The incidence of lung cancer increases with age, with a median age of 70 years at diagnosis.1 Prognosis is determined by a variety of tumor- and patient-related characteristics, which include stage, performance status, and comorbidities. Chronological age has been associated with prognosis2 but not consistently.3,4 Evidence suggests that there are considerable health inequalities in relation to age, involving all aspects of the patient journey from diagnosis to treatment. Data from a large U.K. study revealed that patients over the age of 70 years had a reduced likelihood of receiving both a histological diagnosis and cancer treatment despite adjustments for stage, performance status, and comorbidity.5
Accurate staging is central to providing the most appropriate lung cancer treatment. Results from two recent large population-based studies (136,993 and 26,243 patients, respectively) have both shown that 52% of lung cancer patients in the United Kingdom are recorded as stage one to three at the time of diagnosis.6,7 In other words, the most appropriate lung cancer treatment is dependent on nodal staging in over half of all patients. Noninvasive nodal staging has limitations; for example, a meta-analysis of both computed tomography (CT; sensitivity 51%) and positron emission tomography (PET) scan (sensitivity 75%) showed relatively low sensitivity for the detection of nodal metastases,8 underlining the importance of pathological nodal staging. Until recent years this required mediastinoscopy under general anesthesia, potentially limiting its use in the comorbid elderly. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) allows identification and sampling of mediastinal and hilar lymph nodes as well as of tumor masses lying adjacent to the central airways under conscious sedation. The primary aim of this study was to examine the safety of EBUS-TBNA in elderly patients. The secondary aim was to assess the efficacy of EBUS-TBNA for nodal staging and pathological diagnosis in elderly patients with confirmed or suspected primary lung cancer.
PATIENTS AND METHODS
We conducted a prospective observational cohort study of patients who underwent EBUS-TBNA in the bronchoscopy unit at the University Hospital of South Manchester from March 2010 to August 2012. University Hospital of South Manchester provides a tertiary EBUS-TBNA service for a large cancer network consisting of 11 other National Health Service Trusts. Referral indications for EBUS-TBNA include: nodal staging in suspected or confirmed primary lung cancer, pathological confirmation in suspected advanced lung cancer where nodal staging is not required, isolated mediastinal lymphadenopathy, lymphadenopathy in the context of an extrapulmonary cancer, and pathological diagnosis of a central intrapulmonary lesion deemed accessible with EBUS-TBNA (if both intrapulmonary sampling and nodal staging are required in the same procedure the indication is classified as nodal staging).
All patients who underwent EBUS-TBNA during this time period were included. Ethical approval for the study was not required as the intervention and data collection form part of our standard clinical care. Procedures were performed under conscious sedation, without anesthetic support, using incremental doses of alfentanyl and midazolam. A total of five operators performed all procedures: two lung cancer physicians, a nurse consultant bronchoscopist, and two consecutive interventional bronchoscopy fellows. Two operators were present for all procedures; the primary operator performed the bronchoscopy and the secondary operator was responsible for sampling. Standard diagnostic bronchoscopy was performed before all EBUS procedures by using Olympus (BFF260 or BF6C260; South-on-se, Essex, United Kingdom) bronchoscopes. EBUS-TBNA was performed using an Olympus BF-UC260FW ultrasonic bronchoscope and either 21G or 22G needles. In patients requiring nodal staging for primary lung cancer a systematic examination of the mediastinum was performed and all lymph nodes that met any of the following criteria were sampled: more than 10 mm short axis on CT, abnormal nodal fluorodeoxyglucose avidity above that of the mediastinal blood pool on PET-CT or abnormal ultrasound appearances (defined according to the endobronchial ultrasound image classification system proposed by Fujiwara et al.9: heterogenous echogenicity, round shape, distinct margins, or the presence of a coagulation necrosis sign). N3 nodes were sampled before N2 nodes, followed by N1 nodes. Sampling of lymph nodes from the esophagus was not performed. In those patients undergoing EBUS-TBNA for other indications a targeted procedure was performed based on preprocedure radiology without a systematic mediastinal evaluation.
