LEIDEN, The Netherlands-In a prospective 100-patient study that may have direct applicability to clinical practice, a team of Dutch researchers has demonstrated improved identification of mediastinal tumor invasion (T4) or lymph node metastases (N2/N3) in patients with non-small-cell lung cancer (NSCLC) when preoperative staging employed transesophageal ultrasound-guided fine-needle aspiration (EUS-FNA) in addition to mediastinoscopy. The finding, they said, is attributable to the "complementary reach" of these diagnostic tools in assessing regional lymph node stations and in the ability of EUS-FNA to detect mediastinal tumor invasion.
Given that patients with N2/N3 metastases (stage IIIA/IIIB) or tumors invading the mediastinum (T4, stage IIIB), heart, or central vessels are typically considered ineligible for surgery (with the exception of those with minimal N2 disease), the results are of pivotal importance to patient management.
Although the EUS-FNA results in the study were used for investigative purposes only, with further treatment decisions based solely on results of mediastinoscopy, in analyzing their findings, Jouke T. Annema, MD, PhD, and colleagues concluded that "if the EUS-FNA results had been taken into account in the present study, a thoracotomy could have been prevented in one of six patients." Dr. Annema, from the division of Pulmonary Medicine at Leiden University Medical Center, Leiden, The Netherlands, was lead investigator of the study, which was reported recently in JAMA (294:931-936, 2005).
The investigators said they believe their study is the first to prospectively compare EUS-FNA vs mediastinoscopy in preoperative staging of NSCLC, and is the first in which positive findings with EUS-FNA were verified by surgical-pathological findings.
Prevalence of unnecessary thoracotomies for NSCLC can be as high as 40%, and occur due to imperfect preoperative staging, but unfortunately, Dr. Annema said, "all currently available staging techniques-such as CT of the thorax, PET, transbronchial needle aspiration, and mediastinoscopy-have limited accuracy in selecting those lung cancer patients without regional lymph node metastases."
EUS, however, a less expensive technique than PET, has demonstrated a high sensitivity (88%) and specificity (98%) in diagnosing T4 tumors (Gastrointest Endosc 59:345-348, 2004), and superior specificity vs PET, at 100% vs 72% (Am J Respir Crit Care Med 168:1293-1297, 2003), with comparable sensitivities and negative predictive value reported in various studies in the range of 60% to 70%.
Eligible patients had proven NSCLC without signs of distant metastases after conventional staging and were scheduled for mediastinoscopy. They were asked to undergo an EUS-FNA examination on a voluntary basis for study purposes, and were informed that only the results of mediastinoscopy would be used to guide treatment decisions. A total of 108 patients were enrolled, and of these, 100 were evaluable for the primary outcome measure, improved detection of mediastinal tumor invasion (T4) or lymph node metastases (N2/N3) with EUS-FNA vs mediastinoscopy alone.
All EUS-FNA exams were scheduled prior to mediastinoscopy, "because we wanted to prevent a situation in which all lymph node tissue was removed by mediastinoscopy, which would prevent EUS-FNA from sampling it," Dr. Annema and coinvestigators explained. EUS-FNA was performed in an outpatient setting, with patients under conscious sedation. The EUS-FNA findings were not available to the cardiothoracic surgeons.
Significant Detection Benefit
Dr. Annema and colleagues found the combination of EUS-FNA and mediastinoscopy identified more patients (36%) with mediastinal tumor invasion (T4) or lymph node metastases (N2/N3) than mediastinoscopy alone (20%) or EUS-FNA alone (28%). They reported that EUS-FNA detected advanced disease in 16% of patients with a negative mediastinoscopy by assessing N2 in 9%, T4 in 4%, and both N2 and T4 in 3%.
This indicated 16% of thoracotomies could have been avoided by using EUS-FNA in addition to mediastinoscopy; therefore, a thoracotomy could have been prevented in one of six patients if EUS-FNA results had been taken into account in treatment planning, they said.
In two patients (2%), the EUS-FNA results were false positive; the findings of N2 lymph node metastasis were not confirmed by mediastinoscopy or surgical-pathological staging. Dr. Annema and colleagues explained that these two patients "were overstaged by EUS-FNA because investigators judged a round, well-defined hypoechoic structure located adjacent to a left lower lobe tumor as a subcarinal lymph node," but ".. in retrospect, biopsies had been taken from the tumor itself, and the false-positive results were due to misinterpretation of the EUS-FNA images."
Going forward, the investigators advocated that "a mediastinoscopy should always be performed in patients with lymph nodes located immediately adjacent to the primary tumor."
Sensitivity for assessing mediastinal lymph nodes improved from 76% and 66% for EUS-FNA alone and mediastinoscopy alone, respectively, to 86% for the combination. In comparison, using CT, the sensitivity of assessing mediastinal lymph node metastases was 69%
Add-On or Breakthrough?
Although the findings are preliminary and were not obtained through a randomized study design, the investigators maintain that "these data strongly suggest that additional staging by EUS-FNA reduces unnecessary thoracotomies." They advocate use of EUS-FNA early in preoperative staging of NSCLC, "because EUS-FNA alone in the present study provided proof of lymph node metastases or mediastinal tumor invasion in 28% of patients with NSCLC."
Looking ahead, they said, "the obvious question that remains is whether staging of NSCLC by EUS-FNA is another add-on or a breakthrough in selecting patients for surgical resection." They cautioned that "overall, mediastinoscopy and EUS-FNA have inherent limitations and they should be viewed as complementary in the regional staging of NSCLC."
In the management of NSCLC, they concluded, "a new algorithm is needed for mediastinal lymph node staging in which the place of the following techniques should be defined: bronchoscopy with transbronchial needle aspiration, endobronchial ultrasound-guided transbronchial needle aspiration, EUS-FNA, PET, and mediastinoscopy."