverse events to be acneiform eruption (12.5%), peripheral neuropathy (7.5%), and elevated alanine transaminase levels (7.5%). Grade 3/4 thrombocytopenia and neutropenia occurred only in 5.0% and 2.5% of the patients, respectively. Grade 1 hand-foot syndrome (HFS) was not uncommon (20%), whereas Grade 2/3 HFS occurred in only 3 patients (7.5%). No deaths were reported within 30 days of the last dose. CONCLUSION Cetuximab with XELOX showed a confirmed overall RR of 50%, which was within the previously reported range of RR. The safety profile showed an acceptable rate and severity of adverse events. In light of the several advantages of XELOX, including convenience and the reported cost-saving aspects, further study of this combination therapy is warranted.
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Affiliation(s)
- Shoichi Hazama
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University, Graduate School of Medicine, Ube, Japan
| | | | | | - Ho Min Kim
- Division of Surgery, Osaka Rosai Hospital, Sakai, Japan
| | | | - Kenji Kobayashi
- Department of Surgery, Matsunami General Hospital, Hashima, Japan
| | | | | | - Koji Oba
- Department of Biostatistics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Escalante CP, Chang YC, Liao K, Rouleau T, Halm J, Bossi P, Bhadriraju S, Brito-Dellan N, Sahai S, Yusuf SW, Zalpour A, Elting LS. Meta-analysis of cardiovascular toxicity risks in cancer patients on selected targeted agents. Support Care Cancer 2016; 24:4057-74. [PMID: 27344327 DOI: 10.1007/s00520-016-3310-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 06/07/2016] [Indexed: 12/18/2022]
Abstract
PURPOSE The purpose was to estimate the risk and severity of cardiovascular toxicities associated with selected targeted agents. METHODS We searched English-language literature for randomized clinical trials published between January 1, 2000 and November 30, 2013 of targeted cancer therapy drugs approved by the FDA by November 2010. One hundred ten studies were eligible. Using meta-analytic methods, we calculated the relative risks of several cardiovascular toxicities [congestive heart failure (CHF), decreased left ventricular ejection fraction (DLVEF), myocardial infarction (MI), arrhythmia, and hypertension (HTN)], adjusting for sample size using the inverse-variance technique. For each targeted agent and side effect, we calculated the number needed to harm. RESULTS Regarding CHF, trastuzumab showed significantly greater risk of all-grade and high-grade CHF. There was significant increased risk of all-grade DLVEF with sorafenib, sunitinib, and trastuzumab and high-grade DLVEF with bevacizumab and trastuzumab. Sorafenib was associated with significant increased all-grade risk of MI based on one study. None was associated with high-grade risk of MI or increased risk of arrhythmia. Bevacizumab, sorafenib, and sunitinib had significant increased risk of all-grade and high-grade HTN. CONCLUSIONS Several of the targeted agents were significantly associated with increased risk of specific cardiovascular toxicities, CHF, DLVEF, and HTN. Several had significant increased risk for high-grade cardiovascular toxicities (CHF, DLVEF, and HTN). Patients receiving such therapy should be closely monitored for these toxicities and early and aggressive treatment should occur. However, clinical experience has demonstrated that some of these toxicities may be reversible and due to secondary effects.
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Affiliation(s)
- C P Escalante
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Y C Chang
- Houston Independent School District, Houston, TX, USA
| | - K Liao
- Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - T Rouleau
- Carolinas Medical Center, Charlotte, NC, USA
| | - J Halm
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - P Bossi
- Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy
| | - S Bhadriraju
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - N Brito-Dellan
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - S Sahai
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of General Internal Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - S W Yusuf
- Department of Cardiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - A Zalpour
- Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - L S Elting
- Department of Health Services Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Wen F, Li Q. Treatment dilemmas of cetuximab combined with chemotherapy for metastatic colorectal cancer. World J Gastroenterol 2016; 22:5332-5341. [PMID: 27340349 PMCID: PMC4910654 DOI: 10.3748/wjg.v22.i23.5332] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/02/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
Although monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) have largely enriched the available therapeutic choices for colorectal cancer (CRC), the understanding and management of their associated clinical toxicities are limited. In addition, the combined strategies of administering EGFR mAbs and traditional cytotoxic agents, such as 5-fluorouracil, oxaliplatin and irinotecan, have resulted in a more complicated management of CRC treatment-related side effects compared with EGFR mAb monotherapy. We believe that a thorough recognition of the toxicities of EGFR mAb drugs is essential for physicians to increase the therapeutic index in the treatment of CRC. This review aims to summarize the existing information regarding the treatment dilemmas of cetuximab combined with chemotherapy in the management of metastatic CRC.
