|
1
|
García-Alfonso P, Elez E, Soto-Alsar J, Páez D, Fernández-Montes A, Graña B, Salud A, Yubero A, Gómez-España MA, Macías I, Quintero G, López-López C, Fernández-Rodríguez T, Grávalos C, González-Flores E, Guix M, García Paredes B, Reina JJ, Rodríguez Mowbray JR, Sastre J, Aranda E. Maintenance with 5-FU/LV-aflibercept after induction with FOLFIRI-aflibercept versus FOLFIRI-aflibercept until progression as second-line treatment in older adults with metastatic colorectal cancer: the AFEMA phase II randomized trial. ESMO Open 2024; 9:103986. [PMID: 39608305 PMCID: PMC11635659 DOI: 10.1016/j.esmoop.2024.103986] [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: 07/23/2024] [Revised: 10/14/2024] [Accepted: 10/15/2024] [Indexed: 11/30/2024] Open
Abstract
BACKGROUND The combination chemotherapy i.v. 5-fluorouracil (5-FU), irinotecan, and aflibercept (FOLFIRI-A) is a standard second-line treatment of metastatic colorectal cancer (mCRC). The aim was to assess maintenance treatment in second-line setting in older patients (aged ≥70 years) with mCRC. PATIENTS AND METHODS We evaluated FOLFIRI-A given for six cycles followed by maintenance with 5-FU/leucovorin (LV)-A (arm A) or FOLFIRI-A (arm B) until progression in older adults with mCRC in the AFEMA randomized, open-label, non-inferiority phase II trial (EudraCT2016-004076-21/NCT03279289). Patients aged ≥70 years who previously failed oxaliplatin-fluoropyrimidine were randomly allocated (1 : 1) to either arm A (experimental) or arm B (control). After enrolling 35 patients, the FOLFIRI dose was reduced to level 1 in both arms due to toxicity. The primary endpoint was median progression-free survival (PFS); and secondary endpoints were median overall survival, objective response rate, and safety. Non-inferiority required the upper confidence interval (CI) limit to not exceed a hazard ratio (HR) of 1.5 (one-sided α = 0.075, 80% power). RESULTS A total of 170 patients were randomly allocated to arm A or arm B (n = 85 each). The median follow-up was 12.2 versus 10.9 months in arm A versus arm B. Most patients died (83.5% versus 88.2% in arm A versus arm B), mainly from disease progression. PFS non-inferiority was met (HR = 0.78, 95% CI 0.566-1.076, P = 0.131) with a median PFS of 6.1 versus 5.5 months in arm A versus arm B. Median overall survival was similar in arms A and B (12.2 and 11.5 months, respectively) (HR = 0.89, 95% CI 0.640-1.227, P = 0.467). During the maintenance phase, severe asthenia (4.5% versus 21.6%, P = 0.038), serious adverse events (SAEs) (17.8% versus 37.8%, P = 0.049), and treatment-related SAEs (6.7% versus 10.8%, P = 0.695) were reduced in arm A versus arm B. CONCLUSION In older adults, induction with six cycles of FOLFIRI-A plus maintenance with 5-FU/LV-A was non-inferior to FOLFIRI-A until progression. Severe asthenia, SAEs, and treatment-related SAEs were reduced with 5-FU/LV-A maintenance.
Collapse
Affiliation(s)
- P García-Alfonso
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain.
