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Management of stage III non-small cell lung cancer

Authors
Steven E Schild, MD
Suresh S Ramalingam, MD
Eric Vallières, MD, FRCSC
Section Editors
Rogerio C Lilenbaum, MD, FACP
Joseph S Friedberg, MD
James R Jett, MD
Deputy Editor
Sadhna R Vora, MD

INTRODUCTION

Development of a treatment plan for a patient with lung cancer depends upon the cell type (small cell versus non-small cell), tumor stage, and an assessment of the patient's overall medical condition. Non-small cell lung cancer (NSCLC) includes adenocarcinoma and its bronchioloalveolar subset, squamous cell carcinoma, and large cell carcinoma, in decreasing order frequency of occurrence. (See "Pathology of lung malignancies".)

The management of patients with stage III NSCLC, which usually requires a combined modality approach, will be reviewed here. The treatment approach presented here is consistent with guidelines from the American Society for Radiation Oncology (ASTRO) [1,2], which have been endorsed by American Society of Clinical Oncology (ASCO) [3].

The initial approach to staging of NSCLC and its implications for prognosis are discussed separately. (See "Overview of the initial evaluation, diagnosis, and staging of patients with suspected lung cancer" and "Tumor, node, metastasis (TNM) staging system for non-small cell lung cancer".)

STAGING

TNM staging system — The tumor (T), node (N), metastasis (M) system is used to stage NSCLC (table 1) [4]. Historically stage III lung cancer was defined as locoregionally advanced disease due to primary tumor extension into extrapulmonary structures (T3 or T4) or mediastinal lymph node involvement (N2 or N3) without evidence of distant metastases (M0). With the 2009 revisions to the TNM staging system, stage III lung cancers now include T3 tumors greater than 7 cm in size and T3 tumors with multiple nodules in the same lobe, when associated with N1 involvement. Noncontiguous pleural involvement by tumor is classified as stage IV in the current TNM system (formerly stage III). (See "Tumor, node, metastasis (TNM) staging system for non-small cell lung cancer", section on 'Eighth edition of the TNM system'.)

Patients with stage IIIA disease are stratified clinically into those with bulky or non-bulky mediastinal lymph node disease. The definition of bulky mediastinal lymphadenopathy has never been scientifically validated and varies in the literature and in between institutions. The distinction between non-bulky and bulky stage IIIA disease is primarily useful in selecting potential patients for upfront surgical resection or for resection after induction (neoadjuvant) therapy. Criteria used to define bulkiness are size of a dominant lymph node greater than 2 to 3 cm in short-axis diameter, as measured by computed tomography (CT), groupings of multiple smaller lymph nodes, evidence of extracapsular nodal involvement or involvement of more than two lymph node stations [5,6]. (See 'Potentially resectable disease' below.)

                                      

