Is N2 Disease a Contraindication for Surgical Resection for Superior Sulcus Tumors? No

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1 2. Goldstraw P, Crowley J, Chansky K, et al ; International Association for the Study of Lung Cancer International Staging Committee and Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol ;2(8): Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-smallcell lung cancer: a phase III randomised controlled trial. Lancet ;374(9687): van Meerbeeck JP, Kramer GW, Van Schil PE, et al ; European Organisation for Research and Treatment of Cancer-Lung Cancer Group. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst ;99(6): Ste phe ns RJ, Gi rl ing DJ, Hopwo o d P, Thatcher N ; Medical Research Council Lung Cancer Working Party. A randomised controlled trial of pre-operative chemotherapy followed, if feasible, by resection versus radiotherapy in patients with inoperable stage T3, N1, M0 or T1-3, N2, M0 non-small cell lung cancer. Lung Cancer ; 49 (3): Johnstone DW, Byhardt RW, Ettinger D, S cott CB ; R adiation Therapy Oncology Group. Phase III study comparing chemotherapy and radiotherapy with preoperative chemotherapy and surgical resection in patients with non-small-cell lung cancer with spread to mediastinal lymph nodes (N2); final report of RTOG Int J Radiat Oncol Biol Phys ;54(2): Ramnath N, Dilling TJ, Harris LJ, et al. Treatment of stage III non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest ;143(5_suppl): e314s-e340s. 8. He r t h FJ, An ne ma JT, Eb erhardt R, et a l. Endobronch i a l u lt ras ou nd with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol ;26(20): Nasir BS, Bryant AS, Minnich DJ, Wei B, Dransfield MT, Cerfolio RJ. The efficacy of restaging endobronchial ultrasound in patients with non-small cell lung cancer after preoperative therapy. Ann Thorac Surg ;98(3): Szlubowski A, Zieliński M, Soja J, et al. Accurate and safe mediastinal restaging by combined endobronchial and endoscopic ultrasoundguided needle aspiration performed by single ultrasound bronchoscope. Eur J Cardiothorac Surg ;46(2): De Leyn P, Stroobants S, De Wever W, et al. Prospective comparative study of integrated positron emission tomography-computed tomography scan compared with remediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy-proven stage IIIA-N2 Nonsmall-cell lung cancer: a Leuven Lung Cancer Group Study. J Clin Oncol ;24(21): De Waele M, Hendriks J, Lauwers P, et al. Nodal status at repeat mediastinoscopy determines survival in non-small cell lung cancer with mediastinal nodal involvement, treated by induction therapy. Eur J Cardiothorac Surg ;29(2): De Waele M, Serra-Mitjans M, Hendriks J, et al. Accuracy and survival of repeat mediastinoscopy after induction therapy for non-small cell lung cancer in a combined series of 104 patients. Eur J Cardiothorac Surg ;33 (5 ): Rami-Porta R, Mateu-Navarro M, Serra-Mitjans M, Hernández- Rodríguez H. Remediastinoscopy: comments and updated results. Lung Cancer ;42 (3 ): Marra A, Hillejan L, Fechner S, Stamatis G. Remediastinoscopy in restaging of lung cancer after induction therapy. J Thorac Cardiovasc Surg ;135 (4 ): Zieliński M, Hauer L, Hauer J, Nabiałek T, Szlubowski A, Pankowski J. Non-small-cell lung cancer restaging with transcervical extended mediastinal lymphadenectomy. Eur J Cardiothorac Surg ; 37 (4): Gaspar LE, Chansky K, Albain KS, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-smallcell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol ;23(13): Kernstine KH, Moon J, Kraut MJ, et al ; American College of Surgeons Oncology Group; Cancer and Leukemia Group B; Eastern Cooperative Oncology Group; North Central Cancer Treatment Group; National Cancer Institute of Canada Clinical Trials Group; Southwest Oncology Group. Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-Intergroup Trial S0220. Ann Thorac Surg ;98(2): Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol ;25(3): Kunitoh H, Kato H, Tsuboi M, et al ; Japan Clinical Oncology Group. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806 [published correction appears in J Clin Oncol. 2011;29(33):4472]. J Clin Oncol ;26(4): Ettinger DS, Akerley W, Borghaei H, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version Ft. Washington, PA : National Comprehensive Cancer Network ; Gomez DR, Cox JD, Roth JA, et al. A prospective phase 2 study of surgery followed by chemotherapy and radiation for superior sulcus tumors. Cancer ;118(2): Marra A, Eberhardt W, Pöttgen C, et al. Induction chemotherapy, concurrent chemoradiation and surgery for Pancoast tumour. Eur Respir J ;29(1): COUNTERPOINT: Is N2 Disease a Contraindication for Surgical Resection for Superior Sulcus Tumors? No Wilson W. Li, MD ; Jacobus A. Burgers, MD, PhD ; Houke M. Klomp, MD, PhD ; Koen J. Hartemink, MD, PhD ; Amsterdam, The Netherlands For patients with superior sulcus tumors (SSTs) (ie, lung cancer invading the apical chest wall structures), trimodality therapy has become the mainstay of treatment as recommended by the 2013 American College of Chest Physicians (CHEST) lung cancer guidelines. 1 The guidelines also state that involvement of mediastinal lymph nodes (N2 disease) is associated with poor survival after resection, contraindicating surgical treatment. 1 However, the association of N2 disease with poor survival is AFFILIATIONS: From the Department of Cardiothoracic Surgery (Dr Li), Academic Medical Center, University of Amsterdam; and Department of Thoracic Oncology (Dr Burgers) and Department of Thoracic Surgery (Drs Klomp and Hartemink), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital. CONFLICT OF INTEREST: None declared. CORRESPONDENCE TO: Wilson W. Li, MD, Department of Cardiothoracic Surgery, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; w.w.li@amc.uva.nl 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest

2 based on results derived mainly from the era before the advent of trimodality therapy. Furthermore, this focus on survival bypasses potential palliative indications for resections of SSTs, which can induce severe, disabling pain symptoms. Pain control may be improved by additional surgical resection. 2,3 Because the treatment of pain in these patients is a major priority, 4 a wellbalanced surgical approach should still be considered, 3,5 even in the presence of potential negative prognostic factors for survival, such as N2 disease. In this counterpoint editorial, we provide an overview of the postoperative results of patients with SSTs with N2 disease treated with trimodality therapy. We argue that these contemporary results justify revoking N2 dis ease as an absolute contraindication for surgical resection. N2 Disease Before and After the Advent of Trimodality Therapy Before the introduction of trimodality therapy, mixed protocols usually of bimodality treatment were used to treat SSTs. 4,6 This generally consisted of surgical resection with either preoperative or postoperative chemotherapy or radiotherapy, resulting in 5-year survival rates of 25% to 35%, 4,6 and poor local control with local recurrence rates of up to 72%. 6 In these series, N status was an important prognostic factor of overall survival after surgical resection of SSTs. 4,6 N2 disease was associated with a 5-year postoperative survival of 0% to 10%. 4 On the basis of these early studies, the 2013 CHEST guidelines recommend invasive mediastinal staging for potential surgical candidates and oppose resection when N2 disease is detected. 1 With trimodality therapy, postoperative trends and outcome seem to be changing. Two important multicenter trials 7,8 set the standard of contemporary trimodality treatment in patients with SSTs. Both studies, totaling 145 patients with N0-1 disease, presented similar results of surgical resection after induction chemoradiation. In 89% to 94% of patients, complete R0 resection could be achieved, with a 21% to 36% complete pathologic response. Postoperative mortality was only 2%. Five-year survival was 44% to 56% and was significantly higher in cases of complete resection (70% vs 24%) 8 or complete pathologic response. Local control was good (11% local recurrence) 7 and even better when complete resection was accomplished (4% local recurrence). 