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New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Methods and Technologies Development".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 21096

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Special Issue Editors

Prof. Dr. Marco Alifano

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Guest Editor

Cochin University Hospital, Thoracic Surgery Dpt, 27 Rue Faubourg St Jacques, F-75014 Paris, France
Interests: cell lung cancer; systemic inflammation; skeletal muscle; prognostic factor; weight loss; sarcopenia; survival; chemotherapy; inflammation; meta-analysis
Special Issues, Collections and Topics in MDPI journals

Dr. Mauro Loi

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Guest Editor

Careggi University Hospital, Radiation Oncology Dpt, Florence, Italy
Interests: lung cancer; radiotherapy; stereotactic body radiotherapy; oligometastases; radiobiology; chemotherapy; target therapy; outcome analysis; image-guided radiotherapy; cancer immunology

Prof. Dr. Marie Wislez

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Guest Editor

Paris Centre University Hospitals, Unit of Thoracic Disease, Chest Disease Dpt, Paris, France
Interests: lung cancer; neutrophils; inflammation; immune therapy; targeted therapy

Dr. Antonio Bobbio

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Guest Editor

Cochin University Hospital, Thoracic Surgery Dpt, Paris, France
Interests: Lung Cancer; Surgery; Health Costs; QoL (Quality of Life); Epidemiology; Robot; ERAS (Enhanced Recovery After Surgery)

Special Issue Information

Dear Colleagues,

We have the privilege of announcing the launch of a call for papers for a Special Issue of Cancers (Basel) entitled “New Treatments of Lung Cancer in the Era of Patient and Tumor -Targeted Interventions”.

Lung cancer remains the leading cause of cancer-related deaths worldwide, but optimism in a solution is now rising. In the last ten years, we have faced revolutionary changes in the multidisciplinary management of lung cancer: nosology has been refined; histologic and molecular phenotypes are more and more precisely understood; surgical management has improved thanks to the advent of mini-invasive techniques of staging and resection; the wide diffusion of “Enhanced Recovery After Surgery” programs has allowed even enlarged open resections to be performed with low morbidity and mortality. Radiotherapy has enabled the diffusion of stereotactic techniques, even for central lesions, and refinement of indications of perioperative treatments. Systemic treatments have faced a real revolution thanks to the ongoing development of targeted therapies and immunotherapies, integrated or not with loco-regional treatments. The challenge in the next few years, together with continuous progress in each field, will be to perform the synthesis of different specialties and to develop together not only a “precision medicine” or a “precision surgery” but also a “precision management” integrating medicine, surgery and radiotherapy, with the idea of proposing specific pathways to each patient on the basis of thorough assessment of both the disease and the host. We have now to develop interventions to take into account host characteristics (systemic inflammation, nutritional status, fitness, general metabolism) together with cancer ones (extent of primary tumor, stage, activations of driving oncogenes, expression of immune check points, tumor metabolism ) as well as with features of the host–tumor interface represented by the immune environment. We propose this issue of Cancers as a platform to help in sharing experiences and proposing solutions on the basis of results that each team will present.

Prof. Dr. Marco Alifano
Dr. Mauro Loi
Prof. Dr. Marie Wislez
Dr. Antonio Bobbio
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

lung cancer
surgery
radiotherapy
chemotherapy
targeted therapies
immune check points
immunotherapy
nutrition
fitness
sarcopenia
induction
perioperative management
Early Recovery After Surgery (ERAS)
rehabilitation

Published Papers (8 papers)

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Research

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12 pages, 918 KiB

Open AccessArticle

Survival and Prognostic Factors of Ultra-Central Tumors Treated with Stereotactic Body Radiotherapy

by Viola Salvestrini, Marloes Duijm, Mauro Loi and Joost J. Nuyttens

Cancers 2022, 14(23), 5908; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14235908 - 29 Nov 2022

