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Wang L, Wang R, Wei Z, Wang Y, Chen H, Dong B, Hu X, Ma H, Wang Z, Feng W, Li P, Lin X, Xu Y. Long-term survival and failure patterns in inoperable early-stage non-small cell lung cancer following stereotactic body radiotherapy: a single-institution retrospective study. Sci Rep 2024; 14:30076. [PMID: 39627240 PMCID: PMC11614887 DOI: 10.1038/s41598-024-73177-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 09/16/2024] [Indexed: 12/06/2024] Open
Abstract
This study is to analyse the failure patterns and long-term survival after stereotactic body radiotherapy (SBRT) in patients with T1-3N0M0 inoperable non-small cell lung cancer (NSCLC). Early-stage NSCLC patitents who received SBRT at Zhejiang Cancer Hospital from January 2012 to September 2018 were retrospectively analyzed. The primary endpoint were the patterns of disease progression, which were divided into local recurrence, regional failure, and distant metastasis. Kaplan-Meier method survival analysis was used to calculate overall survival (OS), progression-free survival (PFS). Cox model was used for univariate analysis and multivariate analysis. A total of 215 patients with 224 lesions were enrolled. After the median follow-up time of 50.8 months (1.0-117.9 months), 76 (35.3%) patients progressed, with regional progression occurring in 4 cases (1.8%), local and local-regional progression in 17 cases (7.9%), various distant metastases developing in 55 cases (25.6%). The OS rates at 1, 3, and 5 years were 97.1%, 80.9%, and 63.8%, respectively, with a median OS of 92.2 months (95%CI, 61.5-122.9 months). The PFS rates at 1, 3, and 5 years were 87.5%, 65.9%, and 50.8%, respectively, with a median PFS of 62.2 months (95% CI, 45.0-59.4 months). There was no significant difference in OS (P = 0.832) and PFS (P = 0.672) between the two groups with or without pathology. Multivariate analysis showed that BED and patient age were independent prognostic factors affecting early-stage lung cancer survival (all P < 0.05). Distant metastasis was the main failure pattern of inoperable early-stage NSCLC after SBRT, and the high-risk population should be selected for further systemic treatment.
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Affiliation(s)
- Lin Wang
- Department of Ultrasonography, Affiliated Hospital of Hangzhou Normal University, Hangzhou, Zhejiang Province, China
| | - Ruiqi Wang
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Zhuojun Wei
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Yu Wang
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Huan Chen
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Baiqiang Dong
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China
| | - Xiao Hu
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Honglian Ma
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Zhun Wang
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Wei Feng
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Pu Li
- Department of Radiation Physics, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China
| | - Xiao Lin
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
| | - Yujin Xu
- Department of Thoracic Radiotherapy, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.
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2
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Ng AM, MacKinnon KM, Cook AA, D'Alonzo RA, Rowshanfarzad P, Nowak AK, Gill S, Ebert MA. Mechanistic in silico explorations of the immunogenic and synergistic effects of radiotherapy and immunotherapy: a critical review. Phys Eng Sci Med 2024; 47:1291-1306. [PMID: 39017990 PMCID: PMC11666662 DOI: 10.1007/s13246-024-01458-1] [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: 02/12/2024] [Accepted: 06/17/2024] [Indexed: 07/18/2024]
Abstract
Immunotherapy is a rapidly evolving field, with many models attempting to describe its impact on the immune system, especially when paired with radiotherapy. Tumor response to this combination involves a complex spatiotemporal dynamic which makes either clinical or pre-clinical in vivo investigation across the resulting extensive solution space extremely difficult. In this review, several in silico models of the interaction between radiotherapy, immunotherapy, and the patient's immune system are examined. The study included only mathematical models published in English that investigated the effects of radiotherapy on the immune system, or the effect of immuno-radiotherapy with immune checkpoint inhibitors. The findings indicate that treatment efficacy was predicted to improve when both radiotherapy and immunotherapy were administered, compared to radiotherapy or immunotherapy alone. However, the models do not agree on the optimal schedule and fractionation of radiotherapy and immunotherapy. This corresponds to relevant clinical trials, which report an improved treatment efficacy with combination therapy, however, the optimal scheduling varies between clinical trials. This discrepancy between the models can be attributed to the variation in model approach and the specific cancer types modeled, making the determination of the optimum general treatment schedule and model challenging. Further research needs to be conducted with similar data sets to evaluate the best model and treatment schedule for a specific cancer type and stage.
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Affiliation(s)
- Allison M Ng
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, WA, Australia
| | - Kelly M MacKinnon
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, WA, Australia
- National Centre for Asbestos Related Diseases, The University of Western Australia, Crawley, WA, Australia
| | - Alistair A Cook
- National Centre for Asbestos Related Diseases, The University of Western Australia, Crawley, WA, Australia
- Institute for Respiratory Health, Institute for Respiratory Health, Perth, WA, Australia
- School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Rebecca A D'Alonzo
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, WA, Australia
- National Centre for Asbestos Related Diseases, The University of Western Australia, Crawley, WA, Australia
- Institute for Respiratory Health, Institute for Respiratory Health, Perth, WA, Australia
| | - Pejman Rowshanfarzad
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, WA, Australia
- Centre for Advanced Technologies in Cancer Research (CATCR), Perth, WA, Australia
| | - Anna K Nowak
- National Centre for Asbestos Related Diseases, The University of Western Australia, Crawley, WA, Australia
- Institute for Respiratory Health, Institute for Respiratory Health, Perth, WA, Australia
- Medical School, The University of Western Australia, Crawley, WA, Australia
| | - Suki Gill
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, WA, Australia
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia
| | - Martin A Ebert
- School of Physics, Mathematics and Computing, The University of Western Australia, Crawley, WA, Australia.
- Centre for Advanced Technologies in Cancer Research (CATCR), Perth, WA, Australia.
- Department of Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia.
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Fan M, Liu Q, Ma X, Jiang Y, Wang Y, Jia S, Nie Y, Deng R, Zhou P, Zhang S, Jiang S, Guan M, Hou Y, Miao Y, Zhang Y, Zhang X. ZNF131-BACH1 transcriptionally accelerates RAD51-dependent homologous recombination repair and therapy-resistance of non-small-lung cancer cells by preventing their degradation from CUL3. Theranostics 2024; 14:7241-7264. [PMID: 39629137 PMCID: PMC11610138 DOI: 10.7150/thno.97593] [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: 04/21/2024] [Accepted: 10/13/2024] [Indexed: 12/07/2024] Open
Abstract
Rationale: Both bulk RNA-sequencing and GEO database upon chemotherapy to non-small cell lung cancer (NSCLC) cells reveal that ZNF131 (Zinc Finger Protein 131) maybe a crucial transcriptional factor involved. However, it is a recently discovered protein with largely unexplored expression patterns and biological functions. Methods: Bioinformatics analyses and immunohistochemistry staining were assessed to detect both mRNA and protein levels of ZNF131 in NSCLC specimens and cell lines. Next, colony formation assay, MTT assay, EdU assay, transwell assay, flow cytometric analysis, sphere formation assay, western blotting analysis, mouse xenograft model analysis, immunofluorescence assay, and reverse transcriptase-polymerase chain reaction were performed to investigate the effect of ZNF131 interaction on proliferation, invasion, stemness, chemotherapy sensitivity. RNA-sequencing assay, RNA-microarray, and ChIP-sequencing assay were used to identify candidate downstream target genes. Further, liquid chromatography-tandem mass spectrometry analysis, GST pull-down assay, and immunoprecipitation assays were performed to evaluate the interactions between ZNF131, BACH1, and CUL3. Results: ZNF131 was elevated in NSCLC specimens and cell lines, which significantly correlates with advanced TNM stage and poor prognosis in NSCLC patients. ZNF131 overexpression promotes NSCLC cell proliferation, invasion, and stemness both in vitro and in vivo. ZNF131 appears to target the RAD51 gene within a well-defined region (-668bp to -403bp) of the RAD51 promoter. ZNF131 contributes to RAD51-dependent homologous recombination (HR), primarily through its Zinc Finger and BTB domains. ZNF131-BACH1 interaction, mediated by their respective BTB domains, enhances the stability of both proteins, effectively preventing their ubiquitin-mediated degradation by CUL3. The ZNF131-BACH1 partnership significantly amplifies RAD51-dependent HR, resulting in expedited resistance to both radiotherapy and chemotherapy in NSCLC patients. Desoxyrhaponticin was shown to halt NSCLC progression and orchestrate a synergistic effect together with chemotherapy at least partially by targeting ZNF131. Conclusions: Our findings indicate that ZNF131 exhibits heightened expression in NSCLC, driving essential processes such as proliferation, invasion, and stemness by transcriptionally activating RAD51. The ZNF131-BACH1 interaction serves as a crucial enhancer, further boosting RAD51 transcription and ultimately accelerating therapy resistance in NSCLC.
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Affiliation(s)
- Mingwei Fan
- Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China
- Department of Pathology, The Second Affiliated Hospital of Shandong First Medical University, Shandong, China
| | - Quanbo Liu
- Department of Respiratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xiaowen Ma
- Second Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Yufeng Jiang
- Department of Emergency, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yilong Wang
- Department of Radiation Oncology, First Affiliated Hospital of China Medical University, Shenyang, China
| | - Shuting Jia
- First Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Yingtong Nie
- First Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Ruoyi Deng
- Second Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Pengchong Zhou
- Second Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Shuyu Zhang
- Second Department of Clinical Medicine, China Medical University, Shenyang, China
| | - Siyu Jiang
- Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China
| | - Mengyao Guan
- Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuekang Hou
- Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yuan Miao
- Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yong Zhang
- Department of Pathology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, China
| | - Xiupeng Zhang
- Department of Pathology, College of Basic Medical Sciences and First Affiliated Hospital of China Medical University, Shenyang, China
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Taniguchi Y, Tamiya A, Matsuda Y, Adachi Y, Enomoto T, Azuma K, Kouno S, Tokoro A, Atagi S. Opioids impair nivolumab outcomes: a retrospective propensity score analysis in non-small-cell lung cancer. BMJ Support Palliat Care 2023; 13:e185-e189. [PMID: 33293293 DOI: 10.1136/bmjspcare-2020-002480] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 01/19/2023]
Abstract
OBJECTIVES Opioids are often administered for cancer-related pain relief. However, few reports have evaluated the association between opioids and immune checkpoint inhibitor treatment for patients with non-small-cell lung cancer (NSCLC). The aim of this retrospective study was to reveal the effect of opioids on the prognosis of patients harbouring NSCLC treated with nivolumab. METHODS The medical records of consecutive patients with NSCLC receiving nivolumab at our institution were retrospectively reviewed. We collected clinical data at the time of nivolumab treatment initiation. Propensity score matching (PSM) was performed to minimise potential selection bias. We compared clinical outcomes with and without baseline opioid use. RESULTS Of the 296 patients identified in the study, after PSM, 38 cases with opioid use and matched 38 cases without opioid use were selected. The overall response rate was significantly lower in patients with opioid use than in those without (2.63%, 95% CI 0.47% to 13.49%, vs 21.05%, 95% CI 11.07% to 36.35%; p=0.0284). The median progression-free survival in patients with opioid use was significantly shorter than that in patients without (1.17, 95% CI 0.93 to 1.73 months, vs 2.07 95% CI 1.23 to 4.73 months; p=0.002). The median overall survival in patients with opioid use was significantly shorter than that in patients without (4.20, 95% CI 2.53 to 6.20 months, vs 9.57, 95% CI 2.23 to not reached months; p=0.018). CONCLUSIONS Patients with NSCLC receiving regular opioid administration at nivolumab treatment initiation had a worse nivolumab treatment outcome than patients without opioid use.