| | - E Elez
- Medical Oncology Department, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, CIBERONC, Barcelona, Spain
| | - J Soto-Alsar
- Medical Oncology Department, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Universidad Complutense, Madrid, Spain
| | - D Páez
- Department of Medical Oncology, Hospital Santa Creu i Sant Pau, U705 CIBERER, Barcelona, Spain
| | - A Fernández-Montes
- Department of Medical Oncology, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - B Graña
- Department of Medical Oncology, Complexo Hospitalario Universitario A Coruña, Instituto Investigación Biomédica INIBIC, A Coruña, Spain
| | - A Salud
- Department of Medical Oncology, Hospital Universitario Arnau de Vilanova de Lleida, Lleida, Spain
| | - A Yubero
- Department of Medical Oncology, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
| | - M A Gómez-España
- Department of Medical Oncology IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, Hospital Universitario Reina Sofía, Córdoba, Spain
| | - I Macías
- Department of Medical Oncology, Hospital Parc Taulí de Sabadell, Barcelona, Spain
| | - G Quintero
- Department of Medical Oncology, Hospital Lucus Augusti, Lugo, Spain
| | - C López-López
- Department of Medical Oncology, Hospital Universitario Marqués de Valdecilla, IDIVAL, UNICAN, Santander, Spain
| | | | - C Grávalos
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - E González-Flores
- Department of Medical Oncology, Hospital Virgen de las Nieves, Granada, Spain
| | - M Guix
- Department of Medical Oncology, Hospital del Mar, Barcelona, Spain
| | - B García Paredes
- Department of Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain
| | - J J Reina
- Department of Medical Oncology, Complejo Hospitalario Virgen de la Macarena, Sevilla, Spain
| | | | - J Sastre
- Department of Medical Oncology, Hospital Clínico San Carlos, Instituto de Investigación Hospital Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain
| | - E Aranda
- Department of Medical Oncology IMIBIC, Universidad de Córdoba, CIBERONC, Instituto de Salud Carlos III, Hospital Universitario Reina Sofía, Córdoba, Spain
| |
Collapse
|
|
2
|
Chen J, Chen W, Li X, Ye Y, Huang W, Gao L, Zhang M. CBC-1 as a Cynanbungeigenin C derivative inhibits the growth of colorectal cancer through targeting Hedgehog pathway component GLI 1. Steroids 2024; 206:109421. [PMID: 38614233 DOI: 10.1016/j.steroids.2024.109421] [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: 01/22/2024] [Revised: 03/28/2024] [Accepted: 04/06/2024] [Indexed: 04/15/2024]
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers that results in death in worldwide. The Hedgehog (HH) signalling pathway regulates the initiation and progression of CRC. Inhibiting the HH pathway has been presented as a potential treatment strategy in recent years. Cynanbungeigenin C (CBC) is a new type of C21 steroid that has been previously reported for the treatment of medulloblastoma. However, its further investigation was limited by its poor water solubility. In this study, six new CBC derivatives were synthesized through the structural modification of CBC, and four of them showed better water solubility than CBC. Moreover, their antiproliferative activities on CRC were evaluated. It was found that CBC-1 presented the best inhibitory effect on three types of CRC cell lines, and this effect was superior to that of CBC. Mechanistically, CBC-1 inhibited the proliferation of CRC cells through regulation of mRNA and proteins of the HH pathway according to qRT-PCR and Western blotting analysis. Furthermore, Cellular Thermal Shift Assay results indicated that CBC-1 regulated this signalling pathway by targeting glioma‑associated oncogene (GLI 1).In addition, cell apoptosis was induced increasingly by transfection with GLI 1 siRNA or treatment with CBC-1 to downregulate GLI 1. Last, the in vivo results demonstrated that CBC-1 significantly reduced tumour size and downregulated GLI 1 in CRC. Therefore, this study suggests that CBC-1, a new GLI 1 inhibitor derived from natural products, may be developed as a potential antitumour candidate for CRC treatment.
Collapse
Affiliation(s)
- Jinwen Chen
- Department of Pharmacy, The First People's Hospital of Xiaoshan District, Hangzhou, Zhejiang 311200, China
| | - Wei Chen
- Department of Pharmacy, The First People's Hospital of Xiaoshan District, Hangzhou, Zhejiang 311200, China
| | - Xiaoyu Li
- Department of Pharmacy, The First People's Hospital of Xiaoshan District, Hangzhou, Zhejiang 311200, China.
| | - Yiping Ye
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Wenkang Huang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lijuan Gao
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China.
| | - Meng Zhang
- Department of Pharmacy, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang, China.
| |
Collapse
|
|
3
|
Saadh MJ, Allela OQB, Sattay ZJ, Al Zuhairi RAH, Ahmad H, Eldesoky GE, Adil M, Ali MS. Deciphering the functional landscape and therapeutic implications of noncoding RNAs in the TGF-β signaling pathway in colorectal cancer: A comprehensive review. Pathol Res Pract 2024; 255:155158. [PMID: 38320438 DOI: 10.1016/j.prp.2024.155158] [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: 12/21/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 02/08/2024]
Abstract
Colorectal cancer (CRC) remains a major global health concern, necessitating an in-depth exploration of the intricate molecular mechanisms underlying its progression and potential therapeutic interventions. Transforming Growth Factor-β (TGF-β) signaling, a pivotal pathway implicated in CRC plays a dual role as a tumor suppressor in the early stages and a promoter of tumor progression in later stages. Recent research has shed light on the critical involvement of noncoding RNAs (ncRNAs) in modulating the TGF-β signaling pathway, introducing a new layer of complexity to our understanding of CRC pathogenesis. This comprehensive review synthesizes the current state of knowledge regarding the function and therapeutic potential of various classes of ncRNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the context of TGF-β signaling in CRC. The intricate interplay between these ncRNAs and key components of the TGF-β pathway is dissected, revealing regulatory networks that contribute to the dynamic balance between tumor suppression and promotion. Emphasis is placed on how dysregulation of specific ncRNAs can disrupt this delicate equilibrium, fostering CRC initiation, progression, and metastasis. Moreover, the review provides a critical appraisal of the emerging therapeutic strategies targeting ncRNAs associated with TGF-β signaling in CRC. The potential of these ncRNAs as diagnostic and prognostic biomarkers is discussed, highlighting their clinical relevance. Additionally, the challenges and prospects of developing RNA-based therapeutics, such as RNA interference and CRISPR/Cas-based approaches, are explored in the context of modulating TGF-β signaling for CRC treatment. In conclusion, this review offers a comprehensive overview of the intricate interplay between ncRNAs and the TGF-β signaling pathway in CRC. By unraveling the functional significance of these regulatory elements, we gain valuable insights into the molecular landscape of CRC, paving the way for the development of novel and targeted therapeutic interventions aimed at modulating the TGF-β signaling cascade through the manipulation of ncRNAs.
