Abstract
Introduction
Currently, in early-stage lung cancer, often multiple nodules are present upon presentation, or a second lung lesion develops during follow-up. The nature of this lesion has profound impact on therapeutic options. We set out to assess the need of repeated (minimally invasive) diagnosis and treatment procedures by determining the incidence of second primary lung cancer (SPLC) and recurrence in our navigation bronchoscopy (NB) program for incidental pulmonary lesions.
Methods
We retrospectively reviewed reports of patients referred for NB and diagnosed with early-stage lung cancer between December 2017 and May 2021. Classification of synchronous, metachronous SPLC, or recurrent disease was based on molecular analysis or pathology-based MDT decisions.
Results
In our population of patients referred for NB, 188 patients were diagnosed as (early-stage) lung cancer. Twenty-four percent had a history of lung cancer upon referral for NB. In total, in 40.4% of the patients a new lung lesion that required additional diagnosis and treatment was found. These could be classified as metachronous SPLC in 26% and recurrence in 19%. In newly diagnosed patients, 22% developed SPLC or recurrent disease during a median follow-up time of only 3.3 years (range, 0.5–5.8 years).
Conclusion
Our findings demonstrate that in a patient cohort undergoing NB for peripheral pulmonary nodules, 40.4% had SPLC or recurrent disease. Most of these patients had metachronous SPLC, underlining the need to obtain adequate tissue that allows for molecular analysis. In newly diagnosed lung cancer patients 22% needed new procedures which impact the need for healthcare facilities.
Keywords: Lung cancer, Recurrence, Second primary lung cancer, Navigation bronchoscopy, Lung cancer diagnostics, Healthcare resources, Early-stage lung cancer, Navigation bronchoscopy, Second primary disease, Recurrent disease
Introduction
Lung cancer is the leading cause of mortality from cancer worldwide, with non-small cell lung cancer (NSCLC) representing the majority of cases. Early-stage NSCLC is characterized by small lung tumors without extensive nodal involvement or distant metastases. These early stage cancers frequently do not translate into symptoms and are detected as incidental pulmonary nodules on computed tomography (CT)-scans or in lung cancer screening programs [1]. Nowadays these nodules can be safely and accurately diagnosed using image-guided navigation bronchoscopy (NB) techniques [2]. However, often, multiple nodules are simultaneously detected and second primary lung cancer (SPLC) may occur in 2.5%–20.8% of newly diagnosed lung malignancies [3]. When multiple pulmonary nodules are present, targeted evaluation is required to determine its origin and the relation between the multiple lesions using genomic and molecular characterization to distinguish metastatic disease from SPLC [3, 4].
Besides the clinical need to analyze multiple lesions during a single diagnostic procedure, often these patients had prior episodes of cancers or are referred anew for the analysis of newly arisen nodules detected during follow-up. This translates into a need for larger volume of diagnostic capacity in a nodule care center than based on the incidence of detected incidental nodules in screening or routine clinical care.
Although modern imaging technologies like high resolution CT and 2′-deoxy-2’-[18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography imaging are useful, pathological confirmation remains the gold standard. It can not only enable analysis of an earlier tumor but can also confirm eligibility for targeted therapies. The primary challenge lies in the ability to obtain tissue samples in all cases and/or nodules to determine their relationship between the different tumors, both over time and when detected simultaneously. Also new lesions are frequently detected during follow-up, and we observe a shift in the first line treatment of stage Ia lung cancer in our country where now stereotactic ablative radiotherapy is more frequently offered than surgery [5], where in majority (65%) these patients are treated without tissue [6].
