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Bachet JB, de Gramont A, Raeisi M, Rakez M, Goldberg RM, Tebbutt NC, Van Cutsem E, Haller DG, Hecht JR, Mayer RJ, Lichtman SM, Benson AB, Sobrero AF, Tabernero J, Adams R, Zalcberg JR, Grothey A, Yoshino T, André T, Shi Q, Chibaudel B. Characteristics of Patients and Prognostic Factors Across Treatment Lines in Metastatic Colorectal Cancer: An Analysis From the Aide et Recherche en Cancérologie Digestive Database. J Clin Oncol 2025; 43:2094-2106. [PMID: 40324123 DOI: 10.1200/jco-24-01968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/22/2025] [Accepted: 03/14/2025] [Indexed: 05/07/2025] Open
Abstract
PURPOSE Several lines of treatment can be used sequentially in patients with metastatic colorectal cancer. We investigated the evolution of patient/tumor characteristics and their prognostic impact across treatment lines to develop an overall prognostic score (OPS). PATIENTS AND METHODS Individual patient data from 48 randomized trials were analyzed. The end point was overall survival (from random assignment to death). Missing data were imputed. The complete data set was then separated into construction (80%) and validation sets (20%). The Cox's model was used to define risk groups for survival using the OPS. The discrimination capability was assessed in each treatment-line via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices. Internal validation was done in the validation set. RESULTS A total of 37,560 patients (26,974 in first-line [1L], 7,693 in second-line [2L], and 2,893 in third-line [3L]) were analyzed. Some clinical, biological, and molecular characteristics of patients/tumors included in therapeutic trials evolve over the lines. Seven independent prognostic variables were retained in the final multivariate model common to all lines: Eastern Cooperative Oncology Group performance status, hemoglobin, platelet count, WBC/absolute neutrophil count ratio, lactate dehydrogenase, alkaline phosphatase, and the number of metastatic sites. The OPS was used to define four patient subgroups with significantly different prognoses in 1L, 2L, and 3L, separately, with adequate C-indices: 0.65, 0.66, and 0.69 in the construction set and 0.65, 0.66, and 0.68 in the validation set, respectively. The OPS was not predictive, with 3L drugs (v placebo) or subsequent line (2L/1L or 3L/2L) extending survival in all prognostic groups. CONCLUSION The same prognostic model using practical variables can be used before all treatment lines. The OPS could better stratify patients in future clinical trials and help to therapeutic decision in routine practice.
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Affiliation(s)
- Jean-Baptiste Bachet
- Hepato-gastroenterology and Digestive Oncology Department, Pitié Salpêtrière Hospital, APHP, Sorbonne Université, Paris, France
| | - Aimery de Gramont
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Cancérologie Paris Ouest, Levallois-Perret, France
- ARCAD Foundation, Paris, France
| | | | - Manel Rakez
- Statistical Unit, ARCAD Foundation, Paris, France
| | - Richard M Goldberg
- Department of Medicine, West Virginia University Cancer Institute, Morgantown, WV
| | - Niall C Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Daniel G Haller
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | | | | | - Stuart M Lichtman
- Wilmot Cancer Institute Geriatric Oncology Research Group, University of Rochester, Rochester, NY
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University's Feinberg School of Medicine, Chicago, IL
| | | | - Josep Tabernero
- Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom
| | - John R Zalcberg
- Department of Medical Oncology, Monash University School of Public Health and Preventive Medicine, Alfred Health, Melbourne, VIC, Australia
| | | | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Thierry André
- ARCAD Foundation, Paris, France
- Department of Medical Oncology, Saint Antoine Hospital, APHP, Sorbonne Université, Paris, France
| | - Qian Shi
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
| | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Cancérologie Paris Ouest, Levallois-Perret, France
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Gao Z, Wang XY, Shen ZG, Liu JH, Wang XY, Wu SK, Jin X. Chemotherapy plus bevacizumab with or without anti-programmed death 1 immunotherapy as the second-line therapy in colorectal cancer. World J Gastroenterol 2025; 31:106939. [DOI: 10.3748/wjg.v31.i21.106939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/23/2025] [Accepted: 05/23/2025] [Indexed: 06/06/2025] Open
Abstract
BACKGROUND Patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) typically exhibit an immunosuppressive tumor microenvironment and demonstrate a low response rate to immunotherapy. Reports suggest that chemotherapy and anti-angiogenic therapy may have the potential to enhance the response to immunotherapy in these patients. This study aims to evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-programmed death 1 (PD-1) immunotherapy as the second-line regimen for MSS mCRC.
AIM To evaluate the effectiveness and safety of chemotherapy combined with bevacizumab with or without anti-PD-1 immunotherapy as the second-line regimen for MSS mCRC.
METHODS A retrospective analysis was conducted on patients with MSS mCRC diagnosed at Peking University First Hospital and Jilin Cancer Hospital from January 2020 to December 2024. The patients were divided into two groups: The experimental group receiving second-line chemotherapy combined with bevacizumab and anti-PD-1 immunotherapy, and the control group receiving chemotherapy combined with bevacizumab. Propensity score matching was applied to balance potential prognostic factors, including age, gender, Eastern Cooperative Oncology Group score, number of metastases, and primary tumor site. The progression-free survival, overall survival, disease control rate, objective response rate, and treatment-related adverse reactions were compared between the two groups. Kaplan-Meier analysis and log-rank test were used to compare survival outcomes. Inverse probability of treatment weighting was used for sensitivity analysis.
RESULTS Propensity score matching resulted in 103 matched eligible patients. The median follow-up period was 13.9 months in the matched cohort. The objective response rate was 11.5% and 9% for the experimental and control groups, respectively (P = 0.710), while the disease control rate was 76.9% and 53.2%, respectively (P = 0.058). The median progression-free survival in the experimental group was 8.27 months [95% confidence interval (CI): 6.7-14.7 months], significantly higher than that in the control group, which was 4.63 months (95%CI: 3.9-5.67 months) (hazard ratio = 0.4143, 95%CI: 0.2462-0.6972, P = 0.00066). There was a trend towards the higher median overall survival in the experimental group compared to the control group (hazard ratio = 0.4504, 95%CI: 0.1897-1.07, P = 0.064). The incidences of adverse events were similar between the two groups.
CONCLUSION Compared with the standard second-line chemotherapy combined with bevacizumab regimen, second-line therapy that combines chemotherapy with bevacizumab and anti-PD-1 immunotherapy has demonstrated promising efficacy in the treatment of MSS mCRC, while exhibiting a similar safety profile.
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Affiliation(s)
- Zhao Gao
- Department of Medical Oncology, Peking University First Hospital, Beijing 100034, China
| | - Xiao-Yan Wang
- Department of Pharmacy, Jilin Cancer Hospital, Changchun 130012, Jilin Province, China
| | - Zhi-Gang Shen
- Department of Pharmacy, Jilin Cancer Hospital, Changchun 130012, Jilin Province, China
| | - Jia-Hua Liu
- Department of Pharmacy, Jilin Cancer Hospital, Changchun 130012, Jilin Province, China
| | - Xiao-Yun Wang
- Department of Medical Oncology, Peking University First Hospital, Beijing 100034, China
| | - Shi-Kai Wu
- Department of Medical Oncology, Peking University First Hospital, Beijing 100034, China
| | - Xuan Jin
- Department of Medical Oncology, Peking University First Hospital, Beijing 100034, China
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3
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Swami N, Hwang WT, Mamtani R, O’Hara MH, Chapin WJ. Second-Line Treatment Strategies for Right-Sided, RAS/RAF Wild-Type Colorectal Cancer. JAMA Netw Open 2025; 8:e2515087. [PMID: 40504531 PMCID: PMC12163663 DOI: 10.1001/jamanetworkopen.2025.15087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2025] [Accepted: 04/09/2025] [Indexed: 06/16/2025] Open
Abstract
This comparative effectiveness study investigates anti–vascular endothelial growth factor vs anti–epidermal growth factor receptor therapy in second-line treatment among patients with RAS/RAF wild-type, right-sided cancer.
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Affiliation(s)
- Nishwant Swami
- Department of Internal Medicine, Hospital of the University of Pennsylvania, Philadelphia
| | - Wei-Ting Hwang
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia
| | - Ronac Mamtani
- Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
| | - Mark H. O’Hara
- Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
| | - William J. Chapin
- Division of Hematology and Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia
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Lucchetti J, Angotti L, Parisi A, Basso M, Polito MG, Zoratto F, Di Giacomo E, Nitti D, Minelli A, Salvatore L, Calegari MA, Lo Prinzi F, Gemma D, Signorelli C, Veroli M, Anghelone A, Galbato Muscio L, Di Cocco B, Trombetta G, Morelli C, Schietroma F, Vincenzi B, Cortellini A, Tonini G. Aflibercept-Based and Bevacizumab-Based Second Line Regimens in Patients with Metastatic Colorectal Cancer: Propensity Score Weighted-Analysis from a Multicenter Cohort. Clin Colorectal Cancer 2025; 24:207-217.e5. [PMID: 39856001 DOI: 10.1016/j.clcc.2024.12.007] [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: 02/23/2024] [Revised: 12/23/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025]
Abstract
BACKGROUND Both aflibercept and bevacizumab-based regimens are available II-line treatment options for patients with metastatic colorectal cancer (mCRC). However, no head-to-head trials established the optimal anti-angiogenic strategy for this setting. METHODS We launched a multicenter, retrospective, observational study to assess and compare clinical efficacy of II-line treatments for patients with mCRC. Patients with KRAS/NRAS/BRAF-wild type and KRAS/NRAS mutant tumors were also analyzed separately. FINDINGS 348 patients were included, of whom 153 and 195 were treated with bevacizumab- and aflibercept-based regimens, respectively. Patients treated with aflibercept showed an increased risk of death (corrected [co]-HR 1.92, 95 %CI: 1.37-2.68), of disease progression/death (co-HR 1.43, 95 %CI: 1.12-1.82) and a decreased objective response rate (ORR) (21.5 % vs 34.7 %, p=0.007) in comparison to bevacizumab. Patients treated with II-line bevacizumab were more frequently treated in the third line setting after disease progression (91.1 % vs 68.5 %, p<0.0001). In the KRAS/NRAS mutant cohort, treatment with bevacizumab was associated with longer overall survival (OS) (18.0 months vs 12.5 months, p=0.0069), but similar progression free survival (PFS) (p=0.32) and ORR (p=0.57). In the KRAS/NRAS, BRAF wild type cohort, patients treated with bevacizumab achieved longer OS (20.2 months vs 10.6 months, p=0.013), PFS (8.4 months vs 3.7 months, p=0.0002), and higher ORR (48.6 % vs 15.0 %, p=0.0016), compared to those treated with aflibercept. The results were independently confirmed with inverse probability of treatment weighting and with fixed multivariable Cox-regressions. CONCLUSION These findings support the use of bevacizumab-based over aflibercept-based regimens as II-line treatment in mCRC, especially in KRAS/NRAS and BRAF wild type tumors.
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Affiliation(s)
- Jessica Lucchetti
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy
| | - Lorenzo Angotti
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy.
| | - Alessandro Parisi
- Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria delle Marche, Ancona, Italy
| | - Michele Basso
- Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, Italy
| | - Mariam Grazia Polito
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Federica Zoratto
- Unità Operativa Complessa Oncologia, Ospedale Santa Maria Goretti, Latina, Italy
| | - Emanuela Di Giacomo
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Daniele Nitti
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy
| | - Alessandro Minelli
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Lisa Salvatore
- Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, Italy; Medical Oncology Unit, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Maria Alessandra Calegari
- Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, Italy
| | - Federica Lo Prinzi
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | | | - Carlo Signorelli
- Medical Oncology Unit, Belcolle Hospital, ASL Viterbo, Viterbo, Italy
| | - Margherita Veroli
- Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Roma, Italy
| | - Annunziato Anghelone
- Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, Italy; Medical Oncology Unit, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Luca Galbato Muscio
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Barbara Di Cocco
- Unità Operativa Complessa Oncologia, Ospedale Santa Maria Goretti, Latina, Italy
| | | | - Cristina Morelli
- Medical Oncology Unit, Department of Systems Medicine, University of Rome Tor Vergata, Roma, Italy
| | - Francesco Schietroma
- Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Roma, Italy; Medical Oncology Unit, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Bruno Vincenzi
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Alessio Cortellini
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy; Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College London, London, United Kingdom
| | - Giuseppe Tonini
- Operative Research Unit of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
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Monk BJ, Lorusso D, Fujiwara K, Sehouli J. Optimal bevacizumab treatment strategy in advanced ovarian cancer: A review. Cancer Treat Rev 2025; 137:102945. [PMID: 40349571 DOI: 10.1016/j.ctrv.2025.102945] [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: 01/21/2025] [Revised: 04/17/2025] [Accepted: 04/18/2025] [Indexed: 05/14/2025]
Abstract
Bevacizumab was the first targeted therapy developed for newly diagnosed and recurrent advanced ovarian cancer (AOC). Although bevacizumab has been approved for the treatment of AOC for several years, identifying patients who may benefit most from this treatment is still debated. Bevacizumab has been associated with improved progression-free survival (PFS) regardless of clinical risk, but in some countries the use of bevacizumab in the treatment of newly diagnosed AOC has been restricted to higher-risk patients (stage III inoperable or suboptimally debulked disease, or stage IV disease); this is primarily due to the findings of exploratory subgroup analyses from phase III trials that suggest only higher-risk patients derive an overall survival (OS) advantage with bevacizumab. Recently reported post hoc analyses from the PAOLA-1 trial of maintenance olaparib plus bevacizumab versus bevacizumab alone for patients with newly diagnosed AOC and homologous recombination deficiency-positive tumors suggested PFS and OS benefit was achieved in both lower-risk (with stage III disease who had undergone upfront surgery and had complete resection) and higher-risk (with stage III disease who had undergone upfront surgery and had residual disease or who had received neoadjuvant chemotherapy, or with stage IV disease) patients, prompting reassessment of the role of bevacizumab in lower-risk patients. This review examines the role of bevacizumab in the AOC treatment pathway by discussing its efficacy and safety in the first-line, maintenance and recurrent settings, and evaluates the clinical implications of bevacizumab use across risk groups and lines of therapy.
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Affiliation(s)
- Bradley J Monk
- GOG Foundation, Philadelphia, PA, USA; Division of Gynecologic Oncology, Florida Cancer Specialists and Research Institute, West Palm Beach, FL, USA.
| | - Domenica Lorusso
- Gynecologic Oncology Unit, Humanitas San Pio X, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Keiichi Fujiwara
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, Saitama, Japan
| | - Jalid Sehouli
- Department of Gynecology with Center for Oncological Surgery, Charité-Universitätsmedizin Berlin, Berlin, and North-Eastern German Society of Gynecological Oncology (NOGGO) - Arbeitsgemeinschaft Gynäkologische Onkologie (AGO), Germany
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Sakai D, Kadowaki S, Kawabata R, Hara H, Satake H, Takahashi M, Takeno A, Imai H, Minashi K, Kawakami T, Boku S, Matsuyama J, Sakamoto Y, Sawada K, Kataoka M, Kawakami H, Shimokawa T, Boku N, Satoh T. Randomized Phase III Trial of Ramucirumab Beyond Progression Plus Irinotecan in Patients With Ramucirumab-Refractory Advanced Gastric Cancer: RINDBeRG Trial. J Clin Oncol 2025:JCO2401119. [PMID: 40408613 DOI: 10.1200/jco.24.01119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 11/20/2024] [Accepted: 02/19/2025] [Indexed: 05/25/2025] Open
Abstract
PURPOSE Continuous use of antiangiogenic agents has demonstrated survival benefits in various cancers. This trial aimed to compare the efficacy and safety of ramucirumab plus irinotecan with irinotecan monotherapy as a third- or later-line treatment for patients with advanced or recurrent gastric or gastroesophageal cancer (AGC) that has progressed on previous ramucirumab-based chemotherapy. METHODS Patients age 20 years and older with AGC, who had experienced disease progression during ramucirumab-based chemotherapy, were randomly assigned to receive either ramucirumab plus irinotecan or irinotecan monotherapy. The primary end point was overall survival (OS) expecting a hazard ratio (HR) of 0.77 (a power of 80% and a significance level of one-sided 0.05). Secondary end points included progression-free survival (PFS), response rate, disease control rate (DCR), and safety. RESULTS Between February 2017 and August 2022, 402 patients in Japan were randomly assigned to receive ramucirumab plus irinotecan (n = 202) or irinotecan monotherapy (n = 200). The median OS was 9.4 months in the combination arm and 8.5 months in the monotherapy arm, with an adjusted HR of 0.91 (95% CI, 0.74 to 1.12; P = .49). PFS was improved (median, 3.8 v 2.8 months; HR, 0.72 [95% CI, 0.59 to 0.89]; P = .002), while the DCR was significantly better (64.4% v 52.1%; P = .03) with the combination therapy. The adverse events of the combination therapy were manageable. CONCLUSION Adding ramucirumab to irinotecan does not provide a significant advantage in OS over irinotecan alone in patients with AGC who have progressed during ramucirumab-containing chemotherapy.