Collapse
Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan
| | | | - Zahraa Jasim Sattay
- Department of Medical Laboratory Technology l, University of imam Jaafar Al-Sadiq, Iraq
| | | | - Hijaz Ahmad
- Section of Mathematics, International Telematic University Uninettuno, Corso Vittorio Emanuele II, 39, Rome 00186, Italy; Center for Applied Mathematics and Bioinformatics, Gulf University for Science and Technology, Kuwait; Department of Computer Science and Mathematics, Lebanese American University, Beirut, Lebanon
| | - Gaber E Eldesoky
- Chemistry Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | | | | |
Collapse
|
|
4
|
Tang YL, Li DD, Duan JY, Sheng LM, Wang X. Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments. World J Gastroenterol 2023; 29:926-948. [PMID: 36844139 PMCID: PMC9950860 DOI: 10.3748/wjg.v29.i6.926] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/24/2022] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.
Collapse
Affiliation(s)
- Yuan-Ling Tang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Dan-Dan Li
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yu Duan
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Lei-Ming Sheng
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Radiation Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Abdominal Cancer, Cancer Center, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| |
Collapse
|
|
5
|
Peng BY, Singh AK, Chan CH, Deng YH, Li PY, Su CW, Wu CY, Deng WP. AGA induces sub-G1 cell cycle arrest and apoptosis in human colon cancer cells through p53-independent/p53-dependent pathway. BMC Cancer 2023; 23:1. [PMID: 36597025 PMCID: PMC9808967 DOI: 10.1186/s12885-022-10466-x] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 12/21/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Despite the advancement in chemotherapeutic drugs for colon cancer treatment, it is still a life-threatening disease worldwide due to drug resistance. Therefore, an urgently needed to develop novel drugs for colon cancer therapies. AGA is a combination of traditional Chinese medicine Antler's extract (A), Ganoderma lucidum (G), and Antrodia camphorata (A); it contains a lot of biomolecules like polysaccharides, fatty acids, and triterpenoids that are known to exerting anti-oxidative, anti-inflammatory, anti-microbial and anti-tumor activities in oral cancer. In this study, we investigate AGA anti-proliferative, anti-metastatic and apoptotic activity to explore its anti-cancer activity against colon cancer cells and its underlying mechanism. METHOD Here, in-vitro studies were performed to determine the antiproliferative activity of AGA through MTT and colony formation assays. Wound healing and transwell migration assay were used to evaluate the metastasis. Flow cytometry and protein expression were used to investigate the involved molecular mechanism by evaluating the cell cycle and apoptosis. The in-vivo anti-cancerous activity of AGA was assessed by xenograft mice model of colon cancer cells. RESULTS We found that AGA significantly inhibited the proliferative capacity and metastasis of colon cancer cells in-vitro. In addition, AGA induced cell cycle arrest in the sub-G1 phase through upregulating p21 and downregulating CDK2, CDK6 in SW620, and CDK4 in SW480 and HT29, respectively. Annexin-v assay indicated that colon cancer cells had entered early and late apoptosis after treatment with AGA. Furthermore, a mechanistic protein expressions study revealed that AGA in p53-dependent and independent regulated the apoptosis of colon cancer by downregulating the p53 protein expression in SW620 and SW480 cells but upregulating in a dose-dependent manner in HT29 cells and increasing the expression of Bax and caspase-9 to inhibit the colon cancer cells. In vivo study, we found that AGA significantly reduced the xenograft tumor growth in NOD/SCID mice with no adverse effect on the kidney and liver. CONCLUSION Collectively, AGA has the potential to inhibit colon cancer through inhibiting proliferation, migration, and cell cycle kinase by upregulating p21 protein expression and promoting the apoptotic protein in a p53-dependent and independent manner.