While the risk of recurrence diminishes over time, the risk of developing SPLC remains increased [7–9]. A histologically or clonally distinct tumor that develops in an individual with a previous history of lung cancer is called metachronous SPLC. [10]. Distinguishing between recurrent disease and metachronous SPLC can be difficult, as both can present similarly on imaging but have distinct implications on prognosis, treatment options, and patient counselling. Historically, synchronous or recurrent tumor diagnostic evaluation is based on (large) surgical specimens [11], whereas NB procedures allow for small samples only. With the implementation of novel diagnostic methods, such as NB, it has become feasible to obtain a pathology-confirmed diagnosis and determine the relationship of newly detected and multiple pulmonary lesions suspected for malignancy, which were previously mostly inaccessible for sampling [2, 12].
The effect of the high incidence of newly detected pulmonary nodules during follow-up on the future need for diagnostic and therapeutic interventions is largely unknown. Therefore, we aim to identify the incidence of SPLC and recurrent disease in our cohort of patients referred for diagnostic NB. With this exploration, we aim to better prepare for the future needs and capacity of healthcare resources including the newly developing NB programs in a European population and underline the need for and feasibility of NB-based tissue diagnosis for new, multiple or subsequent lesions in patients in follow-up for treated lung cancer.
Methods
Since the start of our NB program at Radboud university medical center in Nijmegen, the Netherlands, in December 2017 to June 2021, a registry was built to collect data that allowed patient, lesion as well as follow-up analysis. During the inclusion period, patients were referred for diagnosis of an incidentally detected lung nodule by NB from all over the Netherlands, as the Radboud university medical center was the only center performing NB. For this study, we focused on patients diagnosed with NSCLC stage I to IIIA (T1a-T4, N0-N1, and M0) during NB and excluded patients diagnosed with SCLC, N2/3 involvement or referred for (repeat) biopsy of known metastatic disease. Patients were followed at the Radboud university medical center in Nijmegen or at the center from which they were referred for NB. Follow-up data from patients were retrieved from electronic patient files and from thirty-two referring centers. Patients that were lost-to-follow-up were excluded. Tumors were staged according to the eighth edition of the International Association for the Study of Lung Cancer (IASLC) TNM classification system [13].
All patients provided written informed consent to use their data (Reference No. 2017-3,706, 2017-3,707, and 2019-5,148). Patients were excluded when they had indicated to opt-out of all retrospective research or when they received NB for (re-)biopsy for (molecular) analysis of known stage IV disease. Information on all lung cancer diagnoses – in medical history, during NB and in follow-up – was collected. In case of lack of information on family history of lung cancer, surgery type or surgery outcome, this was categorized as unknown.
Pathological Analysis
Synchronous SPLC was defined as the detection of multiple lung tumors that are (suspected) different in origin and have been diagnosed either on the same day through imaging or biopsy or were found in one surgical specimen. Recurrence was defined as a new episode of the same tumor after treatment of curative intent. This includes when recurrent tumor involvement is limited to lymph nodes (based on cytology, histology, or imaging) without a primary lung lesion (cT0 or cTx), this was classified as recurrent disease. To determine if a second lung tumor was metachronous SPLC or recurrent disease, analysis was performed by routine histopathology (morphology and immunochemistry when necessary). In selected cases – based on MDT decision or at the discretion of the pathologist – molecular analysis with additional clonal comparison was performed using either a single-molecule molecular inversion probe using a 53-gene panel (therapy-orientated) or whole exome sequencing. For clonal comparison, it is investigated whether tumors show similarities in genetic aberrations, especially in the TP53 gene. When molecular analysis was not available, the MDT decision on synchronous or metachronous SPLC and/or recurrence was used. The Martini and Melamed criteria were separately applied to the collected data to compare outcomes in the case of SPLC and recurrence [14]. These criteria state that a metachronous tumor can be identified if the histology is different (A) or if histology is the same but the interval between cancers was at least 2 years (B) or the second tumor is a carcinoma in situ (ACIS, C) or the second tumor is in a different lobe or lung and is staged N0 and M0 (D).