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Affiliation(s)
- Daisuke Sakai
- Osaka International Cancer Institute, Osaka, Japan
- Osaka University Hospital, Suita, Japan
| | | | | | | | | | | | - Atsushi Takeno
- National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Hiroo Imai
- Tohoku University Hospital, Sendai, Japan
| | | | | | - Shogen Boku
- Kansai Medical University Hospital, Hirakata, Japan
| | - Jin Matsuyama
- Higashiosaka City Medical Center, Higashi-Osaka, Japan
| | | | | | - Masato Kataoka
- National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Hisato Kawakami
- Tohoku University Hospital, Sendai, Japan
- Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | | | - Narikazu Boku
- IMSUT Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan
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Soler G, Grávalos C, Rivera F, Safont MJ, Virgili AC, Valladares-Ayerbes M, Ferreiro-Monteagudo R, Ortiz-Morales MJ, Polo-Marques E, Kornusova-Bersheva I, Soustre E, Yao W, Élez E. Predictive factors of efficacy for FTD/TPI plus bevacizumab in refractory metastatic colorectal cancer patients: a subanalysis of the Spanish cohort from the SUNLIGHT phase III trial. Clin Transl Oncol 2025:10.1007/s12094-025-03907-z. [PMID: 40338282 DOI: 10.1007/s12094-025-03907-z] [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: 12/20/2024] [Accepted: 03/13/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND The addition of bevacizumab to trifluridine-tipiracil (FTD/TPI) therapy improves outcomes in patients with refractory metastatic colorectal cancer (CRC). However, predictive factors of efficacy for FTD/TPI when used in combination with bevacizumab are not yet fully recognized. METHODS Patients included in the Spanish cohort of the SUNLIGHT trial were evaluated. The primary endpoint of this post-hoc exploratory subanalysis was overall survival (OS). Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), safety and the assessment of potential predictive factors of efficacy for FTD/TPI plus bevacizumab, such as age, KRAS mutational status, the incidence of neutropenia, patient prognosis, and prior administration of bevacizumab. RESULTS A total of 115 patients were analysed, 58 receiving FTD/TPI and 57 FTD/TPI plus bevacizumab. The median OS was 8.5 vs. 10.6 months (p = 0.254), respectively, and the median PFS was 2.4 vs. 4.7 months (p < 0.0001), respectively. Severe neutropenia affected 20% more patients in the experimental arm than in the control arm (51% vs. 31%, respectively). The univariate analysis showed that a benefit of adding bevacizumab to FTD/TPI in terms of PFS was observed in all previously defined patient subgroups and was accompanied by DCR of 69% for FTD/TPI plus bevacizumab vs. 45% in arm of FTD/TPI alone. CONCLUSIONS The addition of bevacizumab to FTD/TPI tends to improve OS probably due to the reduced number of patients included in this cohort and significantly improved PFS in all patient subgroups with metastatic CRC. Prospective studies are needed to confirm these results and to find out additional predictive factors that help us to discriminate which patients would benefit most from FTD/TPI plus bevacizumab.
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Affiliation(s)
- Gemma Soler
- Medical Oncology Department, Institut Catalá d'Oncologia (ICO), Badalona·Applied Research Group in Oncology (B·ARGO), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (IGTP), De Can Ruti Camí de les Escoles s/n, 08916, Badalona, Barcelona, Spain.
| | | | - Fernando Rivera
- Marqués de Valdecilla University Hospital, IDIVAL, Santander, Spain
| | - María José Safont
- General University Hospital Consortium of Valencia, Valencia University, Valencia, Spain
| | | | | | | | | | | | | | - Elsa Soustre
- Department of Medical Affairs, Servier Laboratories, Madrid, Spain
| | - Weiyu Yao
- Department of Biostatistics, Servier Pharmaceuticals LLC, Boston, MA, USA
| | - Elena Élez
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
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8
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Zhao M, Jiang Y, Shao T, Tang W. Safety, efficacy, and cost-effectiveness evaluation of systemic treatments for refractory colorectal cancer: a systematic review and modeling study. HEALTH ECONOMICS REVIEW 2025; 15:33. [PMID: 40214895 PMCID: PMC11987259 DOI: 10.1186/s13561-025-00622-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 03/24/2025] [Indexed: 04/14/2025]
Abstract
OBJECTIVES To conduct pooled estimates and comparative evaluations of safety and efficacy, alongside cost-effectiveness and value-based pricing analyses, for systemic treatments recommended by the National Comprehensive Cancer Network in refractory colorectal cancer. METHODS A comprehensive search for related randomized controlled trials was conducted on PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov. Safety was evaluated by aggregating treatment-related adverse events (TRAEs) and performing Bayesian network meta-analysis (NMA) for indirect comparisons. Pooled survival estimates of overall survival (OS) and progression-free survival (PFS) were conducted to assess treatment efficacy. For NMA of OS and PFS, time-variant fractional polynomial models were employed as the primary analysis, with Cox proportional hazards models used for result validation. Economic evaluations were performed using partitioned survival models from the US public sector perspective. Clinical parameters were sourced from meta-analyses; cost parameters included drug treatment, follow-up and administration, end-of-life care, and adverse event management expenses, which were obtained from the Federal Supply Schedule, public databases or published literature. Utility values were sourced from the CORRECT trial. Price simulations were also conducted. Robustness of results was confirmed by sensitivity and scenario analyses RESULTS: We included nine studies comprising 3,978 patients and incorporating six treatments recommended by NCCN, including best supportive care (BSC), regorafenib, regorafenib dose optimization (REDo), trifluridine/tipiracil (TAS-102), TAS-102 with bevacizumab (TAS-BEV), and fruquintinib. Targeted treatments increased serious TRAEs and grade 3 + TRAEs compared to BSC. However, no significant safety differences were found among the targeted therapies. Regarding efficacy, REDo led in median OS, while fruquintinib led in median PFS. NMA indicated that TAS-BEV had the greatest PFS and OS survival benefit, followed by fruquintinib and REDo. Cost-effectiveness analysis favored BSC as the least expensive and the most cost-effective profile. TAS-BEV had the greatest effectiveness, with TAS-102 being the most cost-effective among targeted therapies. For cost-effectiveness against BSC, the price reductions of TAS-102, fruquintinib, REDoS, regorafenib, and TAS-BEV were 39%, 24%, 14%, 8%, and 7%, respectively. CONCLUSIONS Targeted therapies have comparable safety; TAS-BEV is highly effective, TAS-102 is the top cost-effective targeted therapy. Treatment choice should balance individual patient needs with safety, efficacy, and cost.
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Affiliation(s)
- Mingye Zhao
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yunlin Jiang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Taihang Shao
- School of Public Health, Faculty of Medicine, The Chinese University of Hong Kong, Ma Liu Shui, China
| | - Wenxi Tang
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China.
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, Jiangsu, China.
- Center for Pharmacoeconomics and Outcomes Research, Department of Public Affairs Management, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China.
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9
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Yildirim ME, Karadurmuş N, Ökten İN, Türk HM, Urakçı Z, Arslan Ç, Çelik S, Dane F, Şendur MAN, Bilir C, Karabulut B, Cicin İ, Çubukçu E, Karaca M, Ozcelik M, Artaç M, Tanrikulu E, Alacacioglu A, Açıkgöz Ö, Öven B, Geredeli Ç, Çil T, Harputluoğlu H, Kefeli U, Bozkurt O, Tural D, Sakin A, Yalçın Ş, Gumus M. Real-world treatment outcomes from nationwide Onco-colon Turkey registry in RAS wild-type patients treated with biologics second-line mCRC. J Oncol Pharm Pract 2025; 31:404-411. [PMID: 38613329 DOI: 10.1177/10781552241241004] [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] [Indexed: 04/14/2024]
Abstract
Backgrounds and ObjectivesColorectal cancer is one of the leading causes of mortality both globally and in our country. In Turkey, we conducted a multicenter investigation into the effectiveness of second-line treatments and real-life data for patients with RAS wild-type metastatic colorectal cancer (NCT04757311).Materials and MethodsIn this retrospective analysis, records from 28 centers were collected, and histopathological, molecular, and clinical characteristics were documented. Patients were categorized into groups based on their second-line biological treatments: anti-EGFR (Group A and Group B, panitumumab and cetuximab) and anti-VEGF (Group C, bevacizumab and aflibercept). They were then compared within these groups.ResultsA total of 588 patients with documented RAS wild-type status were evaluated. The median OS was 15.7, 14.3 and 14.7 months in Group A, Group B and Group C, respectively (p = 0.764). The median PFS of the patients in second-line setting that received panitumumab, cetuximab and bevacizumab/aflibercept were 7.8, 6.6 and 7.4 months, respectively (p = 0.848).ConclusionAccording to the results of our real-life data study, there is no significant difference in efficiency between the combination of biological agent and chemotherapy used in the second-line treatments.
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Affiliation(s)
- Mahmut Emre Yildirim
- Medical Oncology Department, İstanbul Dr. Lütfi Kırdar Kartal City Hospital, Istanbu, Türkiye
| | - Nuri Karadurmuş
- Medical Oncology Department, Gulhane Training and Research Hospital, Ankara, Türkiye
| | - İlker Nihat Ökten
- Medical Oncology Department, Medeniyet University Goztepe Training and Research Hospital, Istanbul, Türkiye
| | - Hacı Mehmet Türk
- Department of Medical Oncology, Bezmialem Vakif University Faculty of Medicine, Istanbul, Türkiye
| | - Zuhat Urakçı
- Department of Medical Oncology, Dicle University Medical Faculty, Diyarbakir, Türkiye
| | - Çağatay Arslan
- Medical Oncology, Bahcesehir Universitesi Tip Fakultesi, Istanbul, Türkiye
| | - Sinemis Çelik
- Medical Oncology Department, Istanbul Oncology Hospital, Istanbul, Türkiye
| | - Faysal Dane
- Department of Internal Medicine, Division of Medical Oncology, Marmara University School of Medicine, Istanbul, Türkiye
| | | | - Cemil Bilir
- Medical Oncology Department, Sakarya University Training and Research Hospital, Sakarya, Türkiye
| | - Bülent Karabulut
- Medical Oncology, Ege University Faculty of Medicine, Izmir, Türkiye
| | - İrfan Cicin
- Department of Internal Medicine, Division of Oncology, Trakya University Faculty of Medicine, Edirne, Türkiye
| | - Erdem Çubukçu
- Faculty of Medicine, Medical Oncology, Uludag University, Bursa, Türkiye
| | - Mustafa Karaca
- Medical Oncology Department, Antalya Training and Research Hospital, Antalya, Türkiye
| | - Melike Ozcelik
- Department of Oncology, Umraniye Training and Research Hospital, Istanbul, Türkiye
| | - Mehmet Artaç
- Department of Medical Oncology, Necmettin Erbakan University Medical Faculty, Konya, Türkiye
| | - Eda Tanrikulu
- Medical Oncology, Istanbul Haydarpasa Numune Training and Research Hospital, Istanbul, Türkiye
| | - Ahmet Alacacioglu
- Medical Oncology Department, Ministry of Health İzmir Katip Çelebi University Atatürk Education and Research Hospital, Izmir, Türkiye
| | - Özgür Açıkgöz
- Medical Oncology Department, Istanbul Medipol University, İstanbul, Türkiye
| | - Başak Öven
- Medical Oncology Department, Yeditepe University Hospital, Istanbul, Türkiye
| | - Çağlayan Geredeli
- Department of Medical Oncology, Okmeydani Training and Research Hospital, Istanbul, Türkiye
| | - Timucin Çil
- Department of Medical Oncology, University of Health Sciences, Adana City Education and Research Hospital, Adana, Türkiye
| | | | - Umut Kefeli
- Medical Oncology, Kocaeli University School of Medicine, Kocaeli, Türkiye
| | - Oktay Bozkurt
- Medical Oncology Department, Erciyes Universitesi, Kayseri, Türkiye
| | - Deniz Tural
- Medical Oncology, Istanbul Bakirkoy Dr Sadi Konuk Training and Research Hospital, Istanbul, Türkiye
| | - Abdullah Sakin
- Department of Medical Oncology, Yuzuncu Yil University, Van, Türkiye
| | - Şuayip Yalçın
- Department of Medical Oncology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
| | - Mahmut Gumus
- Department of Medical Oncology, Istanbul Medeniyet University Faculty of Medicine, Istanbul, Türkiye
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10
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Vonica RC, Butuca A, Morgovan C, Pumnea M, Cipaian RC, Frum A, Dobrea CM, Vonica-Tincu AL, Pacnejer AM, Ghibu S, Batar F, Gligor FG. Bevacizumab-Insights from EudraVigilance Database on the Assessments of the Safety Profile of Monoclonal Antibodies Used as Targeted Cancer Treatment. Pharmaceuticals (Basel) 2025; 18:501. [PMID: 40283938 PMCID: PMC12030381 DOI: 10.3390/ph18040501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 03/22/2025] [Accepted: 03/27/2025] [Indexed: 04/29/2025] Open
Abstract
Background/Objectives: Worldwide, colon cancer is a major cause of cancer-related mortality, with an increasing incidence influenced by genetic, environmental, and lifestyle factors. Despite advances in diagnosis and personalized treatments, challenges remain in improving patient prognosis, particularly in metastatic colorectal cancer (mCRC). Bevacizumab (BEV), a monoclonal antibody, is widely used in colorectal cancer treatment. This study aimed to analyze adverse events associated with BEV compared with other therapies based on data from the EudraVigilance (EV) database. Methods: A descriptive and disproportionality analysis was conducted on signals reported in the EV database related to BEV. The study included comparisons with other antineoplastic treatments, such as chemotherapy, targeted therapy, and immunotherapy. Patient demographics, severity of adverse drug reactions (ADRs), and distribution patterns were analyzed to assess the safety profile of BEV in colorectal cancer treatment. Results: The majority of the signals for BEV were from patients aged 18-64 years (39.42%) and 65-85 years (34.08%). Hypertension, thromboembolism, proteinuria, and gastrointestinal disorders have been the most frequently reported. Serious ADRs, including gastrointestinal perforations, hemorrhage, and arterial thromboembolism, were observed in 93.74% of Individual Case Safety Reports. BEV was associated with a higher likelihood of vascular and endocrine disorders compared with chemotherapy and other targeted therapies. Immunotherapy was linked to increased immunological ADRs, while BEV demonstrated fewer immune-related toxicities. Conclusions: Continuous monitoring is necessary to optimize patient management, particularly in elderly patients or those with cardiovascular comorbidities. Understanding BEV's safety profile allows for better personalization of treatment strategies, minimizing risks while enhancing therapeutic outcomes.
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Affiliation(s)
- Razvan Constantin Vonica
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Manuela Pumnea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Remus Calin Cipaian
- Clinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania;
- County Clinical Emergency Hospital of Sibiu, 2–4 Corneliu Coposu Str., 550245 Sibiu, Romania
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Andreea Loredana Vonica-Tincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Aliteia-Maria Pacnejer
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
- Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timişoara, Romania
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Florina Batar
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
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11
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Chitoran E, Rotaru V, Stefan DC, Gullo G, Simion L. Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab-20 Years of Therapeutic Success and Controversy. Cancers (Basel) 2025; 17:1126. [PMID: 40227654 PMCID: PMC11988089 DOI: 10.3390/cancers17071126] [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: 01/07/2025] [Revised: 03/22/2025] [Accepted: 03/26/2025] [Indexed: 04/15/2025] Open
Abstract
The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.
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Affiliation(s)
- Elena Chitoran
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Vlad Rotaru
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Daniela-Cristina Stefan
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy
| | - Laurentiu Simion
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
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12
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Asare A, Previs RA, Spinosa D, Fellman B, Scott AL, Mulder I, Mahmoud M, Enbaya A, Siedel JH, Cobb L, Soliman PT, Sood AK, Coleman RL, Secord AA, Westin SN. Bevacizumab beyond progression: Impact of subsequent bevacizumab re-treatment in patients with ovarian, fallopian tube, and peritoneal cancer after progression. Gynecol Oncol 2025; 194:112-118. [PMID: 39987772 PMCID: PMC12115928 DOI: 10.1016/j.ygyno.2025.02.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 02/16/2025] [Accepted: 02/17/2025] [Indexed: 02/25/2025]
Abstract
BACKGROUND This study evaluated whether patients with epithelial ovarian, fallopian tube, and primary peritoneal carcinoma (OC) who are immediately re-treated with bevacizumab derive benefit after disease progression on a bevacizumab-containing regimen. METHODS This multi-institutional, retrospective study compared patients with high grade non-mucinous epithelial OC who received bevacizumab followed directly by another bevacizumab-containing treatment regimen to patients who received bevacizumab followed by a regimen that did not contain bevacizumab (or received no further treatment). Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier product-limit estimator and modeled via Cox proportional hazards regression. RESULTS Among 226 patients with OC who received bevacizumab as part of a treatment regimen,103 received sequential treatment with bevacizumab and 123 received a bevacizumab-containing regimen followed by a non-bevacizumab-containing regimen at the time of progression. Median follow-up for all subjects was 17.3 months (range, 1.2-138.2 months). Median PFS was 17.2 months (95 % CI, 14.3-21.2) for patients who received sequential bevacizumab re-treatment and 5.1 months (95 % CI, 4.3-6.3) for patients who received bevacizumab without bevacizumab-containing re-treatment (p < 0.001). Median OS was 29.9 months (95 % CI, 26.1-35.4) for patients who received sequential bevacizumab re-treatment (p < 0.001) and 12.4 months (95 % CI, 9.2-16.7) for patients who did not receive bevacizumab-containing re-treatment. CONCLUSION Patients with OC treated with bevacizumab-containing regimens sequentially at the time of progression have prolonged survival compared to patients who received no re-treatment with bevacizumab.
