Neoadjuvant chemoradiotherapy followed by surgery for stage IIIa and IIIb non-small-cell lung cancer (NSCLC): is it still justified?

For stage III non-small-cell lung cancer (NSCLC), overall survival after surgery alone is quite poor, in the range of 5% to 10% at five years, mainly due to the high incidence of local and distant failures. Randomized trials and meta-analyses have shown a modest improvement in survival with neo-adjuvant chemotherapy, however the local and distant failure rates remain high. Numerous retrospective studies and phase II trials have been published on the potential added value of radiotherapy in the neoadjuvant setting and are reviewed here. These studies have shown that the addition of radiotherapy to chemotherapy is followed by a high rate of complete resection, an encouraging rate of complete pathologic response, a high mediastinal clearance in case of N2 disease, all of which represent potential surrogates for survival. Until recently, only small randomized trials have compared neoadjuvant chemoradiation to neoadjuvant chemotherapy, and were not contributory. The recently published Swiss cooperative group (SAKK) phase III randomized trial is the only one to have accrued a sufficient number of patients for interpretation. It showed a superiority of neoadjuvant chemoradiation over neoadjuvant chemotherapy regarding overall response rate, complete resection rate and local control, with no increased haematologic toxicity or post-operative deaths. However there was no difference in the event-free survival (the primary endpoint) nor in overall survival between the two arms. Following the results of this trial, opposite opinions have been expressed regarding the possible causes of failures of this trial, and on the future role or not of radiotherapy associated with neoadjuvant chemotherapy before surgery. It is suggested that under certain conditions, in which the risk of local failures is quite high after surgery, studies on the role of neoadjuvant chemoradiation should be pursued, using novel radiotherapy techniques and schemes, and novel systemic treatments associated with radiotherapy.