Collapse
Affiliation(s)
- Bou-Yue Peng
- grid.412897.10000 0004 0639 0994Department of Dentistry, Taipei Medical University Hospital, 110301 Taipei, Taiwan ,grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan
| | - Abhinay Kumar Singh
- grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan ,grid.412896.00000 0000 9337 0481Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan
| | - Chun-Hao Chan
- grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan ,grid.412896.00000 0000 9337 0481Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan
| | - Yue-Hua Deng
- grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan ,grid.412896.00000 0000 9337 0481Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan
| | - Pin-Ying Li
- grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan
| | - Chun-Wei Su
- grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan ,grid.412896.00000 0000 9337 0481Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan
| | - Chia-Yu Wu
- grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan ,grid.412897.10000 0004 0639 0994Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Medical University Hospital, 110301 Taipei, Taiwan
| | - Win-Ping Deng
- grid.412896.00000 0000 9337 0481School of Dentistry, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan ,grid.412896.00000 0000 9337 0481Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, 110301 Taipei, Taiwan ,grid.256105.50000 0004 1937 1063Graduate Institute of Biomedical and Pharmaceutical Science, Fu Jen Catholic University, 242062 Taipei, Taiwan ,grid.265231.10000 0004 0532 1428Department of Life Science, Tunghai University, 407224 Taichung, Taiwan
| |
Collapse
|
|
6
|
Ren T, Jia H, Wu Q, Zhang Y, Ma Q, Yao D, Gao X, Xie D, Xu Z, Zhao Q, Zhang Y. Inhibition of Angiogenesis and Extracellular Matrix Remodeling: Synergistic Effect of Renin-Angiotensin System Inhibitors and Bevacizumab. Front Oncol 2022; 12:829059. [PMID: 35847929 PMCID: PMC9283643 DOI: 10.3389/fonc.2022.829059] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
Bevacizumab (Bev) is a humanized vascular endothelial growth factor monoclonal antibody that is used with chemotherapeutic drugs for the treatment of metastatic colorectal cancer (mCRC). Bev-induced hypertension (HT) is the most common adverse reaction during clinical practice. However, at present, appropriate antihypertensive agents for Bev-induced HT are unavailable. In this study, retrospective analysis of clinical data from mCRC patients who received renin-angiotensin system inhibitors (RASIs) showed significant survival benefits of overall survival (OS) and progression-free survival (PFS) over patients who received calcium channel blockers (CCBs) and patients who received no antihypertensive drug (NO: Y2020046 retrospectively registered). An experiment of HCT116 colon cancer cell xenografts in mice confirmed that combined treatment of Bev and lisinopril (Lis), a RASI, synergistically inhibited subcutaneous tumor growth and enhanced the concentration of 5-fluorouracil (5-Fu) in tumor tissues. Our results showed that the addition of Lis did not interfere with the vascular normalization effect promoted by Bev, but also inhibited collagen and hyaluronic acid (HA) deposition and significantly downregulated the expression of TGF-β1 and downstream SMAD signaling components which were enhanced by Bev, ultimately remodeling primary extracellular matrix components. In conclusion, RASIs and Bev have synergistic effect in the treatment of colorectal cancer and RASIs might be an optimal choice for the treatment of Bev-induced HT.
Collapse
Affiliation(s)
- Tianshu Ren
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, China
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Hui Jia
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Qiong Wu
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Yan Zhang
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Qun Ma
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Dong Yao
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Xudong Gao
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Danni Xie
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Zihua Xu
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Qingchun Zhao
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, China
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
- *Correspondence: Qingchun Zhao, ; Yingshi Zhang,
| | - Yingshi Zhang
- Department of Life Science and Biochemistry, Shenyang Pharmaceutical University, Shenyang, China
- *Correspondence: Qingchun Zhao, ; Yingshi Zhang,
| |
Collapse
|
|
7
|
Zhang M, Tao Z, Gao L, Chen F, Ye Y, Xu S, Huang W, Li X. Toosendanin inhibits colorectal cancer cell growth through the Hedgehog pathway by targeting Shh. Drug Dev Res 2022; 83:1201-1211. [PMID: 35656621 DOI: 10.1002/ddr.21951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 04/26/2022] [Accepted: 05/09/2022] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. This complex and often fatal disease has a high mortality rate. The Hedgehog (Hh) signaling pathway is crucial in CRC. Many studies have indicated that Shh is overexpressed in cancer stem cells (CSCs), and shh overexpression is positively correlated with CRC tumorigenesis. New drugs that kill CRC cells through the Hh pathway are needed. Toosendanin (TSN), a natural triterpenoid saponin extracted from the bark or fruit of Melia toosendan Sieb. et Zucc, can inhibit various tumors. Here, we investigated the effects of TSN in CRC and explored the possible targets and mechanisms. Shh-Light Ⅱ cells were treated with TSN and tested by dual luciferase reporter assays to determine the relationship with the Hh pathway. Cell Counting Kit-8 (CCK-8) assays were used to test the inhibitory effects of TSN on CRC cells. The expression of Hh components after TSN treatment was detected using western blots and quantitative reverse transcription polymerase chain reaction. Cellular thermal shift assays confirmed the targets of TSN. The same effects of TSN on xenograft tumor growth were investigated in vivo. The average weight, volume of the finally resected tumor, and the expression of Shh in the TSN-treated groups were significantly lower than those of the control group. This result strongly suggested that TSN administration inhibited CRC growth in vivo. Our research preliminarily demonstrated that the target of TSN was Shh and that TSN inhibits CRC cell growth by inhibiting the Hh pathway, identifying a new anticancer molecular mechanism of TSN in CRC.