8 Relapse of disease most often occurred at distant sites (30%-39%), with the brain as most common location. With these promising results, various groups have adopted a broader patient selection strategy, including patients with N2 disease ( Table 1 ). 5, 8-18 Despite more advanced stages of disease, overall long-term results in these contemporary series were comparable with previous trials, reporting 5-year survival rates between 36% and 72% and local recurrence rates of 0% to 18% ( Table 1 ). Operative mortality was also similar, ranging from 0% to 7% in reports published during the past decade. 5,8,11,12,14-18 The premise of this approach was further strengthened by the success of multimodality treatment of stage IIIA (N2) non-small cell lung cancer (NSCLC) outside the superior sulcus, 19 offering better local control and improved progression-free survival 20 for surgical resection after concurrent chemoradiation compared with chemoradiation alone. Focusing on reports in patients with SSTs and mediastinal lymph node involvement ( Table 1 ), N2 disease (either clinical or pathologic) was present in up to 25% of cases. In most of the studies, no specific data were reported on the N2 population. In four studies, 5,11,14,16 N2 status was grouped with other forms of lymph node involvement (N1 or N3) without specific N2 subanalyses. In two of these reports, lymph node status was not associated with survival. 11,16 In three studies with N2 subanalyses, 10,13,18 N2 disease was associated with poor survival in these studies with a low rate of induction therapy (only 10%-15% receiving trimodality treatment and 35%-46% receiving no induction therapy). 10,13 In one study with a 100% trimodality therapy rate, including 19% N2 disease (either clinical or pathologic), 2-year survival between N2 and no N2 disease was not significantly different (40% vs 52%, P 5.50). 18 Th ese data should be interpreted with caution because they are liable to selection and other biases. Nevertheless, they show that surgery on N2-positive SSTs is feasible with an acceptable outcome. The Many Faces of N2 Disease Patients with NSCLC and N2 disease are a heterogeneous group with varying patterns of lymph node involvement. 21 There is a continuum of shades of gray ranging from occult and single-level to multilevel and bulky N2 disease, each group with a different prognosis. 22 Regarding SSTs, only limited and heterogeneous data are available in patients with N2 disease undergoing trimodality therapy. The aforementioned differences in N2 disease patterns and the possible associated differences in treatment outcome cannot be differentiated within existing data. In addition, great disparity 1376 Point and Counterpoint [ 148#6 CHEST DECEMBER 2015 ]

3 TABLE 1 ] Results of Contemporary Trimodality Therapy for Superior Sulcus Tumor From Case Series Including N2 Disease Study/Year No. Patients No. Undergoing Trimodality Therapy c/pn2 (% Undergoing Trimodality Therapy) R0 Resection, % Complete Pathologic Response, % Local Recurrence, % Survival After Trimodality Therapy Martínez-Monge et al 9 / (11) y all patients: 56%; 4 y no CR vs CR: 20% vs 88% ( P NR); no specific data reported in patients with N2 disease Attar et al 10 / (NR) NR NR NR 5 y all patients: 72%; N2 disease was associated with worse survival for all patients; no specific data reported in patients with N2 disease after trimodality therapy Kwong et al 11 / (25) y all patients: 50% a ; 5 y cn1-3 vs cn0: 42% vs 62% a ( P 5.49) Marra et al 5 / (NR) y all patients: 46%; 5 y no CR vs CR: 35% vs 63% ( P 5.10); 5 y cn2-3 vs cn0-1: 21% vs 54% ( P 5.02) Kunitoh et al 8 / (2) b 5 y all patients: 56%; 5 y R1 vs R0 resection: 24% vs 70% ( P NR); no specific data reported in patients with N2 disease Fischer et al 12 / (2) y all patients: 59%; no significant differences in survival between pathologic stages; no specific data reported in patients with N2 disease