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Huang L, Wei M, Li H, Yu M, Wan L, Zhao R, Gao Q, Sun L, Hou X, Mo Y, Huang Q, Zhen L, Yang X, Li J, Wang N, Zhang C, Jin H, Zhou L, Xu Y, Lin H, Zhang X, Li B, Han Y, Yuan J, Zhang R, Wu F, Zhong H, Wei C. GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis. Mol Cancer 2025; 24:151. [PMID: 40414849 DOI: 10.1186/s12943-025-02350-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 05/09/2025] [Indexed: 05/27/2025] Open
Abstract
Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.
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Affiliation(s)
- Linfei Huang
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Meng Wei
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
| | - Huilong Li
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Mingxin Yu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, State Key Laboratory of Digestive Health, Beijing Key Laboratory of Early Gastrointestinal Cancer Medicine and Medical Devices, No. 95 Yong'an Road, Xicheng District, Beijing, 100050, China
| | - Luming Wan
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Ruzhou Zhao
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Qi Gao
- Beijing Youngen Technology Co. Ltd, No. 55 Qingfeng West Road, Daxing District, Beijing, 102629, China
| | - Lijuan Sun
- Beijing Youngen Technology Co. Ltd, No. 55 Qingfeng West Road, Daxing District, Beijing, 102629, China
| | - Xufeng Hou
- Beijing Youngen Technology Co. Ltd, No. 55 Qingfeng West Road, Daxing District, Beijing, 102629, China
| | - Yunhai Mo
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
| | - Qing Huang
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
| | - Lan Zhen
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
| | - Xiaopan Yang
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Jingfei Li
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Nan Wang
- Department of Radiotherapy, Changzhi People's Hospital, No. 502, Changxing Middle Road, Luzhou District, Changzhi, Shanxi, 046000, China
| | - Chundong Zhang
- Department of Surgical Oncology and Central Laboratory, the Fourth Affiliated Hospital of China Medical University, No. 4, Chongshan East Road, Huanggu District, Shenyang, Liaoning, 110032, China
| | - Haoran Jin
- Department of Colorectal Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, No. 44 Xiaoheyan Road, Dadong Distrct, Shenyang, Liaoning, 110042, China
| | - Li Zhou
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Yixin Xu
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China
| | - Haotian Lin
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China
| | - Xuhui Zhang
- Beijing Youngen Technology Co. Ltd, No. 55 Qingfeng West Road, Daxing District, Beijing, 102629, China
| | - Boan Li
- Clinical Laboratory, the Fifth Medical Center of Chinese People's Liberation Army General Hospital, No. 100 Xisihuan Middle Road, Beijing, 100039, China.
| | - Yue Han
- Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan South Road, Chaoyang District, Beijing, 100021, China.
| | - Jing Yuan
- Capital Institute of Pediatrics, Capital Center for Children's Health, Capital Medical University, No. 2 Yabao Road, Chaoyang District, Beijing, 100020, China.
| | - Rui Zhang
- Department of Colorectal Surgery, Liaoning Cancer Hospital and Institute, Cancer Hospital of Dalian University of Technology, No. 44 Xiaoheyan Road, Dadong Distrct, Shenyang, Liaoning, 110042, China.
| | - Feixiang Wu
- Hepatobiliary Surgery Department, Guangxi Medical University Cancer Hospital, No. 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, China.
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Guangxi Medical University, Ministry of Education, Nanning, Guangxi, 530021, China.
| | - Hui Zhong
- Beijing Youngen Technology Co. Ltd, No. 55 Qingfeng West Road, Daxing District, Beijing, 102629, China.
| | - Congwen Wei
- Laboratory of Advanced Biotechnology, Beijing Institute of Biotechnology, No. 20 Dongdajie, Fengtai District, Beijing, 100071, China.
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Schwenk L, Rauchfuss F, Caglayan L, Gkika E, Corradini S, Ernst T, Settmacher U. Multimodale Therapiemöglichkeiten beim oligometastasierten kolorektalen Karzinom. DIE ONKOLOGIE 2025. [DOI: 10.1007/s00761-025-01694-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 02/26/2025] [Indexed: 04/19/2025]
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Gao Y, Fu S, Peng Y, Zhou Y, Zhu J, Zhang X, Cai C, Han Y, Shen H, Zeng S. HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer. Autophagy 2025:1-22. [PMID: 40126194 DOI: 10.1080/15548627.2025.2477443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 02/27/2025] [Accepted: 03/06/2025] [Indexed: 03/25/2025] Open
Abstract
Chemotherapy remains the primary treatment for unresectable or advanced postoperative colorectal cancers. However, its effectiveness is compromised by chemoresistance, which adversely affects patient outcomes. Dysregulated macroautophagy/autophagy is a proposed mechanism behind this resistance, with ubiquitination playing a key regulatory role. In this study, we identify the transcription factor HMBOX1 (homeobox containing 1) as a critical regulator of chemoresistance in colorectal cancer. RNA sequencing revealed that HMBOX1 is downregulated in drug-resistant colorectal cancer cells and tissues, with its low expression linked to poor prognosis. An integrated analysis of genes associated with autophagy and 5-fluorouracil (5-FU) resistance was conducted, verified in the colorectal cancer tissues of patients by single-cell RNA sequencing and immunostaining. Mass-spectrometry-based proteomics and RNA sequencing were used to elucidate the underlying molecular mechanisms. Functionally, upregulation of HMBOX1 enhances the sensitivity of colorectal cancer cells to the first-line treatment with 5-FU by inhibiting autophagy. Mechanistically, HMBOX1 promotes the transcription of the E3 ubiquitin ligase HACE1, which in turn enhances ATG5 K63-ubiquitination and subsequent proteasome-mediated degradation. This results in decreased ATG5 levels, inhibiting autophagy and thus reducing 5-FU resistance in colorectal cancer cells both in vitro and in vivo. Furthermore, we confirm that HMBOX1 expression positively correlates with HACE1 expression and inversely correlates with autophagy levels in clinical colorectal cancer tissues. Our findings suggest that HMBOX1 downregulation drives 5-FU resistance through autophagy enhancement in colorectal cancer, highlighting HMBOX1 as a potential target for improving chemosensitivity and patient prognosis.Abbreviation: 3-MA: 3-methyladenine; 5-FU: 5-fluorouracil; ATG: autophagy related; CASP3: caspase 3; C-CASP3: cleaved caspase 3; C-PARP: cleaved PARP; CCK8: cell counting kit-8; ChIP: chromatin immunoprecipitation; CHX: cycloheximide; CNV: copy number variation; co-IP: co-immunoprecipitation; COAD: colorectal adenocarcinoma; CQ: chloroquine; CRC: colorectal cancer; CR: complete response; FHC: fetal human colon; GEO: Gene Expression Omnibus; HACE1: HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1; HMBOX1: homeobox containing 1; IHC: immunohistochemistry; LC-MS/MS: liquid chromatography-tandem mass spectrometry; mIHC: multiplexed immunohistochemistry; MUT: mutant; NC: negative control; OS: overall survival; PBS: phosphate-buffered saline; PD: progressive disease; PFA: paraformaldehyde; PFS: progression-free survival; PR: partial response; qPCR: quantitative polymerase chain reaction; RAPA: rapamycin; SD: stable disease; TCGA: The Cancer Genome Atlas; TEM: transmission electron microscopy; TF: translation factor; USP22: ubiquitin specific peptidase 22; WT: wild type.
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Affiliation(s)
- Yan Gao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Shenao Fu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yinghui Peng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yulai Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
- Department of Microbiology, Immunology & Molecular Genetics, University of Texas Long School of Medicine, San Antonio, TX, USA
| | - Jiang Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xiangyang Zhang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Changjing Cai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China
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Paramythiotis D, Karlafti E, Tsavdaris D, Apostolidou Kiouti F, Haidich AB, Ioannidis A, Panidis S, Michalopoulos A. The Effect of Hepatic Surgical Margins of Colorectal Liver Metastases on Prognosis: A Systematic Review and Meta-Analysis. J Clin Med 2024; 13:7776. [PMID: 39768699 PMCID: PMC11727772 DOI: 10.3390/jcm13247776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/14/2024] [Accepted: 12/16/2024] [Indexed: 01/16/2025] Open
Abstract
Introduction: Colorectal cancer is the third most common malignancy, with around half of patients developing liver metastases. Hepatectomy is the preferred treatment, but its success depends on several factors, including surgical margins. Various surgical margins have been suggested to achieve optimal results. This systematic review and meta-analysis aim to explore the impact of negative surgical margins ranging from 1 to 10 mm, and >10 mm on survival, with the objective of identifying optimal surgical margins. Methods: A systematic literature search was conducted on the MEDLINE, Scopus, and Cochrane databases. The six included studies that examined the effect of surgical margins at the aforementioned distances on patient survival. Studies were assessed for risk of bias using the Quality in Prognosis Studies tool. Statistical analysis was performed using SPSS software. Results: The results of the meta-analysis revealed the superiority of wider surgical margins (>10) on overall survival compared to smaller margins (1-10 mm), as the HR was calculated to be 1.38 [1.10; 1.73]. Specifically, negative margins between 1 and 10 mm are linked to a 38% increased risk of mortality compared to margins larger than 10 mm. The low heterogeneity indicates consistent findings across studies, and the statistically significant hazard ratio underscores the importance of aiming for larger surgical margins to enhance patient outcomes. In the subgroup that included only studies in which patients received neoadjuvant therapy, the HR was 1.48 [1.06; 2.07], further emphasizing the importance of ensuring negative surgical margins in today's era. Conclusions: In summary, this systematic review and meta-analysis highlights the impact of surgical margin width on the survival of patients with colorectal liver metastases, as well as the importance of margin optimization in surgical management strategies.
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Affiliation(s)
- Daniel Paramythiotis
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Eleni Karlafti
- Emergency Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
- First Propaedeutic Department of Internal Medicine, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Dimitrios Tsavdaris
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Fani Apostolidou Kiouti
- Department of Hygiene, Social-Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece (A.-B.H.)
| | - Anna-Bettina Haidich
- Department of Hygiene, Social-Preventive Medicine and Medical Statistics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece (A.-B.H.)
| | - Aristeidis Ioannidis
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Stavros Panidis
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
| | - Antonios Michalopoulos
- First Propaedeutic Surgery Department, University General Hospital of Thessaloniki AHEPA, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece; (D.P.); (D.T.); (A.I.); (S.P.); (A.M.)
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Su CC, Su YC, Wu CC, Lee PT. Explanatory Role of Conversion Surgery as a Mediator of the Mortality Risk Difference Between Patients With Unresectable Metastatic Colorectal Cancer Treated With First-Line Anti-EGFR Agents Versus Bevacizumab. Clin Colorectal Cancer 2024; 23:364-371. [PMID: 38879376 DOI: 10.1016/j.clcc.2024.05.008] [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: 03/26/2024] [Revised: 05/21/2024] [Accepted: 05/22/2024] [Indexed: 12/01/2024]
Abstract
INTRODUCTION Bevacizumab and antiepidermal growth factor receptor-blocking (anti-EGFR) agents plus chemotherapy are first-line therapies for metastatic colorectal cancer (mCRC). Conversion surgery may improve outcomes; however, the extent to which it explains the difference in mortality rates among treatments is unclear. Herein, we aimed to assess the effects of conversion surgery on survival outcomes of patients with unresectable mCRC treated with bevacizumab and anti-EGFR agents. MATERIALS AND METHODS This retrospective cohort study included patients with mCRC treated with bevacizumab and anti-EGFR agents as first-line therapy. We estimated the direct and indirect effects of treatments by comparing the mortality risk associated with targeted therapy type. Hazard ratios (HR) and the corresponding confidence intervals (CI) were estimated. Mediation analysis was used to estimate hazard ratio differences, and the proportion mediated. RESULTS A total of 5,106 patients were included. The natural indirect effect of conversion surgery reduced mortality risk (HR: 0.95; 95% CI, 0.93-0.97), with a mediated proportion of 42% after propensity score adjustment. In subgroup analyses, KRAS wild-type (HR: 0.94; 95% CI: 0.91-0.97), left tumor sidedness (HR: 0.94; 95% CI, 0.91-0.96), and liver resection (HR: 0.95; 95% CI, 0.93-0.98) were associated with reduced risks of mortality. The controlled and total direct effects of targeted therapy were associated with reduced mortality risk in the anti-EGFR-treated group compared to those in the bevacizumab-treated group; however, this effect was not statistically significant. CONCLUSION Conversion surgery may account for the difference in survival outcomes between users of the anti-EGFR agents and bevacizumab.
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Affiliation(s)
- Chien-Chou Su
- Clinical Innovation and Research Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Chia Su
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Pharmacy, School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
| | - Chih-Chien Wu
- Department of Surgery, Division of Colorectal Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
| | - Pei-Ting Lee
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; Department of Public Health, College of Medicine, National Cheng Kung University, Tainan, Taiwan
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Liu J, Tang W, Ye L, Miao G, Zeng M, Liu L. Estimating Efficacy of Conversion Therapy on Patients with Initially Unresectable Colorectal Cancer Liver Metastases by using MRI: Development of a Predictive Score. Acad Radiol 2024; 31:4478-4487. [PMID: 38734578 DOI: 10.1016/j.acra.2024.04.038] [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: 03/09/2024] [Revised: 04/15/2024] [Accepted: 04/22/2024] [Indexed: 05/13/2024]
Abstract
RATIONALE AND OBJECTIVES The conversion success rate (CSR) has crucial implication for clinical outcomes of initially unresectable colorectal liver metastases (CRLM) following conversion therapy. This study aimed to develop a simple predictive scoring model for identifying CSR according to baseline magnetic resonance imaging (MRI) features, and confirm its performance and prognostic significance in a validation cohort. METHODS A total of 155 consecutive patients with initially unresectable CRLM were retrospectively reviewed in the study. A simple MRI-based predictive scoring model for identifying CSR was developed in the development cohort (n = 104) by using multivariable logistic regression analyzes. The diagnostic performance was evaluated for the predictive score. Thereafter, patients in the validation cohort (n = 51) were stratified into groups with predicted high CSR or low CSR according to the score. The progression-free survival (PFS) and overall survival (OS) were compared between two groups using the log-rank test. RESULTS The predictive score of CSR, named mrNISE, incorporated the number of CRLM ≥ 10, the largest size ≥ 50 mm, poorly defined tumor-liver interface, and peritumoral enhancement. The AUC of the mrNISE score was 0.845 for the development cohort and 0.776 for the validation cohort. According to the score, patients with predicted high CSR had better PFS and OS than those with low CSR in both development and validation cohorts. CONCLUSION The predictive score demonstrated great performance for identifying CSR of initially unresectable CRLM. Stratifying patients by the score, personalized treatment goals can be formulated before conversion therapy to improve clinical prognosis and reduce adverse events caused by ineffective treatment.
