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Guo H, Miao L, Yu C. The efficacy of targeted therapy and/or immunotherapy with or without chemotherapy in patients with colorectal cancer: A network meta-analysis. Eur J Pharmacol 2025; 988:177219. [PMID: 39716565 DOI: 10.1016/j.ejphar.2024.177219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 12/17/2024] [Accepted: 12/18/2024] [Indexed: 12/25/2024]
Abstract
BACKGROUND The use of targeted drugs and immunotherapy has significantly impacted the treatment of Colorectal Cancer. However, horizontal comparison among various regimens is extremely rare. Therefore, we evaluated the survival efficacy of multiple treatment regimens of targeted therapy and/or immunotherapy with or without chemotherapy in patients with Colorectal Cancer. METHODS A systematic search was conducted in PubMed, EMBASE, and Cochrane databases, covering the period from the establishment of the databases to October 29, 2024. To obtain articles that met the inclusion and exclusion criteria and contained the required data for conducting a network meta-analysis (NMA). The NMA evaluated overall survival (OS) and progression-free survival (PFS). RESULTS A total of 90 studies were identified, comprising a sample size of 33,167 subjects. In terms of PFS, compared with simple chemotherapy strategies, most of the other single or combined strategies are significantly effective, among which targeted therapy strategies have more advantages. Encorafenib + Binimetinib + Cetuximab (ENC-BIN-CET) shows significant benefits in all comparisons except when compared with Chemotherapy + Cetuximab + Dalotuzumab (Chemo-CET-DAL), Encorafenib + Cetuximab (ENC-CET), and Panitumumab + Sotorasib (PAN-SOT). The ENC-CET and PAN-SOT targeted strategies also show significant benefits. Pembrolizumab (PEM) monotherapy has advantages over all others except when it is not superior to some targeted strategies. Chemotherapy + Bevacizumab + Atezolizumab is only inferior to some strategies. In terms of OS, the combinations of Chemotherapy + Bevacizumab, ENC-CET, Chemotherapy + Panitumumab, and ENC-BIN-CET are superior to simple chemotherapy regimens. ENC-BIN-CET shows OS benefits in all comparisons except some. ENC-CET significantly improves OS in most cases, and PEM also significantly improves OS in some regimens. In the probability ranking of OS and PFS, ENC-BIN-CET has the best effect, followed by ENC-CET. CONCLUSIONS In conclusion, pembrolizumab is still effective in prolonging survival. Dual- and triple-drug targeted strategies are the best in terms of OS and PFS, and the combination of targeted immunotherapy and chemotherapy also works. However, not all combinations are beneficial. As targeted drugs play an active role, specific drugs for colorectal cancer regimens should be carefully selected.
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Affiliation(s)
- Haoyan Guo
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China
| | - Longjie Miao
- Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, Guangdong, 518104, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Chengdong Yu
- Nanhai Hospital of Traditional Chinese Medicine, Jinan University, No.16, Guicheng South Fifth Road, Foshan, Guangdong, 528200, China; Jinan University, Guangzhou, 510632, China; Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
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2
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Gorría T, Sierra-Boada M, Rojas M, Figueras C, Marin S, Madurga S, Cascante M, Maurel J. Metabolic Singularities in Microsatellite-Stable Colorectal Cancer: Identifying Key Players in Immunosuppression to Improve the Immunotherapy Response. Cancers (Basel) 2025; 17:498. [PMID: 39941865 PMCID: PMC11815897 DOI: 10.3390/cancers17030498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 01/26/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of patients. In this review, we focus on metabolic singularities-at the transcriptomic (either bulk or single cell), proteomic, and post-translational modification levels-that induce immunosuppression in cancer and specifically in MSS CRC. First, we evaluate the current efficacy of ICIs in limited and metastatic disease in MSS CRC. Second, we discuss the latest findings on the potential biomarkers for evaluating ICI efficacy in MSS CRC using strict REMARK criteria. Third, we review the current evidence on metabolic patterns in CRC tumors and immune cell metabolism to advance our understanding of metabolic crosstalk and to pave the way for the development of combination strategies to enhance ICI efficacy.
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Affiliation(s)
- Teresa Gorría
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
- Translational Genomics and Targeted Therapies in Solid Tumors, Agustí Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Medicine Department, University of Barcelona, 08036 Barcelona, Spain
| | - Marina Sierra-Boada
- Medical Oncology Department, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, 08208 Sabadell, Spain;
| | - Mariam Rojas
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
| | - Carolina Figueras
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
| | - Silvia Marin
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08036 Barcelona, Spain;
- Institute of Biomedicine of University of Barcelona (IBUB), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Sergio Madurga
- Department of Material Science and Physical Chemistry, Research Institute of Theoretical and Computational Chemistry (IQTCUB), University of Barcelona, 08028 Barcelona, Spain;
| | - Marta Cascante
- Department of Biochemistry and Molecular Biomedicine, University of Barcelona, 08036 Barcelona, Spain;
- Institute of Biomedicine of University of Barcelona (IBUB), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Joan Maurel
- Medical Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain; (T.G.); (M.R.); (C.F.)
- Translational Genomics and Targeted Therapies in Solid Tumors, Agustí Pi i Sunyer Biomedical Research Institute (IDIBAPS), 08036 Barcelona, Spain
- Medicine Department, University of Barcelona, 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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Ji P, Chen T, Li C, Zhang J, Li X, Zhu H. Comprehensive review of signaling pathways and therapeutic targets in gastrointestinal cancers. Crit Rev Oncol Hematol 2025; 206:104586. [PMID: 39653094 DOI: 10.1016/j.critrevonc.2024.104586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024] Open
Abstract
Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.