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Affiliation(s)
- Amma Asare
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | | | - Daniel Spinosa
- Gynecologic Oncology, University of Colorado Cancer Center, United States of America
| | - Bryan Fellman
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | - Amelia L Scott
- Division of Gynecologic Oncology, Duke University Medical Center, United States of America
| | - Isabelle Mulder
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | - May Mahmoud
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | - Ahmed Enbaya
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | - Jean Hansen Siedel
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | - Lauren Cobb
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | - Pamela T Soliman
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | - Anil K Sood
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America
| | | | | | - Shannon N Westin
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, United States of America.
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13
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Ando K, Satake H, Shimokawa M, Yasui H, Negoro Y, Kinjo T, Kizaki J, Baba K, Orita H, Hirata K, Sakamoto S, Makiyama A, Saeki H, Tsuji A, Baba H, Oki E. A phase two trial evaluating FOLFIRI plus aflibercept after failure of FOLFOXIRI plus bevacizumab in patients with unresectable metastatic colorectal cancer. Int J Clin Oncol 2025; 30:514-523. [PMID: 39891883 DOI: 10.1007/s10147-025-02701-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 01/09/2025] [Indexed: 02/03/2025]
Abstract
BACKGROUND FOLFOXIRI plus bevacizumab (BEV) is an option for first-line treatment of metastatic colorectal cancer (mCRC). However, there is no consensus on the optimal treatment strategy when disease progresses. The EFFORT open-label, multicenter, single-arm phase II study investigated whether FOLFIRI plus aflibercept retains activity after progression of FOLFOXIRI plus BEV treatment. METHODS The patients with unresectable mCRC who failed first-line FOLFOXIRI plus BEV received FOLFIRI plus aflibercept. The primary endpoint was progression-free survival (PFS) in the full analysis set (FAS). Angiogenic biomarkers were measured before treatment initiation. RESULTS From April 2019 to May 2021, 35 patients were enrolled and 34 were analysed in the FAS population (men, 18; median age, 63 years [range: 32-78]). The primary tumor was left-sided in most cases (23/34), 23 patients were RAS mutant, 3 patients had BRAF V600E mutation and 27 patients had liver metastases. The primary end-point was met with a median PFS of 4.3 months [80% confidence interval [CI] 3.7-5.1]. Median overall survival was 15.2 months [95% CI 8.9-22.7]. Per RECIST, there were 1 complete response, 4 partial responses, 21 stable diseases and 8 disease progressions. Overall response rate was 14.7% [95% CI 5.0-31.1], and disease control rate was 76.5% [95% CI 58.8-89.3]. Responses were more common in patients with high VEGF-C, low VEGF-D and low PlGF levels before treatment. CONCLUSION FOLFIRI plus aflibercept, administered after failure of FOLFOXIRI plus BEV, is effective and has a manageable safety profile. This regimen may be a useful second-line treatment option for these patients.
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Affiliation(s)
- Koji Ando
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan
| | - Hironaga Satake
- Department of Medical Oncology, Kochi Medical School, Cancer Treatment Centre, Kansai Medical University Hospital, Kochi, Japan
| | - Mototsugu Shimokawa
- Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Centre General Hospital, Kobe, Japan
| | - Yuji Negoro
- Department of Oncological Medicine, Kochi Health Sciences Centre, Kochi, Japan
| | - Tatsuya Kinjo
- Faculty of Medicine, Department of Digestive and General Surgery, University of the Ryukyus, Nishihara, Japan
| | - Junya Kizaki
- Department of Surgery, Social Insurance Tagawa Hospital, Tagawa, Japan
| | - Kenji Baba
- Department of Surgery, Imamura General Hospital, Kagoshima, Japan
| | - Hiroyuki Orita
- Department of Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan
| | - Keiji Hirata
- Department of Surgery 1, Hospital of the University of Occupational and Environmental Health, Kitakyushu, Japan
| | | | | | - Hiroshi Saeki
- Department of General Surgical Science Graduate School of Medicine, Gunma University, Maebashi, Japan
| | - Akihito Tsuji
- Faculty of Medicine, Department of Clinical Oncology, Kagawa University, Takamatsu, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
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14
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Li J, Ba YI, Lin R, Ke X, Yin X, Ying J, Cheng Y, Xu N, Xu J, Shen Y, Zhou J, Wang J, Qian X, Wu R, Zhang Y, Shen L. Efficacy and Safety of KH903 Plus FOLFIRI as a Second-Line Treatment in Unresectable Recurrent or Metastatic Colorectal Cancer: A Randomized Phase 2 Study. Clin Colorectal Cancer 2025; 24:89-97. [PMID: 39632230 DOI: 10.1016/j.clcc.2024.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 10/20/2024] [Accepted: 10/26/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Patients with recurrent or metastatic advanced colorectal cancer (mCRC) often face the clinical dilemma as this unresectable disease is continuously progressing and endangering the patients' lives. In the current study, we explored the clinical feasibility of KH903 in combination with FOLFIRI chemotherapy as a new clinical indication for mCRC. METHODS Patients (N = 122) were randomized 1:1 to 4mg/kg q1w KH903 or 5mg/kg q2w KH903, and both groups of patients were treated with the fixed regimen of FOLFIRI (every 2 weeks) along with the KH903 therapy. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were Overall Survival (OS), objective response rate (ORR), and disease control rate (DCR). RESULTS As of December 30, 2020, median (m)PFS was 5.68 months (95% CI, 4.67-7.13) with 4mg/kg q1w versus 5.19 months (95% CI, 4.04, 5.78) with 5mg/kg q2w (HR, 0.76; 95% CI, 0.50-1.16),and mOS was 13.14 months (95% CI, 10.61-19.52) versus 16.03 months (95% CI, 10.28- NE), respectively (HR, 1.11; 95% CI, 0.65-1.89), The ORR was 15.9% and 11.9% for both groups, respectively, and The DCR for both groups was 85.7% and 83.1%, respectively. Grade 3 or higher treatment-related adverse event rates for both groups were 68.3% vs.52.5%, respectively. CONCLUSIONS KH903 in combination with FORFIRI in second-line treatment of patients with mCRC showed prolonged mPFS and mOS, comparing to the similar agents (Avastin®, ZALTRAP®, Cyramza®) and no new safety signals were observed.
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Affiliation(s)
- Jian Li
- State Key Laboratory of Holistic integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Y I Ba
- Cancer Center, Peking Union Medical College Hospital, Beijing, China
| | - Rongbo Lin
- Department of Gastrointestinal Oncology, Fujian Cancer Hospital, Beijing, China
| | - Xiao Ke
- Chengdu Kanghong Biotechnology Co.Ltd, Therapeutic Proteins Key Laboratory of Sichuan Province, Beijing, China
| | - Xianli Yin
- Department of Gastroenterology, Urology and Oncology, Hunan Provincial Cancer Hospital, Beijing, China
| | - Jieer Ying
- Department of Hepato-Pancreato-Biliary&Gastric Medical Oncology, Cancer Hospital of the University of Chinese Acdemy of sciences(Zhejiang Cancer Hospital), Beijing, China
| | - Ying Cheng
- Department of Oncology, Jilin Provincial Cancer Hospital, Beijing, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University School of Medicine, Beijing, China
| | - Jiangming Xu
- Department of Medical Oncology, Hospital overview_PLA General Hospital_PLA General Hospital, Beijing, China
| | - Yali Shen
- Abdominal oncology, West China Hospital, Sichuan University, Beijing, China
| | - Jianfeng Zhou
- Department of Medical Oncology, Peking Union Medical College Hospital, Beijing, China
| | - Jufeng Wang
- Department of gastroenterology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Beijing, China
| | - Xiaoping Qian
- Department of Oncology, Nanjing Drum Tower Hospital, Beijing, China
| | - Rong Wu
- Department of Oncology, Shengjing Hospital of China Medical University, Beijing,China
| | - Yanqiao Zhang
- Department of Gastroenterology, Harbin Medical University University Cancer Hospital, Beijing, China.
| | - Lin Shen
- State Key Laboratory of Holistic integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
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Zhang X, Hu J, Fan X, Chen Q, Zheng D, Huang M, Xu Y. The effect of Bevacizumab treatment on the incidence of hypertension in patients with ovarian cancer: a systematic review and meta-analysis. J Oncol Pharm Pract 2025; 31:294-304. [PMID: 39930904 DOI: 10.1177/10781552241307868] [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] [Indexed: 03/14/2025]
Abstract
IntroductionThis study aims to evaluate the effect of bevacizumab treatment on the incidence of hypertension in patients with ovarian cancer.MethodsA comprehensive search of PubMed, Scopus, Embase, Cochrane, Web of Science, and Google Scholar databases was conducted until August 2024. We included only randomized clinical trials that compared ovarian cancer patients treated with Bevacizumab to those treated with other therapies. The primary outcome was the relative risk (RR) of developing hypertension, stratified by grade. Statistical analyses were performed using a random-effects model to account for heterogeneity between studies. Subgroup analyses were conducted based on hypertension severity (grade ≥2 and grade ≥3) and disease stage. Sensitivity analyses and publication bias assessments were also performed.ResultsA total of 11 randomized trials were included, comprising 5212 patients. The meta-analysis revealed that patients receiving Bevacizumab had a significantly higher risk of hypertension compared to controls (RR = 2.91, 95% CI: 1.65-5.16, P = 0.0002). Subgroup analysis showed that the risk of grade ≥2 hypertension was 1.68 times higher (95% CI: 0.92-3.07), and grade ≥3 hypertension was 5.10 times higher (95% CI: 2.46-10.55) in the Bevacizumab group. Sensitivity analysis confirmed the robustness of these findings, and no significant publication bias was detected.ConclusionBevacizumab treatment in ovarian cancer significantly increases the risk of hypertension, particularly severe hypertension (grade ≥3). These findings underscore the need for vigilant blood pressure monitoring and management in patients receiving Bevacizumab to mitigate cardiovascular complications and optimize treatment outcomes.
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Affiliation(s)
- Xiaoyan Zhang
- Pharmaceutical Department, Jinhua Municipal Central Hospital, Jinhua City, China
| | - Jumei Hu
- Department of Gynecology, Jinhua Municipal Central Hospital, Jinhua City, China
| | - Xijing Fan
- Clinical Laboratory, Jinhua Municipal Central Hospital, Jinhua City, China
| | - Qiaoqiao Chen
- Pharmaceutical Department, Jinhua Municipal Central Hospital, Jinhua City, China
| | - Danjun Zheng
- Pharmaceutical Department, Jinhua Municipal Central Hospital, Jinhua City, China
| | - Minjuan Huang
- Pharmaceutical Department, Jinhua Municipal Central Hospital, Jinhua City, China
| | - Yuanqing Xu
- Pharmaceutical Department, Jinhua Municipal Central Hospital, Jinhua City, China
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16
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Ahn DH, Ridinger M, Cannon TL, Mendelsohn L, Starr JS, Hubbard JM, Kasi A, Barzi A, Samuëlsz E, Karki A, Subramanian RA, Yemane D, Kim R, Wu CC, Croucher PJ, Smeal T, Kabbinavar FF, Lenz HJ. Onvansertib in Combination With Chemotherapy and Bevacizumab in Second-Line Treatment of KRAS-Mutant Metastatic Colorectal Cancer: A Single-Arm, Phase II Trial. J Clin Oncol 2025; 43:840-851. [PMID: 39475591 PMCID: PMC11856007 DOI: 10.1200/jco-24-01266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 08/09/2024] [Accepted: 09/19/2024] [Indexed: 11/21/2024] Open
Abstract
PURPOSE This phase II study evaluated the efficacy and tolerability of onvansertib, a polo-like kinase 1 (PLK1) inhibitor, in combination with fluorouracil, leucovorin, and irinotecan (FOLFIRI) + bevacizumab for the second-line treatment of KRAS-mutant metastatic colorectal cancer (mCRC). PATIENTS AND METHODS This multicenter, open-label, single-arm study enrolled patients with KRAS-mutated mCRC previously treated with oxaliplatin and fluorouracil with or without bevacizumab. Patients received onvansertib (15 mg/m2 once daily on days 1-5 and 15-19 of a 28-day cycle) and FOLFIRI + bevacizumab (days 1 and 15). The primary end point was the objective response rate (ORR), and secondary endpoints included progression-free survival (PFS), duration of response (DOR), and tolerability. Translational and preclinical studies were conducted in KRAS-mutant CRC. RESULTS Among the 53 patients treated, the confirmed ORR was 26.4% (95% CI, 15.3 to 40.3). The median DOR was 11.7 months (95% CI, 9.4 to not reached). Grade 3/4 adverse events were reported in 62% of patients. A post hoc analysis revealed that patients with no prior bevacizumab treatment had a significantly higher ORR and longer PFS compared with patients with prior bevacizumab treatment: ORR of 76.9% versus 10.0% (odds ratio of 30.0, P < .001) and median PFS of 14.9 months versus 6.6 months (hazard ratio of 0.16, P < .001). Our translational findings support that prior bevacizumab exposure contributes to onvansertib resistance. Preclinically, we showed that onvansertib inhibited the hypoxia pathway and exhibited robust antitumor activity in combination with bevacizumab through the inhibition of angiogenesis. CONCLUSION Onvansertib in combination with FOLFIRI + bevacizumab showed significant activity in the second-line treatment of patients with KRAS-mutant mCRC, particularly in patients with no prior bevacizumab treatment. These findings led to the evaluation of the combination in the first-line setting (ClinicalTrails.gov identifier: NCT06106308).
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Affiliation(s)
- Daniel H. Ahn
- Division of Medical Oncology, Mayo Clinic, Phoenix, AZ
| | | | | | | | - Jason S. Starr
- Division of Hematology and Oncology, Mayo Clinic, Jacksonville, FL
| | - Joleen M. Hubbard
- Division of Oncology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Anup Kasi
- Division of Medical Oncology, University of Kansas Medical Center, Kansas City, KS
| | - Afsaneh Barzi
- Division of Medical Oncology and Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA
| | | | | | | | | | - Roy Kim
- Cardiff Oncology Inc, San Diego, CA
| | | | | | | | | | - Heinz-Josef Lenz
- Division of Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
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Vonica RC, Morgovan C, Butuca A, Pumnea M, Cipaian RC, Frum A, Dobrea CM, Vonica-Tincu AL, Pacnejer AM, Batar F, Vornicu V, Ghibu S, Gligor FG. Real-World Evidence of Bevacizumab and Panitumumab Drug Resistance and Drug Ineffectiveness from EudraVigilance Database. Cancers (Basel) 2025; 17:663. [PMID: 40002260 PMCID: PMC11853327 DOI: 10.3390/cancers17040663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Revised: 02/02/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world, with an average 5-year overall survival (OS) rate of approximately 60% [...].
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Affiliation(s)
- Razvan Constantin Vonica
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Claudiu Morgovan
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Anca Butuca
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Manuela Pumnea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Remus Calin Cipaian
- Clinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania;
- County Clinical Emergency Hospital of Sibiu, 2-4 Corneliu Coposu Str., 550245 Sibiu, Romania
| | - Adina Frum
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Carmen Maximiliana Dobrea
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Andreea Loredana Vonica-Tincu
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Aliteia-Maria Pacnejer
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
- Department of Toxicology, Drug Industry, Management and Legislation, Faculty of Pharmacy, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania
| | - Florina Batar
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
| | - Vlad Vornicu
- Department IX Surgery, Discipline of Oncology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 2nd Eftimie Murgu Sq., 300041 Timisoara, Romania;
| | - Steliana Ghibu
- Department of Pharmacology, Physiology and Pathophysiology, Faculty of Pharmacy, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Felicia Gabriela Gligor
- Preclinical Department, Faculty of Medicine, “Lucian Blaga” University of Sibiu, 550169 Sibiu, Romania; (R.C.V.); (M.P.); (A.F.); (C.M.D.); (A.L.V.-T.); (A.-M.P.); (F.B.); (F.G.G.)
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Guo H, Miao L, Yu C. The efficacy of targeted therapy and/or immunotherapy with or without chemotherapy in patients with colorectal cancer: A network meta-analysis. Eur J Pharmacol 2025; 988:177219. [PMID: 39716565 DOI: 10.1016/j.ejphar.2024.177219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer. METHODS A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS). RESULTS A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib + Binimetinib + Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy + Cetuximab + Dalotuzumab (Chemo-CET-DAL), Encorafenib + Cetuximab (ENC-CET), and Panitumumab + Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy + Bevacizumab + Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy + Bevacizumab, ENC-CET, Chemotherapy + Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET. CONCLUSIONS In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.
