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1
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Liao PF, Wu TW, Peng TR. Monoclonal Antibodies for First-Line Treatment of Metastatic Colorectal Cancer. Am J Ther 2024; 31:e286-e297. [PMID: 35972911 DOI: 10.1097/mjt.0000000000001547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND In addition to discontinuing treatment at disease progression, cumulative toxicity limitations and genetic mutations play important roles in chemotherapy choice in metastatic colorectal cancer (mCRC). However, in recent years, targeted therapies, such as immune checkpoint inhibitors or monoclonal antibodies (MoAbs), have been used with chemotherapy to improve clinical outcomes in patients with mCRC. AREAS OF UNCERTAINTY Approximately 15% of patients with CRC would be eligible for further targeted therapy with immune checkpoint inhibitors based on genetic testing, but most patients with CRC would not qualify, especially Kirsten rat sarcoma wild-type. Therefore, adding MoAb is only an option for most patients until disease progression or unacceptable toxicity occurs. However, the results are not consistent with the combination of MoAb and different chemotherapy bases. In addition, most results from combining MoAb with different chemotherapy bases are not consistent. DATA SOURCES This meta-analysis includes published of the PubMed and Embase databases, limited to English literature, and patients were treated with MoAb combination. Randomized control trials conducted published up to May 2021 were considered for inclusion. THERAPEUTIC ADVANCES Fluoropyrimidine-based chemotherapy has been the backbone of palliative therapy for mCRC, with demonstrated benefits. This article will review the efficacy and safety of randomized control trials comparing different MoAb with fluoropyrimidine-based chemotherapy as first-line therapy for patients with mCRC, particularly in Kirsten rat sarcoma wild-type. CONCLUSION This meta-analysis revealed that MoAb plus chemotherapy has better progression-free survival and objective response rate than chemotherapy alone. However, treatment-related serious adverse events (grade ≥ 3) should be considered, particularly severe rash, diarrhea, and hypertension.
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Affiliation(s)
- Pei-Fei Liao
- Department of Pharmacy, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan, Republic of China
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Chitkara A, Kaur N, Desai A, Mehta D, Anamika F, Sarkar S, Gowda N, Sethi P, Thawani R, Chen EY. Risks of hypertension and thromboembolism in patients receiving bevacizumab with chemotherapy for colorectal cancer: A systematic review and meta-analysis. Cancer Med 2023; 12:21579-21591. [PMID: 38069531 PMCID: PMC10757147 DOI: 10.1002/cam4.6662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 09/12/2023] [Accepted: 10/03/2023] [Indexed: 12/31/2023] Open
Abstract
BACKGROUND Guidelines show that for metastatic colorectal cancer (mCRC), a combination of three-drug regimens, fluorouracil, leucovorin, and oxaliplatin and bevacizumab (BVZ), is one of the first-line standard therapies. BVZ is generally well tolerated; however, it is associated with infrequent, life-threatening side effects such as severe hypertension (HTN) (5%-18%), Grade ≥3 arterial thromboembolism (ATE) (2.6%), Grade ≥3 hemorrhagic events (1.2%-4.6%), and gastrointestinal perforation (0.3%-2.4%). This meta-analysis aims to evaluate the additive risk of BVZ-induced severe HTN and thromboembolism when BVZ is combined with a standard chemotherapy regime in patients with mCRC. METHODS Our search was conducted from January 29, 2022, to February 22, 2022, through databases of PubMed, clinicaltrial.gov, EMBASE, Web of Science, and Cochrane Library. Data analysis from randomized controlled trials (RCTs) and clinical trials was conducted using Review Manager V.5.4, comparing BVZ-chemotherapy to chemotherapy only, focusing on cardiovascular AE such as HTN and arterial and venous thromboembolism. RESULTS The analysis from 26 clinical trials and RCTs showed that the odds of HTN were about four times higher, and ATE subgroup analysis of 11 studies showed over two times higher odds of ATE in patients being treated with BVZ compared to the chemotherapy-only group. CONCLUSION BVZ, when added to the standard chemotherapy regimen for mCRC, was associated with higher odds of developing HTN and thromboembolism, specifically ATE, than the chemotherapy-only group. Our findings are significant as they provide vital information in analyzing the risk-benefit ratio of adding BVZ to the standard chemotherapy regime in patients with mCRC, especially in patients with vascular comorbidities.
