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Sotelo MJ, Luis García J, Torres-Mattos C, Milián H, Carracedo C, González-Ruiz MÁ, Mielgo-Rubio X, Trujillo-Reyes JC, Couñago F. Recent advances and new insights in the management of early-stage epidermal growth factor receptor-mutated non-small-cell lung cancer. World J Clin Oncol 2021; 12:912-925. [PMID: 34733613 PMCID: PMC8546659 DOI: 10.5306/wjco.v12.i10.912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 07/29/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Patients with early-stage non-small-cell lung cancer (NSCLC) are candidates for curative surgery; however, despite multiple advances in lung cancer management, recurrence rates remain high. Adjuvant chemotherapy has been demonstrated to significantly prolong overall survival (OS), but this benefit is modest and there is an urgent need for effective new therapies to provide a cure for more patients. The high efficacy of tyrosine kinase inhibitors (TKIs) against epidermal growth factor receptor-mutated (EGFR) in patients with advanced EGFR-mutated NSCLC has led to the evaluation of these agents in early stages of the disease. Multiple clinical trials have evaluated the safety and efficacy of EGFR TKIs as an adjuvant treatment, in patients with resected EGFR-mutated NSCLC, and shown that they significantly prolong disease-free survival (DFS), but this benefit does not translate to OS. Recently, an interim analysis of the ADAURA trial demonstrated that, surprisingly, osimertinib improved DFS. This led to the study being stopped early, leaving many unanswered questions about its potential effect on OS and its incorporation as a standard adjuvant treatment in this patient subgroup. These targeted agents are also being evaluated in locally-advanced disease, with promising results, although prospective studies with larger sample sizes are needed to confirm these results. In this article, we review the most relevant studies on the role of EGFR TKIs in the management of early-stage EGFR-mutated NSCLC.
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Affiliation(s)
- Miguel J Sotelo
- Department of Medical Oncology, Hospital María Auxiliadora; Department of Medical Oncology, Centro Oncológico Aliada; Oncological Research Unit, Clínica San Gabriel, Lima 15801, Peru
| | - José Luis García
- Department of Thoracic Surgery, Hospital Universitario La Princesa; Department of Thoracic Surgery, MD Anderson Cancer Center; Department of Thoracic Surgery, Hospital HM, Madrid 28006, Spain
| | - Cesar Torres-Mattos
- Department of Medical Oncology, Hospital Nacional Guillermo Almenara; Oncological Research Unit, Clínica San Gabriel, Lima 15033, Peru
| | - Héctor Milián
- Department of Thoracic Surgery, Hospital Universitario La Princesa, Madrid 28006, Spain
| | - Carlos Carracedo
- Department of Medical Oncology, Centro Oncológico Aliada, Lima 15036, Peru
| | | | - Xabier Mielgo-Rubio
- Department of Oncology, Hospital Universitario Fundación Alcorcón, Alcorcón 28922, Madrid, 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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Erlotinib versus vinorelbine plus cisplatin as adjuvant therapy in Chinese patients with stage IIIA EGFR mutation-positive non-small-cell lung cancer (EVAN): a randomised, open-label, phase 2 trial. THE LANCET RESPIRATORY MEDICINE 2018; 6:863-873. [PMID: 30150014 DOI: 10.1016/s2213-2600(18)30277-7] [Citation(s) in RCA: 211] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/23/2018] [Accepted: 06/14/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Adjuvant chemotherapy after radical resection of stage IIIA non-small-cell lung cancer (NSCLC) has quite poor outcomes. We aimed to investigate whether adjuvant erlotinib therapy improves 2-year disease-free survival compared with chemotherapy in epidermal growth factor receptor (EGFR) mutation-positive stage IIIA NSCLC. METHODS In this randomised, open-label, phase 2 trial, eligible patients aged 18-75 years who had undergone complete (R0) resection of histologically or pathologically confirmed stage IIIA EGFR mutation-positive NSCLC and had not received any previous anticancer therapies were enrolled. Patients were randomly assigned (1:1) to receive either adjuvant erlotinib (150 mg once daily administered orally) or vinorelbine and cisplatin chemotherapy (four cycles of vinorelbine [25 