Surgical Treatment of ⅢA-N2 Stage Non-small Cell Lung Cancer：Controversies and Consensus_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

TAN Zhenbo , GUO Jianfei , CHEN Longqi.

1. Department of Thoracic Surgery，Xingtai People’s Hospital，Xingtai 054031，Hebei，P. R. China;;
2. Department of Thoracic Surgery，West China Hospital，Sichuan University，Chengdu 610041，P. R. China.;

Corresponding author：

Keywords：

Non-small-cell lung cancer; 　N2 stage; Surgery; 　Induction chemotherapy; 　Concurrent chemo-radiotherapy

DOI：

10.7507/1007-4848.20130177

Video：

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The optimal treatment of stage ⅢA-N2 non-small cell lung cancer （NSCLC） remains controversial. Resultsof primary surgery alone are not satisfied. Surgery after induction chemotherapy yields better outcomes compared to resectiononly which has been widely accepted. Randomized studies show induction chemotherapy followed by either radiotherapy or surgery have approximately equivalent survival outcomes，significant improved survival can be achieved by combined surgery in selected patients. Low-grade N2，effective response and mediastinal downstaging after induction therapy，and successful complete resection by lobectomy，are good indications of surgery. Ideal treatments are approached base on theheterogeneity of N2 . Patients with bulky or fixed N2 disease should be considered for radical chemo-radiotherapy，and surgeryshould be a part of multi-modality management for patients with non-fixed，non-bulky，single-zone N2 disease. Further randomized trials of surgery added to multi-modality management in patients with multi-zone N2 disease should be taken in order to establish possible subgroups of patients might be benefitted more from the addition of surgery.

Citation： TAN Zhenbo,GUO Jianfei,CHEN Longqi.. Surgical Treatment of ⅢA-N2 Stage Non-small Cell Lung Cancer：Controversies and Consensus. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2013, 20(5): 577-582. doi: 10.7507/1007-4848.20130177 Copy