Cited by 2 | Viewed by 1263

Abstract

Introduction: Stereotactic body radiotherapy (SBRT) reported excellent outcomes and a good tolerability profile in case of central lung tumors, as long as risk-adapted schedules were adopted. High grade toxicity was more frequently observed for tumors directly touching or overlapping the trachea, proximal bronchial tree (PBT), and esophagus. We aim to identify prognostic factors associated with survival for Ultra-Central (UC) tumors. Methods: We retrospectively evaluated patients treated with SBRT for primary or metastatic UC lung tumors. SBRT schedules ranged from 45 to 60 Gy. Results: A total number of 126 ultra-central lung tumors were reviewed. The Median follow-up time was 23 months. Median Overall Survival (OS) and Progression Free Survival (PFS) was 29.3 months and 16 months, respectively. Local Control (LC) rates at 1 and 2 were 86% and 78%, respectively. Female gender, age < 70 years, and tumor size < 5 cm were significantly associated with better OS. The group of patients with tumors close to the trachea but further away from the PBT also correlated with better OS. The acute G2 dysphagia, cough, and dyspnea were 11%, 5%, and 3%, respectively. Acute G3 dyspnea was experienced by one patient. Late G3 toxicity was reported in 4% of patients. Conclusion: risk-adaptive SBRT for ultra-central tumors is safe and effective, even if it remains a high-risk clinical scenario. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

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15 pages, 2615 KiB

Open AccessArticle

Reducing Immunosuppression in Patients with De Novo Lung Carcinoma after Liver Transplantation Could Significantly Prolong Survival

by Sina Pesthy, Elisa Wegener, Ramin Raul Ossami Saidy, Lea Timmermann, Deniz Uluk, Mustafa Aydin, Tomasz Dziodzio, Wenzel Schoening, Georg Lurje, Robert Öllinger, Nikolaj Frost, Uli Fehrenbach, Jens-Carsten Rückert, Jens Neudecker, Johann Pratschke and Dennis Eurich

Cancers 2022, 14(11), 2748; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112748 - 01 Jun 2022

Cited by 6 | Viewed by 1638

Abstract

(1) Background: Liver transplantation (LT) is an established treatment for selected patients with end-stage liver disease resulting in a subsequent need for long-term immunosuppressive therapy. With cumulative exposure to immunosuppression (IS), the risk for the development of de novo lung carcinoma increases. Due to limited therapy options and prognosis after diagnosis of lung cancer, the question of the mode and extent of IS in this particular situation is raised. (2) Methods: All patients diagnosed with de novo lung cancer in the follow-up after LT were identified from the institution’s register of liver allograft recipients (Charité—Universitätsmedizin Berlin, Germany) transplanted between 1988 and 2021. Survival analysis was performed based on the IS therapy following diagnosis of lung cancer and the oncological treatment approach. (3) Results: Among 3207 adult LTs performed in 2644 patients at our institution, 62 patients (2.3%) developed de novo lung carcinoma following LT. Lung cancer was diagnosed at a median interval of 9.7 years after LT (range 0.7–27.0 years). Median survival after diagnosis of lung carcinoma was 13.2 months (range 0–196 months). Surgical approach with curative intent significantly prolonged survival rates compared to palliative treatment (median 67.4 months vs. 6.4 months). Reduction of IS facilitated a significant improvement in survival (median 38.6 months vs. 6.7 months). In six patients (9.7%) complete IS weaning was achieved with unimpaired liver allograft function. (4) Conclusion: Reduction of IS therapy after the diagnosis of de novo lung cancer in LT patients is associated with prolonged survival. The risk of acute rejection does not appear to be increased with restrictive IS management. Therefore, strict reduction of IS should be an early intervention following diagnosis. In addition, surgical resection should be attempted, if technically feasible and oncologically meaningful. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

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15 pages, 286 KiB

Open AccessArticle

Enhanced Recovery Pathway in Lung Resection Surgery: Program Establishment and Results of a Cohort Study Encompassing 1243 Consecutive Patients

by Yen-Lan Nguyen, Elena Maiolino, Vincent De Pauw, Mathilde Prieto, Antonio Mazzella, Jean-Baptiste Peretout, Agnès Dechartres, Christophe Baillard, Antonio Bobbio, Elisa Daffré and Marco Alifano