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Affiliation(s)
- Akshit Chitkara
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Nirmaljot Kaur
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Aditya Desai
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Devanshi Mehta
- Loma Linda UniversityCalifornia in Internal MedicineCaliforniaUSA
| | - Fnu Anamika
- Internal MedicineHackensack Meridian Ocean UniversityBrickNew JerseyUSA
| | - Srawani Sarkar
- Research LabAlbert Einstein College of MedicineNew YorkNew YorkUSA
| | - Nandini Gowda
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Prabhdeep Sethi
- Internal MedicineUniversity of California RiversideRiversideCaliforniaUSA
| | - Rajat Thawani
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
| | - Emerson Y. Chen
- Division of Hematology and Medical Oncology, Knight Cancer InstituteOregon Health & Sciences UniversityPortlandOregonUSA
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He X, Lan H, Jin K, Liu F. Can immunotherapy reinforce chemotherapy efficacy? a new perspective on colorectal cancer treatment. Front Immunol 2023; 14:1237764. [PMID: 37790928 PMCID: PMC10543914 DOI: 10.3389/fimmu.2023.1237764] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/25/2023] [Indexed: 10/05/2023] Open
Abstract
As one of the main threats to human life (the fourth most dangerous and prevalent cancer), colorectal cancer affects many people yearly, decreases patients' quality of life, and causes irreparable financial and social damages. In addition, this type of cancer can metastasize and involve the liver in advanced stages. However, current treatments can't completely eradicate this disease. Chemotherapy and subsequent surgery can be mentioned among the current main treatments for this disease. Chemotherapy has many side effects, and regarding the treatment of this type of tumor, chemotherapy can lead to liver damage, such as steatohepatitis, steatosis, and sinus damage. These damages can eventually lead to liver failure and loss of its functions. Therefore, it seems that other treatments can be used in addition to chemotherapy to increase its efficiency and reduce its side effects. Biological therapies and immunotherapy are one of the leading suggestions for combined treatment. Antibodies (immune checkpoint blockers) and cell therapy (DC and CAR-T cells) are among the immune system-based treatments used to treat tumors. Immunotherapy targets various aspects of the tumor that may lead to 1) the recruitment of immune cells, 2) increasing the immunogenicity of tumor cells, and 3) leading to the elimination of inhibitory mechanisms established by the tumor. Therefore, immunotherapy can be used as a complementary treatment along with chemotherapy. This review will discuss different chemotherapy and immunotherapy methods for colorectal cancer. Then we will talk about the studies that have dealt with combined treatment.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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4
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André L, Antherieu G, Boinet A, Bret J, Gilbert T, Boulahssass R, Falandry C. Oncological Treatment-Related Fatigue in Oncogeriatrics: A Scoping Review. Cancers (Basel) 2022; 14:2470. [PMID: 35626074 PMCID: PMC9139887 DOI: 10.3390/cancers14102470] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/09/2022] [Accepted: 05/11/2022] [Indexed: 12/17/2022] Open
Abstract
Fatigue is a highly prevalent symptom in both cancer patients and the older population, and it contributes to quality-of-life impairment. Cancer treatment-related fatigue should thus be included in the risk/benefit assessment when introducing any treatment, but tools are lacking to a priori estimate such risk. This scoping review was designed to report the current evidence regarding the frequency of fatigue for the different treatment regimens proposed for the main cancer indications, with a specific focus on age-specific data, for the following tumors: breast, ovary, prostate, urothelium, colon, lung and lymphoma. Fatigue was most frequently reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) versions 3 to 5. A total of 324 regimens were analyzed; data on fatigue were available for 217 (67%) of them, and data specific to older patients were available for 35 (11%) of them; recent pivotal trials have generally reported more fatigue grades than older studies, illustrating increasing concern over time. This scoping review presents an easy-to-understand summary that is expected to provide helpful information for shared decisions with patients regarding the anticipation and prevention of fatigue during each cancer treatment.
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Affiliation(s)
- Louise André
- Hospices Civils de Lyon, Geriatrics Department, Hôpital Lyon Sud, 69230 Saint Genis-Laval, France; (L.A.); (G.A.); (A.B.); (J.B.); (T.G.)
| | - Gabriel Antherieu
- Hospices Civils de Lyon, Geriatrics Department, Hôpital Lyon Sud, 69230 Saint Genis-Laval, France; (L.A.); (G.A.); (A.B.); (J.B.); (T.G.)
| | - Amélie Boinet
- Hospices Civils de Lyon, Geriatrics Department, Hôpital Lyon Sud, 69230 Saint Genis-Laval, France; (L.A.); (G.A.); (A.B.); (J.B.); (T.G.)
| | - Judith Bret
- Hospices Civils de Lyon, Geriatrics Department, Hôpital Lyon Sud, 69230 Saint Genis-Laval, France; (L.A.); (G.A.); (A.B.); (J.B.); (T.G.)
| | - Thomas Gilbert
- Hospices Civils de Lyon, Geriatrics Department, Hôpital Lyon Sud, 69230 Saint Genis-Laval, France; (L.A.); (G.A.); (A.B.); (J.B.); (T.G.)