Collapse
Affiliation(s)
- Meng Zhang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhongyi Tao
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Lijuan Gao
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Fengyang Chen
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Yiping Ye
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Shifang Xu
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Wenkang Huang
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Xiaoyu Li
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, China.,Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou, Zhejiang, China
| |
Collapse
|
|
8
|
Giuliani J, Mantoan B, Bonetti A. Cost-effectiveness of maintenance therapy after first-line treatment in metastatic colorectal cancer. J Oncol Pharm Pract 2021; 28:194-198. [PMID: 34558365 DOI: 10.1177/10781552211038929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
| | | | - Andrea Bonetti
- 18586Department of Oncology, Az. ULSS 9 Scaligera, Italy
| |
Collapse
|
|
9
|
Zhong ZA, Michalski MN, Stevens PD, Sall EA, Williams BO. Regulation of Wnt receptor activity: Implications for therapeutic development in colon cancer. J Biol Chem 2021; 296:100782. [PMID: 34000297 PMCID: PMC8214085 DOI: 10.1016/j.jbc.2021.100782] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 05/05/2021] [Accepted: 05/10/2021] [Indexed: 12/13/2022] Open
Abstract
Hyperactivation of Wnt/β-catenin (canonical) signaling in colorectal cancers (CRCs) was identified in the 1990s. Most CRC patients have mutations in genes that encode components of the Wnt pathway. Inactivating mutations in the adenomatous polyposis coli (APC) gene, which encodes a protein necessary for β-catenin degradation, are by far the most prevalent. Other Wnt signaling components are mutated in a smaller proportion of CRCs; these include a FZD-specific ubiquitin E3 ligase known as ring finger protein 43 that removes FZDs from the cell membrane. Our understanding of the genetic and epigenetic landscape of CRC has grown exponentially because of contributions from high-throughput sequencing projects such as The Cancer Genome Atlas. Despite this, no Wnt modulators have been successfully developed for CRC-targeted therapies. In this review, we will focus on the Wnt receptor complex, and speculate on recent discoveries about ring finger protein 43regulating Wnt receptors in CRCs. We then review the current debate on a new APC-Wnt receptor interaction model with therapeutic implications.
Collapse
Affiliation(s)
- Zhendong A Zhong
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, USA
| | - Megan N Michalski
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, USA
| | - Payton D Stevens
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, USA
| | - Emily A Sall
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, USA
| | - Bart O Williams
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, USA.
| |
Collapse
|
|
10
|
Ren T, Wang S, Shen Z, Xu C, Zhang Y, Hui F, Qi X, Zhao Q. Efficacy and Safety of Bevacizumab Plus Oxaliplatin- or Irinotecan-Based Doublet Backbone Chemotherapy as the First-Line Treatment of Metastatic Colorectal Cancer: A Systematic Review and Meta-analysis. Drug Saf 2021; 44:29-40. [PMID: 33180265 DOI: 10.1007/s40264-020-00997-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2020] [Indexed: 02/07/2023]
Abstract
INTRODUCTION AND OBJECTIVE Guidelines recommend combined doublet backbone chemotherapy based on 5-fluorouracil and oxaliplatin (OX) or irinotecan (IR) as the first-line treatment options for metastatic colorectal cancer. However, it is still unknown which is better when combined with bevacizumab (BEV). This systematic review and meta-analysis were performed to compare BEV-IR with BEV-OX regimens in terms of efficacy and safety. METHODS We searched studies from databases including MEDLINE, EMBASE, CENTRAL, and conference papers. The outcomes were overall response rate, overall survival, progression-free survival, and the incidence of the most common adverse events. The dichotomous data were reported as the risk ratio (RR) and the survival outcomes were extracted as the hazard ratio with 95% confidence interval (CI). RESULTS Eleven studies including 5632 patients were identified. No difference was found in overall survival or overall response rate between BEV-IR and BEV-OX regimens. The pooled progression-free survival was significantly longer in the BEV-IR group than the BEV-OX group (hazard ratio = 0.92, 95% CI 0.87-0.98, p = 0.08). Compared with the BEV-OX group, the BEV-IR group was related to a higher risk of bleeding events (RR = 0.80, 95% CI 0.64-0.98, p = 0.03), venous thromboembolism (RR = 0.60, 95% CI 0.46-0.79, p = 0.0002), and diarrhea (RR = 0.71, 95% CI 0.62-0.80, p < 0.00001). Conversely, the BEV-OX group was related to a higher risk of thrombocytopenia (RR 2.39, 95% CI 1.67-3.42, p < 0.00001) and neuropathy (RR 3.80, 95% CI 1.90-7.64, p = 0.0002). CONCLUSIONS The BEV-IR regimen was superior in improving progression-free survival as the first-line treatment for metastatic colorectal cancer. The two different doublet regimens combined with BEV had their specific features of adverse events.