Cancers 2022, 14(7), 1745; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071745 - 29 Mar 2022

Cited by 4 | Viewed by 1883

Abstract

Introduction: In spite of increasing diffusion, Enhanced Recovery Pathways (ERP) have been scarcely assessed in large scale programs of lung cancer surgery. The aim of this study was auditing our practice. Methods: A two-step audit program was established: the first dealing with our initial ERP experience in patients undergoing non-extended anatomical segmentectomies and lobectomies, the second including all consecutive patients undergoing all kind of lung resections for NSCLC. The first step aimed at auditing results of ERP on occurrence of postoperative complications and at assessing which ERP components are associated with improved short-term outcomes. We also audited late results by assessing long-term survival of patients in the first step of our study. The second step aimed at auditing on large-scale short-term results of the ERP in a real-life setting. Results: Over a one-year period, 166 patients were included. The median number of ERP procedures per patient was three (IQR 3–4). No postoperative death occurred. The overall adverse events rate was 30%. In multivariate analyzes, the only element associated with reduced adverse postoperative events was chest tube withdrawal within POD2 (OR = 0.21, 95% CI (0.10–0.46)). The 1-, 3-, and 5-year survival rates were 97%, 86.1%, and 76.3%, respectively. In the second period, 1077 patients were included in our ERP; 11 patients died during the postoperative period or within 30 days of operation (1.02%). The overall postoperative adverse event rate was 30.3%, major complication occurring in 134 (12.4%), and minor ones in 192 (17.8%). Respiratory complications occurred in 64 (5.9%). Thoracoscore independently predicted postoperative death, the occurrence of complications (all-kind, minor, major, or respiratory ones). Conclusions: Compliance to ERP procedures and early chest tube removal are associated with reduced postoperative events in patients with lung resection surgery. In a large setting scale, ERP can be applied with satisfactory results in terms of mortality and morbidity. Thoracoscore is a useful tool in predicting mortality and postoperative adverse events. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

13 pages, 1352 KiB

Open AccessArticle

EGFR Exon 20 Insertion in Metastatic Non-Small-Cell Lung Cancer: Survival and Clinical Efficacy of EGFR Tyrosine-Kinase Inhibitor and Chemotherapy

by Samy Chelabi, Xavier Mignard, Karen Leroy, Isabelle Monnet, Solenn Brosseau, Nathalie Theou-Anton, Marie-Ange Massiani, Sylvie Friard, Boris Duchemann, Elizabeth Fabre, Etienne Giroux-Leprieur, Jacques Cadranel and Marie Wislez

Cancers 2021, 13(20), 5132; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205132 - 13 Oct 2021

Cited by 9 | Viewed by 3784

Abstract

EGFR exon 20 insertions are rare genetic alterations in non-small-cell lung cancers (NSCLCs) that are usually unresponsive to approved EGFR tyrosine kinase inhibitors (TKIs). In this paper, we describe the clinical characteristics, efficacy of EFGR TKIs and chemotherapy, and resulting survival in this population. We retrospectively collected patients with EGFR exon 20 insertions (Exon20ins) from 11 French genetic platforms and paired them (1:2 ratio) with classic Exon 19/21 EGFR mutation patients (controls). Between 2012 and 2017, 35 Exon20ins patients were included. These patients were younger at diagnosis than the controls. All Exon20ins patients who were treated with first-line EGFR TKIs (n = 6) showed progressive disease as the best tumor response. There was no significant difference in the tumor response or the disease control rate with first-line platinum-based chemotherapy between the two groups. A trend towards shorter overall survival was observed in Exon20ins vs. controls (17 months (14—not reach(NR) 95% confidence interval(CI) vs. 29 months (17–NR 95%CI), p = 0.09), respectively. A significant heterogeneity in amino acid insertion in EGFR exon 20 was observed. EGFR exon 20 insertions are heterogeneous molecular alterations in NSCLC that are resistant to classic EGFR TKIs, which contraindicates their use as a first-line treatment. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

