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      Survival and prognostic factors of non-small cell lung cancer patients with postoperative locoregional recurrence treated with radical radiotherapy

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          Abstract

          Background

          Locoregional recurrence remains the challenge for long-term survival of non-small cell lung cancer (NSCLC) patients after radical surgery, and curative-intent radiotherapy could be a treatment choice. This study aimed to assess the survival and prognostic factors of patients with postoperative locoregionally recurrent NSCLC treated with radical radiotherapy.

          Methods

          We reviewed medical records of 74 NSCLC patients with postoperative locoregional recurrence who received radical radiotherapy between April 2012 and February 2016 at Sun Yat-sen University Cancer Center (Guangzhou, China). The efficacy and safety of radical radiotherapy were analyzed. The probability of survival was estimated using the Kaplan–Meier method and compared using the log-rank test. The Cox proportional hazards model was used to identify prognostic factors.

          Results

          Grade 3/4 adverse events included neutropenia (8 cases, 10.8%), esophagitis (7 cases, 9.5%), pneumonitis (1 case, 1.4%), and vomiting (1 case, 1.4%). The 2-year overall survival, progression-free survival, local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) rates of all patients were 84.2, 42.5, 70.0, and 50.9%, respectively. Univariate and multivariate analyses showed that a higher biological effective dose (BED) of radiation was associated with longer LRFS [hazard ratios (HR) = 0.317, 95% confidence interval (CI) = 0.112–0.899, P = 0.016] and that wild-type epidermal growth factor receptor ( EGFR) was associated with longer DMFS compared with EGFR mutation (HR = 0.383, 95% CI = 0.171–0.855, P = 0.019).

          Conclusions

          Radical radiotherapy is effective and well-tolerated in NSCLC patients with postoperative locoregional recurrence. High BED is a predictor for long LRFS, and the presence of wild-type EGFR is a predictor for long DMFS.

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          Most cited references28

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          Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib.

          This study was undertaken to investigate the effects of epidermal growth factor receptor (EGFR) mutation and its downstream signaling on response and survival in non-small-cell lung cancer (NSCLC) patients treated with gefitinib. For 90 consecutive NSCLC patients who had received gefitinib, EGFR mutation was analyzed by DNA sequencing of exons 18, 19, 21, and 23 in the EGFR tyrosine kinase domain. Expressions of phosphorylated (p) -Akt and p-Erk were determined via immunohistochemistry. Response rate, time to progression (TTP), and overall survival were compared between each group according to EGFR mutation, as well as p-Akt and p-Erk expression. Seventeen patients (18.9%; 95% CI, 10.8 to 27.0) harbored EGFR mutations. These mutations include deletions in exon 19 in seven patients, L858R in six patients, G719A in three patients, and a novel A859T in one patient. Response rate in patients with EGFR mutation was 64.7% (11 of 17 patients; 95% CI, 42.0 to 87.4), in contrast to 13.7% (10 of 73 patients; 95% CI, 5.8 to 21.6) in patients without mutation (P < .001). Moreover, these 17 patients with EGFR mutation had significantly prolonged TTP (21.7 v 1.8 months; P < .001) and overall survival (30.5 v 6.6 months; P < .001) compared with the remaining 73 patients without mutation. Although no significant correlation was detected between EGFR mutation and expressions of p-Akt or p-Erk, p-Akt overexpression was associated with prolonged TTP in patients with EGFR mutation. Our data further support the importance of EGFR mutation with regard to gefitinib sensitivity. In addition to its predictive role, EGFR mutation confers significant survival benefits on NSCLC patients treated with gefitinib.
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            Local recurrence after surgery for early stage lung cancer: an 11-year experience with 975 patients.