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Azadeh P, Mortazavi N, Tahmasebi A, Hosseini Kamal F, Novin K. Cetuximab Plus Various Chemotherapy Regimens for Patients with KRAS Wild-Type Metastatic Colorectal Cancer. Chemotherapy 2015; 61:51-6. [DOI: 10.1159/000440693] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 08/27/2015] [Indexed: 11/19/2022]
Abstract
Background: The aim of this study was to compare the efficacy and hematologic toxicity of cetuximab combined with various types of chemotherapy regimens in patients with KRAS wild-type metastatic colorectal cancer (mCRC). Methods: The response rate, progression-free survival (PFS) and overall survival of the patients were analyzed. Results: In total, 45 patients were included in the study. The overall response rate for the combination of cetuximab and FOLFOX, FOLFIRI and CAPOX was 20, 46 and 30%, respectively, but the differences were not statistically significant. The median PFS for the three groups were 8, 6 and 3.5 months, respectively, but again these differences were not significant. All-grade leukopenia and anemia for the cetuximab plus FOLFOX group were significantly higher than for the other chemotherapy regimens. Conclusion: Our findings suggest that the combination of cetuximab and the three standard chemotherapy regimens resulted in the same outcomes in our patient population of mCRC, with higher hematologic toxicities among the FOLFOX subgroup.
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Miroddi M, Sterrantino C, Simonelli I, Ciminata G, Phillips RS, Calapai G. Risk of grade 3-4 diarrhea and mucositis in colorectal cancer patients receiving anti-EGFR monoclonal antibodies regimens: A meta-analysis of 18 randomized controlled clinical trials. Crit Rev Oncol Hematol 2015; 96:355-71. [PMID: 26160607 DOI: 10.1016/j.critrevonc.2015.06.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Revised: 05/07/2015] [Accepted: 06/10/2015] [Indexed: 12/22/2022] Open
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Rosa B, de Jesus JP, de Mello EL, Cesar D, Correia MM. Effectiveness and safety of monoclonal antibodies for metastatic colorectal cancer treatment: systematic review and meta-analysis. Ecancermedicalscience 2015; 9:582. [PMID: 26557880 PMCID: PMC4631576 DOI: 10.3332/ecancer.2015.582] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The effectiveness of chemotherapy (CT) for select cases of metastatic colorectal cancer (MCRC) has been well established in the literature, however, it provides limited benefits and in many cases constitutes a treatment with high toxicity. The use of specific molecular biological treatments with monoclonal antibodies (MA) has been shown to be relevant, particularly for its potential for increasing the response rate of the host to the tumour, as these have molecular targets present in the cancerous cells and their microenvironment thereby blocking their development. The combination of MA and CT can bring a significant increase in the rate of resectability of metastases, the progression-free survival (PFS), and the global survival (GS) in MCRC patients. OBJECTIVE To assess the effectiveness and safety of MA in the treatment of MCRC. METHODS A systematic review was carried out with a meta-analysis of randomised clinical trials comparing the use of cetuximab, bevacizumab, and panitumumab in the treatment of MCRC. RESULTS Sixteen randomised clinical trials were selected. The quality of the evidence on the question was considered moderate and data from eight randomised clinical trials were included in this meta-analysis. The GS and PFS were greater in the groups which received the MA associated with CT, however, the differences were not statistically significant between the groups (mean of 17.7 months versus 17.1 months; mean difference of 1.09 (CI: 0.10-2.07); p = 0.84; and 7.4 versus 6.9 months. mean difference of 0.76 (CI: 0.08-1.44); p = 0.14 respectively). The meta-analysis was not done for any of the secondary outcomes. CONCLUSION The addition of MA to CT for patients with metastatic colorectal cancer does not prolong GS and PFS.