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Affiliation(s)
| | - Akihiro Tamiya
- Internal Medicine, Kinki-Chuo Chest Medical Center, Sakai, Japan
| | - Yoshinobu Matsuda
- Psychosomatic Internal Medicine, Kinki-Chuo Chest Medical Center, Sakai, Japan
| | - Yuichi Adachi
- Respiratory Medicine and Clinical Immunology, Osaka University School of Medicine Graduate School of Medicine, Suita, Japan
| | - Takatoshi Enomoto
- Respiratory Medicine and Clinical Immunology, Osaka University School of Medicine Graduate School of Medicine, Suita, Japan
| | - Kouji Azuma
- Respiratory Medicine, Kinki Central Hospital of Mutual Aid Association of Public School Teachers, Itami, Japan
| | - Shunichi Kouno
- Respiratory Medicine, Gunma University Graduate School of Medicine School of Medicine, Maebashi, Japan
| | - Akihiro Tokoro
- Psychosomatic Internal Medicine, Kinki-Chuo Chest Medical Center, Sakai, Japan
| | - Shinji Atagi
- Clinical Research Center, Kinki-Chuo Chest Medical Center, Sakai, Japan
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5
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Hasan G, Hassan MI, Sohal SS, Shamsi A, Alam M. Therapeutic Targeting of Regulated Signaling Pathways of Non-Small Cell Lung Carcinoma. ACS OMEGA 2023; 8:26685-26698. [PMID: 37546685 PMCID: PMC10398694 DOI: 10.1021/acsomega.3c02424] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 06/15/2023] [Indexed: 08/08/2023]
Abstract
Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers, including NSCLC. These therapeutic molecules serve as important sources for new drugs that interfere with cellular proliferation, apoptosis, metastasis, and angiogenesis by regulating signaling pathways. These molecules affect several cellular signaling cascades, including p53, NF-κB, STAT3, RAS, MAPK/ERK, Wnt, and AKT/PI3K, and are thus implicated in the therapeutic management of cancers. This review aims to describe the bioactive compounds and small-molecule inhibitors, their anticancer action, and targeting cellular signaling cascades in NSCLC. We highlighted the therapeutic potential of Epigallocatechin gallate (EGCG), Perifosine, ABT-737, Thymoquinine, Quercetin, Venetoclax, Gefitinib, and Genistein. These compounds are implicated in the therapeutic management of NSCLC. This review further offers deeper mechanistic insights into different signaling pathways that could be targeted for NSCLC therapy by phytochemicals and small-molecule inhibitors.
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Affiliation(s)
- Gulam
Mustafa Hasan
- Department
of Biochemistry, College of Medicine, Prince
Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi Arabia
| | - Md. Imtaiyaz Hassan
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
| | - Sukhwinder Singh Sohal
- Respiratory
Translational Research Group, Department of Laboratory Medicine, School
of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston 7001, Tasmania, Australia
| | - Anas Shamsi
- Centre
of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab
Emirates
| | - Manzar Alam
- Centre
for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi 110025, India
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Khalil R, Green RJ, Sivakumar K, Varandani P, Bharadwaj S, Mohapatra SS, Mohapatra S. Withaferin A Increases the Effectiveness of Immune Checkpoint Blocker for the Treatment of Non-Small Cell Lung Cancer. Cancers (Basel) 2023; 15:3089. [PMID: 37370701 PMCID: PMC10295988 DOI: 10.3390/cancers15123089] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/29/2023] Open
Abstract
Treatment of late-stage lung cancers remains challenging with a five-year survival rate of 8%. Immune checkpoint blockers (ICBs) revolutionized the treatment of non-small cell lung cancer (NSCLC) by reactivating anti-tumor immunity. Despite achieving durable responses, ICBs are effective in only 20% of patients due to immune resistance. Therefore, synergistic combinatorial approaches that overcome immune resistance are currently under investigation. Herein, we studied the immunomodulatory role of Withaferin A (WFA)-a herbal compound-and its effectiveness in combination with an ICB for the treatment of NSCLC. Our in vitro results show that WFA induces immunogenic cell death (ICD) in NSCLC cell lines and increases expression of the programmed death ligand-1 (PD-L1). The administration of N-acetyl cysteine (NAC), a reactive oxygen species (ROS) scavenger, abrogated WFA-induced ICD and PD-L1 upregulation, suggesting the involvement of ROS in this process. Further, we found that a combination of WFA and α-PD-L1 significantly reduced tumor growth in an immunocompetent tumor model. Our results showed that WFA increases CD-8 T-cells and reduces immunosuppressive cells infiltrating the tumor microenvironment. Administration of NAC partially inhibited the anti-tumor response of the combination regimen. In conclusion, our results demonstrate that WFA sensitizes NSCLC to α-PD-L1 in part via activation of ROS.
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Affiliation(s)
- Roukiah Khalil
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Ryan J. Green
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Kavya Sivakumar
- Taneja School of Pharmacy, University of South Florida, Tampa, FL 33612, USA
| | - Payal Varandani
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Srinivas Bharadwaj
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Shyam S. Mohapatra
- Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- Taneja School of Pharmacy, University of South Florida, Tampa, FL 33612, USA
- Department of Veterans Affairs, James A. Haley Veterans Hospital, Tampa, FL 33612, USA
| | - Subhra Mohapatra
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- Department of Veterans Affairs, James A. Haley Veterans Hospital, Tampa, FL 33612, USA
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7
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Singh R, Vargo JA, Song S. Concurrent immunoradiation for HPV-associated oropharyngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 2023; 280:797-809. [PMID: 36036274 DOI: 10.1007/s00405-022-07613-2] [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: 07/20/2022] [Accepted: 08/11/2022] [Indexed: 01/21/2023]
Abstract
OBJECTIVES Current trials for HPV-associated oropharyngeal SCCs (OP-SCCs) are evaluating treatment de-escalation including use of concurrent immunotherapy with radiation therapy (I-RT). Given limited prospective data following I-RT, we aimed to examine this question utilizing the National Cancer Data Base (NCDB). METHODS The NCDB was queried for patients with HPV-associated OP-SCCs eligible for current de-escalation studies with AJCC 7th edition T1-T2/N1-N2b and T3/N0-N2b disease. Patients were stratified into I-RT, concurrent chemoradiation (C-RT), and radiation therapy alone (RT) arms. Kaplan-Meier analysis was utilized to compare overall survival (OS) between treatment arms followed by a Cox multivariate (MVA) proportional hazards model controlling for tumor and patient characteristics and propensity-score analyses with inverse probability treatment weighting (IPTW). RESULTS We identified 4768 patients; 313 received I-RT, 3660 patients received C-RT, and 795 received RT. Median age was 62 years (range 27-90) with a median Charlson-Deyo co-morbidity score of 0 (range: 0-3). The vast majority were cN1-N2a (88.8%) and 26.5% were cT3. On MVA, inferior 3-year and 8-year OS was noted following I-RT (81.6% and 70.5%) vs. C-RT (90.6% and 79.4%) (HR = 1.69 (95% CI: 1.29-2.21); p < 0.0001) with no significant difference vs. RT (88.1% and 75.8%) (HR = 1.07; p = 0.80). This was also maintained on IPTW-analysis (HR = 1.62 (95% CI: 1.23-2.15); p = 0.001). CONCLUSIONS I-RT was associated with significantly poorer OS vs. C-RT with no benefit compared to RT for HPV-associated OP-SCCs. I-RT is not recommended outside of currently accruing clinical trials.
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Affiliation(s)
- Raj Singh
- Department of Radiation Oncology, Virginia Commonwealth University Health System, Richmond, VA, 23219, USA.
| | - John Austin Vargo
- Department of Radiation Oncology, University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA, USA
| | - Shiyu Song
- Department of Radiation Oncology, Virginia Commonwealth University Health System, Richmond, VA, 23219, USA
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8
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van der Weijst L, Azria D, Berkovic P, Boisselier P, Briers E, Bultijnck R, Chang-Claude J, Choudhury A, Defraene G, Demontois S, Elliott RM, Ennis D, Faivre-Finn C, Franceschini M, Giandini T, Giraldo A, Gutiérrez-Enríquez S, Herskind C, Higginson DS, Kerns SL, Johnson K, Lambrecht M, Lang P, Ramos M, Rancati T, Rimner A, Rosenstein BS, De Ruysscher D, Salem A, Sangalli C, Seibold P, Sosa Fajardo P, Sperk E, Stobart H, Summersgill H, Surmont V, Symonds P, Taboada-Valladares B, Talbot CJ, Vega A, Veldeman L, Veldwijk MR, Ward T, Webb A, West CML, Lievens Y. The correlation between pre-treatment symptoms, acute and late toxicity and patient-reported health-related quality of life in non-small cell lung cancer patients: Results of the REQUITE study. Radiother Oncol 2022; 176:127-137. [PMID: 36195214 PMCID: PMC10404651 DOI: 10.1016/j.radonc.2022.09.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 09/16/2022] [Accepted: 09/25/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND PURPOSE To investigate the association between clinician-scored toxicities and patient-reported health-related quality of life (HRQoL), in early-stage (ES-) and locally-advanced (LA-) non-small cell lung cancer (NSCLC) patients receiving loco-regional radiotherapy, included in the international real-world REQUITE study. MATERIALS AND METHODS Clinicians scored eleven radiotherapy-related toxicities (and baseline symptoms) with the Common Terminology Criteria for Adverse Events version 4. HRQoL was assessed with the European Organization for Research and Treatment of Cancer core HRQoL questionnaire (EORTC-QLQ-C30). Statistical analyses used the mixed-model method; statistical significance was set at p = 0.01. Analyses were performed for baseline and subsequent time points up to 2 years after radiotherapy and per treatment modality, radiotherapy technique and disease stage. RESULTS Data of 435 patients were analysed. Pre-treatment, overall symptoms, dyspnea, chest wall pain, dysphagia and cough impacted overall HRQoL and specific domains. At subsequent time points, cough and dysphagia were overtaken by pericarditis in affecting HRQoL. Toxicities during concurrent chemo-radiotherapy and 3-dimensional radiotherapy had the most impact on HRQoL. Conversely, toxicities in sequential chemo-radiotherapy and SBRT had limited impact on patients' HRQoL. Stage impacts the correlations: LA-NSCLC patients are more adversely affected by toxicity than ES-NSCLC patients, mimicking the results of radiotherapy technique and treatment modality. CONCLUSION Pre-treatment symptoms and acute/late toxicities variously impact HRQoL of ES- and LA-NSCLC patients undergoing different treatment approaches and radiotherapy techniques. Throughout the disease, dyspnea seems crucial in this association, highlighting the additional effect of co-existing comorbidities. Our data call for optimized radiotherapy limiting toxicities that may affect patients' HRQoL.