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Affiliation(s)
- Jingjing Liu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Medical Imaging, Shanghai, China
| | - Wentao Tang
- Department of General Surgery, Department of Colorectal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lechi Ye
- Department of General Surgery, Department of Colorectal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gengyun Miao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Medical Imaging, Shanghai, China
| | - Liheng Liu
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Institute of Medical Imaging, Shanghai, China.
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Li C, Saladin RJ, Cai W, Chen W. STING-targeted PET imaging: unveiling tumor immunogenicity post-chemotherapy in colorectal cancer. Eur J Nucl Med Mol Imaging 2024; 51:2758-2760. [PMID: 38771515 PMCID: PMC11334692 DOI: 10.1007/s00259-024-06769-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Affiliation(s)
- Chao Li
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Rachel J Saladin
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, K6/562 Clinical Science Center, 600 Highland Ave, Madison, WI, 53705-2275, USA
| | - Weibo Cai
- Departments of Radiology and Medical Physics, University of Wisconsin-Madison, K6/562 Clinical Science Center, 600 Highland Ave, Madison, WI, 53705-2275, USA.
| | - Weiyu Chen
- Department of Respiratory and Critical Care Medicine, Center for Oncology Medicine, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
- Zhejiang Key Laboratory of Precision Diagnosis and Treatment for Lung Cancer, Yiwu, 322000, China.
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Su YC, Wu CC, Chen YH, Su CC, Chang YC, Hsieh MC, Kao Yang YH. Assessing the effectiveness of targeted agents in adjuvant therapy for patients with metastatic colorectal cancer undergoing surgical resection: a retrospective cohort study. Ther Adv Med Oncol 2024; 16:17588359241246427. [PMID: 38655393 PMCID: PMC11036930 DOI: 10.1177/17588359241246427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Background Primary tumor resection and metastasectomy may be beneficial for many patients with metastatic colorectal cancer (mCRC). Objective To assess the differences in postoperative survival outcomes between adjuvant therapy with chemotherapy alone and chemotherapy plus targeted agents (TAs). Design Retrospective cohort study. Methods Patients with mCRC who underwent surgical resection for primary colorectal tumor and distant metastases and received adjuvant therapy from 1 January 2010 to 31 December 2017 were enrolled in the Taiwan Cancer Registry. We analyzed the overall survival of patients with resectable or initially unresectable mCRC who received adjuvant chemotherapy alone and chemotherapy plus TAs. Results We enrolled 1124 and 542 patients with resectable and initially unresectable mCRC, respectively. Adjuvant chemotherapy plus TAs and chemotherapy alone resulted in similar mortality rates among patients with resectable mCRC [adjusted hazard ratio (aHR) = 1.13; 95% confidence interval (CI), 0.93-1.36]; however, it marginally reduced the mortality rate among patients with initially unresectable mCRC who underwent conversion surgery after neoadjuvant therapy (aHR = 0.81; 95% CI, 0.62-1.06). The subgroup analysis of patients who received more than nine cycles of TAs preoperatively and anti-epidermal growth factor receptor agents revealed aHRs of 0.48 (95% CI, 0.27-0.87) and 0.33 (95% CI, 0.18-0.60), respectively. Conclusion Adjuvant chemotherapy plus TAs may improve survival in patients with initially unresectable tumors who underwent conversion surgery following neoadjuvant therapy with TAs, especially in those who respond well to the targeted therapy. Our study underscores the importance of stratifying patients with mCRC based on tumor resectability when selecting the adjuvant therapy regimen.
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Affiliation(s)
- Yi-Chia Su
- Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan
- Department of Nursing, Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan
| | - Chih-Chien Wu
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Surgery, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yu-Hsun Chen
- Division of Colorectal Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Chien-Chou Su
- Clinical Innovation Center, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yu-Ching Chang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Meng-Che Hsieh
- Department of Hematology and Oncology, E-Da Cancer Hospital, Kaohsiung, Taiwan
- College of Medicine, I-Shou University, Kaohsiung, Taiwan
| | - Yea-Huei Kao Yang
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan
- Health Outcome Research Center, National Cheng Kung University, Tainan, Taiwan
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Cheng X, Zhou J, Chen Y, Zhao Y, Zheng H, Wang Q, Li X, Jiang S. Patterns and trends of mortality from metastatic colorectal cancer in Shanghai, China from 2005 to 2021: a population-based retrospective analysis. J Cancer Res Clin Oncol 2024; 150:68. [PMID: 38305905 PMCID: PMC10837271 DOI: 10.1007/s00432-023-05518-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/07/2023] [Indexed: 02/03/2024]
Abstract
PURPOSE Metastatic colorectal cancer (mCRC) is the leading cause of CRC deaths, however, the relative epidemiological research was insufficient. We aimed to analyze the patterns and trends of mortality of mCRC in Shanghai with a more complete system for monitoring the cause of death of the population and find potential methods to reduce the burden of CRC in China. METHODS Mortality data from 2005 to 2021 of mCRC deaths were obtained from the mortality registration system in Shanghai. We analyzed the crude mortality rates, age-standardized mortality rates, and rates of years of life lost (YLL rates) of mCRC. In addition, the trends were quantified using Joinpoint Regression software. RESULTS A total of 4,386 mCRC deaths were included, with 1,937 (44.16%) liver metastases and 1,061 (24.19%) lung metastases. The crude mortality rate and age-standardized mortality rate of mCRC were 9.09 per 105 person-years and 3.78 per 105 person-years, respectively. The YLL was 50,533.13 years, and the YLL rate was 104.67 per 105 person-years. The overall annual crude mortality rate of mCRC increased by 1.47% (95% CI 0.28-2.68%, P < 0.001) from 2005 to 2021. The crude mortality rate of mCRC increased by 3.20% per year (95% CI 1.80-4.70%, P < 0.001) from 2005 to 2013, but the trend of mortality growth remained stable from 2013 to 2021. The YLL rates remained stable between 2005 and 2021. CONCLUSIONS Population aging was the most likely factor responsible for the increase in CRC mortality in Pudong. Physical examinations and screenings for the elderly were possible reasons for reducing the burden of CRC in fast-growing regions.
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Affiliation(s)
- Xuelin Cheng
- Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Zhou
- Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yichen Chen
- Office of Scientific Research and Information Management, Pudong Institute of Preventive Medicine, Pudong New Area, Shanghai, China
| | - Yajun Zhao
- Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Huichao Zheng
- Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qizhe Wang
- Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiaopan Li
- Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China
- Office of Scientific Research and Information Management, Pudong Institute of Preventive Medicine, Pudong New Area, Shanghai, China
| | - Sunfang Jiang
- Department of Health Management Center, Zhongshan Hospital, Fudan University, Shanghai, China.
- Department of General Practice, Zhongshan Hospital, Fudan University, Shanghai, China.
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Liao SW, Zhan JQ, Liu CT, Yu HT, Wen MJ. Survival Benefit of Primary Tumor Resection Combined With Chemotherapy in Patients With Unresectable Colorectal Mucinous Adenocarcinoma With Liver Metastasis. Am J Clin Oncol 2024; 47:30-39. [PMID: 38148710 PMCID: PMC10743404 DOI: 10.1097/coc.0000000000001055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2023]
Abstract
OBJECTIVE To evaluate the survival benefit of combining primary tumor resection (PTR) and chemotherapy in patients with unresectable colorectal mucinous adenocarcinoma with liver metastasis (UCR-MAC-LM). METHODS We obtained data from the surveillance, epidemiology, and end results database for patients with UCR-MAC-LM from 2010 to 2017. Clinicopathological characteristics were analyzed using the χ2 test. Propensity score matching was performed to balance baseline characteristics. Kaplan-Meier analysis and log-rank tests were used to estimate and compare survival outcomes. Univariate and multivariate Cox regression analyses were conducted to identify the prognostic factors. RESULTS A total of 10,178 patients with unresectable colorectal adenocarcinoma with liver metastasis were included, of whom 6.01% (n=612) had UCR-MAC-LM. The UCR-MAC-LM group had a higher proportion of female patients, a greater number of elderly patients, an increased incidence of right colon localization, larger tumor size, and higher T and N staging than the unresectable colorectal non-mucinous adenocarcinoma with liver metastasis group (P<0.05). Multivariate analysis identified several independent prognostic factors (P<0.05). Patients with unresectable colorectal adenocarcinoma with liver metastasis who underwent PTR+C had superior survival rates compared with those who received PTR/C alone or no treatment (cancer-specific survival, P<0.05; overall survival, P<0.05). Subgroup analysis revealed that 17 of 22 groups of patients with UCR-MAC-LM who received PTR+C had significantly prolonged long-term survival compared with those who received PTR/C alone. CONCLUSIONS This surveillance, epidemiology, and end results-based study indicates that PTR+C may offer a survival advantage for a specific subgroup of patients with UCR-MAC-LM compared with PTR/C alone. Nonetheless, additional clinical trials are necessary to validate these findings.
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Affiliation(s)
- Shu-wen Liao
- Department of General Surgery, Guangzhou First People’s Hospital, the Second Affiliated Hospital of South China University of Technology
- Departments of General Surgery
| | - Jie-qun Zhan
- Physical Examination Center, Guangzhou Nansha Central Hospital Affiliated to Guangzhou First People’s Hospital, Guangzhou, Guangdong, China
| | - Chu-tian Liu
- Department of General Surgery, Guangzhou First People’s Hospital, the Second Affiliated Hospital of South China University of Technology
- Departments of General Surgery
| | - Hai-tao Yu
- Department of General Surgery, Guangzhou First People’s Hospital, the Second Affiliated Hospital of South China University of Technology
- Departments of General Surgery
| | - Min-jie Wen
- Department of General Surgery, Guangzhou First People’s Hospital, the Second Affiliated Hospital of South China University of Technology
- Departments of General Surgery
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11
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Marcellinaro R, Spoletini D, Grieco M, Avella P, Cappuccio M, Troiano R, Lisi G, Garbarino GM, Carlini M. Colorectal Cancer: Current Updates and Future Perspectives. J Clin Med 2023; 13:40. [PMID: 38202047 PMCID: PMC10780254 DOI: 10.3390/jcm13010040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 12/12/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
Colorectal cancer is a frequent neoplasm in western countries, mainly due to dietary and behavioral factors. Its incidence is growing in developing countries for the westernization of foods and lifestyles. An increased incidence rate is observed in patients under 45 years of age. In recent years, the mortality for CRC is decreased, but this trend is slowing. The mortality rate is reducing in those countries where prevention and treatments have been implemented. The survival is increased to over 65%. This trend reflects earlier detection of CRC through routine clinical examinations and screening, more accurate staging through advances in imaging, improvements in surgical techniques, and advances in chemotherapy and radiation. The most important predictor of survival is the stage at diagnosis. The screening programs are able to reduce incidence and mortality rates of CRC. The aim of this paper is to provide a comprehensive overview of incidence, mortality, and survival rate for CRC.
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Affiliation(s)
- Rosa Marcellinaro
- Department of General Surgery, S. Eugenio Hospital, 00144 Rome, Italy; (D.S.); (M.G.); (R.T.); (G.L.); (M.C.)
| | - Domenico Spoletini
- Department of General Surgery, S. Eugenio Hospital, 00144 Rome, Italy; (D.S.); (M.G.); (R.T.); (G.L.); (M.C.)
| | - Michele Grieco
- Department of General Surgery, S. Eugenio Hospital, 00144 Rome, Italy; (D.S.); (M.G.); (R.T.); (G.L.); (M.C.)
| | - Pasquale Avella
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy; (P.A.); (M.C.)
- Hepatobiliary and Pancreatic Surgery Unit, Pineta Grande Hospital, Castel Volturno, 81030 Caserta, Italy
| | - Micaela Cappuccio
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy; (P.A.); (M.C.)
| | - Raffaele Troiano
- Department of General Surgery, S. Eugenio Hospital, 00144 Rome, Italy; (D.S.); (M.G.); (R.T.); (G.L.); (M.C.)
| | - Giorgio Lisi
- Department of General Surgery, S. Eugenio Hospital, 00144 Rome, Italy; (D.S.); (M.G.); (R.T.); (G.L.); (M.C.)
| | - Giovanni M. Garbarino
- Department of General Surgery, S. Eugenio Hospital, 00144 Rome, Italy; (D.S.); (M.G.); (R.T.); (G.L.); (M.C.)
| | - Massimo Carlini
- Department of General Surgery, S. Eugenio Hospital, 00144 Rome, Italy; (D.S.); (M.G.); (R.T.); (G.L.); (M.C.)
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12
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Boshell D, Bester L. Radioembolisation of liver metastases. J Med Imaging Radiat Oncol 2023; 67:842-852. [PMID: 37343147 DOI: 10.1111/1754-9485.13549] [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: 01/15/2023] [Accepted: 06/05/2023] [Indexed: 06/23/2023]
Abstract
This review aims to present contemporary data for SIRT in the treatment of secondary hepatic malignancies including colorectal, neuroendocrine, breast and uveal melanoma.