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Affiliation(s)
- Haoyan Guo
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China
| | - Longjie Miao
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, 518104, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chengdong Yu
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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Ji P, Chen T, Li C, Zhang J, Li X, Zhu H. Comprehensive review of signaling pathways and therapeutic targets in gastrointestinal cancers. Crit Rev Oncol Hematol 2025; 206:104586. [PMID: 39653094 DOI: 10.1016/j.critrevonc.2024.104586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024] Open
Abstract
Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.
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Affiliation(s)
- Pengfei Ji
- Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China
| | - Tingting Chen
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Chao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Jinyuan Zhang
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Xiao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China.
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20
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Pinto C, Lonardi S, Maiello E, Martinelli E, Prisciandaro M, Salvatore L, Sartore-Bianchi A, Scartozzi M, Aprile G, Cremolini C, Sobrero A. Trifluridine/tipiracil regimen in combination with bevacizumab for metastatic colorectal cancer in the third line: an expert opinion. Front Oncol 2025; 14:1502185. [PMID: 39911824 PMCID: PMC11794989 DOI: 10.3389/fonc.2024.1502185] [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: 09/26/2024] [Accepted: 10/31/2024] [Indexed: 02/07/2025] Open
Abstract
The prolongation of survival along with the preservation of quality of life, possibly avoiding harmful cumulative toxicities, is the primary therapeutic aim for patients with metastatic colorectal cancer (mCRC) in the third-line setting. Several therapeutic options are now available, although some differences across countries in drug approval and the optimal therapeutic sequencing associated with each peculiar patient subgroup represent a clinical challenge for oncologists. Among various options, the SUNLIGHT trial showed how the combination of trifluridine/tipiracil (FTD/TPI) with bevacizumab is effective with an easily manageable toxicity profile compared to FTD/TPI alone. Of note, the efficacy is confirmed independently from KRAS mutational status and also for patients who had breaks in anti-vascular endothelial growth factor (anti-VEGF) therapy. Herein, we describe the current state of the art in the landscape of treatments after the second progression in mCRC. Based on a critical review of the literature aimed to guide clinicians in their daily decision-making, we point out that the combination of FTD/TPI with bevacizumab produces a clinical benefit in unselected mCRC patients. Therefore, the FTD/TPI plus bevacizumab regimen can represent a new standard of care for the treatment of patients with refractory mCRC who have progressed after two lines of therapy.
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Affiliation(s)
- Carmine Pinto
- Oncologia Medica, Comprehensive Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Evaristo Maiello
- Oncology Unit, Foundation IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Erika Martinelli
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli “, Napoli, Italy
| | - Michele Prisciandaro
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Lisa Salvatore
- Medical Oncology, Università Cattolica del Sacro Cuore, Rome, Italy
- Medical Oncology, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy
| | - Andrea Sartore-Bianchi
- Division of Clinical Research and Innovation, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
- Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy
| | - Mario Scartozzi
- Oncologia Medica, Azienda Ospedaliero Universitaria e Università degli Studi di Cagliari, Cagliari, Italy
| | - Giuseppe Aprile
- Department of Medical Oncology, AULSS8 Berica, Vicenza, Italy
| | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Alberto Sobrero
- Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Liu Y, Wang J, Fang Y, Deng Y, Hu C, Fan Q, Gu K, Zhang Y, Yang C, Liu Z, Tian J, Sun X, Sun S, Cheng Y. The efficacy and safety of suvemcitug, envafolimab, and FOLFIRI in microsatellite-stable or mismatch repair-proficient colorectal cancer: preliminary results of a phase 2 study. Int J Colorectal Dis 2025; 40:20. [PMID: 39836256 PMCID: PMC11750940 DOI: 10.1007/s00384-025-04806-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
PURPOSE This phase II study is designed to evaluate the combination therapy involving suvemcitug and envafolimab with FOLFIRI in microsatellite-stable or mismatch repair-proficient (MSS/pMMR) colorectal cancer (CRC) in the second-line treatment setting. METHODS This study is a non-randomized, open-label prospective study comprising multiple cohorts (NCT05148195). Here, we only report the data from the CRC cohort. Participants received envafolimab, suvemcitug, and FOLFIRI until disease progression, unacceptable toxicity, or voluntary withdrawal. The recommended dose (RD) and objective response rate (ORR) by investigator assessment were primary endpoints. Secondary endpoints comprised progression-free survival (PFS) and duration of response (DoR). Disease control rate (DCR), overall survival (OS), and safety were also analyzed. RESULTS At the data cutoff, no dose-limiting toxicity event was observed in the safety run-in stage, and 2 mg/kg Q2W was declared as RD for suvemcitug combined with envafolimab and FORFIRI. Among 20 patients, 50.0% and 10.0% had been treated with prior antiangiogenic agents and anti-EGFR agents, respectively. ORR and DCR were 25.0% (95% CI 8.7-49.1%) and 90.0% (95% CI 68.3-98.8%), and DoR was 4.1 months (95% CI 3.02, NE). The median PFS and median OS were 5.6 months (95% CI 4.0-8.3) and not reached (95% CI 8.5, NE) by the time of study closure. Neutrophil count decreased, white blood cell count decreased, and hypertension were the most common grade ≥3 treatment-related adverse events (TRAE). CONCLUSIONS The safety profile was manageable and the preliminary anti-tumor efficacy was observed in patients with MSS/pMMR CRC in this study, who had failed prior to one line of therapy.
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Affiliation(s)
- Ying Liu
- Internal Medicine, Jilin Cancer Hospital, Changchun, China
| | - Jufeng Wang
- Gastroenterology Department, Henan Cancer Hospital &, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Fang
- Medical Oncology Dept., Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yanhong Deng
- Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Changlu Hu
- Tumor Chemotherapy Department, Anhui Provincial Cancer Hospital, Hefei, China
| | - Qingxia Fan
- Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kangsheng Gu
- Medical Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yu Zhang
- Mianyang Central Hospital, Oncology, Mianyang, China
| | - Chen Yang
- Clinical Science, Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu Province, China
| | - Zhenru Liu
- Clinical Science, Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu Province, China
| | - Ji Tian
- Clinical Science, Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu Province, China
| | - Xiyang Sun
- Clinical Pharmacology, Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu Province, China
| | - Shuguang Sun
- Clinical Statistics, Simcere Zaiming Pharmaceutical Co., Ltd., Shanghai, China
- State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, Jiangsu Province, China
| | - Ying Cheng
- Internal Medicine, Jilin Cancer Hospital, Changchun, China.
- Department of Thoracic Oncology, Jilin Cancer Hospital, 1066 Jinhu Road, Changchun City, 130000, Jilin Province, China.
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Zhan T, Betge J, Schulte N, Dreikhausen L, Hirth M, Li M, Weidner P, Leipertz A, Teufel A, Ebert MP. Digestive cancers: mechanisms, therapeutics and management. Signal Transduct Target Ther 2025; 10:24. [PMID: 39809756 PMCID: PMC11733248 DOI: 10.1038/s41392-024-02097-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 10/20/2024] [Accepted: 11/29/2024] [Indexed: 01/16/2025] Open
Abstract
Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.
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Affiliation(s)
- Tianzuo Zhan
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Johannes Betge
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Junior Clinical Cooperation Unit Translational Gastrointestinal Oncology and Preclinical Models, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Nadine Schulte
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Lena Dreikhausen
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hirth
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Moying Li
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Philip Weidner
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Antonia Leipertz
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Andreas Teufel
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Matthias P Ebert
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- DKFZ Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.
- Mannheim Cancer Center, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
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Sun C, Fan E, Huang L, Zhang Z. Second-line systemic treatment for metastatic colorectal cancer: A systematic review and Bayesian network meta-analysis based on RCT. PLoS One 2024; 19:e0313278. [PMID: 39715232 DOI: 10.1371/journal.pone.0313278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 10/21/2024] [Indexed: 12/25/2024] Open
Abstract
BACKGROUND The optimal second-line systemic treatment for metastatic colorectal cancer (mCRC) is inconclusive. METHODS We searched PubMed, Web of Science, EMBASE, and Cochrane Library for RCTs comparing second-line systemic treatments for mCRC from the inception of each database up to February 3, 2024. Markov Chain Monte Carlo (MCMC) technique was used in this network meta-analysis (NMA) to generate the direct and indirect comparison results among multiple treatments in progression-free survival (PFS), overall response rate (ORR), overall survival (OS), complete response (CR), partial response (PR), grade 3 and above adverse events (Grade ≥ 3AE), and any adverse events (Any AE). The surface under the cumulative ranking curve (SUCRA) was adopted to evaluate the probability of each treatment being the optimum intervention. Subgroup analyses were performed based on the RAS gene status. RESULTS A total of 47 randomized controlled trials were included, involving 16,925 patients and 44 second-line systemic treatments. In improving OS, FOLFOX + Bevacizumab + Erlotinib exhibited significant superiority (SUCRA:92.7%). In improving PFS, Irinotecan + CMAB009 (SUCRA:86.4%) had advantages over other treatments. FOLFIRI + Trebananib (SUCRA:88.1%) had a significant advantage in improving ORR. Among multiple second-line treatments, the SUCRA values of FOLFOX + Bevacizumab in PFS, OS, ORR, and PR were 83.4%, 74.0%, 81.1%, and 86.1%, respectively, and the safety was not significantly different from other interventions. Subgroup analyses showed that FOLFIRI + Bevacizumab + panitumumab ranked among the top in survival outcomes in the RAS-mutant population (OS SUCRA: 87.9%; PFS SUCRA: 70.2%); whereas in the RAS-wild-type population, FOLFIRI + Bevacizumab significantly improved survival outcomes (OS SUCRA: 73.2%; PFS SUCRA: 65.1%). CONCLUSION For most people, FOLFOX + Bevacizumab may be the best second-line systemic treatment regimen for mCRC. For RAS-mutant populations, FOLFIRI + Bevacizumab + Panitumumab is recommended. However, the therapeutic effect may be affected by the patient's physiological state, and clinicians should apply it based on actual conditions.
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Affiliation(s)
- Chengyu Sun
- Department of Colorectal Surgery, The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Enguo Fan
- State Key Laboratory of Medical Molecular Biology, Department of Microbiology and Parasitology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Luqiao Huang
- Department of Colorectal Surgery, The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
| | - Zhengguo Zhang
- Department of Colorectal Surgery, The Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou Central Hospital, Xuzhou, Jiangsu, China
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24
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Shi M, Yang Y, Huang N, Zeng D, Mo Z, Wang J, Zhang X, Liu R, Wang C, Rong X, Wu Z, Huang Q, Shang H, Tang J, Wang Z, Cai J, Huang G, Guan Y, Guo J, Mu Q, Wang J, Liao W. Genetic and microenvironmental evolution of colorectal liver metastases under chemotherapy. Cell Rep Med 2024; 5:101838. [PMID: 39631402 PMCID: PMC11722126 DOI: 10.1016/j.xcrm.2024.101838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 09/16/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024]
Abstract
Drug resistance limits the efficacy of chemotherapy for colorectal cancer liver metastasis (CRLM). However, the evolution of CRLM during drug treatment remains poorly elucidated. Multi-omics and treatment response data from 115 samples of 49 patients with CRLM undergoing bevacizumab (BVZ)-based chemotherapy show little difference in genomic alterations in 92% of cases, while remarkable differences are observed at the transcriptomic level. By decoupling intrinsic and acquired resistance, we find that hepatocyte and myeloid cell infiltration contribute to 38.5% and 23.1% of acquired resistance, respectively. Importantly, SMAD4 mutations and chr20q copy-number gain are associated with intrinsic chemoresistance. Gene interference experiments suggest that SMAD4R361H/C mutations confer BVZ and 5-fluorouracil (5-FU) resistance through STAT3 signaling. Notably, supplementing BVZ and 5-FU with the STAT3 inhibitor GB201 restores therapeutic efficacy in SMAD4R361H/C cancer cells. Our study uncovers the evolutionary dynamics of CRLM and its microenvironment during treatment and offers strategies to overcome drug resistance.
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Affiliation(s)
- Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China; Foshan Key Laboratory of Translational Medicine in Oncology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China
| | - Yingxi Yang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Na Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Dongqiang Zeng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China; Foshan Key Laboratory of Translational Medicine in Oncology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China
| | - Zongchao Mo
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Jiao Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiaomeng Zhang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Ran Liu
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Chunlin Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Xiaoxiang Rong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Zhenzhen Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Qiong Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Haixia Shang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Jihong Tang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Zhaojun Wang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jianan Cai
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Genjie Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Yijin Guan
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Jian Guo
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
| | - Quanhua Mu
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
| | - Jiguang Wang
- Department of Chemical and Biological Engineering, Division of Life Science and State Key Laboratory of Molecular Neuroscience, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China; SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen 518000, P.R. China.
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China; Cancer Center, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China; Foshan Key Laboratory of Translational Medicine in Oncology, the Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Foshan, China.
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Ren W, Chen H, Huang Y, Zuo J, Shu X, Shu P. The impact of different treatments on thromboelastography and other conventional parameters in patients with colorectal cancer. Discov Oncol 2024; 15:748. [PMID: 39633024 PMCID: PMC11618262 DOI: 10.1007/s12672-024-01311-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 09/03/2024] [Indexed: 12/07/2024] Open
Abstract
OBJECTIVE To comprehend the effects of diverse therapeutic interventions on thromboelastography (TEG) and conventional coagulation parameters among individuals diagnosed with colorectal cancer, this study aims to explore the clinical relevance of both thromboelastography and conventional coagulation metrics in evaluating coagulation function and predicting the incidence of thrombotic and hemorrhagic events in patients with colorectal cancer. METHODS A cohort of 122 patients with colorectal cancer retrospectively recruited and divided into 2 groups: those undergoing surgical intervention (operation group) and those not subjected to surgery (non-operation group). According to the different types of treatment they received, the operation group was divided into chemotherapy-only group and a group receiving a combination of targeted therapy and chemotherapy. Blood samples were collected on admission and subjected to coagulation parameter assessment, including conventional coagulation tests and thromboelastography (TEG) assessment. Receiver operating characteristic (ROC) analysis was performed to predict the occurrence of complications in patients with colorectal cancer. RESULTS Compared with the operation group, the non-operation group showed significant reductions in reaction time(R-time) and kinetics time (K-time), and significant elevation in angle, maximum amplitude (MA), fibrinogen and platelets. Patients receiving targeted therapy and chemotherapy had lower angle and maximum amplitude and higher R-time and K-time, activated partial thromboplastin time and fibrinogen. The area under the curve for TEG in patients without treatment was 0.802. The area under the curve for TEG and conventional coagulation parameters were 0.654 and 0.660 respectively. CONCLUSION Diverse treatments distinctly impact on the coagulation indicators of individuals diagnosed with colorectal cancer. The coagulation parameters observed in patients prior to operation suggest a hypercoagulable state. Nevertheless, following postoperative chemotherapy and targeted therapy, this hypercoagulable state demonstrates a notable improvement, occasionally leading to a propensity for hypocoagulation. The findings of this investigation underscore the unique clinical importance of thromboelastography (TEG) alongside traditional coagulation parameters, demonstrating that these diagnostic tools possess complementary value and cannot be substituted interchangeably.
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Affiliation(s)
- Wenqin Ren
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Hao Chen
- Department of Clinical Laboratory, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Yujie Huang
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Jiaqian Zuo
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Xinyan Shu
- Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China
| | - Peng Shu
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, Jiangsu, China.
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Tougeron D, Bibeau F, Chibaudel B, Kim S, Nguyen T, Phelip JM, Mille D, Bouattour M, Tavan D, Rinaldi Y, Lecomte T, Perrier H, Spaeth D, Caroli Bosc FX, Metges JP, Ferec M, Hautefeuille V, Deslandres-Cruchant M, Danion J, Hammel P, Lewin M, Tasu JP, Angelergues A, DiFiore F, Evrard S, Mansar R, Caillou H, Geffriaud-Ricouard C, Adam R. Resection of colorectal liver metastases with second-line aflibercept plus FOLFIRI: Results from the RESECTION prospective French cohort. Eur J Cancer 2024; 213:115082. [PMID: 39486163 DOI: 10.1016/j.ejca.2024.115082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 10/03/2024] [Accepted: 10/11/2024] [Indexed: 11/04/2024]
Abstract
AIM To evaluate R0/R1 resection rate in patients with colorectal liver metastases (CLM) treated with aflibercept plus FOLFIRI after failure of a prior oxaliplatin-based regimen in daily clinical practice. METHODS This French, multicentre, prospective, observational cohort (NCT05178745) included patients with CLM (alone or predominant; up to 5 lung nodules <2 cm allowed) initiating aflibercept plus FOLFIRI every 2 weeks per physician choice. Primary endpoint was R0/R1 resection rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), radiological and pathological responses, and safety. RESULTS A total of 137 patients (median age 65 years, RAS/BRAF mutant 57 %/9 %) were enrolled at 22 French sites. CLM (median 4) were synchronous in 82 %, bilobar in 71 % and located in liver only in 54 %. Overall, 17 % of patients had R0/R1 resection (21 % for patients with liver-only disease). A major pathological response per Blazer score was observed in 55 % of resected patients, along with significantly longer OS (median 34.8 vs 9.1 months, p < 0.0001) and PFS (median 11.4 vs 4.9 months, p < 0.0001) compared to non-resected patients. Post-operative complications occurred in 17 % of patients (all Dindo-Clavien grade I-II) and there was no post-operative deaths. Overall, 34 % had grade ≥ 3 adverse events, mainly general health deterioration and diarrhea. CONCLUSIONS Results suggest that aflibercept plus FOLFIRI, after failure of a prior oxaliplatin-based regimen, allows R0/R1 resection of CLM in almost 20 % of patients with a major pathological response in most cases and a median OS prolonged by more than 3-fold versus non-resected patients.
