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

D C Betticher, S-F Hsu Schmitz, M Tötsch, E Hansen, C Joss, C von Briel, R A Schmid, M Pless, J Habicht, A D Roth, A Spiliopoulos, R Stahel, W Weder, R Stupp, F Egli, M Furrer, H Honegger, M Wernli, T Cerny, H-B Ris, Swiss Group for Clinical Cancer Research (SAKK), D C Betticher, S-F Hsu Schmitz, M Tötsch, E Hansen, C Joss, C von Briel, R A Schmid, M Pless, J Habicht, A D Roth, A Spiliopoulos, R Stahel, W Weder, R Stupp, F Egli, M Furrer, H Honegger, M Wernli, T Cerny, H-B Ris, Swiss Group for Clinical Cancer Research (SAKK)

Abstract

The aim was to investigate the efficacy of neoadjuvant docetaxel-cisplatin and identify prognostic factors for outcome in locally advanced stage IIIA (pN2 by mediastinoscopy) non-small-cell lung cancer (NSCLC) patients. In all, 75 patients (from 90 enrolled) underwent tumour resection after three 3-week cycles of docetaxel 85 mg m-2 (day 1) plus cisplatin 40 or 50 mg m-2 (days 1 and 2). Therapy was well tolerated (overall grade 3 toxicity occurred in 48% patients; no grade 4 nonhaematological toxicity was reported), with no observed late toxicities. Median overall survival (OS) and event-free survival (EFS) times were 35 and 15 months, respectively, in the 75 patients who underwent surgery; corresponding figures for all 90 patients enrolled were 28 and 12 months. At 3 years after initiating trial therapy, 27 out of 75 patients (36%) were alive and tumour free. At 5-year follow-up, 60 and 65% of patients had local relapse and distant metastases, respectively. The most common sites of distant metastases were the lung (24%) and brain (17%). Factors associated with OS, EFS and risk of local relapse and distant metastases were complete tumour resection and chemotherapy activity (clinical response, pathologic response, mediastinal downstaging). Neoadjuvant docetaxel-cisplatin was effective and tolerable in stage IIIA pN2 NSCLC, with chemotherapy contributing significantly to outcomes.

Figures

Figure 1
Figure 1
Overall survival (patients who underwent surgery, n=75).
Figure 2
Figure 2
Risk of (A) distant metastases stratified by pathological response (percentage of tumour necrosis and fibrosis), (B) distant metastases stratified by mediastinal downstaging (N0/1 vs N2), (C) local relapse stratified by pathological response and (D) local relapse stratified by mediastinal downstaging. The risk of developing distant metastases decreased rapidly after 24 months in patients where chemotherapy was active. Conversely, local relapses occurred throughout the entire observation period.

