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Current status of induction treatment for N2-Stage III non-small cell lung cancer

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Abstract

Locally advanced non-small cell lung cancer (NSCLC), particularly clinical Stage IIIA NSCLC with mediastinal lymph node metastasis, is known to be quite heterogeneous, comprising approximately one-fourth of cases of NSCLC. In this subset, patients with a minor tumor load in the mediastinal lymph nodes, such as microscopically or pathologically proven N2 in the resected specimens, are treated with surgery followed by adjuvant chemotherapy. Meanwhile, the current standard of care for patients with bulky or infiltrative N2 disease is concurrent chemoradiotherapy. The potential role of surgery in multi-modality treatment for clinical N2-Stage IIIA remains controversial. Several prospective clinical trials of this subset have been conducted; however, the heterogeneity of the N2 status and differences in chemotherapy regimens and/or radiation modalities between clinical trials make the results difficult to compare. No optimal chemotherapy regimen has been established to control possible micrometastasis, and radiotherapy is often used to achieve maximum local disease control and minimize post-surgical complications. This review summarizes the findings of prospective clinical trials that assessed the role of surgery in treating clinical N2-Stage IIIA patients within the last two decades and discusses the present status of induction treatment followed by surgery for clinical N2-Stage IIIA NSCLC.

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References

  1. Mountain CF. Revisions in the international system for staging lung cancer. Chest. 1997;111:1710–7.

    Article  PubMed  CAS  Google Scholar 

  2. Sawabata N, Miyaoka E, Asamura H, Nakanishi Y, Eguchi K, Mori M, et al. Japanese lung cancer registry study of 11,663 surgical cases in 2004: demographic and prognosis changes over decade. J Thorac Oncol. 2011;6:1229–35.

    Article  PubMed  Google Scholar 

  3. Goldstraw P, Crowley J, Chansky K, Giroux DJ, Groome PA, Rami-Porta R, et al. 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;2:706–14.

    Article  PubMed  Google Scholar 

  4. Keller SM, Adak S, Wagner H, Johnson DH. Mediastinal lymph node dissection improves survival in patients with stages II and IIIa non-small cell lung cancer. Eastern Cooperative Oncology Group. Ann Thorac Surg. 2000;70:358–65.

    Article  PubMed  CAS  Google Scholar 

  5. Riquet M, Bagan P, Le Pimpec Barthes F, Banu E, Scotte F, Foucault C, et al. Completely resected non-small cell lung cancer: reconsidering prognostic value and significance of N2 metastases. Ann Thorac Surg. 2007;84:1818–24.

    Article  PubMed  Google Scholar 

  6. Ramnath N, Dilling TJ, Harris LJ, Kim AW, Michaud GC, Balekian AA, 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:e314S–40S.

    Article  PubMed  CAS  Google Scholar 

  7. Dillman RO, Seagren SL, Propert KJ, Guerra J, Eaton WL, Perry MC, et al. 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. 1990;323:940–5.

    Article  PubMed  CAS  Google Scholar 

  8. Dillman RO, Herndon J, Seagren SL, Eaton WL, Green MR. Improved survival in stage III non-small-cell lung cancer: 7-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. J Natl Cancer Inst. 1996;88:1210–5.

    Article  PubMed  CAS  Google Scholar 

  9. Belani CP, Choy H, Bonomi P, Scott C, Travis P, Haluschak J, 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;23:5883–91.

    Article  PubMed  CAS  Google Scholar 

  10. Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, 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;17:2692–9.

    PubMed  CAS  Google Scholar 

  11. Jeremic B, Shibamoto Y, Acimovic L, Milisavljevic S. Hyperfractionated radiation therapy with or without concurrent low-dose daily carboplatin/etoposide for stage III non-small-cell lung cancer: a randomized study. J Clin Oncol. 1996;14:1065–70.

    PubMed  CAS  Google Scholar 

  12. Schaake-Koning C, van den Bogaert W, Dalesio O, Festen J, Hoogenhout J, van Houtte P, et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N Engl J Med. 1992;326:524–30.