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Affiliation(s)
- Bruno Rosa
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
| | | | | | - Daniel Cesar
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
| | - Mauro M Correia
- Instituto Nacional de Câncer, Rio de Janeiro 20230-130, Brazil
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Multicenter Phase II study of FOLFOX or biweekly XELOX and Erbitux (cetuximab) as first-line therapy in patients with wild-type KRAS/BRAF metastatic colorectal cancer: The FLEET study. BMC Cancer 2015; 15:695. [PMID: 26467662 PMCID: PMC4607014 DOI: 10.1186/s12885-015-1685-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 10/06/2015] [Indexed: 12/17/2022] Open
Abstract
Background The clinical benefit of cetuximab combined with oxaliplatin-based chemotherapy remains under debate. The aim of the present multicenter open-label Phase II study was to explore the efficacy and safety of biweekly administration of cetuximab and mFOLFOX-6 or XELOX as first-line chemotherapy in patients with metastatic colorectal cancer. Methods Sixty-two patients with previously untreated KRAS/BRAF wild-type metastatic colorectal cancer were recruited to the study between April 2010 and May 2011. Patients received one of two treatment regimens, either cetuximab plus mFOLFOX-6 (FOLFOX + Cmab) or cetuximab plus biweekly XELOX (XELOX + Cmab), according to their own preference. Treatment was continued until disease progression or the appearance of intolerable toxicities. The primary endpoint was response rate; secondary endpoints were progression-free survival, overall survival, disease control rate, dose intensity, conversion rate to surgical resection, and safety. Results The response rates in the FOLFOX + Cmab (n = 37) and XELOX + Cmab (n = 25) groups were 64.9 % (24/37) and 72.0 % (18/25), respectively. The median PFS in the FOLFOX + Cmab and XELOX + Cmab groups was 13.1 months (95 % confidence interval [CI] 12.1–17.5) and 13.4 months (95 % CI 10.1–17.9), respectively. Neutropenia was the most frequent grade 3/4 adverse event in both groups (33.9 %), followed by anorexia, acneiform eruption, skin fissure and paronychia. A waterfall plot of tumor diameter showed prominent shrinkage of the tumors in 88.7 % of patients. Conclusions The results of the present study indicate that biweekly cetuximab plus mFOLFOX-6/XELOX is an effective and tolerable treatment regimen. Biweekly administration of cetuximab requires only one hospital visit every 2 weeks, and may become a convenient treatment option for patients with KRAS/BRAF wild-type metastatic colorectal cancer. Trial registration This study is registered with University Hospital Medical Information Network (UMIN 000003253). Registration date is 02/24/2010. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1685-z) contains supplementary material, which is available to authorized users.
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Chan DL, Pavlakis N, Shapiro J, Price TJ, Karapetis CS, Tebbutt NC, Segelov E. Does the Chemotherapy Backbone Impact on the Efficacy of Targeted Agents in Metastatic Colorectal Cancer? A Systematic Review and Meta-Analysis of the Literature. PLoS One 2015; 10:e0135599. [PMID: 26275292 PMCID: PMC4537274 DOI: 10.1371/journal.pone.0135599] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 07/23/2015] [Indexed: 12/22/2022] Open
Abstract
IMPORTANCE The EGFR inhibitors (EGFR-I) cetuximab and panitumumab and the angiogenesis inhibitors (AIs) bevacizumab and aflibercept have demonstrated varying efficacy in mCRC. OBJECTIVE To document the overall impact of specific chemotherapy regimens on the efficacy of targeted agents in treating patients with mCRC. DATA SOURCES MEDLINE, EMBASE and Cochrane databases were searched to 2014, supplemented by hand-searching ASCO/ESMO conference abstracts. STUDY SELECTION Published RCTs of patients with histologically confirmed mCRC were included if they investigated either 1) chemotherapy with or without a biological agent or 2) different chemotherapy regimens with the same biological agent. EGFR-I trials were restricted to KRAS exon 2 wild-type (WT) populations. DATA EXTRACTION AND SYNTHESIS Data were independently abstracted by two authors and trial quality assessed according to Cochrane criteria. The primary outcome was overall survival with secondary endpoints progression free survival (PFS), overall response rate (ORR) and toxicity. RESULTS EGFR-I added to irinotecan-based chemotherapy modestly improved OS with HR 0.90 (95% CI 0.81-1.00, p = 0.04), but more so PFS with HR 0.77 (95% CI 0.69-0.86, p<0.00001). No benefit was evident for EGFR-I added to oxaliplatin-based chemotherapy (OS HR 0.97 (95% CI 0.87-1.09) and PFS HR 0.92 (95% CI 0.83-1.02)). Significant oxaliplatin-irinotecan subgroup interactions were present for PFS with I2 = 82%, p = 0.02. Further analyses of oxaliplatin+EGFR-I trials showed greater efficacy with infusional 5FU regimens (PFS HR 0.82, 95% CI 0.72-0.94) compared to capecitabine (HR 1.09; 95% CI 0.91-1.30) and bolus 5FU (HR 1.07; 95% CI 0.79-1.45); subgroup interaction was present with I2 = 72%, p = 0.03. The oxaliplatin-irinotecan interaction was not evident for infusional 5FU regimens. For AIs, OS benefit was observed with both oxaliplatin-based (HR 0.83) and irinotecan-based (HR 0.77) regimens without significant subgroup interactions. Oxaliplatin+AI trials showed no subgroup interactions by type of FP, whilst an interaction was present for irinotecan+AI trials although aflibercept was only used with infusional FP (I2 = 89.7%, p = 0.002). CONCLUSION AND RELEVANCE The addition of EGFR-I to irinotecan-based chemotherapy has consistent efficacy, regardless of FP regimen, whereas EGFR-I and oxaliplatin-based regimens were most active with infusional 5FU. No such differential activity was observed with the varying chemotherapy schedules when combined with AIs.
