One size does not fit all: Nuances in postoperative N2 non–small cell lung cancer management

Abstract

Central MessageChoosing optimal therapy for patients with stage IIIA (N2) lung cancer depends on accurate clinical and pathologic assessment of N2 burden and relative risk of locoregional versus systemic recurrence.Feature Editor's Note—N2 lung cancer is one of the most complex and controversial areas within thoracic oncology. To a large extent, this is because N2 disease is embodied by a spectrum of disease states that are often grouped together in clinical studies. The variability in the biologic outcomes of N2 disease states is highlighted by proposals for the American Joint Commission on Cancer 8th edition staging system, which included consideration, on the basis of differential survival outcomes, of N descriptor subsets such as single-station N2 disease in the absence of N1 disease (N2a1), single-station N2 disease in the presence of N1 disease (N2a2), and multistation N2 disease (N2b). This subgrouping was ultimately not included in the stage classification of non–small cell lung cancer because of the difficulties of accurate assessment during clinical staging. Such heterogeneity of N2 non–small cell lung cancer cohorts within clinical studies that inform management guidelines for these patients has often resulted in differences in opinions among the various disciplines of thoracic oncology regarding interpretation of these data and agreement on best available care. In this Feature Expert Opinion article, a multidisciplinary team of authors provides, with remarkable clarity, a balanced view of the common nuances of N2 disease. This piece is centered on a recently published randomized trial on the treatment of yet another subset of this disease, occult N2 disease discovered after surgical resection. The results of this trial are discussed in the context of the current landscape for treatment of patients with resectable N2 non–small cell lung cancer, and the reader is promised an enhanced understanding of the gradations of this heterogeneous disease.Bryan M. Burt, MDSee Editorial Commentary page 374. Choosing optimal therapy for patients with stage IIIA (N2) lung cancer depends on accurate clinical and pathologic assessment of N2 burden and relative risk of locoregional versus systemic recurrence. See Editorial Commentary page 374. Despite more frequent use of computed tomographic screening in populations at high risk for lung cancer development, stage III lung cancer remains a commonly encountered scenario for the practicing thoracic oncologist. Whereas curable stage IIIb disease (7th American Joint Commission on Cancer system) is almost uniformly managed with definitive chemoradiotherapy, the management of stage IIIa disease is widely disparate and continues to be an area of active study and debate. Individual trials involving preselected patients with stage disease IIIa may achieve outcomes that appear promising; however supporting data for the 7th American Joint Commission on Cancer staging manual demonstrates that on a population level, outcomes in stage IIIa remain quite dismal, with 5-year overall survivals (OSs) of 24% for pathologic stage IIIa disease and 19% for clinical stage IIIa disease.1Detterbeck F.C. Boffa D.J. Tanoue L.T. The new lung cancer staging system.Chest. 2009; 136: 260-271Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar These observed prognostic differences between pathologic and clinical stage IIIa disease highlight the fact that stage IIIa disease encompasses a heterogeneous group of patients from both prognostic and therapeutic vantage points. Although the value of systemic therapy in stage IIIa disease is well established and unquestioned, surgical resection and radiotherapy are both used as locoregional treatment modalities. The main debates in stage IIIa non–small cell lung cancer (NSCLC) management revolve around the use and timing of local options—surgery, radiation, or both? A recent randomized study by Sun and colleagues2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar adds a layer of nuance regarding the use of both surgery and postoperative radiotherapy (PORT) in patients with occult stage IIIa (N2) disease who have undergone upfront surgical management. Sun and colleagues2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar deserve credit for a well-conducted study examining adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) followed by chemotherapy in a subset of patients with stage IIIa (N2) NSCLC—those with “surprise” N2 disease burden. Patients (n = 101) were randomly assigned to receive either 4 cycles of adjuvant carboplatin and paclitaxel or CCRT with low-dose cisplatin and paclitaxel with 50 Gy of mediastinal radiotherapy followed by 2 additional cycles of cisplatin plus paclitaxel. The median disease-free survival (primary end point) in the CCRT arm was 24.7 months, not significantly different from the 21.9 months observed in the chemotherapy-alone arm (hazard ratio [HR], 0.94; P = .40). Likewise, the OS (74.3 months in the CCRT arm and 83.5 months in the chemotherapy arm; HR, 1.33; 95% confidence interval, 0.71-2.49) were not significantly different. These results suggest no benefit to PORT in this narrow subset of patients with stage IIIa (N2) disease. These results hold the potential to influence the approach to patients with pathologic stage IIIa disease; however, they deserve careful and thoughtful review before incorporation into daily clinical practice. Nodal status has become one of the most important prognostic features in patients with lung cancer and serves as an integral factor in determining optimal treatment approach.3Rusch V.W. Crowley J. Giroux D.J. Goldstraw P. Im J.G. Tsuboi M. et al.International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating InstitutionsThe IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer.J Thorac Oncol. 2007; 2: 603-612Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar Management of N2 disease remains an area of active debate, and often the therapeutic approach is guided by “how much” N2 disease is present. Currently, in the 7th and 8th editions of the American Joint Commission on Cancer staging manual, lymph node involvement in lung cancer remains categorized according to the location of the metastatic lymph nodes and not according to the number of lymph nodes involved.4Asamura H. Chansky K. Crowley J. Goldstraw P. Rusch V.W. Vansteenkiste J.F. et al.International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Board Members, and Participating InstitutionsThe International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer.J Thorac Oncol. 2015; 10: 1675-1684Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar Studies suggest, however, that the amount of nodal disease burden (number, bulk, extracapsular extension, or multistation involvement) is a factor of prognostic significance, and it has become a method to subdivide stage III disease.4Asamura H. Chansky K. Crowley J. Goldstraw P. Rusch V.W. Vansteenkiste J.F. et al.International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee, Advisory Board Members, and Participating InstitutionsThe International Association for the Study of Lung Cancer Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming 8th edition of the TNM classification for lung cancer.J Thorac Oncol. 2015; 10: 1675-1684Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar, 5Wei S. Asamura H. Kawachi R. Sakurai H. Watanabe S. Which is the better prognostic factor for resected non-small cell lung cancer: the number of metastatic lymph nodes or the currently used nodal stage classification?.J Thorac Oncol. 2011; 6: 310-318Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 6Saji H. Tsuboi M. Shimada Y. Kato Y. Yoshida K. Nomura M. et al.A proposal for combination of total number and anatomical location of involved lymph nodes for nodal classification in non-small cell lung cancer.Chest. 2013; 143: 1618-1625Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar Historically, management of patients with clinical stage IIIa (cN2) NSCLC disease depends on (1) the clinically apparent bulk of nodal disease, (2) the available institutional expertise, and (3) patient factors and preferences. Bulky or multistation cN2 disease is most commonly managed in a similar fashion to N3 disease, with surgery rarely used in lieu of definitive chemoradiotherapy. An intermediate risk category of “potentially resectable” cN2 disease exists, in which N2 disease is clinically apparent on staging workup, and either definitive chemoradiation or induction therapy after surgery (preferably a lobectomy) can reasonably be entertained. A further subcategory of patients with stage IIIa disease comprises those who have “surprise” N2 disease found on pathologic sampling of removed lymph nodes at the time of lobectomy after thorough preoperative staging of disease as stage I or II. This clinical scenario is not rare, but it does depend on the rigor of preresectional invasive staging; a recent analysis demonstrated that 22.4% of patients with resectable NSCLC will have occult lymph node metastases with systematic lymph node inspection at the time of definitive resection.7Rusch V.W. Hawes D. Decker P.A. Martin S.E. Abati A. Landreneau R.J. et al.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: 4313-4319Crossref PubMed Scopus (87) Google Scholar Despite published guidelines, practices vary in terms of preoperative imaging and mediastinal staging techniques and whether induction therapy is pursued before or after surgery.8Rocco G. Nason K. Brunelli A. Varela G. Waddell T. Jones D.R. Management of stage IIIA (N2) non-small-cell lung cancer: a transatlantic perspective†.Eur J Cardiothorac Surg. 2016; 49: 1025-1027Crossref PubMed Scopus (10) Google Scholar, 9Veeramachaneni N.K. Feins R.H. Stephenson B.J. Edwards L.J. Fernandez F.G. Management of stage IIIA non-small cell lung cancer by thoracic surgeons in North America.Ann Thorac Surg. 2012; 94 (discussion 926-8): 922-926Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar In the study by Sun and colleagues,2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar all patients had a positron-emission tomographic scan performed, but only 41% of patients had any invasive staging performed. This is even more surprising because 27% had clinical N1 disease and 65% had T2 or T3 tumors; both clinical factors are associated with occult N2 disease and recommended scenarios for invasive staging.10National Comprehensive Cancer NetworkNCCN clinical practice guidelines in oncology (NCCN Guidelines®): Non-Small Cell Lung Cancer, version 3.2018—February 21, 2018.https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdfDate accessed: January 22, 2018Google Scholar, 11Detterbeck F.C. Lewis S.Z. Diekemper R. Addrizzo-Harris D. Alberts W.M. Executive Summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.Chest. 2013; 143: 7S-37SAbstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar In the groups of patients with surprise N2 disease after surgery and those with resectable clinical N2 disease, PORT has often been recommended to decrease rates of mediastinal recurrence. This practice has not been without controversy, because an often-cited meta-analysis of PORT12Burdett S. Stewart L. PORT Meta-analysis GroupPostoperative radiotherapy in non-small-cell lung cancer: update of an individual patient data meta-analysis.Lung Cancer. 2005; 47: 81-83Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar examining 10 randomized studies (2232 patients) from 1966 through 1997 highlighted the pitfalls of overuse of PORT. Overall, PORT was associated with a reduction in 2-year survival (from 55% to 48%), with patients with N0 or N1 disease strongly demonstrating a negative survival impact with PORT. In patients with N2 disease, there was no OS benefit or detriment from PORT. An early Belgian study included in the meta-analysis is instructive. Van Houtte and associates13Van Houtte P. Rocmans P. Smets P. Goffin J.C. Lustman-Maréchal J. Henry J. Postoperative radiation therapy in lung caner: a controlled trial after resection of curative design.Int J Radiat Oncol Biol Phys. 1980; 6: 983-986Abstract Full Text PDF PubMed Scopus (202) Google Scholar randomized 224 patients with stage clinical I NSCLC to observation versus 60 Gy PORT delivered to the mediastinum through the (now outdated) cobalt technique. Although PORT decreased locoregional failure from 19% to 4%, there was an accompanying apparent OS detriment, from 43% to 24% at 5 years. Collectively, these studies suggest that the likelihood of mediastinal recurrence must be reasonably high if the benefit of disease control in the mediastinum is to outweigh the detrimental cardiopulmonary effects of PORT and that future investigations of PORT should be limited to the N2 population. Subsequent studies examining modern radiation delivery in patients with N2 disease have had a more favorable response to PORT. Three nonrandomized examinations of the National Cancer Database examined PORT in patients with stage IIIa-pN2 disease, and all favored the use of PORT for patients with pN2 disease. Corso and coworkers14Corso C.D. Rutter C.E. Wilson L.D. Kim A.W. Decker R.H. Husain Z.A. Re-evaluation of the role of postoperative radiotherapy and the impact of radiation dose for nonsmall-cell lung cancer using the National Cancer Database.J Thorac Oncol. 