- Research on Healthcare Professionals and Performance RESHAPE, Inserm U1290, Lyon 1 University, 69008 Lyon, France
| | - Rabia Boulahssass
- Geriatric Coordination Unit for Geriatric Oncology (UCOG) PACA Est CHU de Nice, 06000 Nice, France;
- FHU OncoAge, 06000 Nice, France
- Faculty of Medicine, University of Nice Sofia Antilpolis, 06000 Nice, France
| | - Claire Falandry
- Hospices Civils de Lyon, Geriatrics Department, Hôpital Lyon Sud, 69230 Saint Genis-Laval, France; (L.A.); (G.A.); (A.B.); (J.B.); (T.G.)
- FHU OncoAge, 06000 Nice, France
- CarMeN Laboratory, INSERM U.1060/Université Lyon1/INRA U. 1397/INSA Lyon/Hospices Civils Lyon, Bâtiment CENS-ELI 2D, Hôpital Lyon Sud Secteur 2, 69310 Pierre-Bénite, France
- UCOGIR—Auvergne-Rhône-Alpes Ouest–Guyane, Hôpital Lyon Sud, 69495 Pierre-Bénite, France
- Faculty of Medicine and Maieutics Charles Mérieux, Lyon 1 University, 69310 Pierre-Bénite, France
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Jin H, Amonkar M, Aguiar-Ibáñez R, Thosar M, Chase M, Keeping S. Systematic literature review and network meta-analysis of pembrolizumab versus other interventions for previously untreated, unresectable or metastatic, microsatellite instability-high or mismatch repair-deficient colorectal cancer. Future Oncol 2022; 18:2155-2171. [PMID: 35332802 DOI: 10.2217/fon-2021-1633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: To compare pembrolizumab with competing interventions for previously untreated, unresectable or metastatic microsatellite instability-high or mismatch repair-deficient colorectal cancer. Method: Trials were identified via a systematic literature review and synthesized using a Bayesian network meta-analysis with time-varying hazard ratios (HRs). Results: Using intention-to-treat data, HRs for overall survival were generally in favor of pembrolizumab but not statistically significant; however, statistical significance was reached versus all comparators by month 16 when accounting for crossover. Estimated HRs for progression-free survival significantly favored pembrolizumab versus all comparators by month 12. Pembrolizumab was also superior to all comparators in terms of grade ≥3 adverse events. Conclusion: These analyses suggest that pembrolizumab is a highly efficacious and safe treatment in this population.
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Affiliation(s)
- He Jin
- PRECISIONheor, New York, NY 10165, USA
| | | | | | | | | | - Sam Keeping
- PRECISIONheor, Vancouver, BC, V6H 3Y4, Canada
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Gou HF, Zhou L, Huang J, Chen XC. Intraperitoneal oxaliplatin administration inhibits the tumor immunosuppressive microenvironment in an abdominal implantation model of colon cancer. Mol Med Rep 2018; 18:2335-2341. [PMID: 29956798 DOI: 10.3892/mmr.2018.9219] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2017] [Accepted: 06/05/2018] [Indexed: 02/05/2023] Open
Abstract
Recent studies have demonstrated that some chemotherapeutic drugs can enhance antitumor immunity by eliminating and inactivating immunosuppressive cells. Oxaliplatin (OXP) induces immunogenic cell death by increasing the immunogenicity of cancer cells. However, the effects of OXP on the tumor immunosuppressive microenvironment remain unclear. The aim of the present study was to evaluate the antitumor activity of OXP by intraperitoneal (i.p.) administration in an abdominal implantation model of colon cancer and tested the tumor immune microenvironment to observe whether OXP affects the local immune inhibitory cell populations. Abdominal metastasis models were established by inoculation of CT26 cells. The antitumor efficacy of OXP and the tumor immune microenvironment were evaluated. The tumors and spleens of mice were harvested for flow cytometric analysis. Cluster of differentiation (CD)‑8+CD69+ T cells, regulatory T cells (Tregs), CD11b+F4/80high macrophages and myeloid‑derived suppressor cells (MDSCs) were evaluated by flow cytometric analysis. In vivo i.p. administration of OXP inhibited tumor growth in the abdominal metastasis model. Furthermore, OXP was observed to increase tumor‑infiltrating activated CD8+ T cells in tumors, decrease CD11b+F4/80high macrophages in tumors and decrease MDSCs in the spleen. These results suggested that i.p. administration of OXP alone may inhibit tumor cell growth and induce the antitumor immunostimulatory microenvironment by eliminating immunosuppressive cells.
