# Different pathways to lung cancer diagnosis in a real-life setting

Juliette Raëth, Cécile Malbert, Julian Pinsolle, François Arbib, Gilbert Ferretti, Bruno Degano, Justin Benet, Giulia Berardi, Arnaud Fedi, Anne-Claire Toffart

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Juliette Raëth, Cécile Malbert, Julian Pinsolle, François Arbib, Gilbert Ferretti, et al. Different pathways to lung cancer diagnosis in a real-life setting. Respiratory Medicine and Research, 2024, 86, pp.101108. 10.1016/j.resmer.2024.101108. inserm-05216764

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Original article

# Different pathways to lung cancer diagnosis in a real-life setting

Juliette Raëth<sup>a,*</sup>, Cécile Malbert<sup>a</sup>, Julian Pinsolle<sup>b</sup>, François Arbib<sup>a</sup>, Gilbert R. Ferretti<sup>c</sup>, Bruno Degano<sup>a</sup>, Justin Benet<sup>a</sup>, Giulia Berardi<sup>a</sup>, Arnaud Fedi<sup>d</sup>, Anne-Claire Toffart<sup>a</sup>

<figure><img src="image_4.png" /></figure>

ARTICLE INFO

Article History:
Received 14 October 2023
Revised 5 April 2024
Accepted 15 April 2024
Available online 24 April 2024

Keywords:
Lung cancer
Diagnosis
Anticancer treatments
Pathway
Timely care

ABSTRACT

**Background:** Most lung cancers are diagnosed at an advanced stage and therefore have a poor prognosis. One major challenge is to choose the most adapted sampling technique to obtain a rapid pathological diagnosis so as to start treatment as early as possible. A growing number of techniques have been developed in recent years. This study sought to assess the diagnostic efficiency of each, along with the respective duration of the diagnostic pathways.

**Methods:** This retrospective, bicentric, observational study enrolled patients with inoperable lung cancer (stage III or IV) diagnosed in 2018–2019. Diagnostic efficiency was assessed based on the different examinations performed to achieve a precise diagnosis (pathology, immunohistochemistry, and/or molecular biology). The time between the first medical contact and treatment initiation was also assessed.

**Results:** Overall, 625 patients were included (median age 67 years; men 67 %; adenocarcinoma 55 %). The most frequent examinations were bronchial endoscopy (n = 469, 75 %), followed by metastasis biopsy (n = 137, 21.9 %) and guided transthoracic core-needle biopsy (TCNB) (n = 116, 18.6 %). 372 patients had only one procedure (59.5 %), mainly bronchial endoscopy (n = 217, 34.7 %) and metastasis biopsy (n = 71, 11 %). The most efficient examination was thoracic surgery (surgical pleural biopsy, (n = 32, 100 %); mediastinoscopy (n = 26, 96.3 %); surgical pulmonary biopsy (n = 14, 93.3 %). The second most efficient examination was metastasis biopsy (n = 126, 94 %) followed by guided TCNB (n = 108, 93.1 %). The median time from first medical contact to first examination was 4 days (interquartile range 25 %–75 % 1–8). The median time from first medical contact to pathological result was 17 days (10–34). The median time from first medical contact to treatment start was 48 days (30–69).

**Conclusions:** In order to make an accurate and rapid diagnosis of lung cancer, it is crucial to choose the most appropriate technique. Bronchial endoscopy remains the first-line examination for central lesions, as it is efficient and easily accessible. Guided TCNB and metastasis biopsy are the preferred techniques for peripheral lesions. The choice of the diagnostic technique should be part of a multidisciplinary approach and a dedicated pathway to optimize initial management.

© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license

(http://creativecommons.org/licenses/by/4.0/)

Introduction

Lung cancer is the third most common cancer worldwide, with an estimated 236,740 new cases in 2022 [1], and the world's leading cause of cancer death [2]. Most lung cancers are diagnosed at an advanced stage (around 55 % of stage IV) and therefore have a poor prognosis, with 5-year overall survival rates of 7 % and 2 % for stage IIIB and IV, respectively [3].