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Affiliation(s)
- Lotte van der Weijst
- Department of Radiation Oncology, Ghent University Hospital and Ghent University, Ghent, Belgium.
| | - David Azria
- Federation Universitaire d'oncologie radiothérapie d'Occitanie Méditerranée, Univ Montpellier, IRCM Inserm U1194, ICM, Montpellier, France
| | - Patrick Berkovic
- Department of Radiotherapy-oncology, Leuvens Kanker Instituut, UZ Leuven, Leuven, Belgium
| | - Pierre Boisselier
- Federation Universitaire d'oncologie radiothérapie d'Occitanie Méditerranée, Univ Montpellier, IRCM Inserm U1194, ICM, Montpellier, France
| | | | - Renée Bultijnck
- Department of Radiation Oncology, Ghent University Hospital and Ghent University, Ghent, Belgium; Research Foundation - Flanders (FWO), Brussels, Belgium
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Germany
| | - Ananya Choudhury
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, United Kingdom
| | - Gilles Defraene
- Laboratory of Experimental Radiotherapy, Department of Oncology, KULEUVEN, Leuven, Belgium
| | - Sylvian Demontois
- Federation Universitaire d'oncologie radiothérapie d'Occitanie Méditerranée, Univ Montpellier, IRCM Inserm U1194, ICM, Montpellier, France
| | - Rebecca M Elliott
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, United Kingdom
| | - Dawn Ennis
- Royal Derby Hospital, Derby DE22 3NE, United Kingdom
| | - Corinne Faivre-Finn
- University of Manchester, UK, The Christie NHS Foundation Trust, United Kingdom
| | - Marzia Franceschini
- Unit of Radiation Oncology 2, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Tommaso Giandini
- Unit of Medical Physics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alexandra Giraldo
- Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Sara Gutiérrez-Enríquez
- Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Carsten Herskind
- Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Daniel S Higginson
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, United States
| | - Sarah L Kerns
- Departments of Radiation Oncology and Surgery, University of Rochester Medical Center, Rochester, New York, NY, United States
| | - Kerstie Johnson
- Leicester Cancer Research Centre, University of Leicester, Leicester LE1 7RH, United Kingdom
| | - Maarten Lambrecht
- Department of Radiotherapy-oncology, Leuvens Kanker Instituut, UZ Leuven, Leuven, Belgium
| | - Philippe Lang
- Federation Universitaire d'oncologie radiothérapie d'Occitanie, ICG CHU Caremeau, Nîmes, France
| | - Mónica Ramos
- Radiation Oncology Department, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Tiziana Rancati
- Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Andreas Rimner
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, United States
| | - Barry S Rosenstein
- Department of Radiation Oncology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
| | - Dirk De Ruysscher
- Department of Radiation Oncology (Maastro), Maastricht University Medical Center, GROW School for Oncology and Developmental Biology, Maastricht, The Netherlands
| | - Ahmed Salem
- University of Manchester, UK, The Christie NHS Foundation Trust, United Kingdom; Department of Basic Medical Sciences, School of Medicine, Hashemite University, Zarqa, Jordan
| | - Claudia Sangalli
- Unit of Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Petra Seibold
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Paloma Sosa Fajardo
- Department of Radiation Oncology, Hospital Clínico Universitario de Santiago, SERGAS.Instituto de Investigación Sanitaria de Santiago de Compostela, Spain
| | - Elena Sperk
- Department of Radiation Oncology, Universitätsmedizin Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | | | - Holly Summersgill
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, United Kingdom
| | - Veerle Surmont
- Department of Respiratory Medicine, Ghent University Hospital and Ghent University, Ghent, Belgium
| | - Paul Symonds
- Leicester Cancer Research Centre, University of Leicester, Leicester LE1 7RH, United Kingdom
| | - Begoña Taboada-Valladares
- Department of Radiation Oncology, Hospital Clínico Universitario de Santiago, SERGAS.Instituto de Investigación Sanitaria de Santiago de Compostela, Spain
| | - Christopher J Talbot
- Leicester Cancer Research Centre, University of Leicester, Leicester LE1 7RH, United Kingdom
| | - Ana Vega
- Fundación Pública Galega de Medicina Xenómica, Grupo de Medicina Xenómica (USC), Santiago de Compostela, Spain; Instituto de Investigación Sanitaria de Santiago de Compostela, Spain; Biomedical Network on Rare Diseases (CIBERER), Spain
| | - Liv Veldeman
- Department of Radiation Oncology, Ghent University Hospital and Ghent University, Ghent, Belgium
| | - Marlon R Veldwijk
- Department of Radiation Oncology, Universitätsklinikum Mannheim, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
| | - Tim Ward
- Trustee Pelvic Radiation Disease Association, NCRI CTRad Consumer, United Kingdom
| | - Adam Webb
- Department of Genetics and Genome Biology, University of Leicester, United Kingdom
| | - Catharine M L West
- Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital, United Kingdom
| | - Yolande Lievens
- Department of Radiation Oncology, Ghent University Hospital and Ghent University, Ghent, Belgium
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9
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Zhang XY, Collins GP. Checkpoint Inhibitors and the Changing Face of the Relapsed/Refractory Classical Hodgkin Lymphoma Pathway. Curr Oncol Rep 2022; 24:1477-1488. [PMID: 35696020 PMCID: PMC9606050 DOI: 10.1007/s11912-022-01292-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2022] [Indexed: 01/27/2023]
Abstract
PURPOSE OF REVIEW Checkpoint inhibitors (CPIs) targeting PD1 are highly active in relapsed/refractory classical Hodgkin lymphoma. A plethora of recent studies, often small and non-randomised, have raised many questions about how to optimally integrate these into clinical practice. We aim to discuss the use of CPIs in different relapsed/refractory settings in an effort to better define their role and highlight areas of research. RECENT FINDINGS CPIs have shown efficacy at first relapse, as salvage pre- and post-autologous (ASCT) and allogeneic stem cell transplant (alloSCT) and as maintenance post-ASCT. Immune-related adverse events require careful attention, especially when used peri-alloSCT, where it is associated with hyperacute graft-versus-host disease. Newer PD1 inhibitors, as well as strategies to overcome CPI resistance, are being tested. CPIs are increasingly deployed at earlier points in the classical Hodgkin lymphoma pathway. Whilst progress is clearly being made, randomised studies are required to more clearly define the optimal positioning of these agents.
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Affiliation(s)
- Xiao-Yin Zhang
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Graham P Collins
- Department of Clinical Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
- Department of Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, OX3 7LE, UK.
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10
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Jafari M, Kadkhodazadeh M, Shapourabadi MB, Goradel NH, Shokrgozar MA, Arashkia A, Abdoli S, Sharifzadeh Z. Immunovirotherapy: The role of antibody based therapeutics combination with oncolytic viruses. Front Immunol 2022; 13:1012806. [PMID: 36311790 PMCID: PMC9608759 DOI: 10.3389/fimmu.2022.1012806] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Despite the fact that the new drugs and targeted therapies have been approved for cancer therapy during the past 30 years, the majority of cancer types are still remain challenging to be treated. Due to the tumor heterogeneity, immune system evasion and the complex interaction between the tumor microenvironment and immune cells, the great majority of malignancies need multimodal therapy. Unfortunately, tumors frequently develop treatment resistance, so it is important to have a variety of therapeutic choices available for the treatment of neoplastic diseases. Immunotherapy has lately shown clinical responses in malignancies with unfavorable outcomes. Oncolytic virus (OV) immunotherapy is a cancer treatment strategy that employs naturally occurring or genetically-modified viruses that multiply preferentially within cancer cells. OVs have the ability to not only induce oncolysis but also activate cells of the immune system, which in turn activates innate and adaptive anticancer responses. Despite the fact that OVs were translated into clinical trials, with T-VECs receiving FDA approval for melanoma, their use in fighting cancer faced some challenges, including off-target side effects, immune system clearance, non-specific uptake, and intratumoral spread of OVs in solid tumors. Although various strategies have been used to overcome the challenges, these strategies have not provided promising outcomes in monotherapy with OVs. In this situation, it is increasingly common to use rational combinations of immunotherapies to improve patient benefit. With the development of other aspects of cancer immunotherapy strategies, combinational therapy has been proposed to improve the anti-tumor activities of OVs. In this regard, OVs were combined with other biotherapeutic platforms, including various forms of antibodies, nanobodies, chimeric antigen receptor (CAR) T cells, and dendritic cells, to reduce the side effects of OVs and enhance their efficacy. This article reviews the promising outcomes of OVs in cancer therapy, the challenges OVs face and solutions, and their combination with other biotherapeutic agents.
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Affiliation(s)
- Mahdie Jafari
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | | | | | - Nasser Hashemi Goradel
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Arash Arashkia
- Department of Molecular Virology, Pasture Institute of Iran, Tehran, Iran
| | - Shahriyar Abdoli
- School of Advanced Medical Technologies, Golestan University of Medical Sciences, Gorgan, Iran
- *Correspondence: Zahra Sharifzadeh, ; Shahriyar Abdoli,
| | - Zahra Sharifzadeh
- Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
- *Correspondence: Zahra Sharifzadeh, ; Shahriyar Abdoli,
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11
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Donlon NE, Davern M, O’Connell F, Sheppard A, Heeran A, Bhardwaj A, Butler C, Narayanasamy R, Donohoe C, Phelan JJ, Lynam-Lennon N, Dunne MR, Maher S, O’Sullivan J, Reynolds JV, Lysaght J. Impact of radiotherapy on the immune landscape in oesophageal adenocarcinoma. World J Gastroenterol 2022; 28:2302-2319. [PMID: 35800186 PMCID: PMC9185220 DOI: 10.3748/wjg.v28.i21.2302] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/19/2022] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND In the contemporary era of cancer immunotherapy, an abundance of clinical and translational studies have reported radiotherapy (RT) and immunotherapies as a viable option for immunomodulation of many cancer subtypes, with many related clinical trials ongoing. In locally advanced disease, chemotherapy or chemoradiotherapy followed by surgical excision of the tumour remain the principal treatment strategy in oesophageal adenocarcinoma (OAC), however, the use of the host immune system to improve anti-tumour immunity is rapidly garnering increased support in the curative setting. AIM To immunophenotype OAC patients' immune checkpoint (IC) expression with and without radiation and evaluate the effects of checkpoint blockade on cell viability. METHODS In the contemporary era of cancer immunotherapy, an abundance of studies have demonstrated that combination RT and IC inhibitors (ICIs) are effective in the immunomodulation of many cancer subtypes, with many related clinical trials ongoing. Although surgical excision and elimination of tumour cells by chemotherapy or chemoradiotherapy remains the gold standard approach in OAC, the propagation of anti-tumour immune responses is rapidly garnering increased support in the curative setting. The aim of this body of work was to immunophenotype OAC patients' IC expression with and without radiation and to establish the impact of checkpoint blockade on cell viability. This study was a hybrid combination of in vitro and ex vivo models. Quantification of serum immune proteins was performed by enzyme-linked immunosorbent assay. Flow cytometry staining was performed to evaluate IC expression for in vitro OAC cell lines and ex vivo OAC biopsies. Cell viability in the presence of radiation with and without IC blockade was assessed by a cell counting kit-8 assay. RESULTS We identified that conventional dosing and hypofractionated approaches resulted in increased IC expression (PD-1, PD-L1, TIM3, TIGIT) in vitro and ex vivo in OAC. There were two distinct subcohorts with one demonstrating significant upregulation of ICs and the contrary in the other cohort. Increasing IC expression post RT was associated with a more aggressive tumour phenotype and adverse features of tumour biology. The use of anti-PD-1 and anti-PD-L1 immunotherapies in combination with radiation resulted in a significant and synergistic reduction in viability of both radiosensitive and radioresistant OAC cells in vitro. Interleukin-21 (IL-21) and IL-31 significantly increased, with a concomitant reduction in IL-23 as a consequence of 4 Gray radiation. Similarly, radiation induced an anti-angiogenic tumour milieu with reduced expression of vascular endothelial growth factor-A, basic fibroblast growth factor, Flt-1 and placental growth factor. CONCLUSION The findings of the current study demonstrate synergistic potential for the use of ICIs and ionising radiation to potentiate established anti-tumour responses in the neoadjuvant setting and is of particular interest in those with advanced disease, adverse features of tumour biology and poor treatment responses to conventional therapies.