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Affiliation(s)
- Hong-Feng Gou
- Department of Abdominal Cancer, Cancer Center, The State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Lei Zhou
- Department of Abdominal Cancer, Cancer Center, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jia Huang
- Department of Abdominal Cancer, Cancer Center, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Xin-Chuan Chen
- Department of Hematology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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7
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Ba-Sang DZ, Long ZW, Teng H, Zhao XP, Qiu J, Li MS. A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer. Oncotarget 2018; 7:84468-84479. [PMID: 27806321 PMCID: PMC5356673 DOI: 10.18632/oncotarget.12994] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 10/02/2016] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVE A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). RESULTS Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. MATERIALS AND METHODS Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). CONCLUSIONS These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC.
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Affiliation(s)
- Dan-Zeng Ba-Sang
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Zi-Wen Long
- Department of Gastric Cancer and Soft-Tissue Sarcoma Surgery, Fudan university Shanghai Cancer Center, Shanghai 200032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P. R. China
| | - Hao Teng
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Xu-Peng Zhao
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Jian Qiu
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
| | - Ming-Shan Li
- Department of Oncology, Shigatse People's Hospital, Shigatse 857000, Tibet, P. R. China
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8
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Wu DM, Wang YJ, Fan SH, Zhuang J, Zhang ZF, Shan Q, Han XR, Wen X, Li MQ, Hu B, Sun CH, Bao YX, Xiao HJ, Yang L, Lu J, Zheng YL. Network meta-analysis of the efficacy of first-line chemotherapy regimens in patients with advanced colorectal cancer. Oncotarget 2017; 8:100668-100677. [PMID: 29246011 PMCID: PMC5725053 DOI: 10.18632/oncotarget.22177] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 10/13/2017] [Indexed: 12/22/2022] Open
Abstract
This network meta-analysis compared the short-term and long-term efficacies of first-line chemotherapy regimens in patients with advanced colorectal cancer (CRC). The 10 regimens included folinic acid + 5-fluorouracil + oxaliplatin (FOLFOX), folinic acid + 5-fluorouracil + irinotecan (FOLFIRI), folinic acid + 5-fluorouracil + gemcitabine (FFG), folinic acid + 5-fluorouracil + trimetrexate (FFT), folinic acid + 5-fluorouracil (FF), irinotecan + oxaliplatin (IROX), raltitrexed + oxaliplatin (TOMOX), folinic acid + tegafur-uracil (FTU), raltitrexed, and capecitabine. Electronic searches were performed in the Cochrane Library, PubMed and Embase databases from inception to June 2017. Network meta-analysis combined direct and indirect evidence to obtain odds ratios (ORs) and surface under the cumulative ranking curves (SUCRA) of different chemotherapy regimens for advanced CRC. Fourteen randomized controlled trails (RCTs) covering 4,383 patients with advanced CRC were included. The results revealed that FOLFOX, FOLFIRI, IROX, and TOMOX all showed higher overall response rates (ORRs) than FF or raltitrexed. Compared with raltitrexed, the aforementioned four regimens also had higher 1-year progression-free survival (PFS) rates. In addition, FOLFOX and FOLFIRI exhibited higher disease control rates (DCRs) and 1-year PFS rates than FF or raltitrexed. Cluster analysis revealed that FOLFOX, FOLFIRI, and TOMOX had better short-term and long-term efficacies. These findings suggest FOLFOX, FOLFIRI, and TOMOX are superior to other regimens for advanced CRC. These three regimens are therefore recommended for clinical treatment of advanced CRC.
