Elsevier

Lung Cancer

Volume 157, July 2021, Pages 66-74
Lung Cancer

FDG-PET/CT for pretherapeutic lymph node staging in non-small cell lung cancer: A tailored approach to the ESTS/ESMO guideline workflow

https://doi.org/10.1016/j.lungcan.2021.05.003Get rights and content

Highlights

  • Risk factors for missed pN2 defined by current guidelines may be overcautious.

  • In current analysis, missed pN2 was always associated with adenocarcinoma subtype.

  • Most EBUS-TBNA procedures in patients with mediastinal negative PET/CT were confirmatory.

  • The proposed modified workflow could have avoided 82 % of these procedures.

  • In this analysis, additional cases of missed pN2 disease would have remained rare.

Abstract

Objectives

In patients with NSCLC, current ESTS and ESMO guidelines recommend invasive lymph node (LN) staging with EBUS-TBNA even if FDG-PET/CT is negative for mediastinal LNs if at least one of three risk factors is present (cN1, non-peripheral primary or primary >3 cm). Modified workflows to avoid unnecessary invasive procedures were evaluated.

Materials and methods

Monocentric retrospective analysis of pretherapeutic FDG-PET/CT in 247 patients with NSCLC (62 % male; age, 68 [43–88] years) using an analog or digital PET/CT scanner. PET windowing was standardized. LNs were positive if ‘LN uptake > mediastinal blood pool’ or short axis >10 mm. Surgery or EBUS-TBNA served as reference for diagnostic accuracy per LN station. In all patients with negative mediastinal LNs by PET/CT, LN histology from surgery was available.

Results

Among 700 L N stations analyzed, 180 were malignant. Sensitivity and specificity of PET/CT per LN station were 93 % and 71 %. Following current guidelines, 76 patients with mediastinal negative PET/CT required confirmatory invasive staging. Only 5/76 patients had unexpected pN2 (all had adenocarcinoma). In a modified approach, confirmatory invasive staging was confined to patients with mediastinal negative PET/CT who showed all three risk factors. Using this modification, EBUS-TBNA could have been omitted in 62 (82 %) of the 76 patients who required EBUS-TBNA based on current recommendation. Among these 62 patients, only one patient had unsuspected pN2 (single-level) while the remaining 61 of 62 omitted EBUS-TBNA were deemed unnecessary because mediastinal LNs were confirmed to be negative. No multi-level pN2 would have been missed.

Conclusion

In the current analysis, 82 % of EBUS-TBNA procedures in patients with mediastinal negative PET/CT could have been omitted by modifying the current guideline workflow as proposed (i.e., restricting EBUS-TBNA in patients with cN0/1 to those with all three risk factors). This was consistent with different PET/CT scanners. Prospective confirmation is required.

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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