The diagnosis of certainty is based on pathological examination. One major challenge is to choose the most adapted sampling technique to obtain a rapid pathological diagnosis in order to start treatment as early as possible and thus limit clinical deterioration and

**Abbreviations:** CT-guided TCNB, Computerized Tomography-guided Transthoracic Core-Needle Biopsy; cTNM, clinical Tumor Node Metastasis; EBUS- FNA, Endobronchial Ultrasound-guided Fine Needle Aspiration; ECOG-PS, Eastern Cooperative Oncology Group – Performance Status; EGFR, Epidermal Growth Factor Receptor; EUS-B-FNA, Transoesophageal bronchoscopic ultrasound-guided fine-needle aspiration; NGS, Next-Generation Sequencing; NOS, Not Otherwise Specified; NSCLC, Non-Small Cell Lung Cancer; qPCR, quantitative Polymerase Chain Reaction; r-EBUS, radial probe EndoBronchial UltraSound; T0, Time Zero

E-mail address: jraeth@chu-grenoble.fr (J. Raëth).

<footnote><sup>a</sup> Department of Pneumology, CHU Grenoble Alpes Grenoble, Grenoble, France</footnote>

<footnote><sup>b</sup> Department of Pneumology, CH Metropole-Savoie, Chambery, France</footnote>

<footnote><sup>c</sup> Department of Diagnostic and Interventional Radiology, University of Grenoble Alpes, and CHU Grenoble Alpes, Grenoble, France</footnote>

<footnote><sup>d</sup> Department of Pneumology, Centre Henri Bazire, La Sure en Chartreuse, and Clinique Mutualiste, Grenoble, France</footnote>

<footnote>* Corresponding author at: CHU Grenoble Alpes, Service de pneumologie, Boulevard de la Chantourne, CS10217, 38043 Grenoble Cedex 9, France.</footnote>
tumor extension [4,5]. A growing number of tissue sampling (by biopsy) or cellular sampling (by washing, brushing, puncture-aspiration) methods have been developed in recent years, with the use of endoscopic techniques or interventional radiology [6,7].

The development of targeted therapies based on molecular alterations [8,9] and the emergence of immunotherapies [10] have allowed a personalized treatment leading to improved overall survival. It is therefore paramount to obtain enough high-quality samples to determine the pathological characteristics, immunological status, and biomolecular mutations [6]. On the one hand, the choice of the most suitable diagnostic procedure must take into account the patient's general state and comorbidities, as well as the location of the lesions [11]. On the other hand, it is also necessary to favor the examination with the best diagnostic performance within an acceptable time frame.

Among these techniques, bronchial endoscopy should be used for central lesions, due to its availability, low invasiveness, and high diagnostic yield [12]. Special consideration should be given to computed tomography-guided transthoracic core-needle biopsy (CT-guided TCNB) and radial probe endobronchial ultrasound (r-EBUS) for the diagnosis of peripheral lung nodules [13,14]. Endosonography (endobronchial ultrasound-guided fine-needle aspiration [EBUS-FNA], transesophageal bronchoscopic ultrasound-guided fine-needle aspiration [EUS-B-FNA]) has proven suitable for accessing mediastinal lesions. More invasive sampling techniques, such as thoracoscopy and mediastinoscopy, can be implemented in case of lesions inaccessible with bronchial endoscopy. Finally, the sampling of metastasis (pleura, bone, skin, etc.) is also possible.

Many meta-analyses have examined the individual diagnostic performance of the various sampling techniques [12,15–17], which has led to the issuance of recommendations to assist in the selection of the best diagnostic technique for lung cancer [12]. To our knowledge, no study has compared the diagnostic performance of these techniques in a real-life setting so far.

This study sought to determine the efficiency of each technique to achieve a precise diagnosis, along with the respective duration of the diagnostic pathways.

# Materials and methods

## Design and setting

A bicentric retrospective study was conducted between January 2018 and December 2019 at the Grenoble Alpes University Hospital and the Metropole Savoie Hospital, France.