mg/m2 intravenously on days 1 and 8 of each 21-day cycle] plus cisplatin [75 mg/m2 intravenously on day 1 of each 21-day cycle]). Randomisation was done by Simon's minimisation with a random element and was stratified by EGFR activating mutation type (exon 19 vs 21), histology (adenocarcinoma vs non-adenocarcinoma), and smoking status (smoker vs non-smoker). The primary endpoint in the unblinded intention-to-treat analysis was 2-year disease-free survival. This ongoing study is registered with ClinicalTrials.gov, number NCT01683175. FINDINGS Between Sept 8, 2012, and May 21, 2015, 102 patients from 16 centres across China were enrolled and randomly assigned to receive erlotinib (n=51) or chemotherapy (n=51). Median follow-up was 33·0 months (IQR 17·8-43·1). 2-year disease-free survival was 81·4% (95% CI 69·6-93·1) in the erlotinib group and 44·6% (26·9-62·4) in the chemotherapy group (relative risk 1·823 [95% CI 1·194-2·784; p=0·0054). The difference in 2-year disease-free survival between the groups was 36·7% (95% CI 15·5-58·0; p=0·0007). Adverse events of any grade occurred in 29 (58%) of 50 patients in the erlotinib group and 28 (65%) of 43 patients in the chemotherapy group. Grade 3 or worse adverse events occurred in six (12%) of 50 patients in the erlotinib group versus 11 (26%) of 43 in the chemotherapy group; the most common of these in the erlotinib group was rash (in two [4%] of 50 patients) and in the chemotherapy group were decreased neutrophil count (in seven [16%] of 43 patients) and myelosuppression (in four [9%]). No treatment-related deaths were reported. INTERPRETATION Adjuvant erlotinib improved 2-year disease-free survival in patients with EGFR mutation-positive stage IIIA NSCLC compared with chemotherapy, with a better tolerability profile. This study suggests that tyrosine kinase inhibitors could have a potentially important role as adjuvant therapy in EGFR mutation-positive stage IIIA NSCLC. However, this trial was a phase 2 study. Mature overall survival data are also needed. Ongoing studies will hopefully confirm the role of adjuvant EGFR tyrosine kinase inhibitor therapy in patients with NSCLC. FUNDING National Key Research and Development Program of China and Shanghai Roche Pharmaceuticals Ltd.
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Ma X, Siegelman J, Paik DS, Mulshine JL, St Pierre S, Buckler AJ. Volumes Learned: It Takes More Than Size to "Size Up" Pulmonary Lesions. Acad Radiol 2016; 23:1190-8. [PMID: 27287713 DOI: 10.1016/j.acra.2016.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 04/08/2016] [Accepted: 04/10/2016] [Indexed: 12/17/2022]
Abstract
RATIONALE AND OBJECTIVES This study aimed to review the current understanding and capabilities regarding use of imaging for noninvasive lesion characterization and its relationship to lung cancer screening and treatment. MATERIALS AND METHODS Our review of the state of the art was broken down into questions about the different lung cancer image phenotypes being characterized, the role of imaging and requirements for increasing its value with respect to increasing diagnostic confidence and quantitative assessment, and a review of the current capabilities with respect to those needs. RESULTS The preponderance of the literature has so far been focused on the measurement of lesion size, with increasing contributions being made to determine the formal performance of scanners, measurement tools, and human operators in terms of bias and variability. Concurrently, an increasing number of investigators are reporting utility and predictive value of measures other than size, and sensitivity and specificity is being reported. Relatively little has been documented on quantitative measurement of non-size features with corresponding estimation of measurement performance and reproducibility. CONCLUSIONS The weight of the evidence suggests characterization of pulmonary lesions built on quantitative measures adds value to the screening for, and treatment of, lung cancer. Advanced image analysis techniques may identify patterns or biomarkers not readily assessed by eye and may also facilitate management of multidimensional imaging data in such a way as to efficiently integrate it into the clinical workflow.
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Affiliation(s)
- Xiaonan Ma
- Elucid Bioimaging Inc., 225 Main Street, Wenham, MA 01984.