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17 pages, 1571 KiB

Open AccessArticle

The Reality of Lung Cancer Paradox: The Impact of Body Mass Index on Long-Term Survival of Resected Lung Cancer. A French Nationwide Analysis from the Epithor Database

by Marco Alifano, Elisa Daffré, Antonio Iannelli, Laurent Brouchet, Pierre Emmanuel Falcoz, Françoise Le Pimpec Barthes, Alain Bernard, Pierre Benoit Pages, Pascal Alexandre Thomas, Marcel Dahan and Raphael Porcher

Cancers 2021, 13(18), 4574; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184574 - 12 Sep 2021

Cited by 16 | Viewed by 2408

Abstract

Obesity could have a protective effect in patients with lung cancer. We assessed the prognostic role of preoperative BMI on survival in patients who underwent lung resection for NSCLC. A total of 54,631 consecutive patients with resectable lung cancer within a 15-year period were extracted from Epithor (the French Society of Thoracic and Cardiovascular Surgery database). Patient subgroups were defined according to body mass index (BMI): underweight (BMI < 18.5 kg/m²), normal weight (18.5 ≤ BMI < 25 kg/m²), overweight (25 ≤ BMI < 30 kg/m²), and obese (BMI ≥ 30 kg/m²). Underweight was associated with lower survival (unadjusted HRs 1.24 (1.16–1.33)) compared to normal weight, whereas overweight and obesity were associated with improved survival (0.95 (0.92–0.98) and 0.88 (0.84–0.92), respectively). The impact of BMI was confirmed when stratifying for sex or Charlson comorbidities index (CCI). Among patients with obesity, a higher BMI was associated with improved survival. After adjusting for period of study, age, sex, WHO performance status, CCI, side of tumor, extent of resection, histologic type, and stage of disease, the HRs for underweight, overweight, and obesity were 1.51 (1.41–1.63), 0.84 (0.81–0.87), and 0.80 (0.76–0.84), respectively. BMI is a strong and independent predictor of survival in patients undergoing surgery for NSCLC. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

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27 pages, 5624 KiB

Open AccessArticle

Silibinin Suppresses Tumor Cell-Intrinsic Resistance to Nintedanib and Enhances Its Clinical Activity in Lung Cancer

by Joaquim Bosch-Barrera, Sara Verdura, José Carlos Ruffinelli, Enric Carcereny, Elia Sais, Elisabet Cuyàs, Ramon Palmero, Eugeni Lopez-Bonet, Alejandro Hernández-Martínez, Gloria Oliveras, Maria Buxó, Angel Izquierdo, Teresa Morán, Ernest Nadal and Javier A. Menendez

Cancers 2021, 13(16), 4168; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13164168 - 19 Aug 2021

Cited by 7 | Viewed by 3406

Abstract

The anti-angiogenic agent nintedanib has been shown to prolong overall and progression-free survival in patients with advanced non-small-cell lung cancer (NSCLC) who progress after first-line platinum-based chemotherapy and second-line immunotherapy. Here, we explored the molecular basis and the clinical benefit of incorporating the STAT3 inhibitor silibinin—a flavonolignan extracted from milk thistle—into nintedanib-based schedules in advanced NSCLC. First, we assessed the nature of the tumoricidal interaction between nintedanib and silibinin and the underlying relevance of STAT3 activation in a panel of human NSCLC cell lines. NSCLC cells with poorer cytotoxic responses to nintedanib exhibited a persistent, nintedanib-unresponsive activated STAT3 state, and deactivation by co-treatment with silibinin promoted synergistic cytotoxicity. Second, we tested whether silibinin could impact the lysosomal sequestration of nintedanib, a lung cancer cell-intrinsic mechanism of nintedanib resistance. Silibinin partially, but significantly, reduced the massive lysosomal entrapment of nintedanib occurring in nintedanib-refractory NSCLC cells, augmenting the ability of nintedanib to reach its intracellular targets. Third, we conducted a retrospective, observational multicenter study to determine the efficacy of incorporating an oral nutraceutical product containing silibinin in patients with NSCLC receiving a nintedanib/docetaxel combination in second- and further-line settings (n = 59). Overall response rate, defined as the combined rates of complete and partial responses, was significantly higher in the study cohort receiving silibinin supplementation (55%) than in the control cohort (22%, p = 0.011). Silibinin therapy was associated with a significantly longer time to treatment failure in multivariate analysis (hazard ratio 0.43, p = 0.013), despite the lack of overall survival benefit (hazard ratio 0.63, p = 0.190). Molecular mechanisms dictating the cancer cell-intrinsic responsiveness to nintedanib, such as STAT3 activation and lysosomal trapping, are amenable to pharmacological intervention with silibinin. A prospective, powered clinical trial is warranted to confirm the clinical relevance of these findings in patients with advanced NSCLC. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