Data Analysis
Categorical variables were expressed as absolute and relative frequencies, while continuous variables were expressed as mean and standard deviation. Non-normally distributed data were summarized using medians and interquartile ranges (IQR). Descriptive analysis, including scatter plots, and statistical analysis were performed using SPSS statistics (Version 29.0, IBM SPSS Statistics for Windows, USA). Differences in continuous variables between groups were analyzed using an independent samples t-test for normally distributed data, and the Mann-Whitney U test for non-normally distributed data. Differences in categorical variables between groups were analyzed using a chi-square test or Fisher’s exact test where appropriate. A p value <0.05 was considered statistically significant.
Results
Of the 362 included patients that underwent NB between December 2017 and May 2021, a total of 188 NSCLC patients were included for analysis (Fig. 1). In the total group of included patients, the mean follow-up time was 3.3 years (range 0.1–6.3 years) since NB. Baseline characteristics are summarized in Table 1; 98.9% of the patients could be classified as stage I or II disease based on imaging at baseline. Forty-five (23.9%) patients had a history of lung cancer upon referral for NB for the analysis of a new lung lesion.
Fig. 1.
Flowchart of patient inclusion. Frequencies are all relative to patients who received a diagnosis of early-stage lung cancer during NB (n = 188). FU, follow-up, LN, lymph node disease, MA, molecular analysis, MC, morphological characteristics, NB, navigation bronchoscopy, NSCLC, non-small cell lung cancer, SCLC, small cell lung cancer, SPLC, second primary lung cancer.
Table 1.
Patient and tumor characteristics
| Patient baseline characteristics, all lung cancer patients (n = 188) | Frequency |
|---|---|
| Age at first lung cancer diagnosis, median (±IQR), years | 66 (±14) |
| Gender, n (%) | |
| Male | 96 (51.1) |
| Female | 92 (48.9) |
| Family history of lung cancer, n (%) | |
| Yes | 42 (22.3) |
| No | 83 (44.1) |
| Unknown | 63 (33.5) |
| History of (non-lung) cancer, n (%) | 71 (37.8) |
| History of lung cancer, n (%) | 45 (23.9) |
| Smoking history, n (%) | |
| Current | 64 (34.0) |
| Former | 109 (58.0) |
| Never | 15 (8.0) |
| Total number of nodules navigated to, n | 230 |
| Nodules per patient, n | 1.22 |
| Nodule size, mm, median (±IQR) | 17.4 (±8.9) |
| Stage at NB, n (%) | |
| IA | 144 (76.6) |
| IB | 20 (10.6) |
| IIA | 6 (3.2) |
| IIB | 16 (8.5) |
| IIIA | 2 (1.1) |
NB, navigation bronchoscopy; IQR, interquartile range.
Detailed information on demographic data and treatment of the first lung cancer diagnosis of these patients and patients with one lung cancer diagnosis is summarized in Table 2. Patients who received systemic treatment or best supportive care for early-stage disease had comorbidities, for example, other cancer diagnoses. As expected, patients who developed recurrence after surgery for an initial lung cancer (n = 13) were significantly more often diagnosed with pN+ disease (p = 0.002) or pN+, R+ and/or PL+ disease (p = 0.002) compared to patients who did not develop recurrence (n = 91; Table 2).
Table 2.