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Affiliation(s)
- David Tougeron
- Department of Hepato-Gastroenterology, Poitiers University Hospital, Poitiers, France
| | - Frederic Bibeau
- Department of Pathology, Besançon University Hospital, Franche-Comté University, Besançon, France
| | - Benoist Chibaudel
- Department of Medical Oncology, French-British Hospital, Cognacq-Jay Foundation, Cancérologie Paris Ouest, Levallois-Perret, France
| | - Stefano Kim
- Department of Medical Oncology and Clinical Investigational Center 1431, University Hospital of Besançon, Besançon, France
| | - Thierry Nguyen
- Department of Medical Oncology, North Franch-Comté Hospital, Montbeliard, France
| | - Jean-Marc Phelip
- Department of Gastroenterology, Saint-Etienne University Hospital, Saint-Priest-en-Jarez, France
| | - Dominique Mille
- Department of Medical Oncology, Médipole de Savoie, Challes Les Eaux, France
| | - Mohamed Bouattour
- Department of Liver Oncology and Therapeutic Innovation Functional Unit, Beaujon Hospital APHP, Clichy, France
| | - David Tavan
- Department of Gastroenterology, Protestant Infirmary Clinic, Lyon, France
| | - Yves Rinaldi
- Department of Hepato-Gastroenterology, Marseille European Hospital, Marseille, France
| | - Thierry Lecomte
- Department of Hepato-Gastroenterology and Digestive Cancerology, Tours University hospital, Chambray-les-Tours, France
| | - Hervé Perrier
- Department of Hepato-Gastroenterology, Saint Joseph Hospital, Marseille, France
| | - Dominique Spaeth
- Department of Medical Oncology, Oncology Institute of Gentilly, Nancy, France
| | | | | | - Marc Ferec
- Department of Hepato-Gastroenterology and Department of Oncology and Hematology, Pays De Morlaix hospital, Morlaix, France
| | - Vincent Hautefeuille
- Department of Gastroenterology and Digestive Oncology, Amiens-Picardie - North University Hospital, Amiens, France
| | | | - Jerome Danion
- Department of Surgery, Poitiers University Hospital, Poitiers, France
| | - Pascal Hammel
- Department of Digestive and Medical Oncology, Paul Brousse AP-HP hospital, Paris-Saclay University, Villejuif, France
| | - Maïté Lewin
- Department of Radiology, Paul Brousse AP-HP hospital, Paris-Saclay University, Villejuif, France
| | - Jean-Pierre Tasu
- Department of Diagnostic and Interventional Radiology, Poitiers University Hospital, Poitiers, France and LaTim, UMR 1011, University of Brest, Brest, France
| | - Antoine Angelergues
- Department of Medical Oncology, Diaconesses-Croix Saint Simon hospital, Paris, France
| | - Frederic DiFiore
- Department of Hepato-Gastroenterology, Rouen University Hospital, Rouen, France
| | - Serge Evrard
- Digestive Tumors Unit, Bergogné Institute and Bordeaux University, Bordeaux, France
| | - Racha Mansar
- Department of Pathology, Besançon University Hospital, Franche-Comté University, Besançon, France
| | - Hugo Caillou
- Department of Statistics, Excelya Bordeaux, Floirac, France
| | | | - René Adam
- Department of Hepato-Biliary Surgery and Transplantation, AP-HP Paul Brousse Hospital, Paris-Saclay University, Villejuif, France.
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Tasseau C, Gallois C. [Trifluridine-tipiracil plus bevacizumab in refractory metastatic colorectal cancer]. Bull Cancer 2024; 111:1087-1088. [PMID: 39389874 DOI: 10.1016/j.bulcan.2024.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 07/08/2024] [Accepted: 08/10/2024] [Indexed: 10/12/2024]
Affiliation(s)
- Clara Tasseau
- Département d'oncologie médicale, institut Curie, université Paris Cité, 35, rue Dailly, 92210 Saint-Cloud, France.
| | - Claire Gallois
- Département d'oncologie digestive, hôpital européen George-Pompidou, 20, rue Leblanc, 75015 Paris, France
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Sekmek S, Ozsan Çelebi SN, Bayram D, Erol C, Kos FT, Sendur MAN, Altıntas YE, Tuylu T, Yildirim S, Biter S, Kıdı MM, Bayram E, Majidova N, Bayoglu IV, Atak M, Baskurt K, Akbas S, Alkan A, Bayramgil A, Aslan F, Sahin E, Balcik OY, Bayhan AZ, Saray S, Arpaci E, Ergun Y. Bevacizumab versus aflibercept with FOLFIRI after FOLFOX and bevacizumab in RAS mutant metastatic colon cancer a Turkish oncology group study. Sci Rep 2024; 14:29785. [PMID: 39616250 PMCID: PMC11608356 DOI: 10.1038/s41598-024-81371-5] [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] [Received: 10/07/2024] [Accepted: 11/26/2024] [Indexed: 12/06/2024] Open
Abstract
We aimed to compare FOLFIRI and bevacizumab with FOLFIRI and aflibercept in terms of overall survival (OS), progression-free survival (PFS) and safety in patients with RAS-mutant metastatic colon cancer who progressed after first-line FOLFOX or XELOX and bevacizumab treatment. This retrospective study included 243 patients from 15 different centres in Turkey. The endpoints of the study were OS, PFS and safety and side effect outcomes. The median age of the patients included in the study was 60 (21-85) years. Of the patients enrolled in the study, 114 patients (46.9%) received aflibercept and 129 patients (53.1%) received bevacizumab. Median OS was 11.2 (95% CI: 9.1-13.2) months in patients receiving FOLFIRI + aflibercept and 14.1 (95% CI: 11.2-17.1) months in patients receiving FOLFIRI + bevacizumab. The median PFS was 5.7 (95% CI: 4.9-6.5) months in the aflibercept arm and 7.7 (95% CI: 7.1-8.3) months in the bevacizumab arm. Grade 3-4 side effects were observed in 58 (50.9%) patients in the aflibercept arm and 33 (25.6%) patients in the bevacizumab arm. As a result of our study, in patients with metastatic RAS-mutant colon cancer who progressed after first-line oxaliplatin-based doublet chemotherapy and bevacizumab, better OS and PFS results were obtained in patients receiving bevacizumab with FOLFIRI compared to patients receiving aflibercept with FOLFIRI. In addition, the side effect profile was more tolerable in the bevacizumab arm.
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Affiliation(s)
- Serhat Sekmek
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey.
| | | | - Dogan Bayram
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Cihan Erol
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Fahriye Tugba Kos
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | | | - Yunus Emre Altıntas
- Department of Medical Oncology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
| | - Tugba Tuylu
- Department of Medical Oncology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
| | - Sedat Yildirim
- Department of Medical Oncology, Kartal Dr. Lutfi Kirdar City Hospital, Istanbul, Turkey
| | - Sedat Biter
- Department of Medical Oncology, Cukurova University, Adana, Turkey
| | | | - Ertugrul Bayram
- Department of Medical Oncology, Cukurova University, Adana, Turkey
| | - Nargiz Majidova
- Department of Medical Oncology, Marmara University, Istanbul, Turkey
| | | | - Mehmetcan Atak
- Department of Medical Oncology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Kadriye Baskurt
- Department of Medical Oncology, Ankara Etlik City Hospital, Ankara, Turkey
| | - Sinem Akbas
- Department of Medical Oncology, Koc University, Istanbul, Turkey
| | - Ali Alkan
- Department of Medical Oncology, Mugla Sıtkı Kocman University Faculty of Medicine, Mugla, Turkey
| | - Ayberk Bayramgil
- Department of Medical Oncology, Umraniye Training and Research Hospital, Istanbul, Turkey
| | - Ferit Aslan
- Department of Medical Oncology, Medicalpark Ankara Batikent Hospital, Ankara, Turkey
| | - Elif Sahin
- Department of Medical Oncology, Kocaeli City Hospital, Kocaeli, Turkey
| | - Onur Yazdan Balcik
- Department of Medical Oncology, Mardin Training and Research Hospital, Mardin, Turkey
| | - Ahmet Ziya Bayhan
- Department of Medical Oncology, Sivas Numune Hospital, Sivas, Turkey
| | - Seray Saray
- Department of Medical Oncology, Balikesir Ataturk City Hospital, Balıkesir, Turkey
| | - Erkan Arpaci
- Department of Medical Oncology, Sakarya Adatip Hospital, Sakarya, Turkey
| | - Yakup Ergun
- Department of Medical Oncology, Bower Hospital, Diyarbakir, Turkey
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Pesola G, Epistolio S, Cefalì M, Trevisi E, De Dosso S, Frattini M. Neo-RAS Wild Type or RAS Conversion in Metastatic Colorectal Cancer: A Comprehensive Narrative Review. Cancers (Basel) 2024; 16:3923. [PMID: 39682112 DOI: 10.3390/cancers16233923] [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: 11/20/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
The management of metastatic colorectal cancer in patients harboring RAS mutations primarily involves chemotherapy, often combined with bevacizumab, as a standard first-line treatment. However, emerging evidence suggests that tumors in a subset of these patients may experience a conversion from RAS-mutant status to RAS wild type (wt) during or after chemotherapy, a process referred to as "RAS conversion" or "neo-RAS wt". Understanding the mechanisms driving the neo-RAS wt phenomenon is crucial for its application in personalized medicine. Hypotheses suggest that selective pressure from chemotherapy may lead to a decrease in the number of mutant RAS clones or an outgrowth of pre-existing RAS wt clones. Further research is needed to validate these mechanisms and understand the impact of the neo-RAS wt phenomenon on long-term outcomes, such as overall survival and progression-free survival. This review provides a comprehensive overview of the current understanding of the neo-RAS wt phenomenon, including its incidence, potential mechanisms, and clinical implications.
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Affiliation(s)
- Guido Pesola
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland
| | - Samantha Epistolio
- Laboratory of Genetics and Molecular Pathology, Istituto Cantonale di Patologia EOC, 6600 Locarno, Switzerland
| | - Marco Cefalì
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland
| | - Elena Trevisi
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland
| | - Sara De Dosso
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland
| | - Milo Frattini
- Laboratory of Genetics and Molecular Pathology, Istituto Cantonale di Patologia EOC, 6600 Locarno, Switzerland
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Verma Y, Abdelghaffar M, Verma O, Gajjar A, Ghozy S, Kallmes DF. Bevacizumab: The future of chronic subdural hematoma. Interv Neuroradiol 2024:15910199241298727. [PMID: 39569567 PMCID: PMC11580117 DOI: 10.1177/15910199241298727] [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: 09/24/2024] [Accepted: 10/23/2024] [Indexed: 11/22/2024] Open
Abstract
Bevacizumab (BCZ), commercially known as Avastin, is a monoclonal antibody that targets vascular endothelial growth factor (VEGF). Initially recognized as a breakthrough in oncology, it has since gained FDA approval for various ocular conditions and more recently, for the treatment of glioblastoma multiforme (GBM). Bevacizumab's ability to inhibit excessive neovascularization suggests it may have a potential role in treating chronic subdural hematomas (cSDH). Recent studies have shown that the pathophysiology of cSDH is more complex than previously understood, with VEGF concentrations in subdural fluid significantly exceeding those in serum, contributing to the high recurrence rates. Intra-arterial administration of bevacizumab has shown promising results in recent case series against chronic subdural hematoma, and may be a viable alternative to middle meningeal artery embolization. If successful, this treatment could significantly decrease the rate of recurrence and result in lower rates of severe neurological complications such as visual loss. This literature review explores the connection between bevacizumab and cSDH, focusing on the pharmacological, safety, and delivery aspects of this approach while summarizing the current evidence supporting its use.
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Affiliation(s)
- Yash Verma
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Mariam Abdelghaffar
- School of Medicine, Royal College of Surgeons in Ireland, Busaiteen, Bahrain
| | - Onam Verma
- Government Medical College and Hospital, Chandigarh, India
| | - Aryan Gajjar
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
| | - Sherief Ghozy
- Department of Radiology, Mayo Clinic, Rochester, MN, USA
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Underwood PW, Pawlik TM. Precision Medicine for Metastatic Colorectal Cancer: Where Do We Stand? Cancers (Basel) 2024; 16:3870. [PMID: 39594824 PMCID: PMC11593240 DOI: 10.3390/cancers16223870] [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: 10/07/2024] [Revised: 10/30/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Metastatic colorectal cancer is a leading cause of cancer-related death across the world. The treatment paradigm has shifted away from systemic chemotherapy alone to include targeted therapy and immunotherapy. The past two decades have been characterized by increased investigation into molecular profiling of colorectal cancer. These molecular profiles help physicians to better understand colorectal cancer biology among patients with metastatic disease. Additionally, improved data on genetic pathways allow for specific therapies to be targeted at the underlying molecular profile. Investigation of the EGFR, VEGF, HER2, and other pathways, as well as deficient mismatch repair, has led to the development of multiple targeted therapies that are now utilized in the National Comprehensive Cancer Network guidelines for colon and rectal cancer. While these new therapies have contributed to improved survival for metastatic colorectal cancer, long-term survival remains poor. Additional investigation to understand resistance to targeted therapy and development of new targeted therapy is necessary. New therapies are under development and are being tested in the preclinical and clinical settings. The aim of this review is to provide a comprehensive evaluation of molecular profiling, currently available therapies, and ongoing obstacles in the field of colorectal cancer.
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Affiliation(s)
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, 395 W. 12th Ave., Suite 670, Columbus, OH 43210, USA;
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Boland PM, Mukherjee S, Imanirad I, Vijayvergia N, Cohen SD, Gupta M, Iyer RV, Bakin A, Wang J, Chatley S, Cahill B, Vadehra D, Attwood K, Hochster HS, Fountzilas C. TAS-102, Irinotecan, and bevacizumab in pre-treated metastatic colorectal cancer (TABAsCO), a phase II clinical trial. Br J Cancer 2024; 131:1290-1297. [PMID: 39244627 PMCID: PMC11473817 DOI: 10.1038/s41416-024-02845-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 08/17/2024] [Accepted: 08/28/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND The efficacy of FOLFIRI plus an antiangiogenesis biologic agent as 2nd line therapy for metastatic colorectal adenocarcinoma is limited. TAS-102 is a novel oral antimetabolite with a distinct mechanism of action from fluoropyrimidines. We evaluated the antitumour efficacy of TAS-102, irinotecan and bevacizumab in patients with pre-treated, advanced colorectal adenocarcinoma in a multicenter, phase II, single-arm study. METHODS Patients with advanced colorectal adenocarcinoma who had progressed after oxaliplatin and fluoropyrimidine and were eligible for treatment with bevacizumab were treated with irinotecan, bevacizumab, and TAS-102 in 28-day cycles. The primary endpoint was progression-free survival (PFS). RESULTS We enrolled 35 evaluable patients. The study was positive. The median PFS was 7.9 (90% CI 6.2-11.8) months (vs. 6 months in historical control, p = 0.018). The median overall survival was 16.5 (90% CI 9.8-17.5) months. Sixty-seven per cent of patients experienced grade 3 or higher treatment-related adverse events. The most common toxicities were hematological (neutropenia) and gastrointestinal (diarrhoea, nausea, and vomiting). CONCLUSIONS Irinotecan, TAS-102 and bevacizumab is an active 2nd line therapy for patients with metastatic colorectal adenocarcinoma. Neutropenia is common and can affect dose density/intensity mandating use of G-CSF. A randomized study versus standard-of-care therapy is warranted. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov NCT04109924.
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Affiliation(s)
| | - Sarbajit Mukherjee
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | - Iman Imanirad
- Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL, USA
| | | | - Seth D Cohen
- Monmouth Hematology Oncology, RWJBarnanas Health, West Long Branch, NJ, USA
| | - Medhavi Gupta
- Program in Women's Oncology, Women & Infants Hospital, Brown University, Providence, RI, USA
| | - Renuka V Iyer
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | - Andrei Bakin
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | - Jianxin Wang
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | - Sarah Chatley
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | - Beth Cahill
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | - Deepak Vadehra
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | - Kristopher Attwood
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA
| | | | - Christos Fountzilas
- Roswell Park Comprehensive Cancer Center, Elm & Carlton St, Buffalo, NY, USA.
