Journal of the National Cancer Institute Advance Access originally published online on July 24, 2007
JNCI Journal of the National Cancer Institute 2007 99(15):1210-1211; doi:10.1093/jnci/djm052
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© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Response: Re: Randomized Controlled Trial of Resection Versus Radiotherapy After Induction Chemotherapy in Stage IIIA-N2 Non–Small-Cell Lung Cancer
Affiliations of authors: Department of Thoracic and Vascular Surgery, University Hospital of Antwerp, Antwerp, Belgium (PVS); Department of Pulmonary Medicine, University Hospital of Ghent, Gent, Belgium (JVM)
Correspondence to: J. Van Meerbeeck, MD, PhD, Department of Pulmonary Medicine, University Hospital of Ghent, De Pintelaan 185, B-9000 Gent, Belgium (e-mail: jan.vanmeerbeeck{at}ugent.be).
We would first like to thank the authors for their nice comments about our European Organisation for Research and Treatment of Cancer (EORTC) 08941 trial.
Regarding their first remark, the purpose of the EORTC 08941 study was to explore whether patients with proven, initially considered unresectable stage IIIA-N2 non–small-cell lung cancer (NSCLC) who responded to induction chemotherapy had a better prognosis after surgical resection than with radiotherapy. Unresectability was determined by the local oncologic team, including the thoracic surgeon, but guidelines were provided as clearly indicated in the manuscript. The authors state that bulky N2 disease should be separated from limited N2 disease, but no uniform guidelines exist on the precise definition of subcategories of N2 disease—not in 1994 when the study was initiated and not now in 2007. The authors mention two extremes, but there is a large gray zone of N2 involvement in between. We were not especially interested in subdivisions of N2 disease but rather in the rate of downstaging to N0 or N1 disease that could be obtained by induction chemotherapy in patients with N2 involvement and in whom surgery was not indicated as primary treatment. As has been shown in other studies, downstaging of mediastinal lymph nodes represents the most important prognostic marker of NSCLC (1). Unfortunately, 56% of patients in the surgical arm had persisting N2 disease after induction chemotherapy and these patients were not good candidates for additional surgery due to their overall poor prognosis. Moreover, in patients with persisting N2 disease, a complete resection is rarely obtained because the highest mediastinal lymph node will often show residual disease.
Concerning the second remark, many series have reported 5-year survival rates that range from 6% to 35% after surgery (2). These series suggest that preoperative detection of N2 disease, involvement of multiple lymph node levels, subcarinal involvement, and an adenocarcinoma subtype are associated with a worse prognosis. The small number of patients included in these studies and the differences in inclusion criteria clearly account for the heterogeneity of these results and for the confusion concerning the prognosis of N2 patients. In 1994, when this trial was conceived, 25% 5-year survival was thought to accurately reflect the current expectations of surgeons. Therefore, this figure was chosen as an acceptable and clinically significant increase from the baseline of 15% in radiotherapy patients to calculate sample size and power for a randomized trial.
Regarding the quality of surgery in our EORTC trial, mortality and morbidity were within the expected range, and although it was a multicenter, international study, results were equivalent to those reported by expert centers (3). In 1994, when this study was initiated, there were no established guidelines for hilar and mediastinal systemic nodal dissection, as defined by Peter Goldstraw in 1999 (4). In contrast to the statement of Leo et al., surgical results were closely monitored and followed up. Operative and pathology reports and morbidity and mortality data were prospectively collected in this study. Specific categories of complications were well defined on the forms that were provided to the investigators. Also, a strict definition of complete resection was used, as indicated in the manuscript.
Although the rate of pneumonectomies was high, no excessive mortality or morbidity was encountered during the interim analyses. Because we were especially concerned about the quality of surgery, the surgical results of this study were published first (3).
As is often the case when the results of large randomized studies become available, our manuscript raises more questions than it answers. However, we learned much about restaging and surgery for locally advanced NSCLC with N2 involvement. Chest computed tomography is not accurate to adequately determine response after induction therapy; so, we should focus on pathologic restaging by repeat mediastinoscopy or endoscopic esophageal or endobronchial ultrasound (5). Not surprisingly, surgery can be considered in patients with proven mediastinal downstaging only when a lobectomy or sleeve resection can be performed. Persisting N2 disease heralds a poor prognosis, and a right pneumonectomy is associated with a high mortality rate, especially when chemoradiotherapy is given as induction therapy (6,7).
Whether surgery is superior to radiotherapy for local control in patients with proven downstaging of NSCLC N2 disease remains to be proven in subsequent randomized trials. As in our EORTC 08941 study, the quality of surgery will indeed be a critical issue!
REFERENCES
(1) Betticher DC, Hsu Schmitz SF, Totsch 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.[CrossRef][ISI][Medline]
(2) Vansteenkiste JF, De Leyn PR, Deneffe GJ, Lerut TE, Demedts MG. Clinical prognostic factors in surgically treated stage IIIAN2 non small cell lung cancer: analysis of the literature. Lung Cancer (1998) 19:3–13.[CrossRef][ISI][Medline]
(3) Van Schil P, Van Meerbeeck JP, Kramer G, Splinter T, Legrand C, Giaccone G, et al. Morbidity and mortality in the surgery arm of EORTC 08941 trial. Eur Respir J (2005) 26:192–7.
(4) Graham AN, Chan KJ, Pastorino U, Goldstraw P. Systematic nodal dissection in the intrathoracic staging of patients with non-small cell lung cancer. J Thorac Cardiovasc Surg (1999) 117:246–51.
(5) Van Schil P, De Waele M, Hendriks J, Lauwers P. Remediastinoscopy. J Thorac Oncol (2007) 2:365–6.[Medline]
(6) Albain KS, Swann RS, Rusch VR, Turrisi AT, Shepherd FA, Smith CJ, et al. Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA-N2(pN2) non-small cell lung cancer (NSCLC): outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol (2005) 23:624s.
(7) Rusch V, Albain K, Turrisi A, Swann R, Shepherd F, Chen Y, et al. Phase III trial of concurrent chemotherapy and radiotherapy (CT/RT) versus CT/RT followed by surgical resection for stage IIIA-N2 non-small cell lung cancer: outcomes and implications for surgical management in North American Intergroup 0139 (RTOG 9309). Lung Cancer (2005) 49:S15.
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J Natl Cancer Inst 2007 99: 1210.
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