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Counterpoint: Should Ultrasonographic Endoscopy Be the Preferred Modality for Staging of Lung Cancer? NoEBUS for Staging Lung Cancer? No FREE TO VIEW

Farhood Farjah, MD, MPH; Douglas E. Wood, MD, FCCP
Author and Funding Information

From the Department of Surgery/Division of Cardiothoracic Surgery, University of Washington.

Correspondence to: Farhood Farjah, MD, MPH, Department of Surgery/Division of Cardiothoracic Surgery, University of Washington, Box 356310, 1959 NE Pacific, AA-115, Seattle, WA 98195-6310; e-mail: ffarjah@uw.edu


Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(3):449-451. doi:10.1378/chest.13-2724
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Mediastinal staging directs optimal lung cancer therapy and provides the patient with an important initial prognosis. Performed for > 50 years, mediastinoscopy is effective, safe, and efficient. Technologic advances have yielded additional procedures for mediastinal staging, including endobronchial ultrasound (EBUS)- and esophageal ultrasound (EUS)-guided nodal aspiration. Although effective in confirming malignancy in an enlarged lymph node or a lymph node that was positive on PET imaging, these procedures do not reliably and systematically sample all mediastinal nodes or acquire sufficient tissue for molecular analyses. New technology may appropriately be adopted when it is at least as effective as a standard and offers advantages in terms of safety, efficiency, access, and costs. This premise has not been established for EBUS and EUS. Accordingly, the assertion that endosonography should be the preferred modality for invasive mediastinal staging is unsubstantiated.

The rationale for systematically evaluating multiple mediastinal nodal stations prior to first therapy is to fully understand the extent, and, thus, the biology, of the tumor with an eye toward directing appropriate management. Patients with multistation N2 disease generally are not offered a resection as part of multimodality treatment, and patients with N3 disease are not considered eligible for resection.1 Because a single abnormal N2 node on PET scan portends a high risk of multistation or contralateral nodal involvement, confirming cancer only in the radiographically abnormal node is inadequate. Mediastinoscopy lends itself to adequate mediastinal nodal sampling, even in the setting of a radiographically normal mediastinum, and includes sampling of additional ipsilateral, contralateral, and subcarinal lymph nodes. A classification system for the thoroughness of mediastinal invasive staging has been proposed,2 and recent practice guidelines published by the American College of Chest Physicians acknowledge the importance of thoroughly evaluating the mediastinum.3

Another element of effective mediastinal staging in the modern era of lung cancer treatment is acquiring sufficient tissue for genetic testing. Burgeoning knowledge of the molecular determinants of non-small cell lung cancer (NSCLC) has led to targeted therapies for patients with adenocarcinoma4 and, in the near future, for those with squamous cell carcinoma.5 Furthermore, when standard systemic therapy has failed, patients may be enrolled in experimental trials. Modern gene sequencing tests for lung cancer require up to 10 unstained slides.6 Patients who are clearly ineligible for resection on the basis of bulky, multistation nodal or contralateral disease usually still require tissue diagnosis and confirmation of mediastinal disease and, equally importantly, sufficient tissue for molecular analyses. Needle biopsy rarely yields sufficient tissue for such analyses, whereas an appropriately performed mediastinoscopy routinely provides sufficient tissue for genetic testing.

Efficiency and access to care are other important elements of invasive mediastinal staging. A staging algorithm comprising three different procedures is likely to require the patient to see up to three providers on three different occasions. The presumption that endoscopic staging modalities are now preferred over mediastinoscopy assumes that centers have EBUS or EUS and that physicians are appropriately trained in their use, neither of which are valid assumptions. Only 30% of pulmonary and critical care fellowships have a formal protocol to evaluate EBUS competency,7 and the American Board of Thoracic Surgery mandated a minimum EBUS requirement for the first time in 2013. On the other hand, most centers that perform pulmonary resection have access to a mediastinoscope and an experienced surgeon. A preferred algorithm for invasive mediastinal staging in patients who appear to be candidates for resection is to perform the mediastinoscopy during the same admission and same anesthetic. EBUS and EUS require one or two additional physician appointments for assessment plus one or two additional invasive procedures with their attendant costs and associated risks. Although procedural costs may not be substantially different, indirect costs to patients and caregivers for travel, time off work, and postprocedure care are significant. More importantly, unnecessary delays in treatment often span weeks when multiple caregivers are engaged in multiple disparate steps of lung cancer staging.

