Abstract
Lung cancer is the most frequent cause of cancer death worldwide and its global incidence has been steadily increasing during recent decades. A third of patients with newly diagnosed non-small-cell lung cancer (NSCLC) present with locally advanced disease. There is not a single widely accepted standard of care for these patients because of the wide spectrum of presentation of the disease. Although feasible and safe in experienced hands, evidence that surgical resection after induction treatment improves overall survival (OS) is lacking. For resectable or potentially resectable stage III, the findings of two phase III trials suggest that surgical resection should not be considered a standard of care but rather reserved for selected patients after critical multidisciplinary assessment, in whom surgery improves survival after downstaging if pneumonectomy can be avoided or in some T4N0-1 resectable tumours. For unresectable stage III NSCLC the standard of care is a combination of chemotherapy and radiotherapy. In those patients with good performance status and minimal weight loss, the concurrent approach has resulted in a statistically significant improvement in OS rates compared with a sequential approach in randomised clinical trials, although several questions remain unresolved.
Similar content being viewed by others
References
Jemal A, Bray F, Ferlay J et al (2011) Global cancer statistics. CA Cancer J Clin 61:69–90
Roth JA, Fossella F, Komaki R et al (1994) A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst 86:673–680
Rosell R, Gomez-Codina J, Camps C et al (1994) A randomized trial comparing preoperative chemotherapy plus surgery with surgery alone in patients with non-small-cell lung cancer. N Engl J Med 330:153–158
Albain KS, Rusch VW, Crowley JJ et al (1995) Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805. J Clin Oncol 13:1880–1892
Albain KS, Swann RS, Rusch VW et al (2009) Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Lancet 374:379–386
Van Meerbeeck JP, Kramer GW, van Schil PE et al (2007) Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 99:442–450
Higgins K, Chino JP, Marks LB et al (2009) Preoperative chemotherapy versus preoperative chamoradiotherapy for stage III (N2) non-small cell lung cancer. Int J Radiat Oncol Biol Phys 75:1462–1467
Thomas M, Rübe C, Hoffknecht P et al (2008) Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomized trial in stage III non-small cell lung cancer. Lancet Oncol 9:607–608
De Cabanyes Candela S, Detterbeck FC (2010) A systematic review of restaging after induction therapy for stage IIIA lung cancer: prediction of pathologic stage. J Thorac Oncol 5:389–398
National Comprehensive Cancer Network (2011) NCCN Guidelines Version 3. National Comprehensive Cancer Network
Sonett JR, Suntharalingam M, Edelman MJ et al (2004) Pulmonary resection after curative intent radiotherapy (>59 Gy) and concurrent chemotherapy in non-small cell lung cancer. Ann Thorac Surg 78:1200–1205
Bauman JE, Mulligan MS, Martins RG et al (2008) Salvage lung resection after definitive radiation (>59 Gy) for non-small cell lung cancer: surgical and oncologic outcomes. Ann Thorac Surg 86:1632–1639
Hürtgen M, Friedel G, Toomes H et al (2002) Radical video-assisted mediastinoscopic lymphadenectomy (VAMLA): technique and first results. Eur J Cardiothorac Surg 21:348–351
Kuzdzal J, Zielinski M, Papla B et al (2005) Transcervical extended mediastinal lymphadenectomy: the new operative technique and early results in lung cancer staging. Eur J Cardiothorac Surg 27:384–390
Asamura H, Suzuki K, Kondo H et al (2000) Where is the boundary between N1 and N2 stations in lung cancer? Ann Thorac Surg 70:1839–1846
Rusch VW, Crowley J, Giroux DJ et al (2007) International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating; Institutions. The 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 2:603–612
Stefani A, Alifano M, Bobbio A et al (2010) Which patients should be operated on after induction che?motherapy for N2 non-small cell lung cancer? Analysis of a 7-year experience in 175 patients. J Thorac Cardiovasc Surg 140:356–363
Albain K, Rusch V, Crowley J et al (1999) Longterm survival after concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery in bulky, stages IIIA (N2) and IIIB non-small cell lung cancer: 6-year outcomes from Southwest Oncology Group Study 8805. Proc Am Soc Clin Oncol 18:467a (abstr)
