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Point and Counterpoint |

POINT: Is N2 Disease a Contraindication for Surgical Resection for Superior Sulcus Tumors? YesN2 Disease and Sulcus Tumors? Yes FREE TO VIEW

Nichole T. Tanner, MD, MSCR, FCCP; Gerard A. Silvestri, MD, FCCP
Author and Funding Information

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.

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; e-mail: tripici@musc.edu


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.).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(6):1373-1375. doi:10.1378/chest.15-1194
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Facts are stubborn things; and whatever may be our wishes, our inclinations, or the dictates of our passion, they cannot alter the state of facts and evidence.

John Adams

Nearly 36,000 Americans a year present with locally advanced stage IIIA lung cancer,1 with an overall 5-year survivorship of 19%.2 Superior sulcus tumors (SSTs) are either stage IIB (T3N0), IIIA (T3N1-2 or T4N0-1), or IIIB (T4N2), with only a slightly better 5-year survival rate (25%-30%). With such a grim outlook, physicians are inclined to extrapolate the available literature in an effort to provide the best chance for cure. The concept of surgery after induction therapy for SSTs posits that if you could get a response from chemoradiotherapy that shrinks the tumor away from critical structures in the apex of the lung near the brachial plexus and vertebral column, surgery could add benefit and potentially cure the patient. However, a closer look at the available evidence does not support this approach in patients with SSTs and N2 disease. Unfortunately, no level 1 evidence supports the use of induction therapy in patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) without superior sulcus involvement, and only feasibility data support its use in those with Pancoast tumors with N0-1 disease. Furthermore, to our knowledge, induction therapy has never been tested in patients with SSTs with N2 disease and, therefore, cannot be recommended.

The real question is: Does surgery have a place at all in the treatment of patients with N2 disease irrespective of whether the patients have superior sulcus involvement? Stage IIIA (N2) NSCLC is represented in a heterogeneous population of patients, making comparisons across trials difficult. However, there have been two large randomized phase 3 trials of induction therapy followed by surgery vs concurrent chemoradiotherapy for stage III NSCLC, and neither included patients with SSTs.3-6 The overall 2- and 5-year survival was no different between groups.7 A European trial randomized patients (N = 332) with response to induction chemotherapy to either surgery or radiotherapy.4 The progression-free, median, and 5-year survival were similar between groups. The authors concluded that chemoradiotherapy remains the standard of care for patients with stage IIIA (N2) disease because of its lower morbidity and mortality profile compared with surgery.4

The Intergroup 0139 phase 3 trial of induction chemoradiotherapy followed by surgery vs chemoradiotherapy (N = 429) often is used to support the use of surgery in stage IIIA (N2) disease.3 The primary end point of the Intergroup 0139 trial was overall survival, which did not differ between groups. In an unplanned post hoc analysis, a subset of patients had better survival in the surgery arm if they underwent lobectomy. This analysis has become the anchor for justifying the use of surgery in stage IIIA (N2) disease.

Unfortunately, the Intergroup post hoc analysis is suspect because patients in the surgery group who underwent lobectomy were matched to patients in the chemoradiotherapy arm solely by age, sex, performance status, and T stage.3 They could not be matched on arguably the most important factors associated with survival, namely the extent and bulk of N2 disease and the response to therapy, because the nonsurgical arm did not undergo repeat invasive mediastinal staging. Patients who were downstaged in either group may have been those who were destined to do well because downstaging is likely a marker for better outcome. Statistically speaking, the two factors (downstaging and lobectomy) were selected from multivariable analysis and then used to characterize the data from which they were derived (a statistical no-no). Downstaging and completeness of resection are also defined postoperatively and, therefore, should not be used to identify who would benefit from surgery preoperatively. Most surgeons cannot guarantee before surgery that a pneumonectomy will always be avoided. Downstaging the lymph nodes after induction therapy is also difficult because the sensitivity for endoscopic and surgical approaches (mediastinoscopy) for restaging following induction therapy ranges from 50% to 76%8-10 and 29% to 83%,11-15 respectively. Transcervical extended mediastinal lymphadenectomy demonstrates a higher sensitivity for restaging,16 but the technique has not been widely adapted.