2015; 10: 148-155Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar examined 30,552 patients treated from 1998 to 2006 and found by multivariate analysis an association of PORT with improved OS in patients with pN2 disease (HR, 0.85), with a 5-year OS of 34.1% versus 27.8% without PORT. Only 23.8% of patients with pN2 disease received PORT during this time frame. Another group15Mikell J.L. Gillespie T.W. Hall W.A. Nickleach D.C. Liu Y. Lipscomb J. et al.Postoperative radiotherapy is associated with better survival in non-small cell lung cancer with involved N2 lymph nodes: results of an analysis of the National Cancer Data Base.J Thorac Oncol. 2015; 10: 462-471Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar examined a smaller sample of patients from 2004 to 2006 and reached similar conclusions. Robinson and colleagues16Robinson C.G. Patel A.P. Bradley J.D. DeWees T. Waqar S.N. Morgensztern D. et al.Postoperative radiotherapy for pathologic N2 non–small-cell lung cancer treated with adjuvant chemotherapy: a review of the National Cancer Data Base.J Clin Oncol. 2015; 33: 870-876Crossref PubMed Scopus (164) Google Scholar examined a more recent cohort from 2006 to 2010. When restricting the analyses to those patients with pN2 disease who underwent complete resection and received adjuvant chemotherapy, the use of PORT (41.2% of patients) was associated with an improvement in the 5-year OS from 34.8% to 39.3% (HR, 0.886; P = .014). Although these retrospective studies are prone to selection biases, their findings are supported by a Chinese randomized study by Shen and colleagues,17Shen W.Y. Ji J. Zuo Y.S. Pu J. Xu Y.M. Zong C.D. et al.Comparison of efficacy for postoperative chemotherapy and concurrent radiochemotherapy in patients with IIIA-pN2 non-small cell lung cancer: an early closed randomized controlled trial.Radiother Oncol. 2014; 110: 120-125Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar in which 140 patients with stage IIIa-pN2 disease were randomly assigned to either postoperative chemotherapy alone versus postoperative chemoradiotherapy. Although the study closed early because of low accrual, 140 patients received either 4 cycles of adjuvant cisplatin and paclitaxel, or the same chemotherapy with 50.4 Gy of mediastinal radiotherapy given concurrently with the first 2 cycles of chemotherapy (CCRT arm). The CCRT arm had a median survival of 40 months, versus 28 months in the chemotherapy-alone arm; this difference favoring PORT approached statistical significance (HR, 0.69; P = .07). The 5-year disease-free survival (DFS) significantly favored the CCRT (30.3%) arm relative to the chemotherapy-alone arm (18.8%; P = .041). How are we to reconcile the randomized study of Shen and colleagues,17Shen W.Y. Ji J. Zuo Y.S. Pu J. Xu Y.M. Zong C.D. et al.Comparison of efficacy for postoperative chemotherapy and concurrent radiochemotherapy in patients with IIIA-pN2 non-small cell lung cancer: an early closed randomized controlled trial.Radiother Oncol. 2014; 110: 120-125Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar which is suggestive of an OS benefit and a significant 5-year DFS benefit to PORT in patients with stage IIIa-pN2 disease, with the randomized study of Sun and colleagues,2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar which suggested no utility of PORT in patients with stage IIIa-pN2 disease? (Table 1) An examination of the patterns of failures from these 2 studies demonstrates that preoperative staging effectively stratifies the risk of mediastinal recurrence after complete surgical resection. In the study of Sun and colleagues,2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar which examined patients with “surprise” pN2 disease that had been staged as cN0-N1 with thorough preoperative staging, the locoregional-only recurrence rate was 14.0% in the chemotherapy-alone arm. As such, most of the patients did not stand to benefit from PORT but were exposed to the associated toxicities. In contrast, the study of Shen and colleagues17Shen W.Y. Ji J. Zuo Y.S. Pu J. Xu Y.M. Zong C.D. et al.Comparison of efficacy for postoperative chemotherapy and concurrent radiochemotherapy in patients with IIIA-pN2 non-small cell lung cancer: an early closed randomized controlled trial.Radiother Oncol. 