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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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Huang Z, Li C, Huang Y, Liang W, Tao H. Efficacy and safety of PD-1/L1 inhibitors as first-line therapy for metastatic colorectal cancer: a meta-analysis. Front Immunol 2024; 15:1425596. [PMID: 39100666 PMCID: PMC11294095 DOI: 10.3389/fimmu.2024.1425596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 07/08/2024] [Indexed: 08/06/2024] Open
Abstract
Objective To evaluate the efficacy and safety of PD-1/L1 inhibitors as first-line therapy in metastatic colorectal cancer(mCRC). Method Articles evaluating first-line PD-1/L1 inhibitors for mCRC were sought in four databases (Pubmed, Embase, Web of Science, and the Cochrane Library) from the inception of the databases until 11 November 2023. Meta-analyses were conducted to assess the rates of progression-free survival (PFS), overall survival (OS), complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), disease control rate (DCR), and grade ≥ 3 treatment-related adverse events (trAEs). Results Totally nine studies were included for meta-analysis. A subgroup analysis was performed based on mismatch repair(MMR) status and regimens. In patients diagnosed with mismatch repair-deficient(dMMR) mCRC who received PD-1/L1 inhibitors as their first-line treatment, the ORR was 0.54 (95% CI, 0.39 to 0.68), the median PFS was 53.2 months, the Grade≥ 3 TRAEs rate was 0.33(95% CI, 0.12 to 0.60) and the median OS was not determined. For patients with proficient mismatch repair (pMMR) mCRC who underwent a combined treatment of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody and chemotherapy as their first-line therapy, the ORR was 0.62 (95% CI, 0.56 to 0.68), the median PFS was 10.1 months, the median OS was 26.7 months, and the Grade≥ 3 TRAEs rate was 0.59(95% CI, 0.39 to 0.77). Conclusion Our results revealed that the utilization of PD-1/L1 inhibitors as first-line therapy for dMMR mCRC yielded highly favorable outcomes, while maintaining an acceptable level of safety. Administering a combination of PD-1/L1 inhibitors, anti-VEGF monoclonal antibody, and chemotherapy as first-line treatment in patients with pMMR mCRC led to an improved ORR. However, there was no significant improvement in the long-term prognosis of the tumor. Systematic review registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506196, identifier CRD42024506196.
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Affiliation(s)
| | | | | | | | - Haiyun Tao
- The First Affiliated Hospital of Guangxi University of Science and Technology, Guangxi University of Science and Technology, Liuzhou, China
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Naz T, Rehman AU, Shahzad A, Rasool MF, Saleem Z, Hussain R. Impact of bevacizumab on clinical outcomes and its comparison with standard chemotherapy in metastatic colorectal cancer patients: a systematic review and meta-analysis. J Pharm Policy Pract 2024; 17:2354300. [PMID: 38845624 PMCID: PMC11155432 DOI: 10.1080/20523211.2024.2354300] [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] [Indexed: 06/09/2024] Open
Abstract
Background Advances in targeted therapies have expanded the treatment options for colorectal cancer (CRC), allowing for more tailored and effective approaches to managing the disease. In targeted therapy, Bevacizumab is a commonly prescribed anti-VEGF monoclonal antibody that has a direct anti-vascular impact in cancer patients. Vascular Endothelial Growth Factors (VEGFs), especially VEGF-A, are significant agents in promoting tumour angiogenesis. Objective To assess the impact of adding Bevacizumab to chemotherapy on progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer. Methodology Comprehensive searches have been performed on electronic databases such as PubMed, and Google Scholar using the following terms: colorectal cancer, adenocarcinoma, Bevacizumab, chemotherapy, and monoclonal antibody. Results In the meta-analysis, 16 out of the 24 included studies were analysed. In the final analysis, incorporating Bevacizumab with chеmothеrapy demonstrated favourable outcomes for OS with a hazard ratio (HR = 0.689,95%CI: 0.51-0.83, I² = 39%, p <0.01) and for PFS with a hazard ratio (HR = 0.77 95% CI: 0.60-0.96, I² = 54%, p < 0.01). The subgroup analysis of PFS, categorised by study dеsign (prospеctivе vs rеtrospеctivе), reveals that the Hazard Ratio (HR = 0.82, 95% CI: 0.62-0.97, I² = 21%, p < 0.01) and for OS with a hazard ratio (HR = 0.73, 95% CI: 0.52-0.86, I² = 17%, p < 0.01). Conclusion Our findings indicate that combining Bevacizumab with chemotherapy enhances clinical outcomes and results in a significant increase in PFS and OS in patients with metastatic colorectal cancer. Positive outcomes are demonstrated by a substantial 23% increase in PFS and 31% increase in OS in patients with metastatic colorectal cancer who undergo Bevacizumab in conjunction with chemotherapy.
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Affiliation(s)
- Tehnia Naz
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Anees ur Rehman
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Aleena Shahzad
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Muhammad Fawad Rasool
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Zikria Saleem
- Department of Pharmacy Practice, Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan
| | - Rabia Hussain
- Discipline of Social and Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, Penang, Malaysia
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Stucchi E, Bartolini M, Airoldi M, Fazio R, Daprà V, Mondello G, Prete MG, Puccini A, Santoro A. Fruquintinib as new treatment option in metastatic colorectal cancer patients: is there an optimal sequence? Expert Opin Pharmacother 2024; 25:371-382. [PMID: 38568032 DOI: 10.1080/14656566.2024.2336069] [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: 01/23/2024] [Accepted: 03/25/2024] [Indexed: 04/30/2024]
Abstract
INTRODUCTION Available treatments for colorectal cancer are limited. However, in the last few years several advances and new treatment options became available and expanded the continuum of care in metastatic colorectal cancer (mCRC). AREAS COVERED Fruquintinib, a tyrosine kinase inhibitor, has been shown to be effective in heavily pretreated mCRC progressing to trifluridine-tipiracil (FTD/TPI) or regorafenib or both. Preclinical studies have shown that fruquintinib inhibits with high selectivity VEGFR 1-2-3, leading to a blockade in angiogenesis process, but also acts, with weak inhibition, on RET, FGFR-1, and c-kit kinases. Fruquintinib demonstrated good efficacy and tolerance in chemorefractory mCRC in two phase III trial: FRESCO and FRESCO 2. These results led to FDA approval of fruquintinib for pretreated mCRC patients who received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. EXPERT OPINION Fruquintinib is a valid therapeutic option for heavily pretreated mCRC patients. However, an optimal sequence of treatments is yet to be defined. In this review, we propose an algorithm for later lines of treatment to integrate fruquintinib as a standard of care together with the new therapeutic combinations that recently showed clinical benefit for chemorefractory mCRC, in both molecularly selected (e.g. KRASG12C or HER2 amplification) and in non-oncogenic driven patients.
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Affiliation(s)
- Erika Stucchi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Michela Bartolini
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Marco Airoldi
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Roberta Fazio
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Valentina Daprà
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Giuseppe Mondello
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Maria Giuseppina Prete
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Alberto Puccini
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
- Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Italy
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Wang HM, Lou PJ, Yang MH, Chen TH, Lien MY, Lin JC, Chen JP, Lu WC, Lu HJ, Huang TL, Yen CJ, Wu SY, Wang HC, Hsieh MC. Cetuximab Treatment beyond Progression in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: A Nationwide Population-Based Study (THNS-2021-08). Target Oncol 2024; 19:51-58. [PMID: 38285067 PMCID: PMC10830868 DOI: 10.1007/s11523-023-01028-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2023] [Indexed: 01/30/2024]
Abstract
BACKGROUND Little is known regarding the association of cetuximab treatment beyond progression (TBP) with survival among patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC). Although immune checkpoint inhibitors (ICIs) are now considered as first-line treatment, not all patients are suitable for ICIs. OBJECTIVE We conducted a multicenter, retrospective study to evaluate the role of cetuximab TBP in patients with R/M HNSCC after failure of first-line cetuximab-containing chemotherapy. PATIENTS AND METHODS Patients with R/M HNSCC who had tumor progression after first-line cetuximab-containing chemotherapy were included into our study. Oncologic outcomes were estimated including time to cetuximab treatment discontinuation (TTD), progression-free survival 2 (PFS2), overall survival (OS), overall response rate (ORR), and disease control rate (DCR). Multivariate cox regression analysis with survival were conducted. Subgroup analysis with P16 and programmed death ligand 1 expression were performed. RESULTS A total of 498 patients were eligible with 259 patients in the TBP group and 239 patients in the non-TBP group. The most common first-line chemotherapy was the EXTREME regimen in both groups. As for second-line treatment, the most common regimen were TPEx in the TBP group and taxane-based chemotherapy in the non-TBP group. Median TTD was 8.7 months in TBP and 5.5 months in non-TBP (p < 0.001). In terms of survival, median OS1 was significant longer in the TBP group than in the non-TBP group [14.1 months versus 10.9 months (p = 0.016)]. Multivariate analysis demonstrated cetuximab TBP was a factor independently associated with OS. CONCLUSIONS Our retrospective study suggests cetuximab TBP to be effective and to provide better survival for patients with R/M HNSCC after failure of first-line cetuximab-containing chemotherapy. Further prospective studies are warranted to validate the role of cetuximab TBP in R/M HNSCC.
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Affiliation(s)
- Hung-Ming Wang
- Division of Hematology-Oncology, Department of Internal Medicine, Linkou Chang Gung Memorial Hospital/College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC
| | - Pei-Jen Lou
- Department of Otolaryngology, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan, ROC
| | - Muh-Hwa Yang
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Tein-Hua Chen
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ming-Yu Lien
- Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, ROC
| | - Jin-Ching Lin
- Department of Radiation Oncology, Changhua Christian Hospital, Changhua, Taiwan, ROC
| | - Jo-Pai Chen
- Department of Oncology, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan, ROC
| | - Wei-Chen Lu
- Department of Oncology, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan, ROC
| | - Hsueh-Ju Lu
- Division of Hematology and Oncology, Department of Internal Medicine, Chung Shan Medical University Hospital/College of Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan, ROC
| | - Tai-Lin Huang
- Department of Hematology-Oncology, Kaohsiung Chang Gung Memorial Hospital/College of Medicine, Chang Gung University, Kaohsiung, Taiwan, ROC
| | - Chia-Jui Yen
- Department of Oncology, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
| | - Shang-Yin Wu
- Department of Oncology, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
| | - Hui-Ching Wang
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, ROC
| | - Meng-Che Hsieh
- Department of Hematology and Oncology, E-Da Cancer Hospital/College of Medicine, I-Shou University, No.21, E-Da Rd., Yan-Chao Dist., Kaohsiung, 807, Taiwan, ROC.
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Wang K, Xiang YJ, Yu HM, Cheng YQ, Feng JK, Liu ZH, Shan YF, Zheng YT, Ni QZ, Cheng SQ. Overall survival of patients with hepatocellular carcinoma treated with sintilimab and disease outcome after treatment discontinuation. BMC Cancer 2023; 23:1017. [PMID: 37867191 PMCID: PMC10591394 DOI: 10.1186/s12885-023-11485-y] [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: 04/04/2023] [Accepted: 10/06/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. METHODS This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). RESULTS Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). CONCLUSIONS In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab.
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Affiliation(s)
- Kang Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yan-Jun Xiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Hong-Ming Yu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yu-Qiang Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jin-Kai Feng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Zong-Han Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yun-Feng Shan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Yi-Tao Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Qian-Zhi Ni
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shu-Qun Cheng
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China.
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China.
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Otsu S, Hironaka S. Current Status of Angiogenesis Inhibitors as Second-Line Treatment for Unresectable Colorectal Cancer. Cancers (Basel) 2023; 15:4564. [PMID: 37760533 PMCID: PMC10526327 DOI: 10.3390/cancers15184564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/05/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer is the third most common disease and the second most common cause of death around the world. The drug for second-line treatment depends on the drugs used in first-line treatment and the biomarker status. As biomarkers, the RAS gene, BRAF gene, and dMMR/MSI-H, TMB-H, and HER2 statuses have been established in clinical practice, and the corresponding molecularly targeted therapeutic agents are selected based on the biomarker status. Given the frequency of biomarkers, it is assumed that when patients move on to second-line treatment, an angiogenesis inhibitor is selected in many cases. For second-line treatment, three angiogenesis inhibitors, bevacizumab (BEV), ramucirumab (RAM), and aflibercept (AFL), are available, and one of them is combined with cytotoxic agents. These three angiogenesis inhibitors are known to inhibit angiogenesis through different mechanisms of action. Although no useful biomarkers have been established for the selection of angiogenesis inhibitors, previous biomarker studies have suggested that angiogenesis-related factors such as VEGF-A and VEGF-D might be predictors of the therapeutic efficacy of angiogenesis inhibitors. These biomarkers are measured as protein levels in plasma and are considered to be promising biomarkers. We consider that the rationale for selecting among these three angiogenesis inhibitors should be clarified to benefit patients.
