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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EThe level of disease (single or multilevel), the absolute number of involved lymph nodes, the possible presence of bulky disease, and downstaging after induction can all have an impact on outcome and survival of non-small cell lung cancer (NSCLC). This article discusses factors that should be considered prior to surgery for stage III NSCLC, optimal radiotherapy combined with chemotherapy for stage III NSCLC, as well as a review of some of the data and ongoing trials for targeted agents in stage I to III NSCLC.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EAdjuvant\/Neoadjuvant Therapy\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ECancer\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERespiratory Cancers\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003ERadiology\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EThe heterogeneity of disease in the subgroups of stage III non-small cell lung cancer (NSCLC) must be considered when selecting treatments for individual patients and patients for participation in clinical trials. The level of disease (single or multilevel), the absolute number of involved lymph nodes, the possible presence of bulky disease, and downstaging after induction can all have an impact on outcome and survival. Georgios Stamatis, MD, Ruhrlandklini\/University Essen, Essen, Germany, discussed factors that should be considered prior to surgery for stage III NSCLC.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EResults from a study in patients with resected stages II and IIIa NSCLC indicated no difference in survival among patients with left upper lobe NSCLC and metastases to single-level N2 lymph nodes and patients with N1 disease; however, the presence of isolate N2 skip metastases was associated with improved survival when compared with patients with both N1 and N2 disease. The authors suggested that these results may be useful in informing clinical trial development, treatment strategies, and revisions of the tumor node metastasis staging system [Keller SM et al. \u003Cem\u003EJ Thorac Cardiovasc Surg\u003C\/em\u003E 2004]. In another study that compared the prognostic value of the number of metastatic lymph nodes in resected NSCLC with the currently used nodal stage classification, the number of lymph nodes was found to be a better prognostic indicator [Wei S et al. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2011]. Betticher et al. [\u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2003] found that in patients with locally advanced NSCLC with tumor resection, downstaging to N0\u20131 at surgery was prognostic and significantly prolonged event-free survival and overall survival (OS; p=0.0001).\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EClinical studies have shown that concurrent chemoradiotherapy is superior to sequential chemo-radiation in terms of OS. Dirk De Ruysscher, MD, PhD, Leuven Cancer Institute, Leuven, Belgium, discussed optimal radiotherapy combined with chemotherapy for stage III NSCLC.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EResults of a recent meta-analysis that directly compared the 2 approaches in NSCLC patients support the earlier individual studies (HR, 0.84; 95% CI, 0.74 to 0.95; p=0.004 in favor of concurrent therapy) and also indicated that the increased OS was mostly due to improvements in locoregional control [Aup\u00e9rin A et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2010]. Although increasing locoregional control may be one way to improve OS, the rate of local progression was still 30% to 40% and there was no difference in the incidence of distant metastases indicating that additional methods to optimize treatment are needed.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EMost clinical studies are based on the standard concurrent chemoradiotherapy approach for stage III (T4, N2\/3) NSCLC: a radiotherapy schedule of 60 to 66 Gy in 2 Gy\/day fractions 5 times per week with concurrent cisplatin-etoposide, cisplatin-vinorelbine, or carboplatin-paclitaxel (CP). However, some small trials have shown a survival advantage with high-dose radiotherapy. To test this hypothesis, the Radiation Therapy Oncology Group (RTOG) conducted a randomized Phase 3 trial [RTOG 0617; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00533949\u0026amp;atom=%2Fspmdc%2F12%2F15%2F18.atom\u0022\u003ENCT00533949\u003C\/a\u003E]. Patients with NSCLC that had spread to the lymph nodes were treated with weekly CP and either 60 or 74 Gy in 2 Gy QD fractions, either with or without cetuximab, followed by 2 cycles of consolidation CP \u00b1 cetuximab. At the 11-month interim analysis, the high Gy-dose arm showed worse OS compared with patients in the low Gy-dose arm (HR, 1.45; 95% CI, 1.02 to 2.05; p=0.02). Median survival was 21.7 months with 60 Gy versus 20.7 months with 74 Gy [Bradley JD et al. ASTRO 2011. Abstract LB2]. These unexpected results are still being investigated. Possible explanations include the preliminary nature of the results, the possibility of an interaction between 74 Gy and cetuximab, the specific effects of cetuximab (no subanalysis has been released for this group), the potential added toxicity of adjuvant chemotherapy and 74-Gy radiotherapy, and\/or other technical factors. This does not mean that dose intensification is not being pursued. There are trials looking at biological dose escalation (standard total doses given over a shorter overall time) and individualization of treatment using physical and biological approaches to determine which patients would benefit from accelerated or high-dose treatments. For standard practice, current protocols and guidelines should not be changed but emphasis on quality assessment and, if needed, adjustment of the entire diagnostic, treatment and supportive care process should be the main goal, concluded Prof. De Ruysscher.