The study was approved on September 9, 2020 by the Clinical Research and Innovation Office of Grenoble Alpes University Hospital. In accordance with French regulations, there is an institutional review board waiver for this type of research. A letter was sent to each living patient providing information about the research and the possibility to decline participation in the study.

The primary outcome was the proportion of diagnoses (histological and molecular) that could be made by each sampling technique. The secondary outcome was the time to diagnose from the first sample collected, according to the chronological sequence of sampling.

## Study population

All patients with a cytological or histological diagnosis of inoperable lung cancer (stage III or IV) made between January 1, 2018 and December 31, 2019 were included. Exclusion criteria were age under 18 years, patient objection to the use of their data, and patients under judicial protection.

## Data collection

Patients were identified from the thoracic oncology consultation list at the Grenoble Alpes University Hospital and from the multidisciplinary meeting list at the Metropole Savoie Hospital in 2018 and 2019. Data of interest were retrieved from medical charts in the two centers. Patient characteristics at the first consultation in the thoracic oncology department were collected, including age, gender, Charlson comorbidity index [18], smoking status, blood thinner treatment

<figure><img src="image_5.png" /><figcaption>Fig. 1. Study flow-chart.</figcaption></figure>
(antiplatelet agents or anticoagulants), and Eastern Cooperative Oncology Group performance status (ECOG-PS). Cancer-related characteristics were gathered, including clinical Tumor Node Metastasis (cTNM) stage [19] at diagnosis, metastasis sites, chest tumor location, histological diagnosis, and molecular biology. Chest tumor location was specified as either distal or proximal, according to the accessibility with conventional bronchial endoscopy. Indeed, a pulmonary lesion below the segmental bronchial division was classified as a distal location.

All biopsies of a metastasis site, whether obtained radiologically, surgically, or percutaneously, were considered to be “metastasis biopsies”.

Regarding molecular biology, the distinction was made between next-generation sequencing (NGS) and quantitative polymerase chain reaction (qPCR) (Biocartis Idylla™ platform). Biomolecular analysis was performed for adenocarcinoma, not otherwise specified (NOS) carcinoma, and undifferentiated carcinoma, but not for the other histological types.

Patient pathways were recorded from first medical contact to histological diagnosis of lung cancer. This included the different tissue samplings to obtain the cancer diagnosis, their dates, and the results. All durations were calculated from Time Zero (T0), which was the “first medical contact”. “First medical contact” was considered as the first doctor who suspected lung cancer, started an investigation, and referred the patient to the thoracic oncologist. It could be a general practitioner, an emergency physician, a specialist physician, or a pulmonologist not practicing thoracic oncology. The date of the pathological diagnosis was the date on which the pathological and immunohistochemical results were received. Examinations performed after the one that led to the diagnosis (called “diagnostic examination” in our study) were not collected. We considered a pathological result to be diagnostic if it allowed the initiation of a systemic treatment. The result “few carcinoma cells” was not considered as a diagnosis.

Regarding the outcome, the first administered oncological treatment, its date, ECOG-PS at treatment initiation, and vital status at the end of follow-up were collected.

## Statistical analysis

Patient characteristics were described as median (interquartile range) and number (percent) for quantitative and qualitative variables, respectively. All statistical analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).

## Results

### Patient characteristics at inclusion

Among the 1380 screened patients, 625 were included in the analysis (Fig. 1). Most patients were men (67.4 %), current or former smokers (86.5 %), with a median age of 68 years (interquartile range [IQR] 25 %–75 % 60–75). The most common comorbidities were respiratory disease (n = 150, 24 %), prior cancer (n = 135, 22 %), and cardiac insufficiency (n = 75, 12 %). A minority of patients had blood thinner treatments (n = 248, 39.7 %) (Table 1).

Most cancers were stage IV (n = 501, 80 %), adenocarcinoma (n = 31, 55 %), with lymph node involvement (N2, n = 220, 35 % and N3, n = 233, 37 %). The most common metastatic locations were bone (n = 222, 35.5 %), lung (n = 178, 28.5 %), and lymph nodes and central nervous system (n = 138, 22.1 %). Chest tumor location was proximal in 43 % of cases.