References

    1. Albain KS, Rusch VW, Crowley JJ, Rice TW, Turrisi III AT, Weick JK, Lonchyna VA, Presant CA, McKenna RJ, Gandara DR (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
    1. Albain KS, Scott CB, Rusch VR, Turrisi AT, Shepherd SA, Smith C, Gandara DR, Johnson D, Green MR, Miller RC (2003) Phase III study of concurrent chemotherapy and full course radiotherapy (CR/RT) versus CT/RT induction followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): first outcome analysis of North American Intergroup trial 0139 (RTOG 93-09). Lung Cancer 41(Suppl 2): S4 PL-4
    1. Albain KS, Swann RS, Rusch VR, Turrisi AT, Shepherd FA, Smith CJ, Gandara DR, Johnson DH, Green MR, Miller RC, the North American Lung Cancer Intergroup (2005) Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol 23(Suppl 16S): 624s (Abstr 7014)
    1. Andre F, Grunenwald D, Pujol JL, Girard P, Dujon A, Brouchet L, Brichon PY, Westeel V, Le Chevalier T (2001) Patterns of relapse of N2 nonsmall-cell lung carcinoma patients treated with preoperative chemotherapy: should prophylactic cranial irradiation be reconsidered? Cancer 91: 2394–2400
    1. Arriagada R, Bergman B, Dunant A, Le Chevalier T, Pignon JP, Vansteenkiste J, the International Adjuvant Lung Cancer Trial Collaborative Group (2004) Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350: 351–360
    1. Betticher DC, Hsu Schmitz S-F, Tötsch M, Hansen E, Joss C, von Briel C, Schmid RA, Pless M, Habicht J, Roth AD, Spiliopoulos A, Stahel R, Weder W, Stupp R, Egli F, Furrer M, Honegger H, Wernli M, Cerny T, Ris HB (2003) Mediastinal lymph node clearance after docetaxel–cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial. J Clin Oncol 21: 1752–1759
    1. Bueno R, Richards WG, Swanson SJ, Jaklitsch MT, Lukanich JM, Mentzer SJ, Sugarbaker DJ (2000) Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 70: 1826–1831
    1. Burkes RL, Ginsberg RJ, Shepherd FA, Blackstein ME, Goldberg ME, Waters PF, Patterson GA, Todd T, Pearson FG, Cooper JD (1992) Induction chemotherapy with mitomycin, vindesine and cisplatin for stage III unresectable non-small-cell lung cancer: results of the Toronto Phase II Trial. J Clin Oncol 10: 580–586
    1. Burkes RL, Shepherd FA, Blackstein ME, Goldberg ME, Waters PF, Patterson GA, Todd T, Pearson FG, Jones D, Farooq S, McGlaughlin J, Ginsberg RJ (2005) 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 47: 103–109
    1. Choi NC, Carey RW, Daly W, Mathisen D, Wain J, Wright C, Lynch T, Grossbard M, Grillo H (1997) Potential impact on survival of improved tumour downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer. J Clin Oncol 15: 712–722
    1. Darwish S, Minotti V, Crino L, Rossetti R, Fiaschini P, Maranzano E, Checcaglini F, Todisco T, Giansanti M, Mercati U, Vitali R, Latini P, Tonat M (1995) A phase II trial of combined chemotherapy and surgery in stage IIIA non-small cell lung cancer. Lung Cancer 12(Suppl 1): S71–S78
    1. Depierre A, Milleron B, Moro-Sibilot D, Chevret S, Quoix E, Lebeau B, Braun D, Breton JL, Lemarie E, Gouva S, Paillot N, Brechot JM, Janicot H, Lebas FX, Terrioux P, Clavier J, Foucher P, Monchatre M, Coetmeur D, Level MC, Leclerc P, Blanchon F, Rodier JM, Thiberville L, Villeneuve A, Westeel V, Chastang C, the French Thoracic Cooperative Group (2002) 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 20: 247–253
    1. Dillman RO, Herndon J, Seagren SL, Eaton Jr WL, Green MR (1996) 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 88: 1210–1215
    1. Douillard J, Rosell R, Delena M, Legroumellec A, Torres A, Carpagnano F (2005) ANITA: Phase III adjuvant vinorelbine (N) and cisplatin (P) versus observation (OBS) in completely resected (stage I–III) non-small-cell lung cancer (NSCLC) patients (pts): final results after 70-month median follow-up. On behalf of the Adjuvant Navelbine International Trialist Association. J Clin Oncol 23(Suppl 16S): 624s (Abstr 7013)
    1. Eberhardt W, Wilke H, Stamatis G, Stuschke M, Harstrick A, Menker H, Krause B, Mueller MR, Stahl M, Flasshove M, Budach V, Greschuchna D, Konietzko N, Sack H, Seeber S (1998) Preoperative chemotherapy followed by concurrent chemoradiation therapy based on hyperfractionated accelerated radiotherapy and definitive surgery in locally advanced non-small-cell lung cancer: mature results of a phase II trial. J Clin Oncol 16: 622–634
