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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4736-4742 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.0014 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
From the Hospital Ramon y Cajal; Hospital San Carlos; Clinica Puerta de Hierro; Fundacion Jimenez Diaz; Autonomous University of Madrid, Madrid; Hospital Clinico, Valencia; Hospital Clinico; Hospital Miguel Servet, Zaragoza; Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona; Hospital Duran i Reynals, Catalan Institute of Oncology, Bellvitge; Hospital Cruces, Bilbao; and Hospital General, Alicante, Spain Address reprint requests to Rafael Rosell, MD, Chief, Medical Oncology Service, Scientific Director of Oncology Research, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916 Badalona (Barcelona), Spain; e-mail: rrosell{at}ico.scs.es
Purpose: To assess the activity of induction chemotherapy followed by surgery in stage IIIA and selected stage IIIB non–small-cell lung cancer patients. Patients and Methods: Mediastinoscopy proof of either positive N2 (IIIA) or T4N0-1 (IIIB) disease was required. Induction therapy was three cycles of cisplatin/gemcitabine/docetaxel, followed by surgery. Results: From December 1999 to March 2003, 136 patients were entered onto the study; the clinical response rate in 129 assessable patients was 56%. The overall complete resection rate was 68.9% of patients eligible for surgery (72% of stage IIIA patients and 66% of stage IIIB patients) and 48% of all assessable patients. Eight (12.9%) of 62 completely resected patients had a pathologic complete response. Seven patients (7.8%) died during the postoperative period. The median overall survival time was 15.9 months, 3-year survival rate was 36.8%, and 5-year survival rate was 21.1%, with no significant differences in survival between stage IIIA and stage IIIB patients. Median survival time was 48.5 months for 62 completely resected patients, 12.9 months for 13 incompletely resected patients, and 16.8 months for 15 nonresected patients (P = .005). Three- and 5-year survival rates were 60.1% and 41.4% for completely resected patients, 23.1% and 11.5% for incompletely resected patients, and 31.1% and 0% for nonresected patients, respectively. In the multivariate analysis, complete resection (hazard ratio [HR] = 0.35; P < .0001), clinical response (HR = 0.32; P < .0001), and age younger than 60 years (HR = 0.64; P = .027) were the most powerful prognostic factors. Conclusion: Induction chemotherapy followed by surgery is effective in stage IIIA and in selected stage IIIB patients attaining complete resection.
Complete resection plays a central role as a curative treatment for locally advanced (stage IIIA N2) non–small-cell lung cancer (NSCLC) after induction chemotherapy with or without preoperative radiotherapy.1-4 It is also crucial in selected subgroups of stage IIIB NSCLC patients,5-7 where the judgment and skill of the surgeon is of the utmost importance.8 A landmark study of induction chemotherapy in stage IIIA N2 NSCLC reported a 65% complete resection rate among 136 patients, with a median survival time of 27 months and 3- and 5-year survival rates of 41% and 26%, respectively, whereas for incompletely resected or nonresectable patients, median survival time was 12 months, and 3- and 5-year survival rates were 5% (P < .001).9 In a more recent study by the Leuven Lung Cancer Group of 131 stage IIIA N2 patients, the response rate was 54%, the median survival time was 24 months, and 5-year survival rate was 21%.10 The Cancer and Leukemia Group B 8935 study in stage IIIA N2 patients attained complete resection in 23 patients (36.5% of those undergoing thoracotomy); median survival time in these patients was 20.9 months, and 3-year survival rate was 46%.11 Recently, the European Organisation for Research and Treatment of Cancer (EORTC) 08941 randomized trial in stage IIIA N2 patients reported complete resection in 77 of 154 patients in the surgery arm, with a median survival time of 24.1 months and a 5-year survival rate of 27%, whereas the median survival time for incompletely resected patients was 12.1 months, with a 5-year survival rate of 7% (P < .01).12 In addition to complete resection, downstaging of N2 disease has been shown to be a good predictor of longer survival.8 In both the Southwest Oncology Group (SWOG) 8805 trial13 and the Spanish Lung Cancer Group trial,14 median survival time was 13 months, but it increased to 30 months when mediastinal lymph nodes were downgraded. In the subgroup of stage IIIB patients included in the SWOG 8805 study, median survival time was 17 months, with better survival results in T4N0-1 patients, who attained a 6-year survival rate of 49%.13 However, in a second consecutive SWOG study using the same induction chemotherapy regimen with concurrent radiotherapy completed to 61 Gy in the absence of progressive disease but no surgery, 5-year survival rate for T4N0-1 patients was only 17%.15 In a German study of stage IIIB patients, 48% attained complete resection, with a 5-year survival rate of 43%.7 To evaluate the curative role of surgery when complete resection is attained, especially in the absence of mediastinal lymph node metastases, the Spanish Lung Cancer Group performed a phase II trial of induction chemotherapy with a cisplatin-based triplet followed by surgery for stage IIIA N2 and selected stage IIIB (T4N0-1) NSCLC patients. In a complementary prospective analysis, single nucleotide polymorphisms were assessed and correlated with clinical outcome (reported separately).