It is also important to note that although the European Organisation for Research and Treatment of Cancer and Intergroup trials had a better rate of local control in the surgical arm, there was no difference in the number of distant recurrences. A study of combined-modality lung cancer trials demonstrated that in patients with stage III NSCLC, 20% experienced a relapse in the brain, whereas only 6.5% experienced recurrence in the brain and other sites simultaneously.17 The potential for distant metastases is high in SSTs, which average 40% in distant recurrences.18,19

What is the evidence for surgery after induction therapy in Pancoast tumors with N2 disease? The simple answer is none. To our knowledge, no phase 3 trials have used induction therapy in SSTs regardless of nodal status. The only data to support induction therapy have been derived from phase 2 feasibility trials. The three largest trials only enrolled patients with SSTs and N0-1 disease.18-20 In 2001, an intergroup trial published the results of Southwest Oncology Group 9416, a phase 2 feasibility trial of induction chemoradiotherapy followed by surgical resection in patients with solitary, previously untreated T3 or T4N0-1 (confirmed pathologically) SSTs. This trial in 110 participants was the largest performed in SSTs and met its end point of feasibility. Despite it not being a phase 3 trial, the findings of an 80% surgical resection rate and 44% 5-year overall survival resulted in a paradigm shift for treatment of SSTs with N0-1 disease, with major evidence-based guidelines accepting this trimodality approach as standard of care.21 Similarly, Japan Clinical Oncology Group 9806 enrolled 76 patients with Pancoast tumors, the majority of whom had N0 disease. The 5-year overall survival was 56%.20 In a recent phase 2 trial that added consolidation chemotherapy after induction chemoradiation followed by surgery, patients with N2 disease were excluded.18 This trial did not meet its primary end point of feasibility because only 45% of patients completed all treatment. The reported 3-year overall survival was 61%.18

Although it might be argued that these phase 2 findings in aggregate support the use of multimodality therapy in SSTs with N1 disease, given the worse outcomes for N2 disease in all stage III NSCLCs, a closer look at the quality of the evidence for SSTs with N2 disease must be undertaken. The three largest phase 2 trials to date excluded N2 disease,18-20 but there are 10 cases total of induction chemoradiotherapy in SSTs with N2 or N3 disease from two small, single-center phase 2 trials.22,23 The 5-year survival in these patients is not promising. In the trial by Marra et al,23 nine of the 31 patients had N2 or N3 disease. Six patients died, and 5-year survival was significantly less than in patients with pretreated N0-1 disease (21% vs 54%, P = .02). The only other trial to include N2 investigated surgical resection followed by adjuvant chemoradiation in 32 patients presenting with resectable SSTs at a single academic center.22 This trial enrolled a single patient with N2 disease and did not report outcomes based on nodal station.

As much as physicians wish for a better treatment option for SSTs with N2 disease, we cannot alter the evidence. No robust data support the use of induction chemoradiotherapy in SSTs with N2 disease; the 10 cases in the literature amount to a case series for which the outcomes are no better than those in patients treated with chemoradiotherapy. We are being asked to extrapolate weak data on the use of induction therapy for all-comers with stage III (N2) NSCLC (data from an unplanned post hoc, poorly matched subset analysis suggesting benefit to induction therapy followed by surgery only if a lobectomy could be guaranteed) and meld it with data from SSTs with N0-1 disease. It appears that we are stepping farther and farther out on a fairly thin branch. This issue begs for a phase 3 trial taking all-comers with SSTs and N2 disease and randomizing them to induction therapy followed by surgery vs standard-of-care chemoradiotherapy. Until then, we prefer to stick with the evidence, which does not currently support induction therapy followed by surgical treatment of SSTs with N2 disease.

Abbreviations

CHEST

American College of Chest Physicians

NSCLC

non-small cell lung cancer

SST

superior sulcus tumor

American Cancer Society. Cancer Facts and Figures 2015. Atlanta, GA: American Cancer Society; 2014.
 
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. 2007;2(8):706-714. [CrossRef] [PubMed]
 
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. 2009;374(9687):379-386. [CrossRef] [PubMed]
 
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. 2007;99(6):442-450. [CrossRef] [PubMed]
 
Stephens RJ, Girling DJ, Hopwood 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. 2005;49(3):395-400. [CrossRef] [PubMed]
 
Johnstone DW, Byhardt RW, Ettinger D, Scott CB; Radiation 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 89-01. Int J Radiat Oncol Biol Phys. 2002;54(2):365-369. [CrossRef] [PubMed]
 
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 evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):e314S-e340S. [CrossRef] [PubMed]
 
Herth FJ, Annema JT, Eberhardt R, et al. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol. 2008;26(20):3346-3350. [CrossRef] [PubMed]
 
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. 2014;98(3):1008-1012. [CrossRef] [PubMed]
 
Szlubowski A, Zieliński M, Soja J, et al. Accurate and safe mediastinal restaging by combined endobronchial and endoscopic ultrasound-guided needle aspiration performed by single ultrasound bronchoscope. Eur J Cardiothorac Surg. 2014;46(2):262-266. [CrossRef] [PubMed]
 
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 Non-small-cell lung cancer: a Leuven Lung Cancer Group Study. J Clin Oncol. 2006;24(21):3333-3339. [CrossRef] [PubMed]
 
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. 2006;29(2):240-243. [CrossRef] [PubMed]
 