Patients were mainly referred to the onco-pulmonologist by the general practitioner (n = 240, 38.5 %) and the emergency department (n = 165, 26.5 %). The diagnostic strategy was discussed in a multidisciplinary meeting for 46 (7 %) patients.

<caption>**Table 1**</caption>

Demographic and clinical patient characteristics at diagnosis.

<table><thead><tr><th>Patient characteristics</th><th>N = 625</th></tr></thead><tbody><tr><td><strong>Demographic data</strong></td><td></td></tr><tr><td>Male gender</td><td>421 (67.4)</td></tr><tr><td>Age – years</td><td>68 [60; 75]</td></tr><tr><td>Smoking status (Miss. = 1)</td><td></td></tr><tr><td>Current smoker</td><td>253 (40.5)</td></tr><tr><td>Former smoker</td><td>287 (46)</td></tr><tr><td>Never smoker</td><td>84 (13.5)</td></tr><tr><td>Charlson comorbidity index</td><td>1 [0; 2]</td></tr><tr><td>Anticoagulants and/or antiplatelet agents</td><td>248 (39.7)</td></tr><tr><td>ECOG-PS (Miss. = 1)</td><td></td></tr><tr><td>0-1</td><td>443 (71)</td></tr><tr><td>2</td><td>137 (22)</td></tr><tr><td>3-4</td><td>44 (7.1)</td></tr><tr><td><strong>Tumor characteristics</strong></td><td></td></tr><tr><td>Histology</td><td></td></tr><tr><td>Adenocarcinoma</td><td>346 (55.3)</td></tr><tr><td>Squamous cell carcinoma</td><td>119 (19)</td></tr><tr><td>Small-cell carcinoma</td><td>87 (13.9)</td></tr><tr><td>Other NSCLC</td><td>73 (11.6)</td></tr><tr><td>cTNM stage</td><td></td></tr><tr><td>III</td><td>123 (19.7)</td></tr><tr><td>IV</td><td>502 (80.3)</td></tr><tr><td>Lymph node involvement</td><td></td></tr><tr><td>N0-1</td><td>172 (27.6)</td></tr><tr><td>N2</td><td>220 (35.2)</td></tr><tr><td>N3</td><td>233 (21.3)</td></tr><tr><td>Metastatic locations</td><td></td></tr><tr><td>Bone</td><td>222 (35.5)</td></tr><tr><td>Pulmonary</td><td>178 (28.5)</td></tr><tr><td>Central nervous system</td><td>138 (22.1)</td></tr><tr><td>Lymph nodes</td><td>138 (22.1)</td></tr><tr><td>Pleura</td><td>133 (21.3)</td></tr><tr><td>Liver</td><td>117 (18.7)</td></tr><tr><td>Adrenal glands</td><td>110 (17.6)</td></tr><tr><td>Others *</td><td>104 (13.9)</td></tr><tr><td>Tumor thoracic topography</td><td></td></tr><tr><td>Distal</td><td>354 (56.6)</td></tr><tr><td>Proximal</td><td>271 (43.4)</td></tr><tr><td><strong>Diagnostic pathway</strong></td><td></td></tr><tr><td>Input department (Miss. = 2)</td><td></td></tr><tr><td>General practitioner</td><td>240 (38.5)</td></tr><tr><td>Emergency department</td><td>165 (26.5)</td></tr><tr><td>Pulmonologist</td><td>69 (11.1)</td></tr><tr><td>Others**</td><td>150 (24.1)</td></tr><tr><td>Multidisciplinary meeting opinion</td><td>46 (7.4)</td></tr></tbody></table>

cTNM: clinical Tumor Node Metastasis; ECOG-PS: Eastern Cooperative Oncology Group performance status; Miss.: missing data; NSCLC: non-small cell lung carcinoma.

* Including sub-diaphragmatic areas (n = 39), muscles (n = 17), skin (n = 21), heart (n = 22), breasts (n = 2), thyroid gland (n = 1), parotid gland (n = 1), and eye (n = 1).

** Including 100 specialist physicians, 32 surgeons, and 17 oncologists.

Qualitative variables are expressed as n (%) and quantitative variables as median (interquartile range 25 %–75 %).