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Parikh PM, Bahl A, Sharma G, Pramanik R, Wadhwa J, Bajpai P, Jandyal S, Dubey AP, Sarin A, Dadhich SC, Saklani AP, Kumar A, Chandra A, Rawat S, Selvasekar C, Aggarwal S. Management of Metastatic Colorectal Cancer (mCRC): Real-World Recommendations. South Asian J Cancer 2024; 13:287-295. [PMID: 40060353 PMCID: PMC11888815 DOI: 10.1055/s-0044-1791689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025] Open
Abstract
INTRODUCTION Metastatic CRC is considered as a heterogenous disease. Its management is therefore complex and dynamic. In order the give a ready reference to community oncologists, we developed this real world recommendations. METHODS A group of experts with academic background and real world experience in mCRC got together. We reviewed the current literature and the insights gained from our real world experience. Based on the same we put together these recommendations. RECOMMENDATIONS RESULTS Molecular testing should be done wherever possible. Most of these patients will be treated with a palliative approach. Doublet chemotherapy is a long-standing standard of care. Triplet therapy may be offered where a more aggressive approach is indicated. Combination with anti -vascular endothelial growth factor antibodies and/or anti EGFR antibodies is also considered standard. In the first-line setting, pembrolizumab can be used for patients with mCRC and microsatellite instability-high or deficient mismatch repair tumours; Left and right sided tumours are distinct entities. Combination of chemotherapy and targeted therapy is used as per individual patient and tumour characteristics.Oligometastatic disease can be approached with potentially curative intent. Cytoreductive surgery plus chemotherapy can be offered to selected patients with peritoneal only metastases. Stereotactic body radiation therapy can be used as local therapy for patients with oligometastatic liver only disease who cannot be taken up for surgery. New strategies include induction-maintenance chemotherapy and perioperative chemotherapy. All drugs/ regimen included as standard of care in the first line can also be used in subsequent lines. Specific targetable driver mutation tumours can be treated accordingly with their complementary biological therapy. CONCLUSION Multidisciplinary team management and shared decision making are possible when patient and caregivers choose to become active participants.
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Affiliation(s)
- Purvish M. Parikh
- Department of Clinical Hematology, Sri Ram Cancer Center, Mahatma Gandhi University of Medical Sciences and Technology, Jaipur, Rajasthan, India
| | - Ankur Bahl
- Department of Medical Oncology, Fortis Hospital, Gurugram, Haryana, India
| | - Gopal Sharma
- Department of Medical Oncology, Max Healthcare Hospital, New Delhi, India
| | - Raja Pramanik
- Department of Medical Oncology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Jyoti Wadhwa
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Peush Bajpai
- Department of Medical Oncology, Manipal Hospital, New Delhi, India
| | - Sunny Jandyal
- Department of Medical Oncology, Action Cancer Hospital, New Delhi, India
| | - A P. Dubey
- Department of Medical Oncology, Delhi Heart and Lung Institute, New Delhi, India
| | - Aditya Sarin
- Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, India
| | | | - Avinash P. Saklani
- Department of Surgical Gastroenterology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGI), Lucknow, Uttar Pradesh, India
| | - Abhijit Chandra
- Department of Surgical Gastroenterology, King George Medical University, Lucknow, Uttar Pradesh, India
| | - Saumitra Rawat
- Department of Surgical Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India
| | - C. Selvasekar
- Clinical Services and Specialist Surgery, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Shyam Aggarwal
- Department of Medical Oncology, Sir Ganga Ram Hospital, New Delhi, India
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Jung S, Cheong S, Lee Y, Lee J, Lee J, Kwon MS, Oh YS, Kim T, Ha S, Kim SJ, Jo DH, Ko J, Jeon NL. Integrating Vascular Phenotypic and Proteomic Analysis in an Open Microfluidic Platform. ACS NANO 2024; 18:24909-24928. [PMID: 39208278 PMCID: PMC11394367 DOI: 10.1021/acsnano.4c05537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 08/19/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024]
Abstract
This research introduces a vascular phenotypic and proteomic analysis (VPT) platform designed to perform high-throughput experiments on vascular development. The VPT platform utilizes an open-channel configuration that facilitates angiogenesis by precise alignment of endothelial cells, allowing for a 3D morphological examination and protein analysis. We study the effects of antiangiogenic agents─bevacizumab, ramucirumab, cabozantinib, regorafenib, wortmannin, chloroquine, and paclitaxel─on cytoskeletal integrity and angiogenic sprouting, observing an approximately 50% reduction in sprouting at higher drug concentrations. Precise LC-MS/MS analyses reveal global protein expression changes in response to four of these drugs, providing insights into the signaling pathways related to the cell cycle, cytoskeleton, cellular senescence, and angiogenesis. Our findings emphasize the intricate relationship between cytoskeletal alterations and angiogenic responses, underlining the significance of integrating morphological and proteomic data for a comprehensive understanding of angiogenesis. The VPT platform not only advances our understanding of drug impacts on vascular biology but also offers a versatile tool for analyzing proteome and morphological features across various models beyond blood vessels.
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Affiliation(s)
- Sangmin Jung
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Sunghun Cheong
- Interdisciplinary
Program in Bioengineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Yoonho Lee
- Interdisciplinary
Program in Bioengineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Jungseub Lee
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Jihye Lee
- Target
Link Therapeutics, Inc., Seoul 04545, Republic
of Korea
| | - Min-Seok Kwon
- Target
Link Therapeutics, Inc., Seoul 04545, Republic
of Korea
- Department
of Public Health Science, Graduate School of Public Health, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Sun Oh
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
- Target
Link Therapeutics, Inc., Seoul 04545, Republic
of Korea
| | - Taewan Kim
- Department
of Electrical and Computer Engineering, Seoul National University, Seoul 08826, Republic of Korea
| | - Sungjae Ha
- ProvaLabs,
Inc., Seoul 08826, Republic of Korea
| | - Sung Jae Kim
- Department
of Electrical and Computer Engineering, Seoul National University, Seoul 08826, Republic of Korea
- SOFT
Foundry, Seoul National University, Seoul 08826, Republic of Korea
- Inter-university
Semiconductor Research Center, Seoul National
University, Seoul 08826, Republic
of Korea
| | - Dong Hyun Jo
- Department
of Anatomy and Cell Biology, Seoul National
University College of Medicine, Seoul 03080, Republic of Korea
| | - Jihoon Ko
- Department
of BioNano Technology, Gachon University, Seongnam-si, Gyeonggi-do 13120, Republic
of Korea
| | - Noo Li Jeon
- Department
of Mechanical Engineering, Seoul National
University, Seoul 08826, Republic
of Korea
- Interdisciplinary
Program in Bioengineering, Seoul National
University, Seoul 08826, Republic
of Korea
- Institute
of Advanced Machines and Design, Seoul National
University, Seoul 08826, Republic
of Korea
- Qureator, Inc., San
Diego, California 92121, United States
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Cheng Y, Teng Z, Zhang Y, Jin B, Zheng Z, Man L, Wang Z, Teng Y, Yu P, Shi J, Luo Y, Wang Y, Zhang J, Zhang H, Liu J, Chen H, Xiao J, Zhao L, Zhang L, Jiang Y, Chen Y, Zhang J, Wang C, Liu S, Qu J, Qu X, Liu Y. Irinotecan plus raltitrexed as second-line treatment in locally advanced or metastatic colorectal cancer patients: a prospective open-label, single-arm, multi-center, phase II study. BMC Cancer 2024; 24:1082. [PMID: 39223545 PMCID: PMC11368032 DOI: 10.1186/s12885-024-12831-4] [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: 01/22/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. METHODS This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. RESULTS A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. CONCLUSIONS The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.
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Affiliation(s)
- Yu Cheng
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Zan Teng
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Yanqiao Zhang
- Department of Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Bo Jin
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Zhendong Zheng
- Department of Oncology, Northern Theater Command General Hospital, Shenyang, Liaoning Province, China
| | - Li Man
- Department of Oncology, Anshan Cancer Hospital, Anshan, Liaoning Province, China
| | - Zhenghua Wang
- Department of Oncology, The First Affiliated Hospital Of Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Yuee Teng
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Ping Yu
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Jing Shi
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Ying Luo
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Ying Wang
- Department of Oncology, Shengjing Hospital Of China Medical University, Shenyang, Liaoning Province, China
| | - Jingdong Zhang
- Department of Oncology, Liaoning Cancer Hospital, Shenyang, Liaoning Province, China
| | - Huijuan Zhang
- Department of Oncology, Tieling Central Hospital, Tieling, Liaoning Province, China
| | - Jiwei Liu
- Department of Oncology, The First Affiliated Hospital Of Dalian Medical University, Dalian, Liaoning Province, China
| | - Hao Chen
- Department of Oncology, Liaoyang Liaohua Hospital, Liaoyang, Liaoning Province, China
| | - Jiawen Xiao
- Department of Oncology, Shenyang Fifth People Hospital, Shenyang, Liaoning Province, China
| | - Lei Zhao
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Lingyun Zhang
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Yu Jiang
- Department of Oncology, Panjin Central Hospital, Panjin, Liaoning Province, China
| | - Ying Chen
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China
| | - Jian Zhang
- Department of Oncology, Liaoyang City Central Hospital, Liaoyang, Liaoning Province, China
| | - Chang Wang
- Department of Oncology, The First Hospital Of Jilin University, Changchun, Jilin Province, China
| | - Sa Liu
- Department of Oncology, The Fourth Affiliated Hospital Of China Medical University, Shenyang, Liaoning Province, China
| | - Jinglei Qu
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China.
| | - Xiujuan Qu
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China.
| | - Yunpeng Liu
- Department of Oncology, The First Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning Province, China.
- Liaoning Province Clinical Research Center for Cancer, Shenyang, Liaoning Province, China.
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Shenyang, Liaoning Province, China.
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Nishida N, Sakai D, Satoh T. Treatment strategy for HER2-negative advanced gastric cancer: salvage-line strategy for advanced gastric cancer. Int J Clin Oncol 2024; 29:1237-1243. [PMID: 38733489 PMCID: PMC11347465 DOI: 10.1007/s10147-024-02500-8] [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: 12/27/2023] [Accepted: 02/25/2024] [Indexed: 05/13/2024]
Abstract
After immune checkpoint inhibitor (ICI) comes into third-line treatment of advanced gastric cancer, the therapeutic strategy has been dramatically changed. Recent first-line regimen, which consists of ICI and chemotherapeutic agents, prolonged progression-free survival, and subsequent treatment options enabled continuous treatment beyond second-line therapy. Moreover, the advent of vascular endothelial growth factor (VEGF)-targeted agents including angiogenesis inhibitors and TKIs provides an opportunity of considering the interaction between ICI and anti-VEGF agents, and facilitating novel treatment proposal. Although clinical benefit of prolonged VEGF blockade after disease progression has not been confirmed in gastric cancer, combination therapy of cytotoxic agents and anti-VEGF agent, such as irinotecan plus ramucirumab demonstrated favorable objective response rate and progression-free survival in third- or later-line setting. In this review, we discuss recent progress and future directions of later-line treatments of HER2-negative advancer gastric cancer.
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Affiliation(s)
- Naohiro Nishida
- Center for Cancer Genomics and Personalized Medicine, Osaka University Hospital, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan
| | - Daisuke Sakai
- Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Taroh Satoh
- Center for Cancer Genomics and Personalized Medicine, Osaka University Hospital, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
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Zhou Y, Xu Q, Wang J, Leng WB, Cao P, Chen Y, Luo DY, Qiu M, Liu J. Efficacy and safety of RS plus bevacizumab versus RS plus fruquintinib as the third-line therapy in patients with refractory metastatic colorectal cancer: A real-world propensity score matching study. J Evid Based Med 2024; 17:667-674. [PMID: 39327543 DOI: 10.1111/jebm.12652] [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] [Received: 02/29/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024]
Abstract
BACKGROUND This study aims to compare the effectiveness and safety of the combination of raltitrexed, S-1 (RS), and fruquintinib with the combination of RS and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). METHODS This retrospective cohort included mCRC patients who received the RS plus fruquintinib or regorafenib as the third-line therapy from May 2019 to April 2023. A propensity score matching (PSM) analysis was used to balance the baseline characteristics of all patients. Overall survival (OS), progression-free survival (PFS), tumor response, and safety of the two regimens were evaluated. RESULTS Of the 153 patients enrolled, 123 patients received the RS plus bevacizumab and 30 patients received the RS plus fruquintinib. After PSM, 30 pairs were analyzed. Patients treated with RS plus fruquintinib had a longer PFS than those treated with RS plus bevacizumab before PSM (5.0 months vs. 4.3 months, p = 0.008) and after PSM (5.0 months vs. 4.4 months, p = 0.012). A longer OS was also observed in RS plus fruquintinib group before PSM and after PSM, but there was no statistic difference between two groups after PSM. Both objective response rate and disease control rate were higher in the RS plus fruquintinib cohort than those in the RS plus bevacizumab cohort before PSM, and the difference in values between the two groups reduced after PSM. The adverse effects (AEs) of both groups were well tolerated. CONCLUSION In patients with refractory mCRC, RS plus fruquintinib demonstrated a superior OS, PFS than RS plus bevacizumab and had manageable AEs.
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Affiliation(s)
- Yuwen Zhou
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qian Xu
- West China Medical Publishers, West China Hospital of Sichuan University, Chengdu, China
| | - Jialing Wang
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Wei-Bing Leng
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Peng Cao
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Ye Chen
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - De-Yun Luo
- Department of Abdominal Oncology, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
| | - Meng Qiu
- Colorectal Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jiyan Liu
- Department of Biotherapy, Cancer Center, West China Hospital of Sichuan University, Chengdu, China
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Gharib E, Robichaud GA. From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:9463. [PMID: 39273409 PMCID: PMC11395697 DOI: 10.3390/ijms25179463] [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: 07/29/2024] [Revised: 08/19/2024] [Accepted: 08/24/2024] [Indexed: 09/15/2024] Open
Abstract
Colorectal cancer (CRC) represents a significant global health burden, with high incidence and mortality rates worldwide. Recent progress in research highlights the distinct clinical and molecular characteristics of colon versus rectal cancers, underscoring tumor location's importance in treatment approaches. This article provides a comprehensive review of our current understanding of CRC epidemiology, risk factors, molecular pathogenesis, and management strategies. We also present the intricate cellular architecture of colonic crypts and their roles in intestinal homeostasis. Colorectal carcinogenesis multistep processes are also described, covering the conventional adenoma-carcinoma sequence, alternative serrated pathways, and the influential Vogelstein model, which proposes sequential APC, KRAS, and TP53 alterations as drivers. The consensus molecular CRC subtypes (CMS1-CMS4) are examined, shedding light on disease heterogeneity and personalized therapy implications.
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Affiliation(s)
- Ehsan Gharib
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
| | - Gilles A Robichaud
- Département de Chimie et Biochimie, Université de Moncton, Moncton, NB E1A 3E9, Canada
- Atlantic Cancer Research Institute, Moncton, NB E1C 8X3, Canada
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Mechahougui H, Gutmans J, Colarusso G, Gouasmi R, Friedlaender A. Advances in Personalized Oncology. Cancers (Basel) 2024; 16:2862. [PMID: 39199633 PMCID: PMC11352922 DOI: 10.3390/cancers16162862] [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: 06/16/2024] [Revised: 08/12/2024] [Accepted: 08/14/2024] [Indexed: 09/01/2024] Open
Abstract
Advances in next-generation sequencing (NGS) have catalyzed a paradigm shift in cancer treatment, steering the focus from conventional, organ-specific protocols to precision medicine. Emerging targeted therapies offer a cutting-edge approach to cancer treatment, while companion diagnostics play an essential role in aligning therapeutic choices with specific molecular changes identified through NGS. Despite these advances, interpreting the clinical implications of a rapidly expanding catalog of genetic mutations remains a challenge. The selection of therapies in the presence of multiple mutations requires careful clinical judgment, supported by quality-centric genomic testing that emphasizes actionable mutations. Molecular tumor boards can play an increasing role in assimilating genomic data into clinical trials, thereby refining personalized treatment approaches and improving patient outcomes.