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Affiliation(s)
- Pengfei Ji
- Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China
| | - Tingting Chen
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Chao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Jinyuan Zhang
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Xiao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China.
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Qu F, Wu S, Yu W. Progress of Immune Checkpoint Inhibitors Therapy for pMMR/MSS Metastatic Colorectal Cancer. Onco Targets Ther 2024; 17:1223-1253. [PMID: 39735789 PMCID: PMC11681808 DOI: 10.2147/ott.s500281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 12/12/2024] [Indexed: 12/31/2024] Open
Abstract
Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.
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Affiliation(s)
- Fanjie Qu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - Shuang Wu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
| | - WeiWei Yu
- Department of Oncology, Affiliated Dalian Third People’s Hospital of Dalian Medical University, Dalian, Liaoning Province, 116033, People’s Republic of China
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Wang Z, Liu Y, Wang K, Ma L. Efficacy and safety of PD-1 and PD-L1 inhibitors in advanced colorectal cancer: a meta-analysis of randomized controlled trials. BMC Gastroenterol 2024; 24:461. [PMID: 39696009 DOI: 10.1186/s12876-024-03554-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 12/09/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND PD-1 and PD-L1 inhibitors have emerged as promising therapies for advanced colorectal cancer (CRC), but their efficacy and safety profiles require further evaluation. This meta-analysis aims to assess the efficacy and safety of PD-1/PD-L1 inhibitors in this patient population. METHODS A systematic review and meta-analysis were conducted following PRISMA guidelines, with data sourced from PubMed, Embase, CENTRAL, Web of Science, and CNKI up to August 3, 2024. Nine randomized controlled trials (RCTs) involving 1680 patients were included. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR), while safety was assessed through adverse events (AEs) and grade ≥ 3 AEs. Effect sizes were calculated using mean differences (MD) and risk ratios (RR) with 95% confidence intervals (CIs). RESULTS Overall, the meta-analysis showed that PD-1/PD-L1 inhibitors did not significantly extend OS (MD = 0.86, 95% CI: -0.55, 2.27), but they significantly improved PFS (MD = 2.53, 95% CI: 0.92, 4.15). Additionally, PD-1/PD-L1 inhibitors did not significantly increase the ORR compared to controls (RR = 1.19, 95% CI: 0.99, 1.44). In terms of safety, PD-1/PD-L1 inhibitors did not significantly increase the incidence of overall AEs. Subgroup analysis further indicated that PD-1 inhibitors significantly improved OS (MD = 1.24, 95% CI: 0.20, 2.29) and PFS (MD = 6.27, 95% CI: 0.56, 11.97), while PD-L1 inhibitors did not have a significant impact on these outcomes. Additionally, PD-L1 inhibitors were associated with a higher risk of grade ≥ 3 AEs (RR = 1.29, 95% CI: 1.07, 1.57), a risk not observed with PD-1 inhibitors. CONCLUSION PD-1 inhibitors significantly improve PFS and OS in advanced CRC, making them a preferable option over PD-L1 inhibitors, which show limited efficacy and a higher risk of severe AEs. These findings support prioritizing PD-1 inhibitors in clinical practice for this patient group, while caution is warranted with PD-L1 inhibitors due to their safety concerns. TRIAL REGISTRATION PROSPERO (CRD42024611696).
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Affiliation(s)
- Zhenzi Wang
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Yuan Liu
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Kedi Wang
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China
| | - Liyan Ma
- Department of Clinical Laboratory, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
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Tzang CC, Lee YW, Lin WC, Lin LH, Kang YF, Lin TY, Wu WT, Chang KV. Evaluation of immune checkpoint inhibitors for colorectal cancer: A network meta‑analysis. Oncol Lett 2024; 28:569. [PMID: 39390977 PMCID: PMC11465421 DOI: 10.3892/ol.2024.14702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/11/2024] [Indexed: 10/12/2024] Open
Abstract
Colorectal cancer (CRC) is challenging to treat due to its high metastatic rate. Recent strategies have focused on combining immune checkpoint inhibitors (ICIs) with other treatments. The aim of the present study was to conduct a network meta-analysis of randomized controlled trials (RCTs) to assess the efficacy and adverse effects of different ICI treatments for CRC. A literature search for RCTs was conducted using PubMed, the Cochrane Library, Embase, ClinicalTrials.gov and Web of Science databases, covering the period from the inception of each database until April 2024. A total of 12 RCTs involving 2,050 participants were selected for inclusion in the analysis. The network meta-analysis employed the MetaInsight tool to assess multiple endpoints. The criteria for study selection were based on the Population, Intervention, Comparison, Outcome and Studies framework as follows: i) Population, patients with CRC; ii) intervention, studies using ICI to treat CRC; iii) comparison, active comparators, including placebo; iv) outcome, overall survival, progression-free survival, objective response rate and adverse events; and v) study design, RCTs. The results of the analysis revealed that programmed cell death-ligand 1 (PD-L1) inhibitors significantly improved overall survival time [mean difference (MD), 2.28 months; 95% confidence interval (CI), 0.44 to 4.11], while programmed cell death protein 1 (PD-1) inhibitors exhibited a superior progression-free survival time (MD, 4.79 months; 95% CI, 3.18 to 6.40) compared with active comparators. However, none of the ICI treatments had significant differences in odds ratios for the objective response rate and adverse events compared with active comparators. These findings indicate that treatment with PD-L1 and PD-1 inhibitors improved the overall survival time and delayed disease progression in patients with CRC. These findings offer valuable insights for future research aimed at improving CRC patient outcomes.