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. 2008;33(5):824-828. [CrossRef] [PubMed]
 
Rami-Porta R, Mateu-Navarro M, Serra-Mitjans M, Hernández-Rodríguez H. Remediastinoscopy: comments and updated results. Lung Cancer. 2003;42(3):363-364. [CrossRef] [PubMed]
 
Marra A, Hillejan L, Fechner S, Stamatis G. Remediastinoscopy in restaging of lung cancer after induction therapy. J Thorac Cardiovasc Surg. 2008;135(4):843-849. [CrossRef] [PubMed]
 
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. 2010;37(4):776-780. [CrossRef] [PubMed]
 
Gaspar LE, Chansky K, Albain KS, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol. 2005;23(13):2955-2961. [CrossRef] [PubMed]
 
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. 2014;98(2):402-410. [CrossRef] [PubMed]
 
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. 2007;25(3):313-318. [CrossRef] [PubMed]
 
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 inJ Clin Oncol. 2011;29(33):4472]. J Clin Oncol. 2008;26(4):644-649. [CrossRef] [PubMed]
 
Ettinger DS, Akerley W, Borghaei H, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 2.2013. Ft. Washington, PA: National Comprehensive Cancer Network; 2013.
 
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. 2012;118(2):444-451. [CrossRef] [PubMed]
 
Marra A, Eberhardt W, Pöttgen C, et al. Induction chemotherapy, concurrent chemoradiation and surgery for Pancoast tumour. Eur Respir J. 2007;29(1):117-126. [CrossRef] [PubMed]
 

Figures

Tables

References

American Cancer Society. Cancer Facts and Figures 2015. Atlanta, GA: American Cancer Society; 2014.
 
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. 2007;2(8):706-714. [CrossRef] [PubMed]
 
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. 2009;374(9687):379-386. [CrossRef] [PubMed]
 
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. 2007;99(6):442-450. [CrossRef] [PubMed]
 
Stephens RJ, Girling DJ, Hopwood 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. 2005;49(3):395-400. [CrossRef] [PubMed]
 
Johnstone DW, Byhardt RW, Ettinger D, Scott CB; Radiation 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 89-01. Int J Radiat Oncol Biol Phys. 2002;54(2):365-369. [CrossRef] [PubMed]
 
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 evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):e314S-e340S. [CrossRef] [PubMed]
 
Herth FJ, Annema JT, Eberhardt R, et al. Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol. 2008;26(20):3346-3350. [CrossRef] [PubMed]
 
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. 2014;98(3):1008-1012. [CrossRef] [PubMed]
 
Szlubowski A, Zieliński M, Soja J, et al. Accurate and safe mediastinal restaging by combined endobronchial and endoscopic ultrasound-guided needle aspiration performed by single ultrasound bronchoscope. Eur J Cardiothorac Surg. 2014;46(2):262-266. [CrossRef] [PubMed]
 
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 Non-small-cell lung cancer: a Leuven Lung Cancer Group Study. J Clin Oncol. 2006;24(21):3333-3339. [CrossRef] [PubMed]
 
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. 2006;29(2):240-243. [CrossRef] [PubMed]
 
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. 2008;33(5):824-828. [CrossRef] [PubMed]
 
Rami-Porta R, Mateu-Navarro M, Serra-Mitjans M, Hernández-Rodríguez H. Remediastinoscopy: comments and updated results. Lung Cancer. 2003;42(3):363-364. [CrossRef] [PubMed]
 
Marra A, Hillejan L, Fechner S, Stamatis G. Remediastinoscopy in restaging of lung cancer after induction therapy. J Thorac Cardiovasc Surg. 2008;135(4):843-849. [CrossRef] [PubMed]
 
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. 2010;37(4):776-780. [CrossRef] [PubMed]
 
Gaspar LE, Chansky K, Albain KS, et al. Time from treatment to subsequent diagnosis of brain metastases in stage III non-small-cell lung cancer: a retrospective review by the Southwest Oncology Group. J Clin Oncol. 2005;23(13):2955-2961. [CrossRef] [PubMed]
 
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. 2014;98(2):402-410. [CrossRef] [PubMed]
 
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. 2007;25(3):313-318. [CrossRef] [PubMed]
 
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 inJ Clin Oncol. 2011;29(33):4472]. J Clin Oncol. 2008;26(4):644-649. [CrossRef] [PubMed]
 
Ettinger DS, Akerley W, Borghaei H, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 2.2013. Ft. Washington, PA: National Comprehensive Cancer Network; 2013.
 
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. 2012;118(2):444-451. [CrossRef] [PubMed]
 
Marra A, Eberhardt W, Pöttgen C, et al. Induction chemotherapy, concurrent chemoradiation and surgery for Pancoast tumour. Eur Respir J. 2007;29(1):117-126. [CrossRef] [PubMed]
 
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