1.	Martini N， Flehinger BJ， Zaman MB， et al. Prospective study of 445 lung carcinomas with mediastinal lymph node metastases. J Thorac Cardiovasc Surg， 1980 ， 80 （3）：390-399.
2.	Cybulsky IJ， Lanza LA， Ryan MB， et al. Prognostic significance of computed tomography in resected N2 lung cancer. Ann Thorac Surg， 1992 ， 54 （3）：533-537.
3.	Pearson FG， DeLarue NC， Ilves R， et al. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg， 1982， 83 （1）：1-11.
4.	Perez CA， Pajak TF， Rubin P， et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinomaof the lung treated with definitive radiotherapy. Report by the RadiationTherapy Oncology Group. Cancer， 1987， 59 （11）：1874-1881.
5.	Vansteenkiste J， De Leyn P， Deneffe G， et al. Present status of induction treatment in stage ⅢA-N2 non-small cell lung cancer：a review.Eur J Cardiothorac Surg， 1998， 13 （1）：1-12.
6.	Pass HI， Pogrebniak HW， Steinberg SM， et al. Randomized trial of neoadjuvant therapy for lung cancer：interim analysis. Ann Thorac Surg， 1992， 53 （6）：992-998.
7.	Rosell R， Gómez-Codina J， Camps C， et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med， 1994， 330 （3）：153-158.
8.	Roth JA， Fossella F， Komaki R， et al. A randomized trial comparingperioperative chemotherapy and surgery with surgery alone in resectablestage ⅢA non-small-cell lung cancer. J Natl Cancer Inst， 1994， 86 （9）：673-680.
9.	Roth JA， Atkinson EN， Fossella F， et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage ⅢA non-small-cell lung cancer. Lung Cancer， 1998， 21 （1）：1-6.
10.	Depierre A， Milleron B， Moro D， et al. Phase Ⅲ trial of neo-adjuvantchemotherapy in resectable stage Ⅰ （except T1N0）， II and Ⅲa non-smallcell lung cancer：The French experience. J Clin Oncol， 2002 ， 20 （1）：247-253.
11.	Nagai K， Tsuchiya R， Mori T， et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage ⅢA N2 non-small cell lung cancer （JCOG 9209） . J Thorac Cardiovasc Surg， 2003， 125 （2）：254-260.
12.	Pisters KM， Vallières E， Crowley JJ， et al. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer：Southwest Oncology Group Trial S9900， an intergroup， randomized， phase Ⅲ trial. J Clin Oncol， 2010， 28 （11）：1843-1849.
13.	Scagliotti GV， Pastorino U， Vansteenkiste JF， et al. Randomized phase Ⅲ study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages ⅠB to ⅢA non-small-cell lung cancer. J ClinOncol， 2012 ， 30 （2）：172-178.
14.	Dillman RO， Herndon J， Seagren SL， et al. Improved survival in stage Ⅲ non-small-cell lung cancer：seven-year follow-up of cancer and leukemia group B （CALGB） 8433 trial. J Natl Cancer Inst， 1996， 88 （17）：1210-1215.
15.	Le Chevalier T， Arriagada R， Quoix E， et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer：first analysis of a randomized trial in 353 patients. J Natl Cancer Inst， 1991， 83 （6）：417-423.
16.	Sause W， Kolesar P， Taylor SIV， et al. Final results of phase Ⅲtrial in regionally advanced unresectable non-small cell lung cancer：Radiation therapy oncology group， eastern cooperative oncology group，and southwest oncology group. Chest， 2000， 117 （2）：358-364.
17.	Johnstone DW， Byhardt RW， Ettinger D， et al. Phase Ⅲ study comp-aring 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. Radiation therapy oncology group. Int J Radiat Oncol Biol Phys， 2002， 54 （2）：365-369.
18.	Taylor NA， Liao ZX， Cox JD， et al. Equivalent outcome of patients with clinical stage ⅢA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection. Int J Radiat Oncol Biol Phys， 2004， 58 （1）：204-212.
19.	Van Meerbeeck JP， Van Schil PE， Senan S. Reply：randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage ⅢA-N2 non-small cell lung cancer. J Natl Cancer Inst，2007， 2 （12）：1138-1139.
20.	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.
21.	Bosch-Barrera J， García-Franco C， Guillén-Grima F， et al. The multimodal management of locally advanced N2 non-small cell lung cancer：is there a role for surgical resection ? A single institution's experience. Clin Transl Oncol， 2012， 14 （11）：835-841.
22.	Ratto GB， Costa R， Maineri P， et al. Is there a subset of patients with preoperatively diagnosed N2 non-small cell lung cancer who might benefit from surgical resection ? J Thorac Cardiovasc Surg， 2009 ， 138 （4）：849-858.
23.	Funakoshi Y， Takeuchi Y， Kusumoto H， et al. Which subgroup of patients with pathologic N2 non-small cell lung cancer benefit from surgery ? J Cancer Res Clin Oncol， 2012， 138 （6）：1027-1033.
24.	Sakao Y， Okumura S， Mun M， et al. Prognostic heterogeneity in multilevel N2 non-small cell lung cancer patients：importance of lymphadenopathy and occult intrapulmonary metastases. Ann Thorac Surg， 2010， 89 （4）：1060-1063.
25.	Lorent N， De Leyn P， Lievens Y， et al. Long-term survival of surgically staged ⅢA-N2 non-small-cell lung cancer treated with surgical combined modality approach：analysis of a 7-year prospective experience. Ann Oncol， 2004， 15 （11）：1645-1653.
26.	Stefani A， Alifano M， Bobbio A， et al. Which patients should be operated on after induction chemotherapy for N2 non-small cell lung cancer ? Analysis of a 7-year experience in 175 patients. J Thorac Cardiovasc Surg， 2010， 140 （2）：356-363.
27.	Lococo F， Cesario A， Margaritora S， et al. Long-term results in patients with pathological complete response after induction radiochemotherapy followed by surgery for locally advanced non-small-celllung cancer. Eur J Cardiothorac Surg， 2013， 43 （3）：e71-e81.
28.	Bueno R， Richards WG， Swanson SJ， et al. Nodal stage after induc-tion therapy for stage ⅢA lung cancer determines patient survival. AnnThorac Surg， 2000， 70 （6）：1826-1831.
29.	Decaluwé H， De Leyn P， Vansteenkiste J， et al. Surgical multimodality treatment for baseline resectable stage ⅢA-N2 non-small cell lungcancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg， 2009 ， 36 （3）：433-439.
30.	Sawabata N， Keller SM， Matsumura A， et al. The impact of residualmulti-level N2 disease after induction therapy for non-small cell lung cancer. Lung Cancer， 2003， 42 （1）：69-77.
31.	Steger V， Walker T， Mustafi M， et al. Surgery on unfavourable persistent N2/N3 non-small-cell lung cancer after trimodal therapy：do the results justify the risk ? Interact Cardiovasc Thorac Surg， 2012 ， 15 （6）：948-953.
32.	Katakami N， Tada H， Mitsudomi T， et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapybefore surgery in patients with pathologically confirmed N2 stage ⅢA nonsmall cell lung cancer （WJTOG9903） . Cancer， 2012， 118 （24）：6126-6135.
33.	Koshy M， Fedewa SA， Malik R， et al. Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage ⅢA （N2）non-small-cell lung cancer. J Thorac Oncol， 2013， 8 （7）：915-922.
34.	National Institute for Health and Clinical Excellence （NICE）. The Diagnosis and Treatment of Lung Cancer （Update）：Full Guideline. London：National Collaborating Centre for Cancer， 2011. 59-63.
35.	Lim E， Baldwin D， Beckles M， et al. Guidelines on the radical management of patients with lung cancer：British Thoracic Society and the Society for Cardiothoracic surgery in Great Britain and Ireland.Thorax ， 2010， 65 （Suppl Ⅲ）：1-27.
36.	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）：314S-340S.