Treatment types of the initial lung tumor when a patient had one diagnosis of lung cancer, synchronous SPLC, metachronous SPLC, or recurrent disease
| Treatment characteristics | Patients with one lung cancer diagnosis (n = 96) | Patients with synchronous SPLC (n = 16) | Patients with metachronous SPLC (n = 32) | Patients with recurrent lung cancer (n = 22) |
|---|---|---|---|---|
| Age at first diagnosis, median (±IQR), years | 67 (±11) | 68 (±13) | 63 (±12) | 65 (±14) |
| Lung cancer diagnosis before NB, n (%) | 0 (0%) | 0 (0%) | 23 (72%) | 8 (36%) |
| Follow-up available, median (±IQR), years | 2.9 (±2.3) | 3.8 (±2.5) | 6.0 (±4.0) | 3.9 (±2.7) |
| Surgery, n (%) | 57 (59) | 10 (63) | 24 (75) | 13 (59%) |
| Clinical stage distribution of first diagnosis, n (%) | ||||
| IA | 44 (77) | 5 (50) | 15 (63) | 8 (62) |
| IB | 5 (9) | 2 (20) | 5 (21) | 4 (31) |
| IIA | 2 (4) | 1 (10) | – | – |
| IIB | 5 (9) | 2 (20) | 3 (13) | 1 (8) |
| IIIA | 1 (2) | – | 1 (4) | – |
| Surgery type, n (%) | ||||
| (R-)VATS | 53 (93) | 9 (90) | 18 (75) | 9 (62) |
| Thoracotomy | 3 (5) | 1 (10) | 3 (13) | 3 (23) |
| Unknown | 1 (2) | – | 3 (13) | 1 (8) |
| Extensiveness, n (%) | ||||
| Segmentectomy | 10 (18) | 1 (10) | – | – |
| Lobectomy | 46 (81) | 9 (90) | 24 (100) | 13 (100) |
| Bilobectomy | 1 (2) | – | – | – |
| pN-stage, n (%)* | ||||
| pN0 | 50 (88) | 9 (90) | 21 (88) | 7 (54) |
| pN1 | 2 (4) | 1 (10) | 2 (8) | 4 (31) |
| pN2 | 4 (7) | – | 1 (4) | 2 (15) |
| Unknown | 1 (2) | – | – | – |
| pN+, R+ or PL+ stage, n (%)** | 12 (21) | 3 (30) | 4 (17) | 8 (62) |
| Adjuvant therapy, n (%) | 9 (16) | 4 (40) | 7 (29) | 3 (23) |
| Radiotherapy, n (%) | 33 (34) | 5 (31) | 6 (19) | 9 (41) |
| Clinical stage distribution of first diagnosis, n (%) | ||||
| IA | 30 (91) | 5 (100) | 6 (100) | 6 (67) |
| IB | 1 (3) | – | – | 2 (22) |
| IIA | 1 (3) | – | – | – |
| IIB | 1 (3) | – | – | 1 (11) |
| Systemic therapy, n (%) | 2 (2) | 1 (6) | 2 (6) | – |
| Clinical stage distribution of first diagnosis, n (%) | ||||
| IA | – | 1 (100) | 1 (50) | – |
| IB | 1 (50) | – | – | – |
| IIA | – | – | – | – |
| IIB | 1 (50) | – | 1 (50) | – |
| IIIA | – | – | – | – |
| Best supportive care, n (%) | 4 (4) | – | – | – |
| Clinical stage distribution of first diagnosis, n (%) | ||||
| IA | 3 (75) | – | – | – |
| IIA | 1 (25%) | – | – | – |
Patients with multiple episodes (i.e., SPLC and recurrence thereafter) are not included in this table.
NB, navigation bronchoscopy; IQR, interquartile range; SPLC, second primary lung cancer; (R-)VATS, (robotic) video assisted thoracoscopic surgery.
*Significant difference in pN+ disease between patients with recurrence (n = 13) and without recurrence (n = 91) who underwent surgery (p = 0.002).
**Significant difference in patients with N+, R+, and/or PL+ disease between patients with recurrence (n = 13) and without recurrence (n = 91) who underwent surgery (p = 0.002).