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Literature review current through: Nov 2016. | This topic last updated: Mon Nov 28 00:00:00 GMT 2016.
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References
Top
  1. Rodrigues G, Choy H, Bradley J, et al. Definitive radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline. Pract Radiat Oncol 2015; 5:141.
  2. Rodrigues G, Choy H, Bradley J, et al. Adjuvant radiation therapy in locally advanced non-small cell lung cancer: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based clinical practice guideline. Pract Radiat Oncol 2015; 5:149.
  3. Bezjak A, Temin S, Franklin G, et al. Definitive and Adjuvant Radiotherapy in Locally Advanced Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Society for Radiation Oncology Evidence-Based Clinical Practice Guideline. J Clin Oncol 2015; 33:2100.
  4. Mountain CF. Revisions in the International System for Staging Lung Cancer. Chest 1997; 111:1710.
  5. Robinson LA, Wagner H Jr, Ruckdeschel JC, American College of Chest Physicians. Treatment of stage IIIA non-small cell lung cancer. Chest 2003; 123:202S.
  6. Robinson LA, Ruckdeschel JC, Wagner H Jr, et al. Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132:243S.
  7. Lee PC, Port JL, Korst RJ, et al. Risk factors for occult mediastinal metastases in clinical stage I non-small cell lung cancer. Ann Thorac Surg 2007; 84:177.
  8. De Leyn P, Lardinois D, Van Schil P, et al. European trends in preoperative and intraoperative nodal staging: ESTS guidelines. J Thorac Oncol 2007; 2:357.
  9. Meyers BF, Haddad F, Siegel BA, et al. Cost-effectiveness of routine mediastinoscopy in computed tomography- and positron emission tomography-screened patients with stage I lung cancer. J Thorac Cardiovasc Surg 2006; 131:822.
  10. Graeter TP, Hellwig D, Hoffmann K, et al. Mediastinal lymph node staging in suspected lung cancer: comparison of positron emission tomography with F-18-fluorodeoxyglucose and mediastinoscopy. Ann Thorac Surg 2003; 75:231.
  11. Shah AA, Berry MF, Tzao C, et al. Induction chemoradiation is not superior to induction chemotherapy alone in stage IIIA lung cancer. Ann Thorac Surg 2012; 93:1807.
  12. Thomas M, Rübe C, Hoffknecht P, et al. Effect of preoperative chemoradiation in addition to preoperative chemotherapy: a randomised trial in stage III non-small-cell lung cancer. Lancet Oncol 2008; 9:636.
  13. Pless M, Stupp R, Ris HB, et al. Neoadjuvant chemotherapy with or without preoperative irradiation in stage IIIA/N2 non-small cell lung cancer (NSCLC): A randomized phase III trial by the Swiss Group for Clinical Cancer Research (SAKK trial 16/00). J Clin Oncol 31, 2013 (suppl; abstr 7503).
  14. Andre F, Grunenwald D, Pignon JP, et al. Survival of patients with resected N2 non-small-cell lung cancer: evidence for a subclassification and implications. J Clin Oncol 2000; 18:2981.
  15. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985; 312:1604.
  16. Pairolero PC, Trastek VF, Payne WS. Treatment of bronchogenic carcinoma with chest wall invasion. Surg Clin North Am 1987; 67:959.
  17. Piehler JM, Pairolero PC, Weiland LH, et al. Bronchogenic carcinoma with chest wall invasion: factors affecting survival following en bloc resection. Ann Thorac Surg 1982; 34:684.
  18. Harpole DH Jr, Healey EA, DeCamp MM Jr, et al. Chest wall invasive non-small cell lung cancer: patterns of failure and implications for a revised staging system. Ann Surg Oncol 1996; 3:261.
  19. McCaughan BC, Martini N, Bains MS, McCormack PM. Chest wall invasion in carcinoma of the lung. Therapeutic and prognostic implications. J Thorac Cardiovasc Surg 1985; 89:836.
  20. Port JL, Korst RJ, Lee PC, et al. Surgical resection for multifocal (T4) non-small cell lung cancer: is the T4 designation valid? Ann Thorac Surg 2007; 83:397.
  21. Osaki T, Sugio K, Hanagiri T, et al. Survival and prognostic factors of surgically resected T4 non-small cell lung cancer. Ann Thorac Surg 2003; 75:1745.
  22. Nagai K, Sohara Y, Tsuchiya R, et al. Prognosis of resected non-small cell lung cancer patients with intrapulmonary metastases. J Thorac Oncol 2007; 2:282.
  23. Ohta M, Hirabayasi H, Shiono H, et al. Surgical resection for lung cancer with infiltration of the thoracic aorta. J Thorac Cardiovasc Surg 2005; 129:804.
  24. de Perrot M, Fadel E, Mussot S, et al. Resection of locally advanced (T4) non-small cell lung cancer with cardiopulmonary bypass. Ann Thorac Surg 2005; 79:1691.
  25. Mitchell JD, Mathisen DJ, Wright CD, et al. Resection for bronchogenic carcinoma involving the carina: long-term results and effect of nodal status on outcome. J Thorac Cardiovasc Surg 2001; 121:465.