Yang HX, Hou X, Lin P et al (2009) Survival and risk factors of surgically treated mediastinal invasion T4 non-small cell lung cancer. Ann Thorac Surg 88:372–378
Wu L, Xu Z, Zhao X et al (2009) Surgical treatment of lung cancer invading the left atrium or base of the pulmonary vein. World J Surg 33:492–496
Garrido P, González-Larriba JL, Insa A et al (2007) Long-term survival associated with complete resection after induction chemotherapy in stage IIIA (N2) and IIIB (T4N0-1) non small-cell lung cancer patients: the Spanish Lung Cancer Group Trial 9901. J Clin Oncol 25:4736–4742
Bryant AS, Pereira SJ, Miller DL et al (2006) Satellite pulmonary nodule in the same lobe (T4N0) should not be staged as IIIB non-small cell lung cancer. Ann Thorac Surg 82:1808–1813; discussion 13–14
Dartevelle PG, Khalife J, Chapelier A et al (1988) Tracheal sleeve pneumonectomy for bronchogenic carcinoma: a report of 55 cases. Ann Thorac Surg 46:68–72
Mathisen DJ, Grillo HC (1991) Carinal resection for bronchogenic carcinoma. Thorac Cardiovasc Surg 102:16–22; discussion 22–23
Rice TW, Blackstone EH (2002) Radical resections for T4 lung cancer. Surg Clin North Am 82: 573–587
Martin-Ucar AE, Chaudhuri N, Edwards JG et al (2002) Can pneumonectomy of non-small cell lung cancer be avoided? An audit of parenchymal sparing lung surgery. Eur J Cardiothorac Surg 21: 601–605
Melloul E, Egger B, Krueger T et al (2008) Mortality, complications and loss of pulmonary function after pneumonectomy vs. sleeve lobectomy in patients younger and older than 70 years. Interact CardioVasc Thorac Surg 7:986–989
Ferguson MK, Lehman AG (2003) Sleeve lobectomy or pneumonectomy: optimal management strategy using decision analysis techniques. Ann Thorac Surg 76:1782–1788
Ma Z, Dong A, Fan J et al (2007) Does sleeve lobectomy concomitant with or without pulmonary artery reconstruction (double sleeve) have favorable results for non-small cell lung cancer compared with pneumonectomy? A meta-analysis. Eur J Cardiothorac Surg 32:20–28
Allen AM, Mentzer SJ, Yeap BY et al (2008) Pneumonectomy after chemoradiation: the Dana-Farber Cancer Institute/Brigham and Women's Hospital experience. Cancer 112:1106–1113
Thibout Y, Guibert B, Bossard N et al (2009) Is pneumonectomy after induction chemotherapy for non-small cell lung cancer a reasonable procedure? A multicenter retrospective study of 228 cases. J Thorac Oncol 4:1496–1503
Weder W, Collaud S, Eberhardt WE et al (2010) Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III nonsmall-cell lung cancer. J Thorac Cardiovasc Surg 139:1424–1430
Petrella F, Radice D, Borri A et al (2011) The impact of preoperative body mass index on respiratory complications after pneumonectomy for non-small-cell lung cancer. Results from a series of 154 consecutive standard pneumonectomies. Eur J Cardiothorac Surg 39:738–744
D'Amato TA, Ashrafi AS, Schuchert MJ et al (2009) Risk of pneumonectomy after induction therapy for locally advanced non-small cell lung cancer. Ann Thorac Surg 88:1079–1085
Shapiro M, Swanson SJ, Wright CD et al (2010) Predictors of major morbidity and mortality after pneumonectomy utilizing the Society for Thoracic Surgeons General Thoracic Surgery Database. Ann Thorac Surg 90:927–934; discussion 934–935
Leo F, Scanagatta P, Vannucci F et al (2010) Impaired quality of life after pneumonectomy: who is at risk? J Thorac Cardiovasc Surg 139:49–52
Veen EJ, Janssen-Heijnen ML, Ritchie ED et al (2009) Pneumonectomy for bronchogenic carcinoma: analysis of factors predicting short- and long-term outcome. Interact Cardiovasc Thorac Surg 9:260–264
Dillman RO, Seagren SL, Propert KJ et al (1990) A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III non-small-cell lung cancer. N Engl J Med 323:940–945
Sause W, Kolesar P, Taylor S IV et al (2000) Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. Chest 117:358–364
Pritchard RS, Anthony SP (1996) Chemotherapy plus radiotherapy compared with radiotherapy alone in the treatment of locally advanced, unresectable non small cell lung cancer. A metaanalysis. Ann Intern Med 125:723–729
Rolland E, Le Chevalier T, Aupérin A et al (2007) Sequential radio-chemotherapy (RT-CT) versus radiotherapy alone (RT) and concomitant RT-CT versus RT alone in locally advanced non-small cell lung cancer (NSCLC): two meta-analyses using individual patient data (IPD) from randomised clinical trials (RCTs): A1-04. J Thorac Oncol 2: S309–S310
Furuse K, Fukuoka M, Kawahara M et al (1999) Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine and cisplatin in unresectable stage III non small cell lung cancer. J Clin Oncol 17:2692–2699