Collapse
Affiliation(s)
- Tianshu Ren
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China
| | - Shu Wang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Zexu Shen
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Chang Xu
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Yingshi Zhang
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Fuhai Hui
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China
| | - Qingchun Zhao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
- Department of Pharmacy, General Hospital of Northern Theater Command, Shenyang, China.
| |
Collapse
|
|
11
|
Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 2020; 5:22. [PMID: 32296018 PMCID: PMC7082344 DOI: 10.1038/s41392-020-0116-z] [Citation(s) in RCA: 994] [Impact Index Per Article: 198.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/24/2019] [Accepted: 12/31/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.
Collapse
Affiliation(s)
- Yuan-Hong Xie
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
| |
Collapse
|
|
12
|
Ellebrecht DB, Theisen-Kunde D, Kuempers C, Keck T, Kleemann M, Wolken H. Analysis of laparoscopic laser liver resection in standardized porcine model. Surg Endosc 2018; 32:4966-4972. [PMID: 29869079 DOI: 10.1007/s00464-018-6258-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Accepted: 05/29/2018] [Indexed: 01/22/2023]
Abstract
BACKGROUND Hepatocellular carcinoma is a highly prevalent and lethal primary neoplasia of the liver and metastases of other malignancies affect most frequently the liver. Minimally invasive surgical approach for liver resections is advancing. Dissection of liver parenchyma by laparoscopic technique remains challenging and new technologies are in need. Therefore, we asked whether it is feasible to dissect liver tissue comparably in terms of speed and hemostasis with a non-contact 1.9-µm cw-laser device and whether there are differences in the postoperative healing process compared to a gold standard device (ultrasound aspirator) in an experimental model. METHODS Laparoscopic laser and ultrasound aspirator standardized partial liver resections were performed in seven pigs. Resection time, hemostasis time, and blood loss were evaluated. After at least 10 days, representative specimen of the resection areas was collected via re-laparoscopy and biopsy and side effects like hematoma, abscess, or bilioma were noted. Histologically, coagulation necrosis margin, granulation tissue zone, tissue fibrosis, and giant cell count were analyzed. RESULTS Laparoscopic laser liver resection was three times faster compared to the laparoscopic ultrasound aspirator. Blood loss was equal in both groups. No side effects like hematoma or bilioma occurred. Histologically, specimen showed the same expansion of coagulation necrosis zone and granulation tissue. Fibrotic scar could be determined in three cases in both groups, respectively. However, giant cell count was significant higher in the laser resection group. CONCLUSIONS The 1.9-µm cw-laser device enables a safe and fast liver resection in an experimental pig model compared to a gold standard (ultrasound aspirator) laparoscopic liver resection method. Wound healing is not interfered by laser liver resection.
Collapse
Affiliation(s)
- David Benjamin Ellebrecht
- Department of Surgery, University Medical Centre Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
| | | | - Christiane Kuempers
- Pathology of the University Hospital Schleswig-Holstein, Campus Lübeck and the Research Center Borstel, Leibniz Lung Center, Site Luebeck, Department of Pathology, Ratzeburger Allee 160, 23538, Lübeck, Germany
| | - Tobias Keck
- Department of Surgery, University Medical Centre Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
| | - Markus Kleemann
- Department of Surgery, University Medical Centre Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
| | - Heike Wolken
- Department of Medicine, University Medical Centre Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
| |
Collapse
|
|
13
|
Sánchez-Gundín J, Fernández-Carballido AM, Martínez-Valdivieso L, Barreda-Hernández D, Torres-Suárez AI. New Trends in the Therapeutic Approach to Metastatic Colorectal Cancer. Int J Med Sci 2018; 15:659-665. [PMID: 29910669 PMCID: PMC6001415 DOI: 10.7150/ijms.24453] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 03/02/2018] [Indexed: 12/22/2022] Open
Abstract
Important developments in chemotherapy for metastatic colorectal cancer over the last years are reviewed, with an emphasis on the most recently published data from clinical trials. The systematic review of current literature was conducted involving Pubmed Central® research and full articles were obtained and analyzed when appropriate. Fluorouracil still constitutes the backbone of metastatic colorectal cancer treatment; fluorouracil combination plus either irinotecan (FOLFIRI), oxaliplatin (FOLFOX) or capecitabine (CAPOX or XELOX) are chemotherapy protocols established as treatments producing similar outcomes. Actual treatment involves these chemotherapy protocols in combination with new molecular targeted drugs: bevacizumab and aflibercept (anti-vascular endothelial growth factor monoclonal antibody) and cetuximab and panitumumab (anti-epidermal growth factor receptor monoclonal antibody for patients with wild type KRAS) which confer significant survival benefits in select patients as first- or second-line therapies. The factors affecting the decisions for one treatment over other are related to the patient and toxicity drug. Finally, metastatic colorectal cancer patients progressing after all standard therapies (maintaining a good ECOG performance status) could be candidates for further therapies such as regorafenib and TAS-102. Regarding the future, promising therapies are under development for the metastatic colorectal cancer treatment and several agents are currently being evaluated in different clinical trials.