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Affiliation(s)
- Satoshi Otsu
- Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, 1-1, Idaigaoka, Hasama-machi, Yufu City 879-5593, Oita, Japan
| | - Shuichi Hironaka
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka-shi 181-8611, Tokyo, Japan
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Redman JM, O’Sullivan Coyne G, Reed CT, Madan RA, Strauss J, Steinberg SJ, Marté J, Cordes L, Heery C, Gulley JL. Avelumab in Patients With Metastatic Colorectal Cancer. Oncologist 2023; 28:823-e804. [PMID: 37310790 PMCID: PMC10485289 DOI: 10.1093/oncolo/oyad162] [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: 04/19/2023] [Accepted: 05/07/2023] [Indexed: 06/15/2023] Open
Abstract
BACKGROUND Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab. METHODS Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate. RESULTS Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1). CONCLUSION As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).
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Affiliation(s)
- Jason M Redman
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Geraldine O’Sullivan Coyne
- Developmental Therapeutics Clinic, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA
| | - Clay T Reed
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Ravi A Madan
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Julius Strauss
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Seth J Steinberg
- Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Jennifer Marté
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Lisa Cordes
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - Christopher Heery
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
| | - James L Gulley
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
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Huang S, Ye J, Gao X, Huang X, Huang J, Lu L, Lu C, Li Y, Luo M, Xie M, Lin Y, Liang R. Progress of research on molecular targeted therapies for colorectal cancer. Front Pharmacol 2023; 14:1160949. [PMID: 37614311 PMCID: PMC10443711 DOI: 10.3389/fphar.2023.1160949] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 07/26/2023] [Indexed: 08/25/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies, accounting for approximately 10% of global cancer incidence and mortality. Approximately 20% of patients with CRC present metastatic disease (mCRC) at the time of diagnosis. Moreover, up to 50% of patients with localized disease eventually metastasize. mCRC encompasses a complex cascade of reactions involving multiple factors and processes, leading to a diverse array of molecular mechanisms. Improved comprehension of the pathways underlying cancer cell development and proliferation, coupled with the accessibility of relevant targeted agents, has propelled advancements in CRC treatment, ultimately leading to enhanced survival rates. Mutations in various pathways and location of the primary tumor in CRC influences the efficacy of targeted agents. This review summarizes available targeted agents for different CRC pathways, with a focus on recent advances in anti-angiogenic and anti-epidermal growth factor receptor agents, BRAF mutations, and human epidermal growth factor receptor 2-associated targeted agents.
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Affiliation(s)
- Shilin Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Jiazhou Ye
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xing Gao
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Xi Huang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Julu Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Lu Lu
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Cheng Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yongqiang Li
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Min Luo
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Mingzhi Xie
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Yan Lin
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Rong Liang
- Department of Digestive Oncology, Guangxi Medical University Cancer Hospital, Nanning, China
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Takahashi N, Hara H, Nagashima K, Hirata K, Masuishi T, Matsumoto T, Kawakami H, Yamazaki K, Hironaka S, Boku N, Muro K. Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G). BMC Cancer 2023; 23:726. [PMID: 37543568 PMCID: PMC10403909 DOI: 10.1186/s12885-023-11199-1] [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: 04/09/2023] [Accepted: 07/20/2023] [Indexed: 08/07/2023] Open
Abstract
BACKGROUND Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. METHODS This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. DISCUSSION This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. TRIAL REGISTRATION jRCTs041220120.
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Affiliation(s)
- Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, 780 Komuro, Ina-Machi, Kita-Adachi-Gun, Saitama, 362-0807, Japan.
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, 780 Komuro, Ina-Machi, Kita-Adachi-Gun, Saitama, 362-0807, Japan
| | - Kengo Nagashima
- Biostatistics Unit, Clinical and Translational Research Center, Keio University Hospital, 35 Shinanomachi, Tokyo, 160-8582, Japan
| | - Kenro Hirata
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-Ku, Tokyo, 160-8582, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-Ku Nagoya 464-8681, Aichi, Japan
| | - Toshihiko Matsumoto
- Cancer Treatment Center, Kansai Medical University, 2-3-1 Hirakatashinmachi, Hirakata, Osaka, 573-1191, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osakasayama, Osaka, 589-8511, Japan
| | - Kentaro Yamazaki
- Department of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-Cho, Sunto-Gun, Shizuoka, 411-8777, Japan
| | - Shuichi Hironaka
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan
| | - Narikazu Boku
- Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, 4-6-1 Shiroganedai, Minato-Ku, Tokyo, 108-8639, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-Ku Nagoya 464-8681, Aichi, Japan
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11
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Lee WJA, Chung WP, Shao SC, Lai ECC, Chen YC, Ho CH. Risk of retinal vein occlusion in colorectal cancer patients receiving anti-vascular endothelial growth factors - a population-based cohort study. BMC Cancer 2023; 23:545. [PMID: 37316803 DOI: 10.1186/s12885-023-11037-4] [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: 11/19/2022] [Accepted: 06/03/2023] [Indexed: 06/16/2023] Open
Abstract
BACKGROUND Anti-vascular endothelial growth factors (VEGFs) treatment has been associated with an increased risk of thromboembolic events. Therefore, the use of anti-VEGFs for patients with colorectal cancers (CRC) has raised concerns about the potential risk of retinal vein occlusion (RVO), an ocular disease caused by embolism or venous stasis. This study aims to evaluate the risk of RVO in patients with CRC treated with anti-VEGFs. METHOD We conducted a retrospective cohort study using the Taiwan Cancer Registry and National Health Insurance Database. The study cohort comprised patients newly diagnosed with CRC between 2011 and 2017, who received anti-VEGF treatment. For each patient in the study cohort, a control group comprising four patients newly diagnosed with CRC, but not receiving anti-VEGF treatment, was randomly selected. A washout period of 12 months was implemented to identify new cases. The index date was defined as the date of the first prescription of anti-VEGF drugs. The study outcome was the incidence of RVO, as identified by ICD-9-CM (362.35 and 362.36) or ICD-10-CM codes (H3481 and H3483). Patients were followed from their index date until the occurrence of RVO, death or the end of the study period. Covariates, including patients' age at index date, sex, calendar year of CRC diagnosis, stage of CRC and comorbidities related to RVO, were included. Multivariable Cox proportional hazards regression models were used to calculate hazard ratios (HRs) with adjustments for all covariates to compare the risk of RVO between the anti-VEGF and control groups. RESULTS We recruited 6285 patients in the anti-VEGF group and 37,250 patients in the control group, with mean ages of 59.49 ± 12.11 and 63.88 ± 13.17 years, respectively. The incidence rates were 1.06 per 1000 person-years for the anti-VEGF group, and 0.63 per 1000 person-years for the controls. There was no statistically significant difference in RVO risk between the anti-VEGF and control groups (HR: 2.21, 95% CI: 0.87-5.61). CONCLUSION Our results indicated no association between use of anti-VEGF and occurrence of RVO among CRC patients, although the crude incidence rate of RVO was higher in patients receiving anti-VEGF, compared to control patients. Future study with larger sample size is required to confirm our findings.
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Affiliation(s)
- Wan-Ju Annabelle Lee
- Department of Ophthalmology, Chi Mei Medical Center, Tainan, Taiwan
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Wei-Pang Chung
- Department of Oncology, College of Medicine, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
- Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan
| | - Shih-Chieh Shao
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Department of Pharmacy, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Edward Chia-Cheng Lai
- School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Chen Chen
- Department of Medical Research, Chi Mei Medical Center, No 901, Zhonghua Road, Yongkang District, Tainan, 710, Taiwan
| | - Chung-Han Ho
- Department of Medical Research, Chi Mei Medical Center, No 901, Zhonghua Road, Yongkang District, Tainan, 710, Taiwan.
- Department of Information Management, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
- Cancer Center, Taipei Municipal Wanfang Hospital, Taipei Medical University, Taipei, Taiwan.
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12
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Dinu IM, Mihăilă M, Diculescu MM, Croitoru VM, Turcu-Stiolica A, Bogdan D, Miron MI, Lungulescu CV, Alexandrescu ST, Dumitrașcu T, Buică F, Luca IN, Lungulescu C, Negulescu MC, Gramaticu IM, Cazacu IM, Croitoru AE. Bevacizumab Treatment for Metastatic Colorectal Cancer in Real-World Clinical Practice. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:350. [PMID: 36837551 PMCID: PMC9963555 DOI: 10.3390/medicina59020350] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/02/2023] [Accepted: 02/10/2023] [Indexed: 02/16/2023]
Abstract
Background and Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality and morbidity worldwide. Bevacizumab was approved for the treatment of metastatic colorectal cancer (mCRC) based on favorable benefit-risk assessments from randomized controlled trials, but evidence on its use in the real-world setting is limited. The aim of the current study is to evaluate the outcomes and safety profile of bevacizumab in mCRC in a real-world setting in Romania. Patients and Methods: This was an observational, retrospective, multicentric, cohort study conducted in Romania that included patients with mCRC treated with bevacizumab as part of routine clinical practice. Study endpoints were progression-free survival, overall survival, adverse events, and patterns of bevacizumab use. Results: A total of 554 patients were included in the study between January 2008 and December 2018. A total of 392 patients (71%) received bevacizumab in the first line and 162 patients (29%) in the second line. Bevacizumab was mostly combined with a capecitabine/oxaliplatin chemotherapy regimen (31.6%). The median PFS for patients treated with bevacizumab was 8.4 months (interquartile range [IQR], 4.7-15.1 months) in the first line and 6.6 months (IQR, 3.8-12.3 months) in the second line. The median OS was 17.7 months (IQR, 9.3-30.6 months) in the first line and 13.5 months (IQR, 6.7-25.2 months) in the second line. Primary tumor resection was associated with a longer PFS and OS. The safety profile of bevacizumab combined with chemotherapy was similar to other observational studies in mCRC. Conclusions: The safety profile of bevacizumab was generally as expected. Although the PFS was generally similar to that reported in other studies, the OS was shorter, probably due to the less frequent use of bevacizumab after disease progression and the baseline patient characteristics. Patients with mCRC treated with bevacizumab who underwent resection of the primary tumor had a higher OS compared to patients with an unresected primary tumor.
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Affiliation(s)
- Ioana Mihaela Dinu
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Mariana Mihăilă
- Department of Internal Medicine, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Mircea Mihai Diculescu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Gastroenterology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Vlad Mihai Croitoru
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Adina Turcu-Stiolica
- Department of Pharmacoeconomics, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
| | - Diana Bogdan
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Monica Ionela Miron
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Cristian Virgil Lungulescu
- Department of Oncology, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania
- Department of Oncology, County Clinical Emergency Hospital, 200642 Craiova, Romania
| | - Sorin Tiberiu Alexandrescu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Surgery, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Traian Dumitrașcu
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Department of Surgery, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Florina Buică
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, Titu Maiorescu University, 031593 Bucharest, Romania
| | - Ioana Niculina Luca
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Cristina Lungulescu
- Department of Oncology, County Clinical Emergency Hospital, 200642 Craiova, Romania
| | | | | | - Irina Mihaela Cazacu
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Adina Emilia Croitoru
- Department of Oncology, Fundeni Clinical Institute, 022328 Bucharest, Romania
- Department of Surgery, Fundeni Clinical Institute, 022328 Bucharest, Romania
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13
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Current Targeted Therapy for Metastatic Colorectal Cancer. Int J Mol Sci 2023; 24:ijms24021702. [PMID: 36675216 PMCID: PMC9864602 DOI: 10.3390/ijms24021702] [Citation(s) in RCA: 60] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 01/07/2023] [Accepted: 01/13/2023] [Indexed: 01/17/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer deaths worldwide. Surgery or surgery plus radiotherapy and/or chemotherapy for patients with metastatic CRC (mCRC) were accepted as the main therapeutic strategies until the early 2000s, when targeted drugs, like cetuximab and bevacizumab, were developed. The use of targeted drugs in clinical practice has significantly increased patients' overall survival. To date, the emergence of several types of targeted drugs has opened new possibilities and revealed new prospects for mCRC treatment. Therapeutic strategies are continually being updated to select the most suitable targeted drugs based on the results of clinical trials that are currently underway. This review discusses the up-to date molecular evidence of targeted therapy for mCRC and summarizes the Food and Drug Administration-approved targeted drugs including the results of clinical trials. We also explain their mechanisms of action and how these affect the choice of a suitable targeted therapy.
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14
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Adashek JJ, Subbiah V, Westphalen CB, Naing A, Kato S, Kurzrock R. Cancer: slaying the nine-headed Hydra. Ann Oncol 2023; 34:61-69. [PMID: 35931318 PMCID: PMC10923524 DOI: 10.1016/j.annonc.2022.07.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/17/2022] [Accepted: 07/22/2022] [Indexed: 02/03/2023] Open
Abstract
Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance.
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Affiliation(s)
- J J Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore.
| | - V Subbiah
- The University of Texas MD Anderson Cancer Center, Houston, USA
| | - C B Westphalen
- Comprehensive Cancer Center Munich and Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - A Naing
- The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S Kato
- Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California, San Diego
| | - R Kurzrock
- WIN Consortium, San Diego; MCW Cancer Center, Milwaukee; University of Nebraska, Omaha, USA.