Curran W, Scott C, Langer C et al (2003) Longterm benefit is observed in a phase III comparison of sequential versus concurrent chemoradiation for patients with unresected stage III non small cell lung cancer: Radiation Therapy Oncology Group 9410. J Clin Oncol ASCO Annual Meeting Proceedings Part I, Vol 22; 621 (2499)
Fournel P, Robinet G, Thomas P et al (2005) Randomized phase III trial of sequential chemoradiotherapy compared with concurrent chemoradiotherapy in locally advanced non-small-cell lung cancer: Groupe Lyon-Saint-Etienne d'Oncologie Thoracique-Groupe Francais de Pneumo-Cancerologie NPC 95-01 Study. J Clin Oncol 23: 5910–5917
Non-Small Cell Lung Cancer Collaborative Group (1995) Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. BMJ 311:899–909
Auperin A, Le Pechoux C, Pignon JP et al; on behalf of the Meta-Analysis of Cisplatin/Carboplatin Based Concomitant Chemotherapy in Non-small cell Lung Cancer (MAC3-LC) Group (2006) Concomitant radiochemotherapy based on platin compounds in patients with locally advanced nonsmall cell lung cancer (NSCLC): a meta-analysis of individual data from 1764 patients. Ann Oncol 17:473–483
Auperin A, Le Pechoux C, Rolland E et al (2010) Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-smallcell lung cancer. J Clin Oncol 28:2181–2190
Garrido P, Rosell R, Massutí B et al (2009) Predictors of long-term survival in lung cancer patients included in the randomized Spanish Lung Cancer Group 0008 phase II trial using concomitant chemoradiation with docetaxel and carboplatin plus induction or consolidation chemotherapy. Clin Lung Cancer 10:180–186
Albain KS, Crowley JJ, Turrisi AT III et al (2002) Concurrent cisplatin, etoposide, and chest radiotherapy in pathologic stage IIIB non-small-cell lung cancer: a Southwest Oncology Group phase II study, SWOG 9019. J Clin Oncol 20:3454–3460
Gandara DR, Chansky K, Albain KS et al (2003) Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol 21:2004–2010
Hanna N, Neubauer M, Yiannoutsos C et al (2008) Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 26:5755–5760
Vokes EE, Herndon JE II, Crawford J et al (2002) Randomized phase II study of cisplatin with gemcitabine or paclitaxel or vinorelbine as induction chemotherapy followed by concomitant chemoradiotherapy for stage IIIB non-small-cell lung cancer: cancer and leukemia group B study 9431. J Clin Oncol 20:4191–4198
Belani CP, Choy H, Bonomi P et al (2005) Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-smallcell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 23:5883–5891
Vokes EE, Herdon JE II, Kelly MJ et al (2007) Induction chemotherapy followed by chemoradiotherapy compared with chemoradiotherapy alone for regionally advanced unresectable stage III non-small cell lung cancer: Cancer and Leukemia Group B. J Clin Oncol 25:1698–1704
Kelly K, Chansky K, Gaspar LE et al (2008) Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-smallcell lung cancer: SWOG S0023. J Clin Oncol 26:2450–2456
Radiation Therapy Oncology Group. A randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) conformal radiotherapy with concurrent and consolidation carboplatin/paclitaxel +/− cetuximab in patients with stage IIIA/IIIB non-small cell lung cancer. RTOG-0617, NCCTG-N0628, CALGB-30609. ClinicalTrials.gov Id NCT00533949
Provencio M, Sánchez A, Garrido P et al (2010) New molecular targeted therapies integrated with radiation therapy in lung cancer. Clin Lung Cancer 11:91–97
Perez CA, Stanley K, Rubin P et al (1980) A prospective randomized study of various irradiation doses and fractionation schedules in the treatment of inoperable non-oat-cell carcinoma of the lung. Preliminary report by the Radiation Therapy Oncology Group. Cancer 45:2744–2753
Bradley J, Graham MV, Winter K et al (2005) Toxicity and outcome results of RTOG 9311: a phase I-II dose escalation study using three-dimensional conformal radiation therapy in patients with inoperable non-small cell lung carcinoma. Int J Radiat Oncol Biol Phys 61:318–328
Kong F, Gaspar LE, Komaki R et al (2007) Patterns of practice in radiation dose prescription and treatment planning for patients with lung cancer among members of American Society of Therapeutic Radiology and Oncology. Int J Radiat Oncol Biol Phys 69[3 Suppl 1]:S483
Huber RM, Flentje M, Schmidt M et al (2006) Simultaneous chemoradiotherapy compared with radiotherapy alone after induction chemotherapy in inoperable stage IIIA or IIIB non-small-cell lung cancer: study CTRT99/97 by the Bronchial Carcinoma Therapy Group. J Clin Oncol 24:4397–4404