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Affiliation(s)
- David L. Chan
- Royal North Shore Hospital, Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia
- * E-mail:
| | - Nick Pavlakis
- Royal North Shore Hospital, Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia
| | - Jeremy Shapiro
- Department of Medical Oncology, Monash University, Victoria, Australia
| | - Timothy J. Price
- The Queen Elizabeth Hospital and University of Adelaide, South Australia, Australia
| | - Christos S. Karapetis
- Flinders University and Flinders Medical Centre, Flinders Centre for Innovation in Cancer, Bedford Park, South Australia, Australia
| | | | - Eva Segelov
- St Vincent’s Clinical School, University of New South Wales, NSW, Australia
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You B, Chen EX. Anti-EGFR monoclonal antibodies for treatment of colorectal cancers: development of cetuximab and panitumumab. J Clin Pharmacol 2015; 52:128-55. [PMID: 21427284 DOI: 10.1177/0091270010395940] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Over the last decade, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) have been firmly established as essential drugs for the treatment of metastatic colorectal cancer (CRC). Cetuximab and panitumumab have been approved by American and European drug agencies. This review aims at exploring the main outcomes of clinical studies performed during their clinical development, from phase I to III trials, and hence at giving a comprehensive review of the scientific rational and up-to-date evidence sustaining the use of these drugs. Many areas are still under active investigation such as administration schedules, their efficacy in comparison with bevacizumab, their role in adjuvant therapy, molecular predictors, and management of side effects.
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Affiliation(s)
- Benoit You
- Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
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Li XX, Liang L, Huang LY, Cai SJ. Standard chemotherapy with cetuximab for treatment of colorectal cancer. World J Gastroenterol 2015; 21:7022-7035. [PMID: 26078581 PMCID: PMC4462745 DOI: 10.3748/wjg.v21.i22.7022] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Revised: 12/12/2014] [Accepted: 02/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To review and assess the evidence related to cetuximab treatment in metastatic colorectal cancer (mCRC) with regard to KRAS status.
METHODS: PubMed, EMBASE, Cochrane database and American Society of Clinical Oncology meeting abstracts were searched for randomized controlled trials (RCTs) reporting the effect of KRAS status on efficacy of chemotherapy regimen with or without cetuximab in mCRC. Baseline information such as sex and age was summarized from the included studies. Hazard ratios of progression-free survival (PFS) and overall survival (OS) as well as objective response based on KRAS status were extracted for analysis.
RESULTS: A total of 8 RCTs with 6780 patients were included. The combined analysis showed that cetuximab failed to improve the OS and PFS in patients with mCRC. However, in subgroup analysis, the pooled data showed that addition of cetuximab to irinotecan containing chemotherapy regimen was sufficient to improve OS and PFS in wild-type KRAS mCRC patients, but not in patients with mutant-type KRAS. The addition of cetuximab increased the incidence of adverse events such as diarrhea, rash, skin toxicity/rash, and nausea and vomiting. There was no significant publication bias existing in the included studies.
CONCLUSION: The clinical benefit of cetuximab was only confirmed in patients with wild-type KRAS. KRAS status could be considered a biomarker of efficacy of cetuximab.