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15
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Zhang P, Mao R, Zhang C, Qiu Y, Chen M. Gastrointestinal injury induced by immunomodulators: A review article. Therap Adv Gastroenterol 2023; 16:17562848231158549. [PMID: 37113189 PMCID: PMC10126616 DOI: 10.1177/17562848231158549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 02/02/2023] [Indexed: 04/29/2023] Open
Abstract
An increasing number of immunomodulators, either anti-inflammatory or immunity-enhancing, have brought about a revolutionary effect in the management of a variety of autoimmune disorders and malignancies. However, their ability to cause gastrointestinal (GI) injury and induce GI symptoms has been increasingly and unexpectedly recognized. GI injury associated with immunomodulators may demonstrate various histologic and endoscopic patterns. Optimal diagnosis and treatment require a multidisciplinary approach. This review aims to provide an overview of the literature on its pathogenesis, the clinical, endoscopic, and histologic features, and suggested approaches to manage these newly recognized immunomodulator-induced GI adverse effects (AEs). We also reviewed current biomarkers predictive of GI toxicity and potential risk factors to identify susceptible patients. In addition, these immune-mediated AEs were compared with inflammatory bowel disease, a well-documented form of inflammation-driven GI injury. We hope this review will raise awareness and vigilance among clinicians of these entities to increase early diagnosis and rapid referral to specialist care.
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Affiliation(s)
- Pingxin Zhang
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | - Ren Mao
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | - Chuhan Zhang
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
| | | | - Minhu Chen
- Department of Gastroenterology, The First
Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province,
China
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16
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Zhang R, Gan W, Zong J, Hou Y, Zhou M, Yan Z, Li T, Lv S, Zeng Z, Wang W, Zhang F, Yang M. Developing an m5C regulator-mediated RNA methylation modification signature to predict prognosis and immunotherapy efficacy in rectal cancer. Front Immunol 2023; 14:1054700. [PMID: 36911744 PMCID: PMC9992543 DOI: 10.3389/fimmu.2023.1054700] [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: 09/27/2022] [Accepted: 02/09/2023] [Indexed: 02/24/2023] Open
Abstract
Background Currently, a very small number of patients with colorectal cancer (CRC) respond to immune checkpoint inhibitor (ICI) treatment. Therefore, there is an urgent need to investigate effective biomarkers to determine the responsiveness to ICI treatment. Recently, aberrant 5-methylcytosine (m5C) RNA modification has emerged as a key player in the pathogenesis of cancer. Thus, we aimed to explore the predictive signature based on m5C regulator-related genes for characterizing the immune landscapes and predicting the prognosis and response to therapies. Methods The Cancer Genome Atlas (TCGA) cohort was used as the training set, while GEO data sets, real-time quantitative PCR (RT-qPCR) analysis from paired frozen tissues, and immunohistochemistry (IHC) data from tissue microarray (TMA) were used for validation. We constructed a novel signature based on three m5C regulator-related genes in patients with rectal adenocarcinoma (READ) using a least absolute shrinkage and selection operator (LASSO)-Cox regression and unsupervised consensus clustering analyses. Additionally, we correlated the three-gene signature risk model with the tumor immune microenvironment, immunotherapy efficiency, and potential applicable drugs. Results The m5C methylation-based signature was an independent prognostic factor, where low-risk patients showed a stronger immunoreactivity phenotype and a superior response to ICI therapy. Conversely, the high-risk patients had enriched pathways of cancer hallmarks and presented immune-suppressive state, which demonstrated that they are more insensitive to immunotherapy. Additionally, the signature markedly correlated with drug susceptibility. Conclusions We developed a reliable m5C regulator-based risk model to predict the prognosis, clarify the molecular and tumor microenvironment status, and identify patients who would benefit from immunotherapy or chemotherapy. Our study could provide vital guidance to improve prognostic stratification and optimize personalized therapeutic strategies for patients with rectal cancer.
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Affiliation(s)
- Rixin Zhang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenqiang Gan
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jinbao Zong
- Clinical Laboratory, The Affiliated Hospital of Qingdao University, Qingdao, China.,Qingdao Hospital of Traditional Chinese Medicine, The Affiliated Qingdao Hiser Hospital of Qingdao University, Qingdao, China
| | - Yufang Hou
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Mingxuan Zhou
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Yan
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tiegang Li
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Silin Lv
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zifan Zeng
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weiqi Wang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fang Zhang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min Yang
- State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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17
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Jang HR, Lee HY, Song SY, Lim KH. Clinical outcomes of targeted therapies in elderly patients aged ≥ 80 years with metastatic colorectal cancer. World J Clin Cases 2022; 10:10066-10076. [PMID: 36246797 PMCID: PMC9561573 DOI: 10.12998/wjcc.v10.i28.10066] [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: 06/07/2022] [Revised: 07/26/2022] [Accepted: 08/17/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The 5-fluorouracil-based chemotherapy combined with oxaliplatin or irinotecan is usually used in colorectal cancer (CRC). The addition of a targeted agent (TA) to this combination chemotherapy is currently the standard treatment for metastatic CRC. However, the efficacy and safety of combination chemotherapy for metastatic CRC in patients aged above 80 years has yet to be established.
AIM To assess the clinical outcomes and feasibility of combination chemotherapy using a TA in extremely elderly patients with CRC.
METHODS Eligibility criteria were: (1) Age above 80 years; (2) Metastatic colorectal cancer; (3) Palliative chemotherapy naïve; (4) Eastern Cooperative Oncology Group performance status 0-1; and (5) Adequate organ function. Patients received at least one dose of combination chemotherapy with or without TA. Response was evaluated every 8 wk.
RESULTS Of 30 patients, the median age of 15 patients treated with TA was 83.0 years and that of those without TA was 81.3 years. The median progression-free survival (PFS) and overall survival (OS) in patients treated with TA were 7.4 mo and 15.4 mo, respectively, compared with 4.4 mo and 15.6 mo, respectively, in patients treated without TA. There was no significant difference in PFS (P: 0.193) and OS (P: 0.748) between patients treated with and without TA. Common grade 3/4 hematologic toxicities were anemia (16.7%) and neutropenia (10.0%). After disease progression, the median OS of patients who were treated with and without salvage chemotherapy were 23.5 mo and 7.0 mo, respectively, suggesting significant difference in OS (P = 0.001).
CONCLUSION Combination chemotherapy with TA for metastatic CRC may be considered feasible in patients aged above 80 years, when with careful caution. Salvage chemotherapy can help improve OS in some selected of these elderly patients.
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Affiliation(s)
- Hee Ryeong Jang
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
| | - Hui-Young Lee
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
| | - Seo-Young Song
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
| | - Kyu-Hyoung Lim
- Department of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon-si, Gangwon-do 24289, South Korea
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18
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Feng AW, Guo JH, Gao S, Kou FX, Liu SX, Liu P, Chen H, Wang XD, Xu HF, Cao G, Zhu X. A randomized phase II trial of hepatic arterial infusion of oxaliplatin plus raltitrexed versus oxaliplatin plus 5-fluorouracil for unresectable colorectal cancer liver metastases. Front Oncol 2022; 12:913017. [PMID: 36212504 PMCID: PMC9532863 DOI: 10.3389/fonc.2022.913017] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 08/29/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND The purpose was to compare the efficacy and safety of hepatic arterial infusion (HAI) of oxaliplatin plus raltitrexed (TOMOX) to those of oxaliplatin plus 5-fluorouracil (FOLFOX) for unresectable colorectal cancer liver metastases (CRCLM). METHODS Patients with unresectable CRCLM were randomly assigned to receive HAI of TOMOX or FOLFOX. The primary end points were progression-free survival (PFS) measured from the date of randomisation until the date of disease progression and objective response rate (ORR). The secondary end points were overall survival (OS) measured from the date of randomisation until the date of death from any cause, disease control rate (DCR), and adverse events. RESULTS 113 patients were randomly assigned. With a median follow-up of 39.5 months, the PFS was 5.8 months [95% CI, 4.838-6.762]) and 4.6 months [95% CI, 3.419-5.781; P = 0.840], and the median OS was 17.6 months [95% CI, 13.828-21.372] and 13.1 months [95% CI, 11.215-14.985; P = 0.178] for the FOLFOX and TOMOX arm, respectively. The ORR were 26.1% vs 22.4% and DCR were 80.4% vs 71.4% in the FOLFOX and TOMOX arms. The most common severe adverse event was elevation of liver enzymes and pain, which did not differ in the two arms. CONCLUSION HAI chemotherapy was effective for unresectable CRCLM. HAI of FOLFOX has similar efficacy to TOMOX, and HAI of TOMOX had shorter arterial infusion time. CLINICAL TRIAL REGISTRATION https://clinicaltrials.gov/, identifier NCT02557490.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Xu Zhu
- Department of Interventional Therapy, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
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Wu H, Ma T, Li D, He M, Wang H, Cui Y. Circulating vascular endothelial growth factor and cancer risk: A bidirectional mendelian randomization. Front Genet 2022; 13:981032. [PMID: 36159967 PMCID: PMC9489904 DOI: 10.3389/fgene.2022.981032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
In observational studies, circulating vascular endothelial growth factor (VEGF) has been reported to be associated with certain types of cancer. The purpose of this study was to verify whether there is a causal relationship between circulating VEGF and different types of cancer and the direction of the causal relationship. Summary statistical data were obtained from the corresponding genome-wide association studies (GWASs) to investigate the causal relationship between circulating VEGF and the risk of several cancers, including breast cancer, ovarian cancer, lung cancer, colorectal cancer, anus and anal canal cancer, prostate cancer, esophageal cancer, kidney cancer, bladder cancer, thyroid cancer, malignant neoplasm of the brain and malignant neoplasm of the liver and intrahepatic bile ducts. A two-sample bidirectional Mendelian randomization (MR) analysis and sensitivity tests were used to evaluate the validity of causality. A causal relationship was detected between circulating VEGF and colorectal cancer (OR 1.21, 95% CI 1.11–1.32, p < 0.000) and colon adenocarcinoma (OR 1.245, 95% CI 1.10–1.412, p < 0.000). Suggestive evidence of association was detected in VEGF on malignant neoplasms of the rectum (OR 1.16, 95% CI 1.00–1.34, p = 0.049). No causal relationship was found between circulating VEGF and other types of cancer, nor was there a reverse causal relationship from tumors to VEGF (p > 0.05). Circulating VEGF has a causal relationship with specific types of cancer. Our findings highlight and confirm the importance of circulating VEGF in the prevention and treatment of colorectal cancer.
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Affiliation(s)
- Hong Wu
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Tianjun Ma
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Dongli Li
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Mei He
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
| | - Hui Wang
- Department of Orthopaedic Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- *Correspondence: Hui Wang, ; Ying Cui,
| | - Ying Cui
- Department of Research, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, China
- *Correspondence: Hui Wang, ; Ying Cui,
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20
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Xu Z, Teng F, Hao X, Li J, Xing P. Bevacizumab Combined with Continuation of EGFR-TKIs in NSCLC Beyond Gradual Progression. Cancer Manag Res 2022; 14:1891-1902. [PMID: 35693116 PMCID: PMC9176636 DOI: 10.2147/cmar.s363446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 05/28/2022] [Indexed: 11/23/2022] Open
Affiliation(s)
- Ziyi Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Fei Teng
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Xuezhi Hao
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Junling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
- Correspondence: Junling Li; Puyuan Xing, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China, Email ;
| | - Puyuan Xing
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
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21
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Murphy AD, Morgan RD, Clamp AR, Jayson GC. The role of vascular endothelial growth factor inhibitors in the treatment of epithelial ovarian cancer. Br J Cancer 2022; 126:851-864. [PMID: 34716396 PMCID: PMC8927157 DOI: 10.1038/s41416-021-01605-5] [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: 05/10/2021] [Revised: 09/21/2021] [Accepted: 10/13/2021] [Indexed: 12/09/2022] Open
Abstract
Advanced epithelial ovarian, fallopian tube and primary peritoneal cancers (EOC) are a leading cause of gynaecological cancer-associated mortality and angiogenesis plays a key role in their growth. Vascular endothelial growth factor inhibitors (VEGFi) disrupt angiogenesis and improve the response rate, progression-free survival and in some cases, overall survival, when administered with and following cytotoxic chemotherapy, irrespective of the platinum sensitivity of EOC. Recent data have identified new indications for VEGFi in EOC: repeated exposure to VEGFi in the first- and then second-line treatment has sustained clinical efficacy; combinations of VEGFi with poly (ADP-ribose) polymerase inhibitors (PARPi) have proven effective as first-line or second-line maintenance regimens. However, recent trial data have not shown improved outcomes with combinations of VEGFi and immune checkpoint inhibitors. There remains a critical need to optimise patient selection for these effective yet somewhat toxic and expensive treatments. The search continues for validated biomarkers to optimise the use of VEGFi, of which the most promising at present is plasma Tie2. Based upon these studies, we propose a model of care incorporating VEGFi into the treatment of EOC, highlighting the need to change from the prescription of single courses of VEGFi, to allow use and re-use as clinically indicated.
