Comment on “Treatment of Non-small Cell Lung Cancer Stage IIIA: ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)”: Response

Abstract

To the Editor: We are responding to the concerns raised by Rice and colleagues regarding the Lung Cancer Guidelines1Robinson LA Ruckdeschel JC Wagner Jr, H et al.Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines, 2nd edition.Chest. 2007; 132: 243S-265SAbstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar related to the treatment for patients with potentially resectable stage IIIA lung cancer, in which N2 nodal metastases were histologically proven prior to surgery, our stage IIIA3. Our recommendations were based primarily on the randomized trials listed in Table 6.1Robinson LA Ruckdeschel JC Wagner Jr, H et al.Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines, 2nd edition.Chest. 2007; 132: 243S-265SAbstract Full Text Full Text PDF PubMed Scopus (344) Google Scholar The two largest and most recent multicenter trials2van Meerbeeck JP Kramer GWPM Van Schil PEY et al.Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer (EORTC 08941).J Natl Cancer Inst. 2007; 99: 442-450Crossref PubMed Scopus (600) Google Scholar, 3Albain KS Swann RS Rusch VR et al.Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (pN20 non-small cell lung cancer: outcomes update of North American Intergroup 0139 (RTOG 9309).J Clin Oncol. 2005; 23 (abstract 7014)Google Scholar provided the most convincing data. In the European Organisation for Research and Treatment of Cancer (EORTC) 08941 trial,2van Meerbeeck JP Kramer GWPM Van Schil PEY et al.Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer (EORTC 08941).J Natl Cancer Inst. 2007; 99: 442-450Crossref PubMed Scopus (600) Google Scholar patients with histologically proven stage IIIA-N2 non-small cell lung cancer were administered induction chemotherapy. Only responders were randomized to either surgical resection with or without postoperative radiotherapy vs sequential radiotherapy without surgery. Rice et al note the fact that this trial accrued patients with “unresectable N2 disease” and question whether results would be applicable to patients with resectable stage IIIA. In the “Methods” section of their publication,2van Meerbeeck JP Kramer GWPM Van Schil PEY et al.Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer (EORTC 08941).J Natl Cancer Inst. 2007; 99: 442-450Crossref PubMed Scopus (600) Google Scholar the EORTC definition of “unresectable” was as follows: “(1) any N2 involvement by a nonsquamous carcinoma; (2) in the case of squamous cell carcinoma any N2 involvement exceeding level 4R in a right-sided tumor and level 5 and 6 for a left sided-tumor.” Essentially the EORTC considered unresectable all stage IIIA-N2 patients with single or multistation N2 metastases, which is exactly the focus of the stage IIIA chapter. The progression-free survival and the overall survival of the chemotherapy/surgery and chemoradiotherapy groups were not statistically different. The conclusion of the EORTC was “in view of its low morbidity and mortality, radiotherapy should be considered the preferred locoregional treatment for these [Stage IIIA-N2] patients.”2van Meerbeeck JP Kramer GWPM Van Schil PEY et al.Randomized controlled trial of resection versus radiotherapy after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer (EORTC 08941).J Natl Cancer Inst. 2007; 99: 442-450Crossref PubMed Scopus (600) Google Scholar The other large randomized, multicenter trial3Albain KS Swann RS Rusch VR et al.Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (pN20 non-small cell lung cancer: outcomes update of North American Intergroup 0139 (RTOG 9309).J Clin Oncol. 2005; 23 (abstract 7014)Google Scholar was Intergroup 0139, in which stage IIIA-N2 patients received induction chemoradiotherapy. Responders were randomized to surgical resection followed by chemotherapy vs completion of radiotherapy plus more chemotherapy. In this trial,3Albain KS Swann RS Rusch VR et al.Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (pN20 non-small cell lung cancer: outcomes update of North American Intergroup 0139 (RTOG 9309).J Clin Oncol. 2005; 23 (abstract 7014)Google Scholar the 30-day operative mortality was high overall at 7.9% and especially elevated in pneumonectomy patients (25.9%). Although the progression-free survival favored the surgical arm (median survival, 12.8 months in the surgical arm vs 10.5 months in the chemoradiotherapy arm, p = 0.017), overall survival rates at 2 years and 5 years were not significantly different in the two treatment groups. Unfortunately, full data from this study have not been published, so we are unable comment on questions raised about any post hoc subgroup analysis. Of the earlier two small induction therapy studies in Table 6, the trial by Taylor et al4Taylor NA Liao ZX Cox JD 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 resection.Int J Radiat Oncol Biol Phys. 2004; 58: 204-212Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar was indeed retrospective and was included in error. The final study was the earlier, small Radiation Therapy Oncology Group 89-01, a randomized phase III trial5Johnstone DW Byhardt RW Ettinger D et al.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.Intern J Radiat Oncol Biol Phys. 2002; 54: 365-369Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar of stage IIIA patients with histologically proven N2 disease. After induction chemotherapy, patients were randomized to surgery vs sequential radiotherapy followed by additional chemotherapy. There was no significant difference between the two treatment groups in progression-free survival or overall survival. Unfortunately, this study closed prematurely due to poor patient accrual, making the results inconclusive. Intuitively, surgical resection of the cancer seems ideal, particularly to thoracic surgeons (including one of the authors, L.A.R.). The occasional patient with complete N2 node clearing from induction chemotherapy (occurring in perhaps 20% of patients) may truly benefit from surgical resection, although it is likely concurrent radiotherapy in this subgroup would have an equally effective role. This may be the reason that the randomized trials show no superior survival benefit with surgery. After an exhaustive discussion of this controversial subset of stage IIIA reviewing primarily the two large randomized induction therapy trials,3Albain KS Swann RS Rusch VR et al.Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA (pN20 non-small cell lung cancer: outcomes update of North American Intergroup 0139 (RTOG 9309).J Clin Oncol. 2005; 23 (abstract 7014)Google Scholar, 4Taylor NA Liao ZX Cox JD 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 resection.Int J Radiat Oncol Biol Phys. 2004; 58: 204-212Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar the Lung Cancer Guidelines Panel concluded that employing surgery for locoregional control did not provide a superior survival advantage. Therefore, the less morbid modality of radiotherapy added to chemotherapy delivered concurrently, when possible, is the preferred treatment regimen for stage IIIA.