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      Which patients benefit most from stereotactic body radiotherapy or surgery in medically operable non‐small cell lung cancer? An in‐depth look at patient characteristics on both sides of the debate

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      1 , , 1
      Thoracic Cancer
      John Wiley & Sons Australia, Ltd
      Lung cancer, stereotactic radiotherapy, surgery

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          Abstract

          The role of stereotactic body radiotherapy (SBRT) in early stage medically operable non‐small cell lung cancer is currently under debate. SBRT's advantage is its ability to provide high radiotherapy doses to a tumor in a short timeframe, without the risk of postoperative complications and mortality. Currently, in part due to limited prospective data comparing both treatments, international guidelines continue to recommend surgical resection as the gold standard for medically operable patients. However, not all patients possess uniform characteristics, and there is some evidence that certain subgroups of patients would benefit more from one form of treatment ‐ SBRT or surgery ‐ than the other. The aim of this review is to provide a brief summary of the evidence comparing SBRT to surgery, followed by a deeper discussion of the subgroups of patients who would benefit most from surgery: those with large tumors, centrally located tumors, increased risk of occult nodal metastases, increased risk of toxicity from radiotherapy and radioresistant histological tumor subtypes. Meanwhile, patients who could benefit most from SBRT might include elderly patients, those with reduced lung function or cardiac comorbidities, those with synchronous lung nodules, and those with specific tumor mutational status. We hope that this review will aid in the clinical decision‐making process regarding patient selection for either treatment.

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          Most cited references71

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          Randomized trial of lobectomy versus limited resection for T1 N0 non-small cell lung cancer. Lung Cancer Study Group.

          It has been reported that limited resection (segment or wedge) is equivalent to lobectomy in the management of early stage (T1-2 N0) non-small cell lung cancer. A prospective, multiinstitutional randomized trial was instituted comparing limited resection with lobectomy for patients with peripheral T1 N0 non-small cell lung cancer documented at operation. Analysis included locoregional and distant recurrence rates, 5-year survival rates, perioperative morbidity and mortality, and late pulmonary function assessment. There were 276 patients randomized, with 247 patients eligible for analysis. There were no significant differences for all stratification variables, selected prognostic factors, perioperative morbidity, mortality, or late pulmonary function. In patients undergoing limited resection, there was an observed 75% increase in recurrence rates (p = 0.02, one-sided) attributable to an observed tripling of the local recurrence rate (p = 0.008 two-sided), an observed 30% increase in overall death rate (p = 0.08, one-sided), and an observed 50% increase in death with cancer rate (p = 0.09, one-sided) compared to patients undergoing lobectomy (p = 0.10, one-sided was the predefined threshold for statistical significance for this equivalency study). Compared with lobectomy, limited pulmonary resection does not confer improved perioperative morbidity, mortality, or late postoperative pulmonary function. Because of the higher death rate and locoregional recurrence rate associated with limited resection, lobectomy still must be considered the surgical procedure of choice for patients with peripheral T1 N0 non-small cell lung cancer.
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            Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.

            Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.
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              Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.

              Surgical resection is standard therapy in stage I non-small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population. Eligible patients included clinically staged T1 or T2 (< or = 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks. All 70 patients enrolled completed therapy as planned and median follow-up was 17.5 months. The 3-month major response rate was 60%. Kaplan-Meier local control at 2 years was 95%. Altogether, 28 patients have died as a result of cancer (n = 5), treatment (n = 6), or comorbid illnesses (n = 17). Median overall survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occurred in a total of 14 patients. Among patients experiencing toxicity, the median time to observation was 10.5 months. Patients treated for tumors in the peripheral lung had 2-year freedom from severe toxicity of 83% compared with only 54% for patients with central tumors. High rates of local control are achieved with this SBRT regimen in medically inoperable patients with stage I NSCLC. Both local recurrence and toxicity occur late after this treatment. This regimen should not be used for patients with tumors near the central airways due to excessive toxicity.
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                Author and article information

                Contributors
                gail.chua.w.y@nccs.com.sg
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                06 August 2019
                October 2019
                : 10
                : 10 ( doiID: 10.1111/tca.v10.10 )
                : 1857-1867
                Affiliations
                [ 1 ] Division of Radiation Oncology National Cancer Centre Singapore Singapore
                Author notes
                [*] [* ] Correspondence

                Gail Wan Ying Chua, Division of Radiation Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore. Tel: +65 6436 8000

                Email: gail.chua.w.y@ 123456nccs.com.sg

                Author information
                https://orcid.org/0000-0002-2362-521X
                Article
                TCA13160
                10.1111/1759-7714.13160
                6775005
                31389163
                d90713aa-db1d-4b2b-9107-d3db861c6176
                © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 20 May 2019
                : 18 July 2019
                : 20 July 2019
                Page count
                Figures: 0, Tables: 3, Pages: 11, Words: 8747
                Categories
                Mini Review
                Mini Review
                Custom metadata
                2.0
                tca13160
                October 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:02.10.2019

                lung cancer,stereotactic radiotherapy,surgery
                lung cancer, stereotactic radiotherapy, surgery

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