Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial.
BACKGROUND
One of the standard options in the treatment of stage IIIA/N2 non-small-cell lung cancer is neoadjuvant chemotherapy and surgery. We did a randomised trial to investigate whether the addition of neoadjuvant radiotherapy improves outcomes.


METHODS
We enrolled patients in 23 centres in Switzerland, Germany and Serbia. Eligible patients had pathologically proven, stage IIIA/N2 non-small-cell lung cancer and were randomly assigned to treatment groups in a 1:1 ratio. Those in the chemoradiotherapy group received three cycles of neoadjuvant chemotherapy (100 mg/m(2) cisplatin and 85 mg/m(2) docetaxel) followed by radiotherapy with 44 Gy in 22 fractions over 3 weeks, and those in the control group received neoadjuvant chemotherapy alone. All patients were scheduled to undergo surgery. Randomisation was stratified by centre, mediastinal bulk (less than 5 cm vs 5 cm or more), and weight loss (5% or more vs less than 5% in the previous 6 months). The primary endpoint was event-free survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00030771.


RESULTS
From 2001 to 2012, 232 patients were enrolled, of whom 117 were allocated to the chemoradiotherapy group and 115 to the chemotherapy group. Median event-free survival was similar in the two groups at 12·8 months (95% CI 9·7-22·9) in the chemoradiotherapy group and 11·6 months (8·4-15·2) in the chemotherapy group (p=0·67). Median overall survival was 37·1 months (95% CI 22·6-50·0) with radiotherapy, compared with 26·2 months (19·9-52·1) in the control group. Chemotherapy-related toxic effects were reported in most patients, but 91% of patients completed three cycles of chemotherapy. Radiotherapy-induced grade 3 dysphagia was seen in seven (7%) patients. Three patients died in the control group within 30 days after surgery.


CONCLUSIONS
Radiotherapy did not add any benefit to induction chemotherapy followed by surgery. We suggest that one definitive local treatment modality combined with neoadjuvant chemotherapy is adequate to treat resectable stage IIIA/N2 non-small-cell lung cancer.


BACKGROUND
Swiss State Secretariat for Education, Research and Innovation (SERI), Swiss Cancer League, and Sanofi.
Department of Medical Oncology, Kantonsspital Winterthur, Winterthur, Switzerland. Electronic address: miklos.pless@ksw.ch.
Miklos
M
Pless
Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland; Department of Oncology and Cancer Centre, University Hospital Zurich, Zurich Switzerland.
Roger
R
Stupp
Department of Thoracic Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland.
Hans-Beat
HB
Ris
Department of Medical Oncology, University Hospital Zurich, Zurich Switzerland.
Rolf A
RA
Stahel
Department of Thoracic Surgery, University Hospital Zurich, Zurich Switzerland.
Walter
W
Weder
SAKK Coordinating Centre, Bern, Switzerland.
Sandra
S
Thierstein
SAKK Coordinating Centre, Bern, Switzerland.
Marie-Aline
MA
Gerard
SAKK Department of Statistics, Bern, Switzerland.
Alexandros
A
Xyrafas
Department of Medical Oncology, Kantonsspital St Gallen, St Gallen, Switzerland.
Martin
M
Früh
Department of Medical Oncology, Kantonsspital Graubünden, Chur, Switzerland.
Richard
R
Cathomas
Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.
Alfred
A
Zippelius
Department of Medical Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
Arnaud
A
Roth
Department of Thoracic Surgery, Institute for Pulmonary Diseases of Vojvodina, Sremska Kamenica, Serbia.
Milorad
M
Bijelovic
Department of Medical Oncology, University Hospital Bern, Bern, Switzerland.
Adrian
A
Ochsenbein
Department of Radiation Oncology, Kantonsspital Winterthur, Winterthur, Switzerland.
Urs R
UR
Meier
Department of Medical Oncology, Kantonsspital Aarau, Aarau, Switzerland.
Christoph
C
Mamot
Department of Medical Oncology, Regional Hospital, Thun, Switzerland.
Daniel
D
Rauch
Department of Medical Oncology, Kantonsspital Luzern, Lucerne, Switzerland.
Oliver
O
Gautschi
Department of Medical Oncology, HFR Fribourg-Hôpital cantonal, Fribourg, Switzerland.
Daniel C
DC
Betticher
Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland.
René-Olivier
RO
Mirimanoff
Department of Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Vaud, Switzerland.
Solange
S
Peters
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D059186:Chemoradiotherapy, Adjuvant / Q000009:adverse effects / Q000379:methods*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects / Q000379:methods; D009367:Neoplasm Staging; D011013:Pneumonectomy / Q000379:methods; D016019:Survival Analysis; D016896:Treatment Outcome