The Assessment of Surgical Staging vs Endosonographic Ultrasound in Lung Cancer (ASTER), a European multicenter randomized clinical trial, compared the diagnostic performance of an endosonography-based staging algorithm (EBUS/EUS plus selective mediastinoscopy for negative endosonography) to surgical staging with mediastinoscopy alone.8 Included in the trial were patients with suspected, resectable NSCLC and radiographically abnormal mediastinal nodes by CT or PET scan or a centrally located tumor. The endosonography group had a significantly higher sensitivity for N2/N3 disease than the mediastinoscopy group and a lower futile thoracotomy rate. There were no statistically significant differences between groups in terms of long-term survival, health-related quality of life at 6 months, or costs.9

The ASTER trial is cited often as evidence of the superiority of endosonography over mediastinoscopy, although it has several noteworthy limitations that nullify its conclusions. First, a median of three mediastinal nodal stations were assessed in the endosonography group, whereas a median of four mediastinal nodal stations were assessed in the mediastinoscopy arm, firmly establishing that mediastinoscopy lends itself to a more thorough evaluation of the mediastinum. Second, the ASTER trial has limited generalizability to clinical practice because it excluded patients with a radiographically normal mediastinum. Up to 40% of patients with NSCLC have a radiographically normal mediastinum,10 and practice guidelines recommend invasive mediastinal staging for all patients, except perhaps those with a peripheral clinical stage IA tumor.1,11 Third, the ASTER trial used a surrogate end point (sensitivity for N2/N3) as its primary outcome rather than a patient-centered outcome, such as survival. Surrogate end points can have the unintended consequence of potentially misinforming investigators, clinicians, patients, and other stakeholders about the safety and effectiveness of an intervention (or diagnostic test), so much so that surrogate end points were the subject of scrutiny of the US Food and Drug Administration’s accelerated drug approval process.12 Other important outcomes were either not measured (ie, sufficient tissue for molecular analyses, efficiency) or not different between endosonography and mediastinoscopy (ie, negative predictive value, survival, health-related quality of life, complications). Additionally, the ASTER trial used an antiquated clinical end point—futile thoracotomy defined by the finding of N2 disease, a T4 tumor, small cell lung cancer, or benign disease at the time of resection—that has no relevance to modern day thoracic oncologic care. Stage IIIA N2 can now be appropriately treated with adjuvant therapy,13 and practice guidelines do not consider intraoperative (or even preoperative) detection of N2 to be a contraindication to resection.1,11,14 Practice guidelines likewise recognize that technically resectable T4 tumors are appropriately treated with surgery,1 and no modern thoracic oncology center would consider such resections as futile. Pulmonary resection is also a legitimate treatment option for limited-stage small cell lung cancer,15 and lung nodules in patients at high risk for lung cancer often are appropriately managed through resection, even though some of these nodules will be benign.11,16 Finally, the ASTER trial used a clinically invalid experimental group by making the treatment arm essentially a series of progressive steps in invasive staging (EBUS/EUS followed by mediastinoscopy if endoscopic staging was negative) compared with mediastinoscopy alone. The authors provided multiple opportunities for successful staging in the intervention arm compared with only one opportunity, mediastinoscopy, in the control arm, fundamentally making an invalid comparison. The ASTER trial does not provide evidence for the superiority of endosonography over mediastinoscopy but does suggest that a strategy of endosonography results in a less thorough mediastinal evaluation than surgical staging.

EBUS and EUS play an important role in lung cancer staging, particularly in the confirmation of a clinically abnormal mediastinal lymph node. EBUS, EUS, and mediastinoscopy are complementary procedures that provide, when used wisely, the most efficient and safest staging for early to locally advanced lung cancer. It is a mistake to characterize the choice as one of competition or preference because of a perceived (or misperceived) benefit of avoiding the trauma of mediastinoscopy. Guiding principles for the use of endosonography are as follows: (1) demonstrated competence in the use of EBUS and EUS, (2) patient selection through a multidisciplinary team that includes both pulmonologists and thoracic surgeons, (3) optimization of patient safety, (4) avoidance of unnecessary delays in care, and (5) minimization of unnecessary testing. Mediastinoscopy remains the mainstay and gold standard for invasive mediastinal staging because it is effective, safe, and efficient.

References

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology–υ.2.2013: Non-small Cell Lung Cancer. Fort Washington, PA: National Comprehensive Cancer Network; 2013.
 
Detterbeck F, Puchalski J, Rubinowitz A, Cheng D. Classification of the thoroughness of mediastinal staging of lung cancer. Chest. 2010;137(2):436-442. [CrossRef] [PubMed]
 
Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):e211S-e250S. [CrossRef] [PubMed]
 
Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12(2):175-180. [CrossRef] [PubMed]
 
Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers [published correction appears inNature. 2012;492(7423):288]. Nature. 2012;489(7417):519-525. [CrossRef] [PubMed]
 
UW-OncoPlex-Cancer Gene Panel. University of Washington Laboratory Medicine website. http://web.labmed.washington.edu/tests/genetics/UW-OncoPlex. Accessed June 12, 2013.
 