            The objective of the current study was to evaluate the actuarial risk of local failure (LF) after surgery for stage I to II nonsmall cell lung cancer (NSCLC) and assess surgical and pathologic factors affecting this risk. The records, including pertinent radiologic studies, of all patients who underwent surgery for T1 to T2, N0 to N1 NSCLC at Duke University between 1995 and 2005 were reviewed. Risks of disease recurrence were estimated using the Kaplan-Meier method. A multivariate Cox regression analysis assessed factors associated with LF in the entire cohort and a subgroup undergoing optimal surgery for stage IB to II disease. For all 975 consecutive patients, the 5-year actuarial risk of local and/or distant disease recurrence was 36%. First sites of failure were local only (25%), local and distant (29%), and distant only (46%). The 5-year actuarial risk of LF was 23%. On multivariate analysis, squamous/large cell histology (hazards ratio [HR], 1.98), stage > IA (HR, 2.02), and sublobar resections (HR, 1.99) were found to be independently associated with a higher risk of LF. For the subset of patients (n = 445) undergoing at least a lobectomy with negative surgical margins and currently considered for adjuvant chemotherapy (stage IB-II disease), the 5-year actuarial risk of LF was 27%. Within this subgroup, squamous/large cell histology (HR, 2.5) and lymphovascular space invasion (HR, 1.74) were associated with a higher risk of LF. The 5-year rate of LF was 13%, 32%, and 47%, respectively, with 0, 1, or 2 risk factors. Greater than half of disease recurrences after surgery for early stage NSCLC involved local sites. Pathologic factors may help to distinguish those patients at highest risk.
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              Higher biologically effective dose of radiotherapy is associated with improved outcomes for locally advanced non-small cell lung carcinoma treated with chemoradiation: an analysis of the Radiation Therapy Oncology Group.

              Patients treated with chemoradiotherapy for locally advanced non-small-cell lung carcinoma (LA-NSCLC) were analyzed for local-regional failure (LRF) and overall survival (OS) with respect to radiotherapy dose intensity. This study combined data from seven Radiation Therapy Oncology Group (RTOG) trials in which chemoradiotherapy was used for LA-NSCLC: RTOG 88-08 (chemoradiation arm only), 90-15, 91-06, 92-04, 93-09 (nonoperative arm only), 94-10, and 98-01. The radiotherapeutic biologically effective dose (BED) received by each individual patient was calculated, as was the overall treatment time-adjusted BED (tBED) using standard formulae. Heterogeneity testing was done with chi-squared statistics, and weighted pooled hazard ratio estimates were used. Cox and Fine and Gray's proportional hazard models were used for OS and LRF, respectively, to test the associations between BED and tBED adjusted for other covariates. A total of 1,356 patients were analyzed for BED (1,348 for tBED). The 2-year and 5-year OS rates were 38% and 15%, respectively. The 2-year and 5-year LRF rates were 46% and 52%, respectively. The BED (and tBED) were highly significantly associated with both OS and LRF, with or without adjustment for other covariates on multivariate analysis (p < 0.0001). A 1-Gy BED increase in radiotherapy dose intensity was statistically significantly associated with approximately 4% relative improvement in survival; this is another way of expressing the finding that the pool-adjusted hazard ratio for survival as a function of BED was 0.96. Similarly, a 1-Gy tBED increase in radiotherapy dose intensity was statistically significantly associated with approximately 3% relative improvement in local-regional control; this is another way of expressing the finding that the pool-adjusted hazard ratio as a function of tBED was 0.97. Higher radiotherapy dose intensity is associated with improved local-regional control and survival in the setting of chemoradiotherapy. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                ml_1990@126.com
                qiubo@sysucc.org.cn
                zhangjun@sysucc.org.cn
                liqw@sysucc.org.cn
                wangbin@sysucc.org.cn
                zhangxuh@sysucc.org.cn
                qiangmy@sysucc.org.cn
                chenzhl@sysucc.org.cn
                8615913148518 , guosp@sysucc.org.cn
                862087343031 , liuhuisysucc@sina.com
                Journal
                Chin J Cancer
                Chin J Cancer
                Chinese Journal of Cancer
                BioMed Central (London )
                1000-467X
                1944-446X
                11 December 2017
                11 December 2017
                2017
                : 36
                : 93
                Affiliations
                Department of Radiation Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng Road East, Guangzhou, Guangdong 510060 P. R. China
                Article
                261
                10.1186/s40880-017-0261-0
                5725840
                29228994
                8e924ff3-eaa4-4f12-9146-e43d20a2e55c
                © The Author(s) 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 19 January 2017
                : 27 June 2017
                Funding
                Funded by: Science and Technology Planning Project of Guangdong Province, China
                Award ID: 2016A020215190
                Award ID: 2016ZC0030
                Award Recipient :
                Funded by: The Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry; and National Nature Science Fund
                Award ID: 81301932
                Award Recipient :
                Categories
                Original Article
                Custom metadata
                © The Author(s) 2017

                non-small cell lung cancer,locoregional recurrence,radical radiotherapy,biological effective dose,epidermal growth factor receptor

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