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Affiliation(s)
- Noel E Donlon
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Maria Davern
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Fiona O’Connell
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Andrew Sheppard
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Aisling Heeran
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Anshul Bhardwaj
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Christine Butler
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Ravi Narayanasamy
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Claire Donohoe
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - James J Phelan
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Niamh Lynam-Lennon
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Margaret R Dunne
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Stephen Maher
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Jacintha O’Sullivan
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - John V Reynolds
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
| | - Joanne Lysaght
- Department of Surgery, Trinity Translational Medicine Institute, St James Hospital, Dublin D08, Ireland
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12
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Chouaïd C, Grumberg V, Batisse A, Corre R, Giaj Levra M, Gaudin AF, Prodel M, Lortet-Tieulent J, Assié JB, Cotté FE. Machine Learning-Based Analysis of Treatment Sequences Typology in Advanced Non-Small-Cell Lung Cancer Long-Term Survivors Treated With Nivolumab. JCO Clin Cancer Inform 2022; 6:e2100108. [PMID: 35113656 PMCID: PMC8824409 DOI: 10.1200/cci.21.00108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Immune checkpoint inhibitors substantially changed advanced non-small-cell lung cancer (aNSCLC) management and can lead to long-term survival. The aims of this study were (1) to use a machine learning method to establish a typology of treatment sequences on patients with aNSCLC who were alive 2 years after initiating a treatment with anti-programmed death-ligand 1 monoclonal antibody nivolumab and (2) to describe the patients' characteristics according to the typology of treatment sequences. MATERIALS AND METHODS This retrospective observational study was based on data from the comprehensive French hospital discharge database for all patients with lung cancer with at least one line of platinum-based chemotherapy, starting nivolumab between January 1, 2015, and December 31, 2016, and alive 2 years after nivolumab treatment initiation. Patients were followed until December 31, 2018. A typology of most common treatment sequences was established using hierarchical clustering with time sequence analysis. RESULTS Two thousand two hundred twelve study patients were, on average, 63.0 years old, 69.9% of them were men, and 61.9% had a nonsquamous cell carcinoma. During the 2 years after nivolumab treatment initiation, clusters of patients with four basic types of treatment sequences were identified: (1) almost continuous nivolumab treatment (44% of patients); (2) nivolumab most of the time followed by a treatment-free interval or a chemotherapy (15% of patients); and a short or medium nivolumab treatment, followed by (3) a long systemic treatment-free interval (17% of patients) or (4) a long chemotherapy (23% of patients). CONCLUSION This machine learning approach enabled the identification of a typology of four representative treatment sequences observed in long-term survival. It was noted that most long-term survivors were treated with nivolumab for well over 1 year.
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Affiliation(s)
- Christos Chouaïd
- Service de pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France
| | | | | | - Romain Corre
- Centre Hospitalier Intercommunal de Cornouaille, Quimper, France
| | - Matteo Giaj Levra
- Centre Hospitalier Universitaire Grenoble Alpes (CHUGA), Grenoble, France
| | | | | | | | - Jean-Baptiste Assié
- Service de pneumologie, Centre Hospitalier Intercommunal de Créteil, Créteil, France.,Centre de Recherche des Cordeliers, Inserm, Université de Paris, Sorbonne Université, Functional Genomics of Solid Tumors Laboratory, Paris, France
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13
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Peng Y, Zhang C, Rui Z, Tang W, Xu Y, Tao X, Zhao Q, Tong X. A comprehensive profiling of soluble immune checkpoints from the sera of patients with non-small cell lung cancer. J Clin Lab Anal 2022; 36:e24224. [PMID: 35019173 PMCID: PMC8841185 DOI: 10.1002/jcla.24224] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/10/2021] [Accepted: 12/27/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Immunotherapy was widely used for the treatment of non-small cell lung cancer (NSCLC). However, whether inhibition of immune checkpoints individually or simultaneously could improve the therapeutic efficacy of NSCLC remains to be investigated. Here, we explored the aberrant levels of several checkpoints and evaluated their potential diagnostic values for NSCLC. METHODS Serum samples of 89 NSCLC patients and 57 healthy donors were collected from Nanjing Drum Tower Hospital between November 2019 and July 2020. Fourteen human immune checkpoints were quantified by Procarta-Plex Human Immuno-Oncology Checkpoint Panel. RESULTS The expression levels of sTIM-3, sCD137, sCD27, sLAG-3, sIDO, sPD-L2, sCD152, sCD80, and sPD-1 were all significantly increased in serum of NSCLC patients. Especially, sLAG-3 was significantly elevated in serum of NSCLC patients at early-stage (stages I and II), TIM-3, CD137, and CD27 were significantly higher in the advanced NSCLC patients (stages III and IV) than in the early-stage groups. Receiver operating characteristics (ROC) results showed that except for PD-1, all the other immune checkpoint proteins had potential diagnostic values for NSCLC. sTIM-3 had the highest diagnostic accuracy, followed by sLAG-3. Combining sTIM-3, sLAG-3, and sCD137 could increase the accuracy to a higher level. Moreover, sCD27 was correlated with NSCLC cancer type, age, sex, and disease stage, while sCD137 was correlated with age and disease stage. sTIM-3 and sIDO were correlated with stage and age, respectively. CONCLUSIONS TIM-3 and LAG-3 were independent biomarkers for the early diagnosis of NSCLC. The combination of TIM-3, LAG-3, and CD137 could increase the diagnostic accuracy.
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Affiliation(s)
- Ying Peng
- Department of Clinical Laboratory, Liyang People's Hospital, Liyang, China
| | - Chen Zhang
- Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Zhilian Rui
- Department of Clinical Laboratory, Liyang People's Hospital, Liyang, China
| | - Weiming Tang
- Department of Clinical Laboratory, Liyang People's Hospital, Liyang, China
| | - Yan Xu
- Department of Clinical Laboratory, Liyang People's Hospital, Liyang, China
| | - Xiaoxin Tao
- Department of Oncology, Liyang People's Hospital, Liyang, China
| | - Qi Zhao
- Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Xin Tong
- Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
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14
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Luna J, Zafra J, Areses Manrique MC, Rodríguez A, Sotoca A, Fírvida JL, Chicas-Sett R, Mielgo X, Reyes JCT, Couñago F. New challenges in the combination of radiotherapy and immunotherapy in non-small cell lung cancer. World J Clin Oncol 2021; 12:983-999. [PMID: 34909394 PMCID: PMC8641011 DOI: 10.5306/wjco.v12.i11.983] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 07/06/2021] [Accepted: 10/12/2021] [Indexed: 02/06/2023] Open
Abstract
Immunotherapy has represented one of the main medical revolutions of recent decades, and is currently a consolidated treatment for different types of tumors at different stages and scenarios, and is present in a multitude of clinical trials. One of the diseases in which it is most developed is non-small cell lung cancer. The combination of radiotherapy and immunotherapy in cancer in general and lung cancer in particular currently represents one of the main focuses of basic and clinical research in oncology, due to the synergy of this interaction, which can improve tumor response, resulting in improved survival and disease control. In this review we present the biochemical and molecular basis of the interaction between radiotherapy and immunotherapy. We also present the current clinical status of this interaction in each of the stages and cases of non-small cell lung cancer, with the main results obtained in the different studies both in terms of tumor response and survival as well as toxicity. Finally, we mention the main studies underway and the challenges of this interaction in the coming years, including how these treatments should be combined to achieve the greatest efficacy with the fewest possible side effects (dose, type of radiotherapy and drugs, sequence of treatments).
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Affiliation(s)
- Javier Luna
- Department of Radiation Oncology, Oncohealth Institute, Fundación Jiménez Díaz, Madrid 28040, Spain
| | - Juan Zafra
- Department of Radiation Oncology, Dr. Negrín University Hospital of Gran Canaria, Las Palmas 35010, Spain
| | | | - Aurora Rodríguez
- Department of Radiation Oncology, Ruber International Hospital, Madrid 28034, Spain
| | - Amalia Sotoca
- Department of Radiation Oncology, Ruber International Hospital, Madrid 28034, Spain
| | - Jose Luis Fírvida
- Department of Medical Oncology, Ourense University Hospital, Ourense 32005, Spain
| | - Rodolfo Chicas-Sett
- Department of Radiation Oncology, Dr. Negrín University Hospital of Gran Canaria, Las Palmas 35010, Spain
| | - Xabier Mielgo
- Department of Medical Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón 28922, Spain
| | | | - Felipe Couñago
- Department of Radiation Oncology, Hospital Universitario QuirónSalud Madrid, Hospital La Luz, Universidad Europea de Madrid, Madrid 28223, Spain
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15
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Vilinovszki O, Andratschke N, Huellner M, Curioni-Fontecedro A, Kroeze SGC. True abscopal effect in a patient with metastatic non-small cell lung cancer. Radiat Oncol 2021; 16:194. [PMID: 34600561 PMCID: PMC8487536 DOI: 10.1186/s13014-021-01920-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 09/17/2021] [Indexed: 11/27/2022] Open
Abstract
Background Systemic response to local anticancer treatment is a phenomenon called ‘abscopal effect’. The immune system is thought to play a pivotal role in its occurrence. To date, several cases have been reported, particularly in patients receiving combined local treatment and immune checkpoint inhibitors. In such cases, it is impossible to discriminate between the effects of local and systemic treatment. Only a few cases of abscopal effect have been described with radiotherapy alone. Case presentation Here, we report on the case of an 81-year-old woman with recurrent metastatic squamous cell carcinoma of the lung with mediastinal tumor bulk, lymph node and bone metastases. The patient refused to undergo systemic treatment, and palliative stereotactic radiotherapy of the mediastinal tumor was performed. At restaging with FDG-PET/CT, the patient presented with a decrease in size and FDG-avidity both of the irradiated site and of the lymph node and bone metastases (which did not receive radiotherapy). At 25 months after radiotherapy, the patient is still in remission at all sites. Conclusions This is a rare case of an abscopal effect after radiotherapy as monotherapy. It is one of the few hitherto reported for lung cancer. Several ongoing studies with a combination of radiotherapy and immunotherapy are seeking to exploit a potential synergy to induce abscopal effects.