  26. Regnard JF, Perrotin C, Giovannetti R, et al. Resection for tumors with carinal involvement: technical aspects, results, and prognostic factors. Ann Thorac Surg 2005; 80:1841.
  27. Leo F, Bellini R, Conti B, et al. Superior vena cava resection in thoracic malignancies: does prosthetic replacement pose a higher risk? Eur J Cardiothorac Surg 2010; 37:764.
  28. Spaggiari L, Leo F, Veronesi G, et al. Superior vena cava resection for lung and mediastinal malignancies: a single-center experience with 70 cases. Ann Thorac Surg 2007; 83:223.
  29. Grunenwald DH, Mazel C, Girard P, et al. Radical en bloc resection for lung cancer invading the spine. J Thorac Cardiovasc Surg 2002; 123:271.
  30. Albain KS, Rusch VW, Crowley JJ, et al. 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 1995; 13:1880.
  31. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
  32. Pisters KM, Evans WK, Azzoli CG, et al. Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol 2007; 25:5506.
  33. Sawyer TE, Bonner JA, Gould PM, et al. Effectiveness of postoperative irradiation in stage IIIA non-small cell lung cancer according to regression tree analyses of recurrence risks. Ann Thorac Surg 1997; 64:1402.
  34. Postoperative radiotherapy in non-small-cell lung cancer: systematic review and meta-analysis of individual patient data from nine randomised controlled trials. PORT Meta-analysis Trialists Group. Lancet 1998; 352:257.
  35. Bonner JA, Spencer SA. Postoperative radiotherapy in non-small-cell lung cancer warrants further exploration in the era of adjuvant chemotherapy and conformal radiotherapy. J Clin Oncol 2006; 24:2978.
  36. Dautzenberg B, Arriagada R, Chammard AB, et al. A controlled study of postoperative radiotherapy for patients with completely resected nonsmall cell lung carcinoma. Groupe d'Etude et de Traitement des Cancers Bronchiques. Cancer 1999; 86:265.
  37. Lally BE, Zelterman D, Colasanto JM, et al. Postoperative radiotherapy for stage II or III non-small-cell lung cancer using the surveillance, epidemiology, and end results database. J Clin Oncol 2006; 24:2998.
  38. Mikell JL, Gillespie TW, Hall WA, 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.
  39. Lally BE, Detterbeck FC, Geiger AM, et al. The risk of death from heart disease in patients with nonsmall cell lung cancer who receive postoperative radiotherapy: analysis of the Surveillance, Epidemiology, and End Results database. Cancer 2007; 110:911.
  40. Douillard JY, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial. Lancet Oncol 2006; 7:719.
  41. Douillard JY, Rosell R, De Lena M, et al. Impact of postoperative radiation therapy on survival in patients with complete resection and stage I, II, or IIIA non-small-cell lung cancer treated with adjuvant chemotherapy: the adjuvant Navelbine International Trialist Association (ANITA) Randomized Trial. Int J Radiat Oncol Biol Phys 2008; 72:695.
  42. Wang EH, Corso CD, Rutter CE, et al. Postoperative Radiation Therapy Is Associated With Improved Overall Survival in Incompletely Resected Stage II and III Non-Small-Cell Lung Cancer. J Clin Oncol 2015; 33:2727.
  43. Vallières E, Van Houtte P, Travis WD, et al. Carcinoma in situ at the bronchial resection margin: a review. J Thorac Oncol 2011; 6:1617.
  44. Kawaguchi T, Watanabe S, Kawachi R, et al. The impact of residual tumor morphology on prognosis, recurrence, and fistula formation after lung cancer resection. J Thorac Oncol 2008; 3:599.
  45. Massard G, Doddoli C, Gasser B, et al. Prognostic implications of a positive bronchial resection margin. Eur J Cardiothorac Surg 2000; 17:557.
  46. Snijder RJ, Brutel de la Rivière A, Elbers HJ, van den Bosch JM. Survival in resected stage I lung cancer with residual tumor at the bronchial resection margin. Ann Thorac Surg 1998; 65:212.
  47. 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; 8:915.
  48. Katakami N, Tada H, Mitsudomi T, et al. A phase 3 study of induction treatment with concurrent chemoradiotherapy versus chemotherapy before surgery in patients with pathologically confirmed N2 stage IIIA nonsmall cell lung cancer (WJTOG9903). Cancer 2012; 118:6126.
  49. Girard N, Mornex F, Douillard JY, et al. Is neoadjuvant chemoradiotherapy a feasible strategy for stage IIIA-N2 non-small cell lung cancer? Mature results of the randomized IFCT-0101 phase II trial. Lung Cancer 2010; 69:86.
  50. Pless M, Stupp R, Ris HB, et al. Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet 2015; 386:1049.
  51. Allen AM, Mentzer SJ, Yeap BY, et al. Pneumonectomy after chemoradiation: the Dana-Farber Cancer Institute/Brigham and Women's Hospital experience. Cancer 2008; 112:1106.