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Affiliation(s)
| | - Robert D Morgan
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
- Division of Cancer Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Andrew R Clamp
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
- Division of Cancer Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
| | - Gordon C Jayson
- The Christie NHS Foundation Trust, Manchester, M20 4BX, UK
- Division of Cancer Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
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22
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Redman JM, Tsai YT, Weinberg BA, Donahue RN, Gandhy S, Gatti-Mays ME, Abdul Sater H, Bilusic M, Cordes L, Steinberg SM, Marte JL, Jochems C, Kim SS, Marshall JL, McMahon S, Redmond E, Schlom J, Gulley JL, Strauss J. A Randomized Phase II Trial of mFOLFOX6 + Bevacizumab Alone or with AdCEA Vaccine + Avelumab Immunotherapy for Untreated Metastatic Colorectal Cancer. Oncologist 2022; 27:198-209. [PMID: 35274710 PMCID: PMC8914498 DOI: 10.1093/oncolo/oyab046] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 11/05/2021] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND FOLFOX plus bevacizumab is a standard of care (SOC) for first-line treatment of microsatellite-stable metastatic colorectal cancer (MSS mCRC). This study randomized patients to SOC or SOC plus avelumab (anti-PD-L1) plus CEA-targeted vaccine. METHODS Patients with untreated MSS mCRC enrolled to a lead-in arm assessing safety of SOC + immuno-oncology agents (IO). Next, patients were randomized to SOC or SOC + IO. The primary endpoint was progression-free survival (PFS). Multiple immune parameters were analyzed. RESULTS Six patients enrolled to safety lead-in, 10 randomized to SOC, and 10 to SOC + IO. There was no difference in median PFS comparing SOC versus SOC + IO (8.8 months (95% CI: 3.3-17.0 months) versus 10.1 months (95% CI: 3.6-16.1 months), respectively; hazard ratio 1.061 [P = .91; 95% CI: 0.380-2.966]). The objective response rate was 50% in both arms. Of patients analyzed, most (8/11) who received SOC + IO developed multifunctional CD4+/CD8+ T-cell responses to cascade antigens MUC1 and/or brachyury, compared to 1/8 who received SOC alone (P = .020). We detected post-treatment changes in immune parameters that were distinct to the SOC and SOC + IO treatment arms. Accrual closed after an unplanned analysis predicted a low likelihood of meeting the primary endpoint. CONCLUSIONS SOC + IO generated multifunctional MUC1- and brachyury-specific CD4+/CD8+ T cells despite concurrent chemotherapy. Although a tumor-directed immune response is necessary for T-cell-mediated antitumor activity, it was not sufficient to improve PFS. Adding agents that increase the number and function of effector cells may be required for clinical benefit.
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Affiliation(s)
- Jason M Redman
- Corresponding author: Jason M. Redman, MD, Cancer Immunotherapy Program, Genitourinary Malignancies Branch and Laboratory of Tumor Immunology and Biology, Medical Oncology Service, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 13N240, Bethesda, MD 20892-1750, USA. Tel: +1 240-858-3305;
| | - Yo-Ting Tsai
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Benjamin A Weinberg
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Renee N Donahue
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shruti Gandhy
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Margaret E Gatti-Mays
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Houssein Abdul Sater
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Marijo Bilusic
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lisa M Cordes
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Office of the Clinical Director, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jennifer L Marte
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Caroline Jochems
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sunnie S Kim
- University of Colorado Cancer Center, Aurora, CO, USA
| | - John L Marshall
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA
| | - Sheri McMahon
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Erica Redmond
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jeffrey Schlom
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - James L Gulley
- Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Julius Strauss
- Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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23
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Treatment-driven tumour heterogeneity and drug resistance: lessons from solid tumours. Cancer Treat Rev 2022; 104:102340. [DOI: 10.1016/j.ctrv.2022.102340] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 01/16/2022] [Accepted: 01/17/2022] [Indexed: 02/07/2023]
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Comparison of safety and efficacy of fluorouracil + oxaliplatin + irinotecan (FOLFOXIRI) and modified FOLFOXIRI with bevacizumab for metastatic colorectal cancer: data from clinical practice. Int J Colorectal Dis 2022; 37:337-348. [PMID: 34767074 DOI: 10.1007/s00384-021-04064-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/05/2021] [Indexed: 02/04/2023]
Abstract
PURPOSE The efficacy of fluorouracil + oxaliplatin + irinotecan with bevacizumab (FOLFOXIRI + BV) has been verified for metastatic colorectal cancer (mCRC). In clinical practice, the original (O-FOLFOXIRI + BV) and modified dose settings (M-FOLFOXIRI + BV) are adopted for Asian patients. We aimed to compare the real-world efficacy and safety of these two regimens. METHODS This retrospective cohort study reviewed clinical data of all consecutive mCRC patients treated with FOLFOXIRI + BV at a cancer centre in Japan. One hundred patients were divided into two groups: one that received O-FOLFOXIRI + BV (group O, n = 30) and another that received M-FOLFOXIRI + BV (group M, n = 70). Progression-free survival (PFS) was set as the primary endpoint, with overall survival (OS), overall response rate (ORR), and safety as secondary endpoints. RESULTS PFS was superior in group M (median PFS; 8.7 vs. 11.5 months, P = 0.098). The use of O-FOLFOXIRI + BV emerged as an independent risk factor of poor PFS (hazard ratio = 2.155, P = 0.012). Both ORR (43.3 vs. 65.7%, P = 0.047) and OS (median OS; 17.9 vs. 27.0 months, P = 0.127) were more favourable in group M. Grade ≥ 3 adverse events were more frequently observed in group O (90 vs. 74.3%, P = 0.108), whereas dose intensity was higher in group M because a shorter duration was required for cytotoxic drug administration (2.9 vs. 2.6 weeks/course, P = 0.051) in the induction term. CONCLUSION We found that M-FOLFOXIRI + BV had more favourable efficacy and safety than O-FOLFOXIRI + BV, which may be a better fit for Asian patients and can be potentially used as an alternative for upfront chemotherapy for mCRC.
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25
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Ostlund T, Alotaibi F, Kyeremateng J, Halaweish H, Kasten A, Iram S, Halaweish F. Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer. Steroids 2022; 177:108950. [PMID: 34933058 DOI: 10.1016/j.steroids.2021.108950] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 11/08/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
1,2,3-triazoles have continuously shown effectiveness as biologically active systems towards various cancers, and when used in combination with steroid skeletons as a carrier, which can act as a drug delivery system, allows for a creation of a novel set of analogs that may be useful as a pharmacophore leading to a potential treatment option for cancer. A common molecular target for cancer inhibition is that of the Epidermal Growth Factor Receptor/Mitogen Activated Protein Kinase pathways, as inhibition of these proteins is associated with a decrease in cell viability. Estradiol-Triazole analogs were thus designed using a molecular modeling approach. Thirteen of the high scoring analogs were then synthesized and tested in-vitro on an ovarian cancer cell line (A2780) and colorectal cancer cell line (HT-29). The most active compound, Fz25, shows low micromolar activity in both the ovarian (15.29 ± 2.19 µM) and colorectal lines (15.98 ± 0.39 µM). Mechanism of action studies proved that Fz25 moderately arrests cells in the G1 phase of the cell cycle, specifically inhibiting STAT3 in both cell lines. Additionally, Fz57 shows activity in the colorectal line (24.19 ± 1.37 µM). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR, STAT3, ERK, and mTOR. To further study their effects as therapeutics, Fz25 and Fz57 were studied against drug efflux proteins, which are associated with drug resistance, and were found to inhibit the ABC transporter P-glycoprotein. We can conclude that these estradiol-triazole analogs provide a key for future studies targeting protein inhibition and drug resistance in cancer.
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Affiliation(s)
- Trevor Ostlund
- Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD 57007, United States
| | - Faez Alotaibi
- Department of Chemistry & Biochemistry, North Dakota State University, Fargo, ND 58105, United States
| | - Jennifer Kyeremateng
- Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD 57007, United States
| | - Hossam Halaweish
- Division of Basic & Translational Research, Department of Surgery, University of Minnesota, 420 Delaware St SE. MMC 195, Minneapolis, MN 55455, United States
| | - Abigail Kasten
- Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD 57007, United States
| | - Surtaj Iram
- Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD 57007, United States
| | - Fathi Halaweish
- Department of Chemistry & Biochemistry, South Dakota State University, Brookings, SD 57007, United States.
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26
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Howe JR. The impact of DNA testing on management of patients with colorectal cancer. Ann Gastroenterol Surg 2022; 6:17-28. [PMID: 35106411 PMCID: PMC8786701 DOI: 10.1002/ags3.12526] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/18/2021] [Accepted: 10/28/2021] [Indexed: 12/15/2022] Open
Abstract
Knowledge of the genetic basis of colorectal cancer has evolved over the past decades, allowing for the pre-symptomatic identification of affected patients in those with familial syndromes and to the understanding of the multi-step progression to carcinogenesis in tumors. Knowledge of the genes and pathways involved in colorectal cancer has allowed for targeted therapies in patients in addition to standard chemotherapy for those with metastases. Next-generation sequencing technologies have now also allowed for the sensitive detection of circulating mutations derived from tumors, which can give insight into the presence of residual disease and has implications for changing the standard paradigms for treatment. This article will specifically review advances in targeted therapy in metastatic colon cancer and the progress being made in using circulating tumor DNA in patient management.
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Affiliation(s)
- James R. Howe
- Department of SurgeryUniversity of Iowa Carver College of MedicineIowa CityIowaUSA
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27
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Mennitto A, Zattarin E, Di Maio M, Bimbatti D, De Giorgi U, Buti S, Santini D, Casadei C, Sorarù M, Messina C, Mucciarini C, Di Lorenzo G, Roviello G, Buttigliero C, Stellato M, Sepe P, Claps M, Guadalupi V, Ottini A, Pignata S, De Braud FG, Verzoni E, Procopio G. Cabozantinib beyond progression improves survival in advanced renal cell carcinoma patients: the CABEYOND study (Meet-URO 21). Expert Rev Anticancer Ther 2022; 22:115-121. [PMID: 34738499 DOI: 10.1080/14737140.2022.2002688] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 10/25/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Cabozantinib improves survival in metastatic renal cell carcinoma (mRCC) after prior antiangiogenics. The best treatment at disease progression (PD) is unknown. Being also a AXL/MET inhibitor, involved in acquired resistance, we hypothesized a prolonged tumor growth control in patients continuing cabozantinib despite PD. RESEARCH DESIGN AND METHODS This retrospective multicenter study enrolled patients receiving cabozantinib after the first line between 2014 and 2020. We compared patients maintaining cabozantinib after first PD due to clinical benefit and good tolerability with those who changed therapy. The postprogression survival (PPS) of both was our primary endpoint. RESULTS We analyzed 89 patients: 45 received cabozantinib beyond PD and 44 switched therapy. 40.4%, 31.5%, and 28.1% of patients received 1, 2, or >2 prior treatment, respectively. 84.3% were intermediate-poor International Metastatic Renal Cell Carcinoma Database risk. Patients continuing cabozantinib showed a higher response rate to cabozantinib before PD (46.7% vs 25%, p = 0.03) and were more heavily pretreated. Continuing cabozantinib showed a significantly longer PPS compared with switching therapy (median PPS 16.9 vs 13.2 months, HR 0.66, 95%CI 0.48-0.92, p = 0.011). CONCLUSIONS We observed longer PPS in patients continuing cabozantinib beyond PD, suggesting that this could be an effective option.