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Efficacy and toxicity of adding cetuximab to chemotherapy in the treatment of metastatic colorectal cancer: a meta-analysis from 12 randomized controlled trials. Tumour Biol 2014; 35:11741-50. [PMID: 25417200 DOI: 10.1007/s13277-014-2227-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 06/11/2014] [Indexed: 01/29/2023] Open
Abstract
Cetuxiamb, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been used in combination with chemotherapy for patients with metastatic colorectal cancer (mCRC). However, the efficacy of combined therapies of cetuximab and different chemotherapy regimens remains controversial. Therefore, we conducted a meta-analysis to evaluate the efficacy and toxicity of adding cetuximab to oxaliplatin-based or irinotecan-based chemotherapeutic regimens for the treatment of patients with mCRC with wild-type/mutated KRAS tumors. Randomized controlled trials (RCTs), published in Pubmed and Embase were systematically reviewed to assess the survival benefits and toxicity profile mCRC patients treated with cetuximab plus chemotherapy. Outcomes included overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicities. Results were expressed as the hazard ratio (HR) with 95 % confidence intervals (CI). Pooled estimates were generated by using a fixed-effects model or a randomized-effects model, depending on the heterogeneity among studies. A total of 12 trials involving 6,297 patients met the inclusion criteria and were included in this meta-analysis. All patients were administered oxaliplatin-based or irinotecan-based chemotherapy with or without cetuximab. Pooled results showed that the addition of cetuximab did not significantly improve the OS (HR = 0.99, 95 % CI = 0.89-1.09; Z = 0.28, P = 0.78) or PFS (HR = 0.94, 95 % CI = 0.81-1.10; Z = 0.76, P = 0.49), but did improve ORR (RR = 1.34, 95 % CI = 1.08-1.65; Z = 2.72, P = 0.00), when compared with chemotherapy alone. Subgroup analysis showed the highest PFS benefit in patients with wild-type KRAS tumors (HR = 0.80, 95 % CI = 0.65-0.99; Z = 2.1, P = 0.04) or wild-type KRAS/BRAF tumors (HR = 0.64, 95 % CI = 0.52-0.79; Z = 4.15, P = 0.00). When combined with cetuximab, irinotecan-based chemotherapy was significantly associated with prolonged PFS (HR = 0.79, 95 % CI = 0.66-0.96; Z = 2.36, P = 0.02) for all patients with differing gene-status. The incidence of grade 3/4 adverse events, including skin toxicity, diarrhea, hypertension, anorexia, and mucositis/stomatitis, was slightly higher in the combined therapy group than in the chemotherapy-only group. Based on the current evidence, the addition of cetuximab to chemotherapy significantly improves the PFS in patients with wild-type KRAS or wild-type KRAS/BRAF tumors as well as the ORR in all patients. In addition, irinotecan-based combination therapy showed a beneficial effect on the PFS in all patients. These findings confirm the use of cetuximab in combination with chemotherapy for the treatment of patients with mCRC with wild-type KRAS tumors. Further multi-center RCTs are needed to indentify these findings.
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Giuliani J, Mercanti A, Muraro S, Trolese AR, Durante E, Greco F, Piacentini P, Tognetto M, Bonetti A. The pharmacological costs of complete liver resections in unselected advanced colorectal cancer patients: a review of published Phase II and III trials. Expert Rev Pharmacoecon Outcomes Res 2014; 15:101-10. [PMID: 25399933 DOI: 10.1586/14737167.2015.982099] [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: 11/08/2022]
Abstract
The pharmacological costs of regimens used as front-line therapy in advanced colorectal cancer patients and their impact on the liver resection rates have not been considered. In this paper, we made a review of published randomized Phase II and III trials that reported the liver resection rates following upfront chemotherapy and linked this outcome to the pharmacological costs of drugs used. The costs are calculated based on the price at Pharmacy of our Hospital in Legnago (Italy), and as a measure of activity, we used the number of patients needed to treat to get one complete liver resection. Number needed to treat is highly variable among the different trials according to patient's characteristics, tumor biology and the efficacy of chemotherapy administered. The range of activity is greatly amplified when the costs are compared.