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Affiliation(s)
- David Boshell
- Department of Radiology, St Vincent's Hospital, Sydney, New South Wales, Australia
| | - Lourens Bester
- Department of Radiology, University of Notre Dame, Sydney, New South Wales, Australia
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13
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Fariman SA, Jahangard Rafsanjani Z, Hasanzad M, Niksalehi K, Nikfar S. Upfront DPYD Genotype-Guided Treatment for Fluoropyrimidine-Based Chemotherapy in Advanced and Metastatic Colorectal Cancer: A Cost-Effectiveness Analysis. Value Health Reg Issues 2023; 37:71-80. [PMID: 37329861 DOI: 10.1016/j.vhri.2023.04.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 03/26/2023] [Accepted: 04/29/2023] [Indexed: 06/19/2023]
Abstract
OBJECTIVES Fluoropyrimidines are the most widely used chemotherapy drugs for advanced and metastatic colorectal cancer (CRC). Individuals with certain DPYD gene variants are exposed to an increased risk of severe fluoropyrimidine-related toxicities. This study aimed to evaluate the cost-effectiveness of preemptive DPYD genotyping to guide fluoropyrimidine therapy in patients with advanced or metastatic CRC. METHODS Overall survival of DPYD wild-type patients who received a standard dose and variant carriers treated with a reduced dose were analyzed by parametric survival models. A decision tree and a partitioned survival analysis model with a lifetime horizon were designed, taking the Iranian healthcare perspective. Input parameters were extracted from the literature or expert opinion. To address parameter uncertainty, scenario and sensitivity analyses were also performed. RESULTS Compared with no screening, the genotype-guided treatment strategy was cost-saving ($41.7). Nevertheless, due to a possible reduction in the survival of patients receiving reduced-dose regimens, it was associated with fewer quality-adjusted life-years (9.45 vs 9.28). In sensitivity analyses, the prevalence of DPYD variants had the most significant impact on the incremental cost-effectiveness ratio. The genotyping strategy would remain cost-saving, as long as the genotyping cost is < $49 per test. In a scenario in which we assumed equal efficacy for the 2 strategies, genotyping was the dominant strategy, associated with less costs (∼$1) and more quality-adjusted life-years (0.1292). CONCLUSIONS DPYD genotyping to guide fluoropyrimidine treatment in patients with advanced or metastatic CRC is cost-saving from the perspective of the Iranian health system.
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Affiliation(s)
- Soroush Ahmadi Fariman
- Department of Pharmacoeconomics and Pharmaceutical administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mandana Hasanzad
- Medical Genomics Research Center, Tehran University of Medical Sciences, Tehran, Iran; Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Kimia Niksalehi
- Department of Pharmacoeconomics and Pharmaceutical administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Department of Pharmacoeconomics and Pharmaceutical administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
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Berardi G, Chou J, Gonen M, Balachandran VP, Drebin J, Jarnagin WR, Kingham TP, Soares KC, Wei A, D'Angelica M. A Model to Predict Treatment Failure in Patients Undergoing Upfront Surgery for Resectable Colorectal Liver Metastases. Ann Surg Oncol 2023; 30:2820-2827. [PMID: 36692613 PMCID: PMC10089972 DOI: 10.1245/s10434-023-13113-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 12/07/2022] [Indexed: 01/25/2023]
Abstract
INTRODUCTION Patients who recur in the first year after resection of colorectal liver metastases (CRLM) do poorly. The aim of our study was to predict treatment failure in patients undergoing upfront resection with a nomogram. METHODS Data from patients resected between 1991 and 2019 were randomly split (70:30) into two cohorts. Treatment failure was defined as any recurrence or death within 12 months. A nomogram was constructed using multivariable logistic regression on the training cohort and validated using the testing cohort. RESULTS Overall, 783 patients were included. Primary tumor characteristics included 50% left-sided: 75.2% T3/4 and 56.5% node-positive. The median disease-free interval was 10 months, median number of metastases was 1 (1-50), and with a median size of 3.6 cm (0.2-22); 222 (28.3%) patients recurred within 1 year. Recurrence was mostly extrahepatic with or without liver involvement (150/222, 67.6%). Curative-intent treatment was possible in 37.8% of these patients. Primary location, T-stage and node status, disease-free interval, and number and size of metastases were associated with treatment failure. The area under the curve from the validation of the model was 0.6 (95% confidence interval 0.52-0.68). Patients with a high-risk of treatment failure (≥40%) had a worse survival from the landmark time of 12 months from surgery compared with those with low-risk (2-years: 82% vs. 70%; p = 0.0002). CONCLUSIONS Primary location, T stage, node status, disease-free interval, and number and size of metastases are associated with treatment failure. The survival of patients with a probability of treatment failure ≥40% is unfavorable. Future trials investigating the role of neoadjuvant therapy in these high-risk patients are warranted.
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Affiliation(s)
- Giammauro Berardi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Joanne Chou
- Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mithat Gonen
- Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jeffrey Drebin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - William R Jarnagin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - T Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin C Soares
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alice Wei
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael D'Angelica
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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15
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Zhao J, Zhu J, Huang C, Yuan R, Zhu Z. Impact of primary tumor resection on the survival of patients with unresectable colon cancer liver metastasis at different colonic subsites: a propensity score matching analysis. Acta Chir Belg 2023; 123:132-147. [PMID: 34278951 DOI: 10.1080/00015458.2021.1956799] [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: 01/14/2021] [Accepted: 07/13/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE To investigate the effect of primary tumor resection (PTR) on the prognosis of patients with unresectable colon cancer liver metastasis (UCCLM) at seven colonic subsites using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS Propensity score matching (PSM) was performed to balance selection bias using all available variables that could be of potential relevance. After matching, the groups were redefined in a 1:1 ratio using the nearest method. Cancer-specific survival (CSS) was compared among the patients of PTR and non-PTR groups. Cox regression models were used to identify the prognostic factors for CSS. RESULTS CSS was significantly different between all groups. Cox regression analysis showed that PTR was an independent prognostic factor for all groups. After PSM, PTR significantly prolonged CSS for all groups. Subgroup analysis showed that PTR did not improve the prognosis of N2 stage patients in the cecum, ascending colon, and descending colon groups; T1 + T2 stage patients in the hepatic flexure group; and patients with a tumor size ≤5 cm in the splenic flexure group. Segmental colectomy could prolong CSS of patients in the cecum, ascending colon, transverse colon, splenic flexure, and sigmoid colon groups, while extended colectomy could prolong CSS of patients in the hepatic flexure and descending colon groups. CONCLUSION At different colonic subsites, UCCLM patients had different CSS. PTR could improve their prognosis, however, N stage, T stage, and tumor size are important reference indicators. In addition to patients in the hepatic flexure and descending colon groups, we suggested that patients in other groups should choose segmental colectomy.
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Affiliation(s)
- Jiefeng Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jinfeng Zhu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Chao Huang
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Rongfa Yuan
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhengming Zhu
- Department of General Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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Parmar KL, O'Reilly D, Valle J, Braun M, Malcomson L, Jones RP, Balaa F, Rees M, Welsh FKS, Filobbos R, Renehan AG. Protocol for the CoNoR Study: A prospective multi-step study of the potential added benefit of two novel assessment tools in colorectal liver metastases technical resectability decision-making. BMJ Open 2023; 13:e059369. [PMID: 36997247 PMCID: PMC10069542 DOI: 10.1136/bmjopen-2021-059369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023] Open
Abstract
INTRODUCTION Liver resection is the only curative treatment for colorectal liver metastases (CLM). Resectability decision-making is therefore a key determinant of outcomes. Wide variation has been demonstrated in resectability decision-making, despite the existence of criteria. This paper summarises a study protocol to evaluate the potential added value of two novel assessment tools in assessing CLM technical resectability: the Hepatica preoperative MR scan (MR-based volumetry, Couinaud segmentation, liver tissue characteristics and operative planning tool) and the LiMAx test (hepatic functional capacity). METHODS AND ANALYSIS This study uses a systematic multistep approach, whereby three preparatory workstreams aid the design of the final international case-based scenario survey:Workstream 1: systematic literature review of published resectability criteria.Workstream 2: international hepatopancreatobiliary (HPB) interviews.Workstream 3: international HPB questionnaire.Workstream 4: international HPB case-based scenario survey.The primary outcome measures are change in resectability decision-making and change in planned operative strategy, resulting from the novel test results. Secondary outcome measures are variability in CLM resectability decision-making and opinions on the role for novel tools. ETHICS AND DISSEMINATION The study protocol has been approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences. Manuscripts will be published. REGISTRATION DETAILS The CoNoR Study is registered with ClinicalTrials.gov (registration number NCT04270851). The systematic review is registered on the PROSPERO database (registration number CRD42019136748).
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Affiliation(s)
- Kat L Parmar
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester Cancer Research Centre, Manchester, UK
| | - Derek O'Reilly
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- Department of Hepatobiliary Surgery, Manchester University NHS Foundation Trust, Manchester, UK
| | - Juan Valle
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Michael Braun
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Lee Malcomson
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester Cancer Research Centre, Manchester, UK
| | - Robert P Jones
- Department of Hepatobiliary Surgery, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
| | - Fady Balaa
- Department of Surgery, Ottawa Hospital, Ottawa, Ontario, Canada
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Myrddin Rees
- Department of Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, UK
| | - Fenella K S Welsh
- Department of Surgery, Basingstoke and North Hampshire Hospital, Basingstoke, UK
| | - Rafik Filobbos
- Department of Radiology, Manchester University NHS Foundation Trust, Manchester, UK
| | - Andrew G Renehan
- Division of Cancer Sciences, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester Cancer Research Centre, Manchester, UK
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Rauff R, Abedeera SM, Schmocker S, Xie J, Abeysirigunawardena SC. Peptides Targeting RNA m 6 A Methylations Influence the Viability of Cancer Cells. ChemMedChem 2023; 18:e202200549. [PMID: 36567478 PMCID: PMC9957953 DOI: 10.1002/cmdc.202200549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/13/2022] [Accepted: 12/17/2022] [Indexed: 12/27/2022]
Abstract
N6-methyladenosine (m6 A) is the most abundant nucleotide modification observed in eukaryotic mRNA. Changes in m6 A levels in transcriptome are tightly correlated to expression levels of m6 A methyltransferases and demethylases. Abnormal expression levels of methyltransferases and demethylases are observed in various diseases and health conditions such as cancer, male infertility, and obesity. This research explores the efficacy of m6 A-modified RNA as an anticancer drug target. We discovered a 12-mer peptide that binds specifically to m6 A-modified RNA using phage display experiments. Our fluorescence-based assays illustrate the selected peptide binds to methylated RNA with lower micromolar affinity and inhibit the binding of protein FTO, a demethylase enzyme specific to m6 A modification. When cancer cell lines were treated with mtp1, it led to an increase in m6 A levels and a decrease in cell viability. Hence our results illustrate the potential of mtp1 to be developed as a drug for cancer.
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Affiliation(s)
- Rushdhi Rauff
- Department of Chemistry and Biochemistry, Kent State University, 1175 Risman Drive, Kent, OH 44242, USA
| | - Sudeshi M Abedeera
- Department of Chemistry and Biochemistry, Kent State University, 1175 Risman Drive, Kent, OH 44242, USA
| | - Stefani Schmocker
- Department of Chemistry and Biochemistry, Kent State University, 1175 Risman Drive, Kent, OH 44242, USA
| | - Jiale Xie
- Department of Chemistry and Biochemistry, Kent State University, 1175 Risman Drive, Kent, OH 44242, USA
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Zeineddine FA, Zeineddine MA, Yousef A, Gu Y, Chowdhury S, Dasari A, Huey RW, Johnson B, Kee B, Lee MS, Morelli MP, Morris VK, Overman MJ, Parseghian C, Raghav K, Willis J, Wolff RA, Kawaguchi Y, Vauthey JN, Sun R, Kopetz S, Shen JP. Survival improvement for patients with metastatic colorectal cancer over twenty years. NPJ Precis Oncol 2023; 7:16. [PMID: 36781990 PMCID: PMC9925745 DOI: 10.1038/s41698-023-00353-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 35.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 01/16/2023] [Indexed: 02/15/2023] Open
Abstract
Over the past two decades of successive clinical trials in metastatic colorectal cancer (CRC), the median overall survival of both control and experimental arms has steadily improved. However, the incremental change in survival for metastatic CRC patients not treated on trial has not yet been quantified. We performed a retrospective review of 1420 patients with de novo metastatic CRC who received their primary treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 2004 through 2019. Median OS was roughly stable for patients diagnosed between 2004 and 2012 (22.6 months) but since has steadily improved for those diagnosed in 2013 to 2015 (28.8 months), and 2016 to 2019 (32.4 months). Likewise, 5-year survival rate has increased from 15.7% for patients diagnosed from 2004 to 2006 to 26% for those diagnosed from 2013 to 2015. Notably, survival improved for patients with BRAFV600E mutant as well as microsatellite unstable (MSI-H) tumors. Multivariate regression analysis identified surgical resection of liver metastasis (HR = 0.26, 95% CI, 0.19-0.37), use of immunotherapy (HR = 0.44, 95% CI, 0.29-0.67) and use of third line chemotherapy (regorafenib or trifluridine/tipiracil, HR = 0.74, 95% CI, 0.58-0.95), but not year of diagnosis (HR = 0.99, 95% CI, 0.98-1), as associated with better survival, suggesting that increased use of these therapies are the drivers of the observed improvement in survival.
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Affiliation(s)
- Fadl A Zeineddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mohammad A Zeineddine
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abdelrahman Yousef
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yue Gu
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Saikat Chowdhury
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Arvind Dasari
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ryan W Huey
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Benny Johnson
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bryan Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael S Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Maria Pia Morelli
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christine Parseghian
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jason Willis
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Robert A Wolff
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yoshikuni Kawaguchi
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ryan Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John Paul Shen
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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19
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Cai C, Luo Q, Liu Y, Peng Y, Zhang X, Jiang Z, Feng Z, Qi Y, Gao Y, Liu Y, Liu P, Chen Y, Guo C, Shen H, Zeng S, Han Y. The optimal first-line treatment for patients with left-sided RAS wild-type metastatic colorectal cancer: Double-drug regimen or triple-drug regimen therapy. Front Pharmacol 2022; 13:1015510. [PMID: 36249804 PMCID: PMC9561342 DOI: 10.3389/fphar.2022.1015510] [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: 08/09/2022] [Accepted: 09/12/2022] [Indexed: 12/24/2022] Open
Abstract
There are many treatments for metastatic colorectal cancer (mCRC). Among them, uncertainty remains especially concerning the clinical benefit of different regimens for left-sided RAS wild-type (WT) mCRC in the triple-drug therapy era. No studies have been conducted to answer this critical clinical issue. We performed a comprehensive analysis of published data and real-world data. First, we conducted analyses of the published trials to show the landscape of efficacy and safety in the treatments of left-sided RAS WT mCRC. Then, we initiated a multicenter real-world study as the validation dataset. This study included six published randomized controlled trials (RCTs) and a total of 1925 patients. The double-drug regimen plus cetuximab/panitumumab (D + C/P) achieved the longest overall survival (OS) in patients with left-sided mCRC (HR = 0.74, 95%CI: 0.57-0.98), while triple-drug regimen with bevacizumab (T + B, HR = 1.1, 95%CI: 0.63-2.0), compared with double-drug with bevacizumab (D + B). The D + C/P had the highest overall response rate (ORR) in patients with left-sided mCRC (OR = 1.8, 95%CI: 0.89-3.8), while T + B (OR = 1.8, 95%CI: 0.70-4.8), compared with D + B. The multicenter real-world cohort showed the double-drug regimen plus cetuximab had longer progression-free survival (PFS) in left-sided mCRC patients than the triple-drug regimen with bevacizumab. The safety analysis showed the incidence of the adverse events (grade≥3) in the triple-drug therapy plus bevacizumab was higher than that in the double-drug therapy plus cetuximab/panitumumab. This work demonstrates the ranking of three regimens for therapeutic efficacy and safety in patients with left-sided RAS WT mCRC. The double-drug regimen plus cetuximab/panitumumab appears more effective and safer than double-drug and triple-drug based regimens with bevacizumab. Further trials and cohort analyses on this topic would increase confidence in these results.