    Article  PubMed  CAS  Google Scholar 

  13. Zatloukal P, Petruzelka L, Zemanova M, Havel L, Janku F, Judas L, et al. Concurrent versus sequential chemoradiotherapy with cisplatin and vinorelbine in locally advanced non-small cell lung cancer: a randomized study. Lung Cancer. 2004;46:87–98.

    Article  PubMed  Google Scholar 

  14. Ettinger DS, Akerley W, Bepler G, Blum MG, Chang A, Cheney RT, et al. Non-small cell lung cancer. J Natl Compr Canc Netw. 2010;8:740–801.

    PubMed  CAS  Google Scholar 

  15. Atkins BZ, D’Amico TA. Controversial issues regarding the use of induction chemotherapy for lung cancer. Semin Thorac Cardiovasc Surg. 2005;17:191–4.

    Article  PubMed  Google Scholar 

  16. Yamaguchi M, Toyokawa G, Ohba T, Sasaki T, Kometani T, Hamatake M, et al. Preoperative concurrent chemoradiotherapy of S-1/cisplatin for stage III non-small cell lung cancer. Ann Thorac Surg. 2013;96:1783–9.

    Article  PubMed  Google Scholar 

  17. Taylor NA, Liao ZX, Cox JD, Stevens C, Roth J, Walsh G, 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;58:204–12.

    Article  PubMed  Google Scholar 

  18. Caglar HB, Baldini EH, Othus M, Rabin MS, Bueno R, Sugarbaker DJ, et al. Outcomes of patients with stage III nonsmall cell lung cancer treated with chemotherapy and radiation with and without surgery. Cancer. 2009;115:4156–66.

    Article  PubMed  CAS  Google Scholar 

  19. Perrot E, Guibert B, Mulsant P, Blandin S, Arnaud I, Roy P, et al. Preoperative chemotherapy does not increase complications after nonsmall cell lung cancer resection. Ann Thorac Surg. 2005;80:423–7.

    Article  PubMed  Google Scholar 

  20. Pass HI, Pogrebniak HW, Steinberg SM, Mulshine J, Minna J. Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg. 1992;53:992–8.

    Article  PubMed  CAS  Google Scholar 

  21. Roth JA, Fossella F, Komaki R, Ryan MB, Putnam JB, Lee JS, et al. A randomized trial comparing perioperative chemotherapy and surgery with surgery alone in resectable stage IIIA non-small-cell lung cancer. J Natl Cancer Inst. 1994;86:673–80.

    Article  PubMed  CAS  Google Scholar 

  22. Rosell R, Gómez-Codina J, Camps C, Maestre J, Padille J, Cantó A, 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;330:153–8.

    Article  PubMed  CAS  Google Scholar 

  23. Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, et al. Preoperative chemotherapy followed by surgery compared with primary surgery in resectable stage I (except T1N0), II, and IIIa non-small-cell lung cancer. J Clin Oncol. 2002;20:247–53.

    Article  PubMed  Google Scholar 

  24. Nagai K, Tsuchiya R, Mori T, Tada H, Ichinose Y, Koike 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;125:254–60.

    Article  PubMed  Google Scholar 

  25. Roth JA, Atkinson EN, Fossella F, Komaki R, Bernadette Ryan M, Putnam JB, 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;21:1–6.

    Article  PubMed  CAS  Google Scholar 

  26. Rosell R, Gómez-Codina J, Camps C, Javier Sánchez J, Maestre J, Padilla J, et al. Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer. 1999;26:7–14.

    Article  PubMed  CAS  Google Scholar 

  27. Berghmans T, Paesmans M, Meert AP, Mascaux C, Lothaire P, Lafitte JJ, et al. Survival improvement in resectable non-small cell lung cancer with (neo)adjuvant chemotherapy: results of a meta-analysis of the literature. Lung Cancer. 2005;49:13–23.

    Article  PubMed  CAS  Google Scholar 

  28. Burdett S, Stewart LA, Rydzewska L. A systematic review and meta-analysis of the literature: chemotherapy and surgery versus surgery alone in non-small cell lung cancer. J Thorac Oncol. 2006;1:611–21.