The data collected prospectively included patient characteristics, procedural and outcome-related information. Complications were recorded by the primary operator after the procedure, following patient recovery. Complications were categorized as major or minor based on U.K. national guidelines.10 Major complications included: major bleeding (defined as the need for resuscitation, transfusion, critical care admission, or death), cardiac arrhythmia requiring intervention, seizure, myocardial infarction or pulmonary edema, pneumothorax requiring intercostals chest drain or aspiration, oversedation requiring ventilatory support or sedation reversal, unplanned hospital admission, or death. Minor complications included: mild or moderate bleeding (defined as the need for continual suctioning or vasoconstrictors), cardiac arrhythmia not requiring intervention, hypotension requiring intervention, and poor tolerance of the procedure requiring early termination). EBUS-TBNA sampling was only classified as a true negative if surgical sampling and/or 6 months of follow-up did not demonstrate evidence of malignancy. EBUS-TBNA samples were examined by a specialist thoracic pathologist and classified according to standard pathological criteria using both morphology and immunohistochemistry. Samples deemed inadequate by the reporting pathologist were classified as a negative EBUS-TBNA and subsequently categorized into “true-negative” or “false-negative” based on subsequent sampling and/or 6 months of clinical–radiological follow-up.
Patients were divided into less than 70 (<70yrs) or 70 and older (≥70yrs) age categories for analysis. The primary outcome measure was procedure safety and we postulated that the risks for elderly patients with confirmed or suspected lung cancer undergoing EBUS-TBNA would be the same for elderly people undergoing EBUS-TBNA for all other indications. For this reason, all patients regardless of indication were included in the safety analysis. Secondary outcome measures were procedure efficacy in nodal staging and pathological confirmation in advanced disease. Efficacy analysis was therefore restricted to patients undergoing EBUS-TBNA for these specific indications. Data were analyzed using SPSS (version 20.0.0). Categorical data are presented as frequencies and χ2 tests used to determine significance. Continuous data are presented as mean values with standard deviations and t tests used to detect differences. We estimated a complication rate in this study of 10% based on two prospective studies of standard flexible bronchoscopy11,12; a sample size of 440 (assuming 20% higher recruitment in patients below the age of 70) has 80% power to detect a 10% difference in complication rate between the groups at a 0.05 two-sided significance level (STATA version 10.1).
Patient and Procedure Characteristics
Four hundred and fifty-one patients underwent EBUS-TBNA, over half were men (242 of 451, 53.7%) and mean age was 66.9 ± 11.9 years (range, 20–93 years). Two hundred and fifty-three patients were less than 70yrs (56.1%) and 198 (43.9%) were 70yrs or older. Fifty-six patients were aged over 80 yrs. There was no significant difference in sex (p=0.30). Performance status was significantly lower in patients who were 70yrs or older (p=0.0001). Nodal staging was a more common indication in the 70yrs and older-age category (131 of 198, 66.2% versus 142 of 253, 56.1%, p=0.03), whereas significantly more patients aged less than 70yrs underwent EBUS-TBNA for investigation of isolated mediastinal/hilar lymphadenopathy (51 of 253, 20.2% versus 19 of 198, 9.6%, p=0.002; Table 1). The final diagnosis was primary lung cancer in 328 patients (173, 68.4% in <70yrs and 155, 78.3% in ≥70yrs; p=0.02), extrathoracic malignancy in 32 patients (17, 6.7% in <70yrs and 15, 7.6% in ≥70yrs), and benign disease in 91 patients (63, 24.9% in <70yrs and 28, 14.1% in ≥70yrs; p=0.005).
Mean doses of sedation were lower in the 70yrs and older category but the duration of procedure did not differ (Table 1). Overall, 32 complications were recorded (7.1% of all procedures). Two (0.4%) were classified as major complications and 30 (6.7%) as minor complications. Both major complications occurred in the 70yrs and older category. The two major complications consisted of: (1) an approximately 50 ml of self-limiting hemoptysis after EBUS-TBNA leading to overnight admission for observation (defined as major complication because of unplanned hospital admission rather than bleeding) and (2) persistent postprocedure hypoxia with reduced respiratory effort requiring sedation reversal leading to resolution of symptoms and full recovery. There was no significant difference in the rate of minor (p=0.057) or major (p=0.19) complications between age groups, though poor procedural tolerance was significantly more common in the less than 70yrs age group (p=0.036) despite the higher levels of sedation. No complications (major or minor) were recorded in the 56 patients aged over 80 years. There was no statistically significant difference in complication rate between the two age cohorts according to indication for EBUS or performance status (Table 2).