Demir et al 13 / NR 90 NR NR 5 y all patients: 41%; N2 disease and incomplete resection were poor prognostic factors Bolton et al 14 / (NR) NR NR NR Positive lymph node status (N1-3) was associated with worse survival and higher recurrence rate in all patients; no specific data reported in patients with N2 disease after trimodality therapy Kappers et al 15 / (NR) y all patients: 37%; 5 y no CR vs CR: 17% vs 56% ( P 5.12); no specific data reported in patients with N2 disease Li et al 16 / (23) y all patients: 36%; no differences between N0 vs N1-2 disease Tagawa et al 17 / (15) 89 7 NR 5 y all patients: 65%; N status not correlated with survival; no specific data reported in patients with N2 disease Vos et al 18 / (19) y all patients: 50%; 2 y N2 vs no N2 disease: 40% vs 52% ( P 5.50); 2 y R1 vs R0 resection: 20% vs 57% ( P 5.022); 2 y no CR vs CR: 37% vs 81% ( P 5.003) CR 5 complete resection; NR 5 not reported. a Numerical survival data derived from survival graphs. b Local recurrence rate in patients with CR. 1377

4 exists between studies on how N2 disease was diagnosed (either radiologically or pathologically and either before or after induction therapy); therefore, we can only draw lessons from other forms of NSCLC outside the superior sulcus. There is increasing evidence that surgical resection after induction therapy is beneficial in select cases of N2 disease. The major benefits are for the groups with discrete or single-level N2 where downstaging is accomplished and pneumonectomy not required. 20 As recommended in the 2013 CHEST guidelines, 21 a treatment plan in these patients should be made on a case-by-case basis by a multidisciplinary team. Pain and Local Control Pain is the most common presenting symptom of SSTs, with 69% to 97% of patients reporting shoulder pain on diagnosis. 23,24 Based on data from early studies, palliative radiotherapy is advised when curative-intent treatment is not possible. 1 These series reported 63% to 86% pain relief by radiotherapy alone However, long-term failure of local tumor control is a problematic issue. Despite an initial good response, median duration of pain palliation is only 11 to 12 months, 25,26 and recurrence of symptoms is mostly due to local recurrence. 27 Adjuvant surgical resection has been advocated to improve long-term pain control in patients with SSTs. 2,3 In early studies on surgical treatment, usually after induction radiotherapy, 72% to 88% of patients had longterm lasting relief of pain symptoms. 2,3 Interestingly, in contemporary studies on trimodality treatment, pain is a neglected issue. Pain was assessed in none of the 12 studies presented in Table 1. However, if we link the success of pain palliation with the rate of local control, 27 one can deduce that surgical resection will contribute to long-term pain relief. As mentioned earlier, local recurrence after trimodality therapy is considerably lower than after any of the previously attempted treatment strategies. Additionally, complete pathologic response is achieved in only 20% to 60% of patients after concurrent chemoradiation, as demonstrated in the surgical series ( Table 1 ), suggesting that local recurrence is an eventual rather than a possible future event when surgery is omitted. This is clearly illustrated by Kappers et al, 15 who reported that in a group of 64 patients with 6% N2 disease, local recurrence was much lower after trimodality therapy compared with a nonsurgical group (0% vs 40%). Management Implications Although the currently available data are limited and heterogenous, several observations can be safely stated. Adjuvant resection after chemoradiation for SSTs can be safely performed with acceptable survival outcome in properly selected patients with N2 disease. Longterm survival of these patients seems to be better with trimodality therapy compared with other treatment regimens. In several studies, N2 disease is not associated with inferior long-term survival after trimodality therapy, although some reports have shown mixed results. Moreover, local