Incidence of SPLC and Recurrence
Of the 188 NSCLC patients, 96 (51.1%) had only one diagnosis of a lung tumor during follow-up; in 84 patients, 2 lung cancers were diagnosed which could be subdivided in synchronous (n = 16), metachronous (n = 41) SPLSs, or recurrence (n = 27); additionally n = 8 cases had more than 2 diagnosis of lung cancer in different combinations (Fig. 1). When combined and grouped as synchronous, metachronous SPLC or recurrent cancer, a total of 32 patients had a diagnosis of two synchronous SPLC (17.0%), 49 patients had a diagnosis of metachronous SPLC (26.1%), and 35 patients had a diagnosis of recurrent disease (18.6%), across the whole cohort of included patients. Some patients received multiple of these diagnoses: nine patients were diagnosed with both synchronous and metachronous SPLC; 5 patients were diagnosed with synchronous SPLC and recurrent disease; and 6 patients were diagnosed with metachronous SPLC and recurrent disease of one of the prior lung tumors (3.2%). There were 2 patients diagnosed with synchronous SPLC, metachronous SPLC and recurrent disease of one of these cancers (1.1%); all proven by molecular analysis. Of the 76% of patients that were diagnosed with lung cancer for the first time during NB, 22% developed metachronous SPLC or recurrence after a median follow-up time of only 3.3 years (range, 0.5–5.8 years) in this subgroup.
Pathological Assessment of Relationship between Multiple Diagnoses
Of the 33 diagnoses of synchronous SPLC in 32 patients, a total of 18 diagnoses (54.5%) were based on molecular analysis (n = 7, 21.2%) or distinctly different tumor type by routine histopathological analysis (n = 11, 33.3%). Of the total 59 diagnoses of metachronous SPLC in 49 patients, 21 (35.6%) diagnoses were based on molecular analysis (n = 14, 23.7%) or routine histopathological analysis (n = 7, 11.9%). Of the 39 diagnoses of recurrence in 35 patients in this cohort, a total of 15 (38.5%) diagnoses were made based on molecular analysis (n = 6, 15.4), routine histopathological analysis (n = 2, 5.1%) or based on findings in the lymph nodes without a primary lung lesion (n = 7, 17.9%). In the remaining cases without a pathology proven relationship to earlier lung tumors, the relationship of tumors was based on MDT decision who took patient medical history, lung cancer history, presentation, and CT and [18F]FDG-positron emission tomography imaging features into account in addition to pathology consultation (77 diagnoses, 58.8%).
Simulation of Application of Martini and Melamed Criteria in This Cohort
When the Martini and Melamed criteria based on time interval and basic-histology would have been applied to distinguish recurrent and SPLC incidences in this cohort, 14 lung lesions diagnosed as recurrent disease would have been classified as SPLC (from 39 diagnoses to 25 diagnoses) by Martini and Melamed. The other way around, only one lung lesion diagnosed as SPLC was classified as recurrence by the Martini and Melamed criteria (from 33 diagnoses to 32 diagnoses).
Time-Interval Analysis of Patients with Proven SPLC versus Recurrent Disease
For time analysis, we excluded patients with more than two lung cancers diagnosed by NB. Thirty-two patients were diagnosed with metachronous SPLC with a mean interval time between first and SPLC of 3.3 years (range, 0.1–17.1 years, Fig. 2). In 22 patients, recurrent disease was confirmed after a mean interval time between first diagnosis and recurrence of 1.7 years (range, 0.7–6.1 years, Fig. 2). Based on an independent samples t-test (p = 0.015), these time intervals are significantly different (Fig. 2). When looking at the duration of follow-up between these two groups, the median duration of FU in patients with metachronous SPLC was 6.0 years (range, 1.5–25.5 years) and in patients with recurrence was 3.9 years (range, 1.1–12.0 years) and this was significantly different (p = 0.045). However, it should also be noted that 11 out of the 22 patients diagnosed with recurrence died during follow-up and only 8 out of 32 patients with metachronous SPLC, prolonging the follow-up time.
Fig. 2.
Subgroup analysis of time between initial lung cancer and recurrence (n = 22) or metachronous SPLC (n = 32). Seven patients with recurrence (31.8%) and 24 patients with metachronous SPLC (75%) were diagnosed after 2 years. *p = 0.015.