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Affiliation(s)
- Oliver Vilinovszki
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.
| | - Nicolaus Andratschke
- Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Martin Huellner
- Department of Nuclear Medicine, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Alessandra Curioni-Fontecedro
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Stephanie G C Kroeze
- Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland
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16
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Batool S, Bin-T-Abid D, Batool H, Shahid S, Saleem M, Khan AU, Hamid A, Mahmood MS, Ashraf NM. Development of multi-epitope vaccine constructs for non-small cell lung cancer (NSCLC) against USA human leukocyte antigen background: an immunoinformatic approach toward future vaccine designing. Expert Opin Biol Ther 2021; 21:1525-1533. [PMID: 34547976 DOI: 10.1080/14712598.2021.1981285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
OBJECTIVES The design of peptide-based vaccines for cancer is a promising immunotherapy that can induce a cancer-specific cytotoxic response in tumor cells. METHODS Herein, we used the immunoinformatic approach in designing a multi-epitope vaccine targeting G-protein coupled receptor 87 (GPCR-87), cystine/glutamate transporter (SLC7A11), Immunoglobulin binding protein 1 (IGBP1), and thioredoxin domain-containing protein 5 (TXNDC5), which can potentially contribute to NSCLC. The MHC-I and MHC-II epitopes selected for the fusion construct were evaluated for their antigenic and non-allergenic natures via VaxiJen and AllerTop. RESULTS A total of five epitopes, four class-I (FIFYLKNIV, CRYTSVLFY, RYLKVVKPF, and RQAKIQRYK), and one class-II (NQVRGYPTLLWFRDG), having combined USA population coverage of 100%, were used to make ten possible multi-epitope fusion constructs. In these constructs, PADRE, a universal T-helper epitope, and RSO9, a TLR4 agonist, were fused as adjuvants. The molecular docking analysis revealed that two constructs were showing significant binding affinities toward HLA-A*02:01, the most prevalent HLA allele in USA. Moreover, MD simulations marked one construct as a promising therapeutic candidate. CONCLUSION The multi-epitope vaccine constructs designed using immunogenic, and non-allergenic peptides of NSCLS tumor-associated proteins are likely to pose significant therapeutic efficacies in cancer immunotherapy due to their high binding affinities toward HLA molecules.
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Affiliation(s)
- Sana Batool
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan.,School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Duaa Bin-T-Abid
- School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Hina Batool
- Department of Life Science, School of Science, University of Management Technology, Lahore, Pakistan
| | - Saher Shahid
- School of Biological Sciences, University of the Punjab, Lahore, Pakistan
| | - Mahjabeen Saleem
- School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Azmat Ullah Khan
- Department of Biochemistry and Biotechnology, University of Gujrat, Gujrat Pakistan
| | | | - Malik Siddique Mahmood
- School of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan.,Department of Biochemistry, Nur International University, Lahore, Pakistan
| | - Naeem Mahmood Ashraf
- Department of Biochemistry and Biotechnology, University of Gujrat, Gujrat Pakistan
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Cai Z, Lim D, Liu G, Chen C, Jin L, Duan W, Ding C, Sun Q, Peng J, Dong C, Zhang F, Feng Z. Valproic Acid-Like Compounds Enhance and Prolong the Radiotherapy Effect on Breast Cancer by Activating and Maintaining Anti-Tumor Immune Function. Front Immunol 2021; 12:646384. [PMID: 34054811 PMCID: PMC8149798 DOI: 10.3389/fimmu.2021.646384] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Inadequate sustained immune activation and tumor recurrence are major limitations of radiotherapy (RT), sustained and targeted activation of the tumor microenvironment can overcome this obstacle. Here, by two models of a primary rat breast cancer and cell co-culture, we demonstrated that valproic acid (VPA) and its derivative (HPTA) are effective immune activators for RT to inhibit tumor growth by inducing myeloid-derived macrophages and polarizing them toward the M1 phenotype, thus elevate the expression of cytokines such as IL-12, IL-6, IFN-γ and TNF-α during the early stage of the combination treatment. Meanwhile, activated CD8+ T cells increased, angiogenesis of tumors is inhibited, and the vasculature becomes sparse. Furthermore, it was suggested that VPA/HPTA can enhance the effects of RT via macrophage-mediated and macrophage-CD8+ T cell-mediated anti-tumor immunity. The combination of VPA/HPTA and RT treatment slowed the growth of tumors and prolong the anti-tumor effect by continuously maintaining the activated immune response. These are promising findings for the development of new effective, low-cost concurrent cancer therapy.
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Affiliation(s)
- Zuchao Cai
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - David Lim
- School of Health Sciences, Western Sydney University, Campbelltown, NSW, Australia
- College of Medicine and Public Health, Flinders University, Bedford Park, SA, Australia
| | - Guochao Liu
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chen Chen
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Liya Jin
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wenhua Duan
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chenxia Ding
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Qingjie Sun
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Junxuan Peng
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Chao Dong
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Fengmei Zhang
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Zhihui Feng
- Department of Occupational Health and Occupational Medicine, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, China
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18
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Yu XH, Huang J, Ge NJ, Yang YF, Zhao JY. Recurrent undifferentiated embryonal sarcoma of the liver in adult patient treated by pembrolizumab: A case report. World J Clin Cases 2021; 9:2281-2288. [PMID: 33869604 PMCID: PMC8026828 DOI: 10.12998/wjcc.v9.i10.2281] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/30/2020] [Accepted: 01/26/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Undifferentiated embryonal sarcoma of the liver (UESL) is a neoplasm that rarely develops in adults. The main treatments for UESL are upfront gross total surgical resection and adjuvant multiagent chemotherapy. Here, we report a case of recurrent UESL in an adult treated with pembrolizumab and discuss a method to identify proper candidates for antibody of programmed cell death protein 1 (anti-PD-1) treatment.
CASE SUMMARY A 69-year-old woman was admitted for abdominal pain that developed for 1 wk. Computed tomography showed a 16 cm mass in the right lobe of the liver. Right hemihepatectomy and lymphadenectomy were performed, and histological diagnosis was UESL. Six months later, the patient suffered from painless obstructive jaundice, and positron emission tomography-computed tomography revealed multiple metastases. Then, percutaneous transhepatic cholangial drainage was applied to reduce jaundice, and radiofrequency ablation was used to control the lesion near the hepatic hilum. However, the patient suffered from a serious fever caused by the tumor. The patient received treatment with pembrolizumab, and the prescribed dosage was 2 mg/kg every 3 wk. After the seventh dose, positron emission tomography-computed tomography revealed that the multiple metastases had nearly disappeared. Radiologic exam was used to evaluate the disease state, and no new lesions were found. Next-generation sequencing and immunohistology were applied to determine the reason why the patient had such a favorable response to pembrolizumab. Tumor mutation burden, microsatellite instability, and programmed death ligand 1 expression can be combined to predict the effect of PD-1 antibodies. When every one of these biomarkers are detected in a tumor patient, the patient may be a proper candidate for PD-1 antibodies.
CONCLUSION Anti-PD-1 treatment for tumors needs further research to identify indications and proper biomarkers.
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Affiliation(s)
- Xiao-He Yu
- Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China
- Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai 200092, China
| | - Jian Huang
- Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China
| | - Nai-Jian Ge
- Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China
| | - Ye-Fa Yang
- Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200438, China
| | - Jin-Yan Zhao
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China
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19
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Goff PH, Zeng J, Rengan R, Schaub SK. Radiation and Modulation of the Tumor Immune Microenvironment in Non-Small Cell Lung Cancer. Semin Radiat Oncol 2021; 31:133-139. [PMID: 33610270 DOI: 10.1016/j.semradonc.2020.11.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Immune checkpoint inhibitors are approved for a variety of indications for locally advanced and metastatic non-small cell lung cancer (NSCLC), and trials are ongoing in the early-stage setting. There is an unmet need to understand which patients may derive benefit from immunotherapies and how to harness combined modality therapies to improve overall response rates and durability. Here, we review studies from the bench-to-bedside to examine the role of radiation therapy (RT) on the tumor immune microenvironment in NSCLC with an eye toward augmenting antitumor immunity. Together, these data provide a foundation for developing future clinical trials harnessing RT to augment antitumor immunity and highlight the need for correlative translational studies to directly characterize the impact of RT on the human NSCLC tumor immune microenvironment.
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Affiliation(s)
- Peter H Goff
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA.
| | - Jing Zeng
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA
| | - Ramesh Rengan
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA
| | - Stephanie K Schaub
- University of Washington School of Medicine, Department of Radiation Oncology, Seattle WA
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20
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Frąk M, Krawczyk P, Kalinka E, Milanowski J. Molecular and Clinical Premises for the Combination Therapy Consisting of Radiochemotherapy and Immunotherapy in Non-Small Cell Lung Cancer Patients. Cancers (Basel) 2021; 13:1222. [PMID: 33799560 PMCID: PMC8000833 DOI: 10.3390/cancers13061222] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 03/05/2021] [Accepted: 03/08/2021] [Indexed: 12/25/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common malignancies around the world. Due to the advanced stage of the disease at the time of diagnosis, most patients require systemic treatment. Immunotherapy with immune checkpoints inhibitors is becoming the main treatment method for many cancers, including NSCLC. Numerous studies have shown greater efficacy of immunotherapy used monoclonal antibodies anti-PD-1 (pembrolizumab and nivolumab) or anti-PD-L1 (atezolizumab and durvalumab) compared to chemotherapy. Unfortunately, cancer cells can develop a number of mechanisms to escape from immune surveillance, including avoidance of cancer cells by the immune system (immune desert), production of immunosuppressive compounds (prostaglandins, IDO, TGF-beta), or direct immune checkpoints interactions. Therapy based on the use of radiochemotherapy with subsequent immunotherapy is becoming the main focus of research in the field of new NSCLC therapies. Radiation therapy stimulates the immune response multidirectionally, affects production of neoantigens and proinflammatory compounds, which transform non-immunogenic ("cold") tumors into highly immunogenic ("hot") tumors. As a result, the mechanisms of escape of cancer cells from immune surveillance break down and the effectiveness of immunotherapy increases significantly. The results of clinical trials in this area bring new hope and indicate greater effectiveness of such treatment in terms of prolongation of progression-free survival and overall survival.
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Affiliation(s)
- Małgorzata Frąk
- Chair and Department of Pneumology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland; (P.K.); (J.M.)
| | - Paweł Krawczyk
- Chair and Department of Pneumology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland; (P.K.); (J.M.)
| | - Ewa Kalinka
- Department of Oncology, Polish Mother’s Memorial Hospital Research Institute in Lodz, 93-338 Lodz, Poland;
| | - Janusz Milanowski
- Chair and Department of Pneumology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland; (P.K.); (J.M.)