control is superior after trimodality treatment, which is key to long-term pain control. In our opinion, this rationale justifies additional surgery, even in the setting of N2 disease, as long as a radical resection can be accomplished. Conclusions We challenge the established proclamation that N2 disease is a contraindication for surgical resection in the current trimodality era. Specific subsets of patients with N2 disease should be identified that will benefit the most from additional resectional therapy after induction therapy. Learning from other forms of NSCLC outside the thoracic outlet, we propose that patients with discrete or single-level N2 disease should still be considered for surgical treatment when a radical resection can be performed. Considering the rarity of the disease, we predict that sufficiently powered randomized clinical trials will not be realized to answer these clinical questions. We eagerly await further results from high-volume centers with precise definitions of N2 disease, standardized preoperative staging algorithms, and detailed subgroup analyses to guide us in proper case selection for surgical treatment in patients with SSTs. References 1. Kozower BD, L arner JM, Detterbeck FC, Jones DR. Special treatment issues in non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest ;143(5_suppl): e369s-e399s. 2. Wr ig ht CD, Monc ure AC, Shep ard JA, Wi l k ins EW Jr, Mat his en DJ, Grillo HC. Superior sulcus lung tumors. Results of combined treatment (irradiation and radical resection). J Thorac Cardiovasc Surg ;94(1): Maggi G, Casadio C, Pischedda F, et al. Combined radiosurgical treatment of Pancoast tumor. Ann Thorac Surg ; 57 ( 1 ): Foroulis CN, Zarogoulidis P, Darwiche K, et al. Superior sulcus (Pancoast) tumors: current evidence on diagnosis and radical treatment. J Thorac Dis ;5(suppl 4 ):S342-S Marra A, Eberhardt W, Pöttgen C, et al. Induction chemotherapy, concurrent chemoradiation and surgery for Pancoast tumour. Eur Respir J ;29(1): Rusch VW. Management of Pancoast tumours. Lancet Oncol ; 7 (12): Rusch VW, Giroux DJ, Kraut MJ, et al. Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol ;25(3): Point and Counterpoint [ 148#6 CHEST DECEMBER 2015 ]

5 8. Kunitoh H, Kato H, Tsuboi M, et al ; Japan Clinical Oncology Group. Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806 [published correction appears in J Clin Oncol. 2011;29(33):447]. J Clin Oncol ;26 (4 ): Martínez-Monge R, Herreros J, Aristu JJ, Aramendía JM, Azinovic I. Combined treatment in superior sulcus tumors. Am J Clin Oncol ;17 (4 ): Attar S, Krasna MJ, Sonett JR, et al. Superior sulcus (Pancoast) tumor: experience with 105 patients. Ann Thorac Surg ; 66 (1 ): Kwong KF, Edelman MJ, Suntharalingam M, et al. High-dose radiotherapy in trimodality treatment of Pancoast tumors results in high pathologic complete response rates and excellent long-term survival. J Thorac Cardiovasc Surg ;129(6): Fischer S, Darling G, Pierre AF, et al. Induction chemoradiation therapy followed by surgical resection for non-small cell lung cancer (NSCLC) invading the thoracic inlet. Eur J Cardiothorac Surg ;33(6): Demir A, Sayar A, Kocaturk CI, et al. Surgical treatment of superior sulcus tumors: results and prognostic factors. Thorac Cardiovasc Surg ;57(2): Bolton WD, Rice DC, Goodyear A, et al. Superior sulcus tumors with vertebral body involvement: a multimodality approach. J Thorac Cardiovasc Surg ;137(6): Kappers I, van Sandick JW, Burgers JA, et al. Results of combined modality treatment in patients with non-small-cell lung cancer of the superior sulcus and the rationale for surgical resection. Eur J Cardiothorac Surg ;36(4): Li J, Dai CH, Shi SB, Bao QL, Yu LC, Wu JR. Induction concurrent chemoradiotherapy compared with induction radiotherapy for superior sulcus non-small cell lung cancer: a retrospective study. Asia Pac J Clin Oncol ;6(1): Tagawa T, Osoegawa A, Yamazaki K, et al. Non-small cell lung carcinoma of the superior sulcus: the evolution of treatment outcomes with multimodality treatment at a single