Eligibility Criteria Patients were eligible if they had untreated, newly diagnosed resectable stage IIIA (T1-3N2) NSCLC with mediastinoscopy proof of positive N2 nodes or selected stage IIIB (T4N0-1) NSCLC. Stage IIIB disease was defined by invasion of mediastinal structures (including recurrent laryngeal nerve palsy), heart, great vessels, trachea, carina, esophagus, or vertebral body or by presence of ipsilateral satellite pulmonary nodules in the same lobe. Prestudy consultations by an attending radiation oncologist, thoracic surgeon, medical oncologist, and pulmonologist were required. The trial was approved by the institutional review board of each institution, and all patients gave their written informed consent.
Pretreatment Evaluation
Study Design and Treatment Plan A resection was considered to be complete if, after review of the surgery and pathology report, both surgical margins and the highest mediastinal lymph node were found to be free of tumor. Patients with complete resection and no lymph node involvement did not receive any additional treatment. Nonresectable or incompletely resected patients received docetaxel 20 mg/m2/wk concurrent with thoracic irradiation (60 Gy). Patients with N2 disease (pN2) received two adjuvant cycles of the induction chemotherapy regimen.
Statistical Analyses
Patient Characteristics Patient accrual was initiated in December 1999 and completed in March 2003. One hundred thirty-six patients were accrued in 19 Spanish centers. Patient characteristics are listed in Table 1. Sixty-nine patients (50.7%) were stage IIIA N2; six (4.4%) were T1N2, 41 (30.1%) were T2N2, and 22 (16.2%) were T3N2. Sixty-seven patients (49.3%) were stage IIIB T4N0-1; 57 (41.9%) were T4N0, and 10 (7.4%) were T4N1. The tumor infiltrated great vessels in 34 patients (50.7%), trachea in two patients (3.0%), carina in six patients (9.0%), esophagus in two patients (3.0%), heart in four patients (4.5%), mediastinum in 22 patients (32.8%), vertebral body in one patient (1.5%), and more than one structure in eight patients (12%). Five patients (7.5%) had a satellite nodule in the same lobe.
Induction Chemotherapy All 136 patients received at least one chemotherapy dose, and 124 completed three cycles. Seven patients were withdrawn from the study early, six patients as a result of toxicity (one myocardial infarction 48 hours after the first chemotherapy dose, one angina pectoris after the first dose of the second cycle of chemotherapy, two mesenteric ischemia, one grade 3 hepatic toxicity, and one abrupt decline in performance status) and one patient as a result of early death from unknown causes (Fig 1). Thus, 129 patients were assessable for response. The overall response rate was 56% (95% CI, 47.2% to 64.4%), including four patients with complete responses, 68 with partial responses, 36 with stable disease, and 21 with progressive disease.
Dose-Intensity Three hundred ninety-one cycles were administered; 124 patients received three cycles, seven patients received two cycles, and five patients received one cycle. The median dose-intensity per week was 25 mg/m2/wk (98%) for cisplatin, 634 mg/m2/wk (95%) for gemcitabine, and 17 mg/m2/wk (85%) for docetaxel. Fifty-seven cycles were delayed in 46 patients, 31 as a result of hematologic toxicity. Docetaxel dose was reduced in 59 patients (40.7%), gemcitabine was reduced in 17 patients (12.5%), and cisplatin was reduced in seven patients (5.1%). Dose omission of docetaxel, gemcitabine, and cisplatin was required in 74 patients (54.4%), 15 patients (11%), and one patient (0.7%), respectively. The principal reason for dose modification of docetaxel was hematologic toxicity on day 15.