### Performed biopsy examinations

In total, 964 examinations were performed in 625 patients (Table 2): 372 patients had one examination (59.5 %), 202 had two (32.3 %), 51 had three to five (8.2 %).

The most frequently performed examination was bronchial endoscopy (n = 469, 75 %), followed by metastasis biopsy (n = 137, 21.9 %), and ultrasound or guided TCNB (n = 116, 18.6 %). For metastasis biopsy, the most frequently biopsied sites were: lymph node (n = 41, 29.9 %), bone (n = 31, 22.6 %), liver (n = 20, 14.6 %), and central nervous system (n = 16, 11.7 %).

Bronchial endoscopy was the first examination performed in 412 patients (65.9 %) and it was the only examination in 217 (34.7 %). Twenty-two patients underwent two bronchial endoscopies (4.7 %).
<table><caption>**Table 2**

Characteristics of performed biopsies and conclusive biopsy examinations.</caption><thead><tr><th></th><th>Patients who underwent the examination (n)</th><th>Ranking in the sequence of examinations</th><th>Time from first contact to examination (days)</th><th>Achieved a diagnosis* (n)</th><th>Biomolecular analysis (n)</th></tr></thead><tbody><tr><td><strong>Bronchial endoscopy</strong></td><td>469 (75)*</td><td>1 [1; 1]</td><td>4 [1; 8]</td><td></td><td></td></tr><tr><td>Biopsy</td><td>330/469 (70.4)</td><td></td><td></td><td>227/330 (68.8)</td><td>107 (85.6)</td></tr><tr><td>Bronchial brushing</td><td>206/469 (43.9)</td><td></td><td></td><td>32/206 (15.5)</td><td>0</td></tr><tr><td>Aspiration</td><td>391/469 (83.4)</td><td></td><td></td><td>60/391 (15.3)</td><td>3 (18.8)</td></tr><tr><td>Bronchoalveolar lavage</td><td>33/469 (7)</td><td></td><td></td><td>5/33 (15.2)</td><td>1 (100)</td></tr><tr><td>Wang needle biopsy</td><td>10 (1.6)</td><td>2 [2; 3]</td><td>6.5 [1; 17]</td><td>5 (50)</td><td>3 (100)</td></tr><tr><td>EBUS</td><td>17 (2.7)</td><td>3 [2; 3]</td><td>10 [6; 16]</td><td>12 (70.6)</td><td>5 (55.6)</td></tr><tr><td><strong>Metastasis biopsy<sup>1</sup></strong></td><td>137 (21.9)**</td><td>1 [1; 2]</td><td>7 [1; 21]</td><td>126 (94)</td><td>78 (82.1)</td></tr><tr><td><strong>Guided TCNB<sup>2</sup></strong></td><td>116 (18.6)***</td><td>2 [1; 2]</td><td>22 [10; 37]</td><td>108 (93.1)</td><td>73 (90.1)</td></tr><tr><td><strong>Echo-endoscopy</strong></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>EBUS-FNA</td><td>70 (11.2)</td><td>2 [1; 2]</td><td>22 [12; 39]</td><td>58 (82.9)</td><td>35 (85.4)</td></tr><tr><td>EUS-B-FNA</td><td>7 (1.1)</td><td>2 [1; 3]</td><td>31 [1; 67]</td><td>6 (85.7)</td><td>3 (75)</td></tr><tr><td><strong>Pleural puncture</strong></td><td>67 (10.7)****</td><td>1 [1; 2]</td><td>2 [1; 6]</td><td>37 (55.2)</td><td>20 (58.8)</td></tr><tr><td><strong>Thoracic surgery</strong></td><td></td><td></td><td>33 [16; 49]</td><td></td><td></td></tr><tr><td>Surgical pleural biopsy</td><td>32 (5.1)</td><td>2.5 [2;3]</td><td>31.5 [13; 46]</td><td>32 (100)</td><td>29 (96.7)</td></tr><tr><td>Mediastinoscopy</td><td>27 (4.3)</td><td>2 [1;2]</td><td>33 [16; 51]</td><td>26 (96.3)</td><td>16 (88.9)</td></tr><tr><td>Surgical pulmonary biopsy</td><td>15 (2.4)</td><td>2 [2;3]</td><td>39 [24; 51]</td><td>14 (93.3)</td><td>12 (100)</td></tr></tbody></table>

EBUS-FNA: endobronchial ultrasound-guided fine-needle aspiration; EUS-B-FNA: transesophageal bronchoscopic ultrasound-guided fine-needle aspiration; r-EBUS: radial probe endobronchial ultrasound; TCNB: transthoracic core-needle biopsy.

