Despite the clear value of systematic performance of staging
Despite the clear value of ‘systematic’ performance of staging techniques on sensitivity and unforeseen N2 rates, no studies have reported favourable effect on patient reported outcome measures and only few on survival. In the ASTER-trial unforeseen N2 was found in 14.3% of patients after mediastinoscopy only versus 6.9% after endosonography and mediastinoscopy . Despite this difference in unforeseen N2 disease, 5-year survival was exactly the same in both groups . Therefore future research should not only focus on training and concentration of technically demanding diagnostics in qualified centres in order to improve diagnostic accuracy, but also on the clinically relevant effects of improved (systematic) staging on treatment and outcome.
Funding This retrospective analysis is part of the MEDIASTrial which is funded by ZonMw (project number 843004109) and The Dutch Cancer Society (project number 11313).
Role of the funding source
Conflict of interest
Introduction Immune checkpoint inhibitor (ICI) therapy, especially programmed death-ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) inhibition, has revolutionized the therapeutic landscape in advanced non-small cell lung cancer (NSCLC). Still, only a minority benefits from such therapies and individual patient response is hard to foresee. Extensive research effort is currently being made to identify predictive biomarkers. Immunohistochemical staining for PD-L1 status has been used to predict response to ICI therapies from the first clinical trials on, but also PD-L1 negative patients may benefit and a positive status does not guarantee a therapeutic effect [1,2]. Also, more elaborate composite biomarkers like the Teff score reflecting Angeli’s Salt T-cell gene expression have been proposed . More recently, tumor mutational burden (TMB) measured in tumor tissue or peripheral blood has been introduced, identifying a partly different ICI-responsive patient collective. However, due to high cost and current lack of a consensus on methods, TMB is not yet widely available in clinical practice [1,2,4,5]. Other reported predictors of response to ICI in NSCLC include Eastern Cooperative Oncology Group (ECOG) performance status, routine laboratory parameters like lactate dehydrogenase and peripheral blood cell counts [6,7]. Recent research results suggest, that rather than single biomarkers, composite approaches may be the future of response prediction to ICI therapies: A currently proposed model relies on the genetic tumor profile reflected by TMB as well as on the immune phenotype, referring to the presence and reactivity of T-cells within the tumor. TMB is usually high in the context of increased neoantigen-formation, whereas immunosuppressant tumor mechanisms like PD-L1 expression or indoleamine 2,3-dioxygenase (IDO) may be surrogate parameters of enhanced T-cell inflammation . Notably, some authors have reported on a prognostic relevance of baseline serum tumor marker (STM) concentrations like carcinoembryonic antigen (CEA) or cytokeratin-19 fragments (CYFRA 21-1) in retrospective study settings in ICI treated patients [7,8]. More recently, Dal Bello et al. reported, that the also the dynamics of STM, especially decreases in CYFRA 21-1 and CEA under treatment with nivolumab might a predictor of therapy efficacy [9,10]. Analyzing STM is not routinely recommended in either diagnosis or follow-up of NSCLC . However, besides the aforementioned studies on ICI treated patients, there is evidence that tumor markers like CEA, CA19-9 and CYFRA 21-1 can be used in treatment monitoring and longitudinal follow-up in patients undergoing chemotherapy or target therapy [11,12]. Ideal biomarkers should be easily obtainable by peripheral blood draw, inexpensive to analyze and allow serial measurement for longitudinal observation , all of which applies to STM. We have used STM as additional longitudinal biomarkers of disease activity in NSCLC for several years and have experienced, that STM provide clinically relevant information especially when radiological examination results leave uncertainty. In ICI therapies, we have seen distinct and especially sustained tumor responses, when STM had decreased upon first restaging . Based on such observations, this analysis aimed to examine whether STM response at first restaging had implications on overall- (OS) and progression-free survival (PFS) compared to computed tomography (CT) evaluation in patients with advanced NSCLC treated with PD-1/PD-L1 directed ICI therapies.