institution. J Surg Oncol ;101 (6 ): Vos CG, Hartemink KJ, Blaauwgeers JL, et al. Trimodality therapy for superior sulcus tumours: evolution and evaluation of a treatment protocol. Eur J Surg Oncol ;39(2): Ripley RT, Rusch VW. Role of induction therapy: surgical resection of non-small cell lung cancer after induction therapy. Thorac Surg Clin ;23(3): Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet ;374(9687): Ramnath N, Dilling TJ, Harris LJ, et al. Treatment of stage III nonsmall cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest ;143 (5_suppl ):e314s-e340s. 22. Legras A, Mordant P, Arame A, et al. Long-term survival of patients with pn2 lung cancer according to the pattern of lymphatic spread. Ann Thorac Surg ;97 (4 ): Hagan MP, Choi NC, Mathisen DJ, Wain JC, Wright CD, Grillo HC. Superior sulcus lung tumors: impact of local control on survival. J Thorac Cardiovasc Surg ;117 (6 ): Komaki R, Roth JA, Walsh GL, et al. Outcome predictors for 143 patients with superior sulcus tumors treated by multidisciplinary approach at the University of Texas M. D. Anderson Cancer Center. Int J Radiat Oncol Biol Phys ;48 (2 ): Komaki R, Roh J, Cox JD, Lopes da Conceicao A. Superior sulcus tumors: results of irradiation of 36 patients. Cancer ;48 (7 ): Van Houtte P, MacLennan I, Poulter C, Rubin P. External radiation in the management of superior sulcus tumor. Cancer ;54 (2 ): Ahmad K, Fayos JV, Kirsh MM. Apical lung carcinoma. Cancer ;54 (5 ): R ebutt a l From D rs Tan ne r and Silvestri Nichole T. Tanner, MD, MSCR, FCCP ; Gerard A. Silvestri, MD, FCCP ; Charleston, SC Dr Li and colleagues 1 make four arguments in favor of adding surgery to current guideline-directed standardof-care chemoradiotherapy alone for treatment of patients who present with superior sulcus tumor (SST) and mediastinal (N2) lymphadenopathy. The first assertion is that research regarding treatment strategies in this population occurred before the trimodality era and, therefore, should be revisited. We agree. Patients with SSTs treated before trimodality therapy did not do well, and those with N2 disease did even worse. The trials that used trimodality therapy for SSTs had better outcomes, but the majority excluded patients with N2 disease. These findings led to the 2013 American College of Chest Physicians (CHEST) lung cancer guidelines recommending this approach for patients with SSTs and N0-1 disease 2-5 as well as to the rationale for why the guidelines recommend against surgery in patients with SSTs and N2 disease. 2 Armed with these data, our colleagues suggest that the promising results from the aforementioned trials should lead us to consider broadening the patient selection strategy to include N2 disease, and they point to several studies to augment this position, the second tenant of their argument. Dr Li and colleagues 1 point to 12 studies in which contemporary trimodality therapy was used in patients with SSTs and N2 disease. Unfortunately, eight of the 12 studies did not report data on outcomes by lymph node status and, thus, cannot be used to make inferences regarding the utility of trimodality therapy in AFFILIATIONS: From the Ralph H. Johnson Veterans Affairs Hospital (Dr Tanner), Health Equity and Rural Outreach Innovation Center; and the Division of Pulmonary and Critical Care, Allergy and Sleep Medicine (Drs Tanner and Silvestri), Medical University of South Carolina. CONFLICT OF INTEREST: N. T. T. has received grant funding from the CHEST Foundation OneBreath Initiative, American Cancer Society, Olympus Corporation of the Americas, and Cook Medical Inc and consulting fees from Integrated Diagnostics Inc; Cook Medical Inc; Veran Medical Technologies, Inc; and Olympus Corporation of the Americas. None declared (G. A. S.). CORRESPONDENCE TO: Nichole T. Tanner, MD, MSCR, FCCP, Division of Pulmonary and Critical Care, Allergy and Sleep Medicine, Medical University of South Carolina, 96 Jonathan Lucas St, Ste 812-CSB, Charleston, SC 29425; tripici@musc.edu 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: /chest