* 22 patients had two bronchial endoscopies.

** 1 patient had two metastasis biopsies.

*** 1 patient had two TCNBs.

**** 5 patients had two pleural punctures.

¹ Including adenopathy (n = 41), bone (n = 31), liver (n = 20), central nervous system (n = 16), skin (n = 6), pericardial effusion (n = 5), digestive tube (n = 5), adrenal glands (n = 4), blood (n = 4), muscles (n = 2), vocal cords (n = 1), and thyroid gland (n = 1).

² 8 ultrasound-guided TCNBs and 108 CT-guided TCNBs.

Qualitative variables are expressed as n (%) and quantitative variables as median (interquartile range 25%–75%).

In most cases, aspirations (n = 391, 62.6 %), biopsies (n = 330, 52.8 %), and bronchial brushing (n = 206, 33 %) were performed. Metastasis biopsy was the first examination performed in 84 patients (13.4 %) and it was the only examination in 71 (11.4 %). Guided TCNB was the first examination performed in 36 patients (5.8 %) and it was the only examination in 33 (5.3 %).

## Temporal sequence of biopsy examinations

Fifty different diagnostic sequences of biopsy examinations were identified. The eleven most common diagnostic sequences are reported in Fig. 2. The median number of performed examinations to reach a diagnosis was one (IQR 25%–75% 1–2).

For 372 (59.5 %) patients, the first examination performed was the only one and the one that was efficient. That was mainly bronchial endoscopy (n = 217, 34.7 %) and metastasis biopsy (n = 71, 11 %). After a non-diagnostic bronchial endoscopy, patients mostly underwent a guided TCNB (n = 60, 10 %), a metastasis biopsy (n = 38, 6 %), or an echo-endoscopy (n = 30, 5 %).

Through the diagnostic pathway, the initial ECOG-PS of patients remained unchanged. ECOG-PS 1 was the most prevalent at treatment initiation (253 patients, 48 %). In total, 529 patients (85 %) were given a systemic treatment.

## Conclusive biopsy examination

The diagnostic efficiency is summarized in Table 2. The most efficient examination was thoracic surgery (surgical pleural biopsy, n = 32 (100 %)); mediastinoscopy n = 26 (96.3 %); surgical pulmonary biopsy, n = 14 (93.3 %). The second most efficient examination was metastasis biopsy (n = 126, 94 %). Among the histologies where biomolecular analysis was indicated, metastasis biopsy (n = 95) provided a conclusive biomolecular result in 78/95 (82.1 %) cases. The third most efficient examination was guided TCNB (n = 108, 93.1 %), and molecular biology analyses were conclusive in 73/81 (90.1 %) patients. Among patients who underwent a bronchial endoscopy,

biopsies were conclusive in 227/330 (68.8 %), and the biomolecular analyses were available in 107/125 patients (85.6 %).

Regarding biomolecular analysis, 64 % were performed by NGS and 36 % by qPCR (Biocartis Idylla™ platform).

## Time to conclusive examination from the first medical contact

The median time from first medical contact to the different examinations is shown in Table 2. The durations are summarized schematically in Fig. 3. The median time from first medical contact to access to the first examination was 4 days (IQR 25%–75 % 1–8). Then, the median time from first medical contact and pathological results was 17 days (IQR 25%–75 % 10–34). The median time between anatomo-pathological diagnosis and molecular biology analysis was 13 days (IQR 25%–75 % 4–21). This duration varied according to the molecular biology method: it was 1 day (IQR 25%–75 % 1–6) with the IDYLLA™ system and 16 days (IQR 25%–75 % 13–25) with NGS. Finally, the median time between first medical contact and treatment initiation was 48 days (IQR 25%–75 % 30–69).

