Postoperative Radiotherapy for Pathologic N2 Non-Small-Cell Lung Cancer Treated With Adjuvant Chemotherapy: Need for Randomized Evidence

The recent article by Robinson et al1 showed that the issue of postoperative radiotherapy (PORT) in patients with resected non–small-cell lung cancer (NSCLC) is once again a topic of interest. That study, which used the National Cancer Data Base, identified 4,483 patients who were treated between 2006 and 2010, who had pathologic N2 disease exclusively, and who underwent complete resection and adjuvant chemotherapy. According to the authors, “modern PORT seems to confer an additional OS advantage beyond that achieved with adjuvant chemotherapy alone.” The Robinson et al article relaunches the debate on the role of PORT in the setting of patients with completely resected N2 NSCLC who have had adjuvant chemotherapy. Although population-based cohort studies may be relevant in the context of rare clinical situations, they cannot contribute to defining standard of care in a disease that occurs as frequently as NSCLC, which has become the leading cause of cancer death.Since the PORT meta-analysis article was published in 1998, there have been significant changes in the selection of patients and in treatment options and the technology available for this group of patients. Recent studies have revisited and updated data that were included in the landmark PORT meta-analysis. Burdett et al2 updated the meta-analysis by including two additional clinical trials and by using a new method for statistical analysis. They found less compelling evidence that the effect of PORT varied by stage and nodal status in particular. Billiet et al3,4 investigated the effect of modern PORT on local recurrence and survival by stratifying randomized controlled trials of PORT according to use or nonuse of linear accelerators. They could not conclude, as described in the corrigendum of a literature based meta-analysis, that “modern postoperative radiotherapy for stage III non–small-cell lung cancer may improve local control and survival.”Therefore, on the basis of evidence from published randomized trials, there are no new data available and PORT should not be routinely used in completely resected NSCLC.5 We have noted that in 2015, the outcome for completely resected N2 patients staged with positron emission tomography and computed tomography scans and brain imaging has improved. The reasons for that improvement are progress in thoracic surgery and/or intensive care and implementation of adjuvant chemotherapy per international guidelines. Furthermore, there is indirect evidence that modern radiotherapy planning and delivery could improve the outcome of PORT through a decline in the risk of heart disease mortality associated with this treatment.6However, the role of PORT in completely resected N2 patients in the era of modern radiotherapy is still highly controversial and needs to be supported by robust evidence from randomized controlled trials. Institutional retrospective studies and well-documented database studies suggest a role for PORT in N2 patients,1,7 but interpreting the results of those studies may require some caution because there are many undocumented confounding factors regarding the quality of surgery, radiotherapy, and chemotherapy that should be taken into account. For example, in the article by Robinson et al,1 the authors state that 10% of patients had single-agent chemotherapy, and approximately 40% of patients likely received concomitant chemoradiotherapy, which is not routinely recommended in the postoperative setting.5 In addition, because the PORT group is defined a posteriori by a treatment administered at some time after diagnosis, patients in the PORT group cannot, by construction, die before PORT and therefore their survival in the first months after diagnosis is artificially high. The statistical analysis should use appropriate methods, such as landmark analysis, at a time guided by the maximum delay between surgery and PORT (8 months in the Robinson study).8 Finally, PORT may also contribute to overadded acute and late toxicity, which is not well evaluated by retrospective or database studies.7In conclusion, only randomized trials can establish whether differences in outcome between patients treated with and without PORT may be attributable to the addition of radiotherapy. As mentioned by the authors, the ongoing randomized intergroup LUNG ART (NCT00410683; Radiation Therapy in Treating Patients With Non Small Cell Lung Cancer That Has Been Completely Removed by Surgery) trial is evaluating PORT in this patient population by using modern three-dimensional conformal radiation technique, with attention being paid to sparing the organs at risk, particularly lung and heart, to reduce the risk of radiotherapy-related toxicity.9 Quality assurance of radiotherapy and quality of surgery, particularly nodal exploration, are closely monitored. There is an urgent need to include more patients with stage III NSCLC into trials; we owe it to these potentially curable patients to provide robust evidence to support their treatments.