FDG-PET/CT for pretherapeutic lymph node staging in non-small cell lung cancer: A tailored approach to the ESTS/ESMO guideline workflow
Introduction
Accurate thoracic lymph node (LN) staging including [18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is crucial for appropriate treatment planning in patients with non-small cell lung cancer (NSCLC). Specifically, patients with extensive or unresectable mediastinal LN involvement (N2) must be identified. FDG-PET/CT is the first step in this work-up and helps to guide invasive staging methods such as endobronchial ultrasound-guided transbronchial needle aspiration/biopsy (EBUS-TBNA) [1,2]. However, due to potential false negative results of FDG-PET/CT, invasive staging is recommended to confirm negative mediastinal LNs and to avoid unsuspected postoperative pN2/3. Specifically, current guidelines by the European Society of Thoracic Surgeons (ESTS) and the European Society for Medical Oncology (ESMO) recommend invasive staging (EBUS-TBNA) for confirmation of negative PET/CT in case of either cN1, a primary tumor with >3 cm diameter or non-peripheral location (i.e., not confined to the outer third of the lung) [1,2]. However, these recommendations entail that only 6.5 % of patients can directly undergo surgery without further invasive staging [3]. As most patients with negative mediastinal LNs by PET/CT will be confirmed to be negative, most of these confirmatory invasive procedures could be unnecessary. Therefore, more differentiated and specific staging recommendations could avoid invasive procedures in these patients.
However, this requires accurate and reliable interpretation of the information provided by FDG-PET/CT. Schmidt-Hansen et al. [4] reported varying sensitivity (17–100%) and specificity (33–100%) of FDG-PET between studies and centres due to different criteria for PET positivity (e.g., ‘LN uptake > mediastinal background’, ‘LN SUVmax ≥ 2.5′, ‘mixed’). Variability also resulted from PET/CT scanners with different performance metrics [4]. Moreover, this meta-analysis did not cover more recent developments in PET/CT technology with their potential to improve accuracy of LN staging [[5], [6], [7]]. These included advances in PET detector materials [8,9] and photomultiplier technology [10] as well as image reconstruction algorithms [5,[11], [12], [13], [14], [15]]. Therefore, reevaluation of possible approaches to tailored staging recommendations should reflect the clinical variability of PET criteria for positive LNs, state-of-the-art PET/CT technology, and inter-scanner performance differences.
This article sets out to investigate different approaches to a more tailored diagnostic workflow for LN staging in patients with NSCLC. The aim was to identify strategies in order to avoid unnecessary invasive procedures compared to the current standard workflow recommended by the ESTS/ESMO. For broader applicability, this analysis included a comparison of two PET/CT scanners with considerably different performance metrics. Furthermore, the effect of different LN assessment criteria was studied systematically using a previously proposed standardized approach to visual PET assessment [16,17].
Section snippets
Patients
Datasets of 602 consecutive patients with newly diagnosed NSCLC or suspicion for lung cancer but unsuccessful biopsy attempts who underwent FDG-PET/CT as part of clinical routine care between February 2016 and September 2020 were identified. Examinations were performed using two different dedicated PET/CT scanners: a) a PET/CT scanner with analog detector technology (“AS cohort”) between February 2016 and January 2019, or b) a PET/CT scanner with digital detector technology (“DS cohort”)
Standard of reference (SOR)
Surgery with systematic lymph node dissection was performed in 189 of 248 patients (77 %; Table 1), and surgery was performed in all patients with mediastinal negative LNs according to PET/CT (cut-off ‘LN > MBPS’). Among 700 L N stations included in the analysis, 180 (26 %) were metastatic. Metastatic LN stations were similarly frequent in the AS cohort (117/448 L N stations [26 %]) compared to the DS cohort (63/252 [25 %]; Fisher’s exact test, p = 0.75). According to the eligibility criteria
Discussion
To the best of our knowledge, this is the first study to provide a systematic evaluation of the accuracy of FDG-PET/CT for LN staging in NSCLC with a differentiation of the imaging-derived risk factors for unexpected pN2 defined by the ESTS and ESMO guidelines (cN1, primary tumor >3 cm or non-peripheral tumor) [1,2]. This facilitated comparison of three different modified approaches to the diagnostic workflow with the aim of omitting unnecessary (confirmatory) invasive staging in patients that
Conclusion
We propose a modification to the ESTS/ESMO guidelines for LN staging in NSCLC. In the current patient sample, invasive staging (i.e., EBUS-TBNA) could have been omitted in patients with PET/CT negative for mediastinal LNs and less than three of the risk factors proposed by the ESTS and ESMO guideline. This could have safely avoided approximately 80 % of confirmatory EBUS-TBNA procedures in patients with mediastinal negative PET/CT. This observation was consistent in both investigated patient
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Julian M.M. Rogasch: Conceptualization, Methodology, Formal analysis, Investigation, Writing - original draft. Nikolaj Frost: Conceptualization, Visualization, Writing - review & editing. Stephanie Bluemel: Investigation. Liza Michaels: Investigation. Tobias Penzkofer: Methodology, Data curation. Maximilian von Laffert: Supervision, Writing - review & editing. Bettina Temmesfeld-Wollbrück: Writing - review & editing. Jens Neudecker: Methodology, Writing - review & editing. Jens-Carsten Rückert:
Declaration of Competing Interest
None.
Acknowledgements
Dr. Julian Rogasch (JMMR) is participant in the BIH-Charité Digital Clinician Scientist Program funded by the Charité – Universitätsmedizin Berlin and the Berlin Institute of Health and the German Research Foundation (DFG).
Dr. Penzkofer was supported by Berlin Institute of Health (Clinician Scientist Grant, Platform Grant) and reports research agreements (no personal payments, outside of submitted work) with AGO, Aprea AB, ARCAGY-GINECO, Astellas Pharma Global Inc. (APGD), Astra Zeneca, Clovis
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