Mediastinal lymph node clearance and anti-PD-1 induction in resected NSCLC
Authors: F. Manapov, C. Eze, L. Käsmann, M. Dantes, O. Roengvoraphoj
Journal: Annals of Oncology (2018)

In locally advanced node-positive non-small-cell lung cancer (NSCLC), neoadjuvant therapy may play a key role because of poor loco-regional control and survival in these patients following surgery alone. However, intensification of induction therapy, e.g. combination of chemotherapy and thoracic irradiation remains questionable based on the results of previous randomized trials. Recently, Forde et al. [1.Forde P.M. Chaft J.E. Smith K.N. et al.Neoadjuvant PD-1 blockade in resectable lung cancer.N Engl J Med. 2018; Crossref Scopus (1021) Google Scholar] reported on the feasibility and efficacy of neoadjuvant nivolumab in patients with resectable Union Internationale Contre le Cancer stage I–IIIA NSCLC. Induction therapy constituted the administration of two infusions and was well tolerated inducing a major primary tumor pathological response rate of 45%. Importantly, in patients’ peripheral blood a clonal expansion of neoantigen-specific T cells was documented. Also, a divergence between radiologic (preoperative RECIST) and pathologic primary tumor responses was described in 60% of cases. The authors supposed an extensive immune cell infiltration of the primary tumor and subsequently enlarged tumor volume. Despite the impressive pathological remission rate of the primary tumor, comprehensive radiologic and pathologic analysis of the achieved mediastinal lymph node clearance (MC) was not described. A prognostic role of MC after induction therapy in resected node positive NSCLC is well established [2.Betticher D.C. Hsu Schmitz S.-F. Totsch M. et al.Mediastinal lymph node clearance after docetaxel-cisplatin neoadjuvant chemotherapy is prognostic of survival in patients with stage IIIA pN2 non-small-cell lung cancer: a multicenter phase II trial.J Clin Oncol. 2003; 21: 1752-1759Crossref PubMed Scopus (379) Google Scholar, 3.Vyfhuis M.A.L. Burrows W.M. Bhooshan N. et al.Implications of pathologic complete response beyond mediastinal nodal clearance with high-dose neoadjuvant chemoradiation therapy in locally advanced, non-small cell lung cancer.Int J Radiat Oncol Biol Phys. 2018; 101: 445-452Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 4.Suntharalingam M. Paulus R. Edelman M.J. et al.Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung.Int J Radiat Oncol Biol Phys. 2012; 84: 456-463Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar]. There is also evidence that residual nodal disease after multimodal induction has a negative impact on progression-free and overall survival. In the current trial, a total of one-fourth patients with preoperative N2 disease were down-staged. Furthermore, in the preoperative N0 subgroup (eight patients), there were two patients that were upstaged to ypN1 after resection. In previous studies, MC rate was dependent on therapy modalities. If neoadjuvant chemoradiation was applied, a reported MC rate was relatively high between 33% and 74%. This finding of possible response discrepancy between primary tumor and involved lymph node compartment after induction with nivolumab in resected NSCLC may be of clinical relevance. An explanation could be a potentially different activity of PD-1 inhibitors in both treated sites. There is a paucity of data demonstrating a potentially different PD-L1 expression in the primary tumor and involved lymph nodes in NSCLC. Additionally, the single-center study from Gettinger et al. [5.Gettinger S.N. Wurtz A. Goldberg S.B. et al.Clinical features and management of acquired resistance to PD-1 axis inhibitors in 26 patients with advanced non-small cell lung cancer.J Thorac Oncol. 2018; Abstract Full Text Full Text PDF Scopus (68) Google Scholar] investigated clinical features of acquired resistance to PD-1 axis inhibitors in advanced NSCLC and revealed that involved lymph nodes more often appear as a site of resistance. The risk of divergent pathologic response to nivolumab induction in different compartments (primary tumor versus involved lymph nodes) needs further clarification before integration of anti-PD-1 inhibitors as induction therapy in clinical practice. None declared.