Efficacy of EBUS-TBNA in Lung Cancer Staging
A total of 273 patients underwent EBUS-TBNA for nodal staging of suspected or confirmed primary lung cancer (n=142, 52.0% <70yrs and n=131, 48.0% ≥70yrs). On the basis of the pre-EBUS staging CT scan early nodal stage (clinical stage N0/1) was significantly more frequent, compared with advanced nodal stage (N2/3), in elderly patients (45 of 131, 34.4% versus 31/142, 21.8%; p=0.02; Table 3). The frequency of PET-CT before EBUS did not differ according to age category (75.4% <70yrs versus 80.9% ≥70yrs, p=0.3). Primary lung cancer was diagnosed in 255 patients (93.4%), including 48 with small-cell and 207 with non–small-cell lung cancer (NSCLC; including 17 clinical NSCLC without pathological confirmation). A further 17 patients (6.2%) had benign disease and one patient was confirmed to have a nonprimary lung malignancy (Table 3). There was no significant differences between pathological subtypes of lung cancer between the two age categories, however, patients aged 70yrs or above were more likely to have a clinical diagnosis of lung cancer (not confirmed with pathology; p=0.0007; Table 3).
A total of 436 nodes were sampled (234 nodes <70yrs and 202 nodes ≥70yrs). The overall prevalence of nodal malignancy was significantly lower in the 70yrs or above category (113 of 202, 55.9% versus 169 of 234, 72.2%, p=0.0004). In keeping with this, early pathological nodal staging (N0/1), compared with advanced nodal staging (N2/3), was more frequent in the older cohort (p=0.015; Table 4). Furthermore, in patients aged less than 70yrs there were significantly more lymph nodes with a rounded shape on ultrasound (a feature suggestive of malignancy,9 p=0.0001) and a nonsignificant increase in additional characteristics of malignancy in younger patients (heterogeneous echogenicity on ultrasound and larger mean short axis size on CT, p=0.08 and p=0.09, respectively; Table 3). The frequency of inadequate EBUS-TBNA sampling was almost identical across the two age categories (5.1%, 12 of 234, in the <70yrs and 5.0%, 10 of 202, in the ≥70yrs, p=1.0). The sensitivity (92.9% versus 86.4%; p=0.12) of EBUS-TBNA in lung cancer nodal staging was similar between the groups but negative predictive value (91.8% versus 73.9%; p=0.001) and diagnostic accuracy (96.0% versus 90.2%; p=0.02) was significantly higher in the 70yrs or above category (Table 3). The proportion of lymph nodes that underwent subsequent surgical sampling after negative EBUS-TBNA was significantly higher in the less than 70yrs category (40 of 88, 45.5% <70yrs versus 15 of 97, 15.5% ≥70yrs; p=0.0001).
The vast majority of patients diagnosed with NSCLC subsequently went on to have anticancer treatment. Only 8.2% (17 of 207) of patients in the study received no anticancer treatment and were managed with best supportive care. There was no significant difference in the proportion of patients receiving best supportive care alone between the two age categories. The proportion of patients treated with radical radiotherapy was significantly higher in the 70yrs or above category (40.8% versus 9.2%; p<0.0001) whereas the proportion of patients treated with chemotherapy alone was significantly higher in the less than 70yrs category (40.4% versus 23.5%; p=0.011). Surgical resection occurred more frequently in the less than 70yrs age group, but this difference did not reach statistical significance (27.5% versus 17.3%; p=0.097; Table 4).
Efficacy of EBUS-TBNA in Advanced-Stage Primary Lung Cancer (Only Pathological Confirmation Required)
Overall 51 patients (26 patients <70yrs and 25 patients ≥70yrs) underwent EBUS-TBNA in whom the pretest radiology was consistent with advanced-stage primary lung cancer, unsuitable for radical therapy, such that formal nodal staging was not required and pathological confirmation was the aim of the procedure. In 25 of 26 patients less than 70yrs, pathological confirmation was achieved (14 adenocarcinoma, 5 squamous cell carcinoma, 3 small-cell carcinoma and 2 NSCLC–not otherwise specified [NOS]) but one patient required a further procedure after a nondiagnostic EBUS-TBNA (a bone biopsy that confirmed metastatic melanoma). In all 25 patients aged 70yrs or above pathological confirmation was achieved (10 adenocarcinoma, 7 squamous cell carcinoma, 5 small-cell carcinoma, 1 NSCLC-NOS, 1 metastatic breast carcinoma, and 1 metastatic pancreatic carcinoma).
Pathological Subtyping and Molecular Testing
Overall, 244 patients were diagnosed with NSCLC using EBUS-TBNA. The NSCLC-NOS rate was low, 5.9% (8 of 136) of patients less than 70yrs compared with 7.4% (8 of 108) of patients 70yrs or above (p=0.63). EBUS-TBNA provided adequate tissue for epidermal growth factor receptor (EGFR) mutation testing in 94.5% (n=52 of 55 aged <70yrs and n=29 of 30 aged ≥70yrs; p=1.0) of patients.