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Affiliation(s)
- Alessia Mennitto
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
| | - Emma Zattarin
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Turin, Ordine Mauriziano Hospital, Turin, Italy
| | - Davide Bimbatti
- Medical Oncology 1 Unit, Department of Oncology, Istituto Oncologico Veneto Iov Irccs, Padua, Italy
| | - Ugo De Giorgi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per Lo Studio E La Cura Dei Tumori (Irst), Irccs, Meldola, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Daniele Santini
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Chiara Casadei
- Department of Medical Oncology, Istituto Scientifico Romagnolo per Lo Studio E La Cura Dei Tumori (Irst), Irccs, Meldola, Italy
| | - Mariella Sorarù
- Medical Oncology, Camposampiero Hospital, Camposampiero (Padua), Italy
| | - Carlo Messina
- Department of Medical Oncology, Santa Chiara Hospital, Trento, Italy
| | | | - Giuseppe Di Lorenzo
- Oncology Unit, Andrea Tortora Hospital, ASL Salerno, Pagani, Italy
- Department of Medicine and Health Sciences Vincenzo Tiberio, University of Molise, Campobasso, Italy
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | | | - Marco Stellato
- Department of Medical Oncology, Campus Bio-Medico University of Rome, Rome, Italy
| | - Pierangela Sepe
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
| | - Melanie Claps
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
| | - Valentina Guadalupi
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
| | - Arianna Ottini
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
| | - Sandro Pignata
- Department of Urology and Gynecology, Istituto Nazionale Tumori Irccs Fondazione "G. Pascale", Naples, Italy
| | - Filippo G De Braud
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
- Oncology and Hemato-Oncology Department, University of Milan, Milan, Italy
| | - Elena Verzoni
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
| | - Giuseppe Procopio
- Department of Medical Oncology, Fondazione Irccs Istituto Nazionale Dei Tumori, Milan, Italy
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Shoji T, Enomoto T, Abe M, Okamoto A, Nagasawa T, Oishi T, Nagase S, Mori M, Inokuchi Y, Kamiura S, Komiyama S, Takeshima N, Sugiyama T. Efficacy and safety of standard of care with/without bevacizumab for platinum-resistant ovarian/fallopian tube/peritoneal cancer previously treated with bevacizumab: The Japanese Gynecologic Oncology Group study JGOG3023. Cancer Sci 2021; 113:240-250. [PMID: 34716979 PMCID: PMC8748228 DOI: 10.1111/cas.15185] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/04/2021] [Accepted: 10/20/2021] [Indexed: 11/28/2022] Open
Abstract
We investigated the efficacy and safety of further bevacizumab therapy in patients with platinum-resistant ovarian cancer whose disease had progressed after bevacizumab plus chemotherapy. In this multicenter, open-label, phase II trial (JGOG3023), patients were randomized 1:1 to a single-agent chemotherapy alone (either pegylated liposomal doxorubicin [40 or 50 mg/m2 administered intravenously], topotecan [1.25 mg/m2 intravenously], paclitaxel [80 mg/m2 intravenously], or gemcitabine [1000 mg/m2 intravenously]) or single-agent chemotherapy + bevacizumab (15 mg/m2 intravenously). The primary endpoint was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary endpoints were overall survival (OS), objective response rate (ORR), and response rate according to Gynecological Cancer Intergroup cancer antigen 125 criteria. In total, 103 patients were allocated to chemotherapy (n = 51) or chemotherapy + bevacizumab (n = 52). Median investigator-assessed PFS was 3.1 and 4.0 mo in each group, respectively (hazard ratio [HR] = 0.54, 95% confidence interval [CI]: 0.32-0.90, P = .0082). Median OS was 11.3 and 15.3 mo in each group, respectively (HR = 0.67, 95% CI: 0.38-1.17, P = .1556). Respective ORRs were 13.7% and 25.0% (P = .0599) and response rates were 16.7% and 21.4% (P = .8273). The incidence of grade ≥3 treatment-related AEs was 42.0% in the chemotherapy group and 54.9% in the chemotherapy + bevacizumab group; AEs were well tolerated, with only 2 and 12 events leading to discontinuation of therapy, respectively. Bevacizumab was effective beyond progressive disease and AEs were manageable. The observed improvement in PFS requires further verification.
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Affiliation(s)
- Tadahiro Shoji
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Iwate, Japan
| | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Niigata University School of Medicine, Niigata, Japan
| | - Masakazu Abe
- Department of Gynecology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Aikou Okamoto
- Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan
| | - Takayuki Nagasawa
- Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Iwate, Japan
| | - Tetsuro Oishi
- Department of Obstetrics and Gynecology, Tottori University School of Medicine, Tottori, Japan
| | - Satoru Nagase
- Department of Obstetrics and Gynecology, Faculty of Medicine, Yamagata University, Yamagata, Japan
| | - Masahiko Mori
- Department of Gynecology, Aichi Cancer Center Hospital, Aichi, Japan
| | - Yuki Inokuchi
- Department of Biostatistics, Kitasato Academic Research Organization, Kitasato University, Tokyo, Japan
| | - Shoji Kamiura
- Department of Gynecologic Oncology, Osaka International Cancer Institute, Osaka, Japan
| | - Shinichi Komiyama
- Department of Obstetrics and Gynecology, Faculty of Medicine, Toho University, Tokyo, Japan
| | | | - Toru Sugiyama
- Department of Obstetrics and Gynecology, St. Mary's Hospital, Fukuoka, Japan
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Yamamoto S, Nagashima K, Kawakami T, Mitani S, Komoda M, Tsuji Y, Izawa N, Kawakami K, Yamamoto Y, Makiyama A, Yamazaki K, Masuishi T, Esaki T, Nakajima TE, Okuda H, Moriwaki T, Boku N. Second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab for patients with metastatic colorectal cancer. BMC Cancer 2021; 21:1159. [PMID: 34715820 PMCID: PMC8555183 DOI: 10.1186/s12885-021-08890-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 10/19/2021] [Indexed: 12/28/2022] Open
Abstract
Background The ML18174 study, which showed benefits of bevacizumab (BEV) continuation beyond progression (BBP) for metastatic colorectal cancer (mCRC), excluded patients with first-line progression-free survival (PFS) shorter than 3 months. The present study was conducted to evaluate the efficacy of second-line chemotherapy after early disease progression during first-line chemotherapy containing bevacizumab. Methods The subjects of this study were mCRC patients who experienced disease progression < 100 days from commencement of first-line chemotherapy containing BEV initiated between Apr 2007 and Dec 2016. Second-line chemotherapy regimens were classified into two groups with and without BEV/other anti-angiogenic agents (BBP and non-BBP) and efficacy and safety were compared using univariate and multivariate analysis. Results Sixty-one patients were identified as subjects of this study. Baseline characteristics were numerically different between BBP (n = 37) and non-BBP (n = 25) groups, such as performance status (0–1/> 2/unknown: 89/8/3 and 56/40/4%), RAS status (wild/mutant/unknown: 32/54/16 and 76/16/8%). Response rate was 8.6% in BBP group and 9.1% in non-BBP group (p = 1.00). Median PFS was 3.9 months in BBP group and 2.8 months in non-BBP group (HR [95%CI]: 0.79 [0.46–1.34], p = 0.373, adjusted HR: 0.87 [0.41–1.82], p = 0.707). Median overall survival was 8.5 months in BBP group and 5.4 months in non-BBP group (HR 0.66 [0.38–1.12], p = 0.125, adjusted HR 0.53 [0.27–1.07], p = 0.078). Conclusion In mCRC patients who experienced early progression in first-line chemotherapy, second-line chemotherapy showed poor clinical outcomes regardless use of anti-angiogenic agents. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08890-6.
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Affiliation(s)
- Shun Yamamoto
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 1040045, Japan.,Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 1040045, Japan
| | - Kengo Nagashima
- Research Center for Medical and Health Data Science, the Institute of Statistical Mathematics, Tokyo, 1908562, Japan
| | - Takeshi Kawakami
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, 4118777, Japan
| | - Seiichiro Mitani
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, 4648681, Japan
| | - Masato Komoda
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, 8111395, Japan
| | - Yasushi Tsuji
- Department of Medical Oncology, Tonan Hospital, Hokkaido, 0600004, Japan
| | - Naoki Izawa
- Department of Clinical Oncology, St. Marianna University School of Medical Hospital, Kanagawa, 2168511, Japan
| | - Kentaro Kawakami
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Hokkaido, 0030027, Japan
| | - Yoshiyuki Yamamoto
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, 3058575, Japan
| | - Akitaka Makiyama
- Department of Hematology/Oncology, Japan Community Healthcare Organization Kyushu Hospital, Fukuoka, 8068501, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, 4118777, Japan
| | - Toshiki Masuishi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Aichi, 4648681, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, 8111395, Japan
| | - Takako Eguchi Nakajima
- Department of Clinical Oncology, St. Marianna University School of Medical Hospital, Kanagawa, 2168511, Japan
| | - Hiroyuki Okuda
- Department of Medical Oncology, Keiyukai Sapporo Hospital, Hokkaido, 0030027, Japan
| | - Toshikazu Moriwaki
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Ibaraki, 3058575, Japan
| | - Narikazu Boku
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tsukiji 5-1-1, Chuo-ku, Tokyo, 1040045, Japan. .,Department of Medical Oncology and General Medicine, IMS Hospital, Institute of Medical Science, University of Tokyo, Tokyo, 1088639, Japan.
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Giordano G, Parcesepe P, Bruno G, Piscazzi A, Lizzi V, Remo A, Pancione M, D’Andrea MR, De Santis E, Coppola L, Pietrafesa M, Fersini A, Ambrosi A, Landriscina M. Evidence-Based Second-Line Treatment in RAS Wild-Type/Mutated Metastatic Colorectal Cancer in the Precision Medicine Era. Int J Mol Sci 2021; 22:7717. [PMID: 34299337 PMCID: PMC8307359 DOI: 10.3390/ijms22147717] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/05/2021] [Accepted: 07/09/2021] [Indexed: 02/08/2023] Open
Abstract
Target-oriented agents improve metastatic colorectal cancer (mCRC) survival in combination with chemotherapy. However, the majority of patients experience disease progression after first-line treatment and are eligible for second-line approaches. In such a context, antiangiogenic and anti-Epidermal Growth Factor Receptor (EGFR) agents as well as immune checkpoint inhibitors have been approved as second-line options, and RAS and BRAF mutations and microsatellite status represent the molecular drivers that guide therapeutic choices. Patients harboring K- and N-RAS mutations are not eligible for anti-EGFR treatments, and bevacizumab is the only antiangiogenic agent that improves survival in combination with chemotherapy in first-line, regardless of RAS mutational status. Thus, the choice of an appropriate therapy after the progression to a bevacizumab or an EGFR-based first-line treatment should be evaluated according to the patient and disease characteristics and treatment aims. The continuation of bevacizumab beyond progression or its substitution with another anti-angiogenic agents has been shown to increase survival, whereas anti-EGFR monoclonals represent an option in RAS wild-type patients. In addition, specific molecular subgroups, such as BRAF-mutated and Microsatellite Instability-High (MSI-H) mCRCs represent aggressive malignancies that are poorly responsive to standard therapies and deserve targeted approaches. This review provides a critical overview about the state of the art in mCRC second-line treatment and discusses sequential strategies according to key molecular biomarkers.
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Affiliation(s)
- Guido Giordano
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
| | - Pietro Parcesepe
- Department of Diagnostics and Public Health—Section of Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy;
| | - Giuseppina Bruno
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
| | - Annamaria Piscazzi
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
| | - Vincenzo Lizzi
- General Surgey Unit, Policlinico Riuniti, 71122 Foggia, Italy;
| | - Andrea Remo
- Pathology Unit “Mater Salutis” Hospital, ULSS9, Legnago, 37045 Verona, Italy;
| | - Massimo Pancione
- Department of Sciences and Technologies, University of Sannio, 82100 Benevento, Italy;
| | | | - Elena De Santis
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, 00185 Rome, Italy;
| | - Luigi Coppola
- UOC Anatomia ed Istologia Patologica e Citologia Diagnostica, Dipartimento dei Servizi Diagnostici e della Farmaceutica, Ospedale Sandro Pertini, ASL Roma 2, 00157 Roma, Italy;
| | - Michele Pietrafesa
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, 85028 Potenza, Italy;
| | - Alberto Fersini
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (A.F.); (A.A.)
| | - Antonio Ambrosi
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (A.F.); (A.A.)
| | - Matteo Landriscina
- Unit of Medical Oncology and Biomolecular Therapy, Department of Medical and Surgical Sciences, University of Foggia, Policlinico Riuniti, 71122 Foggia, Italy; (G.B.); (A.P.)
- Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture, 85028 Potenza, Italy;
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Ribatti D, Solimando AG, Pezzella F. The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer. Cancers (Basel) 2021; 13:cancers13143433. [PMID: 34298648 PMCID: PMC8304542 DOI: 10.3390/cancers13143433] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/24/2021] [Accepted: 07/06/2021] [Indexed: 02/07/2023] Open
Abstract
Resistance to anti-vascular endothelial growth factor (VEGF) molecules causes lack of response and disease recurrence. Acquired resistance develops as a result of genetic/epigenetic changes conferring to the cancer cells a drug resistant phenotype. In addition to tumor cells, tumor endothelial cells also undergo epigenetic modifications involved in resistance to anti-angiogenic therapies. The association of multiple anti-angiogenic molecules or a combination of anti-angiogenic drugs with other treatment regimens have been indicated as alternative therapeutic strategies to overcome resistance to anti-angiogenic therapies. Alternative mechanisms of tumor vasculature, including intussusceptive microvascular growth (IMG), vasculogenic mimicry, and vascular co-option, are involved in resistance to anti-angiogenic therapies. The crosstalk between angiogenesis and immune cells explains the efficacy of combining anti-angiogenic drugs with immune check-point inhibitors. Collectively, in order to increase clinical benefits and overcome resistance to anti-angiogenesis therapies, pan-omics profiling is key.
