Neoadjuvant combination chemotherapy for unresectable stage III non–small cell lung cancer

In this issue of Cancer, Ou and colleagues describe the results from a phase 2 trial of neoadjuvant chemotherapy plus bevacizumab delivered for 4 cycles in patients with “unresectable” stage III adenocarcinoma of the lung. The authors hypothesized that the addition of bevacizumab would increase response rates and thereby increase resectability rates and subsequently improve survival. Their hypothesis was based on an assumption that the resectability rate in these patients would be 40% with standard neoadjuvant chemotherapy and would increase by 20% if the bevacizumab was efficacious. The study was small (42 patients), included only a single arm, and had many nonstandard approaches. These nonstandard approaches included the use of 4 cycles of chemotherapy (instead of 2 or 3 cycles), the use of prophylactic growth factors (granulocyte-colony–stimulating factor), and the inclusion of N3 (supraclavicular) and bulky N2 disease. Details regarding the criteria used to determine whether a patient was deemed initially unresectable and what determined postchemotherapy/bevacizumab resectability are unfortunately not provided. This study reported an objective response in 23 of 42 patients (55%) and a surgical resection rate of 74% including a complete (R0) resection in 52% and an incomplete (R1) resection in 21%. The median event-free survival (EFS) was 15 months, and the 2-year EFS rate was about 35%. The median EFS was only 9 months in those who underwent R1 resection. The authors conclude that “neoadjuvant bevacizumab in combination with pemetrexed and carboplatin followed by surgery is a feasible and safe treatment option for patients with unresectable stage III lung adenocarcinoma. ” The study is relatively well reported, but the median follow-up of just 14 months is quite short, and the data do not yet justify the conclusion that such an experimental approach could be used on a routine basis. These patients have disease that is potentially curable using concurrent chemoradiation, with a median survival in the range of 2 years in large cooperative group studies. Similar operability results with higher rates of lymph node response can be obtained using preoperative chemoradiation therapy. The results may justify further study with a larger randomized trial focusing on a single question, such as the role of bevacizumab. However, considerable thought should be given to whether such a trial is warranted; and, if such a trial were instituted, then the eligibility criteria should be well defined. Current chemotherapy regimens produce no complete pathologic responses, and it is likely that such responses would be necessary to have a major impact on cure rates. The addition of bevacizumab to platinum doublet chemotherapy in advanced disease increased the response rate and prolonged progression-free survival in randomized trials in the United States and in Europe. However, survival was prolonged only in the Eastern Cooperative Oncology Group 4599 trial, and that gain was modest. Furthermore, complete responses were rare. Erlotinib alone provided a slight survival improvement in patients with advanced, refractory NSCLC; but response rates were low, and there were no complete responses. In the adjuvant setting, results from recent, large, phase 3 randomized trials of erlotinib (RADIANT) and bevacizumab (E1505) combined with chemotherapy were reported. Both were negative for any effect on survival. Thus, although both bevacizumab and erlotinib may prolong the survival of patients with advanced NSCLC, neither prolonged survival in the adjuvant setting in those early stage adjuvant trials. Similarly, bevacizumab failed to improved survival in adjuvant trials in other early stage cancers, even when there was some survival