The complication rate of EBUS-TBNA in this study was low and comparable with that of previous reports.13–15 There was no difference in overall complication rate when analyzed according to age, despite significantly lower performance status in the 70yrs or above cohort and one in three patients being aged 80yrs or older. Indeed tolerance of the procedure, as measured by the requirement for early termination, was significantly better in the older-age cohort.
The efficacy of EBUS-TBNA was assessed in patients undergoing nodal staging with confirmed or suspected lung cancer. No difference in sensitivity was seen according to age threshold, however, negative predictive value and diagnostic accuracy were significantly higher in those aged 70yrs or above. This was a surprise finding and most likely reflects a higher rate of false-negative sampling in the younger cohort. A possible explanation is the higher rate of surgical sampling (via mediastinoscopy or lymph node dissection during resection) in the younger-age group, which may increase the probability of a false-negative sample being detected. Older patients had lower rates of repeat invasive sampling and as a consequence a higher reliance on clinical–radiological follow-up to define the final lymph node diagnosis. This may not be as reliable as surgical sampling. In addition, reduced procedure tolerance in some younger patients may have resulted in less-effective sampling, although the frequency of sample inadequacy was the same for both age cohorts. Regardless of the differences between the age categories, it is clear nodal staging can be performed effectively in elderly patients.
The analysis of EBUS-TBNA efficacy for staging was performed on patients with pathologically confirmed NSCLC requiring nodal staging to define treatment and also patients with a high radiological suspicion of NSCLC where nodal sampling could both define nodal stage and provide pathological confirmation. This second group of patients comprised those who were subsequently found to have a benign pathology (e.g., an inflammatory lung lesion with reactive lymphadenopathy) and those with small-cell lung cancer. These patients were kept in the analysis, rather than restricting it to those with NSCLC only, to ensure that the performance of EBUS-TBNA was assessed in a real-life cohort referred for nodal staging. There was no difference in the prevalence of benign disease and small-cell lung cancer in the two age categories and this therefore should not bias the analysis. Patients in whom EBUS-TBNA was performed because of isolated mediastinal lymphadenopathy, lymphadenopathy in the context of an extrapulmonary cancer or to sample an intrapulmonary mass, and in whom NSCLC was subsequently diagnosed, were not included in the staging analysis as our approach to formal staging during EBUS with systematic mediastinal examination was not performed.
The overall prevalence of nodal malignancy was significantly lower in the 70yrs or above category and patients aged less than 70yrs were referred for EBUS-TBNA with significantly higher nodal staging based on pre-EBUS CT (N2/3 versus N0/1). This could reflect a selection bias in our study population. It is possible that physicians referring elderly patients for EBUS-TBNA tend to refer those with early-stage disease, N0/1, rather than those with a suspicion of N2/3 disease on CT. Worryingly, this could reflect a willingness to attempt pathological confirmation of suspected N2/3 disease in younger patients but a reliance on noninvasive staging in elderly patients with the same radiological findings. This is in keeping with the final pathological nodal staging where a significantly higher proportion of patients aged 70yrs or above were N0. This difference in population characteristics may explain why treatments given to patients differed according to age. Older patients, who were more likely to be staged as N0 but were of poorer performance status, were more likely to receive radical radiotherapy and less likely to have a surgical resection (although this did not reach statistical significance). Younger patients were also more likely to be treated with chemotherapy, reflecting more advanced disease.
The overall NSCLC-NOS rate of 6.6% was lower than previously reported values of 20% to 23% from EBUS-TBNA lymph node sampling16,17 and is a reflection of the appropriate handling of tissue samples and the use of immunohistochemistry. In addition, the advent of targeted therapies for tumors with specific DNA mutations, for example, EGFR mutation, has emphasized the importance of accurate histological typing and sufficient tissue for molecular testing. EGFR mutation analysis was successfully achieved in 96.5% of EBUS-TBNA samples and comparable with that in a recent large multicenter study.17
In conclusion, this large prospective study of EBUS-TBNA has specifically addressed patient safety and procedural outcomes in elderly patients (defined as ≥70yrs to correspond to the median age of lung cancer diagnosis and a common cutoff point in clinical trials).18 EBUS-TBNA is safe and highly effective in achieving accurate nodal staging, pathological confirmation, and morphological subtyping, while allowing sufficient tissue for molecular testing and can therefore be safely offered to elderly patients with suspected lung cancer as part of an integrated management program and will facilitate access to the most appropriate cancer treatment.
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Bronchoscopy; Endobronchial ultrasound; Geriatric oncology; Non–small-cell lung cancer
Copyright © 2014 by the European Lung Cancer Conference and the International Association for the Study of Lung Cancer.