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Affiliation(s)
- Changjing Cai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qingqing Luo
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, China
| | - Yihan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yinghui Peng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiangyang Zhang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Zhaohui Jiang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ziyang Feng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yaru Qi
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Gao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yongting Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ping Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Yihong Chen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Cao Guo
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
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20
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Chan KM, Hung HC, Lee JC, Wu TH, Wang YC, Cheng CH, Lee CF, Wu TJ, Chou HS, Lee WC. Individualized Selection Criteria Based on Tumor Burden in Future Remnant Liver for Staged Hepatectomy of Advanced CRLM: Conventional TSH or ALPPS. Cancers (Basel) 2022; 14:3553. [PMID: 35884613 PMCID: PMC9324888 DOI: 10.3390/cancers14143553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 07/08/2022] [Accepted: 07/19/2022] [Indexed: 02/05/2023] Open
Abstract
Staged hepatectomy is a promising strategy for curative resection of advanced colorectal liver metastasis (CRLM) to prevent inadequate future remnant liver (FRL). However, the selection criteria for conventional two-stage hepatectomy (cTSH) and associating liver partitioning and portal vein ligation for staged hepatectomy (ALPPS) remain unclear. This study aimed to propose a selection criterion for determining the optimal staged hepatectomy for patients with advanced CRLM. A selection criterion based on the degree of metastatic tumors within the FRL was established to determine staged hepatectomy approaches. Generally, ALPPS is recommended for patients with ≤3 metastatic nodules and whose nodules do not measure >3 cm in the FRL. cTSH is performed for patients whose tumor burden in FRL beyond the selection criteria. Data of 37 patients who underwent staged hepatectomy and curative intent of CRLM were analyzed. The clinical characteristics and outcomes of the two approaches were compared. Overall, cTSH and ALPPS were performed for 27 (73.0%) and 10 (27.0%) patients, respectively. Of those, 20 patients in the cTSH group and all patients in the ALPPS group had completed staged hepatectomy. The 1-, 3-, and 5-year survival rates were 91.6%, 62.4%, and 45.4% for all patients, respectively. The outcomes of patients who had successfully completed the staged hepatectomy were significantly better than those of other patients who failed to achieve staged hepatectomy. However, no significant difference was observed in the overall survival of patients who underwent staged hepatectomy between the two groups, but those in the ALPPS group had 100% survival at the end of this study. The individualized selection criteria based on tumor burden in the FRL that could balance the operative risk and oncologic outcome appear to be a promising strategy for achieving complete staged hepatectomy in patients with advanced CRLM.
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Affiliation(s)
- Kun-Ming Chan
- Department of General Surgery, Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan; (H.-C.H.); (J.-C.L.); (T.-H.W.); (Y.-C.W.); (C.-H.C.); (C.-F.L.); (T.-J.W.); (H.-S.C.); (W.-C.L.)
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21
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Lin J, Sun H, Zhang W, Hong Z, Lu Z, Pan Z, Hou Z, Peng J. Conversion therapy with the intent to perform radical local treatment may not be suitable for patients with 10 or more liver metastases from colorectal cancer. Cancer Med 2022; 11:4225-4235. [PMID: 35466587 DOI: 10.1002/cam4.4775] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 02/18/2022] [Accepted: 04/01/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The number of colorectal cancer liver metastases (CRLMs) is usually considered a contradictory indicator to surgical resection. However, some patients with initially unresectable CRLMs can receive radical local treatment after conversion therapy. This study aimed to evaluate the effect of radical local treatment after conversion therapy and the prognosis of patients with more than 10 initially unresectable CRLMs. METHODS Data for a total of 229 patients with initially unresectable CRLMs were retrospectively reviewed between December 2012 and January 2020. Among these patients, 107 had ≥10 CRLMs, and 122 had <10 CRLMs. Overall survival (OS) and progression-free survival (PFS) were used to reflect the prognosis of different groups of patients. Conversion therapy was defined as an initially unresectable liver metastasis converted into an R0 resectable lesion after systemic chemotherapy. Radical local treatment included hepatectomy and radiofrequency ablation (RFA). RESULTS Patients with ≥10 CRLMs had a lower conversion rate (42.7% vs. 56.6%, p = 0.001). Baseline clinical N stage 1-2, ≥8 first-line chemotherapy courses, and stable disease (SD) according to the Response Evaluation Criteria in Solid Tumours (RECIST) were independent factors predictive of conversion failure. Primary tumour location in the right colon, RECIST response of SD, and the absence of targeted therapy were independent factors predictive of unfavourable OS. The survival curves revealed that the OS of patients with or without conversion could be distinguished only among patients with <10 CRLMs (89.9% [95% CI, 82.5%-98.0%] vs. 58.9% [95% CI, 45.2%-76.7%], p < 0.001); this cut-off point could also distinguish patients with a successful conversion outcome according to OS (89.9% [95% CI, 82.5-98.0%] vs. 58.2% [95% CI, 42.2-80.4%], p = 0.008). CONCLUSION For CRLMs ≥ 10, patients with a successful conversion outcome cannot be distinguished from those without successful conversion outcome according to OS. Thus, conversion therapy with the intent to perform radical local treatment may not be suitable for patients with 10 or more liver metastases from colorectal cancer.
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Affiliation(s)
- Junzhong Lin
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Hui Sun
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, P. R. China
| | - Weili Zhang
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Zhigang Hong
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Zhenhai Lu
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Zhizhong Pan
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Zhenlin Hou
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
| | - Jianhong Peng
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P. R. China
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22
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Sugiyama M, Uehara H, Shin Y, Shiokawa K, Fujimoto Y, Mano Y, Komoda M, Nakashima Y, Sugimachi K, Yamamoto M, Morita M, Toh Y. Indications for conversion hepatectomy for initially unresectable colorectal cancer with liver metastasis. Surg Today 2022; 52:633-642. [PMID: 34762175 DOI: 10.1007/s00595-021-02403-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/22/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE Selected patients with initially unresectable colorectal cancer (CRC) and liver metastases undergo conversion surgery after appropriate chemotherapy. The prognosis of these patients is good, with some even cured of the disease. This retrospective, single-institution study analyzes the clinical importance of patient characteristics on the outcomes of conversion hepatectomy. METHODS We evaluated 229 consecutive patients with initially unresectable CRC and liver metastasis, who underwent systemic chemotherapy. The patients were assigned to groups depending on conversion hepatectomy. RESULTS Conversion hepatectomy was performed in 30 patients (13.1%). The proportion of patients with extrahepatic metastasis was significantly lower in the conversion group than in the unresectable group (30.0 vs. 66.8%; P < 0.01). The rate of left-sided primary colorectal tumors was significantly higher in the conversion group than in the unresectable group (96.7 vs. 65.8%; P < 0.01). Multivariate analyses identified that left-sided tumors, no extrahepatic metastasis, H1 or H2 grade CLM, and treatment with molecular-targeted agents were associated with conversion hepatectomy (odds ratios: 16.314, 4.216, 7.631, and 4.070; P < 0.01). Overall survival was significantly longer in the conversion group than in the unresectable group (MST: 50.0 versus 14.7 months; P < 0.01). CONCLUSION Left-sided primary tumors, absence of extrahepatic metastases, H1 or H2 grade, and use of molecular-targeted agents were associated with successful conversion hepatectomy; thus, patients with these characteristics may be candidates for conversion therapy.
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Affiliation(s)
- Masahiko Sugiyama
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan.
| | - Hideo Uehara
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
| | - Yuki Shin
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
| | - Keiichi Shiokawa
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
| | - Yoshiaki Fujimoto
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
| | - Yohei Mano
- Hepato-Biliary-Pancreatic Surgery, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan
| | - Masato Komoda
- Gastrointestinal and Medical Oncology, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan
| | - Yuichiro Nakashima
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
| | - Keishi Sugimachi
- Hepato-Biliary-Pancreatic Surgery, National Hospital Organization, Kyushu Cancer Center, Fukuoka, Japan
| | - Manabu Yamamoto
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
| | - Masaru Morita
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
| | - Yasushi Toh
- Gastroenterological Surgery, National Hospital Organization, Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka, Fukuoka, 811-1395, Japan
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23
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Rasbach E, Birgin E, Betzler A, Rahbari NN, Reissfelder C. Therapiestrategien beim synchron metastasierten Kolonkarzinom. COLOPROCTOLOGY 2022. [DOI: 10.1007/s00053-022-00601-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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24
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Wang L, Qiao Y, Zong H, Han L, Ke Y, Pan Z, Chen J, Lu J, Li J, Ying T, Zhang B, Zhu J. IgG-like Bispecific Antibody CD3×EpCAM Generated by Split Intein Against Colorectal Cancer. Front Pharmacol 2022; 13:803059. [PMID: 35281893 PMCID: PMC8905292 DOI: 10.3389/fphar.2022.803059] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/31/2022] [Indexed: 12/17/2022] Open
Abstract
Background: Colorectal cancer is a commonly diagnosed cancer with high mortality worldwide. Postoperative recidivation and metastasis still are the main challenges in clinical treatments. Thus, it is urgent to develop new therapies against colorectal cancer. Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in colorectal cancer cells and strongly associated with cancer development. Bispecific antibody (BsAb) is a kind of promising immunotherapy, which could recognize T cells and cancer cells simultaneously to achieve the anti-tumor effects. Methods: A bispecific antibody targeting EpCAM and CD3 with IgG format was genereated by split intein based on the Bispecific Antibody by Protein Splicing" platform. In vitro, the affinity of CD3×EpCAM BsAb was determined by Biolayer interferometry, its cytotoxicity was detected by LDH release assay, T cell recruitment and activation was detected by Flow Cytometry. In vivo, its pharmacokinetic parameters were detected, and anti-tumor effects were evaluated on the tumor cell xenograft mouse model. Results: The results showed that the CD3×EpCAM BsAb could activate and recruit T cells via binding colorectal cells and T cells, which could lead to more potent cytotoxicity to various colorectal cell lines than its parent EpCAM monoclonal antibody (mAb) in vitro. The CD3×EpCAM BsAb had similar pharmacokinetic parameters with EpCAM mAb and inhibits tumor growth on the SW480 tumor cell xenograft mouse model. Conclusion: The CD3×EpCAM BsAb could be a promising candidate for colorectal cancer treatment.
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Affiliation(s)
- Lei Wang
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Yu Qiao
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Huifang Zong
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Han
- Jecho Institute, Co. Ltd., Shanghai, China
- Jecho Biopharmaceuticals Co. Ltd., Tianjin, China
| | - Yong Ke
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - ZhiDi Pan
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Chen
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jun Lu
- School of Science, and School of Interprofessional Health Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Tianlei Ying
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Baohong Zhang
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
| | - Jianwei Zhu
- Engineering Research Center of Cell and Therapeutic Antibody, MOE, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- Jecho Institute, Co. Ltd., Shanghai, China
- Jecho Biopharmaceuticals Co. Ltd., Tianjin, China
- Jecho Laboratories, Inc., Frederick, MD, United States
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25
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Matsuhashi N, Tomita H, Tanaka H, Iwata Y, Matsui S, Imai H, Fukada M, Mizutani C, Takahashi T, Yasufuku I, Suetsugu T, Mori R, Tanaka Y, Okumura N, Futamura M, Yoshida K. Evaluation of histopathological heterogeneity of colorectal cancer liver metastasis sites after preoperative chemotherapy. Mol Clin Oncol 2022; 16:61. [PMID: 35127086 PMCID: PMC8771193 DOI: 10.3892/mco.2022.2494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 07/14/2021] [Indexed: 11/30/2022] Open
Abstract
Patients with liver metastases from colorectal cancer (CRLMs) frequently receive chemotherapy prior to liver resection. Histopathological assessment of the resected specimen can evaluate the response to chemotherapy. The present study analyzed the association between histopathological changes in the primary site and liver metastases. The present study comprised 45 patients with resectable CRLMs at the Surgical Oncology Department of Gifu University School of Medicine (Gifu, Japan) between January 2006 and August 2015. The study included 24 men and 21 women. The primary colonic tumor was located in the right side in 13 (28.9%) patients and the left side in 32 (71.9%) patients. The present study evaluated patients with metastatic colorectal cancer (31/45) after excluding those in whom histopathological heterogeneity between the primary and liver metastasis changed to grade 3 after chemotherapy. The group that underwent hepatectomy after chemotherapy (n=25) was compared with the group that underwent hepatectomy alone (n=6). In 16 (53.3%) out of 25 patients, histopathological heterogeneity of the liver metastasis was lost (P=0.04). In conclusion, chemotherapy appeared to change histopathological heterogeneity. The present study suggested that the histopathological change of intratumoral heterogeneity is reflected by the response to chemotherapy.