Regarding the main examinations performed, the median time to access to bronchial endoscopy was 4 days (IQR 25%–75 % 1–8) (Table 2). It was 7 days (IQR 25%–75 % 1–21) for metastasis biopsy, 22 days (IQR 25%–75 % 10–37) for guided TCNB, 22 days (IQR 25%–75 % 12–39) for EBUS-FNA, and 33 days (IQR 25%–75 % 16–49) for thoracic surgery. The most accessible examination was pleural puncture, with 1 day of organization (IQR 25%–75 % 1–3).

Among the patients who underwent multiple examinations, the median time between the first examination performed and the conclusive examination was 19 days (IQR 25%–75 % 8–33).

## Discussion

This study reported the diagnostic pathways of 625 patients with advanced lung cancer. Bronchial endoscopy was performed in 75 % of patients. Metastasis biopsy and guided TCNB contributed to the diagnosis in 94 % and 93 % of patients, respectively. Median time between
<figure><img src="image_6.png" /><figcaption>Fig. 2. Temporal sequence.</figcaption></figure>

the first medical contact and the pathological results was 17 days. This time increased with the number of examinations performed.

Bronchial endoscopy was performed in three quarters of patients and it was the only examination in almost 35 % of cases. More than one third of biopsies by bronchial endoscopy were not conclusive. The predictive factors for successful biopsies are central location of lesion, bronchial invasion, and lesion size greater than 2 cm [12]. Indeed, the diagnostic yield of bronchoscopy decreases for peripheral lesions [20]. A meta-analysis by the American College of Chest Physicians studied the diagnostic efficiency according to the thoracic

topography. For central, visible, and endobronchial lesions, the sensitivity of biopsy was 74 % [21]. Our study included more than 50 % of peripheral lesions, which could explain our lower efficiency. R-EBUS was available in only one of the two participated centers from January 2019. So only few patients (n = 17) could benefit from this procedure.

We did not analyze the global efficiency of bronchial endoscopy, although it has been proven that combining several samples during a bronchial endoscopy increases efficiency [22]. In a prospective study, McLean et al. showed that biopsies were positive in 82 %, while the total histological yield was 87 % when adding bronchial brushing and bronchoalveolar lavage [22]. A possible reason why bronchial endoscopy is often performed and sometimes not indicated is the short access time (4 days, IQR 25 %–75 % 1–8). Ultimately, this means that bronchial endoscopy should not be carried out systematically as the first examination, but that the best examination based on the topography of the lesions should be considered beforehand.

Two other examinations have an important place in the diagnostic pathway, especially for peripheral locations: guided TCNB and metastasis biopsy. The efficiency of guided TCNB (93.1 %) is close to the sensitivity found in Rivera et al. meta-analysis (90 % confidence interval 88–91 %) [12]. In our two hospitals, access to the technical platform was limited and few physicians were trained in this procedure. As for metastasis biopsy, to our knowledge, no study comparing the diagnostic efficiency of the different sites has been conducted so far. However, few studies looked at bone lesion biopsy. In a prospective study, Confavreux et al. found a 96 % diagnostic efficiency rate with CT-guided biopsy of bone lesions [23]. A retrospective study revealed a diagnostic efficiency of 100 % with CT-guided biopsy of bone lesions [24]. Bone metastasis biopsy must be considered in the diagnostic pathway due to its high efficiency, especially since the possibility of performing molecular biology has improved over time [23].

To sample mediastinal lymph nodes, EBUS-FNA is an established method to obtain a diagnosis [12]. Its diagnostic efficiency in our study was similar to that found in the large-scale prospective study on lung cancer published by Herth et al. [25]. A study conducted in five expert centers showed an access time to EBUS-FNA of 6 days [26], which is shorter than in our study but it not comparable since the T0 in this study is unknown. This difference is probably due to the fact that this technique was not widely available in our two centers in 2018 and 2019, with limited access to the operating theatre for this procedure. When delay for EBUS-FNA was considered too long, a mediastinoscopy was proposed and performed. That is why we have an important number of mediasticonscopy. It would be interesting to look at the current access times.