Discussion
In our cohort of patients referred for evaluation of newly detected pulmonary nodules by image-guided NB, we found a high incidence (40.4%) of second lung malignancy, consisting of metachronous SPLC (26%) or recurrent disease (19%). Upon initial presentation, 24% of patients had a history of lung cancer. Of the 76% of patients that were diagnosed with lung cancer for the first time during NB, 22% developed new lesions after a median follow-up time of only 3.3 years. These results suggest that this patient cohort has a high need for additional (minimally invasive) diagnostic procedures and subsequent treatments, which has profound implications for the healthcare capacity and needed volume of NB-programs in the future.
The proportion attributed to recurrent disease of 19% can be considered relatively low compared to literature standards (26%–45% according to 9th edition of the TNM staging) [15]. More of our patients with new nodules were diagnosed as metachronous SPLC (26%). Compared to previous studies that investigated cohorts of patients receiving curative surgical or radiotherapeutic therapy collected between the early 2000s and 2015, our cohort shows a noteworthy increase in this SPLC incidence [9, 16–22]. Chang et al. [21] reported an incidence in the STARS and ROSEL trial, of only 3 patients with SPLC (5.2%), either treated with surgery (n = 2) or SABR (n = 1) and reported a 15.5% recurrence rate after a median follow-up of 3.4 years. Choi et al. [9] found an incidence of metachronous SPLC of 5.7% amongst a cohort of 8,448 patients diagnosed with lung cancer between 1997 and 2006, who were followed through 2018. Fink-Neuboeck et al. [19] recently reported that among their 342 consecutive surgical patients with NSCLC, 50.3% of patients developed recurrence, while 7.3% was diagnosed with SPLC and 2.3% of patients developed both SPLC and recurrence during 10–16 years follow-up, all proven by immunohistochemical processing. To the best of our knowledge, the highest incidence of metachronous SPLC is documented by Leroy et al. [18] who saw an incidence of 16.1% in a cohort of 522 surgically treated patients with stage I-III NSCLC with a median follow-up of 4.9 years. All these incidence reports, however, included patients over 10 years ago. Advanced NB has since become available and implemented in routine practice in many centers around the world, enabling early diagnoses of small peripheral lung nodules. In new referrals, these nodules are found either as incidental findings, or in a screening program, but also, as we show here in 24% of cases, as newly detected lesions during follow-up after initial lung cancer diagnosis and treatment. The incidence found in this study is higher than in earlier reported studies, which may have been influenced by patient selection, different cohorts, or improved CT-imaging quality and better detection, or changes in type of curative treatment over time. Also, the total number chest CTs and of incidental pulmonary nodules found in these chest CT has been doubled over the last decade, offering the chance to diagnose more stage I lung cancers [1].
Given the large group of patients that present with multiple or secondary lung lesions, there seems to be an even greater need for extensive tissue acquisition as well as a need for tissue sparing treatments to allow re-intervention. This is underlined by the number of patients that did not receive a diagnosis based on morphological or molecular analysis but only on MDT decision (58.8%). Moreover, the increased incidence of second lung cancer diagnoses implies that stratification of patient referral is present in this cohort and that the implementation of such a program can have consequences on patient care complexity. This complexity and the small subgroups as identified in this analysis does not allow to identify certain risk factors, as has been done by Leroy et al. [18] and Han et al. [23].