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Affiliation(s)
- Nobuhisa Matsuhashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hidenori Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yoshinori Iwata
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Satoshi Matsui
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Hisashi Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Masahiro Fukada
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Chika Mizutani
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Itaru Yasufuku
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Tomonari Suetsugu
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Ryutaro Mori
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yoshihiro Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Naoki Okumura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Manabu Futamura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
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26
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Riedesser JE, Ebert MP, Betge J. Precision medicine for metastatic colorectal cancer in clinical practice. Ther Adv Med Oncol 2022; 14:17588359211072703. [PMID: 35237350 PMCID: PMC8882813 DOI: 10.1177/17588359211072703] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 12/17/2021] [Indexed: 12/22/2022] Open
Abstract
Globally, metastatic colorectal cancer is one of the leading causes for cancer-related death. Treatment limited to conventional chemotherapeutics extended life for only a few months. However, advances in surgical approaches and medical treatment regimens have greatly increased survival, even leading to long-term remission in selected patients. Advances in multiomics analysis of tumors have built a foundation for molecular-targeted therapies. Furthermore, immunotherapies are on the edge of revolutionizing oncological practice. This review summarizes recent advances in the growing toolbox of personalized treatment for patients with metastatic colorectal cancer. We provide an overview of current multimodal therapy and explain novel immunotherapy and targeted therapy approaches in detail. We emphasize clinically relevant therapies, such as inhibitors of MAPK signaling, and give recommendations for clinical practice. Finally, we describe the potential predictive impact of molecular subtypes and provide an outlook on novel concepts, such as functional precision medicine.
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Affiliation(s)
- Julian E. Riedesser
- Junior Clinical Cooperation Unit Translational
Gastrointestinal Oncology and Preclinical Models, German Cancer Research
Center (DKFZ), Heidelberg, Germany
| | - Matthias P. Ebert
- Department of Medicine II, University Medical
Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim,
GermanyMannheim Cancer Center, University Medical Center Mannheim, Medical
Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Johannes Betge
- Junior Clinical Cooperation Unit Translational
Gastrointestinal Oncology and Preclinical Models, German Cancer Research
Center (DKFZ), Im Neuenheimer Feld 580, Heidelberg 69120, GermanyDKFZ-Hector
Cancer Institute at University Medical Center Mannheim, Mannheim,
Germany.Department of Medicine II, University Medical Center Mannheim,
Medical Faculty Mannheim, Heidelberg University, Mannheim, GermanyMannheim
Cancer Center, University Medical Center Mannheim, Medical Faculty Mannheim,
Heidelberg University, Mannheim, Germany
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27
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Cassar N, Geoghegan J, Hoti E. Shifting concepts in the management of colorectal liver metastases. Surgeon 2022; 20:363-372. [PMID: 34998701 DOI: 10.1016/j.surge.2021.12.005] [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: 06/24/2021] [Revised: 11/21/2021] [Accepted: 12/14/2021] [Indexed: 02/07/2023]
Abstract
Management of patients with colorectal liver metastases has evolved considerably due to a better understanding of the biology of the disease with concurrent improvements in surgical techniques, oncological strategies and radiological interventions. This review article examines the factors that have contributed to this radical change. Management will be discussed in relation to chemotherapy, surgery and interventional radiology. The addition of chemotherapy and biological agents has greatly extended the reach and scope of surgery. Parenchymal sparing resections, repeat resections, two stage hepatectomy and Associating Liver Partition and Portal Vein ligation are all available to the hepatobiliary surgeon who deals with colorectal liver metastases. Interventional radiology techniques like liver venous deprivation may also replace established surgical practice. Whilst traditionally it was thought that only a few liver metastases could be treated effectively, nowadays tumour number is no longer a limiting factor provided enough functioning liver can be spared and the patient can tolerate the operation.
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Affiliation(s)
- Noel Cassar
- Department of Hepatobiliary Surgery and Liver Transplantation, St Vincent's University Hospital, Elm Park, Dublin 4 D04 T6F4, Ireland.
| | - Justin Geoghegan
- Department of Hepatobiliary Surgery and Liver Transplantation, St Vincent's University Hospital, Elm Park, Dublin 4 D04 T6F4, Ireland
| | - Emir Hoti
- Department of Hepatobiliary Surgery and Liver Transplantation, St Vincent's University Hospital, Elm Park, Dublin 4 D04 T6F4, Ireland
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28
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Chan KM, Wang YC, Wu TH, Cheng CH, Lee CF, Wu TJ, Chou HS, Lee WC. Comment on "ALPPS Improves Survival Compared With TSH in Patients Affected of CRLM Survival Analysis From the Randomized Controlled Trial LIGRO": Metastatic Tumor Burden in the Future Liver Remnant for Decision-making of Staged Hepatectomy. Ann Surg 2021; 274:e749-e750. [PMID: 32590542 DOI: 10.1097/sla.0000000000004017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Kun-Ming Chan
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Yu-Chao Wang
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Tsung-Han Wu
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chih-Hsien Cheng
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chen-Fang Lee
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Ting-Jung Wu
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Hong-Shiue Chou
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Wei-Chen Lee
- Department of General Surgery and Chang Gung Transplantation Institute, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
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29
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Colorectal cancer liver metastases: An update of treatment strategy and future perspectives. SURGERY IN PRACTICE AND SCIENCE 2021. [DOI: 10.1016/j.sipas.2021.100042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
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30
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Response to the Comment on "ALPPS Improves Survival Compared With TSH in Patients Affected of CRLM: Survival Analysis From the Randomized Controlled Trial LIGRO-Metastatic Tumor Burden in the Future Liver Remnant for Decision-making of Staged Hepatectomy". Ann Surg 2021; 274:e750-e751. [PMID: 32590545 DOI: 10.1097/sla.0000000000004014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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31
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Bai L, Lin ZY, Lu YX, Chen Q, Zhou H, Meng Q, Lin CP, Huang WL, Wan YL, Pan ZZ, Wang DS. The prognostic value of preoperative serum lactate dehydrogenase levels in patients underwent curative-intent hepatectomy for colorectal liver metastases: A two-center cohort study. Cancer Med 2021; 10:8005-8019. [PMID: 34636145 PMCID: PMC8607270 DOI: 10.1002/cam4.4315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 08/18/2021] [Accepted: 09/08/2021] [Indexed: 12/13/2022] Open
Abstract
Background The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative‐intent surgery for colorectal liver metastases (CRLM). Patients and Methods Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative‐intent CRLM resection from Sun Yat‐sen University Cancer Center (434 patients) and Sun Yat‐sen University Sixth Affiliated Hospital (146 patients) in 2000–2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. Results At the median follow‐up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22–2.44; p < 0.001). Patients with elevated LDH levels showed impaired OS than patients with normal LDH levels (27.6 months vs. 68.8 months). Five‐year survival rates were 53.7% and 22.5% in the LDH‐normal group and LDH‐high group, respectively. Similar results were also confirmed in each cohort. In the subgroup analysis, LDH could distinguish the survival regardless of most established prognostic factors (number and size of CRLM, surgical margin, extrahepatic metastases, CEA, and CA19‐9 levels, etc.). Integrating LDH into the Fong score contributed to an improvement in the predictive value. Conclusion Our study implicates serum LDH as a reliable and independent laboratory biomarker to predict the clinical outcome of curative‐intent surgery for CRLM. Composite of LDH and Fong score is a potential stratification tool for CRLM resection. Prospective, international studies are needed to validate these results across diverse populations.
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Affiliation(s)
- Long Bai
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of VIP region, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Ze-Yu Lin
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yun-Xin Lu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Qin Chen
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Han Zhou
- Department of Medical Administration, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qi Meng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Chun-Ping Lin
- Department of Oncology, Jieyang Affiliated Hospital, Sun Yat-sen University, Jieyang, China
| | - Wan-Lan Huang
- Department of Oncology, Jieyang Affiliated Hospital, Sun Yat-sen University, Jieyang, China
| | - Yun-Le Wan
- Department of Hepatobiliary Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Zhong Pan
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Colorectal Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - De-Shen Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.,Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou, China.,Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Rocca A, Scacchi A, Cappuccio M, Avella P, Bugiantella W, De Rosa M, Costa G, Polistena A, Codacci-Pisanelli M, Amato B, Carbone F, Ceccarelli G. Robotic surgery for colorectal liver metastases resection: A systematic review. Int J Med Robot 2021; 17:e2330. [PMID: 34498805 DOI: 10.1002/rcs.2330] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/10/2021] [Accepted: 09/07/2021] [Indexed: 12/18/2022]
Abstract
BACKGROUND The role of robotic surgery for colorectal cancer liver metastases (CRCLMs) has never been investigated in large series. METHODS A systematic literature review was carried out on PubMed and Cochrane libraries. RESULTS We selected nine studies between 2008 and 2021. Two hundred sixty-two patients were included. One hundred thirty-one patients underwent simultaneous resections. The mean blood loss was 309.4 ml (range, 200-450 ml), the mean operative time was 250.5 min (range, 198.5-449.0 min). The mean length of hospital stay was 7.98 days (range, 4.5 to 12 days). The overall postoperative mortality was 0.4%. The overall morbidity rate was 37.0%, Clavien-Dindo grade III-IV complications were 8.4%. The mean 3-year overall survival was 55.25% (range, 44.4-66.1%), the mean 3-year disease free survival was 37% (range, 33.3-41.9%) CONCLUSION: We can conclude that robotic-assisted surgery might be considered as a technical upgrade option for minimally invasive approach to CRCLM resections even for simultaneous operations and challenging cases.
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Affiliation(s)
- Aldo Rocca
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Andrea Scacchi
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Micaela Cappuccio
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Pasquale Avella
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy
| | - Walter Bugiantella
- General Surgery Department, ASL 2 Umbria, San Giovanni Battista, Foligno, Italy
| | - Michele De Rosa
- General Surgery Department, ASL 2 Umbria, San Giovanni Battista, Foligno, Italy
| | - Gianluca Costa
- Department of Medical and Surgical Sciences and Translational Medicine, Faculty of Medicine and Psychology, St Andrea Hospital, Sapienza University, Rome, Italy
| | - Andrea Polistena
- UOC General Surgery and Laparoscopic Surgery, Department of Surgery "P. Valdoni", Sapienza, University of Study of Rome, University Policlinic Umberto I, Rome, Italy
| | - Massimo Codacci-Pisanelli
- UOC General Surgery and Laparoscopic Surgery, Department of Surgery "P. Valdoni", Sapienza, University of Study of Rome, University Policlinic Umberto I, Rome, Italy
| | - Bruno Amato
- Division of General Surgery, Department of Clinical Medicine and Surgery, School of Medicine, University of Naples "Federico II", Naples, Italy
| | - Fabio Carbone
- Department of Advanced Biomedical Sciences, Università di Napoli - "Federico II", Naples, Italy
| | - Graziano Ceccarelli
- General Surgery Department, ASL 2 Umbria, San Giovanni Battista, Foligno, Italy
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33
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Rocca A, Cipriani F, Belli G, Berti S, Boggi U, Bottino V, Cillo U, Cescon M, Cimino M, Corcione F, De Carlis L, Degiuli M, De Paolis P, De Rose AM, D'Ugo D, Di Benedetto F, Elmore U, Ercolani G, Ettorre GM, Ferrero A, Filauro M, Giuliante F, Gruttadauria S, Guglielmi A, Izzo F, Jovine E, Laurenzi A, Marchegiani F, Marini P, Massani M, Mazzaferro V, Mineccia M, Minni F, Muratore A, Nicosia S, Pellicci R, Rosati R, Russolillo N, Spinelli A, Spolverato G, Torzilli G, Vennarecci G, Viganò L, Vincenti L, Delrio P, Calise F, Aldrighetti L. The Italian Consensus on minimally invasive simultaneous resections for synchronous liver metastasis and primary colorectal cancer: A Delphi methodology. Updates Surg 2021; 73:1247-1265. [PMID: 34089501 DOI: 10.1007/s13304-021-01100-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 05/12/2021] [Indexed: 12/17/2022]
Abstract
At the time of diagnosis synchronous colorectal cancer, liver metastases (SCRLM) account for 15-25% of patients. If primary tumour and synchronous liver metastases are resectable, good results may be achieved performing surgical treatment incorporated into the chemotherapy regimen. So far, the possibility of simultaneous minimally invasive (MI) surgery for SCRLM has not been extensively investigated. The Italian surgical community has captured the need and undertaken the effort to establish a National Consensus on this topic. Four main areas of interest have been analysed: patients' selection, procedures, techniques, and implementations. To establish consensus, an adapted Delphi method was used through as many reiterative rounds were needed. Systematic literature reviews were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses instructions. The Consensus took place between February 2019 and July 2020. Twenty-six Italian centres participated. Eighteen clinically relevant items were identified. After a total of three Delphi rounds, 30-tree recommendations reached expert consensus establishing the herein presented guidelines. The Italian Consensus on MI surgery for SCRLM indicates possible pathways to optimise the treatment for these patients as consensus papers express a trend that is likely to become shortly a standard procedure for clinical pictures still on debate. As matter of fact, no RCT or relevant case series on simultaneous treatment of SCRLM are available in the literature to suggest guidelines. It remains to be investigated whether the MI technique for the simultaneous treatment of SCRLM maintain the already documented benefit of the two separate surgeries.
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Affiliation(s)
- Aldo Rocca
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, Campobasso, Italy.