Toxicities
Thoracotomy Registration
The median number of lymph nodes resected was nine (range, one to 29 nodes). The median number of positive lymph nodes was zero (range, zero to nine nodes). Eight patients (one stage IIIA N2 and seven T4N0-1 patients) had pathologic complete response. Nine (27.3%) of 33 completely resected stage IIIA patients had N0 disease (Table 2). Two patients were upgraded to N3. Four stage IIIB patients who were originally N0-1 were upgraded to N2 disease.
Surgical Morbidity and Mortality
Postoperative Treatment
Survival
Median survival time was 48.5 months (95% CI, 36.5 to 60.3 months) for 62 completely resected patients, 12.9 months (95% CI, 0 to 31.7 months) for 13 incompletely resected patients, and 16.8 months (95% CI, 2.5 to 31.2 months) for 15 nonresected patients (P = .005; Fig 3A). Three- and 5-year survival rates were 60.1% and 41.4% for completely resected patients, 23.1% and 11.5% for incompletely resected patients, and 31.1% and 0% for nonresected patients, respectively. For 33 completely resected stage IIIA patients, median survival time was 36.9 months (95% CI, 9.3 to 64.6 months; Fig 3B), 3-year survival rate was 50.2%, and 5-year survival rate was 31.6%. For 29 completely resected stage IIIB patients, median survival time was 60.6 months (95% CI, 38 to 83.2 months; Fig 3B), 3-year survival rate was 71.4%, and 5-year survival rate was 53.2%.
Median survival time was not reached in 35 patients with pN0, whereas it was 22.9 months (95% CI, 11.1 to 34.6 months) in 55 pN1-3 patients and 7.3 months (95% CI, 6 to 8.7 months) in 46 patients who did not undergo surgery (P < .0001; Fig 3C). Three- and 5-year survival rates were 67.7% and 51.6% for pN0 patients, 38.5% and 17.6% for pN1-3 patients, and 11.3% and 0% for nonresected patients, respectively. For eight completely resected stage IIIA patients with pN0, median survival time was 26.1 months (95% CI, 0 to 78.6 months; Fig 3D), 3-year survival rate was 50%, and 5-year survival rate was 37.5%. For 27 completely resected stage IIIB patients with pN0, median survival time was not reached (Fig 3D), 3-year survival rate was 73.1%, and 5-year survival rate was 57%. With a median follow-up time of 53.5 months, median survival time for eight patients with complete pathologic response has not been reached. When patients were grouped according to clinical response, for those attaining complete or partial response, median survival time was 47.6 months (95% CI, 30.8 to 64.4 months), 3-year survival rate was 56.9%, and 5-year survival rate was 33%. For nonresponders, median survival time was 8 months (95% CI, 5 to 10.9 months), 3-year survival rate was 14.3%, and 5-year survival rate was 8% (Appendix Fig A1, online only). There were no differences in survival according to surgical procedure. For 33 patients undergoing lobectomy, median survival time was 36.9 months (95% CI, 18.7 to 55.1 months), 3-year survival rate was 52.7%, and 5-year survival rate was 36.1%. For 37 patients undergoing pneumonectomy, median survival time was 40.4 months (95% CI, 7.1 to 73.8 months), 3-year survival rate was 51.4%, and 5-year survival rate was 34% (P = .665; Appendix Fig A2, online only). Among the 37 patients undergoing pneumonectomy, survival was significantly better in stage IIIB patients than in stage IIIA patients. Median survival time was not reached for 19 stage IIIB patients, whereas it was 14.8 months (95% CI, 1.5 to 28 months) for 18 stage IIIA patients (P = .013; Appendix Fig A3, online only). Results of the multivariate analysis for survival showed that complete resection (hazard ratio [HR] = 0.35; P < .0001), clinical response (HR = 0.32; P < .0001), and age younger than 60 years (HR = 0.64; P = .027) were the most powerful prognostic factors.