Our durations can hardly be compared with those in the literature. We calculated the "time to diagnosis" from the first medical contact, while other articles calculated it from the first pathological CT-scan [27–29]. In some studies, the "date of diagnosis" was the date of sampling, whereas for us, it was the date of the pathological result [30]. In the literature, the data regarding the impact of time to treatment on overall survival are conflicting. A Canadian study that assessed the diagnostic pathways showed that shorter diagnostic times were associated with a poor prognosis (6.8 versus 11.8 months, *p* = 0.027) [31]. This could be accounted for by the fact that symptomatic patients (hemoptysis, recurrent infection, superior cava syndrome, etc.) access faster to diagnostic exams than asymptomatic patients. A Norwegian study did not find a statistical link between the time to treatment and survival [32].

The main strength of our study was the large number (n = 625) of diagnostic pathways analyzed. Another strength was its bicentric design, with a university hospital and a peripheral hospital, which increases the applicability of the results and thus their external validity. Furthermore, we had few missing data despite an exhaustive data collection. In addition, it was an original study that investigated the performance of the main diagnostic techniques for lung cancer but
<figure><img src="image_7.png" /><figcaption>**Fig. 3.** Diagnostic pathway duration (median, interquartile range 25%–75%).</figcaption></figure>

also their access times. One weakness of this study is its retrospective design. Besides, another weakness is the geographical proximity of the two centers (around 50 kilometers): they are used to work together and the study may therefore be more reflective of the practice in the Alpine Arc than in France in general. Our study concerns the years 2018 and 2019; however, new diagnostic techniques have become more widely used since then, notably the EBUS and mini-probe.

Of note, 40 % of patients had a non-conclusive first examination and 15 % could note access a systemic treatment. The relevance of upstream diagnostic reflection is highlighted here. This also raises an ethical question: Should we aim to diagnose all patients? It is therefore essential to optimize care, organized along two main lines: multidisciplinary care and an organized care pathway. In recent years, coordinated healthcare circuits aimed at optimizing the diagnostic pathway have emerged [28,33]. This is the case of the Time To Treat program set up in Canada, which offers a single point of entry for any patient likely to have lung cancer. This program has shortened the time to treatment from 128 to 20 days [33]. The diagnostic pathway should strive to optimize the patient's orientation as soon as lung cancer is suspected and thus limit unnecessary examinations. This type of program has recently been implemented in our center in Grenoble ("Parcours opacité pulmonaire"). It would be interesting to evaluate its impact in a future study.

## Conclusion

In an unselected large population of patients with inoperable lung cancer, the most frequent sampling technique used for diagnosis was bronchial endoscopy, but it was not conclusive in 30 % of the cases. Although less frequently used, metastasis biopsy and CT-guided TCNB were often performed in second intention and were efficient in more than 90 % of cases. In order to make an accurate and rapid diagnosis of lung cancer, it is crucial to choose the most appropriate technique. Bronchial endoscopy remains the first-line examination for central lesions, as it is efficient and easily accessible. Guided TCNB and metastasis biopsy are the preferred techniques for peripheral lesions. The choice of the diagnostic technique should be part of a multidisciplinary approach and a dedicated pathway to optimize initial patient management.

## Authors' contributions

Arnaud Fedi, Cécile Malbert, Juliette Raëth and Anne-Claire Toffart were involved in planning the study, conducting the study, and evaluating the results of the study. Anne-Claire Toffart supervised the research. All authors contributed to the writing of the final manuscript. All authors approved the final version of the manuscript.

## Funding

JR has received a 5000€ scholarship for this study from the Association “De l’Air” and 13,000€ from the Gefluc Grenoble.

## Declaration of competing interest

The authors declare that they have no competing interests.

## Acknowledgments

The authors would like to thank the Gefluc Grenoble and the “De l’Air” association for their financial support of the study. The authors also thank Stéphane Ruckly for the statistics.

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