- Center for Hepatobiliary and Pancreatic Surgery, Pineta Grande Hospital, Castel Volturno, Italy.
| | - Federica Cipriani
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Giulio Belli
- Department of General and HPB Surgery, Loreto Nuovo Hospital, Naples, Italy
| | - Stefano Berti
- Department of Surgery, Hospital S Andrea La Spezia, La Spezia, Italy
| | - Ugo Boggi
- Division of General and Transplant Surgery, Pisa University Hospital, Pisa, Italy
| | - Vincenzo Bottino
- Department of Obesity and Metabolic Surgery, Ospedale Evangelico Betania, Naples, Italy
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padua, Italy
| | - Matteo Cescon
- General Surgery and Transplant Unit, IRCCS AOU Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Matteo Cimino
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Clinical and Research Center, IRCCS, Humanitas University, Rozzano, MI, Italy
| | - Francesco Corcione
- Department of Public Health, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Luciano De Carlis
- Division of General Surgery and Abdominal Transplantation, ASST Grande Ospedale Metropolitano Niguarda, School of Medicine, University of Milano-Bicocca, Milan, Italy
| | - Maurizio Degiuli
- Department of Oncology, Digestive and Surgical Oncology, San Luigi University Hospital, University of Torino, Orbassano, Italy
| | - Paolo De Paolis
- General Surgery Department, Ospedale Gradenigo, Turin, Italy
| | - Agostino Maria De Rose
- Hepatobiliary Surgery Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Domenico D'Ugo
- General Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, Rome, Italy
| | - Fabrizio Di Benedetto
- Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Ugo Elmore
- Vita-Salute San Raffaele University, Milan, Italy
- Division of Gastrointestinal Surgery, San Raffaele Scientific Institute, Milan, Italy
| | - Giorgio Ercolani
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forli, Italy
| | - Giuseppe M Ettorre
- Department of General Surgery and Transplantation, San Camillo-Forlanini General Hospital, Rome, Italy
| | - Alessandro Ferrero
- Department of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Turin, Italy
| | - Marco Filauro
- General and Hepatobiliopancreatic Surgery Unit, Department of Abdominal Surgery, E.O. Galliera Hospital, Genoa, Italy
| | - Felice Giuliante
- Hepatobiliary Surgery Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Salvatore Gruttadauria
- Abdominal Surgery and Organ Transplantation Unit, Department for the Treatment and Study of Abdominal Diseases and Abdominal Transplantation, ISMETT, Palermo, Italy
| | - Alfredo Guglielmi
- Unit of HPB Surgery, Department of Surgery, GB Rossi University Hospital, Verona, Italy
| | - Francesco Izzo
- Divisions of Hepatobiliary Surgery, Istituto Nazionale Dei Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Elio Jovine
- Department of Surgery, AOU Sant'Orsola Malpighi, IRCCS, Bologna, Italy
| | - Andrea Laurenzi
- General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forli, Italy
| | - Francesco Marchegiani
- Hepatobiliary Surgery and Liver Transplantation Unit, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padua, Italy
| | - Pierluigi Marini
- The Department of General and Emergency Surgery, San Camillo-Forlanini Regional Hospital, Rome, Italy
| | - Marco Massani
- Department of Surgery, Regional Hospital of Treviso, Treviso, Italy
| | - Vincenzo Mazzaferro
- Department of Gastrointestinal Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy
| | - Michela Mineccia
- Department of General Surgery and Transplantation, San Camillo-Forlanini General Hospital, Rome, Italy
| | - Francesco Minni
- Division of Pancreatic Surgery, Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Andrea Muratore
- General Surgery Unit, E. Agnelli Hospital, Pinerolo, TO, Italy
| | - Simone Nicosia
- Department of Surgery, AOU Sant'Orsola Malpighi, IRCCS, Bologna, Italy
| | - Riccardo Pellicci
- General Surgery Unit, Santa Corona Hospital, Pietra Ligure, SV, Italy
| | - Riccardo Rosati
- Vita-Salute San Raffaele University, Milan, Italy
- Division of Gastrointestinal Surgery, San Raffaele Scientific Institute, Milan, Italy
| | - Nadia Russolillo
- Department of HPB and Digestive Surgery, Ospedale Mauriziano Umberto I, Turin, Italy
| | - Antonino Spinelli
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090, Pieve Emanuele, MI, Italy
- Division of Colon and Rectal Surgery, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Gaya Spolverato
- Surgery Unit, Department of Surgical Oncology and Gastroenterology Sciences (DiSCOG), University of Padua, Padua, Italy
| | - Guido Torzilli
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Clinical and Research Center, IRCCS, Humanitas University, Rozzano, MI, Italy
| | - Giovanni Vennarecci
- Laparoscopic, Hepatic, and Liver Transplant Unit, AORN A. Cardarelli, Naples, Italy
| | - Luca Viganò
- Division of Hepatobiliary and General Surgery, Department of Surgery, Humanitas Clinical and Research Center, IRCCS, Humanitas University, Rozzano, MI, Italy
| | - Leonardo Vincenti
- Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy
| | - Paolo Delrio
- Colorectal Surgical Oncology-Abdominal Oncology Department, Istituto Nazionale per lo Studio e la Cura dei Tumori, 'Fondazione Giovanni Pascale' IRCCS, 80131, Naples, Italy
| | - Fulvio Calise
- Center for Hepatobiliary and Pancreatic Surgery, Pineta Grande Hospital, Castel Volturno, Italy
| | - Luca Aldrighetti
- Hepatobiliary Surgery Division, IRCCS San Raffaele Scientific Institute, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
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34
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Chiorean EG, Nandakumar G, Fadelu T, Temin S, Alarcon-Rozas AE, Bejarano S, Croitoru AE, Grover S, Lohar PV, Odhiambo A, Park SH, Garcia ER, Teh C, Rose A, Zaki B, Chamberlin MD. Treatment of Patients With Late-Stage Colorectal Cancer: ASCO Resource-Stratified Guideline. JCO Glob Oncol 2021; 6:414-438. [PMID: 32150483 PMCID: PMC7124947 DOI: 10.1200/jgo.19.00367] [Citation(s) in RCA: 113] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE To provide expert guidance to clinicians and policymakers in resource-constrained settings on the management of patients with late-stage colorectal cancer. METHODS ASCO convened a multidisciplinary, multinational Expert Panel that reviewed existing guidelines, conducted a modified ADAPTE process, and used a formal consensus process with additional experts for two rounds of formal ratings. RESULTS Existing sets of guidelines from four guideline developers were identified and reviewed; adapted recommendations from five guidelines form the evidence base and provided evidence to inform the formal consensus process, which resulted in agreement of ≥ 75% on all recommendations. RECOMMENDATIONS Common elements of symptom management include addressing clinically acute situations. Diagnosis should involve the primary tumor and, in some cases, endoscopy, and staging should involve digital rectal exam and/or imaging, depending on resources available. Most patients receive treatment with chemotherapy, where chemotherapy is available. If, after a period of chemotherapy, patients become candidates for surgical resection with curative intent of both primary tumor and liver or lung metastatic lesions on the basis of evaluation in multidisciplinary tumor boards, the guidelines recommend patients undergo surgery in centers of expertise if possible. On-treatment surveillance includes a combination of taking medical history, performing physical examinations, blood work, and imaging; specifics, including frequency, depend on resource-based setting. Additional information is available at www.asco.org/resource-stratified-guidelines.
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Affiliation(s)
- E Gabriela Chiorean
- University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Govind Nandakumar
- Columbia Asia Hospitals, Bangalore, India.,Weill Cornell Medical College, New York, NY
| | | | - Sarah Temin
- American Society of Clinical Oncology, Alexandria, VA
| | | | - Suyapa Bejarano
- Excelmedica, Liga Contra el Cancer Honduras, San Pedro Sulal, Honduras
| | | | | | | | - Andrew Odhiambo
- University of Nairobi, College of Health Sciences, Nairobi, Kenya
| | | | | | - Catherine Teh
- Philippine Association of HPB Surgeons/Makati Medical Center, Makati City, Philippines
| | - Azmina Rose
- Independent Colorectal Patient Representative, London, United Kingdom
| | - Bassem Zaki
- Dartmouth-Hitchcock Medical Center, Lebanon, NH
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Combinatorial therapy in tumor microenvironment: Where do we stand? Biochim Biophys Acta Rev Cancer 2021; 1876:188585. [PMID: 34224836 DOI: 10.1016/j.bbcan.2021.188585] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/28/2021] [Accepted: 06/23/2021] [Indexed: 01/09/2023]
Abstract
The tumor microenvironment plays a pivotal role in tumor initiation and progression by creating a dynamic interaction with cancer cells. The tumor microenvironment consists of various cellular components, including endothelial cells, fibroblasts, pericytes, adipocytes, immune cells, cancer stem cells and vasculature, which provide a sustained environment for cancer cell proliferation. Currently, targeting tumor microenvironment is increasingly being explored as a novel approach to improve cancer therapeutics, as it influences the growth and expansion of malignant cells in various ways. Despite continuous advancements in targeted therapies for cancer treatment, drug resistance, toxicity and immune escape mechanisms are the basis of treatment failure and cancer escape. Targeting tumor microenvironment efficiently with approved drugs and combination therapy is the solution to this enduring challenge that involves combining more than one treatment modality such as chemotherapy, surgery, radiotherapy, immunotherapy and nanotherapy that can effectively and synergistically target the critical pathways associated with disease pathogenesis. This review shed light on the composition of the tumor microenvironment, interaction of different components within tumor microenvironment with tumor cells and associated hallmarks, the current status of combinatorial therapies being developed, and various growing advancements. Furthermore, computational tools can also be used to monitor the significance and outcome of therapies being developed. We addressed the perceived barriers and regulatory hurdles in developing a combinatorial regimen and evaluated the present status of these therapies in the clinic. The accumulating depth of knowledge about the tumor microenvironment in cancer may facilitate further development of effective treatment modalities. This review presents the tumor microenvironment as a sweeping landscape for developing novel cancer therapies.
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Willis MA, Schwenk W, Post S, Nothacker M, Follmann M, Vilz TO. [Background, Necessity and Methodology of the S3 Guideline "Perioperative Management of Gastrointestinal Tumours (POMGAT)"]. Zentralbl Chir 2021; 146:241-248. [PMID: 34154005 DOI: 10.1055/a-1481-9394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Malignancies are among the most common diseases, especially in old age, and are responsible for 25% of all deaths in Germany. Especially carcinomas of the gastrointestinal tract can be cured in most cases only through extensive surgery with significant morbidity. About 25 years ago, the multimodal, perioperative Fast Track (FT) concept for reducing postoperative complications was introduced and additional elements were added in the following years. Meanwhile, there is growing evidence that adherence to the key elements of more than 70% leads to reduction in postoperative adverse events as well as a shorter hospital stay and could be associated with an improved oncological outcome. Despite the high level of awareness and the proven advantages of the FT concept, the implementation and maintenance of the measures is difficult and results in an adherence of only 20 - 40%. There are many reasons for this: In addition to a lack of interdisciplinary and interprofessional cooperation and the time consuming and extended logistical efforts, limited human resources are often listed as one of the main causes. We took these aspects as an opportunity and started to develop a S3 guideline for perioperative treatment to accelerate the recovery of patients with gastrointestinal malignancies. By creating a consensus- and evidence-based, multidisciplinary guideline, many of the problems listed above could probably be solved by optimising and standardising interdisciplinary care, which is particularly important in a setting with many different disciplines and their competing interests. Furthermore, the standardisation of the perioperative procedures will reduce the time and logistical effort. The presentation of the evidence allows increased transparency and justifies the additional personnel expenditure on hospital medicine and health insurance companies. In addition, the evidence-based quality indicators generated during the development of the guideline make it possible to include perioperative standards in certification systems and thus to measure and check the quality of perioperative care.
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Affiliation(s)
- Maria A Willis
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Deutschland
| | | | - Stefan Post
- ehemals Chirurgische Klinik, Universitätsklinikum Mannheim, Mannheim, Deutschland
| | - Monika Nothacker
- Philipps-Universität Marburg, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V., Marburg, Deutschland
| | - Markus Follmann
- Office des Leitlinienprogrammes Onkologie, Deutsche Krebsgesellschaft e. V., Berlin, Deutschland
| | - Tim O Vilz
- Klinik und Poliklinik für Allgemein-, Viszeral-, Thorax- und Gefäßchirurgie, Universitätsklinikum Bonn, Deutschland
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37
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Kato T, Matsuhashi N, Tomita H, Takahashi T, Iwata Y, Fukada M, Yasufuku I, Suetsugu T, Imai T, Mori R, Imai H, Tanaka Y, Okumura N, Hara A, Yoshida K. MYC Up-regulation Is a Useful Biomarker for Preoperative Neoadjuvant Chemotherapy Combined With Anti-EGFR in Liver Metastasis from Colorectal Cancer. In Vivo 2021; 35:203-213. [PMID: 33402467 DOI: 10.21873/invivo.12249] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 10/02/2020] [Accepted: 10/15/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIM At present, there are no biomarkers to predict the effects of molecular targeted drugs in patients with CRC with liver metastasis. Thus, we performed this study to explore potential biomarkers for these patients. MATERIALS AND METHODS We obtained cancer tissue specimens from liver metastasis-bearing CRC patients who received the following preoperative neoadjuvant chemotherapies with molecular targeted drugs: i) no therapy (n=3), ii) 5-FU+oxaliplatin+anti-EGFR (n=3), iii) and 5-FU+oxaliplatin+anti-VEGF (n=3). RESULTS We investigated the RNA expression of 84 genes related to cancer drug resistance using an RT-PCR array. The MYC gene was the only gene that was significantly up-regulated in CRC tissue specimens from anti-EGFR group in comparison to the anti-VEGF group. CONCLUSION MYC up-regulation in the primary CRC tissues may be a potentially useful biomarker for selecting anti-EGFR combination therapy in neoadjuvant chemotherapy for CRC with liver metastasis.
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Affiliation(s)
- Takazumi Kato
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan;
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshinori Iwata
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masahiro Fukada
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Itaru Yasufuku
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomonari Suetsugu
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Takeharu Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Ryutaro Mori
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisashi Imai
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Yoshihiro Tanaka
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Naoki Okumura
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan
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38
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Zhai S, Sun X, Du L, Chen K, Zhang S, Shi Y, Yuan F. Role of Surgical Approach to Synchronous Colorectal Liver Metastases: A Retrospective Analysis. Cancer Manag Res 2021; 13:3699-3711. [PMID: 33994810 PMCID: PMC8112857 DOI: 10.2147/cmar.s300890] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Accepted: 04/07/2021] [Indexed: 12/16/2022] Open
Abstract
PURPOSE This study is a retrospective analysis of exploring the efficiency of surgical management on patients with synchronous colorectal liver metastasis (SCLM). PATIENTS AND METHODS Nine hundred fifty-three consecutive patients with SCLM from Weifang People's Hospital of Shandong Province between January 2006 and December 2015 were reviewed. The values of different factors were analyzed, such as different surgical indications of liver metastases, simultaneous or staged resection of primary colorectal cancer and liver metastases, and primary tumor resection (PTR) of asymptomatic patients with unresectable liver metastases. RESULTS Median survival time (47.3 months) and 5-year survival rate (31%) for patients with resected liver metastases were significantly superior to that of with nonoperative treatment (17.2 months, 4%, P<0.001); enlarging the standard of liver metastases resection can improve the resection rates (31.0% vs 13.6%, P<0.001); for patients with resectable liver metastases, the in-hospital cost for simultaneous resection group was lower than that in the staged resection group (36,698 vs 45,134 RMB, P<0.001); for patients of the asymptomatic primary tumor with unresectable liver metastases, PTR was associated with improved median survival (18.0 vs 15.0 months, P=0.006). CONCLUSION For patients with SCLM, liver resection is considered the best treatment; expanding indications of liver resection can improve the resection rates. Simultaneous resection of the primary tumor and liver metastases were indicated in patients with resectable SCLM; PTR was recommended for asymptomatic patients with unresectable hepatic metastases.