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Affiliation(s)
- Chih-Chen Tzang
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
| | - Yen-Wei Lee
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan, R.O.C
| | - Wei-Chen Lin
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
| | - Long-Huei Lin
- School of Physical Therapy and Graduate Institute of Rehabilitation Science, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan, R.O.C
| | - Yuan-Fu Kang
- School of Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
| | - Ting-Yu Lin
- Department of Physical Medicine and Rehabilitation, Lo-Hsu Medical Foundation, Inc., Lotung Poh-Ai Hospital, Yilan 265, Taiwan, R.O.C
| | - Wei-Ting Wu
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei 108, Taiwan, R.O.C
| | - Ke-Vin Chang
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100, Taiwan, R.O.C
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei 108, Taiwan, R.O.C
- Center for Regional Anesthesia and Pain Medicine, Wang-Fang Hospital, Taipei Medical University, Taipei 116, Taiwan, R.O.C
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Antoniotti C, Rossini D, Pietrantonio F, Salvatore L, Lonardi S, Tamberi S, Marmorino F, Moretto R, Prisciandaro M, Tamburini E, Tortora G, Passardi A, Bergamo F, Raimondi A, Ritorto G, Borelli B, Conca V, Ugolini C, Aprile G, Antonuzzo L, Gelsomino F, Martinelli E, Pella N, Masi G, Boni L, Galon J, Cremolini C. Upfront Fluorouracil, Leucovorin, Oxaliplatin, and Irinotecan Plus Bevacizumab With or Without Atezolizumab for Patients With Metastatic Colorectal Cancer: Updated and Overall Survival Results of the ATEZOTRIBE Study. J Clin Oncol 2024; 42:2637-2644. [PMID: 38865678 DOI: 10.1200/jco.23.02728] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/17/2024] [Accepted: 04/18/2024] [Indexed: 06/14/2024] Open
Abstract
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 4-year results of the phase II randomized AtezoTRIBE study. Eligible patients with metastatic colorectal cancer (mCRC) received first-line fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI)/bevacizumab (control group, n = 73) or FOLFOXIRI/bevacizumab plus atezolizumab (experimental group, n = 145). We present overall survival (OS) and updated outcomes according to tumor immune-related biomarkers, both in the intention-to-treat (ITT) population and the cohort of patients with proficient mismatch repair (pMMR) tumors. Median follow-up was 45.2 months (IQR, 42.6-49.2). In the ITT population, median OS was 33.0 and 27.2 months for experimental and control groups, respectively (hazard ratio [HR], 0.78 [80% CI, 0.61 to 0.98]; P = .084). An interaction effect between Immunoscore Immune-Checkpoint (IC) and treatment arm was observed (Pint, .089), with higher benefit from atezolizumab in the Immunoscore IC-high group. In the pMMR cohort (N = 202), median OS was 30.8 and 29.2 months for experimental and control groups, respectively (HR, 0.80 [80% CI, 0.63 to 1.02]; P = .117). Interactions between treatment group and tumor mutational burden (TMB) and Immunoscore IC were reported (Pint, .043 and .092, respectively), with patients bearing TMB-high and Immunoscore IC-high tumors deriving higher benefit from the addition of atezolizumab. First-line FOLFOXIRI/bevacizumab plus atezolizumab improves OS in patients with mCRC. In the pMMR group, patients with Immunoscore IC-high and/or TMB-high tumors are identified as a subgroup of interest to further develop this treatment.
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Affiliation(s)
- Carlotta Antoniotti
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Daniele Rossini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Lisa Salvatore
- Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
- Oncologia Medica, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Stefano Tamberi
- Oncology Unit, Ravenna Hospital, AUSL Romagna, Ravenna, Italy
| | - Federica Marmorino
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Roberto Moretto
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
| | - Michele Prisciandaro
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Emiliano Tamburini
- Department of Oncology and Palliative Care, Cardinale G Panico, Tricase City Hospital, Tricase, Italy
| | - Giampaolo Tortora
- Oncologia Medica, Comprehensive Cancer Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
- Oncologia Medica, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori", Meldola, Italy
| | - Francesca Bergamo
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy
| | - Alessandra Raimondi
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Giuliana Ritorto
- SSD ColoRectal Cancer Unit, Department of Oncology, AOU Città della Salute e della Scienza di Torino, Torino, Italy
| | - Beatrice Borelli
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
| | - Veronica Conca
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Clara Ugolini
- Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy
| | - Giuseppe Aprile
- Department of Oncology, San Bortolo General Hospital, Vicenza, Italy
| | - Lorenzo Antonuzzo
- Clinical Oncology Unit, Careggi University Hospital, Firenze, Italy
- Department of Experimental and Clinical Medicine, University of Florence, Firenze, Italy
| | - Fabio Gelsomino
- Division of Oncology, Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Erika Martinelli
- Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy
| | - Nicoletta Pella
- Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale University Hospital, Udine, Italy
| | - Gianluca Masi
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Luca Boni
- Clinical Epidemiology Unit, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Jerome Galon
- INSERM, Laboratory of Integrative Cancer Immunology, Paris, France
- Sorbonne Université, Université de Paris, Centre de Recherche des Cordeliers, Paris, France
- Equipe Labellisée Ligue Contre le Cancer, Paris, France
| | - Chiara Cremolini
- Unit of Medical Oncology 2, University Hospital of Pisa, Pisa, Italy
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
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8
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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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Lenz HJ, Parikh A, Spigel DR, Cohn AL, Yoshino T, Kochenderfer M, Elez E, Shao SH, Deming D, Holdridge R, Larson T, Chen E, Mahipal A, Ucar A, Cullen D, Baskin-Bey E, Kang T, Hammell AB, Yao J, Tabernero J. Modified FOLFOX6 plus bevacizumab with and without nivolumab for first-line treatment of metastatic colorectal cancer: phase 2 results from the CheckMate 9X8 randomized clinical trial. J Immunother Cancer 2024; 12:e008409. [PMID: 38485190 PMCID: PMC10941175 DOI: 10.1136/jitc-2023-008409] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2024] [Indexed: 03/17/2024] Open
Abstract
BACKGROUND Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8). METHODS CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed. RESULTS From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3-4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified. CONCLUSIONS The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted. TRIAL REGISTRATION NUMBER NCT03414983.