Saunders M, Dische S, Barret A et al (1997) Continuous hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: a randomized multicentre trial. CHART Steering Committee. Lancet 350:161–169
Saunders M, Dische S, Barret A et al (1999) Continuous hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cáncer: mature data from the randomized multicentre trial. CHART Steering Committee. Radiother Oncol 52: 137–143
Belani CP, Wang W, Johnson DH et al (2005) Phase III study of the Eastern Cooperative Oncology Group (ECOG 2597): induction chemotherapy followed by either standard thoracic radiotherapy or hyperfractionated accelerated radiotherapy for patients with unresectable stage IIIA and B nonsmall cell lung cancer. J Clin Oncol 23:3760–3769
Schild SE, Stella PJ, Geyer SM et al (2002) Phase III trial comparing chemotherapy plus once-daily or twice-daily radiotherapy in Stage III non-smallcell lung cancer. Int J Radiat Oncol Biol Phys 54:370–378
Kong FM, Ten Haken RK, Schipper MJ et al (2005) High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. Int J Radiat Oncol Biol Phys 63:324–333
Wang L, Correa CR, Zhao L et al (2009) The effect of radiation dose and chemotherapy on overall survival in 237 patients with Stage III nonsmall-cell lung cancer. Int J Radiat Oncol Biol Phys 73:1383–1390
Bradley J, Graham MV, Winter K et al (2005) Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using threedimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys 61:318–328
Rosenman JG, Halle JS, Socinski MA et al (2002) High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. Int J Radiat Oncol Biol Phys 54:348–356
Schild SE, McGinnis WL, Graham D et al (2006) Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 65:1106–1111
Bradley JD, Moughan J, Graham MV et al (2010) A phase I/II radiation dose escalation study with concurrent chemotherapy for patients with inoperable stages I to III non-small-cell lung cancer: phase I results of RTOG 0117. Int J Radiat Oncol Biol Phys 77:367–372
ICRU Report 62 (1999) Prescribing, recording and reporting photon beam therapy (Supplement to ICRU Report 50). International Commission on Radiation Units and Measurements
MacManus M, Nestle U, Rosenzweig KE et al (2009) Use of PET and PET/CT for radiation therapy planning: IAEA expert report 2006–2007. Radiother Oncol 91:85–94
De Ruysscher D, Kirsch CM (2010) PET scans in radiotherapy planning of lung cancer. Radiother Oncol 96:335–338
Yuan S, Sun X, Li M et al (2007) A randomized study of involved-field irradiation versus elective nodal irradiation in combination with concurrent chemotherapy for inoperable stage III non-small cell lung cancer. Am J Clin Oncol 30:239–244
Rosenzweig KE, Sura S, Jackson A et al (2007) Involved-field radiation therapy for inoperable non small-cell lung cancer. J Clin Oncol 25:5557–5561
Sulman EP, Komaki R, Klopp AH et al (2009) Exclusion of elective nodal irradiation is associated with minimal elective nodal failure in non-small cell lung cancer. Radiat Oncol 30:4–5
Sanuki-Fujimoto N, Sumi M, Ito Y et al (2009) Relation between elective nodal failure and irradiated volume in non-small-cell lung cancer (NSCLC) treated with radiotherapy using conventional fields and doses. Radiother Oncol 91:433–437
Fernandes AT, Shen J, Finlay J et al (2010) Elective nodal irradiation (ENI) vs. involved field radiotherapy (IFRT) for locally advanced non-small cell lung cancer (NSCLC): a comparative analysis of toxicities and clinical outcomes. Radiother Oncol 95:178–184
Belderbos JS, Kepka L, Spring Kong FM et al (2008) Report from the International Atomic Energy Agency (IAEA) consultants’ meeting on elective nodal irradiation in lung cancer: nonsmall-cell lung cancer (NSCLC). Int J Radiat Oncol Biol Phys 72:335–342
Liao ZX, Komaki RR, Thames HD Jr et al (2010) Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy. Int J Radiat Oncol Biol Phys 76:775–781
Author information
Authors and Affiliations
Corresponding author
Additional information
Supported by an unrestricted educational grant from MSD Oncology
Rights and permissions
About this article
Cite this article
Ocaña, C.V., López, P.G. & Trueba, I.M. Multidisciplinary approach in stage III non-small-cell lung cancer: standard of care and open questions. Clin Transl Oncol 13, 629–635 (2011). https://doi.org/10.1007/s12094-011-0708-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12094-011-0708-8