An article published online first and in an upcoming edition of The Lancet concludes that radiotherapy plus chemotherapy, with or without surgery, are both treatment options for patients with stage IIIA (N2) non-small-cell lung cancer. The article is written by Dr Kathy Albain, Loyola University Chicago Stritch School of Medicine, Cardinal Bernardin Cancer Center, Maywood, Illinois, USA, and colleagues.

Non-small-cell lung cancer makes up some 80 percent of lung cancers, and its most common cause is long-term exposure to tobacco smoke. Of all cases of non-small-cell lung cancer, the disease is locally advanced in the chest only in about 30 percent (stage IIIA), where front-line surgery cannot cure the disease because it has already spread to lymph nodes in the centre of the chest (N2). In this phase III randomised controlled trial, the authors compared concurrent chemotherapy and radiotherapy followed by surgery with standard concurrent chemotherapy and radiotherapy without surgery, the current standard for this group patients.

Patients with stage IIIA (N2) non-small-cell lung cancer were randomly assigned to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m² on days 1, 8, 29, and 36] and etoposide [50 mg/m² on days 1–5 and 29–33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent surgery and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS).

202 patients (median age 59 years, range 31–77) were assigned to group 1 and 194 (61 years, 32–78) to group 2. Median OS was 23•6 months in group 1 versus 22•2 months in group 2 (a non-statistically significant difference). Number of patients alive at 5 years was 37 in group 1 and 24 in group 2. Progression free survival (PFS) seemed better in group 1 than in group 2, median 12•8 months versus 10•5 months; the number of patients without disease progression at 5 years was 32 (group 1) versus 13 (group 2). Lower white blood cell counts (neutropenia) and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38 percent] and 20 [10 percent], respectively) and group 2 (80 [41 percent] and 44 [23 percent], respectively). In group 1, 16 (8 percent) deaths were treatment related versus 4 (2 percent) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy.

The authors suggest the reason for an absence of effect of surgery could be inadequate power in the trial or reduced delivery of later chemotherapy (cycles 3 and 4) in the surgery group. However they say the mostly likely reason could be increased mortality following pneumonectomy, mainly due to acute respiratory distress syndrome and other respiratory causes. The authors conclude: "Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA (N2) non-small-cell lung cancer... medically healthy patients with stage IIIA (N2) non-small-cell lung cancer should be assessed by a team skilled in multimodality treatment, and treatment options can be considered during assessment. On the basis of the findings of our study, patients should be counselled about the risks and potential benefits of definitive chemotherapy plus radiotherapy with and without a surgical resection (preferably by lobectomy)."

In an accompanying comment, Dr Wilfried E E Eberhardt, West German Tumour Centre, University Hospital Essen of the University Duisburg-Essen, Essen, Germany, and colleagues say: "Can we undertake surgery in patients with stage IIIA (N2) NSCLC after induction chemoradiotherapy from now on? Yes, we can—selectively in patients with less extensive resection (eg, lobectomy) than pneumonectomy."

Article: "Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial." Kathy S Albain, R Suzanne Swann, Valerie W Rusch, Andrew T Turrisi III, Frances A Shepherd, Colum Smith, Yuhchyau Chen, Robert B Livingston, Richard H Feins, David R Gandara, Willard A Fry, Gail Darling, David H Johnson, Mark R Green, Robert C Miller, Joanne Ley, Willliam T Sause, James D Cox, The Lancet; Published Online July 27, 2009 (DOI:10.1016/S0140-6736(09)60737-6)