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Affiliation(s)
- Dong-Mei Wu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Yong-Jian Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Shao-Hua Fan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Juan Zhuang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China.,School of Environment Science and Spatial Informatics, China University of Mining and Technology, Xuzhou 221008, P.R. China.,Jiangsu Key Laboratory for Eco-Agricultural Biotechnology around Hongze Lake, School of Life Sciences, Huaiyin Normal University, Huaian 223300, P.R. China
| | - Zi-Feng Zhang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Qun Shan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Xin-Rui Han
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Xin Wen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Meng-Qiu Li
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Bin Hu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Chun-Hui Sun
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Ya-Xing Bao
- Department of Orthopaedics, The Affiliated Municipal Hospital of Xuzhou Medical University, Xuzhou 221009, P.R. China
| | - Hai-Juan Xiao
- Department of Oncology, Hospital Affiliated to Shaanxi University of Chinese Medicine, Xianyang 712000, P.R. China
| | - Lin Yang
- Department of Hepatobiliary Surgery, Xianyang Central Hospital, Xianyang 712000, P.R. China
| | - Jun Lu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
| | - Yuan-Lin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou 221116, P.R. China
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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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10
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Wang XS, Shi Q, Dougherty PM, Eng C, Mendoza TR, Williams LA, Fogelman DR, Cleeland CS. Prechemotherapy Touch Sensation Deficits Predict Oxaliplatin-Induced Neuropathy in Patients with Colorectal Cancer. Oncology 2016; 90:127-35. [PMID: 26882477 DOI: 10.1159/000443377] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Accepted: 12/09/2015] [Indexed: 12/27/2022]
Abstract
OBJECTIVE We examined the emergence of chemotherapy-induced peripheral neuropathy (CIPN), a dose-limiting toxicity of oxaliplatin, over the course of oxaliplatin-based chemotherapy for colorectal cancer (CRC). Predicting which patients will likely develop CIPN is an ongoing clinical challenge. METHODS Oxaliplatin-naïve patients with CRC underwent quantitative sensory testing (QST) before beginning oxaliplatin-based chemotherapy and then rated CIPN-related symptoms via the MD Anderson Symptom Inventory (MDASI) weekly for 26 weeks. Mixed modeling examined the value of QST for predicting higher CIPN (MDASI numbness/tingling) during treatment. Trajectory analysis identified a patient subgroup with consistently higher CIPN symptoms. RESULTS Numbness/tingling was the most frequent, most severe symptom, with 51% of patients clustering into a high CIPN subgroup. Touch sensation deficits (Bumps Detection test) significantly predicted the development of more severe numbness/tingling [estimate (est) = 0.106, p = 0.0003]. The high CIPN subgroup reported increased pain (est = 0.472, p < 0.0001) and interference with walking (est = 0.840, p < 0.0001). In the high CIPN subgroup, patient-reported numbness/tingling worsened rapidly in weeks 0-5 (est = 0.57, p < 0.0001) and then more gradually in weeks 6-26 (est = 0.07, p < 0.0001). CONCLUSION Prechemotherapy screening with a simple, easily administered objective measure of touch sensation deficits (Bumps Detection test) and monitoring of patient-reported numbness/tingling during the first 2-3 chemotherapy cycles may support improved personalized care of CRC patients with oxaliplatin-induced CIPN.
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Affiliation(s)
- Xin Shelley Wang
- Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Tex., USA
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Zhao H, Wang Y, Yu J, Wei F, Cao S, Zhang X, Dong N, Li H, Ren X. Autologous Cytokine-Induced Killer Cells Improves Overall Survival of Metastatic Colorectal Cancer Patients: Results From a Phase II Clinical Trial. Clin Colorectal Cancer 2016; 15:228-35. [PMID: 27052743 DOI: 10.1016/j.clcc.2016.02.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Revised: 12/31/2015] [Accepted: 02/03/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND This randomized clinical study was conducted to evaluate the therapeutic benefits of cytokine-induced killer (CIK) cell immunotherapy in combination with chemotherapy in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS Sixty-one patients in group 1 (cell therapy group) received autologous CIK cell immunotherapy in combination with chemotherapy (5-Fluorouridine, leucovorin and oxaliplatin [FOLFOX4] plan). Another 61 patients in group 2 (the control group) received chemotherapy (FOLFOX4 plan) alone. The primary study end points were overall survival (OS) and progression-free survival (PFS). The secondary end points were treatment response and adverse events. RESULTS The 3-year PFS and OS in group 1 were 20% and 48%, respectively, compared with 13% and 23%, respectively, in group 2 (P = .131 and P < .001, respectively). The median OS in group 1 was significantly increased compared with that in group 2 (OS, 36 vs. 16 months; P < .001). Furthermore, there was a trend toward superior PFS in group 1 compared with that in group 2 (PFS, 16 vs. 10 months; P = .072). Using univariate analysis, we found that Karnofsky performance status <80, number of metastases >1, and increased platelet levels were significantly associated with poorer prognosis in group 1. Alternatively, the cycle count of CIK cell treatment was significantly associated with good prognosis in group 1. Toxicity was mild in patients who received CIK therapy. CONCLUSION This study shows that CIK cell immunotherapy in combination with chemotherapy is well tolerated and improves the OS of mCRC patients.