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10 pages, 1836 KiB

Open AccessArticle

Combined Assessment of Preoperative Frailty and Sarcopenia Allows the Prediction of Overall Survival in Patients with Lung Cancer (NSCLC) and Surgically Treated Brain Metastasis

by Inja Ilic, Anton Faron, Muriel Heimann, Anna-Laura Potthoff, Niklas Schäfer, Christian Bode, Valeri Borger, Lars Eichhorn, Frank A. Giordano, Erdem Güresir, Andreas H. Jacobs, Yon-Dschun Ko, Jennifer Landsberg, Felix Lehmann, Alexander Radbruch, Ulrich Herrlinger, Hartmut Vatter, Patrick Schuss and Matthias Schneider

Cancers 2021, 13(13), 3353; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13133353 - 03 Jul 2021

Cited by 19 | Viewed by 3102

Abstract

Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients’ physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty and sarcopenia as assessment tools for physiological integrity in patients with non-small cell lung cancer (NSCLC) who had undergone surgery for BM. Between 2013 and 2018, 141 patients were surgically treated for BM from NSCLC at the authors’ institution. The preoperative physical condition was assessed by the temporal muscle thickness (TMT) as a surrogate parameter for sarcopenia and the modified frailty index (mFI). For the ≥65 aged group, median overall survival (mOS) significantly differed between patients classified as ‘frail’ (mFI ≥ 0.27) and ‘least and moderately frail’ (mFI < 0.27) (15 months versus 11 months (p = 0.02)). Sarcopenia revealed significant differences in mOS for the <65 aged group (10 versus 18 months for patients with and without sarcopenia (p = 0.036)). The present study confirms a predictive value of preoperative frailty and sarcopenia with respect to OS in patients with NSCLC and surgically treated BM. A combined assessment of mFI and TMT allows the prediction of OS across all age groups. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

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Review

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21 pages, 624 KiB

Open AccessReview

How to Improve SBRT Outcomes in NSCLC: From Pre-Clinical Modeling to Successful Clinical Translation

by Marina Milic, Michele Mondini and Eric Deutsch

Cancers 2022, 14(7), 1705; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071705 - 27 Mar 2022

Cited by 4 | Viewed by 1851

Abstract

Despite major research and clinical efforts, lung cancer remains the leading cause of cancer-related death. While the delivery of conformal radiotherapy and image guidance of stereotactic body radiotherapy (SBRT) have revolutionized the treatment of early-stage non-small-cell lung cancer (NSCLC), additional research is needed to elucidate underlying mechanisms of resistance and identify novel therapeutic combinations. Clinical progress relies on the successful translation of pre-clinical work, which so far has not always yielded expected results. Improved clinical modelling involves characterizing the preclinical models and selecting appropriate experimental designs that faithfully mimic precise clinical scenarios. Here, we review the current role of SBRT and the scope of pre-clinical armamentarium at our disposal to improve successful clinical translation of pre-clinical research in the radiation oncology of NSCLC. Full article

(This article belongs to the Special Issue New Treatments of Lung Cancer in the Era of Patient and Tumor Targeted Therapies)

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