| | - Jenifer Siegelman
- Department of Radiology, Brigham and Women's Hospital, Boston Massachusetts; Department of Radiology (hospital-based), Harvard Medical School, Boston, Massachusetts
| | - David S Paik
- Elucid Bioimaging Inc., 225 Main Street, Wenham, MA 01984
| | - James L Mulshine
- Department of Internal Medicine, Rush University, Chicago, Illinois
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Qiu X, Liang Y, Sellers RS, Perez-Soler R, Zou Y. Aerosol azacytidine inhibits orthotopic lung cancers in mice through Its DNA demethylation and gene reactivation effects. PLoS One 2014; 9:e109874. [PMID: 25347303 PMCID: PMC4210052 DOI: 10.1371/journal.pone.0109874] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 09/12/2014] [Indexed: 11/18/2022] Open
Abstract
We devised an aerosol based demethylation therapy to achieve therapeutic efficacy in premalignant or in situ lesions of lung cancer, without systemic toxicity. Optimum regimens of aerosolized azacytidine (Aza) were designed and used in orthotopic human non-small cell lung cancer xenograft models. The therapeutic efficacy and toxicity of aerosol Aza were compared with intravenously administered Aza. We observed that 80% of the droplets of the aerosol Aza measured ∼0.1–5 microns, which resulted in deposition in the lower bronchial airways. An animal model that phenocopies field carcinogeneisis in humans was developed by intratracheal inoculation of the human lung cancer cells in mice, thus resulting in their distribution throughout the entire airway space. Aerosolized Aza significantly prolonged the survival of mice bearing endo-bronchial lung tumors. The aerosol treatment did not cause any detectable lung toxicity or systemic toxicity. A pre-pharmacokinetic study in mice demonstrated that lung deposition of aerosolized Aza was significantly higher than the intravenous route. Lung tumors were resected after aerosol treatment and the methylation levels of 24 promoters of tumor-suppresser genes related to lung cancer were analyzed. Aerosol Aza significantly reduced the methylation level in 9 of these promoters and reexpressed several genes tested. In conclusion, aerosol Aza at non-cytotoxic doses appears to be effective and results in DNA demethylation and tumor suppressor gene re-expression. The therapeutic index of aerosol Aza is >100-fold higher than that of intravenous Aza. These results provide a preclinical rationale for a phase I clinical trial of aerosol Aza to be initiated at our Institution.
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Affiliation(s)
- Xuan Qiu
- Departments of Medicine, Division of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Yuanxin Liang
- Departments of Medicine, Division of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Rani S. Sellers
- Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Roman Perez-Soler
- Departments of Medicine, Division of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States of America
| | - Yiyu Zou
- Departments of Medicine, Division of Medical Oncology, Albert Einstein College of Medicine, Bronx, NY, United States of America
- * E-mail:
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Stevenson M, Mostertz W, Acharya C, Kim W, Walters K, Barry W, Higgins K, Tuchman SA, Crawford J, Vlahovic G, Ready N, Onaitis M, Potti A. Characterizing the clinical relevance of an embryonic stem cell phenotype in lung adenocarcinoma. Clin Cancer Res 2012; 15:7553-61. [PMID: 19996213 DOI: 10.1158/1078-0432.ccr-09-1939] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear whether these phenotypic similarities are the result of a common biological phenotype, such as regulatory pathways. EXPERIMENTAL DESIGN Lung cancer cell lines with corresponding gene expression data and genes associated with an embryonic stem cell identity were used to develop a signature of embryonic stemness (ES) activity specific to lung adenocarcinoma. Biological characteristics were elucidated as a function of cancer biology/oncogenic pathway dysregulation. The ES signature was applied to three independent early-stage (I-IIIa) lung adenocarcinoma data sets with clinically annotated gene expression data. The relationship between the ES phenotype and cisplatin (current standard of care) sensitivity was evaluated. RESULTS Pathway analysis identified specific regulatory networks [Ras (P = 0.0005), Myc (P = 0.0224), wound healing (P < 0.0001), chromosomal instability (P < 0.0001), and invasiveness (P < 0.0001)] associated with the ES phenotype. The prognostic relevance of the ES signature, as related to patient survival, was characterized in three cohorts [CALGB 9761 (n = 82; P = 0.0001), National Cancer Institute Director's Challenge Consortium (n = 442; P = 0.0002), and Duke (n = 45; P = 0.06)]. The ES signature was not prognostic in prostate, breast, or ovarian adenocarcinomas. Lung tumors (n = 569) and adenocarcinoma cell lines (n = 31) expressing the ES phenotype were more likely to be resistant to cisplatin (P < 0.0001 and P = 0.006, respectively). CONCLUSIONS Lung adenocarcinomas that share a common gene expression pattern with normal human embryonic stem cells were associated with decreased survival, increased biological complexity, and increased likelihood of resistance to cisplatin. This indicates the aggressiveness of these tumors.