  52. Weder W, Collaud S, Eberhardt WE, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non-small-cell lung cancer. J Thorac Cardiovasc Surg 2010; 139:1424.
  53. Barnett SA, Rusch VW, Zheng J, et al. Contemporary results of surgical resection of non-small cell lung cancer after induction therapy: a review of 549 consecutive cases. J Thorac Oncol 2011; 6:1530.
  54. Burkes RL, Shepherd FA, Blackstein ME, et al. Induction chemotherapy with mitomycin, vindesine, and cisplatin for stage IIIA (T1-3, N2) unresectable non-small-cell lung cancer: final results of the Toronto phase II trial. Lung Cancer 2005; 47:103.
  55. Weiden PL, Piantadosi S. Preoperative chemotherapy (cisplatin and fluorouracil) and radiation therapy in stage III non-small-cell lung cancer: a phase II study of the Lung Cancer Study Group. J Natl Cancer Inst 1991; 83:266.
  56. 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; 374:379.
  57. Refai M, Brunelli A, Rocco G, et al. Does induction treatment increase the risk of morbidity and mortality after pneumonectomy? A multicentre case-matched analysis. Eur J Cardiothorac Surg 2010; 37:535.
  58. van Meerbeeck JP, Kramer GW, Van Schil PE, et al. Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small-cell lung cancer. J Natl Cancer Inst 2007; 99:442.
  59. Eberhardt WE, Pöttgen C, Gauler TC, et al. Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol 2015; 33:4194.
  60. 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; 88:1210.
  61. Sause WT, Scott C, Taylor S, et al. Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer. J Natl Cancer Inst 1995; 87:198.
  62. Sause W, Kolesar P, Taylor S IV, et al. 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 2000; 117:358.
  63. Okawara G, Mackay JA, Evans WK, et al. Management of unresected stage III non-small cell lung cancer: a systematic review. J Thorac Oncol 2006; 1:377.
  64. O'Rourke N, Roqué I Figuls M, Farré Bernadó N, Macbeth F. Concurrent chemoradiotherapy in non-small cell lung cancer. Cochrane Database Syst Rev 2010; :CD002140.
  65. Curran WJ Jr, Paulus R, Langer CJ, et al. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst 2011; 103:1452.
  66. Furuse K, Fukuoka M, Kawahara M, et al. 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 1999; 17:2692.
  67. Furuse K, Hosoe S, Masuda N, et al. Impact of tumor control on survival in unresectable stage III non-small cell lung cancer (NSCLC) treated with concurrent thoracic radiotherapy and chemotherapy (abstract). Proc Am Soc Clin Oncol 2000.
  68. Arrieta O, Gallardo-Rincón D, Villarreal-Garza C, et al. High frequency of radiation pneumonitis in patients with locally advanced non-small cell lung cancer treated with concurrent radiotherapy and gemcitabine after induction with gemcitabine and carboplatin. J Thorac Oncol 2009; 4:845.
  69. Albain KS, Crowley JJ, Turrisi AT 3rd, et al. 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 2002; 20:3454.
  70. Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small-cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol 2003; 21:2004.
  71. Hanna N, Neubauer M, Yiannoutsos C, et al. 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 2008; 26:5755.
  72. Belani CP, Choy H, Bonomi P, et al. Combined chemoradiotherapy regimens of paclitaxel and carboplatin for locally advanced non-small-cell lung cancer: a randomized phase II locally advanced multi-modality protocol. J Clin Oncol 2005; 23:5883.
  73. Senan S, Brade A, Wang LH, et al. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2016; 34:953.
  74. Perez CA, Bauer M, Edelstein S, et al. Impact of tumor control on survival in carcinoma of the lung treated with irradiation. Int J Radiat Oncol Biol Phys 1986; 12:539.
  75. Bradley JD, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 2015; 16:187.
  76. Mauguen A, Le Péchoux C, Saunders MI, et al. Hyperfractionated or accelerated radiotherapy in lung cancer: an individual patient data meta-analysis. J Clin Oncol 2012; 30:2788.
  77. Vokes EE, Herndon JE 2nd, Kelley MJ, et al. 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 2007; 25:1698.
  78. Jalal SI, Riggs HD, Melnyk A, et al. Updated survival and outcomes for older adults with inoperable stage III non-small-cell lung cancer treated with cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology. Ann Oncol 2012; 23:1730.
  79. Ahn JS, Ahn YC, Kim JH, et al. Multinational Randomized Phase III Trial With or Without Consolidation Chemotherapy Using Docetaxel and Cisplatin After Concurrent Chemoradiation in Inoperable Stage III Non-Small-Cell Lung Cancer: KCSG-LU05-04. J Clin Oncol 2015; 33:2660.