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Affiliation(s)
- Heinz-Josef Lenz
- Department of Medical Oncology, USC Norris Comprehensive Cancer Center, Los Angeles, California, USA
| | - Aparna Parikh
- Department of Medicine, Division of Hematology and Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - David R Spigel
- Department of Oncology, Sarah Cannon Research Institute, Nashville, Tennessee, USA
| | - Allen L Cohn
- Department of Medical Oncology, US Oncology Research, Rocky Mountain Cancer Centers, Denver, Colorado, USA
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center-Hospital East, Kashiwa, Chiba, Japan
| | | | - Elena Elez
- Department of Medical Oncology, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | - Dustin Deming
- Departments of Medicine and Oncology, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA
| | - Regan Holdridge
- Comprehensive Cancer Centers of Nevada, Henderson, Nevada, USA
| | - Timothy Larson
- Department of Medical Oncology, Minnesota Oncology Hematology, Minneapolis, Minnesota, USA
| | - Eric Chen
- Department of Medical Oncology and Hematology, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada
| | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA
| | - Antonio Ucar
- Miami Cancer Institute (part of Baptist Health South Florida), Miami, Florida, USA
| | - Dana Cullen
- Oncology Clinical Science, Bristol Myers Squibb, Princeton, New Jersey, USA
| | | | - Tong Kang
- Biostatistics, Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Amy B Hammell
- Precision Medicine, Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Jin Yao
- Translational Bioinformatics, Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Josep Tabernero
- Department of Medical Oncology, Vall d'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain
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10
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Albadari N, Xie Y, Li W. Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling. Front Pharmacol 2024; 14:1340401. [PMID: 38269272 PMCID: PMC10806212 DOI: 10.3389/fphar.2023.1340401] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024] Open
Abstract
In 2023, colorectal cancer (CRC) is the third most diagnosed malignancy and the third leading cause of cancer death worldwide. At the time of the initial visit, 20% of patients diagnosed with CRC have metastatic CRC (mCRC), and another 25% who present with localized disease will later develop metastases. Despite the improvement in response rates with various modulation strategies such as chemotherapy combined with targeted therapy, radiotherapy, and immunotherapy, the prognosis of mCRC is poor, with a 5-year survival rate of 14%, and the primary reason for treatment failure is believed to be the development of resistance to therapies. Herein, we provide an overview of the main mechanisms of resistance in mCRC and specifically highlight the role of drug transports, EGFR, and HGF/c-MET signaling pathway in mediating mCRC resistance, as well as discuss recent therapeutic approaches to reverse resistance caused by drug transports and resistance to anti-EGFR blockade caused by mutations in EGFR and alteration in HGF/c-MET signaling pathway.
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Affiliation(s)
| | | | - Wei Li
- College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United States
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11
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Mollica V, Rizzo A, Marchetti A, Tateo V, Tassinari E, Rosellini M, Massafra R, Santoni M, Massari F. The impact of ECOG performance status on efficacy of immunotherapy and immune-based combinations in cancer patients: the MOUSEION-06 study. Clin Exp Med 2023; 23:5039-5049. [PMID: 37535194 DOI: 10.1007/s10238-023-01159-1] [Citation(s) in RCA: 108] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 07/24/2023] [Indexed: 08/04/2023]
Abstract
ECOG performance status (PS) is a pivotal prognostic factor in a wide number of solid tumors. We performed a meta-analysis to assess the role of ECOG PS in terms of survival in patients with ECOG PS 0 or ECOG PS 1 treated with immunotherapy alone or combined with other anticancer treatments. Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, all phase II and III randomized clinical trials that compared immunotherapy or immune-based combinations in patients with solid tumors were retrieved. The outcomes of interest were overall survival (OS) and progression-free survival (PFS). We also performed subgroup analyses focused on type of therapy (ICI monotherapy or combinations), primary tumor type, setting (first line of treatment, subsequent lines). Overall, 60 studies were included in the analysis for a total of 35.020 patients. The pooled results showed that immunotherapy, either alone or in combination, reduces the risk of death or progression in both ECOG PS 0 and 1 populations. The survival benefit was consistent in all subgroups. Immune checkpoint inhibitors monotherapy or immune-based combinations are associated with improved survival irrespective of ECOG PS 0 or 1. Clinical trials should include more frail patients to assess the value of immunotherapy in these patients.