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Affiliation(s)
- Shengyong Zhai
- Department of Oncology Surgery, Weifang People’ s Hospital, Weifang Medical College, Weifang City, Shandong Province, 261041, People’s Republic of China
| | - Xiaojing Sun
- School of Management and Information, Shandong Transport Vocational College, Weifang City, Shandong Province, 261041, People’s Republic of China
| | - Longfeng Du
- Department of Oncology Surgery, Weifang People’ s Hospital, Weifang Medical College, Weifang City, Shandong Province, 261041, People’s Republic of China
| | - Kai Chen
- Department of Oncology Surgery, Weifang People’ s Hospital, Weifang Medical College, Weifang City, Shandong Province, 261041, People’s Republic of China
| | - Shanshan Zhang
- School of Management and Information, Shandong Transport Vocational College, Weifang City, Shandong Province, 261041, People’s Republic of China
| | - Yiran Shi
- Department of Oncology Surgery, Weifang People’ s Hospital, Weifang Medical College, Weifang City, Shandong Province, 261041, People’s Republic of China
| | - Fei Yuan
- Department of Oncology Surgery, Weifang People’ s Hospital, Weifang Medical College, Weifang City, Shandong Province, 261041, People’s Republic of China
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39
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Sakai N, Furukawa K, Takayashiki T, Kuboki S, Takano S, Ohtsuka M. Differential effects of KRAS mutational status on long-term survival according to the timing of colorectal liver metastases. BMC Cancer 2021; 21:412. [PMID: 33858364 PMCID: PMC8048293 DOI: 10.1186/s12885-021-08144-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Background The relationship between KRAS mutational status and timing of colorectal liver metastasis (CRLM) remains unclear. This study evaluated the relationship between KRAS mutational status and long-term survival in patients with synchronous CRLM. Methods Of the 255 patients who underwent initial hepatic resection for CRLM between January 2001 and December 2018, the KRAS mutational status was examined in 101 patients. Medical records of these patients were reviewed to evaluate recurrence and survival outcomes. Results KRAS mutant status was identified in 38 patients (37.6%). The overall survival (OS) was significantly better in patients with wild-type KRAS than in those with mutant KRAS status. In patients with synchronous metastases, the OS of patients with wild-type KRAS was significantly better than those with mutant KRAS. Multivariate analyses indicated shorter OS to be independently associated with positive primary lymph node, and large tumor size and R1 resection in patients with metachronous metastasis, whereas to be independently associated with mutant KRAS status in patients with synchronous metastasis. Furthermore, in the subgroup of patients with synchronous metastases, the repeat resection rate for hepatic recurrence was significantly high in those with wild type KRAS than in those with mutant KRAS. Conclusion KRAS mutation is an independent prognostic factor in patients with synchronous CRLM, but not in patients with metachronous CRLM.
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Affiliation(s)
- Nozomu Sakai
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
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40
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Nozawa H, Ishizawa T, Yasunaga H, Ishii H, Sonoda H, Emoto S, Murono K, Sasaki K, Kawai K, Akamatsu N, Kaneko J, Arita J, Hasegawa K, Ishihara S. Open and/or laparoscopic one-stage resections of primary colorectal cancer and synchronous liver metastases: An observational study. Medicine (Baltimore) 2021; 100:e25205. [PMID: 33726015 PMCID: PMC7982201 DOI: 10.1097/md.0000000000025205] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 02/14/2021] [Accepted: 02/25/2021] [Indexed: 01/05/2023] Open
Abstract
One-stage resections of primary colorectal cancer and liver metastases have been reported to be feasible and safe. Minimally invasive approaches have become more common for both colorectal and hepatic surgeries. This study aimed to investigate outcomes of these combined surgical procedures among different approaches.We retrospectively analyzed patients diagnosed as having primary colorectal cancer with synchronous liver metastases and who underwent 1-stage primary resection and hepatectomy with curative intent in our hospital. According to the surgical approach for the primary tumor and hepatic lesions, namely open laparotomy (Op) or laparoscopic approach (Lap), patients were classified into Op-Op, Lap-Op (laparoscopic colorectal resection plus open hepatectomy), and Lap-Lap groups, respectively. Clinicopathological factors were reviewed, and short- and long-term outcomes were compared among the groups.The Op-Op, Lap-Op, and Lap-Lap groups comprised 36, 18, and 17 patients, respectively. The superior/posterior hepatic segments were more frequently resected via an open approach. There was no laparoscopic major hepatectomy. The median volume of intraoperative blood loss was smaller in the Lap-Lap and Lap-Op groups (290 and 270 mL) than in the Op-Op group (575 mL, P = .008). The hospital stay after surgery was shorter in the Lap-Lap and Lap-Op groups (median: 17 days and 15 days, vs 19 days for the Op-Op group, P = .033). The postoperative complication rates and survivals were similar among the groups.Application of laparoscopy to 1-stage resections of primary colorectal cancer and liver metastases may offer advantages of enhanced recovery from surgical treatment, given appropriate patient selection.
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Affiliation(s)
| | - Takeaki Ishizawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan
| | | | | | | | | | | | | | - Nobuhisa Akamatsu
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine
| | - Junichi Kaneko
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine
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41
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Perfecto A, Gastaca M, Prieto M, Cervera J, Ruiz P, Ventoso A, Palomares I, García JM, Valdivieso A. Totally laparoscopic simultaneous resection of colorectal cancer and synchronous liver metastases: a single-center case series. Surg Endosc 2021; 36:980-987. [PMID: 33666752 DOI: 10.1007/s00464-021-08362-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 02/09/2021] [Indexed: 10/22/2022]
Abstract
BACKGROUND The aim of the study is to analyze the feasibility, the safety and short- and medium-term survival of totally laparoscopic simultaneous resections (LSR) of colorectal cancer (CRC) and synchronous liver metastases (LM). METHODS This is a retrospective study of a single-center series. Patients ASA IV, ECOG ≥ 2, major hepatectomies (≥ 3 segments), symptomatic CRC as well as low rectal tumors were excluded from indication. The difficulty level of all liver resections was classified as low or intermediate according to the Iwate Criteria. Dindo-Clavien classification for postoperative complications evaluation was used. RESULTS 15 Patients with 21 liver lesions were included. Laparoscopic liver surgery was performed first in every case. Median size of the lesions was 20 mm (r 8-69). Major complications (Dindo-Clavien ≥ 3) occurred in 3 patients (20%); median hospital stay was 7 days (r 4-35), and only one patient (6.6%) was readmitted upon the first month from the surgery. 90-day mortality rate was 0%. After a median follow-up of 24 months (r 7-121), disease-free survival at 1, 2 and 3 years was 58%, 36% and 24%, respectively; overall survival at 1, 2 and 3 years was 92.3%. CONCLUSIONS In selected patients, LSR of CRC and LM is technically feasible and has an acceptable morbidity rate and mid-term survival.
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Affiliation(s)
- Arkaitz Perfecto
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain
| | - Mikel Gastaca
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain. .,University of the Basque Country, Leioa, Spain.
| | - Mikel Prieto
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain.,University of the Basque Country, Leioa, Spain
| | - Jorge Cervera
- University of the Basque Country, Leioa, Spain.,Coloproctology Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain
| | - Patricia Ruiz
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain
| | - Alberto Ventoso
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain
| | - Ibone Palomares
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain
| | - José María García
- University of the Basque Country, Leioa, Spain.,Coloproctology Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain
| | - Andrés Valdivieso
- Hepatobiliary Surgery and Liver Transplantation Unit, Cruces University Hospital, Biocruces Bizkaia Health Research Institute, Plaza Cruces S/N, Barakaldo, 48903, Spain.,University of the Basque Country, Leioa, Spain
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42
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Boraschi P, Donati F, Cervelli R, Pacciardi F, Tarantini G, Castagna M, Urbani L, Lencioni R. Colorectal liver metastases: ADC as an imaging biomarker of tumor behavior and therapeutic response. Eur J Radiol 2021; 137:109609. [PMID: 33647779 DOI: 10.1016/j.ejrad.2021.109609] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/16/2021] [Accepted: 02/21/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE To correlate the ADC values of colorectal liver metastases, evaluated before (preADC) and after (postADC) neoadjuvant chemotherapy (ChT), as well as their difference (ΔADC), with the histological tumor regression grade (TRG) and to determine whether the preADC value can be predictive of the lesion ChT response. METHOD Twenty-four patients with colorectal liver metastases, who had undergone 3 T-MRI before and after ChT and were subsequently treated by parenchymal-spearing surgery, were retrospectively included. Diffusion-weighted MRI (DW-MRI) was performed using a spin-echo echo-planar sequence with multiple b values, obtaining an ADC map. Fitted ADC values were calculated for each lesion before and after ChT. The maximum diameter of each lesion in both examinations was recorded. Diameter variations and RECIST1.1 criteria were assessed. All MRI findings were histopathologically correlated to TRG of resected liver metastases. Statistical analysis was performed on a per-lesion basis. RESULTS A total of 58 colorectal liver metastases were analysed; after ChT, 8 out of 58 lesions disappeared. TRG1, TRG2, TRG3, TRG4 and TRG5 were observed in 6, 12, 12, 13 and 7 lesions, respectively. The preADC values showed a different distribution according to the TRG scores (p = 0.0027), even though the distribution was not linear. The postADC and ΔADC values were significant different based on the TRG system (both p < 0.0001). A significant correlation between the lesion TRG and the evaluation according to RECIST1.1 criteria was observed by a per-lesion analysis (p = 0.0009). CONCLUSIONS PostADC and ΔADC could be proposed as reliable biomarkers to assess tumor treatment response after preoperative ChT in patients with colorectal liver metastases.
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Affiliation(s)
- Piero Boraschi
- Department of Diagnostic Imaging, Pisa University Hospital, Via Paradisa 2, Pisa, 56124, Italy.
| | - Francescamaria Donati
- Department of Diagnostic Imaging, Pisa University Hospital, Via Paradisa 2, Pisa, 56124, Italy
| | - Rosa Cervelli
- Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, Pisa, 56124, Italy
| | - Federica Pacciardi
- Department of Diagnostic Imaging, Pisa University Hospital, Via Paradisa 2, Pisa, 56124, Italy
| | - Gaia Tarantini
- Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, Pisa, 56124, Italy
| | - Maura Castagna
- Unit of Pathology, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 67, Pisa, 56126, Italy
| | - Lucio Urbani
- Department of General Surgery, Pisa University Hospital, Via Paradisa 2, Pisa, 56124, Italy
| | - Riccardo Lencioni
- Diagnostic and Interventional Radiology, University of Pisa, Via Paradisa 2, Pisa, 56124, Italy
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43
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Parmar KL, O'Reilly D, Valle JW, Braun M, Naish JH, Williams SR, Lloyd WK, Malcomson L, Cresswell K, Bamford C, Renehan AG. Prospective study of change in liver function and fat in patients with colorectal liver metastases undergoing preoperative chemotherapy: protocol for the CLiFF Study. BMJ Open 2020; 10:e027630. [PMID: 32967864 PMCID: PMC7513559 DOI: 10.1136/bmjopen-2018-027630] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Preoperative chemotherapy in patients undergoing resection for colorectal liver metastases (CLM) improves oncological outcomes. However, chemotherapy-associated liver injury (occurring in two patterns: vascular and fat deposition) is a real clinical concern prior to hepatic resection. After major liver resection, regeneration of the residual liver is a prerequisite for recovery and avoidance of liver failure, but this regenerative capacity may be hindered by chemotherapy. Thus, there is a need to predict for this serious complication. Over the past two decades, several tests and derived indices have been developed, which have failed to achieve clinical utility, mainly as they were indirect measurements of liver function. Here, we will use a novel test of liver function (the liver maximum capacity (LiMAx) test), and measure liver fat using MRI. METHODS AND ANALYSIS This prospective study will assess changes in liver function longitudinally, measured by the LiMAx test, and liver fat, measured by advanced MRI using both MR spectroscopy and the modified Dixon method, in up to 35 patients undergoing preoperative chemotherapy for CLM. The primary outcomes will be the changes in liver function and fat compared with baseline prechemotherapy measurements. Secondary outcome measures include: routinely measured liver function blood tests, anthropometric measurements, postoperative histology and digital quantification of fat, postoperative complications and mortality and quality of life. ETHICS AND DISSEMINATION The study was approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences and the National Institute for Health Research network. Manuscripts will be published. TRIAL REGISTRATION NUMBER This study is registered online at www.clinicaltrials.gov (registration number NCT03562234).