Despite the fact that complete resection has been identified as an independent prognostic marker for survival in NSCLC,16 not many studies have been carried out in patients with stage IIIB T4N0-1. In the present study, completely resected stage IIIA and IIIB patients (68.9% of those eligible for surgery) had an impressive median survival time of 48.5 months, with a 5-year survival rate of 41.4%. For completely resected stage IIIB patients, median survival time was 60.6 months, and 5-year survival rate was 53.2%. In the absence of mediastinal lymph nodes, median survival time for these patients was not reached, and 5-year survival rate was 57%. Other investigators have reported a benefit for complete resection in stage IIIB patients, with a 5-year survival rate of 42% for patients who were N0-1 after induction chemoradiotherapy.17 Similar rates of survival were observed in 50 completely resected stage IIIA and IIIB patients after induction chemoradiotherapy, with a median survival time of 42 months and a 3-year survival rate of 46%.18 Other studies of preoperative chemoradiotherapy in stage IIIB patients have reported similar 5-year survival rates of 43%7 and 56%.19 Little emphasis has been placed on the fact that clinical response to induction chemotherapy, followed by surgery, could influence survival. In stage IIIA patients, a median survival time of 21 months and a 5-year survival rate of 19% were attained in responders compared with 12 months and 7%, respectively, in nonresponders.9 In the present study, median survival time for responders was 47.6 months, and 5-year survival rate was 33% compared with 8 months and 8%, respectively, for nonresponders. Other investigators have shown that chemotherapy activity, including clinical response and mediastinal downstaging, is associated with longer survival in resected patients.20 Studies using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography have shown that significant reduction of standardized uptake values after neoadjuvant chemotherapy significantly predicts survival.21,22 In the present study, downstaging in stage IIIA patients significantly predicted survival, as has been previously documented.11-13,16,20,23,24 Age was also identified as a prognostic marker of survival in our study, as has been found in other studies.16 Pneumonectomy has been reported to have a significant negative influence on survival,12,16 mainly in stage IIIA disease, where one study20 identified only right pneumonectomy as a poor prognostic factor. Other studies,6,7,13,17-19 including both stage IIIA and IIIB or only stage IIIB patients, have not reported an association between pneumonectomy and survival. In our study, surgical procedure had no effect on overall survival, although the mortality rate of patients with right pneumonectomy was high (30%, six of 20 patients). This is similar to the rate reported in other series; for example, the mortality rate for this subgroup of patients in the North American Intergroup Trial 0139 was 38% (11 of 29 patients).25 Complete resection has also been identified as a determinant of longer survival.9 However, neither the North American Intergroup Trial 013925 nor the EORTC 08941 study12 reported a benefit for surgery in patients with N2 disease treated with induction chemoradiotherapy25 or chemotherapy.12 In the EORTC 08941 study,12 median survival time in the surgery arm was 16.4 months, although it increased to 25 months in patients undergoing lobectomy and to 24 months in patients attaining complete resection. The EORTC 08941 study12 used several different neoadjuvant chemotherapy combinations, mainly platinum/gemcitabine and platinum/taxanes, with an overall response rate of 61%.12 However, the response rate for patients treated with cisplatin/docetaxel was 45%,12,26 which was lower than the 66% previously reported by the Swiss Group for Clinical Cancer Research.24 An Italian trial27 in 42 stage IIIA and IIIB patients used gemcitabine/cisplatin/paclitaxel as induction chemotherapy and attained a clinical response of 71% and complete resection in 16 patients (38%). Our study confirms previous findings of induction chemotherapy trials in stage IIIA and IIIB NSCLC and highlights the relevance of surgery in the specific subset of stage IIIB patients without mediastinal involvement, for whom clinical response and complete resection are crucial to long-term survival.
The author(s) indicated no potential conflicts of interest.
Conception and design: Pilar Garrido, Rafael Rosell Provision of study materials or patients: Pilar Garrido, José Luis González-Larriba, Amelia Insa, Mariano Provencio, Antonio Torres, Dolores Isla, José Miguel Sanchez, Felipe Cardenal, Manuel Domine, Jose Ramon Barcelo, Vicente Tarrazona, Andres Varela, Rafael Aguilo, Julio Astudillo, Ignacio Muguruza, Angel Artal, Florentino Hernando-Trancho, Bartomeu Massuti Collection and assembly of data: Pilar Garrido, José Luis González-Larriba, Amelia Insa, Mariano Provencio, Antonio Torres, Dolores Isla, José Miguel Sanchez, Felipe Cardenal, Manuel Domine, Jose Ramon Barcelo, Vicente Tarrazona, Andres Varela, Rafael Aguilo, Julio Astudillo, Ignacio Muguruza, Angel Artal, Florentino Hernando-Trancho, Bartomeu Massuti Data analysis and interpretation: Pilar Garrido, Antonio Torres, Maria Sanchez-Ronco, Rafael Rosell Manuscript writing: Pilar Garrido, Rafael Rosell Final approval of manuscript: Pilar Garrido, José Luis González-Larriba, Amelia Insa, Antonio Torres, Dolores Isla, José Miguel Sanchez, Felipe Cardenal, Manuel Domine, Jose Ramon Barcelo, Vicente Tarrazona, Andres Varela, Rafael Aguilo, Julio Astudillo, Ignacio Muguruza, Angel Artal, Florentino Hernando-Trancho, Bartomeu Massuti, Maria Sanchez-Ronco, Rafael Rosell
Eligibility Criteria Further eligibility criteria included Karnofsky performance score  70; age 18 years; a predicted postoperative forced expiratory volume in 1 second greater than 1 L/sec; adequate cardiac and bone marrow (absolute neutrophil count 1,500/µL, platelets 100 x 10/L, and hemoglobin 10 g/dL), hepatic (bilirubin within normal limits, AST and ALT  1.5x upper limit of normal), and kidney (creatinine clearance 65 mL/min) function; and no other concurrent or previous malignancy. Patients were ineligible if they had experienced cardiac infarction or unstable angina pectoris within 6 months before study entry or class III or greater cardiac disability according to New York Heart Association criteria.