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Affiliation(s)
- Veronica Mollica
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Andrea Marchetti
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Valentina Tateo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Elisa Tassinari
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Matteo Rosellini
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | | | - Francesco Massari
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
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12
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Gacche RN. Changing landscape of anti-angiogenic therapy: Novel approaches and clinical perspectives. Biochim Biophys Acta Rev Cancer 2023; 1878:189020. [PMID: 37951481 DOI: 10.1016/j.bbcan.2023.189020] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/03/2023] [Accepted: 11/04/2023] [Indexed: 11/14/2023]
Abstract
Targeting angiogenesis has remained one of the important aspects in disease biology in general and cancer in particular. Currently (June 2023), over 593 clinical trials have been registered at ClinicalTrials.gov having inference of term 'angiogenesis'. A panel of 14 anti-angiogenic drugs have been approved by FDA for the treatment of variety of cancers and other human ailments. Although the anti-angiogenic therapy (AAT) has gained significant clinical attention as a promising approach in the treatment of various diseases, particularly cancer, however, sizable literature has accumulated in the recent past describing the aggressive nature of tumours after the drug holidays, evolving drug resistance and off-target toxicities. Nevertheless, the emergence of inscrutable compensatory or alternative angiogenic mechanisms is limiting the efficacy of anti-angiogenic drugs and focussing the therapeutic regime as a puzzle of 'Lernaean hydra'. This review offers an overview of recent updates on the efficacy of antiangiogenic therapy and the current clinical performance of aaRTK inhibitors. Additionally, it also explores the changing application landscape of AAT, focusing on its role in diabetic nephropathy, age-related macular degeneration and other neovascular ocular disorders. Combination therapy with antiangiogenic drugs and immune check point inhibitors (ICIs) has emerged as a potential strategy to enhance the therapeutic index of cancer immunotherapy. While clinical studies have demonstrated the clinical efficacy of this approach, they also highlight the complex and sometimes unpredictable adverse events associated with it. Normalizing tumour vasculature has been identified as a key factor in unlocking the full potential of ICIs, thereby providing hope for improved treatment outcomes. The future prospects and challenges of AAT have been described with special reference to integration of technological advances for enhancing its efficacy and applications beyond its discovery.
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Affiliation(s)
- Rajesh N Gacche
- Department of Biotechnology, Savitribai Phule Pune University, Pune 411007, MS, India.
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13
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Zlotnik O, Krzywon L, Bloom J, Kalil J, Altubi I, Lazaris A, Metrakos P. Targeting Liver Metastases to Potentiate Immunotherapy in MS-Stable Colorectal Cancer-A Review of the Literature. Cancers (Basel) 2023; 15:5210. [PMID: 37958384 PMCID: PMC10649257 DOI: 10.3390/cancers15215210] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 10/26/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Immunotherapy has revolutionized the treatment of several cancers, including melanoma and lung cancer. However, for colorectal cancer, it is ineffective for 95% of patients with microsatellite-stable disease. Recent evidence suggests that the liver's immune microenvironment plays a pivotal role in limiting the effectiveness of immunotherapy. There is also evidence to show that targeting liver metastases with locoregional therapies, such as surgery or irradiation, could potentiate immunotherapy for these patients. This review presents evidence from preclinical studies regarding the underlying mechanisms and from clinical studies that support this approach. Furthermore, we outline potential directions for future clinical trials. This innovative strategy could potentially establish immunotherapy as an effective treatment for MS-stable colorectal cancer patients, which are currently considered resistant.
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Affiliation(s)
- Oran Zlotnik
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
| | - Lucyna Krzywon
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
| | - Jessica Bloom
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
| | - Jennifer Kalil
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
| | - Ikhtiyar Altubi
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
| | - Anthoula Lazaris
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
| | - Peter Metrakos
- Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; (O.Z.); (L.K.); (J.B.); (J.K.); (A.L.)
- Division of General Surgery, McGill University, Montreal, QC H4A 3J1, Canada;
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14
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Matteucci L, Bittoni A, Gallo G, Ridolfi L, Passardi A. Immunocheckpoint Inhibitors in Microsatellite-Stable or Proficient Mismatch Repair Metastatic Colorectal Cancer: Are We Entering a New Era? Cancers (Basel) 2023; 15:5189. [PMID: 37958363 PMCID: PMC10648369 DOI: 10.3390/cancers15215189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/21/2023] [Accepted: 10/26/2023] [Indexed: 11/15/2023] Open
Abstract
Colorectal cancer (CRC) is the third most frequent cancer and the second leading cause of cancer-related deaths in Europe. About 5% of metastatic CRC (mCRC) are characterized by high microsatellite instability (MSI) due to a deficient DNA mismatch repair (dMMR), and this condition has been related to a high sensitivity to immunotherapy, in particular to the Immune Checkpoint Inhibitors (ICIs). In fact, in MSI-H or dMMR mCRC, treatment with ICIs induced remarkable response rates and prolonged survival. However, the majority of mCRC cases are mismatch-repair-proficient (pMMR) and microsatellite-stable (MSS), and unfortunately these conditions involve resistance to ICIs. This review aims to provide an overview of the strategies implemented to overcome ICI resistance and/or define subgroups of patients with MSS or dMMR mCRC who may benefit from immunotherapy.