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Affiliation(s)
- Hiba Mechahougui
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (H.M.)
| | - James Gutmans
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (H.M.)
| | - Gina Colarusso
- Oncology Department, Geneva University Hospital (HUG), 1205 Geneva, Switzerland; (H.M.)
| | - Roumaïssa Gouasmi
- Cancer Research Center of Lyon, CNRS UMR5286, Inserm U1052, University of Lyon, 69100 Lyon, France
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Shi X, Wang X, Yao W, Shi D, Shao X, Lu Z, Chai Y, Song J, Tang W, Wang X. Mechanism insights and therapeutic intervention of tumor metastasis: latest developments and perspectives. Signal Transduct Target Ther 2024; 9:192. [PMID: 39090094 PMCID: PMC11294630 DOI: 10.1038/s41392-024-01885-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 05/29/2024] [Accepted: 06/10/2024] [Indexed: 08/04/2024] Open
Abstract
Metastasis remains a pivotal characteristic of cancer and is the primary contributor to cancer-associated mortality. Despite its significance, the mechanisms governing metastasis are not fully elucidated. Contemporary findings in the domain of cancer biology have shed light on the molecular aspects of this intricate process. Tumor cells undergoing invasion engage with other cellular entities and proteins en route to their destination. Insights into these engagements have enhanced our comprehension of the principles directing the movement and adaptability of metastatic cells. The tumor microenvironment plays a pivotal role in facilitating the invasion and proliferation of cancer cells by enabling tumor cells to navigate through stromal barriers. Such attributes are influenced by genetic and epigenetic changes occurring in the tumor cells and their surrounding milieu. A profound understanding of the metastatic process's biological mechanisms is indispensable for devising efficacious therapeutic strategies. This review delves into recent developments concerning metastasis-associated genes, important signaling pathways, tumor microenvironment, metabolic processes, peripheral immunity, and mechanical forces and cancer metastasis. In addition, we combine recent advances with a particular emphasis on the prospect of developing effective interventions including the most popular cancer immunotherapies and nanotechnology to combat metastasis. We have also identified the limitations of current research on tumor metastasis, encompassing drug resistance, restricted animal models, inadequate biomarkers and early detection methods, as well as heterogeneity among others. It is anticipated that this comprehensive review will significantly contribute to the advancement of cancer metastasis research.
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Affiliation(s)
- Xiaoli Shi
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu, China
- School of Medicine, Southeast University, Nanjing, Jiangsu, China
| | - Xinyi Wang
- The First Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wentao Yao
- Department of Urology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, Jiangsu, China
| | - Dongmin Shi
- Department of Medical Oncology, Shanghai Changzheng Hospital, Shanghai, China
| | - Xihuan Shao
- The Fourth Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhengqing Lu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu, China
| | - Yue Chai
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu, China
| | - Jinhua Song
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu, China.
| | - Weiwei Tang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu, China.
| | - Xuehao Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences; NHC Key Laboratory of Hepatobiliary Cancers, Nanjing, Jiangsu, China.
- School of Medicine, Southeast University, Nanjing, Jiangsu, China.
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Cohen R, Raeisi M, Chibaudel B, Shi Q, Yoshino T, Zalcberg JR, Adams R, Cremolini C, Van Cutsem E, Heinemann V, Tabernero J, Punt CJA, Arnold D, Hurwitz HI, Douillard JY, Venook AP, Saltz LB, Maughan TS, Kabbinavar F, Bokemeyer C, Grothey A, Mayer RJ, Kaplan R, Tebbutt NC, Randolph Hecht J, Giantonio BJ, Díaz-Rubio E, Sobrero AF, Peeters M, Koopman M, Goldberg RM, Andre T, de Gramont A. Prognostic value of liver metastases in colorectal cancer treated by systemic therapy: An ARCAD pooled analysis. Eur J Cancer 2024; 207:114160. [PMID: 38896997 DOI: 10.1016/j.ejca.2024.114160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 05/27/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024]
Abstract
BACKGROUND The liver is the most frequent site of metastases in colorectal cancer (CRC). This study aimed to assess the response rate and survival outcomes in metastatic CRC patients with non-liver metastases (NLM) compared to those with liver metastases (LM) across different lines of treatment. METHODS A total of 17,924 mCRC patients included in 26 trials from the ARCAD CRC database were analyzed. The analysis was conducted based on the presence or absence of LM across different treatment groups: chemotherapy (CT) alone, CT + anti-VEGF, CT + anti-EGFR in KRAS wild-type tumors, within the first-line (1 L) and second-line (2 L), and patients enrolled in third-line (≥3 L) trials treated with trifluridine/tipiracil or regorafenib or placebo. The endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). RESULTS Out of the 17,924 patients, 14,066 had LM (30.6 % with only liver involvement and 69.4 % with liver and other metastatic sites), while 3858 patients had NLM. In the CT alone and CT + anti-VEGF subgroups, NLM patients showed better OS and PFS in the 1 L and 2 L settings. However, in the CT + anti-EGFR 1 L and 2 L subgroups, there was no significant difference in OS and PFS between NLM and LM patients. In the ≥ 3 L subgroups, better OS and PFS were observed in NLM patients. ORRs were higher in LM patients than in NLM patients across all cohorts treated in the 1 L and only in the anti-EGFR cohort in the 2 L. CONCLUSION LM is a poor prognostic factor for mCRC increasing from 1 L to ≥ 3 L except for patients in 1 L and 2 L receiving CT+anti-EGFR. These data justify using LM as a stratification factor in future trials for patients with unresectable mCRC.
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Affiliation(s)
- Romain Cohen
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France
| | | | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Hospital, Fondation Cognacq-Jay, Levallois-Perret, France
| | - Qian Shi
- Department of Quantitative Health Science, Mayo Clinic, Rochester, USA
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - John R Zalcberg
- Monash University School of Public Health and Preventive Medicine and Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia
| | - Richard Adams
- Cardiff University and Velindre Cancer Centre, Cardiff, United Kingdom
| | - Chiara Cremolini
- Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy
| | - Eric Van Cutsem
- Department of Gastrointestinal and Liver Diseases, Digestive Oncology Unit, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Volker Heinemann
- Department of Medical Oncology, LMU Hospital, University of Munich, Munich, Germany
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology (VHIO), IOB-Quiron, Barcelona, Spain
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, Asklepios Klinik Altona, Hamburg, Germany
| | | | - Jean-Yves Douillard
- Medical Oncology Department, Integrated Centers for Oncology Nantes, Nantes, France
| | - Alan P Venook
- Department of Medicine, The University of California San Francisco, San Francisco, CA, USA
| | | | | | | | - Carsten Bokemeyer
- Department of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Niall C Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer, Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - J Randolph Hecht
- David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, USA
| | | | | | | | | | - Miriam Koopman
- University Medical Center Utrecht, Utrecht, the Netherlands
| | - Richard M Goldberg
- Department of Medicine, West Virginia University Cancer Institute, Morgantown, USA
| | - Thierry Andre
- Sorbonne University, Department of Medical Oncology, Hôpital Saint-Antoine, AP-HP, and INSERM UMRS 938, Équipe Instabilité des Microsatellites et Cancer, Équipe Labellisée par la Ligue Nationale Contre le Cancer, SIRIC CURAMUS, Centre de recherche Saint Antoine, Paris, France; ARCAD Foundation, Paris, France
| | - Aimery de Gramont
- ARCAD Foundation, Paris, France; Department of Medical Oncology, Franco-British Hospital, Levallois-Perret, France
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Hu X, Ye K, Bo S, Xiao Z, Ma M, Pan J, Zhong X, Zhang D, Mo X, Yu X, Chen M, Luo L, Shi C. Monitoring imatinib decreasing pericyte coverage and HIF-1α level in a colorectal cancer model by an ultrahigh-field multiparametric MRI approach. J Transl Med 2024; 22:712. [PMID: 39085929 PMCID: PMC11293104 DOI: 10.1186/s12967-024-05497-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 07/10/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Excessive pericyte coverage promotes tumor growth, and a downregulation may solve this dilemma. Due to the double-edged sword role of vascular pericytes in tumor microenvironment (TME), indiscriminately decreasing pericyte coverage by imatinib causes poor treatment outcomes. Here, we optimized the use of imatinib in a colorectal cancer (CRC) model in high pericyte-coverage status, and revealed the value of multiparametric magnetic resonance imaging (mpMRI) at 9.4T in monitoring treatment-related changes in pericyte coverage and the TME. METHODS CRC xenograft models were evaluated by histological vascular characterizations and mpMRI. Mice with the highest pericyte coverage were treated with imatinib or saline; then, vascular characterizations, tumor apoptosis and HIF-1α level were analyzed histologically, and alterations in the expression of Bcl-2/bax pathway were assessed through qPCR. The effects of imatinib were monitored by dynamic contrast-enhanced (DCE)-, diffusion-weighted imaging (DWI)- and amide proton transfer chemical exchange saturation transfer (APT CEST)-MRI at 9.4T. RESULTS The DCE- parameters provided a good histologic match the tumor vascular characterizations. In the high pericyte coverage status, imatinib exhibited significant tumor growth inhibition, necrosis increase and pericyte coverage downregulation, and these changes were accompanied by increased vessel permeability, decreased microvessel density (MVD), increased tumor apoptosis and altered gene expression of apoptosis-related Bcl-2/bax pathway. Strategically, a 4-day imatinib effectively decreased pericyte coverage and HIF-1α level, and continuous treatment led to a less marked decrease in pericyte coverage and re-elevated HIF-1α level. Correlation analysis confirmed the feasibility of using mpMRI parameters to monitor imatinib treatment, with DCE-derived Ve and Ktrans being most correlated with pericyte coverage, Ve with vessel permeability, AUC with microvessel density (MVD), DWI-derived ADC with tumor apoptosis, and APT CEST-derived MTRasym at 1 µT with HIF-1α. CONCLUSIONS These results provided an optimized imatinib regimen to achieve decreasing pericyte coverage and HIF-1α level in the high pericyte-coverage CRC model, and offered an ultrahigh-field multiparametric MRI approach for monitoring pericyte coverage and dynamics response of the TME to treatment.
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Affiliation(s)
- Xinpeng Hu
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Kunlin Ye
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Shaowei Bo
- Department of Medical Imaging, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Xingang Middle Road No. 466, Guangzhou, 510317, China
| | - Zeyu Xiao
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
- Engineering Research Center of Medical Imaging Artificial Intelligence for Precision Diagnosis and Treatment, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Mengjie Ma
- Department of Radiology, Guangzhou First People's Hospital, Panfu Road No. 1, Guangzhou, 510080, China
| | - Jinghua Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Xing Zhong
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Dong Zhang
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Xukai Mo
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Xiaojun Yu
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China
| | - Minfeng Chen
- College of Pharmacy, Jinan University, West Huangpu Avenue No.601, Guangzhou, 510632, China.
| | - Liangping Luo
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China.
- Engineering Research Center of Medical Imaging Artificial Intelligence for Precision Diagnosis and Treatment, West Huangpu Avenue No. 613, Guangzhou, 510630, China.
| | - Changzheng Shi
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, West Huangpu Avenue No. 613, Guangzhou, 510630, China.
- Engineering Research Center of Medical Imaging Artificial Intelligence for Precision Diagnosis and Treatment, West Huangpu Avenue No. 613, Guangzhou, 510630, China.
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Eng C, Yoshino T, Ruíz-García E, Mostafa N, Cann CG, O'Brian B, Benny A, Perez RO, Cremolini C. Colorectal cancer. Lancet 2024; 404:294-310. [PMID: 38909621 DOI: 10.1016/s0140-6736(24)00360-x] [Citation(s) in RCA: 63] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/15/2024] [Accepted: 02/21/2024] [Indexed: 06/25/2024]
Abstract
Despite decreased incidence rates in average-age onset patients in high-income economies, colorectal cancer is the third most diagnosed cancer in the world, with increasing rates in emerging economies. Furthermore, early onset colorectal cancer (age ≤50 years) is of increasing concern globally. Over the past decade, research advances have increased biological knowledge, treatment options, and overall survival rates. The increase in life expectancy is attributed to an increase in effective systemic therapy, improved treatment selection, and expanded locoregional surgical options. Ongoing developments are focused on the role of sphincter preservation, precision oncology for molecular alterations, use of circulating tumour DNA, analysis of the gut microbiome, as well as the role of locoregional strategies for colorectal cancer liver metastases. This overview is to provide a general multidisciplinary perspective of clinical advances in colorectal cancer.
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Affiliation(s)
- Cathy Eng
- Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, Cancer Center Hospital East, Kashiwa, Japan
| | - Erika Ruíz-García
- Department of Gastrointestinal Tumors and Translational Medicine Laboratory, Instituto Nacional de Cancerologia, Mexico City, Mexico
| | | | - Christopher G Cann
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Brittany O'Brian
- Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | - Amala Benny
- Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
| | | | - Chiara Cremolini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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Chitoran E, Rotaru V, Ionescu SO, Gelal A, Capsa CM, Bohiltea RE, Mitroiu MN, Serban D, Gullo G, Stefan DC, Simion L. Bevacizumab-Based Therapies in Malignant Tumors-Real-World Data on Effectiveness, Safety, and Cost. Cancers (Basel) 2024; 16:2590. [PMID: 39061228 PMCID: PMC11274419 DOI: 10.3390/cancers16142590] [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: 06/30/2024] [Revised: 07/08/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Overall, it is estimated that more than 3,500,000 patients have received Bevacizumab as part of systemic oncologic treatment. Bevacizumab and its biosimilars are currently marketed in over 130 countries. Given the wide usage of Bevacizumab in current oncological practice, it is very important to compare the "real-world" results to those obtained in controlled clinical trials. This study aims to describe the clinical experience of using Bevacizumab in a large cohort of cancer patients in "non-controlled real-world" conditions with regard to effectiveness, safety, and cost of therapy. METHODS For this purpose, we conducted an open, observational, retrospective study involving all patients treated for solid malignant tumors in the Bucharest Institute of Oncology with "Prof. Dr. Al. Trestioreanu" with Bevacizumab-based systemic therapy, between 2017 and 2021. RESULTS The study consisted of 657 treatment episodes in 625 patients (F/B = 1.62/1, with a median age of 57.6 years) which were treated for malignant tumors (majority colorectal, non-small cell lung, ovarian, and breast cancer). First-line treatment was administered in 229 patients, and the rest received Bevacizumab as second or subsequent lines of treatment. The overall response rate to Bevacizumab-based therapies was around 60-65% across all indication except for subsequent treatment lines in colorectal and ovarian cancers, where lower values were recorded (27.1%, and 31.5% respectively). Median PFS for the entire cohort was 8.2 months (95% CI 6.8-9.6), and the median OS was 13.2 months (95% CI 11.5-14.9). Usual bevacizumab-related toxicities were observed, including bleeding, hypertension, wound-healing complications, gastrointestinal perforation, other types of fistulas, septic complications, and thromboembolic events. Although the clinical benefits are undeniable, the addition of Bevacizumab to standard chemotherapy increased the overall treatment cost by 213%. CONCLUSIONS Bevacizumab remains a high-cost therapy, but it can add to clinical benefits (like overall survival, progression-free survival, and response rate) when used in conjunction with standard chemotherapy. Similar results as those presented in various controlled trials are observable even on unselected cohorts of patients in the uncontrolled conditions of "real-world" oncological practice. Off-label usage is encountered in clinical practice, and this aspect should be monitored given the potential adverse effects of the therapy.
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Affiliation(s)
- Elena Chitoran
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Vlad Rotaru
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Sinziana-Octavia Ionescu
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Aisa Gelal
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Cristina-Mirela Capsa
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Radiology Department, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
| | - Roxana-Elena Bohiltea
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Obstetrics and Gynecology Department, “Filantropia” Clinical Hospital, 011132 Bucharest, Romania
| | - Madalina-Nicoleta Mitroiu
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Obstetrics and Gynecology Department, “Filantropia” Clinical Hospital, 011132 Bucharest, Romania
| | - Dragos Serban
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Surgery Department 4, Bucharest University Emergency Hospital, 050098 Bucharest, Romania
| | - Giuseppe Gullo
- Department of Obstetrics and Gynecology, Villa Sofia Cervello Hospital, University of Palermo, 90146 Palermo, Italy
| | - Daniela-Cristina Stefan
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Laurentiu Simion
- Medicine School, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- General Surgery and Surgical Oncology Department I, Bucharest Institute of Oncology “Prof. Dr. Al. Trestioreanu”, 022328 Bucharest, Romania
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Jiang Y, Zhao M, Tang W, Zheng X. Comparison of systemic treatments for previously treated patients with unresectable colorectal liver metastases: a systematic review and network meta-analysis. Front Oncol 2024; 14:1293598. [PMID: 39050571 PMCID: PMC11266080 DOI: 10.3389/fonc.2024.1293598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 06/24/2024] [Indexed: 07/27/2024] Open
Abstract
Background There is limited evidence of comparative results among different treatments for patients with unresectable colorectal liver metastases (CRLM) who have failed at least one line of previous systemic therapy. We aimed to compare the efficacy of systemic treatments among these patients through this investigation. Methods We collected randomized controlled trials (RCTs) reported in English up until July 2023, from databases including PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and prominent conference databases, for this Bayesian network meta-analysis. Phase II or III trials that evaluated at least two therapeutic regimens were included. Primary outcome was overall survival (OS), secondary outcome was progression-free survival (PFS). Hazards ratios (HRs) with 95% confidence intervals (CIs) were used as effect size. Subgroup analysis was performed based on metastatic sites. The current systematic review protocol was registered on PROSPERO (CRD42023420498). Results 30 RCTs were included, with a total of 13,511 patients. Compared to chemotherapy, multi-targeted therapy (HR 0.57, 95% CI 0.37-0.87) and targeted therapy plus chemotherapy (HR 0.78, 95% CI 0.67-0.91) show significant advantages. Targeted therapy (HR 0.92, 95% CI 0.54-1.57) and local treatment plus chemotherapy (HR 1.03, 95% CI 0.85-1.23) had comparable performance. For patients with liver metastases, TAS-102 plus bevacizumab, aflibercept plus fluorouracil-based combination chemotherapy (CTFU), and bevacizumab plus capecitabine-based combination chemotherapy (CTCA) showed the best outcomes in terms of OS. Bevacizumab plus intensified CTFU, bevacizumab plus CTCA, and HAI followed by single-agent chemotherapy (SingleCT) performed the best regarding PFS. For patients with liver-limited metastases, aflibercept plus CTFU is the optimal choice in OS. For PFS, the best options were HAI followed by SingleCT, aflibercept plus CTFU, and panitumumab plus CTFU. For patients with multiple-site metastases, the best treatments were TAS-102 plus bevacizumab, bevacizumab plus CTCA, bevacizumab plus CTFU, and aflibercept plus CTFU. Conclusion Multi-targeted therapy and targeted therapy plus chemotherapy are the best treatment mechanisms. TAS-102 plus bevacizumab is superior in OS, the combination of anti-VEGF drugs like bevacizumab and aflibercept with standard chemotherapy is the preferred option for CRLM patients.