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21
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The NIPRO Study: An Observational, Retrospective, Multicenter Study on the Safety of the Radiotherapy and Immunotherapy Combination for Advanced-Stage NSCLC. Clin Lung Cancer 2021; 22:e767-e773. [PMID: 33766477 DOI: 10.1016/j.cllc.2021.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 12/29/2020] [Accepted: 02/05/2021] [Indexed: 02/07/2023]
Abstract
INTRODUCTION In this observational, retrospective, multicenter study, we aimed to assess the safety of the combination of local metastasis-directed radiotherapy (RT) and immunotherapy (IT) in a cohort of advanced non-small-cell lung cancer (aNSCLC) patients. MATERIAL AND METHODS We collected clinical data of aNSCLC patients who received concomitant RT and anti-PD-1/PD-L1 inhibitors in seven Italian centers from September 2015 to June 2019. Concomitant RT was defined as delivered ≤4 weeks before or after the first or last administration of immunotherapy, or within two consecutive cycles of ICI. All adverse events apparently related to RT and/or IT were graded according to the Common Terminology Criteria for Adverse Events, version 4.0, and reported in terms of incidence and severity as immune related or RT related, or combined. RESULTS We analyzed the clinical charts of 187 patients. Median follow-up time was 23 months, and median overall survival was 16.5 months (range, 3-162). Thirteen patients developed pure RT-related side effects, and 43 patients (23.9%) developed immune-related side effects. No additive toxic effects were observed. A case of grade 5 pulmonary toxicity was recorded as a possible consequence of a combined effect. CONCLUSION This analysis suggests that the combination of concomitant RT and anti-PD-1/PD-L1 agents is safe, and the two toxicity profiles are independent.
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22
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Suraweera A, Duijf PHG, Jekimovs C, Schrobback K, Liu C, Adams MN, O’Byrne KJ, Richard DJ. COMMD1, from the Repair of DNA Double Strand Breaks, to a Novel Anti-Cancer Therapeutic Target. Cancers (Basel) 2021; 13:830. [PMID: 33669398 PMCID: PMC7920454 DOI: 10.3390/cancers13040830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/24/2022] Open
Abstract
Lung cancer has the highest incidence and mortality among all cancers, with non-small cell lung cancer (NSCLC) accounting for 85-90% of all lung cancers. Here we investigated the function of COMMD1 in the repair of DNA double strand breaks (DSBs) and as a prognostic and therapeutic target in NSCLC. COMMD1 function in DSB repair was investigated using reporter assays in COMMD1-siRNA-depleted cells. The role of COMMD1 in NSCLC was investigated using bioinformatic analysis, qRT-PCR and immunoblotting of control and NSCLC cells, tissue microarrays, cell viability and cell cycle experiments. DNA repair assays demonstrated that COMMD1 is required for the efficient repair of DSBs and reporter assays showed that COMMD1 functions in both non-homologous-end-joining and homologous recombination. Bioinformatic analysis showed that COMMD1 is upregulated in NSCLC, with high levels of COMMD1 associated with poor patient prognosis. COMMD1 mRNA and protein were upregulated across a panel of NSCLC cell lines and siRNA-mediated depletion of COMMD1 decreased cell proliferation and reduced cell viability of NSCLC, with enhanced death after exposure to DNA damaging-agents. Bioinformatic analyses demonstrated that COMMD1 levels positively correlate with the gene ontology DNA repair gene set enrichment signature in NSCLC. Taken together, COMMD1 functions in DSB repair, is a prognostic maker in NSCLC and is potentially a novel anti-cancer therapeutic target for NSCLC.
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Affiliation(s)
- Amila Suraweera
- School of Biomedical Sciences, Centre for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology (QUT), 37 Kent Street, Woolloongabba, QLD 4102, Australia; (P.H.G.D.); (C.J.); (K.S.); (M.N.A.); (K.J.O.)
- Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD 4102, Australia
| | - Pascal H. G. Duijf
- School of Biomedical Sciences, Centre for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology (QUT), 37 Kent Street, Woolloongabba, QLD 4102, Australia; (P.H.G.D.); (C.J.); (K.S.); (M.N.A.); (K.J.O.)
- Centre for Data Science, Queensland University of Technology (QUT), Brisbane, QLD 4000, Australia
- University of Queensland Diamantina Institute, University of Queensland, Brisbane, QLD 4102, Australia
| | - Christian Jekimovs
- School of Biomedical Sciences, Centre for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology (QUT), 37 Kent Street, Woolloongabba, QLD 4102, Australia; (P.H.G.D.); (C.J.); (K.S.); (M.N.A.); (K.J.O.)
| | - Karsten Schrobback
- School of Biomedical Sciences, Centre for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology (QUT), 37 Kent Street, Woolloongabba, QLD 4102, Australia; (P.H.G.D.); (C.J.); (K.S.); (M.N.A.); (K.J.O.)
| | - Cheng Liu
- QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia;
- Envoi Specialist Pathologists, 5/38 Bishop Street, Kelvin Grove, QLD 4059, Australia
| | - Mark N. Adams
- School of Biomedical Sciences, Centre for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology (QUT), 37 Kent Street, Woolloongabba, QLD 4102, Australia; (P.H.G.D.); (C.J.); (K.S.); (M.N.A.); (K.J.O.)
- Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD 4102, Australia
| | - Kenneth J. O’Byrne
- School of Biomedical Sciences, Centre for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology (QUT), 37 Kent Street, Woolloongabba, QLD 4102, Australia; (P.H.G.D.); (C.J.); (K.S.); (M.N.A.); (K.J.O.)
- Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD 4102, Australia
| | - Derek J. Richard
- School of Biomedical Sciences, Centre for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology (QUT), 37 Kent Street, Woolloongabba, QLD 4102, Australia; (P.H.G.D.); (C.J.); (K.S.); (M.N.A.); (K.J.O.)
- Princess Alexandra Hospital, 199 Ipswich Road, Woolloongabba, QLD 4102, Australia
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23
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Procureur A, Simonaggio A, Bibault JE, Oudard S, Vano YA. Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments. Cancers (Basel) 2021; 13:678. [PMID: 33567530 PMCID: PMC7915834 DOI: 10.3390/cancers13040678] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.
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Affiliation(s)
- Adrien Procureur
- Hôpital Européen Georges Pompidou, Service d’Oncologie Médicale, Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, F-75015 Paris, France; (A.P.); (A.S.); (S.O.)
| | - Audrey Simonaggio
- Hôpital Européen Georges Pompidou, Service d’Oncologie Médicale, Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, F-75015 Paris, France; (A.P.); (A.S.); (S.O.)
| | - Jean-Emmanuel Bibault
- Hôpital Européen Georges Pompidou, Service d’Oncologie Radiothérapie, Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, F-75015 Paris, France;
| | - Stéphane Oudard
- Hôpital Européen Georges Pompidou, Service d’Oncologie Médicale, Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, F-75015 Paris, France; (A.P.); (A.S.); (S.O.)
| | - Yann-Alexandre Vano
- Hôpital Européen Georges Pompidou, Service d’Oncologie Médicale, Assistance Publique-Hôpitaux de Paris (AP-HP) Paris-Centre, F-75015 Paris, France; (A.P.); (A.S.); (S.O.)
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, F-75006 Paris, France
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24
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Donlon NE, Power R, Hayes C, Davern M, Reynolds JV, Lysaght J. Radiation and Immunotherapy in Upper Gastrointestinal Cancers: The Current State of Play. Int J Mol Sci 2021; 22:1071. [PMID: 33499003 PMCID: PMC7865314 DOI: 10.3390/ijms22031071] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 02/06/2023] Open
Abstract
Radiotherapy remains one of the contemporary cornerstones of cancer treatment in the neoadjuvant, curative, adjuvant and palliative settings, either in isolation or as a multimodal approach. Moreover, recent advances in targeted immune checkpoint therapy have firmly established immunotherapy as the fourth pillar in cancer therapy alongside surgery, chemotherapy and notably radiotherapy. There is emerging evidence to suggest both radioresistance and reduced efficacy of immune checkpoint blockade (ICB) are potentiated by the tumour microenvironment (TME) and in fact modulating aspects of this immunosuppressive milieu is instrumental to unlocking anti-tumour immunity. The response rates of Upper Gastrointestinal (UGI) malignancies to ICB remains modest at 10-15%, compared to melanoma at 20-40%. Harnessing the effects of radiotherapy through remodelling of the TME using ICB as a radiosensitisor is an avenue showing promise. Here we explore the rationale behind combining radiotherapy with ICB, as a symbiotic relationship in shifting the balance in favour of anti-tumour immunity. We discuss the effects of radiotherapy on immunogenic cell death, the concept of the abscopal effect, the importance of the cGAS STING pathway, and their relevance in the context of the tumour microenvironment. Furthermore, dosing and timing of radiotherapy and ICB is now being evaluated for its synergistic effects on host tumour immunity, and we review the ongoing efforts and current available literature for single agent and dual agent ICB in combination multimodal therapy for both locally advanced operable and metastatic disease of the upper gastrointestinal tract.
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Affiliation(s)
- Noel E. Donlon
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin 8, Ireland; (N.E.D.); (R.P.); (C.H.); (M.D.); (J.V.R.)
- Trinity St James’ Cancer Institute, St James’s Hospital Dublin, Dublin 8, Ireland
| | - Robert Power
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin 8, Ireland; (N.E.D.); (R.P.); (C.H.); (M.D.); (J.V.R.)
- Trinity St James’ Cancer Institute, St James’s Hospital Dublin, Dublin 8, Ireland
| | - Conall Hayes
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin 8, Ireland; (N.E.D.); (R.P.); (C.H.); (M.D.); (J.V.R.)
- Trinity St James’ Cancer Institute, St James’s Hospital Dublin, Dublin 8, Ireland
| | - Maria Davern
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin 8, Ireland; (N.E.D.); (R.P.); (C.H.); (M.D.); (J.V.R.)
- Trinity St James’ Cancer Institute, St James’s Hospital Dublin, Dublin 8, Ireland
| | - John V. Reynolds
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin 8, Ireland; (N.E.D.); (R.P.); (C.H.); (M.D.); (J.V.R.)
- Trinity St James’ Cancer Institute, St James’s Hospital Dublin, Dublin 8, Ireland
| | - Joanne Lysaght
- Department of Surgery, School of Medicine, Trinity College Dublin, Dublin 8, Ireland; (N.E.D.); (R.P.); (C.H.); (M.D.); (J.V.R.)