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Affiliation(s)
- Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy
- Correspondence: ; Tel.: +39-080-547832
| | - Antonio Giovanni Solimando
- Guido Baccelli Unit of Internal Medicine, Department of Biomedical Sciences and Human Oncology, School of Medicine, Aldo Moro University of Bari, 70124 Bari, Italy;
- IRCCS Istituto Tumori “Giovanni Paolo II” of Bari, 70124 Bari, Italy
| | - Francesco Pezzella
- Nuffield Division of Laboratory Science, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX39DU, UK;
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Clinical benefit of continuing pembrolizumab treatment beyond progression in patients with metastatic urothelial carcinoma. Cancer Immunol Immunother 2021; 71:229-236. [PMID: 34100985 DOI: 10.1007/s00262-021-02980-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/02/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND There has been no clinical evidence to justify continued pembrolizumab therapy beyond progression in patients with metastatic urothelial carcinoma (UC). MATERIALS AND METHODS We conducted a multicenter retrospective study evaluating the clinical efficacy of continued use of pembrolizumab beyond progression in patients with metastatic UC. Data from 51 patients with metastatic UC, who developed progression during second-line pembrolizumab therapy, were analyzed. Progression was defined based on the Immunotherapy Response Evaluation Criteria in Solid Tumors. The outcome was overall survival (OS). The association between continued treatment, OS, and the risk of all-cause mortality was tested using log-rank test, conventional and time-dependent Cox regression models. RESULTS No significant difference in patient characteristics was noted between patients continuing pembrolizumab beyond progression (N = 21) and those discontinuing pembrolizumab (N = 30). Median OS was significantly longer in the continuation group (17.8 vs. 8.8 months; P = 0.038). A multivariable conventional Cox regression model identified continued pembrolizumab administration as a significant independent prognostic factor of all-cause mortality (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.05-0.90, P = 0.036), irrespective of the time from treatment initiation to progression and concurrent clinical progression. Further, longer duration of pembrolizumab treatment beyond progression was independently associated with a reduced risk of all-cause mortality in a multivariable time-dependent Cox regression model, when used as a time-dependent variable (HR: 0.07, 95% CI: 0.01-0.45, P = 0.006). CONCLUSIONS Continued pembrolizumab administration beyond progression might be beneficial in patients with metastatic UC who were clinically stable.
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Dunn C, Hong W, Gibbs P, Ackland S, Sjoquist K, Tebbutt NC, Price T, Burge M. Personalizing First-Line Systemic Therapy in Metastatic Colorectal Cancer: Is There a Role for Initial Low-Intensity Therapy in 2021 and Beyond? A Perspective From Members of the Australasian Gastrointestinal Trials Group. Clin Colorectal Cancer 2021; 20:245-255. [PMID: 34103264 DOI: 10.1016/j.clcc.2021.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 04/16/2021] [Accepted: 05/02/2021] [Indexed: 01/18/2023]
Abstract
Palliative chemotherapy is the cornerstone of treatment for the majority of patients with metastatic colorectal cancer, with the aim of increasing length and quality of life. Although guidelines outline the available treatment options in the first line, they provide limited guidance on choice and intensity of the chemotherapy backbone. Data from the TRIBE and TRIBE2 studies confirm a survival benefit with triplet FOLFOXIRI and bevacizumab, and this is a preferred option for younger patients with good performance status able to tolerate it. However, the relative benefit of a fluoropyrimidine doublet with oxaliplatin or irinotecan over single-agent fluoropyrimidine with or without a biologic is less certain; the available data demonstrate that single-agent fluoropyrimidine plus a biologic with planned sequencing of subsequent agents can produce similar overall survival outcomes with reduced toxicity. Our analysis of local real-world registry data suggests that this is an underutilized approach, particularly in younger and fitter patients. Established prognostic factors, including patient age, performance status, tumor sidedness, and biomarkers such as RAS/BRAF, are key in treatment selection; patients with left-sided RAS/BRAF wild-type disease or patients with low tumor bulk may be ideal for a less intensive regimen. Further studies are required to confirm the value of less-intensive regimens in the modern era, where the incorporation of biologic therapies has become routine and where non-chemotherapy options are emerging as viable options for molecularly defined patient subsets.
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Affiliation(s)
- Catherine Dunn
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia.
| | - Wei Hong
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia
| | - Peter Gibbs
- Gibbs Lab, Personalised Medicine Division, Walter and Eliza Hall Institute, Melbourne, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia; Department of Medical Oncology, Western Health, Melbourne, Victoria, Australia
| | - Stephen Ackland
- Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia; Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Katrin Sjoquist
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia; Cancer Care Centre, St. George Hospital, Kogarah, New South Wales, Australia
| | - Niall C Tebbutt
- Department of Medical Oncology, Austin Health, Melbourne, Victoria, Australia; Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia
| | - Matthew Burge
- Department of Medical Oncology, Royal Brisbane Hospital, Herston, Queensland, Australia
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Lisby AN, Flickinger JC, Bashir B, Weindorfer M, Shelukar S, Crutcher M, Snook AE, Waldman SA. GUCY2C as a biomarker to target precision therapies for patients with colorectal cancer. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021; 6:117-129. [PMID: 34027103 DOI: 10.1080/23808993.2021.1876518] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction Colorectal cancer (CRC) is one of the most-deadly malignancies worldwide. Current therapeutic regimens for CRC patients are relatively generic, based primarily on disease type and stage, with little variation. As the field of molecular oncology advances, so too must therapeutic management of CRC. Understanding molecular heterogeneity has led to a new-found promotion for precision therapy in CRC; underlining the diversity of molecularly targeted therapies based on individual tumor characteristics. Areas covered We review current approaches for the treatment of CRC and discuss the potential of precision therapy in advanced CRC. We highlight the utility of the intestinal protein guanylyl cyclase C (GUCY2C), as a multi-purpose biomarker and unique therapeutic target in CRC. Here, we summarize current GUCY2C-targeted approaches for treatment of CRC. Expert opinion The GUCY2C biomarker has multi-faceted utility in medicine. Developmental investment of GUCY2C as a diagnostic and therapeutic biomarker offers a variety of options taking the molecular characteristics of cancer into account. From GUCY2C-targeted therapies, namely cancer vaccines, CAR-T cells, and monoclonal antibodies, to GUCY2C agonists for chemoprevention in those who are at high risk for developing colorectal cancer, the utility of this protein provides many avenues for exploration with significance in the field of precision medicine.
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Affiliation(s)
- Amanda N Lisby
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - John C Flickinger
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Babar Bashir
- Department of Medical Oncology, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Megan Weindorfer
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Sanjna Shelukar
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Madison Crutcher
- Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Adam E Snook
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
| | - Scott A Waldman
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, United States
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Yoshida Y, Yamada T, Kamiyama H, Kosugi C, Ishibashi K, Yoshida H, Ishida H, Yamaguchi S, Kuramochi H, Fukazawa A, Sonoda H, Yoshimatsu K, Matsuda A, Hasegawa S, Sakamoto K, Otsuka T, Koda K. Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study. Int J Clin Oncol 2021; 26:111-117. [PMID: 33083913 DOI: 10.1007/s10147-020-01794-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 09/22/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND TAS-102 improved the overall survival of metastatic colorectal cancer (CRC) patients with a median progression-free survival (PFS) in the RECOURSE trial. Subsequently, the combination of TAS-102 and bevacizumab was shown to extend the median PFS (C-TASK FORCE study). However, the study included patients who received second- and third-line treatment. Our study exclusively examined patients receiving this combination as a third-line treatment to investigate the clinical impact beyond cytotoxic doublets. METHODS This investigator-initiated, open-label, single-arm, multi-centered phase II study was conducted in Japan. Eligible CRC patients were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in first- and second-line therapy. TAS-102 (35 mg/m2) was given orally twice daily on days 1-5 and 8-12 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion every 2 weeks. The primary endpoint was PFS and the secondary endpoints were time-to-treatment failure, response rate, overall survival (OS), and safety. RESULTS Between June 2016 and August 2017, 32 patients were enrolled. All patients previously received bevacizumab. The median PFS was 4.5 months; the median overall survival was 9.3 months. Partial response was observed in two patients. The most common adverse events above grade 3 were neutropenia followed by thrombocytopenia. There were no non-hematological adverse events above grade 3 and no treatment-related deaths occurred. CONCLUSIONS This study met its primary endpoint of PFS, which is comparable to the results of the C-TASK FORCE study. The TAS-102 and bevacizumab combination has the potential to be a therapeutic option for third-line treatment of metastatic CRC.
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Affiliation(s)
- Yoichiro Yoshida
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
| | - Takeshi Yamada
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Hirohiko Kamiyama
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Chihiro Kosugi
- Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan
| | - Keiichiro Ishibashi
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Hideyuki Ishida
- Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Satoru Yamaguchi
- Department of Surgical Oncology, Dokkyo Medical University, Tochigi, Japan
| | - Hidekazu Kuramochi
- Department of Chemotherapy, Tokyo Women's Medical University Yachiyo Medical Center, Chiba, Japan
| | - Atsuko Fukazawa
- Department of Gastroenterological Surgery, Iwata City Hospital, Shizuoka, Japan
| | - Hiromichi Sonoda
- Department of Surgery, Shiga University of Medical Science, Shiga, Japan
| | | | - Akihisa Matsuda
- Department of Surgery, Nippon Medical School Chiba Hokuso Hospital, Chiba, Japan
| | - Suguru Hasegawa
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Kazuhiro Sakamoto
- Department of Coloproctological Surgery, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Toshiaki Otsuka
- Dept of Hygiene and Public Health, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, Chiba, Japan
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Jácome AA, Kee B, Fogelman D, Dasari A, Shureiqi I, Raghav K, Morris V, Johnson B, Overman M, Wolff R, Kopetz S, Rogers J, Ahmed SU, Mehdizadeh A, Rothschild N, Eng C. FOLFOXIRI Versus Doublet Regimens in Right-Sided Metastatic Colorectal Cancer: Focus on Subsequent Therapies and Impact on Overall Survival. Clin Colorectal Cancer 2020; 19:248-255.e6. [DOI: 10.1016/j.clcc.2020.05.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 05/14/2020] [Accepted: 05/26/2020] [Indexed: 12/14/2022]
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Goedegebuure RSA, Wentink MQ, van der Vliet HJ, Timmerman P, Griffioen AW, de Gruijl TD, Verheul HMW. A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26-104/RFASE in Patients with Advanced Solid Malignancies. Oncologist 2020; 26:e218-e229. [PMID: 33105058 PMCID: PMC7873342 DOI: 10.1002/onco.13576] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Accepted: 10/16/2020] [Indexed: 12/22/2022] Open
Abstract
LESSONS LEARNED The novel therapeutic vaccine hVEGF26-104 /RFASE was found to be safe and well tolerated in patients with cancer. hVEGF26-104 /RFASE failed to induce seroconversion against native hVEGF165 and, accordingly, neither a decrease in circulating vascular endothelial growth factor (VEGF) levels nor clinical benefit was observed. Remarkably, hVEGF26-104 /RFASE induced VEGF165 -neutralizing antibodies in a nonhuman primate model. The absence of seroconversion in human calls for caution in the interpretation of efficacy of human vaccines in nonhuman primates. BACKGROUND Targeting vascular endothelial growth factor-A (VEGF) is a well-established anticancer therapy. We designed a first-in-human clinical trial to investigate the safety and immunogenicity of the novel vaccine hVEGF26-104 /RFASE. METHODS Patients with advanced solid malignancies with no standard treatment options available were eligible for this phase I study with a 3+3 dose-escalation design. On days 0, 14, and 28, patients received intramuscular hVEGF26-104 , a truncated synthetic three-dimensional (3D)-structured peptide mimic covering the amino acids 26-104 of the human VEGF165 isoform, emulsified in the novel adjuvant Raffinose Fatty Acid Sulphate Ester (RFASE), a sulpholipopolysaccharide. Objectives were to determine safety, induction of VEGF-neutralizing antibodies, and the maximum tolerated dose. Blood was sampled to measure VEGF levels and antibody titers. RESULTS Eighteen of 27 enrolled patients received three immunizations in six different dose-levels up to 1,000 μg hVEGF26-104 and 40 mg RFASE. No dose-limiting toxicity was observed. Although in four patients an antibody titer against hVEGF26-104 was induced (highest titer: 2.77 10 log), neither a reduction in VEGF levels nor neutralizing antibodies against native VEGF165 were detected. CONCLUSION Despite having an attractive safety profile, hVEGF26-104 /RFASE was not able to elicit seroconversions against native VEGF165 and, consequently, did not decrease circulating VEGF levels. Deficient RFASE adjuvant activity, as well as dominant immunoreactivity toward neoepitopes, may have impeded hVEGF26-104 /RFASE's efficacy in humans.