  80. Owonikoko TK, Ragin CC, Belani CP, et al. Lung cancer in elderly patients: an analysis of the surveillance, epidemiology, and end results database. J Clin Oncol 2007; 25:5570.
  81. Sequist LV, Lynch TJ. Aggressive treatment for the fit elderly with non-small-cell lung cancer? Yes! J Clin Oncol 2003; 21:3186.
  82. Schild SE, Stella PJ, Geyer SM, et al. The outcome of combined-modality therapy for stage III non-small-cell lung cancer in the elderly. J Clin Oncol 2003; 21:3201.
  83. Rocha Lima CM, Herndon JE 2nd, Kosty M, et al. Therapy choices among older patients with lung carcinoma: an evaluation of two trials of the Cancer and Leukemia Group B. Cancer 2002; 94:181.
  84. Schild SE, Mandrekar SJ, Jatoi A, et al. The value of combined-modality therapy in elderly patients with stage III nonsmall cell lung cancer. Cancer 2007; 110:363.
  85. Atagi S, Kawahara M, Yokoyama A, et al. Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301). Lancet Oncol 2012; 13:671.
  86. Hardy D, Liu CC, Cormier JN, et al. Cardiac toxicity in association with chemotherapy and radiation therapy in a large cohort of older patients with non-small-cell lung cancer. Ann Oncol 2010; 21:1825.
  87. Bradley J, Masters GA, Hu C, et al. An intergroup randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) chemoradiotherapy (CRT) +/- cetuximab (cetux) for stage III non-small cell lung cancer (NSCLC): Results on cetux from RTOG 0617 (abstract PL03.05). IASLC 15th World Conference on Lung Cancer, 2013.
  88. Kelly K, Chansky K, Gaspar LE, et al. Phase III trial of maintenance gefitinib or placebo after concurrent chemoradiotherapy and docetaxel consolidation in inoperable stage III non-small-cell lung cancer: SWOG S0023. J Clin Oncol 2008; 26:2450.
  89. Roswit B, Patno ME, Rapp R, et al. The survival of patients with inoperable lung cancer: a large-scale randomized study of radiation therapy versus placebo. Radiology 1968; 90:688.
  90. Johnson DH, Einhorn LH, Bartolucci A, et al. Thoracic radiotherapy does not prolong survival in patients with locally advanced, unresectable non-small cell lung cancer. Ann Intern Med 1990; 113:33.
  91. Basaki K, Abe Y, Aoki M, et al. Prognostic factors for survival in stage III non-small-cell lung cancer treated with definitive radiation therapy: impact of tumor volume. Int J Radiat Oncol Biol Phys 2006; 64:449.
  92. Sundstrøm S, Bremnes R, Aasebø U, et al. Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 2004; 22:801.
  93. Falk SJ, Girling DJ, White RJ, et al. Immediate versus delayed palliative thoracic radiotherapy in patients with unresectable locally advanced non-small cell lung cancer and minimal thoracic symptoms: randomised controlled trial. BMJ 2002; 325:465.
  94. 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; 23:2955.
  95. Carolan H, Sun AY, Bezjak A, et al. Does the incidence and outcome of brain metastases in locally advanced non-small cell lung cancer justify prophylactic cranial irradiation or early detection? Lung Cancer 2005; 49:109.
  96. Chen AM, Jahan TM, Jablons DM, et al. Risk of cerebral metastases and neurological death after pathological complete response to neoadjuvant therapy for locally advanced nonsmall-cell lung cancer: clinical implications for the subsequent management of the brain. Cancer 2007; 109:1668.
  97. Lester JF, MacBeth FR, Coles B. Prophylactic cranial irradiation for preventing brain metastases in patients undergoing radical treatment for non-small-cell lung cancer: a Cochrane Review. Int J Radiat Oncol Biol Phys 2005; 63:690.
  98. Pöttgen C, Eberhardt W, Grannass A, et al. Prophylactic cranial irradiation in operable stage IIIA non small-cell lung cancer treated with neoadjuvant chemoradiotherapy: results from a German multicenter randomized trial. J Clin Oncol 2007; 25:4987.
  99. Gore EM, Bae K, Wong SJ, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: primary analysis of radiation therapy oncology group study RTOG 0214. J Clin Oncol 2011; 29:272.
  100. Sun A, Bae K, Gore EM, et al. Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis. J Clin Oncol 2011; 29:279.
  101. Li N, Zeng ZF, Wang SY, et al. Randomized phase III trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA-N2 nonsmall-cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy. Ann Oncol 2015; 26:504.
  102. Gore EM, Paulus R, Wong S, et al. Phase III comparison of prophylactic cranial irradiation versus observation in patients with locally advanced non-small-cell lung cancer: Updated analysis of RTOG 0214 (abstract 5). J Thorac Oncol 2012; 7:S204.
  103. Scagliotti GV, Kosmidis P, de Marinis F, et al. Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study. Ann Oncol 2012; 23:2082.