- Trinity St James’ Cancer Institute, St James’s Hospital Dublin, Dublin 8, Ireland
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25
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Sun R, Sundahl N, Hecht M, Putz F, Lancia A, Rouyar A, Milic M, Carré A, Battistella E, Alvarez Andres E, Niyoteka S, Romano E, Louvel G, Durand-Labrunie J, Bockel S, Bahleda R, Robert C, Boutros C, Vakalopoulou M, Paragios N, Frey B, Soria JC, Massard C, Ferté C, Fietkau R, Ost P, Gaipl U, Deutsch E. Radiomics to predict outcomes and abscopal response of patients with cancer treated with immunotherapy combined with radiotherapy using a validated signature of CD8 cells. J Immunother Cancer 2020; 8:jitc-2020-001429. [PMID: 33188037 PMCID: PMC7668366 DOI: 10.1136/jitc-2020-001429] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/29/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Combining radiotherapy (RT) with immuno-oncology (IO) therapy (IORT) may enhance IO-induced antitumor response. Quantitative imaging biomarkers can be used to provide prognosis, predict tumor response in a non-invasive fashion and improve patient selection for IORT. A biologically inspired CD8 T-cells-associated radiomics signature has been developed on previous cohorts. We evaluated here whether this CD8 radiomic signature is associated with lesion response, whether it may help to assess disease spatial heterogeneity for predicting outcomes of patients treated with IORT. We also evaluated differences between irradiated and non-irradiated lesions. METHODS Clinical data from patients with advanced solid tumors in six independent clinical studies of IORT were investigated. Immunotherapy consisted of 4 different drugs (antiprogrammed death-ligand 1 or anticytotoxic T-lymphocyte-associated protein 4 in monotherapy). Most patients received stereotactic RT to one lesion. Irradiated and non-irradiated lesions were delineated from baseline and the first evaluation CT scans. Radiomic features were extracted from contrast-enhanced CT images and the CD8 radiomics signature was applied. A responding lesion was defined by a decrease in lesion size of at least 30%. Dispersion metrices of the radiomics signature were estimated to evaluate the impact of tumor heterogeneity in patient's response. RESULTS A total of 94 patients involving multiple lesions (100 irradiated and 189 non-irradiated lesions) were considered for a statistical interpretation. Lesions with high CD8 radiomics score at baseline were associated with significantly higher tumor response (area under the receiving operating characteristic curve (AUC)=0.63, p=0.0020). Entropy of the radiomics scores distribution on all lesions was shown to be associated with progression-free survival (HR=1.67, p=0.040), out-of-field abscopal response (AUC=0.70, p=0.014) and overall survival (HR=2.08, p=0.023), which remained significant in a multivariate analysis including clinical and biological variables. CONCLUSIONS These results enhance the predictive value of the biologically inspired CD8 radiomics score and suggests that tumor heterogeneity should be systematically considered in patients treated with IORT. This CD8 radiomics signature may help select patients who are most likely to benefit from IORT.
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Affiliation(s)
- Roger Sun
- Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France.,Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France.,Paris-Saclay University Faculty of Medicine, Le Kremlin-Bicetre, Île-de-France, France
| | - Nora Sundahl
- Department of Radiation Oncology, University Hospital Ghent, Gent, Oost-Vlaanderen, Belgium
| | - Markus Hecht
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Florian Putz
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Andrea Lancia
- Department of Radiation Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Lombardia, Italy
| | - Angela Rouyar
- Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France
| | - Marina Milic
- Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France
| | - Alexandre Carré
- Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France.,Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France
| | - Enzo Battistella
- Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France
| | - Emilie Alvarez Andres
- Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France.,TheraPanacea, Paris, France
| | - Stéphane Niyoteka
- Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France
| | - Edouard Romano
- Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France
| | - Guillaume Louvel
- Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France
| | | | - Sophie Bockel
- Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France.,Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France.,Paris-Saclay University Faculty of Medicine, Le Kremlin-Bicetre, Île-de-France, France
| | - Rastilav Bahleda
- Drug Development Department, Gustave Roussy, Villejuif, Île-de-France, France
| | - Charlotte Robert
- Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France.,Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France
| | - Celine Boutros
- Departement of Medicine, Gustave Roussy, Villejuif, Île-de-France, France
| | | | - Nikos Paragios
- TheraPanacea, Paris, France.,CentraleSupélec, Gif-sur-Yvette, Île-de-France, France
| | - Benjamin Frey
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Jean-Charles Soria
- Departement of Medicine, Gustave Roussy, Villejuif, Île-de-France, France
| | - Christophe Massard
- Paris-Saclay University Faculty of Medicine, Le Kremlin-Bicetre, Île-de-France, France.,Drug Development Department, Gustave Roussy, Villejuif, Île-de-France, France
| | - Charles Ferté
- Departement of Medicine, Gustave Roussy, Villejuif, Île-de-France, France
| | - Rainer Fietkau
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Piet Ost
- Department of Radiation Oncology, University Hospital Ghent, Gent, Oost-Vlaanderen, Belgium
| | - Udo Gaipl
- Department of Radiation Oncology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Eric Deutsch
- Department of Radiation Oncology, Gustave Roussy, Villejuif, Île-de-France, France .,Institut Gustave Roussy, Inserm, Radiothérapie Moléculaire et Innovation Thérapeutique, Paris-Saclay University, Villejuif, Île-de-France, France.,Paris-Saclay University Faculty of Medicine, Le Kremlin-Bicetre, Île-de-France, France
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Outcomes in Patients With Non-small-cell Lung Cancer With Brain Metastases Treated With Pembrolizumab-based Therapy. Clin Lung Cancer 2020; 22:58-66.e3. [PMID: 33279417 DOI: 10.1016/j.cllc.2020.10.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 10/06/2020] [Accepted: 10/22/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND Patients with metastatic non-small-cell lung cancer (mNSCLC) and untreated brain metastases (BM) have been excluded from most trials of immune checkpoint inhibitors (ICIs). Real-world evidence on efficacy and survival outcomes of ICIs in patients with BM is limited. PATIENTS AND METHODS We conducted a single-center retrospective study of patients with mNSCLC treated with pembrolizumab with or without chemotherapy and compared progression-free survival (PFS) and overall survival (OS) between patients with and without BM using Kaplan-Meier and Cox methodology. We also characterized systemic and intracranial objective response rate (ORR) and treatment details, including timing of cranial irradiation. RESULTS Between Augutst 2013 and December 2018, 570 patients with mNSCLC treated with pembrolizumab-based therapy were analyzed. Of 126 (22.1%) patients with BM, 96 (76.2%) had treated BM (local therapy prior to pembrolizumab), and 30 (23.8%) had untreated BM. Of patients with untreated BM, 17 (56.7%) underwent radiation within 30 days after pembrolizumab initiation. In the remaining 13 (43.3%) treated with pembrolizumab-based therapy alone, intracranial ORR was 36.4%. Patients with and without BM did not have significantly different systemic ORR (27.8% vs. 29.7%; P = .671), PFS (mPFS 9.2 vs. 7.7 months; P = .609), or OS (mOS 18.0 vs. 18.7 months; P = .966). Factors associated with improved survival on Cox analysis included female gender, performance status, adenocarcinoma histology, and first-line therapy. CONCLUSIONS Patients with BM did not have inferior survival to patients without BM after treatment with pembrolizumab-based therapy. In the current era, BM may not automatically confer inferior survival, and should not exclude patients from receiving pembrolizumab-based therapy.
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Zou L, Chu L, Xia F, Zhou L, Yang X, Ni J, Chen J, Zhu Z. Is clinical target volume necessary?-a failure pattern analysis in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy using intensity-modulated radiotherapy technique. Transl Lung Cancer Res 2020; 9:1986-1995. [PMID: 33209618 PMCID: PMC7653148 DOI: 10.21037/tlcr-20-523] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Background Our previous dosimetric study showed that for locally advanced non-small cell lung cancer (LA-NSCLC), radiotherapy with intensity-modulated radiotherapy (IMRT) technique could deliver sufficient dose coverage to subclinical regions and reduce the dose to normal tissues with the omission of clinical target volume (CTV). To further clinically validate this strategy, we conducted the current study to analyze the failure pattern for patients with LA-NSCLC treated with concurrent chemotherapy and CTV-omitted IMRT. We also investigated the effects of target volumes on lymphopenia during radiotherapy to further test the potential benefits of CTV omission in anti-tumor immunotherapy. Methods A total of 63 patients with LA-NSCLC treated with CTV-omitted IMRT with concurrent chemotherapy were enrolled in this study. Their planning target volume (PTV) (also PTV-g) was expanded directly from gross tumor volume (GTV). A virtual CTV was expanded from GTV, and the PTV generated from virtual CTV was named planning target volume with CTV expansion (PTV-c). Treatment failures were divided into local, regional, and distant failures, and local–regional recurrences were classified into inside PTV-g (IN-PTV-g), between PTV-g and PTV-c (PTV-g-c), and outside PTV-c (OUT-PTV-c). The relationship between lymphopenia during radiotherapy and the target volumes was also evaluated using Spearman’s correlation analysis. Results Among the 60 patients with detailed follow-up data for recurrences, 46 (76.7%) experienced recurrences, with 18 (30.0%) being local recurrence, 5 (8.4%) being regional failure, and 33 (55.0%) being distant failure. For the 21 patients with local–regional recurrences, 16, 6, and 1 were IN-PTV-g, OUT-PTV-c, and PTV-g-c recurrences, respectively. Lymphopenia during radiotherapy was associated with both GTV and PTV, with larger volumes linked to severe lymphopenia. Conclusions CTV omission is feasible for LA-NSCLC treated with concurrent chemoradiotherapy and does not compromise failure inside the subclinical region. The radiation volumes were associated with lymphopenia during radiotherapy, with larger volumes related to severe lymphopenia. This finding supports the further exploration of CTV omission for immunotherapy.
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Affiliation(s)
- Liqing Zou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Li Chu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Lijun Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Xi Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Jianjiao Ni
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Junchao Chen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China
| | - Zhengfei Zhu
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Fudan University Shanghai Medical College, Shanghai, China.,Institute of Thoracic Oncology, Fudan University, Shanghai, China
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Bhargava A, Mishra DK, Tiwari R, Lohiya NK, Goryacheva IY, Mishra PK. Immune cell engineering: opportunities in lung cancer therapeutics. Drug Deliv Transl Res 2020; 10:1203-1227. [PMID: 32172351 DOI: 10.1007/s13346-020-00719-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Engineered immune cells offer a prime therapeutic alternate for some aggressive and frequently occurring malignancies like lung cancer. These therapies were reported to result in tumor regression and overall improvement in patient survival. However, studies also suggest that the presence of cancer cell-induced immune-suppressive microenvironment, off-target toxicity, and difficulty in concurrent imaging are some prime impendent in the success of these approaches. The present article reviews the need and significance of the currently available immune cell-based strategies for lung cancer therapeutics. It also showcases the utility of incorporating nanoengineered strategies and details the available formulations of nanocarriers. In last, it briefly discussed the existing methods for nanoparticle fuctionalization and challenges in translating basic research to the clinics. Graphical Abstract.
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Affiliation(s)
- Arpit Bhargava
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Kamla Nehru Hospital,, Building (Gandhi Medical College Campus), Bhopal, Madhya Pradesh, 462001, India
| | | | - Rajnarayan Tiwari
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Kamla Nehru Hospital,, Building (Gandhi Medical College Campus), Bhopal, Madhya Pradesh, 462001, India
| | | | - Irina Yu Goryacheva
- Department of General and Inorganic Chemistry, Saratov State University, Saratov, Russian Federation
| | - Pradyumna Kumar Mishra
- Department of Molecular Biology, ICMR-National Institute for Research in Environmental Health, Kamla Nehru Hospital,, Building (Gandhi Medical College Campus), Bhopal, Madhya Pradesh, 462001, India.