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Affiliation(s)
- Jacopo Giuliani
- Mater Salutis Hospital-AULSS 21 della Regione Veneto - Medical Oncology, Legnago (VR), Italy
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Incidence and risk of severe infections associated with anti-epidermal growth factor receptor monoclonal antibodies in cancer patients: a systematic review and meta-analysis. BMC Med 2014; 12:203. [PMID: 25369798 PMCID: PMC4236487 DOI: 10.1186/s12916-014-0203-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 10/03/2014] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Anti-epidermal growth factor receptor (EGFR)-monoclonal antibodies (MoAbs) have been widely used in a variety of malignancies. Severe infections (≥grade 3) are potentially life-threatening adverse events with these drugs. However, the contribution of anti-EGFR MoAbs to infections is still unknown. We performed this meta-analysis to determine the overall incidence and risk of severe infections in cancer patients treated with these drugs. METHODS The databases of PubMed and abstracts presented at oncology conferences and published in the proceedings were searched for relevant studies from January 2000 to May 2014. Summary incidences, relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS A total of 14,066 patients from 26 randomized controlled trials (RCTs) were included. The use of anti-EGFR-MoAbs significantly increased the risk of developing severe infections (RR 1.34, 95%CI: 1.10 to 1.62, P=0.003) in cancer patients, but not for fatal infections (RR 1.62, 95%CI: 0.81 to 3.26, P=0.18). Meta-regression indicated the infections might possibly occur early in the treatment with anti-EGFR MoAbs. On sub-group analysis, the risk of severe infections significantly varied with tumor type (P=0.001). When stratified by specific anti-EGFR MoAbs, a significantly increased risk of infections with cetuximab was observed (P<0.001), but not for panitumumab (P=0.98). Additionally, the use of anti-EGFR MoAbs significantly increased the risk of severe infections when used in conjunction with cisplatin (RR 1.48, 95%CI 1.22 to 1.79, P<0.001) or irinotecan (RR 1.53, 95%CI 1.12 to 2.10, P=0.008). When stratified by specific infectious events, anti-EGFR-MoAbs significantly increased the risk of developing severe sepsis (RR 4.30, 95%CI: 1.80 to 10.27; P=0.001). CONCLUSIONS Anti-EGFR MoAbs treatment significantly increases the risk of developing severe infectious events in cancer patients. The risk may vary with tumor types. Clinicians should be aware of the risks of severe infections with the administration of these drugs in cancer patients.
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Qi WX, Shen Z, Tang LN, Yao Y. Does the addition of targeted biological agents to first-line chemotherapy for advanced colorectal cancer increase complete response? A systematic review and meta-analysis. Colorectal Dis 2014; 16:O300-7. [PMID: 24766530 DOI: 10.1111/codi.12647] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Accepted: 03/05/2014] [Indexed: 12/14/2022]
Abstract
AIM The study assessed whether the addition of monoclonal antibodies (MoAbs) to first-line chemotherapy for advanced colorectal cancer (CRC) increases the complete response (CR) compared with controls. METHOD PubMed was reviewed for randomized clinical trials (RCTs) with approved MoAbs (bevacizumab, cetuximab and panitumumab) vs non-MoAbs as first-line therapy for patients with advanced CRC. The incidence and ratio of CR events were calculated in patients assigned to MoAbs compared with controls. RESULTS A total of 3790 patients from nine RCTs were included for analysis. The overall incidence of CR in patients treated with MoAbs was 2.4% (95% CI: 1.7-3.3%) compared with 1.3% (95% CI: 0.8-2.2%) in controls. Comparison of the different types of MoAbs showed that the incidence of CR was higher for bevacizumab (3.1%, 95% CI: 2.1-4.3%) than for cetuximab (0.8%, 95% CI: 0.4-1.8%). The addition of MoAbs to chemotherapy significantly increased the OR of obtaining a CR compared with controls (OR = 1.96; 95% CI: 1.12-3.46; P = 0.02). No significant differences in the OR were observed in any of the subgroups. CONCLUSION The CR is a rare event in advanced CRC; however, the addition of MoAbs to first-line chemotherapy significantly increases the curative rate of metastatic disease compared with controls.
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Affiliation(s)
- W X Qi
- Department of Oncology, Shanghai Jiao Tong University affiliated Sixth People's Hospital. No. 600, Shanghai, China
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Akhtar R, Chandel S, Sarotra P, Medhi B. Current status of pharmacological treatment of colorectal cancer. World J Gastrointest Oncol 2014; 6:177-183. [PMID: 24936228 PMCID: PMC4058725 DOI: 10.4251/wjgo.v6.i6.177] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Accepted: 05/09/2014] [Indexed: 02/05/2023] Open
Abstract
AIM: To review the clinical trials for the development in drugs for chemotherapeutic treatment of colorectal cancer (CRC).
METHODS: A systematic review identified randomized controlled trials (RCTs) assessing drugs for the treatment of CRC or adenomatous polyps from www.clinicaltrials.gov. Various online medical databases were searched for relevant publications.
RESULTS: Combination treatment regimens of standard drugs with newer agents have been shown to improve overall survival, disease-free survival, time to progression and quality of life compared to that with standard drugs alone in patients with advanced colorectal cancer. The FOLFOXIRI regimen has been associated with a significantly higher response rate, progression-free survival and overall survival compared to the FOLFIRI regimen.