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Affiliation(s)
- Ruben S A Goedegebuure
- Amsterdam UMC, VUmc location, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Madelon Q Wentink
- Amsterdam UMC, VUmc location, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Hans J van der Vliet
- Amsterdam UMC, VUmc location, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.,Lava Therapeutics, Utrecht, The Netherlands
| | | | - Arjan W Griffioen
- Amsterdam UMC, VUmc location, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Tanja D de Gruijl
- Amsterdam UMC, VUmc location, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Henk M W Verheul
- Radboud UMC, Department of Medical Oncology, Nijmegen, The Netherlands
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Kashiwa M, Matsushita R. Comparative Cost-effectiveness of Aflibercept and Ramucirumab in Combination with Irinotecan and Fluorouracil-based Therapy for the Second-line Treatment of Metastatic Colorectal Cancer in Japan. Clin Ther 2020; 42:1361-1375. [PMID: 32616433 DOI: 10.1016/j.clinthera.2020.05.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 03/31/2020] [Accepted: 05/19/2020] [Indexed: 11/22/2022]
Abstract
PURPOSE The addition of aflibercept (AFL) or ramucirumab (RAM) to folinic acid, fluorouracil, and irinotecan (FOLFIRI) prolongs overall survival and progression-free survival compared with FOLFIRI alone in patients with metastatic colorectal cancer (mCRC) as second-line therapy. Although these combination regimens are recommended among the standard therapies, significant additional cost is a concern. The comparative cost-effectiveness of AFL and RAM was examined from the perspective of the Japanese health care payer. METHODS A partitioned survival analysis was constructed. The data sources were the VELOUR (Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen) and RAISE (Ramucirumab Versus Placebo in Combination With Second-Line FOLFIRI in Patients With Metastatic Colorectal Carcinoma That Progressed During or After First-Line Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine) trials, which compared FOLFIRI alone with AFL or RAM in second-line treatment for mCRC. The cost and effectiveness of the combination of AFL or RAM with FOLFIRI were compared with those of FOLFIRI alone and examined between both agents in a 10-year time horizon. The health outcomes were life-years (LYs) and quality-adjusted life-years (QALYs). The costs were 2019 revisions to the drug prices and medical fees. The robustness of the model was verified by 1-way sensitivity analyses and a probability sensitivity analysis. A 2% annual discount was applied to the expenses and QALYs. A willingness-to-pay threshold of ¥7.5 million was used. FINDINGS Compared with FOLFIRI alone, combination AFL or RAM with FOLFIRI had incremental effects of 0.173 QALYs (0.253 LYs) and 0.137 QALYs (0.197 LYs), incremental costs of ¥3,423,481 (US $31,010) and ¥5,766,106 (US $52,229), and incremental cost-effectiveness ratios of ¥19, 836, 504 (US $179,678) and ¥41, 947, 989 (US $379,964) per QALY, respectively. Results of 1-way sensitivity analyses and probability sensitivity analysis all exceeded a willingness-to-pay threshold of ¥7.5 million. In the comparison of the 2 agents, AFL was a dominant over RAM. IMPLICATIONS Adding AFL or RAM to FOLFIRI in the second line of mCRC treatment was not cost-effective in the Japanese health care system. On the basis of the results of this study, in the treatment of mCRC, it will be necessary to adjust the prices of AFL and RAM with the improvement of clinical parameters, such as survival time and adverse events. Of the 2 agents, AFL was more cost-effective than RAM.
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Affiliation(s)
- Munenobu Kashiwa
- Division of Pharmacy, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan; Department of Pharmacy, First Towakai Hospital, Takatsuki, Japan.
| | - Ryo Matsushita
- Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
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Hanovich E, Asmis T, Ong M, Stewart D. Rechallenge Strategy in Cancer Therapy. Oncology 2020; 98:669-679. [DOI: 10.1159/000507816] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Accepted: 04/08/2020] [Indexed: 11/19/2022]
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Donini M, Buti S, Massari F, Mollica V, Rizzo A, Montironi R, Bersanelli M, Santoni M. Management of oligometastatic and oligoprogressive renal cell carcinoma: state of the art and future directions. Expert Rev Anticancer Ther 2020; 20:491-501. [PMID: 32479120 DOI: 10.1080/14737140.2020.1770601] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION The aim of this paper was to perform a narrative review of the literature on the available approaches in the treatment of two emerging subpopulations of metastatic renal cell carcinoma (mRCC) patients: the oligometastatic disease (less than 5 metastasis) and the oligoprogressive disease, defined as worsening in maximum 3-5 sites while all other tumor sites are controlled by systemic therapy. AREAS COVERED We explore all possible approaches in these settings of patients: the role of local therapies, considering both surgical metastasectomy and/or ablative techniques, the efficacy of systemic therapies and the rationale behind active surveillance. We also discuss ongoing clinical trials in these settings. EXPERT OPINION Two different strategies are emerging as the most promising for the approach to the oligometastatic/oligoprogressive mRCC patient: (1) the use of immunocheckpoint inhibitors following metastasectomy; (2) the use of stereotactic radiotherapy alone or combined with immunotherapy for oligometastatic disease. The lack of validated biomarkers of response in these mRCC patient subpopulations is opening the way to the employment of novel technologies. Among them, the use of artificial intelligence seems to be the candidate to contribute to precision oncology in patients with mRCC.
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Affiliation(s)
- Maddalena Donini
- Division of Oncology, Medical Department, Azienda Socio Sanitaria Territoriale (ASST) of Cremona , Cremona, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma , Parma, Italy
| | | | - Veronica Mollica
- Division of Oncology, S. Orsola-Malpighi Hospital , Bologna, Italy
| | - Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital , Bologna, Italy
| | - Rodolfo Montironi
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals , Ancona, Italy
| | | | - Matteo Santoni
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals , Ancona, Italy.,Oncology Unit, Macerata Hospital , Macerata, Italy
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Youn SH, Kim YJ, Seo SS, Kang S, Lim MC, Chang HK, Park SY, Kim JY. Effect of addition of bevacizumab to chemoradiotherapy in newly diagnosed stage IVB cervical cancer: a single institution experience in Korea. Int J Gynecol Cancer 2020; 30:764-771. [PMID: 32276937 DOI: 10.1136/ijgc-2020-001200] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 02/20/2020] [Accepted: 02/25/2020] [Indexed: 11/04/2022] Open
Abstract
OBJECTIVE The aim of this study was to compare the clinical outcomes of chemoradiotherapy with or without bevacizumab in patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer. METHODS 41 patients with stage IVB cervical cancer who underwent chemoradiotherapy between August 2015 and December 2017 were retrospectively analyzed. This study included 11 patients who received bevacizumab before or after radiotherapy (group A) and 30 patients who received conventional chemoradiotherapy without bevacizumab (group B). We excluded the following patients: those with dual primary cancers; those whose pathologic diagnosis was neither squamous cell carcinoma nor adenocarcinoma; those who did not undergo radiotherapy; or those from whom follow-up data could not be collected. We analyzed the treatment responses, toxicities, progression-free survival, and overall survival rates. RESULTS A total of 41 patients were included in the analysis. The median follow-up was 19 months (range 3-108). The response rates at 3 months after treatment were 90.9% in group A and 83.3% in group B (p=0.54). After completing all treatments, the complete response rates were 81.8% in group A and 47% in group B (p=0.04). Grade ≥3 gastrointestinal toxicities, including bleeding, fistula, perforation, and obstruction, were more frequent in group A (54.5%) than in group B (6.7%) (p=0.003). The 12 month progression-free survival and overall survival rates were similar in both arms (12 month progression-free survival: 45.5% vs 46.7%, respectively, p=0.22; 12 month overall survival: 81.8% vs 72.9%, respectively, p=0.57). Patients with node-only metastasis had better 12 month progression-free survival in group B than in group A (59.1% vs 42.9%, respectively, p=0.04). However, the responses to both treatments did not differ in patients with organ metastasis. CONCLUSIONS Bevacizumab for stage IVB cervical cancer is associated with higher complete response rates. However, patients treated with bevacizumab experienced more bowel toxicities. Bevacizumab did not improve progression-free survival among patients with node-only metastasis.
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Affiliation(s)
- Sang Hee Youn
- Proton Therapy Center, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
| | - Yeon-Joo Kim
- Proton Therapy Center, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
| | - Sang-Soo Seo
- Center for Uterine Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
| | - Sokbom Kang
- Center for Uterine Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
| | - Myong Cheol Lim
- Center for Uterine Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
| | - Ha Kyun Chang
- Center for Uterine Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
| | - Sang-Yoon Park
- Center for Uterine Cancer, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
| | - Joo-Young Kim
- Proton Therapy Center, National Cancer Center, Goyang-si, Gyeonggi-do, the Republic of Korea
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Kalantzis I, Nonni A, Pavlakis K, Delicha EM, Miltiadou K, Kosmas C, Ziras N, Gkoumas K, Gakiopoulou H. Clinicopathological differences and correlations between right and left colon cancer. World J Clin Cases 2020; 8:1424-1443. [PMID: 32368535 PMCID: PMC7190956 DOI: 10.12998/wjcc.v8.i8.1424] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 02/28/2020] [Accepted: 04/16/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The differences in histopathology and molecular biology between right colon cancer (RCC) and left colon cancer (LCC) were first reported in the literature by Bufill in 1990. Since then, a large number of studies have confirmed their differences in epidemiology, clinical presentation, comorbidities and biological behaviours, which may be related to the difference in prognosis and overall survival (OS) between the two groups.
AIM To investigate statistically significant differences between Greek patients with LCC and RCC.
METHODS The present observational study included 144 patients diagnosed with colon cancer of any stage who received chemotherapy in a Greek tertiary oncology hospital during a 2.5-year period. Clinical information, comorbidities, histopathologic characteristics and molecular biomarkers were collected from the patients’ medical records retrospectively, while administered chemotherapy regimens, targeted agents, progression-free survival (PFS) periods with first- and second-line chemotherapy and OS were recorded retroactively and prospectively. Data analysis was performed with the SPSS statistical package.
RESULTS Eighty-six males and 58 females participated in the study. One hundred (69.4%) patients had a primary lesion in the left colon, and 44 (30.6%) patients had a primary lesion in the right colon. Patients with RCC were more likely to display anaemia than patients with LCC [odds ratio (OR) = 3.09], while LCC patients were more likely to develop rectal bleeding (OR = 3.37) and a feeling of incomplete evacuation (OR = 2.78) than RCC patients. Considering comorbidities, RCC patients were more likely to suffer from diabetes (OR = 3.31) and coronary artery disease (P = 0.056) than LCC patients. The mucinous differentiation rate was higher in the right-sided group than in the left-sided group (OR = 4.49), as was the number of infiltrated lymph nodes (P = 0.039), while the percentage of high-grade differentiation was higher in the group of patients with left-sided colon cancer than in RCC patients (OR = 2.78). RAS wild-type patients who received anti-epidermal growth factor receptor (EGFR): Treatment experienced greater benefit (PFS: 16.5 mo) than those who received anti-vascular endothelial growth factor treatment (PFS: 13.7 mo) (P = 0.05), while among RAS wild-type patients who received anti-EGFR treatment, LCC patients experienced greater benefit (PFS: 15.8 mo) than the RCC subgroup (PFS: 5.5 mo) in the first-line chemotherapy setting (P = 0.034). BRAF-mutant patients had shorter PFS (9.3 mo) than BRAF wild-type patients (14.5 mo) (P = 0.033). RCC patients showed a shorter tumour recurrence period (7.7 mo) than those with LCC (14.5 mo) (P < 0.001), as well as shorter (OS) (58.4 mo for RCC patients; 82.4 mo for LCC patients) (P = 0.018).
CONCLUSION RCC patients present more comorbidities, worse histological and molecular characteristics and a consequently higher probability of tumour recurrence, poor response to targeted therapy and shorter OS than LCC patients.
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Affiliation(s)
- Ioannis Kalantzis
- Department of Gastroenterology, Korgialenio-Mpenakeio Hellenic Red Cross Hospital, Athens 11526, Greece
- Department of Oncology, Metaxa Anticancer Hospital, Piraeus 18537, Greece
| | - Afroditi Nonni
- First Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens 11527, Greece
| | - Kitty Pavlakis
- First Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens 11527, Greece
| | - Eumorphia-Maria Delicha
- Independent Biostatistical Consultant, ASTAT, Statistics in Clinical Research, Glyfada 16675, Greece
| | - Konstantinos Miltiadou
- Hepatogastroenterology Unit, Second Department of Internal Medicine, Attikon University General Hospital, Athens 12462, Greece
- Department of Oncology, Metaxa Anticancer Hospital, Piraeus 18537, Greece
| | - Christos Kosmas
- Department of Oncology, Metaxa Anticancer Hospital, Piraeus 18537, Greece
| | - Nikolaos Ziras
- Department of Oncology, Metaxa Anticancer Hospital, Piraeus 18537, Greece
| | - Konstantinos Gkoumas
- Department of Gastroenterology, Korgialenio-Mpenakeio Hellenic Red Cross Hospital, Athens 11526, Greece
| | - Harikleia Gakiopoulou
- First Department of Pathology, National and Kapodistrian University of Athens, Medical School, Athens 11527, Greece
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The Role of Anti-Angiogenics in Pre-Treated Metastatic BRAF-Mutant Colorectal Cancer: A Pooled Analysis. Cancers (Basel) 2020; 12:cancers12041022. [PMID: 32326305 PMCID: PMC7226019 DOI: 10.3390/cancers12041022] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/10/2020] [Accepted: 04/20/2020] [Indexed: 12/22/2022] Open
Abstract
Background. FOLFOXIRI plus Bevacizumab is one of the most frequently used first-line treatments for patients with BRAF-mutant colorectal cancer (CRC), while second-line treatment requires extensive further research. In this pooled analysis, we evaluate the impact of anti-angiogenics in patients with pre-treated BRAF-mutant CRC. Methods. We monitored patients in randomized, controlled studies who had advanced CRC and were undergoing second-line chemotherapy in addition to utilizing Bevacizumab, Ramucirumab or Aflibercept treatments. These data were pooled together with the data and results of BRAF-mutant patients enrolled in two phase III trials (TRIBE and TRIBE-2 study), who had been treated with second-line treatment both with or without Bevacizumab. Overall survival (OS), in relation to BRAF mutational status, was the primary focus. Results. Pooled analysis included 129 patients. Anti-angiogenics were found to have a significant advantage over the placebo in terms of OS (HR 0.50, 95%CI 0.29-0.85) (p = 0.01). Conclusions. Our pooled analysis confirms the efficacy of anti-angiogenics in pre-treated BRAF-mutant CRC, establishing the combination of chemotherapy plus Bevacizumab or Ramucirumab or Aflibercept as a valid treatment option.