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Affiliation(s)
- Hua Zhao
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Yang Wang
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Jinpu Yu
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Feng Wei
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Shui Cao
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Xinwei Zhang
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China
| | - Nan Dong
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China
| | - Hui Li
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China.
| | - Xiubao Ren
- National Clinical Research Center for Cancer, Key Laboratory Cancer and Therapy, Tianjin, PR China; Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, PR China; Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, PR China.
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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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Petrelli F, Coinu A, Ghilardi M, Cabiddu M, Zaniboni A, Barni S. Efficacy of oxaliplatin-based chemotherapy + bevacizumab as first-line treatment for advanced colorectal cancer: a systematic review and pooled analysis of published trials. Am J Clin Oncol 2015; 38:227-33. [PMID: 25806713 DOI: 10.1097/coc.0b013e3182a2d7b8] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVES Oxaliplatin and either capecitabine or infusional/bolus 5-fluorouracil (5FU)-based chemotherapy + bevacizumab (XELOX + B and FOLFOX + B) represent 2 of the approved first-line treatments for advanced colorectal cancer (CRC). However, the addition of B did not offer a survival benefit compared with FOLFOX/XELOX alone in the phase III, NO16966 trial. The aim of this review was to aggregate all published data on the efficacy of XELOX and FOLFOX-B in prospective and retrospective studies as first-line therapy for stage IV CRC. METHODS We performed a systematic review, through PubMed and EMBASE, of all published studies exploring the efficacy of fluoropyrimidines + oxaliplatin + B-based chemotherapy as first-line chemotherapy in advanced CRC patients. Pooled estimates of the response rates, weighted medians of progression-free survival, and overall survival from all FOLFOX + B and XELOX + B arms were calculated. RESULTS A total of 25 studies were retrieved, with a total of 7878 patients. Overall, the pooled response rates (n=20 publications) was 49.1%. The median progression-free survival and overall survival (n=21 and 22 publications, respectively) were 10.3 and 23.7 months, respectively. The pooled median rate of surgical resection of metastases (n=13 publications) was 14%. CONCLUSIONS XELOX + B and FOLFOX + B are active combinations as first-line treatment of advanced CRC. The efficacy is confirmed for the first time from this pooled analysis of 25 trials. Both the XELOX + B and the FOLFOX + B arms represent 2 of the cornerstone combinations when B is used as first-line therapy.
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Affiliation(s)
- Fausto Petrelli
- *Oncology Department, Medical Oncology Unit, Azienda Ospedaliera Treviglio-Caravaggio, Treviglio (BG) †UO Oncologia, Dipartimento Oncologico, Istituto Ospedaliero Fondazione Poliambulanza, Brescia (BS), Italy
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14
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Lee KW, Kim YJ, Lee KH, Han SW, Kim TY, Oh DY, Im SA, Kim TY, Bang YJ, Choi IS, Kim JH. Phase II trial of gemcitabine plus UFT as salvage treatment in oxaliplatin, irinotecan and fluoropyrimidine-refractory metastatic colorectal cancer. Cancer Chemother Pharmacol 2014; 74:447-455. [PMID: 24947909 DOI: 10.1007/s00280-014-2515-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 06/08/2014] [Indexed: 12/22/2022]
Abstract
PURPOSE To investigate the efficacy of gemcitabine plus uracil-tegafur (UFT) combination chemotherapy as a salvage treatment in patients with metastatic colorectal cancer (MCRC). METHODS This single-arm phase II study was conducted at three institutions in Korea. Patients with MCRC refractory to fluoropyrimidine, oxaliplatin and irinotecan were enrolled. Gemcitabine 800 mg/m(2) was administered intravenously on days 1, 8 and 15. UFT 200 mg/m(2)/day was taken orally in three divided doses on days 1-21. Cycles were repeated every 4 weeks, and tumor evaluation was carried out every 8 weeks. The primary endpoint of this study was 8-week progression-free survival (PFS) rate. RESULTS Forty-one patients were enrolled. Fourteen patients received gemcitabine/UFT as a third-line treatment and 37 patients as a fourth-line or later-line therapy. Toxicities were easily manageable, and non-hematologic toxicities of ≥grade 3 were rare. The most common toxicity of ≥grade 3 was neutropenia (20.0 %). One patient showed partial response (response rate, 2.4 %) and 14 (34.1 %) showed stable disease. The 8-week PFS rate was 42.3 %. The median PFS was 1.7 months [95 % confidence interval (CI) 1.6-1.8 months], and the median overall survival was 9.2 months (95 % CI 5.8-12.6 months). CONCLUSIONS Overall efficacy of gemcitabine/UFT in refractory MCRC was unsatisfactory. However, we could find a minor proportion of patients who showed prolonged tumor stabilization to gemcitabine/UFT. Further studies are warranted to identify a patient subgroup that might have benefits from gemcitabine/UFT therapy.