1. 　Martini N， Flehinger BJ， Zaman MB， et al. Prospective study of 445 lung carcinomas with mediastinal lymph node metastases. J Thorac Cardiovasc Surg， 1980 ， 80 （3）：390-399.
2. 　Cybulsky IJ， Lanza LA， Ryan MB， et al. Prognostic significance of computed tomography in resected N2 lung cancer. Ann Thorac Surg， 1992 ， 54 （3）：533-537.
3. 　Pearson FG， DeLarue NC， Ilves R， et al. Significance of positive superior mediastinal nodes identified at mediastinoscopy in patients with resectable cancer of the lung. J Thorac Cardiovasc Surg， 1982， 83 （1）：1-11.
4. 　Perez CA， Pajak TF， Rubin P， et al. Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinomaof the lung treated with definitive radiotherapy. Report by the RadiationTherapy Oncology Group. Cancer， 1987， 59 （11）：1874-1881.
5. 　Vansteenkiste J， De Leyn P， Deneffe G， et al. Present status of induction treatment in stage ⅢA-N2 non-small cell lung cancer：a review.Eur J Cardiothorac Surg， 1998， 13 （1）：1-12.
6. 　Pass HI， Pogrebniak HW， Steinberg SM， et al. Randomized trial of neoadjuvant therapy for lung cancer：interim analysis. Ann Thorac Surg， 1992， 53 （6）：992-998.
7. 　Rosell R， Gómez-Codina J， Camps C， et al. A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med， 1994， 330 （3）：153-158.
8. 　Roth JA， Fossella F， Komaki R， et al. A randomized trial comparingperioperative chemotherapy and surgery with surgery alone in resectablestage ⅢA non-small-cell lung cancer. J Natl Cancer Inst， 1994， 86 （9）：673-680.
9. 　Roth JA， Atkinson EN， Fossella F， et al. Long-term follow-up of patients enrolled in a randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage ⅢA non-small-cell lung cancer. Lung Cancer， 1998， 21 （1）：1-6.
10. 　Depierre A， Milleron B， Moro D， et al. Phase Ⅲ trial of neo-adjuvantchemotherapy in resectable stage Ⅰ （except T1N0）， II and Ⅲa non-smallcell lung cancer：The French experience. J Clin Oncol， 2002 ， 20 （1）：247-253.
11. 　Nagai K， Tsuchiya R， Mori T， et al. A randomized trial comparing induction chemotherapy followed by surgery with surgery alone for patients with stage ⅢA N2 non-small cell lung cancer （JCOG 9209） . J Thorac Cardiovasc Surg， 2003， 125 （2）：254-260.
12. 　Pisters KM， Vallières E， Crowley JJ， et al. Surgery with or without preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer：Southwest Oncology Group Trial S9900， an intergroup， randomized， phase Ⅲ trial. J Clin Oncol， 2010， 28 （11）：1843-1849.
13. 　Scagliotti GV， Pastorino U， Vansteenkiste JF， et al. Randomized phase Ⅲ study of surgery alone or surgery plus preoperative cisplatin and gemcitabine in stages ⅠB to ⅢA non-small-cell lung cancer. J ClinOncol， 2012 ， 30 （2）：172-178.
14. 　Dillman RO， Herndon J， Seagren SL， et al. Improved survival in stage Ⅲ non-small-cell lung cancer：seven-year follow-up of cancer and leukemia group B （CALGB） 8433 trial. J Natl Cancer Inst， 1996， 88 （17）：1210-1215.
15. 　Le Chevalier T， Arriagada R， Quoix E， et al. Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer：first analysis of a randomized trial in 353 patients. J Natl Cancer Inst， 1991， 83 （6）：417-423.
16. 　Sause W， Kolesar P， Taylor SIV， et al. Final results of phase Ⅲtrial in regionally advanced unresectable non-small cell lung cancer：Radiation therapy oncology group， eastern cooperative oncology group，and southwest oncology group. Chest， 2000， 117 （2）：358-364.
17. 　Johnstone DW， Byhardt RW， Ettinger D， et al. Phase Ⅲ study comp-aring 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. Radiation therapy oncology group. Int J Radiat Oncol Biol Phys， 2002， 54 （2）：365-369.
18. 　Taylor NA， Liao ZX， Cox JD， et al. Equivalent outcome of patients with clinical stage ⅢA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection. Int J Radiat Oncol Biol Phys， 2004， 58 （1）：204-212.