CONCLUSION: Oxaliplatin plus intravenous bolus fluorouracil and leucovorin has been shown to be superior for disease-free survival when compared to intravenous bolus fluorouracil and leucovorin. In addition, oxaliplatin regimens were more likely to result in successful surgical resections. First line treatment with cetuximab plus fluorouracil, leucovorin and irinotecan has been found to reduce the risk of metastatic progression in patients with epidermal growth factor receptor-positive colorectal cancer with unresectable metastases. The addition of bevacizumab has been shown to significantly increase overall and progression-free survival when given in combination with standard therapy.
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Belum VR, Cercek A, Sanz-Motilva V, Lacouture ME. Dermatologic adverse events to targeted therapies in lower GI cancers: clinical presentation and management. Curr Treat Options Oncol 2014; 14:389-404. [PMID: 23996476 DOI: 10.1007/s11864-013-0254-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OPINION STATEMENT Rapid advances in drug discovery and the regulatory approval of a number of novel anticancer agents during the past decade pose unique challenges to the oncology community. While the benefits of such therapies receive most attention, adverse events (AEs), especially those pertaining to subspecialties (e.g., dermatology), often are underemphasized. To ensure best clinical outcomes, it would be important to bridge the gap between approval of a new drug and devising effective management strategies for the AEs. With the incorporation of targeted therapies to the treatment paradigm of gastrointestinal malignancies, there has been a significant rise in dermatologic AEs among those treated. In addition to significantly affecting patients' quality of life, these AEs represent a growing problem and are relatively unfamiliar to many oncologists. The issue is further complicated by the lack of evidence-based management guidelines for such AEs in the oncology setting, the "generalizing" of terminology (e.g., rash) for some AEs, as well as an insufficient number of oncodermatologists for assistance with their management. It is important for the oncologist to gain familiarity with the most common, manageable and predictable AEs. Their identification is usually based on medical history, clinical features, and full-body skin examination (FBSE) and at times by obtaining a skin biopsy to aid in diagnosis. Although efforts are underway, presently, there is a paucity of biomarkers (e.g., serologic, genetic) to predict dermatologic AEs. Management often requires a multifaceted approach and includes topical, systemic, surgical, and physical (e.g., cryotherapy) modalities of treatment. Unfortunately, very few clinical trials have focused on this aspect of supportive care; therefore, most data on management derives from anecdotal data. Patients should be encouraged to actively report skin problems, while oncologists should play a vital role in addressing these AEs in their patients. Lastly, further research at the molecular and cellular level may assist in the elucidation of the mechanisms underlying these AEs and their clinical correlates, paving way for the design of effective therapies in this subset of patients.
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Affiliation(s)
- Viswanath Reddy Belum
- Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, Rockefeller Outpatient Pavilion, Suite 228, 160 E 53rd St., New York, NY, 10022, USA
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Bekaii-Saab T, Wu C. Seeing the forest through the trees: a systematic review of the safety and efficacy of combination chemotherapies used in the treatment of metastatic colorectal cancer. Crit Rev Oncol Hematol 2014; 91:9-34. [PMID: 24534706 DOI: 10.1016/j.critrevonc.2014.01.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 12/20/2013] [Accepted: 01/09/2014] [Indexed: 12/15/2022] Open
Abstract
Combinations of fluoropyrimidines with oxaliplatin or irinotecan plus a biologic agent are standard treatments for metastatic colorectal cancer (mCRC). Recent approvals of first-line cetuximab, second-line ziv-aflibercept, and regorafenib as salvage therapy have increased the complexity of the treatment armamentarium. To define optimal regimens, we systematically reviewed combination chemotherapy trials (N=83). Descriptive analyses focusing on fluoropyrimidine formulation, oxaliplatin vs irinotecan combinations, and compatibility with biologics indicated the following: infusional 5-fluorouracil (5-FU) yielded better efficacy and safety than bolus 5-FU. Capecitabine had similar outcomes and better safety than 5-FU with oxaliplatin but not irinotecan. First-line oxaliplatin and irinotecan appeared equivalent. Antiangiogenics, such as bevacizumab and ziv-aflibercept, and epidermal growth factor receptor-targeted monoclonal antibodies cetuximab and panitumumab further improved efficacy. The treatment landscape for mCRC has become complex, and we are approaching individualized therapy based on predictive factors, including KRAS mutational status. Appropriate administration of chemotherapy/biologic combinations is critical.