Tanner NT, Pastis NJ, Silvestri GA. Training for linear endobronchial ultrasound among US pulmonary/critical care fellowships: a survey of fellowship directors. Chest. 2013;143(2):423-428. [CrossRef] [PubMed]
 
Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA. 2010;304(20):2245-2252. [CrossRef] [PubMed]
 
Sharples LD, Jackson C, Wheaton E, et al. Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. Health Technol Assess. 2012;16(18):1-75. [PubMed]
 
Little AG, Gay EG, Gaspar LE, Stewart AK. National survey of non-small cell lung cancer in the United States: epidemiology, pathology and patterns of care. Lung Cancer. 2007;57(3):253-260. [CrossRef] [PubMed]
 
Gould MK, Fletcher J, Iannettoni MD, et al. Evaluation of patients with pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical practice guidelines (2nd ed). Chest. 2007;132(3_suppl):108S-130S. [CrossRef] [PubMed]
 
Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Aff (Millwood). 2005;24(1):67-78. [CrossRef] [PubMed]
 
Pignon JP, Tribodet H, Scagliotti GV, et al; LACE Collaborative Group. Lung Adjuvant Cisplatin Evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559. [CrossRef] [PubMed]
 
Martins RG, D’Amico TA, Loo BW Jr, et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. J Natl Compr Canc Netw. 2012;10(5):599-613. [PubMed]
 
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology–υ.2.2013: Small Cell Lung Cancer. Fort Washington, PA: National Comprehensive Cancer Network; 2013.
 
Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. [CrossRef] [PubMed]
 

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References

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology–υ.2.2013: Non-small Cell Lung Cancer. Fort Washington, PA: National Comprehensive Cancer Network; 2013.
 
Detterbeck F, Puchalski J, Rubinowitz A, Cheng D. Classification of the thoroughness of mediastinal staging of lung cancer. Chest. 2010;137(2):436-442. [CrossRef] [PubMed]
 
Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):e211S-e250S. [CrossRef] [PubMed]
 
Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol. 2011;12(2):175-180. [CrossRef] [PubMed]
 
Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers [published correction appears inNature. 2012;492(7423):288]. Nature. 2012;489(7417):519-525. [CrossRef] [PubMed]
 
UW-OncoPlex-Cancer Gene Panel. University of Washington Laboratory Medicine website. http://web.labmed.washington.edu/tests/genetics/UW-OncoPlex. Accessed June 12, 2013.
 
Tanner NT, Pastis NJ, Silvestri GA. Training for linear endobronchial ultrasound among US pulmonary/critical care fellowships: a survey of fellowship directors. Chest. 2013;143(2):423-428. [CrossRef] [PubMed]
 
Annema JT, van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA. 2010;304(20):2245-2252. [CrossRef] [PubMed]
 
Sharples LD, Jackson C, Wheaton E, et al. Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. Health Technol Assess. 2012;16(18):1-75. [PubMed]
 
Little AG, Gay EG, Gaspar LE, Stewart AK. National survey of non-small cell lung cancer in the United States: epidemiology, pathology and patterns of care. Lung Cancer. 2007;57(3):253-260. [CrossRef] [PubMed]
 
Gould MK, Fletcher J, Iannettoni MD, et al. Evaluation of patients with pulmonary nodules: when is it lung cancer? ACCP evidence-based clinical practice guidelines (2nd ed). Chest. 2007;132(3_suppl):108S-130S. [CrossRef] [PubMed]
 
Fleming TR. Surrogate endpoints and FDA’s accelerated approval process. Health Aff (Millwood). 2005;24(1):67-78. [CrossRef] [PubMed]
 
Pignon JP, Tribodet H, Scagliotti GV, et al; LACE Collaborative Group. Lung Adjuvant Cisplatin Evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559. [CrossRef] [PubMed]
 
Martins RG, D’Amico TA, Loo BW Jr, et al. The management of patients with stage IIIA non-small cell lung cancer with N2 mediastinal node involvement. J Natl Compr Canc Netw. 2012;10(5):599-613. [PubMed]
 
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology–υ.2.2013: Small Cell Lung Cancer. Fort Washington, PA: National Comprehensive Cancer Network; 2013.
 
Aberle DR, Adams AM, Berg CD, et al; National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395-409. [CrossRef] [PubMed]
 
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