19. 　Van Meerbeeck JP， Van Schil PE， Senan S. Reply：randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage ⅢA-N2 non-small cell lung cancer. J Natl Cancer Inst，2007， 2 （12）：1138-1139.
20. 　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.
21. 　Bosch-Barrera J， García-Franco C， Guillén-Grima F， et al. The multimodal management of locally advanced N2 non-small cell lung cancer：is there a role for surgical resection ? A single institution's experience. Clin Transl Oncol， 2012， 14 （11）：835-841.
22. 　Ratto GB， Costa R， Maineri P， et al. Is there a subset of patients with preoperatively diagnosed N2 non-small cell lung cancer who might benefit from surgical resection ? J Thorac Cardiovasc Surg， 2009 ， 138 （4）：849-858.
23. 　Funakoshi Y， Takeuchi Y， Kusumoto H， et al. Which subgroup of patients with pathologic N2 non-small cell lung cancer benefit from surgery ? J Cancer Res Clin Oncol， 2012， 138 （6）：1027-1033.
24. 　Sakao Y， Okumura S， Mun M， et al. Prognostic heterogeneity in multilevel N2 non-small cell lung cancer patients：importance of lymphadenopathy and occult intrapulmonary metastases. Ann Thorac Surg， 2010， 89 （4）：1060-1063.
25. 　Lorent N， De Leyn P， Lievens Y， et al. Long-term survival of surgically staged ⅢA-N2 non-small-cell lung cancer treated with surgical combined modality approach：analysis of a 7-year prospective experience. Ann Oncol， 2004， 15 （11）：1645-1653.
26. 　Stefani A， Alifano M， Bobbio A， et al. Which patients should be operated on after induction chemotherapy for N2 non-small cell lung cancer ? Analysis of a 7-year experience in 175 patients. J Thorac Cardiovasc Surg， 2010， 140 （2）：356-363.
27. 　Lococo F， Cesario A， Margaritora S， et al. Long-term results in patients with pathological complete response after induction radiochemotherapy followed by surgery for locally advanced non-small-celllung cancer. Eur J Cardiothorac Surg， 2013， 43 （3）：e71-e81.
28. 　Bueno R， Richards WG， Swanson SJ， et al. Nodal stage after induc-tion therapy for stage ⅢA lung cancer determines patient survival. AnnThorac Surg， 2000， 70 （6）：1826-1831.
29. 　Decaluwé H， De Leyn P， Vansteenkiste J， et al. Surgical multimodality treatment for baseline resectable stage ⅢA-N2 non-small cell lungcancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg， 2009 ， 36 （3）：433-439.
30. 　Sawabata N， Keller SM， Matsumura A， et al. The impact of residualmulti-level N2 disease after induction therapy for non-small cell lung cancer. Lung Cancer， 2003， 42 （1）：69-77.
31. 　Steger V， Walker T， Mustafi M， et al. Surgery on unfavourable persistent N2/N3 non-small-cell lung cancer after trimodal therapy：do the results justify the risk ? Interact Cardiovasc Thorac Surg， 2012 ， 15 （6）：948-953.
32. 　Katakami N， Tada H， Mitsudomi T， et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapybefore surgery in patients with pathologically confirmed N2 stage ⅢA nonsmall cell lung cancer （WJTOG9903） . Cancer， 2012， 118 （24）：6126-6135.
33. 　Koshy M， Fedewa SA， Malik R， et al. Improved survival associated with neoadjuvant chemoradiation in patients with clinical stage ⅢA （N2）non-small-cell lung cancer. J Thorac Oncol， 2013， 8 （7）：915-922.
34. 　National Institute for Health and Clinical Excellence （NICE）. The Diagnosis and Treatment of Lung Cancer （Update）：Full Guideline. London：National Collaborating Centre for Cancer， 2011. 59-63.
35. 　Lim E， Baldwin D， Beckles M， et al. Guidelines on the radical management of patients with lung cancer：British Thoracic Society and the Society for Cardiothoracic surgery in Great Britain and Ireland.Thorax ， 2010， 65 （Suppl Ⅲ）：1-27.
36. 　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）：314S-340S.

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