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Affiliation(s)
- Laura Matteucci
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Bittoni
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Graziana Gallo
- Operative Unit of Pathologic Anatomy, Azienda USL della Romagna, “Maurizio Bufalini” Hospital, 47521 Cesena, Italy
| | - Laura Ridolfi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
| | - Alessandro Passardi
- Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
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15
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Cherri S, Oneda E, Zanotti L, Zaniboni A. Optimizing the first-line treatment for metastatic colorectal cancer. Front Oncol 2023; 13:1246716. [PMID: 37909027 PMCID: PMC10614157 DOI: 10.3389/fonc.2023.1246716] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 10/02/2023] [Indexed: 11/02/2023] Open
Abstract
Colorectal cancer represents an important oncological challenge both for its incidence, which makes it an important health problem, and for its biological complexity, which has made clinical results very difficult in terms of outcome for this category of patients. To date these diseases should not be treated as a single entity but it is necessary to distinguish colorectal cancers based on characteristics that nowadays are essential to have greater therapeutic benefits. These include the sideness of the disease, the state of microsatellites, the presence of prognostic and predictive mutations of response to treatments currently available in clinical practice, which are associated with new therapeutic targets. The greatest challenge in the future will be to circumvent the resistance mechanisms that make this disease very difficult to treat with good long-term results by studying effective combination treatments with a good toxicity profile. Once such combinations or targeted treatments are consolidated, it will be desirable to shift the best therapies to the first line treatment to make them immediately accessible to the patient. It will also be essential to refine the selection of patients who can benefit from these treatments.
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Affiliation(s)
- Sara Cherri
- Department of Clinical Oncology, Fondazione Poliambulanza, Brescia, Italy
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16
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He X, Lan H, Jin K, Liu F. Can immunotherapy reinforce chemotherapy efficacy? a new perspective on colorectal cancer treatment. Front Immunol 2023; 14:1237764. [PMID: 37790928 PMCID: PMC10543914 DOI: 10.3389/fimmu.2023.1237764] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 08/25/2023] [Indexed: 10/05/2023] Open
Abstract
As one of the main threats to human life (the fourth most dangerous and prevalent cancer), colorectal cancer affects many people yearly, decreases patients' quality of life, and causes irreparable financial and social damages. In addition, this type of cancer can metastasize and involve the liver in advanced stages. However, current treatments can't completely eradicate this disease. Chemotherapy and subsequent surgery can be mentioned among the current main treatments for this disease. Chemotherapy has many side effects, and regarding the treatment of this type of tumor, chemotherapy can lead to liver damage, such as steatohepatitis, steatosis, and sinus damage. These damages can eventually lead to liver failure and loss of its functions. Therefore, it seems that other treatments can be used in addition to chemotherapy to increase its efficiency and reduce its side effects. Biological therapies and immunotherapy are one of the leading suggestions for combined treatment. Antibodies (immune checkpoint blockers) and cell therapy (DC and CAR-T cells) are among the immune system-based treatments used to treat tumors. Immunotherapy targets various aspects of the tumor that may lead to 1) the recruitment of immune cells, 2) increasing the immunogenicity of tumor cells, and 3) leading to the elimination of inhibitory mechanisms established by the tumor. Therefore, immunotherapy can be used as a complementary treatment along with chemotherapy. This review will discuss different chemotherapy and immunotherapy methods for colorectal cancer. Then we will talk about the studies that have dealt with combined treatment.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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17
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Bonilla CE, Montenegro P, O’Connor JM, Hernando-Requejo O, Aranda E, Pinto Llerena J, Llontop A, Gallardo Escobar J, Díaz Romero MDC, Bautista Hernández Y, Graña Suárez B, Batagelj EJ, Wali Mushtaq A, García-Foncillas J. Ibero-American Consensus Review and Incorporation of New Biomarkers for Clinical Practice in Colorectal Cancer. Cancers (Basel) 2023; 15:4373. [PMID: 37686649 PMCID: PMC10487247 DOI: 10.3390/cancers15174373] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 09/10/2023] Open
Abstract
Advances in genomic technologies have significantly improved the management of colorectal cancer (CRC). Several biomarkers have been identified in CRC that enable personalization in the use of biologic agents that have shown to enhance the clinical outcomes of patients. However, technologies used for their determination generate massive amounts of information that can be difficult for the clinician to interpret and use adequately. Through several discussion meetings, a group of oncology experts from Spain and several Latin American countries reviewed the latest literature to provide practical recommendations on the determination of biomarkers in CRC based on their clinical experience. The article also describes the importance of looking for additional prognostic biomarkers and the use of histopathology to establish an adequate molecular classification. Present and future of immunotherapy biomarkers in CRC patients are also discussed, together with several techniques for marker determination, including liquid biopsy, next-generation sequencing (NGS), polymerase chain reaction (PCR), and fecal immunohistochemical tests. Finally, the role of Molecular Tumor Boards in the diagnosis and treatment of CRC is described. All of this information will allow us to highlight the importance of biomarker determination in CRC.
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Affiliation(s)
- Carlos Eduardo Bonilla
- Fundación CTIC—Centro de Tratamiento e Investigación sobre Cáncer, Bogotá 1681442, Colombia
| | - Paola Montenegro
- Institución AUNA OncoSalud e Instituto Nacional de Enfermedades Neoplásicas, Lima 15023, Peru
| | | | | | - Enrique Aranda
- Departamento de Oncología Médica, Hospital Reina Sofía, IMIBIC, UCO, CIBERONC, 14004 Cordoba, Spain;
| | | | - Alejandra Llontop
- Instituto de Oncología Ángel H. Roffo, Ciudad Autónoma de Buenos Aires C1437FBG, Argentina
| | | | | | | | - Begoña Graña Suárez
- Servicio de Oncología Médica, Hospital Universitario de A Coruña, Servicio Galego de Saúde (SERGAS), 15006 A Coruña, Spain;
| | | | | | - Jesús García-Foncillas
- Hospital Universitario Fundación Jiménez Díaz, Universidad Autónoma de Madrid, 28040 Madrid, Spain
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18
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Olguin JE, Mendoza-Rodriguez MG, Sanchez-Barrera CA, Terrazas LI. Is the combination of immunotherapy with conventional chemotherapy the key to increase the efficacy of colorectal cancer treatment? World J Gastrointest Oncol 2023; 15:251-267. [PMID: 36908325 PMCID: PMC9994043 DOI: 10.4251/wjgo.v15.i2.251] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 11/03/2022] [Accepted: 01/10/2023] [Indexed: 02/14/2023] Open
Abstract
Colorectal cancer (CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAN predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence, and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer; thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages III and IV. Despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors (smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus, the individual mechanisms involved in developing the CRC microenvironment, their causes, and their consequences need to be understood from a genetic and immunological perspective. This review highlighted the importance of altering the immune response in CRC. It focused on drugs that may modulate the immune response and show specific efficacy and contrasted with evidence that immunosuppression or the promotion of the immune response is the answer to generating effective treatments with combined chemotherapeutic drugs.