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Amin S, Baine MJ, Meza JL, Lin C. The Association of the Sequence of Immunotherapy With the Survival of Unresectable Pancreatic Adenocarcinoma Patients: A Retrospective Analysis of the National Cancer Database. Front Oncol 2020; 10:1518. [PMID: 32983998 PMCID: PMC7492650 DOI: 10.3389/fonc.2020.01518] [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: 04/28/2020] [Accepted: 07/15/2020] [Indexed: 12/21/2022] Open
Abstract
Background: Immunotherapy has shown great success in various malignancies. However, its efficacy in pancreatic ductal adenocarcinoma (PDAC) remains a challenge, and the lack of understanding about the appropriate timing of immunotherapy with other standard-of-care cancer treatments may be one of the causes. The objective of the current study is to investigate the impact of the timing of immunotherapy with chemotherapy and radiation therapy (RT) on the overall survival (OS) of PDAC patients who did not receive surgical resection of the pancreatic tumor. Materials and Methods: Patients with pancreatic adenocarcinoma who did not receive surgical resection of the pancreatic tumor were identified from the National Cancer Database (NCDB). Cox proportional hazard models were employed to compare the OS between patients who received immunotherapy with chemotherapy or RT with a different sequence of treatment. The multivariable analysis was adjusted for age of diagnosis, race, sex, place of living, income, education, treatment facility type, insurance status, and year of diagnosis. Results: In total, 705 patients received chemotherapy and immunotherapy, while 226 received radiation therapy and immunotherapy. In the multivariable analysis, there was no significant difference in the OS of patients who started immunotherapy 31–90 days before the start of chemotherapy with a hazard ratio (HR) of [HR:1.057 (CI: 0.716–1.56; p < 0.781)] and patients who started immunotherapy 91–180 days before the start of chemotherapy [HR: 0.900 (CI: 0.584–1.388; p < 0.635)] compared to patients who started chemotherapy and immunotherapy within 30 days of each other. There was also no significant difference in the OS of patients who started RT> 30 days before the start of immunotherapy [HR: 0.636 (CI: 0.346–1.171; p < 0.146)] and patients who started immunotherapy > 30 days before the start of RT [HR: 0.660 (CI: 0.328–1.329; p < 0.246)] compared to patients who started RT and immunotherapy within 30 days of each other. Conclusion: The sequence of immunotherapy with chemotherapy or RT was not associated with improved OS. Future studies with a larger subgroup sample size investigating the impact of the timing of immunotherapy with chemotherapy and RT on the OS of PDAC patients who do not receive surgical resection of the pancreatic tumor are needed.
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Affiliation(s)
- Saber Amin
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Michael J Baine
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Jane L Meza
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, United States
| | - Chi Lin
- Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States
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30
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Li L, Yue HC, Han YW, Liu W, Xiong LG, Zhang JW. Relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy and conventional fractionation radiotherapy in non-small cell lung Cancer. BMC Cancer 2020; 20:893. [PMID: 32942998 PMCID: PMC7500556 DOI: 10.1186/s12885-020-07403-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 09/14/2020] [Indexed: 02/08/2023] Open
Abstract
Background The effect of brachytherapy on lymphocytes and cytokines in the tumor microenvironment is unclear. This study aimed to analyze the relationship between the invasion of lymphocytes and cytokines in the tumor microenvironment and the interval after single brachytherapy hypofractionated radiotherapy (SBHFRT) and conventional fractionation radiotherapy (CFRT) in non-small cell lung cancer (NSCLC). Methods Lewis tumor-bearing mice were randomly divided into control, CFRT, and SBHFRT groups. On days 7 and 14 after radiation, the expression levels of CD86+, CD4+, CD8+, and Foxp3+ cells, and levels of Ki-67+ protein were detected by immunohistochemistry, and the tumor necrosis rate was calculated. Following this, the levels of interleukin-10 (IL-10), IL-12, and interferon-γ (IFN-γ) were detected by enzyme-linked immunosorbent assay. The apoptosis rate was evaluated via flow cytometry. The tumor volume and tumor growth inhibition rate (TGIR) were calculated on day 14. Tumor metabolism was assessed via 18F-FDG micropositron emission tomography/computer tomography. Results The tumor volume reduced by 22.0% and TGIR increased by 92.2% (p < 0.05) in the SBHFRT group. Further, on days 7 and 14 after radiation, tumor metabolism, Ki-67+ and Foxp3+ expression levels, and IL-10 levels were lower, and tumor necrosis and apoptosis rates; CD86+, CD4+, and CD8+ expression levels; and IL-12 and IFN-γ levels were higher in the SBHFRT group than in the CFRT group, particularly on day 7. Conclusion SBHFRT could lead to more accumulation of dendritic cells, anti-tumor lymphocytes, and cytokines, and further reduce the aggregation of immunosuppressive lymphocytes and cytokines in the tumor microenvironment compared with CFRT, and the difference was the most obvious on day 7 after radiation. The clinical significance of the findings remains to be further verified.
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Affiliation(s)
- Lin Li
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China
| | - Hong Cheng Yue
- Department of Oncology, Central Hospital of Bazhong, Bazhong, Sichuan, 636000, People's Republic of China
| | - Yun Wei Han
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China.,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People's Republic of China
| | - Wei Liu
- Department of Oncology, People's Hospital of Dazu District, Banan District, Chongqing, 402360, People's Republic of China
| | - Liang Geng Xiong
- Department of Oncology, People's Hospital of Chongqing Banan District, Banan District, Chongqing, 401320, People's Republic of China.
| | - Jian Wen Zhang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, 646000, People's Republic of China. .,Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou, Sichuan, People's Republic of China. .,Academician (Expert) workstation of Sichuan Province, Luzhou, Sichuan, People's Republic of China.
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31
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Li X, Wang L, Chen S, Zhou F, Zhao J, Zhao W, Su C. Adverse impact of bone metastases on clinical outcomes of patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer 2020; 11:2812-2819. [PMID: 32779372 PMCID: PMC7529562 DOI: 10.1111/1759-7714.13597] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/09/2020] [Accepted: 07/12/2020] [Indexed: 01/09/2023] Open
Abstract
Background Bone metastasis (BoM) is common in patients with advanced non‐small cell lung cancer (NSCLC) and considered as one of the negative prognostic factors. However, the impact of BoM on clinical outcomes of patients with advanced NSCLC treated with immune checkpoint inhibitors (ICIs) remains unclear. Methods A total of 103 patients treated with ICI monotherapy and 101 patients treated with ICIs combined with chemotherapy or antiangiogenesis therapy were retrospectively analyzed. The differences in progression‐free survival (PFS), overall survival (OS) and objective response rate (ORR) between BoM+ and BoM− were investigated. Results Of those 101 patients who received combination therapy, no significant difference between BoM− and BoM+ in terms of both median PFS and median OS (median PFS, 10.1 vs. 12.1 months, P = 0.6; median OS, NR vs. 24.6 months, P = 0.713) was determined. In contrast, of the 103 patients who received ICI monotherapy, BoM+ patients had an inferior PFS (4.2 vs. 6.7 months, P = 0.0484) and OS (12.5 vs. 23.9 months, P = 0.0036) compared with BoM− patients. The univariate and multivariate analysis in the ICI monotherapy group also identified BoM as an independent factor attenuating the efficacy of ICI monotherapy. Of all BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS (palliative radiotherapy: 12.5 vs. 16.7 months, P = 0.487; bisphosphonate drugs: 12.5 vs. 9.7 months, P = 0.568). Conclusions BoM attenuated the efficacy of ICI monotherapy in patients with advanced NSCLC. Of BoM+ patients who received ICI monotherapy, neither palliative radiotherapy nor bisphosphonate drugs improved OS. Other therapeutic strategies are needed for patients with BoM.
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Affiliation(s)
- Xing Li
- Medical Oncology Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China.,Department of Immuno-oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lei Wang
- Medical Oncology Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China
| | - Shanhao Chen
- Medical Oncology Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China
| | - Fei Zhou
- Medical Oncology Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China
| | - Jing Zhao
- Medical Oncology Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China
| | - Wencheng Zhao
- Medical Oncology Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China
| | - Chunxia Su
- Medical Oncology Department, Tongji University School of Medicine Affiliated Shanghai Pulmonary Hospital, Shanghai, China
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32
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Kuhara Y, Ninomiya M, Hirahara S, Doi H, Kenji S, Toyota K, Yano R, Kobayashi H, Hashimoto Y, Yokoyama Y, Sakashita Y, Miyamoto K. A long-term survival case of unresectable gastric cancer with multidisciplinary therapy including immunotherapy and abscopal effect. Int Cancer Conf J 2020; 9:193-198. [PMID: 32904110 DOI: 10.1007/s13691-020-00433-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Accepted: 07/13/2020] [Indexed: 01/13/2023] Open
Abstract
The prognosis of unresectable gastric cancer remains poor. Multidisciplinary treatment of unresectable gastric cancer is, therefore, thought to be essential for improving patients' outcomes. Here, we report a successful case of multidisciplinary therapy for unresectable gastric cancer. The patient was a 69-year-old woman who was diagnosed with type 2 gastric cancer with remote lymph node metastases and peritoneal dissemination. Although shrinkage of the primary lesion and remote lymph nodes were observed following chemotherapy, we performed distal gastrectomy to deal with continuous bleeding from the primary lesion. Combination therapy with radiation and chemotherapy was effective for multiple metastases in both subclavian lymph nodes and metachronous multiple axillary lymph nodes. Nivolumab combined with radiation therapy also induced regression of remote lymph node metastases, peritoneal dissemination, and adrenal metastasis. Abscopal effects, i.e., shrinkage of the non-irradiated lesions, were also observed. Thus far, the patient has been able to maintain a good quality of life while receiving continued nivolumab therapy. Multidisciplinary therapy including immunotherapy and abscopal effect may improve the quality of life and contribute to long-term survival of patients with unresectable gastric cancer.
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Affiliation(s)
- Yuta Kuhara
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Motoki Ninomiya
- Digestive Disease Center, Hiroshima Memorial Hospital, Hiroshima, Japan
| | - Satoshi Hirahara
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Hirofumi Doi
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Shirakawa Kenji
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Kazuhiro Toyota
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Raita Yano
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Hironori Kobayashi
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Yasushi Hashimoto
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Yujiro Yokoyama
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Yoshihiro Sakashita
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
| | - Katsunari Miyamoto
- Department of Surgery, Hiroshima Memorial Hospital, 1-4-3, Honkawatyo, Nakaku, Hiroshima, Hiroshimashi Japan
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Henon C, Remon J, Hendriks LE. Combination treatments with immunotherapy in brain metastases patients. Future Oncol 2020; 16:1691-1705. [PMID: 32412817 DOI: 10.2217/fon-2020-0156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Immune checkpoint inhibitors (ICI) have revolutionized the treatment of many advanced cancers. However, in most pivotal trials, patients with brain metastases (BM) were either excluded, or only selected patients were allowed. Therefore, there are still some concerns about the safety/efficacy ratio of ICI in patients with BM. In this special report we will provide an overview on the biological rationale for using ICI in the treatment of BM, the reported BM-related outcomes of clinical trials with a focus on ICI plus chemotherapy and ICI plus ICI combinations. Last, we will provide future challenges with this strategy, as well as directions for future research.
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Affiliation(s)
- Clemence Henon
- Department of Medical Oncology, Gustave Roussy Cancer Campus, Institut d'Oncologie Thoracique (IOT), Gustave Roussy, Villejuif, France
| | - Jordi Remon
- Department of Medical Oncology, Centro Integral Oncológico Clara Campal (HM CIOCC), Hospital HM Delfos, HM Hospitales, Barcelona, Spain
| | - Lizza El Hendriks
- Department of Pulmonary Diseases, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Center+, Maastricht, The Netherlands
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