2014; 110: 120-125Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar did not incorporate preoperative positron-emission tomographic and computed tomographic staging, and in the chemotherapy-alone arm, 49.2% of patients had locoregional failure after surgical resection. PORT use reduced this to 27.3%, and this significant improvement in locoregional control translated into the smaller gains in OS and 5-year DFS.Table 1Summary of 2 randomized studies of mediastinal postoperative radiotherapy for stage IIIa-pN2 non–small cell lung cancerAuthor, yNNSCLC patient populationRandomized armLocal relapse∗Includes both locoregional-only relapse and simultaneous distant and locoregional relapses.Median OS (mo)P valueMedian DFS (mo)P valueShen et al,17Shen W.Y. Ji J. Zuo Y.S. Pu J. Xu Y.M. Zong C.D. et al.Comparison of efficacy for postoperative chemotherapy and concurrent radiochemotherapy in patients with IIIA-pN2 non-small cell lung cancer: an early closed randomized controlled trial.Radiother Oncol. 2014; 110: 120-125Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar 2014135All IIIa-pN2Adjuvant chemotherapy49.3%28.07318.041CCRT27.3%4028Sun et al,2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar 2017101Clinical stage I-II with “surprise” pN2 diseaseAdjuvant chemotherapy24%83.5.3821.9.40CCRT15.7%74.324.7NSCLC, Non–small cell lung cancer; OS, overall survival; DFS, disease-free survival; CCRT, concurrent chemoradiotherapy.∗ Includes both locoregional-only relapse and simultaneous distant and locoregional relapses. Open table in a new tab NSCLC, Non–small cell lung cancer; OS, overall survival; DFS, disease-free survival; CCRT, concurrent chemoradiotherapy. Recent reports have investigated the morbidity and mortality associated with thoracic radiotherapy in a more robust fashion. Wang and associates18Wang K. Eblan M.J. Deal A.M. Lipner M. Zagar T.M. Wang Y. et al.Cardiac toxicity After radiotherapy for stage III non–small-cell lung cancer: pooled analysis of dose-escalation trials delivering 70 to 90 Gy.J Clin Oncol. 2017; 35: 1387-1394Crossref PubMed Scopus (259) Google Scholar reported symptomatic cardiac events in 23% of patients enrolled in prospective clinical trials delivering dose-escalated definitive thoracic radiotherapy for stage III NSCLC. These events occurred at a median of 26 months after radiotherapy, and significant correlation with cardiac dosimetric parameters was demonstrated. Similarly, a recent analysis of the Radiation Therapy Oncology Group 0617 study examining definitive CCRT showed that higher levels of radiation to the heart are associated with worse OS.19Chun S.G. Hu C. Choy H. Komaki R.U. Timmerman R.D. Schild S.E. et al.Impact of intensity-modulated radiation therapy technique for locally advanced non–small-cell lung cancer: a secondary analysis of the NRG Oncology RTOG 0617 Randomized Clinical Trial.J Clin Oncol. 2017; 35: 56-62Crossref PubMed Scopus (456) Google Scholar Although these analyses suggest that advanced radiation techniques. such as intensity-modulated radiotherapy. may reduce some of these toxicities, it is vital to not expose patients at low risk of mediastinal recurrence to these potential detrimental effects. The use of PORT in patients with stage IIIa-pN2 disease therefore deserves careful consideration according to the likelihood of residual mediastinal disease. One criticism of the study of Sun and colleagues2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar is that it delivered PORT with concurrent low-dose chemotherapy before adequate delivery of full-dose adjuvant chemotherapy. This resulted in 25% of patients in the CCRT arm not receiving the scheduled full-dose adjuvant chemotherapy cycles after CCRT, clearly a concern in a population in which distant recurrence (∼40% in both arms) remains the dominant pattern of recurrence. Current National Comprehensive Cancer Network guidelines recommend that systemic therapy precede PORT10National Comprehensive Cancer NetworkNCCN clinical practice guidelines in oncology (NCCN Guidelines®): Non-Small Cell Lung Cancer, version 3.2018—February 21, 2018.https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdfDate accessed: January 22, 2018Google Scholar; the study of Sun and colleagues2Sun J.M. Noh J.M. Oh D. Kim H.K. Lee S.H. Choi Y.S. et al.Randomized phase II trial comparing chemoradiotherapy with chemotherapy for completely resected unsuspected N2-positive non-small cell lung cancer.J Thorac Oncol. 