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Affiliation(s)
- Marvaretta Stevenson
- Division of Oncology, Department of Medicine, Duke University, Durham, North Carolina. USA
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Swedish Lung Cancer Radiation Study Group: Predictive value of histology for radiotherapy response in patients with non-small cell lung cancer. Eur J Cancer 2011; 47:2415-21. [DOI: 10.1016/j.ejca.2011.06.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 06/03/2011] [Indexed: 11/19/2022]
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Rusch VW, Hawes D, Decker PA, Martin SE, Abati A, Landreneau RJ, Patterson GA, Inculet RI, Jones DR, Malthaner RA, Cohen RG, Ballman K, Putnam JB, Cote RJ. Occult metastases in lymph nodes predict survival in resectable non-small-cell lung cancer: report of the ACOSOG Z0040 trial. J Clin Oncol 2011; 29:4313-9. [PMID: 21990404 DOI: 10.1200/jco.2011.35.2500] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
PURPOSE The survival of patients with non-small-cell lung cancer (NSCLC), even when resectable, remains poor. Several small studies suggest that occult metastases (OMs) in pleura, bone marrow (BM), or lymph nodes (LNs) are present in early-stage NSCLC and are associated with a poor outcome. We investigated the prevalence of OMs in resectable NSCLC and their relationship with survival. PATIENTS AND METHODS Eligible patients had previously untreated, potentially resectable NSCLC. Saline lavage of the pleural space, performed before and after pulmonary resection, was examined cytologically. Rib BM and all histologically negative LNs (N0) were examined for OM, diagnosed by cytokeratin immunohistochemistry (IHC). Survival probabilities were estimated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used to compare survival of groups of patients. P < .05 was considered significant. RESULTS From July 1999 to March 2004, 1,047 eligible patients (538 men and 509 women; median age, 67.2 years) were entered onto the study, of whom 50% had adenocarcinoma and 66% had stage I NSCLC. Pleural lavage was cytologically positive in only 29 patients. OMs were identified in 66 (8.0%) of 821 BM specimens and 130 (22.4%) of 580 LN specimens. In univariate and multivariable analyses OMs in LN but not BM were associated with significantly worse disease-free survival (hazard ratio [HR], 1.50; P = .031) and overall survival (HR, 1.58; P = .009). CONCLUSION In early-stage NSCLC, LN OMs detected by IHC identify patients with a worse prognosis. Future clinical trials should test the role of IHC in identifying patients for adjuvant therapy.
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Affiliation(s)
- Valerie W Rusch
- Thoracic Surgery Service, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065, USA.
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The use of volumetric CT as an imaging biomarker in lung cancer. Acad Radiol 2010; 17:100-6. [PMID: 19969253 DOI: 10.1016/j.acra.2009.07.030] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2009] [Revised: 06/18/2009] [Accepted: 06/18/2009] [Indexed: 11/20/2022]
Abstract
RATIONALE AND OBJECTIVES Lung cancer is the leading cause of cancer death in the United States. Mortality outcomes have improved only modestly over the past 30 years. There is intense focus on the development of better treatments for lung cancer. Major issues include the cost and time duration of the clinical trials required to establish the utility of a drug so that it can be formally approved by regulatory agencies. In clinical settings, biomarkers that accelerate assessments of responses to treatment could benefit patients by providing earlier diagnoses of progressive disease, particularly when there are multiple options for treatment, and the effects of toxicity from one treatment tend to limit the ability to administer the next line of therapy. MATERIALS AND METHODS Quantifying longitudinal changes in tumor volumes using computed tomography could eventually become a more useful surrogate endpoint for assessing tumor responses or progression events than simple unidimensional measurements. RESULTS The authors review the historical development of response measurements in lung cancer, set out the medical context for specifying volumetric imaging requirements and goals, compare volumetric technique to conventional methods, and identify the imaging profiles being pursued. CONCLUSION The Quantitative Imaging Biomarkers Alliance is investigating volumetric computed tomographic acquisition and analytic methods to increase the analytic power per subject enrolled in clinical trials to reduce the number of total subjects needed or shorten the length of time an individual needs to be followed to reliably establish drug response.
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Post-Operative Radiation Therapy (PORT) in Completely Resected Non-Small-Cell Lung Cancer. Curr Treat Options Oncol 2009; 9:343-56. [DOI: 10.1007/s11864-009-0090-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Accepted: 02/11/2009] [Indexed: 11/27/2022]
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