    1. Elias A, Skarin A, Leong T, Mentzer S, Strauss G, Lynch T, Shulman L, Jacobs C, Abner A, Baldini EH, Frei III E, Sugarbaker DJ (1997) Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung. Lung Cancer 17: 147–161
    1. Johnstone DW, Byhardt RW, Ettinger D, Scott CB (2002) 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 54: 365–369
    1. Keller SM, Adak S, Wagner H, Herskovic A, Komaki R, Brooks BJ, Perry MC, Livingston RB, Johnson DH (2000) A randomized trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIA non-small-cell lung cancer. Eastern Cooperative Oncology Group. N Engl J Med 343: 1217–1222
    1. Le Chevalier T, Arriagada R, Quoix E, Ruffie P, Martin M, Tarayre M, Lacombe-Terrier MJ, Douillard JY, Laplanche A (1991) 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 83: 417–423
    1. Mamon HJ, Yeap BY, Janne PA, Reblando J, Shrager S, Jaklitsch MT, Mentzer S, Lukanich JM, Sugarbaker DJ, Baldini EH, Berman S, Skarin A, Bueno R (2005) High risk of brain metastases in surgically staged IIIA non-small-cell lung cancer patients treated with surgery, chemotherapy, and radiation. J Clin Oncol 23: 1530–1537
    1. Martini N, Kris MG, Flehinger BJ, Gralla RJ, Bains MS, Burt ME, Heelan R, McCormack PM, Pisters KM, Rigas JR (1993) Preoperative chemotherapy for stage IIIa (N2) lung cancer: the Sloan-Kettering experience with 136 patients. Ann Thorac Surg 55: 1365–1373; discussion 1373–1374
    1. Mountain CF, Dresler CM (1997) Regional lymph node classification for lung cancer staging. Chest 111: 1718–1723
    1. 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. Br Med J 311: 899–909
    1. Pass HI, Pogrebniak HW, Steinberg SM, Mulshine J, Minna J (1992) Randomized trial of neoadjuvant therapy for lung cancer: interim analysis. Ann Thorac Surg 53: 992–998
    1. Pisters K, Vallieres E, Bunn P, Crowley J, Ginsberg R, Ellis P, Meyers B, Marks R, Treat J, Gandara D (2005) S9900: A phase III trial of surgery alone or surgery plus preoperative (preop) paclitaxel/carboplatin (PC) chemotherapy in early stage non-small cell lung cancer (NSCLC): preliminary results. J Clin Oncol 23(Suppl 16S): 624s (Abstr LBA 7012)
    1. Robnett TJ, Machtay M, Stevenson JP, Algazy KM, Hahn SM (2001) Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma. J Clin Oncol 19: 1344–1349
    1. Rosell R, Gomez-Codina J, Camps C, Javier Sanchez J, Maestre J, Padilla J, Canto A, Abad A, Roig J (1999) Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial. Lung Cancer 26: 7–14
    1. Rosell R, Gomez-Codina J, Camps C, Maestre J, Padille J, Canto A, Mate JL, Li S, Roig J, Olazabal A, Canela M, Ariza A, Skacel Z, Morera-Prat J, Abad A (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
    1. Roth JA, Fossella F, Komaki R, Ryan MB, Putnam Jr JB, Lee JS, Dhingra H, De Caro L, Chasen M, McGavran M (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
    1. Sause WT, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, Emami B, Curran WJ, Byhardt RW, Turrisi AT (1995) 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 87: 198–205
    1. Strauss GM, Herndon J, Maddaus MA, Johnstone DW, Johnson EA, Watson DM, Sugarbaker DJ, Schilsky RL, Green MR (2004) Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer (NSCLC): report of Cancer and Leukemia Group B (CALGB) Protocol 9633. J Clin Oncol 22(Suppl 14): 621s A7019
    1. Van Meerbeeck JP, Kramer G, Van Schil PE, Legrand C, Smit EF, Schramel FM, Biesma B, Tjan-Heijnen VC, van Zandwijk N, Giaccone G, the EORTC-Lung Cancer Group (2005) A randomised trial of radical surgery (S) versus thoracic radiotherapy (TRT) in patients (pts) with stage IIIA-N2 non-small cell lung cancer (NSCLC) after response to induction chemotherapy (ICT) (EORTC 08941). J Clin Oncol 23(Suppl 16S): 624s (Abstr LBA 7015)
    1. Van Zandwijk N, Smit EF, Kramer GW, Schramel F, Gans S, Festen J, Termeer A, Schlosser NJ, Debruyne C, Curran D, Giaccone G (2000) Gemcitabine and cisplatin as induction regimen for patients with biopsy-proven stage IIIA N2 non-small-cell lung cancer: a phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group (EORTC 08955). J Clin Oncol 18: 2658–2664
    1. Winton TL, Livingston R, Johnson D, Rigas J, Cormier Y, Butts C, Ding K, Seymour L, Magoski N, Shepard F (2004) A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage IB and II non small cell lung cancer (NSCLC). J Clin Oncol 22(Suppl 14): 621s A7018

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