Guidelines on Surveillance
International guidelines generally recommended that early-stage lung cancer patients who have undergone curative treatment are followed with regular computed tomography (CT) scans – every 6 months for the first 2 years, and annually for the next 3 years [24]. Our study shows that this specific cohort of patients diagnosed with lung cancer during NB not only has a high incidence of SPLC (of which 25% was diagnosed 5 years after initial diagnosis) but also patients diagnosed with recurrent disease even after 5 years. Several other groups have furthermore studied the risk of developing SPLC, revealing that patients with a history of lung cancer seem significantly more prone to developing (new) lung cancer(s) compared to the general population, regardless of smoking history [9, 17, 20]. We would advise to continue CT follow-up in lung cancer survivors after the 5-year-mark, based on our observations. Specifically in countries like the Netherlands, where no screening program has (yet) been implemented while the chance to develop SPLC does not decrease for these patients [25]. By prolonging surveillance and implementing diagnostic efforts when a lesion is identified, SPLC or recurrence could be diagnosed in an early stage, enabling more (curative) treatment options.
Criteria to Identify Metachronous SPLC
Recently, van Rossum et al. [6] reported that in the Netherlands, 66% of patients treated with SABR, did not receive a definitive pathological diagnosis but that diagnosis was based on clinical information only. This lack of pathological confirmation could not only cause overtreatment but also creates challenges in follow-up, as no pathological comparison can be made to determine the relationship between the treated tumor and a newly identified lesion. In our cohort, 54 of 131 multiple lung cancers diagnoses could be confirmed as either SPLC or recurrence, distinct morphology, or clinical presentation of recurrence in the lymph nodes (41.2%), leaving a considerable proportion of cases reliant on MDT decisions (58.8%). We have also seen that without molecular information, the relationship of multiple diagnoses of lung cancer differs significantly between MDT decision and the Martini and Melamed criteria, highlighting substantial discrepancies between these methods. Tian et al. [26] showed that the pooled sensitivity and specificity for distinguishing SPLC and intrapulmonary metastases based on the Martini and Melamed criteria were 78% and 47%. Meanwhile, current guidelines suggest that MDT decisions are a suitable alternative when comparable tumor tissue is unavailable, allowing detailed evaluation of patient and tumor information [27, 28], tissue confirmation is still the gold standard. Therefore, we strongly recommend obtaining biopsies of all lesions to enable current and future histopathological and molecular analysis.
Kaaki and D’Amico [29] mention that taking biopsies of all lung nodules can be challenging and the quality of the biopsies is of high importance for subsequent histopathological and molecular analysis when comparing two lung cancer specimens. Besides a different tumor histology or tumor subtype, all other modalities used to distinguish lung tumors are not necessarily confirmatory but more suggestive and could aid in the MDT decision. However, Chiang et al. [4] found that histologic interpretation was discordant with next-generation sequencing in 22% of cases. The molecular analyses on small tissue biopsies can be performed but is challenging due to limited amount of DNA. The performance of NB is therefore important to be able to acquire enough tissue in a minimally invasive fashion to not only distinguish tumor(s) now but also in future follow-up when new lung tumors could be found.
Strengths and Limitations
The strength of this study is that we have evaluated all patients referred for analysis of pulmonary nodules and performed a detailed analysis of clinical follow-up in a representative European cohort of patients with early-stage lung cancer irrespective of the treatment chosen. This population of patients referred for NB is specific, specifically since our (and most) NB program(s) exclude patients with a high suspicion of clear mediastinal or EBUS-accessible hilar lymph node involvement thus selecting patients with early-stage lung cancer rather than advanced stage disease. This strict case selection is also a limitation in comparison to earlier publications, but may serve as future reference for other nodule care center populations.
Patients with a history of lung cancer that develop recurrence could also have tumor manifestations in other organs as the only site of recurrence. These patients will not be referred for NB and this could influence the incidence ratio found here. A potential weakness is that this is a single center cohort from a university reference center, the median follow-up time of 3.3 years for the complete cohort and 3.9 and 6.0 years for the patients with a diagnosis of recurrence and metachronous SPLC, respectively, is relatively short. Additionally, not all diagnoses were proven by molecular or morphological analysis. Additional metachronous SPLC or recurrent lung cancers could potentially be identified with a longer follow-up period, further increasing the incidence of SPLC and recurrent disease and defining additional care needs of these patients.