2017; 12: 1806-1813Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar does not fully address the utility of PORT after adequate systemic therapy has been delivered. Further, this study used a carboplatin-based adjuvant chemotherapy regimen, despite lack of evidence for survival benefit with carboplatin in the adjuvant setting.20Strauss G.M. Herndon II, J.E. Maddaus M.A. Johnstone D.W. Johnson E.A. Harpole D.H. et al.Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups.J Clin Oncol. 2008; 26: 5043-5051Crossref PubMed Scopus (780) Google Scholar, 21Pignon J.P. Tribodet H. Scagliotti G.V. Douillard J.Y. Shepherd F.A. Stephens R.J. et al.Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group.J Clin Oncol. 2008; 26: 3552-3559Crossref PubMed Scopus (1773) Google Scholar Multiple adjuvant chemotherapy trials in lung cancer have established cisplatin doublets as the optimal strategy for stage II-IIIA disease, and such regimens are endorsed by National Comprehensive Cancer Network, the American Society of Clinical Oncology, and Cancer Care Ontario.22Kris M.G. Gaspar L.E. Chaft J.E. Kennedy E.B. Azzoli C.G. Ellis P.M. et al.Adjuvant systemic therapy and adjuvant radiation therapy for stage I to IIIA completely resected non-small-cell lung cancers: American Society of Clinical Oncology/Cancer Care Ontario clinical practice guideline update.J Clin Oncol. 2017; 35: 2960-2974Crossref PubMed Scopus (202) Google Scholar Finally, the primary end point of DFS should not replace the objective of 5-year OS when pursuing curative intent therapy. Nonetheless, some important takeaways can be gleaned. First, the predominant pattern of failure for pN2 disease remains distant. We should therefore redouble our efforts to use invasive staging appropriately at the time of original diagnosis. If N2 disease can be identified at the time of preresectional staging, then neoadjuvant chemotherapy can be delivered, with the expectation of even better control of systemic micrometastatic disease, while minimizing the risk that chemotherapy delivery is delayed, dose reduced, or compromised by surgical or radiotherapy complications. Patients with clinically apparent N2 disease before surgical resection will likely derive more benefit from PORT than will patients with “surprise” N2 disease. Adjuvant systemic therapy should be prioritized in these “surprise” patients, and it likely should precede if not supplant PORT, rather than be given concurrently. In addition, the ongoing European LUNG ART study23Le Pechoux C. Dunant A. Radiation Therapy in Treating Patients With Non Small Cell Lung Cancer That Has Been Completely Removed by Surgery (LUNG ART).https://clinicaltrialsgov/ct2/show/NCT00410683Google Scholar examining PORT in a randomized fashion will shed further light on patient subgroups that may derive benefit from PORT. In the meanwhile, balanced discussions of potential oncologic benefit versus the risk of cardiopulmonary detriment are needed to guide patient-centered decision making. Authors have nothing to disclose with regard to commercial support. Let's just do what we mustThe Journal of Thoracic and Cardiovascular SurgeryVol. 156Issue 1PreviewThe excellent editorial by Kruser and colleagues1 about the article by Sun and colleagues2 is rightfully centered on the postoperative options for N2 disease and the outcome differences noted when occult N2 is treated compared with N2 identified at preoperative staging. The analysis of the literature shows that, irrespective of the N2 subsets, mediastinal nodal involvement carries a significant risk for distant recurrence.1 Conversely, the efficacy of preoperative staging predicts the likelihood of mediastinal local recurrence after surgical resection. Full-Text PDF Open Archive