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Affiliation(s)
- Jonadab E Olguin
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
| | - Monica G Mendoza-Rodriguez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
| | - C Angel Sanchez-Barrera
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
| | - Luis I Terrazas
- Laboratorio Nacional en Salud, Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-degenerativas, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 54090, Estado de Mexico, Mexico
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19
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Ducreux M, Tabernero J, Grothey A, Arnold D, O'Dwyer PJ, Gilberg F, Abbas A, Thakur MD, Prizant H, Irahara N, Tahiri A, Schmoll HJ, Van Cutsem E, de Gramont A. Clinical and exploratory biomarker findings from the MODUL trial (Cohorts 1, 3 and 4) of biomarker-driven maintenance therapy for metastatic colorectal cancer. Eur J Cancer 2023; 184:137-150. [PMID: 36921494 DOI: 10.1016/j.ejca.2023.01.023] [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: 11/10/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
PURPOSE MODUL is an adaptable, signal-seeking trial of biomarker-driven maintenance therapy following first-line induction treatment in patients with metastatic colorectal cancer (mCRC). We report findings from Cohorts 1 (BRAFmut), 3 (human epidermal growth factor 2 [HER2]+) and 4 (HER2‒/high microsatellite instability, HER2‒/microsatellite stable [MSS]/BRAFwt or HER2‒/MSS/BRAFmut/RASmut). METHODS Patients with unresectable, previously untreated mCRC without disease progression following standard induction treatment (5-fluorouracil/leucovorin [5-FU/LV] plus oxaliplatin plus bevacizumab) were randomly assigned to control (fluoropyrimidine plus bevacizumab) or cohort-specific experimental maintenance therapy (Cohort 1: vemurafenib plus cetuximab plus 5-FU/LV; Cohort 3: capecitabine plus trastuzumab plus pertuzumab; Cohort 4: cobimetinib plus atezolizumab). The primary efficacy end-point was progression-free survival (PFS). RESULTS Cohorts 1, 3 and 4 did not reach target sample size because of early study closure. In Cohort 1 (n = 60), PFS did not differ between treatment arms (hazard ratio, 0.95; 95% confidence intervals 0.50-1.82; P = 0.872). However, Cohort 1 exploratory biomarker data showed preferential selection for mitogen-activated protein kinase (MAPK) pathway mutations (mainly KRAS, NRAS, MAP2K1 or BRAF) in the experimental arm but not the control arm. In Cohort 3 (n = 5), PFS ranged from 3.6 to 14.7 months versus 4.0 to 5.4 months in the experimental and control arms, respectively. In Cohort 4 (n = 99), PFS was shorter in the experimental arm (hazard ratio, 1.44; 95% confidence intervals 0.90-2.29; P = 0.128). CONCLUSIONS Vemurafenib plus cetuximab plus 5-FU/LV warrants further investigation as first-line maintenance treatment for BRAFmut mCRC. MAPK-pathway emergent genomic alterations may offer novel therapeutic opportunities in BRAFmut mCRC. Cobimetinib plus atezolizumab had an unfavourable benefit:risk ratio in HER2‒/MSS/BRAFwt mCRC. New strategies are required to increase the susceptibility of MSS mCRC to immunotherapy. TRIAL REGISTRATION ClinicalTrials.gov: NCT02291289.
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Affiliation(s)
- Michel Ducreux
- Université Paris-Saclay, Gustave Roussy, Villejuif, France.
| | - Josep Tabernero
- Vall D'Hebron Hospital Campus and Institute of Oncology (VHIO), IOB-Quiron, UVic-UCC, Barcelona, Spain.
| | | | - Dirk Arnold
- Asklepios Tumorzentrum Hamburg, AK Altona, Hamburg, Germany.
| | - Peter J O'Dwyer
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
| | | | | | | | - Hen Prizant
- F. Hoffmann-La Roche Ltd, Basel, Switzerland.
| | | | | | | | - Eric Van Cutsem
- University Hospitals Gasthuisberg, Leuven and KU Leuven, Leuven, Belgium.