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Affiliation(s)
- Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82, Gumi-Ro 173 Beon-Gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-707, Republic of Korea
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Shin DH, Xuan S, Kim WY, Bae GU, Kim JS. CD133 antibody-conjugated immunoliposomes encapsulating gemcitabine for targeting glioblastoma stem cells. J Mater Chem B 2014; 2:3771-3781. [DOI: 10.1039/c4tb00185k] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Lu X, Pan J, Li S, Shen S, Chi P, Lin H, Huang Y, Xu Z, Huang S. Establishment of a predictive genetic model for estimating chemotherapy sensitivity of colorectal cancer with synchronous liver metastasis. Cancer Biother Radiopharm 2013; 28:552-558. [PMID: 23721165 PMCID: PMC3741425 DOI: 10.1089/cbr.2012.1431] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE We examined the whole genome expression profile in advanced colorectal cancer (ACC) patients who had received FOLFOX4 chemotherapy to establish a genetic biomarker model predicting chemotherapy sensitivity. METHODS Eligible ACC patients were divided into two groups, based on postchemotherapy evaluation results: specifically, the sensitive group (experimental group) and the resistant group (control group). The genome expression profiles of colorectal cancer tissues were examined using DNA microarray analysis, and differential gene expression was identified using a significance analysis of the microarray. The probe signal log ratios were used to produce the area-under-the-curve, sensitivity, and specificity for candidate genes. Genes exhibiting differential expression and significant predictive power were used to simulate a genetic model for estimating chemotherapy sensitivity. RESULTS Totally, 30 ACC patients were eligible for the study, 13 assigned to the experimental group and 17 to the control group. In total, 30 genes showing significant differential expression were identified. Seven candidate genes (NKX2-3, FXYD6, TGFB1I1, ACTG2, ANPEP, HOXB8, and KLK11), which exhibited positive or negative correlations, were incorporated into a genetic model, with an overall accurate predication rate of 93.3%. CONCLUSIONS The predictive model involving the seven genes listed had high accuracy in estimating chemotherapy sensitivity to the FOLFOX4 regimen.
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Affiliation(s)
- Xingrong Lu
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Jie Pan
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Shaotang Li
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Songfei Shen
- Department of Medical Oncology, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Pan Chi
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Huiming Lin
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Ying Huang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Zhongbin Xu
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
| | - Shenghui Huang
- Department of Colorectal Surgery, Union Hospital, Fujian Medical University, Fuzhou, China
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Pavlidis ET, Pavlidis TE. Role of bevacizumab in colorectal cancer growth and its adverse effects: a review. World J Gastroenterol 2013; 19:5051-5060. [PMID: 23964138 PMCID: PMC3746376 DOI: 10.3748/wjg.v19.i31.5051] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 07/07/2013] [Accepted: 07/19/2013] [Indexed: 02/06/2023] Open
Abstract
Angiogenesis affects both wound healing and malignant cell growth through nutrients and oxygen. Vascular endothelial growth factor (VEGF) is the most important element involved in this complex process. Inhibition of VEGF influences angiogenesis and may restrict tumor growth and metastatic ability. Modern anti-angiogenic therapy is based on this theory. Bevacizumab is a recombinant humanized monoclonal antibody (immunoglobulin G1) which binds with VEGF-A forming a large molecule. It can not be bound with VEGF tyrosine kinase receptors preventing VEGF-A incorporation; thus its activity is inhibited inducing blockage of VEGF-mediated angiogenesis. Bevacizumab, in combination with chemotherapy or other novel targeted therapeutic agents, is currently used more frequently in clinical practice, mainly for managing advanced colorectal cancer. It is also used for managing other malignancies, such as breast cancer, pancreatic cancer, prostate cancer, non small-cell lung cancer, metastatic renal carcinoma and ovarian tumors. Although it is generally considered a safe treatment, there are reports of some rare side effects which should be taken into account. Recent experiments in rats and mice show promising results with a wider therapeutic range.