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Affiliation(s)
- Yunlin Jiang
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
- Graduate School of Nanjing University of Chinese Medicine, Nanjing, China
| | - Mingye Zhao
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Wenxi Tang
- Department of Pharmacoeconomics, School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Xueping Zheng
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
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Modest DP, Heinemann V, Schütt P, Angermeier S, Haberkorn M, Waidmann O, Graeven U, Wille K, Kunzmann V, Henze L, Constantin C, de Wit M, Denzlinger C, Ballhausen A, Kurreck A, Jelas I, Alig AHS, Stahler A, Stintzing S, Oettle H. Sequential therapy of refractory metastatic pancreatic cancer with 5-FU/LV/irinotecan (FOLFIRI) vs. 5-FU/LV/oxaliplatin (OFF). The PANTHEON trial (AIO PAK 0116). J Cancer Res Clin Oncol 2024; 150:332. [PMID: 38951245 PMCID: PMC11217046 DOI: 10.1007/s00432-024-05827-x] [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: 04/02/2024] [Accepted: 05/31/2024] [Indexed: 07/03/2024]
Abstract
PURPOSE In patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy. PATIENTS AND METHODS The primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016-004640-11. RESULTS The trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3-2.6) months with FOLFIRI vs 2.4 (95% CI 2.2-2.7) months with OFF (HR: 0.80, 95% CI 0.45-1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54-1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed. CONCLUSION The exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.
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Affiliation(s)
- Dominik Paul Modest
- Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany.
| | - Volker Heinemann
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Department of Medicine III & Comprehensive Cancer Center, Hospital of the University (LMU), Munich, Germany
| | | | - Stefan Angermeier
- Department of Gastroenterology, Hematology and Oncology, Hospital Ludwigsburg, Ludwigsburg, Germany
| | | | - Oliver Waidmann
- Centrum für Hämatologie und Onkologie Bethanien, Im Prüfling 17-19, 60389, Frankfurt, Germany
| | - Ullrich Graeven
- Department of Hematology, Oncology and Gastroenterology, Klinken Maria Hilf GmbH, Mönchengladbach, Germany
| | - Kai Wille
- University Clinic for Haematology, Oncology, Haemostaseology and Palliative Care, Johannes Wesling Medical Center Minden, University of Bochum, Bochum, Germany
| | - Volker Kunzmann
- Medical Clinic and Polyclinic II - IOT, University Hospital Würzburg, Würzburg, Germany
| | - Larissa Henze
- Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, Germany
| | - Christian Constantin
- Department for Oncology and Hematology, Clinical Center Lippe-Lemgo, Lemgo, Germany
| | - Maike de Wit
- Department for Internal Medicine-Hematology and Oncology, VIVANTES Hospital Neukölln, Berlin, Germany
| | | | - Alexej Ballhausen
- Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Annika Kurreck
- Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Ivan Jelas
- Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Annabel Helga Sophie Alig
- Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Arndt Stahler
- Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Sebastian Stintzing
- Charité - Universitätsmedizin Berlin, Department of Hematology, Oncology, and Cancer Immunology, Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
- German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Helmut Oettle
- Practice for Internal Medicine, Joint Practice and Day Clinic, Friedrichshafen, Germany
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Kagawa Y, Wang C, Piao Y, Jin L, Tanizawa Y, Cai Z, Sunakawa Y. Real-World Evidence of FOLFIRI Combined with Anti-Angiogenesis Inhibitors or Anti-EGFR Antibodies for Patients with Early Recurrence Colorectal Cancer After Adjuvant FOLFOX/CAPOX Therapy: A Japanese Claims Database Study. Target Oncol 2024; 19:575-585. [PMID: 38691296 PMCID: PMC11231005 DOI: 10.1007/s11523-024-01063-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2024] [Indexed: 05/03/2024]
Abstract
BACKGROUND Oxaliplatin-containing adjuvant regimens (folinic acid, fluorouracil, and oxaliplatin/capecitabine and oxaliplatin [FOLFOX/CAPOX]) are used after curative resection of colorectal cancer (CRC). However, real-world evidence regarding treatment sequences and outcomes in patients with early recurrence CRC after adjuvant chemotherapy is limited. OBJECTIVE We aimed to describe the patient characteristics, treatment sequence, and overall duration of second-line (2L) therapy in patients with early recurrence CRC who received adjuvant chemotherapy (FOLFOX/CAPOX) followed by folinic acid, fluorouracil, and irinotecan (FOLFIRI) + anti-angiogenesis drugs (AA) or FOLFIRI + anti-epidermal growth factor receptor (EGFR) antibodies. METHODS This retrospective study analyzed Japanese administrative data from November 2014 to March 2023 of adult patients who underwent CRC resection surgery, started FOLFOX/CAPOX ≤3 months (mo) after surgery, and had early CRC recurrence. Early recurrence was defined as initiation of FOLFIRI+AA or FOLFIRI+anti-EGFR antibodies as 2L therapy, ≤12 mo of discontinuing adjuvant chemotherapy. Patient characteristics, treatment sequence, median time to treatment discontinuation (mTTD), i.e., duration between the start and end dates of 2L therapy (Kaplan-Meier method), and factors associated with 2L time to treatment discontinuation constituted the study outcomes (Cox regression model). Subgroup analyses were performed for timing of early CRC recurrence (≤6 mo and 6-12 mo) and tumor sidedness. RESULTS Among the 832 selected patients (median age [minimum-maximum] 67 (24-86) years, 56.4% male), CAPOX (71.3%) was more commonly used than FOLFOX (28.7%) as adjuvant therapy. FOLFIRI+AA (72.5%) was used more commonly than FOLFIRI+anti-EGFR antibodies (27.5%) in 2L. AA and anti-EGFR antibodies groups had similar mTTD: 6.2 mo (95% confidence interval 5.8, 6.9) and 6.1 mo (95% confidence interval 5.2, 7.4). Age ≥70 years showed significant association with shorter 2L treatment duration (hazard ratio 1.2, 95% confidence interval 1.0, 1.4; p = 0.03). The AA cohort's mTTD was numerically shorter in the ≤6 mo recurrence subgroup compared with the 6-12 mo recurrence subgroup (6.1 mo vs 8.1 mo); the anti-EGFR antibodies cohort had similar mTTD (5.8 mo vs 6.2 mo). The AA and anti-EGFR antibodies cohorts also had similar mTTD in the left-sided CRC subgroup (6.5 mo vs 6.2 mo), but not in the right-sided subgroup (5.6 mo vs 3.9 mo). CONCLUSIONS This is the first administrative data-based real-world evidence on treatment sequence and outcomes for patients with early recurrence CRC treated with FOLFIRI+AAs or FOLFIRI+ anti-EGFR antibodies after adjuvant FOLFOX/CAPOX therapy in Japan. Both regimens had similar TTD, but relapse timing and tumor sidedness may influence their efficacy.
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Affiliation(s)
- Yoshinori Kagawa
- Osaka General Medical Center, 3 Chome-1-56 Bandaihigashi, Sumiyoshi Ward, Osaka, 558-8558, Japan.
- Osaka International Cancer Institute, Osaka, Japan.
| | | | | | - Long Jin
- Eli Lilly Japan K.K., Kobe, Japan
| | | | | | - Yu Sunakawa
- St. Marianna University School of Medicine, Kawasaki, Japan
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Hu H, Fu Z, Liu J, Zhang C, Li S, Zhang Y, You R. Pulmonary haemorrhage and haemoptysis associated with bevacizumab-related treatment regimens: a retrospective, pharmacovigilance study using the FAERS database. Front Pharmacol 2024; 15:1339505. [PMID: 38978981 PMCID: PMC11228312 DOI: 10.3389/fphar.2024.1339505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 05/28/2024] [Indexed: 07/10/2024] Open
Abstract
Background: Bevacizumab (BV) is widely used in routine cancer treatment and clinical therapy in combination with many other agents. This study aims to describe and analyse post-market cases of pulmonary haemorrhage and haemoptysis reported with different BV treatment regimens by mining data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: Data were collected from the FAERS database between 2004 Q1 and 2023 Q1. Disproportionality analysis including the reporting odds ratio (ROR) was employed to quantify the signals of disproportionate reporting of pulmonary haemorrhage and haemoptysis adverse events (AEs) associated with BV-related treatment regimens. The demographic characteristics, time to onset and outcomes were further clarified. Results: A total of 55,184 BV-associated reports were extracted from the FAERS database, of which 497 reports related to pulmonary haemorrhage and haemoptysis. Overall, the median onset time of pulmonary haemorrhage and haemoptysis AEs was 43 days (interquartile range (IQR) 15-117 days). In the subgroup analysis, BV plus targeted therapy had the longest median onset time of 90.5 days (IQR 34-178.5 days), while BV plus chemotherapy had the shortest of 40.5 days (IQR 14-90.25). BV plus chemotherapy disproportionately reported the highest percentage of death (148 deaths out of 292 cases, 50.68%). Moreover, the BV-related treatments including four subgroups in our study demonstrated the positive signals with the association of disproportionate reporting of pulmonary haemorrhage and haemoptysis. Notably, BV plus chemotherapy showed a significant higher reporting risk in pulmonary haemorrhage and haemoptysis signals of disproportionate reporting in comparison to BV monotherapy (ROR 5.35 [95% CI, 4.78-6.02] vs. ROR 4.19 [95% CI, 3.56-4.91], p = 0.0147). Conclusion: This study characterized the reporting of pulmonary haemorrhage and haemoptysis, along with the time to onset and demographic characteristics among different BV-related treatment options. It could provide valuable evidence for further studies and clinical practice of BV.
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Affiliation(s)
- Huiping Hu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhiwen Fu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinmei Liu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cong Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shijun Li
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruxu You
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
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Mazard T, Mollevi C, Loyer EM, Léger J, Chautard R, Bouché O, Borg C, Armand-Dujardin P, Bleuzen A, Assenat E, Lecomte T. Prognostic value of the tumor-to-liver density ratio in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy. A post-hoc study of the STIC-AVASTIN trial. Cancer Imaging 2024; 24:77. [PMID: 38886836 PMCID: PMC11181627 DOI: 10.1186/s40644-024-00722-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 06/10/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND The Response Evaluation Criteria in Solid Tumors (RECIST) are often inadequate for the early assessment of the response to cancer therapy, particularly bevacizumab-based chemotherapy. In a first cohort of patients with colorectal cancer liver metastases (CRLM), we showed that variations of the tumor-to-liver density (TTLD) ratio and modified size-based criteria determined using computed tomography (CT) data at the first restaging were better prognostic criteria than the RECIST. The aims of this study were to confirm the relevance of these radiological biomarkers as early predictors of the long-term clinical outcome and to assess their correlation with contrast-enhanced ultrasound (CEUS) parameters in a new patient cohort. METHODS In this post-hoc study of the multicenter STIC-AVASTIN trial, we retrospectively reviewed CT data of patients with CRLM treated with bevacizumab-based regimens. We determined the size, density and TTLD ratio of target liver lesions at baseline and at the first restaging and also performed a morphologic evaluation according to the MD Anderson criteria. We assessed the correlation of these parameters with progression-free survival (PFS) and overall survival (OS) using the log-rank test and a Cox proportional hazard model. We also examined the association between TTLD ratio and quantitative CEUS parameters. RESULTS This analysis concerned 79 of the 137 patients included in the STIC-AVASTIN trial. PFS and OS were significantly longer in patients with tumor size reduction > 15% at first restaging, but were not correlated with TTLD ratio variations. However, PFS was longer in patients with TTLD ratio > 0.6 at baseline and first restaging than in those who did not reach this threshold. In the multivariate analysis, only baseline TTLD ratio > 0.6 was a significant survival predictor. TTLD ratio > 0.6 was associated with improved perfusion parameters. CONCLUSIONS Although TTLD ratio variations did not correlate with the long-term clinical outcomes, TTLD absolute values remained a good predictor of survival at baseline and first restaging, and may reflect tumor microvascular features that might influence bevacizumab-based treatment efficiency. TRIAL REGISTRATION NCT00489697, registration number of the STIC-AVASTIN trial.
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Affiliation(s)
- Thibault Mazard
- Medical Oncology Department, Montpellier Cancer Institute (ICM), University of Montpellier, Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, 208 avenue des apothicaires, Parc Euromédecine, Montpellier Cedex 5, Montpellier, 34298, France.
| | - Caroline Mollevi
- Institute Desbrest of Epidemiology and Public Health, University of Montpellier, INSERM, Cancer Institute of Montpellier, Montpellier, France
| | - Evelyne M Loyer
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Julie Léger
- INSERM CIC 1415, CHRU de Tours, Tours Cedex 9, 37044, France
| | - Romain Chautard
- Department of Hepatogastroenterology and Digestive Oncology, UMR INSERM U 1069, Hôpital Trousseau, CHRU de Tours, Université de Tours, Tours Cedex 9, 37044, France
| | - Olivier Bouché
- Department of Hepatogastroenterology, Hôpital Robert Debré, CHU de Reims, Avenue Général Koenig, Reims Cedex, 51092, France
| | - Christophe Borg
- Department of Medical Oncology, Hôpital Jean Minjoz, CHRU de Besançon, 3 Boulevard Alexandre Fleming, Besançon, 25000, France
| | | | - Aurore Bleuzen
- Department of Radiology, CHRU de Tours, Tours Cedex 9, 37044, France
| | - Eric Assenat
- Medical Oncology Department, Montpellier Cancer Institute (ICM), University of Montpellier, CHU Montpellier, Montpellier, France
| | - Thierry Lecomte
- Department of Hepatogastroenterology and Digestive Oncology, UMR INSERM U 1069, Hôpital Trousseau, CHRU de Tours, Université de Tours, Tours Cedex 9, 37044, France
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50
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Seufferlein T, Lausser L, Stein A, Arnold D, Prager G, Kasper-Virchow S, Niedermeier M, Müller L, Kubicka S, König A, Büchner-Steudel P, Wille K, Berger AW, Kestler AMR, Kraus JM, Werle SD, Perkhofer L, Ettrich TJ, Kestler HA. Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer-Results of the prospective multicenter PERMAD trial. PLoS One 2024; 19:e0304324. [PMID: 38875244 PMCID: PMC11178165 DOI: 10.1371/journal.pone.0304324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Accepted: 05/08/2024] [Indexed: 06/16/2024] Open
Abstract
BACKGROUND Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. PATIENTS AND METHODS 15 German and Austrian centers prospectively recruited 50 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). RESULTS Using random forests, we developed a predictive machine learning model that discriminated between the situations of "no progress within 100 days before radiological progress" and "progress within 100 days before radiological progress". We could further identify a combination of ten out of the 102 CAF markers, which fulfilled this task with 78.2% accuracy, 71.8% sensitivity, and 82.5% specificity. CONCLUSIONS We identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress.
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Affiliation(s)
- Thomas Seufferlein
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Ludwig Lausser
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
- Faculty of Computer Science, Technische Hochschule Ingolstadt, Ingolstadt, Germany
| | - Alexander Stein
- Hematology-Oncology Practice Eppendorf, University Cancer Center Hamburg, Hamburg, Germany
| | - Dirk Arnold
- Asklepios Cancer Center Hamburg, AK Altona, Hamburg, Germany
| | - Gerald Prager
- Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria
| | - Stefan Kasper-Virchow
- Medical Oncology, University Hospital Essen West German Cancer Center, Essen, Germany
| | | | | | - Stefan Kubicka
- Cancer Center Reutlingen, Reutlingen Hospital, Reutlingen, Germany
| | - Alexander König
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Goettingen, Göttingen, Germany
| | | | - Kai Wille
- Hematology, Oncology, University Hospital Ruhr-University-Bochum, Minden, Germany
| | - Andreas W. Berger
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | | | - Johann M. Kraus
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
| | - Silke D. Werle
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
| | - Lukas Perkhofer
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Thomas J. Ettrich
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Hans A. Kestler
- Institute of Medical Systems Biology, Ulm University, Ulm, Germany
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