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Affiliation(s)
- Tanios Bekaii-Saab
- The Ohio State University Comprehensive Cancer Center, A454 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, United States.
| | - Christina Wu
- The Ohio State University Comprehensive Cancer Center, A454 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH 43210, United States.
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Iida M, Brand TM, Campbell DA, Starr MM, Luthar N, Traynor AM, Wheeler DL. Targeting AKT with the allosteric AKT inhibitor MK-2206 in non-small cell lung cancer cells with acquired resistance to cetuximab. Cancer Biol Ther 2014; 14:481-91. [PMID: 23760490 DOI: 10.4161/cbt.24342] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is a central regulator of tumor progression in human cancers. Cetuximab is an anti-EGFR monoclonal antibody that has been approved for use in oncology. Despite clinical success the majority of patients do not respond to cetuximab and those who initially respond frequently acquire resistance. To understand how tumor cells acquire resistance to cetuximab we developed a model of resistance using the non-small cell lung cancer line NCI-H226. We found that cetuximab-resistant (Ctx (R) ) clones manifested strong activation of EGFR, PI3K/AKT and MAPK. To investigate the role of AKT signaling in cetuximab resistance we analyzed the activation of the AKT pathway effector molecules using a human AKT phospho-antibody array. Strong activation was observed in Ctx (R) clones for several key AKT substrates including c-jun, GSK3β, eIF4E, rpS6, IKKα, IRS-1 and Raf1. Inhibition of AKT signaling by siAKT1/2 or by the allosteric AKT inhibitor MK-2206 resulted in robust inhibition of cell proliferation in all Ctx (R) clones. Moreover, the combinational treatment of cetuximab and MK-2206 resulted in further decreases in proliferation than either drug alone. This combinatorial treatment resulted in decreased activity of both AKT and MAPK thus highlighting the importance of simultaneous pathway inhibition to maximally affect the growth of Ctx (R) cells. Collectively, our findings demonstrate that AKT activation is an important pathway in acquired resistance to cetuximab and suggests that combinatorial therapy directed at both the AKT and EGFR/MAPK pathways may be beneficial in this setting.
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Affiliation(s)
- Mari Iida
- Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Wisconsin Institute for Medical Research, Madison, WI, USA
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Barugel ME, Vargas C, Krygier Waltier G. Metastatic colorectal cancer: recent advances in its clinical management. Expert Rev Anticancer Ther 2014; 9:1829-47. [DOI: 10.1586/era.09.143] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
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Qi WX, Sun YJ, Shen Z, Yao Y. Risk of anti-EGFR monoclonal antibody-related skin rash: an up-to-date meta-analysis of 25 randomized controlled trials. J Chemother 2013; 26:359-68. [DOI: 10.1179/1973947813y.0000000155] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Cheng YD, Yang H, Chen GQ, Zhang ZC. Molecularly targeted drugs for metastatic colorectal cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2013; 7:1315-22. [PMID: 24204124 PMCID: PMC3817019 DOI: 10.2147/dddt.s52485] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The survival rate of patients with metastatic colorectal cancer (mCRC) has significantly improved with applications of molecularly targeted drugs, such as bevacizumab, and led to a substantial improvement in the overall survival rate. These drugs are capable of specifically targeting the inherent abnormal pathways in cancer cells, which are potentially less toxic than traditional nonselective chemotherapeutics. In this review, the recent clinical information about molecularly targeted therapy for mCRC is summarized, with specific focus on several of the US Food and Drug Administration-approved molecularly targeted drugs for the treatment of mCRC in the clinic. Progression-free and overall survival in patients with mCRC was improved greatly by the addition of bevacizumab and/or cetuximab to standard chemotherapy, in either first- or second-line treatment. Aflibercept has been used in combination with folinic acid (leucovorin)-fluorouracil-irinotecan (FOLFIRI) chemotherapy in mCRC patients and among patients with mCRC with wild-type KRAS, the outcomes were significantly improved by panitumumab in combination with folinic acid (leucovorin)-fluorouracil-oxaliplatin (FOLFOX) or FOLFIRI. Because of the new preliminary studies, it has been recommended that regorafenib be used with FOLFOX or FOLFIRI as first- or second-line treatment of mCRC chemotherapy. In summary, an era of new opportunities has been opened for treatment of mCRC and/or other malignancies, resulting from the discovery of new selective targeting drugs.
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Affiliation(s)
- Ying-dong Cheng
- Department of General Surgery, Xinqiao Hospital, Third Military Medical University, Chongqing, People's Republic of China
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