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François E, Mineur L, Deplanque G, Laplaige P, Smith D, Gourgou S, Tanang A, Ionescu-Goga M, Veerabudun K, Lelarge Y, Kim S, Rollot F. Efficacy and Safety of Bevacizumab Combined With First-Line Chemotherapy in Elderly (≥75 Years) Patients With Metastatic Colorectal Cancer: A Real-World Study. Clin Colorectal Cancer 2020; 19:e100-e109. [PMID: 32299778 DOI: 10.1016/j.clcc.2020.02.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 01/12/2020] [Accepted: 02/04/2020] [Indexed: 11/17/2022]
Abstract
BACKGROUND Although elderly patients are the first concerned by colorectal cancer (CRC), they are underrepresented in clinical trials. The real-world CASSIOPEE study was thus conducted in elderly patients treated for metastatic CRC (mCRC). METHODS This French prospective, multicenter, noninterventional study aimed to estimate 1-year progression-free survival (PFS) and overall survival (OS), and describe treatments, patient autonomy (Instrumental Activities of Daily Living; Balducci scale), and safety over 24 months, in patients older than 75 with mCRC, starting first-line bevacizumab plus chemotherapy (NCT01555762). RESULTS From 2012 to 2014, 402 patients were included (safety population: n = 383, efficacy population: n = 358). Patient characteristics were as follows: mean age, 81 ± 4 years (<80 years, 46%; 80-85 years, 44%; >85 years, 10%); men, 52%; colon primary tumor, 80%; main metastatic site, liver 66%; Eastern Cooperative Oncology Group performance 0-1, 81%. Median PFS was 9.1 months (95% confidence interval [CI]: 8.3-10.2). It was superior for patients ≤85 years (<80 years: 9.3 months; 80-85 years: 9.5 months) compared with patients >85 years (8.3 months). Median OS was 19.0 months (95% CI, 16.5-21.5) and decreased in the 2 oldest groups (20.6, 17.8, and 13.0 months). Autonomy assessments decreased over time leading to nonconclusive results. Twenty-six percent of patients experienced serious adverse events (SAEs): 7% bevacizumab-related SAEs, and 6% bevacizumab-targeted SAEs. Two fatal bevacizumab-related adverse events were reported (hemorrhagic stroke and intestinal ischemia). CONCLUSIONS This large French real-world study showed that medically fit older patients with mCRC could have a benefit/risk balance similar to that of younger patients when treated with first-line bevacizumab plus chemotherapy. Improvements in geriatric assessments are needed to better define this population.
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Affiliation(s)
- Eric François
- Oncologie médicale, Centre Antoine Lacassagne, Nice, France.
| | - Laurent Mineur
- Radiation Oncology, Gastro-Intestinal and Liver Cancer Unit, Institut Sainte-Catherine, Avignon, France
| | - Gaël Deplanque
- Oncologie médicale, Groupe hospitalier Paris Saint Joseph, Paris, France
| | - Philippe Laplaige
- Oncologie et chimiothérapie ambulatoire, Polyclinique de Blois, La Chaussée St Victor, France
| | - Denis Smith
- Hépato-gastro-entérologie, Hôpital Saint André, Bordeaux, France
| | - Sophie Gourgou
- Unité de Biométrie, Institut du Cancer de Montpellier, Montpellier, France
| | - Alexandre Tanang
- Medical Department, Oncology, Roche SAS, Boulogne Billancourt, France
| | | | | | - Yoann Lelarge
- Medical Department, Oncology, Roche SAS, Boulogne Billancourt, France
| | - Stefano Kim
- Oncologie médicale, Centre Hospitalier Régional Universitaire de Besançon, Besançon, France
| | - Florence Rollot
- Soins de support en oncologie/onco-gériatrie, Institut Curie, Paris, France
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Xie YH, Chen YX, Fang JY. Comprehensive review of targeted therapy for colorectal cancer. Signal Transduct Target Ther 2020; 5:22. [PMID: 32296018 PMCID: PMC7082344 DOI: 10.1038/s41392-020-0116-z] [Citation(s) in RCA: 1000] [Impact Index Per Article: 200.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/24/2019] [Accepted: 12/31/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is among the most lethal and prevalent malignancies in the world and was responsible for nearly 881,000 cancer-related deaths in 2018. Surgery and chemotherapy have long been the first choices for cancer patients. However, the prognosis of CRC has never been satisfying, especially for patients with metastatic lesions. Targeted therapy is a new optional approach that has successfully prolonged overall survival for CRC patients. Following successes with the anti-EGFR (epidermal growth factor receptor) agent cetuximab and the anti-angiogenesis agent bevacizumab, new agents blocking different critical pathways as well as immune checkpoints are emerging at an unprecedented rate. Guidelines worldwide are currently updating the recommended targeted drugs on the basis of the increasing number of high-quality clinical trials. This review provides an overview of existing CRC-targeted agents and their underlying mechanisms, as well as a discussion of their limitations and future trends.
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Affiliation(s)
- Yuan-Hong Xie
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, State Key Laboratory for Oncogenes and Related Genes, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, 200001, Shanghai, China.
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Masoumi J, Jafarzadeh A, Khorramdelazad H, Abbasloui M, Abdolalizadeh J, Jamali N. Role of Apelin/APJ axis in cancer development and progression. Adv Med Sci 2020; 65:202-213. [PMID: 32087570 DOI: 10.1016/j.advms.2020.02.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/26/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023]
Abstract
Apelin is an endogenous peptide, which is expressed in a vast board of organs such as the brain, placenta, heart, lungs, kidneys, pancreas, testis, prostate and adipose tissues. The apelin receptor, called angiotensin-like-receptor 1 (APJ), is also expressed in the brain, spleen, placenta, heart, liver, intestine, prostate, thymus, testis, ovary, lungs, kidneys, stomach, and adipose tissue. The apelin/APJ axis is involved in a number of physiological and pathological processes. The apelin expression is increased in various kinds of cancer and the apelin/APJ axis plays a key role in the development of tumors through enhancing angiogenesis, metastasis, cell proliferation and also through the development of cancer stem cells and drug resistance. The apelin also stops the apoptosis of cancer cells. The apelin/APJ axis was considered in this review as an attractive therapeutic target for cancer treatment.
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A phase II study of the combination chemotherapy of bevacizumab and gemcitabine in women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Ovarian Res 2020; 13:14. [PMID: 32028974 PMCID: PMC7006142 DOI: 10.1186/s13048-020-0617-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 01/28/2020] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION Bevacizumab and gemcitabine are key drugs for treating recurrent epithelial ovarian cancer. However, information about the combination of bevacizumab and gemcitabine is insufficient. We conducted a phase II study to assess the feasibility, clinical activity, and toxicity of this combination chemotherapy. METHODS This study included women with platinum-resistant recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer who received one to three regimens of platinum-based chemotherapy between April 1, 2015 and December 31, 2018. The patients received bevacizumab 15 mg/kg intravenously on day 1 and gemcitabine 1000 mg/m2 intravenously on days 1 and 8 every 21 days until disease progression or unacceptable toxicity. The primary endpoint was the completion rate of three cycles of chemotherapy. This study was registered in the University Medical Information Network (UMIN) Clinical Trials Registry (UMIN000016619). RESULTS Among the 19 patients, 18 (95%) received ≥3 and 9 (47%) received ≥6 cycles of the study therapy. The objective response rate was 42% (complete response of 16% and partial response of 26%), and the clinical control rate was 84%. Hematological toxicity included neutropenia grade 3/4 in 9 patients (47%), anemia grade 3/4 in 2 (11%), and thrombocytopenia grade 3/4 in 1 (5%). One patient (5%) had grade 3 hypertension, and 1 (5%) had grade 3 protein urea. Possibly related grade 3 pulmonary toxicity was observed in 1 patient. Three patients needed dose reduction of gemcitabine to 800 mg/m2 due to treatment delay by 15 to 21 days on day1. There was no treatment delay more than 14 days on day 8. The median progression-free survival duration was 5.1 months and median overall survival duration was 21.3 months. CONCLUSION The combination chemotherapy with gemcitabine and bevacizumab was feasible, effective and safe. This combination chemotherapy may be explored in a further randomized trial.
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Ma H, Wu X, Tao M, Tang N, Li Y, Zhang X, Zhou Q. Efficacy and safety of bevacizumab-based maintenance therapy in metastatic colorectal cancer: A meta-analysis. Medicine (Baltimore) 2019; 98:e18227. [PMID: 31852082 PMCID: PMC6922481 DOI: 10.1097/md.0000000000018227] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE To identify the optimal treatment strategy after first-line induction chemotherapy for metastatic colorectal cancer (mCRC). METHODS We conducted a meta-analysis of randomized controlled trials comparing bevacizumab-based maintenance therapy, observation, and continuous chemotherapy.We searched the PubMed, Embase, and Cochrane databases for relevant articles published through March 2018. All randomized phase-III trials evaluating bevacizumab-based maintenance treatment after bevacizumab-based induction treatment were eligible for inclusion. The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Hazard ratios (HRs) with 95% confidence intervals (CIs) or data for calculating HRs with 95% CIs were extracted. The RevMan v5.3 (Copenhagen, Denmark) software was used for data analysis. RESULTS Nine trials (3121 patients) were included in this meta-analysis. Compared with observation alone, bevacizumab-based maintenance therapy significantly improved PFS (HR: 0.62, 95% CI: 0.47-0.82) and showed a trend toward prolonged OS (HR: 0.93, 95% CI: 0.83-1.05). The incidence of grade 3/4 toxicity, including hypertension and fatigue, was higher after maintenance therapy than after observation alone. PFS (HR: 0.91, 95% CI: 0.70-1.18) and OS (HR: 0.88, 95% CI: 0.74-1.04) did not differ between the maintenance treatment and continuous chemotherapy groups. Grade 3/4 toxicity, including diarrhea and sensory neuropathy, was less common after maintenance therapy than after continuous chemotherapy. CONCLUSION Bevacizumab-based maintenance therapy significantly improved PFS, showed a trend toward prolonged OS, and reduced cumulative grade 3/4 toxicity relative to continuous chemotherapy with comparable efficacy. Although maintenance therapy was beneficial, the optimal strategy should be individualized.
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Affiliation(s)
- Hongbo Ma
- The Fuling Center Hospital of Chongqing City
| | - Xiaoli Wu
- The Fuling Center Hospital of Chongqing City
| | | | - Nan Tang
- The Fuling Center Hospital of Chongqing City
| | - Yanyan Li
- The Fuling Center Hospital of Chongqing City
| | - Xianquan Zhang
- The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qi Zhou
- The Fuling Center Hospital of Chongqing City
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Dynamic Angiogenic Switch as Predictor of Response to Chemotherapy-Bevacizumab in Patients With Metastatic Colorectal Cancer. Am J Clin Oncol 2019; 42:56-59. [PMID: 29975196 DOI: 10.1097/coc.0000000000000474] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Previous studies have shown that metastatic colorectal carcinoma (mCRC) patients treated with bevacizumab, experience variation in the plasma levels of angiogenesis growth factors and related cytokines, called angiogenic switch (AS). The aim of the present study was to analyze the relationship between AS and the clinical response during standard chemotherapy-bevacizumab treatment. PATIENTS AND METHODS Patients with Eastern Cooperative Oncology Group 0-1 mCRC were eligible. Patients received treatment with standard dose capecitabine plus either oxaliplatin or irinotecan and bevacizumab for 6 cycles. Initial treatment was followed by maintenance therapy with bevacizumab plus capecitabine until progression. Plasma levels of angiogenic-related cytokines (hepatocyte growth factor, placental growth factor, macrophage chemoattractant protein-3, MM-9, eotaxin, basic fibroblast growth factor, and interleukin 18) were prospectively analyzed at baseline and every 8 weeks. Progression-free survival (PFS) was calculated using the Kaplan-Meier method. RESULTS A total of 71 patients were enrolled. AS was observed in 45 patients (63.4%), 28 of whom experienced AS at the first evaluation after treatment start. Disease control, which includes partial/complete response and stable disease, was seen in 96% of AS patients (43/45), but only in 15/26 (58%) for the remaining patients without evidence of AS (P<0.001). The median PFS of AS patients was 11.4 months (95% confidence interval, 8.6-15.8) versus 8.3 months for patients without AS (95% confidence interval, 5.6-16.4; P=0.04). CONCLUSIONS Chemotherapy plus Bevacizumab combination in mCRC patients results in dynamic changes in plasma cytokines, which is associated with better disease control and longer PFS. These new findings support continuing studying AS as a potential marker of angiogenesis inhibitor effectiveness.
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The role of vascular endothelial growth factor in the hypoxic and immunosuppressive tumor microenvironment: perspectives for therapeutic implications. Med Oncol 2019; 37:2. [PMID: 31713115 DOI: 10.1007/s12032-019-1329-2] [Citation(s) in RCA: 153] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/30/2019] [Indexed: 12/12/2022]
Abstract
The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological "cold tumors" into the "hot tumors". Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.
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