Conclusion
In this cohort of patients referred for NB in a European center, 188 patients were diagnosed with early-stage lung cancer. Of those patients, 40.4% were diagnosed with a second lung lesion, either during NB or after NB. We observed a high incidence of synchronous SPLC (n = 32, 17%), metachronous SPLC (n = 49, 26%) and a considerable group of patients with recurrent disease (n = 35, 19%). A history of lung cancer was present in 24% of patients and of the 76% of patients that were diagnosed with lung cancer for the first time with NB, 22% developed SPLC or recurrence after a median follow-up time of only 3.3 years. This volume of patients has significant implications for healthcare resources including the capacity of emerging navigation programs and comes on top of the volume of newly detected peripheral pulmonary nodules (as incidental findings or in screening programs) and the volume of patients that need a diagnostic NB for benign nodules or repeated biopsy during metastatic disease treatments. Our findings also underline the importance of obtaining extensive tissue sampling, especially in patients undergoing SABR, to facilitate molecular or morphological analysis to differentiate between SPLC and recurrence. And lastly, since 25% of patients with metachronous SPLC were diagnosed later than 5 years after initial treatment, a continued follow-up beyond the routine 5-year term may be considered to detect recurrent disease and metachronous SPLC in time. These observations underline the need for a critical reappraisal of current standards for follow-up imaging, the definition of “actionable” nodules (i.e., standardizing the criteria for obtaining tissue biopsy) and the methodology used therein (robotic assisted bronchoscopy versus manual technologies like CBCT-NB).
Statement of Ethics
The medical ethical committee Oost-Nederland approved the study (Reference No. 2017–3706, 2017–3707 and 2019–5148). Written informed consent was obtained from all subjects involved in the study.
Conflict of Interest Statement
R.L.J.V. reports unrestricted research grants to the department from Astra Zeneca Oncology, Pentax Medical, Philips, Johnson & Johnson, KWF (national cancer fund), and IMAGIO (Innovative Health Initiative-EU fund); consulting fees to the department from Johnson & Johnson, Intuitive and NLC; travel arrangements from Johnson & Johnson and Intuitive; is chair of the Dutch Society of Technical Physicians (NVvTG); and received in-kind support for conducting this study from Philips Medical and other loan of equipment for performing a clinical study from Intuitive. E.H.F.M.v.d.H. reports unrestricted research grants to the department from Astra Zeneca Oncology, Pentax Medical, Philips, Johnson & Johnson, Intuitive, KWF (national cancer fund), and IMAGIO (Innovative Health Initiative—EU fund); consulting fees to the department from Johnson & Johnson, Intuitive and NLC; speaker fees to the department from Janssen-Cilag, Siemens, Pentax, Ethicon, Astra Zeneca, Intuitive and Philips, travel arrangements from Siemens; is an Executive Board member of European Association for Bronchology and Interventional Pulmonology (EABIP); and received in-kind support for conducting this study from Philips Medical and other loan of equipment for performing a clinical study from Intuitive and Pentax. All other authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Conceptualization, project administration, visualization, and formal analysis: D.K.M.t.W., R.L.J.V., and E.H.F.M.v.d.H.; data curation, writing – original draft, and investigation: D.K.M.t.W.; methodology and writing – review and editing: D.K.M.t.W., R.L.J.V., A.F.T.M.V., S.V., E.H.J.G.A., and E.H.F.M.v.d.H.; supervision: R.L.J.V., A.F.T.M.V., S.V., E.H.J.G.A., and E.H.F.M.v.d.H.; validation: D.K.M.t.W., R.L.J.V., and E.H.F.M.v.d.H.
Funding Statement
This study was not supported by any sponsor or funder.
Data Availability Statement
The data that support the findings of this study are not publicly at this time because the dataset is being used for ongoing analyses but are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are not publicly at this time because the dataset is being used for ongoing analyses but are available from the corresponding author upon reasonable request.