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Maletzki C, Stier S, Gruenert U, Gock M, Ostwald C, Prall F, Linnebacher M. Establishment, characterization and chemosensitivity of three mismatch repair deficient cell lines from sporadic and inherited colorectal carcinomas. PLoS One 2012; 7:e52485. [PMID: 23300683 PMCID: PMC3534085 DOI: 10.1371/journal.pone.0052485] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2012] [Accepted: 11/14/2012] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) represents a morphologic and molecular heterogenic disease. This heterogeneity substantially impairs drug effectiveness and prognosis. The subtype of mismatch repair deficient (MMR-D) CRCs, accounting for about 15% of all cases, shows particular differential responses up to resistance towards currently approved cytostatic drugs. Pre-clinical in vitro models representing molecular features of MMR-D tumors are thus mandatory for identifying biomarkers that finally help to predict responses towards new cytostatic drugs. Here, we describe the successful establishment and characterization of three patient-derived MMR-D cell lines (HROC24, HROC87, and HROC113) along with their corresponding xenografts. METHODOLOGY MMR-D cell lines (HROC24, HROC87, and HROC113) were established from a total of ten clinicopathological well-defined MMR-D cases (120 CRC cases in total). Cells were comprehensively characterized by phenotype, morphology, growth kinetics, invasiveness, and molecular profile. Additionally, response to clinically relevant chemotherapeutics was examined in vitro and in vivo. PRINCIPAL FINDINGS Two MMR-D lines showing CIMP-H derived from sporadic CRC (HROC24: K-ras(wt), B-raf(mut), HROC87: K-ras(wt), B-raf(mut)), whereas the HROC113 cell line (K-ras(mut), B-raf(wt)) was HNPCC-associated. A diploid DNA-status could be verified by flow cytometry and SNP Array analysis. All cell lines were characterized as epithelial (EpCAM(+)) tumor cells, showing surface tumor marker expression (CEACAM(+)). MHC-class II was inducible by Interferon-γ stimulation. Growth kinetics as well as invasive potential was quite heterogeneous between individual lines. Besides, MMR-D cell lines exhibited distinct responsiveness towards chemotherapeutics, even when comparing in vitro and in vivo sensitivity. CONCLUSIONS These newly established and well-characterized, low-passage MMR-D cell lines provide a useful tool for future investigations on the biological characteristics of MMR-D CRCs, both of sporadic and hereditary origin. Additionally, matched patient-derived immune cells allow for comparative genetic studies.
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Affiliation(s)
- Claudia Maletzki
- Division of Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
| | - Saskia Stier
- Division of Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
| | - Ulrike Gruenert
- Division of Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
| | - Michael Gock
- Department of General, Thoracic, Vascular and Transplantation Surgery, University of Rostock, Rostock, Germany
| | | | - Friedrich Prall
- Institute of Pathology, University of Rostock, Rostock, Germany
| | - Michael Linnebacher
- Division of Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
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Hao WH, Wang JJ, Hsueh SP, Hsu PJ, Chang LC, Hsu CS, Hsu KY. In vitro and in vivo studies of pharmacokinetics and antitumor efficacy of D07001-F4, an oral gemcitabine formulation. Cancer Chemother Pharmacol 2012; 71:379-88. [PMID: 23143189 DOI: 10.1007/s00280-012-2017-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2012] [Accepted: 10/21/2012] [Indexed: 12/01/2022]
Abstract
PURPOSE The chemotherapy agent gemcitabine is currently administered intravenously because the drug has poor oral bioavailability. In order to assess the pharmacokinetics and antitumor activity of D07001-F4, a new self-microemulsifying oral drug delivery system preparation of gemcitabine, this study was performed to compare the effect of D07001-F4 with administered gemcitabine in vitro and in vivo. METHODS D07001-F4 pharmacokinetics was examined by evaluation of in vitro deamination of D07001-F4 and gemcitabine hydrochloride by recombinant human cytidine deaminase (rhCDA) and in vivo evaluation of D07001-F4 pharmacokinetics in mice. Antitumor activity was evaluated by comparing the effect of D07001-F4 and gemcitabine hydrochloride in inhibiting growth in nine cancer cell lines and by examining the effect of D07001-F4 and gemcitabine in two xenograft tumor models in mice. RESULTS In vitro deamination of D07001-F4 by rhCDA was 3.3-fold slower than deamination of gemcitabine hydrochloride. Growth inhibition by D07001-F4 of 7 of the 8 cancer cell lines was increased compared with that seen with gemcitabine hydrochloride, and D07001-F4 inhibited the growth of pancreatic and colon cancer xenografts. In vivo pharmacokinetics showed the oral bioavailability of D07001-F4 to be 34%. CONCLUSIONS D07001-F4 was effective against several cancer types, was metabolized more slowly than gemcitabine hydrochloride, and exhibited enhanced oral bioavailability.
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Affiliation(s)
- Wei-Hua Hao
- InnoPharmax Inc, 9F, No 22, Lane 478, Rueiguang Rd, Neihu District, Taipei 11492, Taiwan
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