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Li DD, Tang YL, Wang X. Challenges and exploration for immunotherapies targeting cold colorectal cancer. World J Gastrointest Oncol 2023; 15:55-68. [PMID: 36684057 PMCID: PMC9850757 DOI: 10.4251/wjgo.v15.i1.55] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/28/2022] [Accepted: 12/07/2022] [Indexed: 01/10/2023] Open
Abstract
In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of various tumors, greatly improving clinical efficacy. As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery, chemotherapy, radiotherapy and targeted therapy, the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells, features that are also important when distinguishing malignant tumors from “cold tumors” or “hot tumors”. At present, only a small proportion of colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) or who are microsatellite instability-high (MSI-H) can benefit from ICI treatments because these patients have the characteristics of a “hot tumor”, with a high tumor mutational burden (TMB) and massive immune cell infiltration, making the tumor more easily recognized by the immune system. In contrast, a majority of CRC patients with proficient MMR (pMMR) or who are microsatellite stable (MSS) have a low TMB, lack immune cell infiltration, and have almost no response to immune monotherapy; thus, these tumors are “cold”. The greatest challenge today is how to improve the immunotherapy response of “cold tumor” patients. With the development of clinical research, immunotherapies combined with other treatment strategies (such as targeted therapy, chemotherapy, and radiotherapy) have now become potentially effective clinical strategies and research hotspots. Therefore, the question of how to promote the transformation of “cold tumors” to “hot tumors” and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration. Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.
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Affiliation(s)
- Dan-Dan Li
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yuan-Ling Tang
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Wang
- Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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21
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Gandini A, Puglisi S, Pirrone C, Martelli V, Catalano F, Nardin S, Seeber A, Puccini A, Sciallero S. The role of immunotherapy in microsatellites stable metastatic colorectal cancer: state of the art and future perspectives. Front Oncol 2023; 13:1161048. [PMID: 37207140 PMCID: PMC10189007 DOI: 10.3389/fonc.2023.1161048] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 04/21/2023] [Indexed: 05/21/2023] Open
Abstract
Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide, despite several advances has been achieved in last decades. Few prognostic and predictive biomarkers guide therapeutic choice in metastatic CRC (mCRC), among which DNA mismatch repair deficiency and/or microsatellite instability (dMMR/MSI) holds a crucial role. Tumors characterized by dMMR/MSI benefit from immune checkpoint inhibitors. However, most of the mCRC patients (around 95%) are microsatellite stable (MSS), thereby intrinsically resistant to immunotherapy. This represents a clear unmet need for more effective treatments in this population of patients. In this review, we aim to analyze immune-resistance mechanisms and therapeutic strategies to overcome them, such as combinations of immunotherapy and chemotherapy, radiotherapy or target therapies specifically in MSS mCRC. We also explored both available and potential biomarkers that may better select MSS mCRC patients for immunotherapy. Lastly, we provide a brief overview on future perspectives in this field, such as the gut microbiome and its potential role as immunomodulator.
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Affiliation(s)
- Annalice Gandini
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Silvia Puglisi
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Chiara Pirrone
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Valentino Martelli
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Fabio Catalano
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Simone Nardin
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
| | - Andreas Seeber
- Department of Haematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Alberto Puccini
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
- IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Medical Oncology and Haematology Unit, Rozzano, Milan, Italy
| | - Stefania Sciallero
- Medical Oncology Unit 1, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
- *Correspondence: Stefania Sciallero,
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22
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Lote H, Starling N, Pihlak R, Gerlinger M. Advances in immunotherapy for MMR proficient colorectal cancer. Cancer Treat Rev 2022; 111:102480. [DOI: 10.1016/j.ctrv.2022.102480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 10/23/2022] [Accepted: 10/26/2022] [Indexed: 11/02/2022]
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Maiorano BA, Parisi A, Maiello E, Ciardiello D. The Interplay between Anti-Angiogenics and Immunotherapy in Colorectal Cancer. LIFE (BASEL, SWITZERLAND) 2022; 12:life12101552. [PMID: 36294987 PMCID: PMC9604892 DOI: 10.3390/life12101552] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 09/30/2022] [Accepted: 10/02/2022] [Indexed: 11/06/2022]
Abstract
Simple Summary Colorectal cancer is a frequent and lethal neoplasm. The tumor often creates new vessels to grow and spread—a process called ‘angiogenesis’. Therefore, drugs blocking angiogenesis are effective against this malignancy. On the other side, immune checkpoint inhibitors, which unleash the immune system to fight against tumors, have limited efficacy in patients carrying instability of DNA regions called microsatellites. However, there is an interaction between angiogenic factors and the immune system. This gives a chance to combine anti-angiogenic agents and immune checkpoint inhibitors to improve the efficacy of treating this malignancy. Abstract Angiogenesis, a hallmark of cancer, plays a fundamental role in colorectal cancer (CRC). Anti-angiogenic drugs and chemotherapy represent a standard of care for treating metastatic disease. Immune checkpoint inhibitors (ICIs) have changed the therapeutic algorithm of many solid tumors. However, the efficacy of ICIs is limited to mCRC patients carrying microsatellite instability (MSI-H), which represent approximately 3–5% of mCRC. Emerging evidence suggests that anti-angiogenic drugs could exhibit immunomodulatory properties. Thus, there is a strong rationale for combining anti-angiogenics and ICIs to improve efficacy in the metastatic setting. Our review summarizes the pre-clinical and clinical evidence regarding the combination of anti-angiogenics and ICIs in mCRC to deepen the possible application in daily clinical practice.
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Affiliation(s)
- Brigida Anna Maiorano
- Oncology Unit, IRCCS Foundation Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
- Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, 00168 Rome, Italy
- Correspondence:
| | - Alessandro Parisi
- Department of Oncology, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, 60126 Ancona, Italy
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy
| | - Evaristo Maiello
- Oncology Unit, IRCCS Foundation Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
| | - Davide Ciardiello
- Oncology Unit, IRCCS Foundation Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy
- Medical Oncology Unit, Department of Precision Medicine, “Luigi Vanvitelli” University of Campania, 80131 Naples, Italy
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