Collapse
Affiliation(s)
- Julia Sánchez-Gundín
- Hospital Pharmacist. Hospital Pharmacy Department. Virgen de la Luz Hospital, Hermandad de Donantes de Sangre, s/n, 16002 Cuenca (Spain).,Department of Pharmacy and Pharmaceutical Technology. Complutense University of Madrid, 28040 Madrid (Spain)
| | - Ana María Fernández-Carballido
- Department of Pharmacy and Pharmaceutical Technology. Complutense University of Madrid, 28040 Madrid (Spain).,Institute of Industrial Pharmacy. Complutense University of Madrid, 28040 Madrid (Spain)
| | - Lidia Martínez-Valdivieso
- Hospital Pharmacist. Hospital Pharmacy Department. Virgen de la Luz Hospital, Hermandad de Donantes de Sangre, s/n, 16002 Cuenca (Spain)
| | - Dolores Barreda-Hernández
- Hospital Pharmacist. Hospital Pharmacy Department. Virgen de la Luz Hospital, Hermandad de Donantes de Sangre, s/n, 16002 Cuenca (Spain)
| | - Ana Isabel Torres-Suárez
- Department of Pharmacy and Pharmaceutical Technology. Complutense University of Madrid, 28040 Madrid (Spain).,Institute of Industrial Pharmacy. Complutense University of Madrid, 28040 Madrid (Spain)
| |
Collapse
|
|
14
|
Rivera F, Valladares M, Gea S, López-Martínez N. Cost-effectiveness analysis in the Spanish setting of the PEAK trial of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer. J Med Econ 2017; 20:574-584. [PMID: 28107090 DOI: 10.1080/13696998.2017.1285780] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To assess the cost-effectiveness of panitumumab in combination with mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin) vs bevacizumab in combination with mFOLFOX6 as first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC) in Spain. METHODS A semi-Markov model was developed including the following health states: Progression free; Progressive disease: Treat with best supportive care; Progressive disease: Treat with subsequent active therapy; Attempted resection of metastases; Disease free after metastases resection; Progressive disease: after resection and relapse; and Death. Parametric survival analyses of patient-level progression free survival and overall survival data from the PEAK Phase II clinical trial were used to estimate health state transitions. Additional data from the PEAK trial were considered for the dose and duration of therapy, the use of subsequent therapy, the occurrence of adverse events, and the incidence and probability of time to metastasis resection. Utility weightings were calculated from patient-level data from panitumumab trials evaluating first-, second-, and third-line treatments. The study was performed from the Spanish National Health System (NHS) perspective including only direct costs. A life-time horizon was applied. Probabilistic sensitivity analyses and scenario sensitivity analyses were performed to assess the robustness of the model. RESULTS Based on the PEAK trial, which demonstrated greater efficacy of panitumumab vs bevacizumab, both in combination with mFOLFOX6 first-line in wild-type RAS mCRC patients, the estimated incremental cost per life-year gained was €16,567 and the estimated incremental cost per quality-adjusted life year gained was €22,794. The sensitivity analyses showed the model was robust to alternative parameters and assumptions. LIMITATIONS The analysis was based on a simulation model and, therefore, the results should be interpreted cautiously. CONCLUSIONS Based on the PEAK Phase II clinical trial and taking into account Spanish costs, the results of the analysis showed that first-line treatment of mCRC with panitumumab + mFOLFOX6 could be considered a cost-effective option compared with bevacizumab + mFOLFOX6 for the Spanish NHS.