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Affiliation(s)
- Kat L Parmar
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Manchester Cancer Research Centre, Manchester, UK
| | - Derek O'Reilly
- Hepatobiliary Surgery, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Juan W Valle
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Oncology, Christie NHS Foundation Trust, Manchester, UK
| | - Michael Braun
- Oncology, Christie NHS Foundation Trust, Manchester, UK
| | - Jo H Naish
- Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK
| | - Steve R Williams
- Centre for Imaging Sciences, University of Manchester, Manchester, UK
| | - William K Lloyd
- Centre for Imaging Sciences, University of Manchester, Manchester, UK
| | - Lee Malcomson
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Surgery, Christie NHS Foundation Trust, Manchester, UK
| | - Katharine Cresswell
- Public Programmes Team, Research and Innovation Division, Manchester University NHS Foundation Trust, Manchester, UK
| | - Colin Bamford
- Cancer Patient and Public Advisory Group, NIHR Manchester Biomedical Research Centre, Manchester, UK
| | - Andrew G Renehan
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
- Surgery, Christie NHS Foundation Trust, Manchester, UK
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44
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Wisneski AD, Jin C, Huang CY, Warren R, Hirose K, Nakakura EK, Corvera CU. Synchronous Versus Metachronous Colorectal Liver Metastasis Yields Similar Survival in Modern Era. J Surg Res 2020; 256:476-485. [PMID: 32798995 DOI: 10.1016/j.jss.2020.06.038] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 06/07/2020] [Accepted: 06/16/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Synchronous colorectal cancer liver metastasis (CRLM) has been viewed as being more aggressive and having shorter survival than metachronous disease. Advances in CRLM management led us to examine differences in treatment characteristics of synchronous versus metachronous CRLM patients along with survival and recurrence. MATERIALS AND METHODS A retrospective review of hepatic resection for CRLM at a tertiary academic medical center was performed for two periods: a historic cohort from 1992 to 2010 (n = 121), and a modern cohort (n = 179) from 2012 to 2018. Clinical variables were compared between the patient groups, and survival outcomes were characterized. RESULTS Five-year disease-specific survival for the modern synchronous group compared to the historic synchronous group was 71.7% versus 44.3% (P = 0.02). Modern metachronous versus modern synchronous 5-y disease-specific survival rates were 49.8% versus 71.7% (P = 0.31). Compared to the historic cohort, the modern one had significantly different timing of hepatic resection (P < 0.01) with increased use of liver-first (30.1% versus 7.5%) and simultaneous liver-colon resections (24.1% versus 10.4%), along with greater use of neoadjuvant chemotherapy (96.4% versus 65.6%; P < 0.01). Significantly more patients in the modern synchronous cohort had disease-free or alive-with-disease status at last follow-up, compared to the historic group (P < 0.01), and experienced less disease recurrence (62.7% versus 77.6%; P < 0.05). CONCLUSIONS Modern synchronous CRLM patients who underwent hepatic resection experienced significantly improved survival compared to a historic cohort. We postulate that increased use of neoadjuvant chemotherapy and liver-first/simultaneous liver-colon resections in the modern synchronous cohort contributed to improved survival.
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Affiliation(s)
- Andrew D Wisneski
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Chengshi Jin
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California
| | - Chiung-Yu Huang
- Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California
| | - Robert Warren
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Kenzo Hirose
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Eric K Nakakura
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Carlos U Corvera
- Department of Surgery, University of California San Francisco, San Francisco, California.
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Pérez-Santiago L, Dorcaratto D, Garcés-Albir M, Muñoz-Forner E, Huerta Álvaro M, Roselló Keranën S, Sabater L. The actual management of colorectal liver metastases. MINERVA CHIR 2020; 75:328-344. [PMID: 32773753 DOI: 10.23736/s0026-4733.20.08436-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Colorectal cancer is one of the most frequent cancers in the world and between 50% and 60% of patients will develop colorectal liver metastases (CRLM) during the disease. There have been great improvements in the management of CRLM during the last decades. The combination of modern chemotherapeutic and biological systemic treatments with aggressive surgical resection strategies is currently the base for the treatment of patients considered unresectable until few years ago. Furthermore, several new treatments for the local control of CRLM have been developed and are now part of the arsenal of multidisciplinary teams for the treatment of these complex patients. The aim of this review was to summarize and update the management of CRLM, its controversies and relevant evidence.
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Affiliation(s)
- Leticia Pérez-Santiago
- Unit of Liver, Biliary and Pancreatic Surgery, Department of Surgery, Clinic Hospital, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Dimitri Dorcaratto
- Unit of Liver, Biliary and Pancreatic Surgery, Department of Surgery, Clinic Hospital, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain -
| | - Marina Garcés-Albir
- Unit of Liver, Biliary and Pancreatic Surgery, Department of Surgery, Clinic Hospital, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Elena Muñoz-Forner
- Unit of Liver, Biliary and Pancreatic Surgery, Department of Surgery, Clinic Hospital, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Marisol Huerta Álvaro
- Department of Medical Oncology, Clinic Hospital, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Susana Roselló Keranën
- Department of Medical Oncology, Clinic Hospital, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Luis Sabater
- Unit of Liver, Biliary and Pancreatic Surgery, Department of Surgery, Clinic Hospital, INCLIVA Biomedical Research Institute, University of Valencia, Valencia, Spain
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Timing of Perioperative Chemotherapy Does Not Influence Long-Term Outcome of Patients Undergoing Combined Laparoscopic Colorectal and Liver Resection in Selected Upfront Resectable Synchronous Liver Metastases. World J Surg 2020; 43:3110-3119. [PMID: 31451846 DOI: 10.1007/s00268-019-05142-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to compare patients undergoing combined colorectal and hepatic surgery with and without neoadjuvant chemotherapy to clarify the prognostic advantage of preoperative oncological treatment in a case-matched analysis using propensity scores and to identify factors predictive of good prognosis in a selected population of Synchronous ColoRectal Liver Metastases (SCRLM). METHODS A total of 73 patients who underwent upfront elective combined surgery without preoperative CT for SCRLM in two European tertiary referral centers were selected and constituted the study group (NoNACT group). The NoNACT group was matched (ratio 1:1) with patients who were operated after chemotherapy with neoadjuvant intent (NACT group, the control group). The matching was achieved based on six covariates representative of patients and disease characteristics. RESULTS While the characteristics of both colorectal and hepatic procedures were similar, the NoNACT group, as compared to the NACT group, had lower blood loss (200 mL vs. 550 mL). Postoperative stay (9 vs. 12 days) and morbidity rate (24.7% vs. 32.9%) were reduced in the NoNACT compared with the NACT group. Mid- and long-term outcomes were comparable. At multivariable analysis, predictors of long-term outcome were: right colonic neoplasms, RAS mutational status, CRS score ≥3 and the absence of perioperative chemotherapy. CONCLUSION Preoperative neoadjuvant chemotherapy in patients with colorectal cancer and synchronous resectable liver metastases does not influence the risk of recurrence in patients with favorable tumor biology, while it was associated with increased intraoperative blood loss and morbidity. There is no strong evidence to recommend upfront chemotherapy in the absence of negative prognostic factors.
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Ghiasloo M, Pavlenko D, Verhaeghe M, Van Langenhove Z, Uyttebroek O, Berardi G, Troisi RI, Ceelen W. Surgical treatment of stage IV colorectal cancer with synchronous liver metastases: A systematic review and network meta-analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2020; 46:1203-1213. [PMID: 32178961 DOI: 10.1016/j.ejso.2020.02.040] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 12/13/2019] [Accepted: 02/29/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND The ideal treatment approach for colorectal cancer (CRC) with synchronous liver metastases (SCRLM) remains debated. We performed a network meta-analysis (NMA) comparing the 'bowel-first' approach (BFA), simultaneous resection (SIM), and the 'liver-first' approach (LFA). METHODS A systematic search of comparative studies in CRC with SCRLM was undertaken using the Embase, PubMed, Web of Science, and CENTRAL databases. Outcome measures included postoperative complications, 30- and 90-day mortality, chemotherapy use, treatment completion rate, 3- and 5-year recurrence-free survival, and 3- and 5-year overall survival (OS). Pairwise and network meta-analysis were performed to compare strategies. Heterogeneity was assessed using the Higgins I2 statistic. RESULTS One prospective and 43 retrospective studies reporting on 10 848 patients were included. Patients undergoing the LFA were more likely to have rectal primaries and a higher metastatic load. The SIM approach resulted in a higher risk of major morbidity and 30-day mortality. Compared to the BFA, the LFA more frequently resulted in failure to complete treatment as planned (34% versus 6%). Pairwise and network meta-analysis showed a similar 5-year OS between LFA and BFA and a more favorable 5-year OS after SIM compared to LFA (odds ratio 0.25-0.90, p = 0.02, I2 = 0%), but not compared to BFA. CONCLUSION Despite a higher tumor load in LFA compared to BFA patients, survival was similar. A lower rate of treatment completion was observed with LFA. Uncertainty remains substantial due to imprecise estimates of treatment effects. In the absence of prospective trials, treatment of stage IV CRC patients should be individually tailored.
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Affiliation(s)
- Mohammad Ghiasloo
- Department of Human Structure and Repair, Faculty of Medicine, Ghent University, Belgium; Department of Surgery, Division of GI Surgery, Ghent University Hospital, Belgium
| | - Diana Pavlenko
- Department of Human Structure and Repair, Faculty of Medicine, Ghent University, Belgium
| | - Marzia Verhaeghe
- Department of Human Structure and Repair, Faculty of Medicine, Ghent University, Belgium
| | - Zoé Van Langenhove
- Department of Human Structure and Repair, Faculty of Medicine, Ghent University, Belgium
| | - Ortwin Uyttebroek
- Department of Surgery, Division of General and HPB Surgery, Ghent University Hospital, Belgium
| | - Giammauro Berardi
- Department of Surgery, Division of General and HPB Surgery, Ghent University Hospital, Belgium
| | - Roberto I Troisi
- Department of Human Structure and Repair, Faculty of Medicine, Ghent University, Belgium; Department of Clinical Medicine and Surgery, Federico II University Naples, Italy
| | - Wim Ceelen
- Department of Human Structure and Repair, Faculty of Medicine, Ghent University, Belgium; Department of Surgery, Division of GI Surgery, Ghent University Hospital, Belgium; Cancer Research Institute Ghent (CRG), Ghent University, Belgium.
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48
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Konishi T, Yoshidome H, Shimizu H, Yoshitomi H, Furukawa K, Takayashiki T, Kuboki S, Takano S, Miyazaki M, Ohtsuka M. Splenic enlargement induced by preoperative chemotherapy is a useful indicator for predicting liver regeneration after resection for colorectal liver metastases. World J Surg Oncol 2020; 18:139. [PMID: 32576191 PMCID: PMC7313099 DOI: 10.1186/s12957-020-01918-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 06/15/2020] [Indexed: 11/13/2022] Open
Abstract
Background Conversion chemotherapy may downsize unresectable colorectal liver metastases (CRLMs), but may cause liver injury and splenic enlargement. The effect of preoperative chemotherapy on liver regeneration after liver resection remains undetermined. The aim of this study was to examine whether splenic enlargement induced by preoperative chemotherapy is an indicator to identify high-risk patients for impaired liver regeneration and liver dysfunction after resection. Methods We retrospectively reviewed 118 Japanese patients with CRLMs. Fifty-one patients had conversion chemotherapy. The other 67 patients underwent up-front liver resection. We clarified effects of conversion chemotherapy on splenic volume, liver function, and postoperative liver regeneration. Perioperative outcome was also analyzed. Results A ratio of the splenic volume before and after chemotherapy (SP index) in the oxaliplatin-based chemotherapy group was significantly greater than other chemotherapy groups after 9 or more chemotherapy cycles. Patients whose SP index was 1.2 or more had significantly higher indocyanine green retention rate at 15 min (ICG-R15) than patients without chemotherapy. Analyses of covariance showed liver regeneration rate after resection was decreased in patients whose SP index was 1.2 or more. The incidence of postoperative liver dysfunction in patients whose SP index was 1.2 or more was significantly greater than patients without chemotherapy. Multivariate analysis showed SP index was a significant predictive factor of impaired liver regeneration. Conclusions Splenic enlargement induced by preoperative chemotherapy was a useful indicator for impaired liver regeneration after resection and a decision-making tool of treatment strategy for unresectable CRLMs.
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Affiliation(s)
- Takanori Konishi
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hiroyuki Yoshidome
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan. .,Department of Surgery, Oami Municipal Hospital, 884-1 Tomida, Oami-Shirasato-shi, Chiba, 299-3221, Japan.
| | - Hiroaki Shimizu
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Hideyuki Yoshitomi
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Katsunori Furukawa
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Tsukasa Takayashiki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Satoshi Kuboki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Shigetsugu Takano
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
| | - Masaru Miyazaki
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan.,Surgery and Digestive Disease Center, International University of Health and Welfare, Mita Hospital, 1-4-3 Mita, Minato-Ku, Tokyo, 108-8329, Japan
| | - Masayuki Ohtsuka
- Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-Ku, Chiba, 260-8670, Japan
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Abstract
This article deals with the treatment of metastatic colorectal cancer (stage IV). The treatment goals and approaches are determined by the resectability status of the metastases: resectable liver and lung metastases are primarily resected and perioperative chemotherapy appears to be dispensable. In potentially resectable metastases, a conversion therapy is attempted to enable a potentially curative resection. In the case of nonresectability the treatment goal is palliative. Induction and maintenance therapy as well as drug holidays are suggested in an attempt to achieve extended survival while maintaining the quality of life, beginning with the best possible individual treatment. For some patients with stage IV, molecular targeted therapies are available. The study situation and approval status are dealt with in detail. With improved molecular characterization of tumors the treatment can be further individualized.
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Anticancer effect of X-Ray triggered methotrexate conjugated albumin coated bismuth sulfide nanoparticles on SW480 colon cancer cell line. Int J Pharm 2020; 582:119320. [PMID: 32278720 DOI: 10.1016/j.ijpharm.2020.119320] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Revised: 04/06/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022]
Abstract
The application of nanoparticles (NPs) as radio-sensitizers and carriers has opened up a new horizon to overcome the limitations of chemo and radiotherapy. In this study, bovine serum albumin-coated Bi2S3 NPs (Bi2S3@BSA NPs) were synthesized and evaluated in terms of their ability to be used as a radio-sensitizer and carrier for methotrexate (MTX). Physicochemical properties of MTX conjugated Bi2S3@BSA NPs (Bi2S3@BSA-MTX NPs) were characterized by DLS, TEM, FTIR, UV/Vis, and XRD analyses. After the evaluation of cellular uptake and intracellular localization, the cytotoxicity of the combination of Bi2S3@BSA-MTX NPs and X-Ray radiation was analyzed against the SW480 cell line. The synthesized NPs exhibited spherical-like shapes and homogenous morphology, possessing a hydrodynamic diameter of 140.2 ± 5.71 nm (mean ± SD) and zeta potential of -25 mV. Also, the release study showed that the release of MTX is faster and higher in the presence of the proteinase K enzyme than the absence of the enzyme. The results of in-vitro chemo-radiation therapy indicated that the viability of treated cells with Bi2S3@BSA-MTX NPs is significantly lower than the cells treated with Bi2S3@BSA NPs. Furthermore, cells treated with Bi2S3@BSA-MTX NPs showed a lower degree of viability when combined with X-Ray radiation in comparison with the absence of irradiation, which confirmed the ability of the Bi2S3@BSA-MTX NPs as radio-sensitizer.
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