    Article  PubMed  Google Scholar 

  29. Group NM-aC. Preoperative chemotherapy for non-small cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383:1561–71.

    Article  Google Scholar 

  30. Jeremic B, Shibamoto Y, Acimovic L, Djuric L. Randomized trial of hyperfractionated radiation therapy with or without concurrent chemotherapy for stage III non-small-cell lung cancer. J Clin Oncol. 1995;13:452–8.

    PubMed  CAS  Google Scholar 

  31. Yamamoto N, Nakagawa K, Nishimura Y, Tsujino K, Satouchi M, Kudo S, et al. Phase III study comparing second- and third-generation regimens with concurrent thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer: west Japan Thoracic Oncology Group WJTOG0105. J Clin Oncol. 2010;28:3739–45.

    Article  PubMed  Google Scholar 

  32. Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi AT, Weick JK, 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;13:1880–92.

    PubMed  CAS  Google Scholar 

  33. Katakami N, Okazaki M, Nishiuchi S, Fukuda H, Horikawa T, Nishiyama H, et al. Induction chemoradiotherapy for advanced stage III non-small cell lung cancer: long-term follow-up in 42 patients. Lung Cancer. 1998;22:127–37.

    Article  PubMed  CAS  Google Scholar 

  34. Thomas M, Rübe C, Semik M, von Eiff M, Freitag L, Macha HN, et al. Impact of preoperative bimodality induction including twice-daily radiation on tumor regression and survival in stage III non-small-cell lung cancer. J Clin Oncol. 1999;17:1185.

    PubMed  CAS  Google Scholar 

  35. Betticher DC, Hsu Schmitz SF, Tötsch M, Hansen E, Joss C, von Briel C, et al. Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study. Br J Cancer. 2006;94:1099–106.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Suntharalingam M, Paulus R, Edelman MJ, Krasna M, Burrows W, Gore E, et al. Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys. 2012;84:456–63.

    Article  PubMed  Google Scholar 

  37. Stephens RJ, Girling DJ, Hopwood P, Thatcher N, Party MRCLCW. 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;49:395–400.

    Article  PubMed  Google Scholar 

  38. Johnstone DW, Byhardt RW, Ettinger D, Scott CB. 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. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys. 2002;54:365–9.

    Article  PubMed  Google Scholar 

  39. van Meerbeeck JP, Kramer GW, Van Schil PE, Legrand C, Smit EF, Schramel F, 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;99:442–50.

    Article  PubMed  Google Scholar 

  40. Thomas M, Rübe C, Hoffknecht P, Macha HN, Freitag L, Linder A, 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;9:636–48.

    Article  PubMed  Google Scholar 

  41. Albain KS, Swann RS, Rusch VW, Turrisi AT, Shepherd FA, Smith C, 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;374:379–86.

    Article  PubMed  CAS  Google Scholar 

  42. Katakami N, Tada H, Mitsudomi T, Kudoh S, Senba H, Matsui K, 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;118:6126–35.

    Article  PubMed  CAS  Google Scholar 

  43. Crinò L, Weder W, van Meerbeeck J, Felip E, Group EGW. Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: eSMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Suppl 5):v103–15.

    Google Scholar 

  44. Mansour Z, Kochetkova EA, Ducrocq X, Vasilescu MD, Maxant G, Buggenhout A, et al. Induction chemotherapy does not increase the operative risk of pneumonectomy! Eur J Cardiothorac Surg. 2007;31:181–5.

    Article  PubMed  Google Scholar 

  45. Weder W, Collaud S, Eberhardt WE, Hillinger S, Welter S, Stahel R, et al. Pneumonectomy is a valuable treatment option after neoadjuvant therapy for stage III non-small-cell lung cancer. J Thorac Cardiovasc Surg. 2010;139:1424–30.

    Article  PubMed  Google Scholar 

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Correspondence to Kenji Sugio.

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Yamaguchi, M., Sugio, K. Current status of induction treatment for N2-Stage III non-small cell lung cancer. Gen Thorac Cardiovasc Surg 62, 651–659 (2014). https://doi.org/10.1007/s11748-014-0447-1

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