Collapse
Affiliation(s)
- Fernando Rivera
- a Hospital Universitario Marqués de Valdecilla , Santander , Spain
| | | | - Salvador Gea
- c Unidad de Farmacoeconomía e Investigación de Resultados en Salud, AMGEN , S . A. , Barcelona , Spain
| | | |
Collapse
|
|
15
|
Bai L, Wang F, Li ZZ, Ren C, Zhang DS, Zhao Q, Lu YX, Wang DS, Ju HQ, Qiu MZ, Wang ZQ, Wang FH, Xu RH. Chemotherapy plus bevacizumab versus chemotherapy plus cetuximab as first-line treatment for patients with metastatic colorectal cancer: Results of a registry-based cohort analysis. Medicine (Baltimore) 2016; 95:e4531. [PMID: 28002313 PMCID: PMC5181797 DOI: 10.1097/md.0000000000004531] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The present observational cohort study was designed to elucidate the efficacy and safety profile of bevacizumab or cetuximab with chemotherapy as the first-line treatment in Chinese patients with metastatic colorectal cancer (mCRC). Clinical data were collected from a single-center registry study where mCRC patients received first-line fluoropyrimidine-based chemotherapy combined with either bevacizumab (188 patients with KRAS wild-type or mutated tumors) or cetuximab (101 patients with KRAS wild-type tumors) between January 2009 and December 2013. The Kaplan-Meier method was used for survival analysis. Cox proportional hazards model was used for estimating the prognostic and predictive values of clinicopathological characteristics. No statistically significant difference was observed between the bevacizumab and cetuximab groups in terms of median progression-free survival (PFS) (10.6 vs 8.7 months, P = 0.317), median overall survival (OS) (27.7 vs 28.3 months, P = 0.525), or overall response rate (43.1% vs 53.5%, P = 0.108). For the subset of patients with peritoneal dissemination, bevacizumab-based triplet appears to be superior to cetuximab-based triplet as measured by PFS (9.6 vs 6.1 months) and OS (26.3 vs 12.7 months), but not for patients without peritoneal dissemination (PFS, 10.6 vs 9.1 months; OS, 27.9 vs 30.7 months) (all unadjusted and adjusted interaction P < 0.05). Our study suggests that bevacizumab- or cetuximab-based regimens have similar effectiveness as first-line treatment of mCRC in Chinese population. Patients with peritoneal dissemination were likely to gain more benefit from bevacizumab than cetuximab treatment. Future prospective studies are required to further confirm these results.
Collapse
Affiliation(s)
- Long Bai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Feng Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Zhe-zhen Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Chao Ren
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Dong-sheng Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Qi Zhao
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yun-xin Lu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - De-shen Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Huai-qiang Ju
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Miao-zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Zhi-qiang Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Feng-hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| | - Rui-hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center
- Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou
| |
Collapse
|
|
16
|
Bowel strangulation caused by massive intraperitoneal adhesion due to effective chemotherapy for multiple peritoneal metastases originating from descending colon cancer. Clin J Gastroenterol 2016; 9:306-11. [PMID: 27568034 PMCID: PMC5035323 DOI: 10.1007/s12328-016-0679-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 08/11/2016] [Indexed: 11/07/2022]
Abstract
We describe a case of bowel strangulation caused by massive peritoneal adhesion as a result of effective chemotherapy. A 71-year-old man, who had obstructive descending colon cancer with massive peritoneal metastases and, therefore, received palliative surgery consisting of diverting colostomy and sampling of peritoneal nodules, developed bowel strangulation on day 4 of the 2nd course of chemotherapy, including irinotecan, l-leucovorin, and 5-fluorouracil. Emergent celiotomy showed a massive intraperitoneal adhesion formed around several intestinal loops, which were not observed at the prior surgery. One loop was strangled, but recovered by adhesiotomy alone. Intestinal loops were formed around aggregates of peritoneal nodules as the centers, several of which were then sampled. We closed the abdomen after all intestinal loops were eradicated by total enterolysis. Fortunately, the patient has been doing well and received chemotherapy without recurrent bowel obstruction 10 months after the present episode. Histological findings of the aggregates causing intestinal loops demonstrated extensive necrosis of cancerous tissue surrounded by fibrosis with abundant lymphocyte infiltration. These findings were not observed in the specimen sampled before chemotherapy, suggesting that intestinal loops were caused by inflammatory adhesion occurring around the peritoneal metastases as a result of effectiveness of chemotherapy.
Collapse
|
|
17
|
Use of Bevacizumab in the Management of Potentially Resectable Colorectal Liver Metastases: Safety, Pathologic Assessment and Benefit. CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0326-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
|
18
|
Wang H, He C, Yang Z, Gao S, Li L, Sun X, Fang L, Liu N, Li H. Proteomics analysis of up-regulated NPM1 protein in colorectal cancer. Chem Res Chin Univ 2016; 32:402-405. [DOI: 10.1007/s40242-016-5519-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|