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003ETargeted agents are promising for selected patients with resectable stage I to III NSCLC, but it is clear at present that this is not a standard of care and patients for whom such therapy is being considered should be enrolled in clinical trials. Oliver Gautschi, MD, Luzerner Kantonsspital, Lucerne, Switzerland, reviewed some of the data and ongoing trials for targeted agents in stage I to III NSCLC.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EAlthough improving, there is clearly much that can still be done to increase the OS in patients with early NSCLC. Tumor mutations can affect prognosis and may be useful to help guide the administration of specific types of adjuvant therapy [Marks JL et al. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2008; Tsao MS et al. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2011]. Treatment with the EGFR inhibitor gefitinib was associated with a significant reduction in survival when it was evaluated in a maintenance setting in molecularly unselected patients with stage III NSCLC who were post radiation [SWOG 0023; Kelly K et al. \u003Cem\u003EJ Clin Oncol\u003C\/em\u003E 2008]. In the NCIC CTG BR.19 trial, OS with adjuvant gefitinib after complete resection of NSCLC was not different from placebo in the overall population, and \u003Cem\u003EKRAS\u003C\/em\u003E and \u003Cem\u003EEGFR\u003C\/em\u003E mutations were neither prognostic nor predictive of benefit from gefitinib by subgroup analysis [Goss GD et al. ASCO 2010. LBA7005].\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EIn a retrospective cohort study that evaluated adjuvant EGFR tyrosine kinase inhibitors (TKIs) in patients with stage IV lung adenocarcinoma and \u003Cem\u003EEGFR\u003C\/em\u003E mutation at the MSKCC, adjuvant TKI therapy was associated with a trend toward improvement in 2-year disease-free survival (DFS HR, 0.53; 95% CI, 0.28 to 1.03; p=0.06; \u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1A\u003C\/a\u003E) but no difference in OS (\u003Ca id=\u0022xref-fig-1-2\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1B\u003C\/a\u003E) [Janjigian YY et al. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2011]. In a follow-up of the same cohort, the investigators concluded that recurrence of \u003Cem\u003EEGFR\u003C\/em\u003E-mutant lung cancer after stopping adjuvant TKI should not preclude a trial of TKI retreatment [Oxnard GR et al. \u003Cem\u003EJ Clin Cancer\u003C\/em\u003E 2011] This was recently confirmed by the results of the Surgery for Early Lung Cancer with Preoperative Erlotinib: A Clinical Phase II Trial [SELECT; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00462995\u0026amp;atom=%2Fspmdc%2F12%2F15%2F18.atom\u0022\u003ENCT00462995\u003C\/a\u003E] evaluating the safety and efficacy of adjuvant erlotinib in EGFR mutation-positive NSCLC, which showed a 2-year DFS of 94% (95% CI, 0.80 to 0.99) [Neal JW et al. ASCO 2010. Abstract 7010] and successful reintroduction of the TKI after relapse. Several other trials evaluating the use of TKIs in the adjuvant setting are ongoing, including RADIANT [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT00373425\u0026amp;atom=%2Fspmdc%2F12%2F15%2F18.atom\u0022\u003ENCT00373425\u003C\/a\u003E] and ADJUVANT [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01405079\u0026amp;atom=%2Fspmdc%2F12%2F15%2F18.atom\u0022\u003ENCT01405079\u003C\/a\u003E]. In the neoadjuvant setting, so called \u201cwindow-of-opportunity\u201d trials are also ongoing, and are important and suitable to explore and validate new drugs and predictive markers. Presently, targeted therapies in the neoadjuvant setting remain experimental, but they are promising and may replace neoadjuvant chemotherapy in selected patients in the near future.\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/15\/18\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Memorial Sloan-Kettering Cancer Center Cohort: DFS and OS.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-991617612\u0022 data-figure-caption=\u0022Memorial Sloan-Kettering Cancer Center Cohort: DFS and OS.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/15\/18\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/15\/18\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/12\/15\/18\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/14524\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-10\u0022 class=\u0022first-child\u0022\u003EMemorial Sloan-Kettering Cancer Center Cohort: DFS and OS.\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EJanjigian YY et al. Impact on Disease-Free Survival of Adjuvant Erlotinib or Gefitinib in Patients with Resected Lung Adenocarcinomas that Harbor EGFR Mutations. \u003Cem\u003EJ Thorac Oncol\u003C\/em\u003E 2011;6(3):569\u2013575.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2012 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/12\/15\/18.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzn861\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzn861\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}