Study Design and Treatment Plan Dexamethasone (8 mg) was administered orally 12 hours before and after chemotherapy and intravenously 30 minutes before each docetaxel infusion. Serotonin antagonists were also administered.
We thank the other investigators who participated in this trial: Juan Lago (Hospital Ramon y Cajal, Madrid, Spain); Luis Madrigal (Clinica Puerta de Hierro, Madrid, Spain); Jose Zapatero (Fundacion Jimenez Diaz, Madrid, Spain); Juan Jose Rivas (Hospital Miguel Servet, Zaragoza, Spain); Joaquin Pac, Juan Casanova (Hospital Cruces, Bilbao, Spain); Josefa Terrasa, Montero (Hospital Son Dureta, Palma de Mallorca, Spain); Manuel Rodriguez-Paniagua (Hospital General, Alicante, Spain); Marta Lopez-Brea, Roberto Mons, Miguel Carbajo (Hospital Marques de Valdecilla, Santander, Spain); Carlos Camps, Antonio Canto, Arnau (Hospital General, Valencia, Spain); Remei Blanco, Santiago Alvarez (Consorcio Hospitalario de Terrassa); Francisca Vazquez-Rivera (Hospital Arquitecto Marcide, Ferrol, Spain); Pedro Menendez-Fernandez, Javier Gomez-Castaño (Hospital Gomez Ulla, Madrid, Spain); Pedro Lopez de Castro, Ignacio Escobar, Teresa Moran (Hospital Germans Trias i Pujol, Catalan Institute of Oncology, Badalona, Spain). We also thank Peter Goldstraw (Royal Brompton Hospital, London, United Kingdom) and Tatsuro Okamoto (National Kyushu Cancer Center, Fukuoka, Japan) for their comments on earlier versions of the manuscript, Juan Luis Sanz (Biometrica, Madrid, Spain) for data collection and statistical analyses, Prof Jose Javier Sanchez (Autonomous University of Madrid) for his advice on the statistical analyses, Renée O'Brate for writing and editorial support, and Lourdes Franquet for technical assistance.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Eberhardt W, Wilke H, Stamatis G, et al: 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, 1998[Abstract] 19. Ichinose Y, Fukuyama Y, Asoh H, et al: Induction chemoradiotherapy and surgical resection for selected stage IIIB non-small-cell lung cancer. Ann Thorac Surg 76:1810-1814, 2003 20. Betticher DC, Hsu Schmitz SF, Totsch M, 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 94:1099-1106, 2006[CrossRef][Medline] 21. Hoekstra CJ, Stroobants SG, Smit EF, et al: Prognostic relevance of response evaluation using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with locally advanced non-small-cell lung cancer. 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Albain KS, Swann RS, Rusch V, et al: 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 23:624s, 2005 (suppl; abstr 7014) 26. Biesma B, Manegold C, Smit HJ, et al: Docetaxel and cisplatin as induction chemotherapy in patients with pathologically-proven stage IIIA N2 non-small cell lung cancer: A phase II study of the European Organization for Research and Treatment of Cancer (EORTC 08984). Eur J Cancer 42:1399-1406, 2006[CrossRef][Medline] 27. Cappuzzo F, De Marinis F, Nelli F, et al: Phase II study of gemcitabine-cisplatin-paclitaxel triplet as induction chemotherapy in inoperable, locally-advanced non-small cell lung cancer. Lung Cancer 42:355-361, 2003[CrossRef][Medline] Submitted April 2, 2007; accepted June 28, 2007. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
