Originally published as JCO Early Release 10.1200/JCO.2008.16.5258 on June 2 2008

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Lung Cancer Staging Techniques and Induction Therapy: Maybe Timing Is Everything

Harvey I. Pass

Department of Cardiothoracic Surgery, Division of Thoracic Surgery, New York University School of Medicine, New York, NY

Medical and radiation oncologists, as well as thoracic surgeons, have struggled with the appropriate management of stage IIIA lung cancer for close to 30 years, and there still are no consistent guidelines regarding the type of induction therapy (chemotherapy or concurrent chemoradiotherapy), whether to perform surgery (is lobectomy reasonable but not pneumonectomy?), or whether to treat with consolidation therapy after induction. From the multitude of phase II studies, and from the results of the two most often quoted phase III trials examining the role of surgery in locally advanced non–small-cell lung cancer, there seems to be one unifying finding that most of the disciplines involved seem to agree on: Sterilization of the lymph nodes in the mediastinum after induction is a good thing. How good? Multivariable analysis of survival in the European Organisation for Research and Treatment of Cancer study revealed that mediastinal clearance was one of three factors leading to statistically significant survival.¹ In the Southwest Oncology Group Intergroup study, 46% of the surgical patients underwent sterilization of the mediastinal nodes with a 3-year overall survival of 53% in that subgroup.² In addition, the median survival was not reached for those individuals on the Swiss Group for Clinical and Epidemiological Cancer Research trial of cisplatin and taxotere induction who were downstaged to N0.³

Surgeons would argue that this is exactly the group for which the greatest benefit will be seen by using surgery as a local modality, whereas medical oncologists will extol the benefits of chemotherapy and argue that maybe this subgroup of patients with such a fabulous response don't need surgery at all. The bottom line is, How do we convince ourselves that we can query the mediastinum with the greatest fidelity at some reasonable time point after treating the patient, with the least cost to our patients and to us? What we, as clinicians, do with this mediastinal information (which, up to this point, has been difficult to procure without a surgeon invading some cavity) is the subject of other editorials.

When all else fails, it is time to invoke new technology. Specifically for this question of mediastinal response, the first new technology invoked was positron emission tomography (PET)-computed tomography (CT). In a frenzy of articles, culminating in De Leyn's⁴ comparison of repeat mediastinoscopy to PET-CT study, it was determined that the sensitivity, specificity, and accuracy of PET-CT were 77%, 92%, and 83%, respectively, whereas those for repeat mediastinoscopy were 29%, 100%, and 60%, respectively. Moreover, sensitivity (P < .0001) and accuracy (P = .012) were significantly better for PET-CT compared with repeat mediastinoscopy. No matter which is better, it is apparent that PET-CT and histologic confirmation are, for the time being, immutably linked at the hip to classify these patients because the vagaries of PET-CT including the timing of when to do it, the influence of background inflammatory reaction, and the added influence of radiotherapy in combined modality inductions keeping it from achieving 100% accuracy. Proponents of repeat mediastinoscopy rightfully argue that the sensitivity in the De Leyn study was unusually low, and that present sensitivity, specificity, and accuracy for repeat mediastinoscopy are 70%, 100%, and 80% in the hands of the few surgeons who routinely perform mediastinoscopy.⁵ Repeat mediastinoscopy is technically challenging, not so much because of induction chemotherapy with or without radiotherapy, but because the procedure is performed in an inflamed mature or immature scar that limits dissection and decreases enthusiasm for further exploration, potentially leading to incomplete examinations.^6,7

Endobronchial ultrasound (EBUS), now employing real-time linear images so that the endoscopist can literally see the needle sucking the lymphocytes out of some shadowy image on a video monitor, has graduated from new technology to must-have technology, and it is only appropriate that the article by Herth et al⁸ in this issue of Journal of Clinical Oncology reflects the collected experience of restaging with EBUS by reknowned experts in the technology. In various publications, these experts have demonstrated the effectiveness of EBUS (with validation of their findings by same patient surgical mediastinal lymph node dissections) by (1) introducing the largest series of patients⁹ using real-time EBUS (n = 502) with a sensitivity, specificity, and positive predictive value of 94%, 100% and 100%, respectively; (2) aspirating lymph nodes smaller than 1 cm with a sensitivity, specificity, and negative predictive value of 92%, 100%, and 96%, respectively¹⁰; and (3) combining EBUS with endoesophageal ultrasound to enlarge the number of stations available to be biopsied resulting in an accuracy of 94%.¹¹ These studies have been validated in a number of subsequent publications, and for the experts, these examinations take only from 4 to 29 minutes. In light of this background, the report from Herth et al could be construed as disappointing, because in the population of restaging patients with IIIA disease, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 76%, 100%, 100%, 20%, and 77%, respectively. There were no complications from the examinations. The loss of sensitivity is attributed to potentially fibrotic nodes with sequestration of cancer cells. Particularly worrisome, but not surprising, was the negative predictive value of 20%, which hints that, just as with a fine-needle aspiration of a suspicious lung mass, a negative cytology should demand further investigation, possibly with a more invasive procedure. For the mediastinum, that procedure would be a mediastinoscopy.

It is difficult to improve on the results of world-renowned experts, but others can recognize how to exploit these findings and hopefully move to a next level of accuracy for the restaging of the mediastinum. This would involve compulsive use of PET-CT (which the Herth team did not implement) and immediate cytologic reading of the EBUS aspirates. This so-called roadmap approach, using EBUS to concentrate on the abnormal nodes while also allowing accurate sampling of nonenlarged, non-PET avid nodes seen on the monitor, will preserve the accuracy of first-time mediastinal evaluation and ensure a relatively virgin mediastinum for postinduction assessment. Hence, a concerted effort should be made at those institutions that have real-time EBUS technology to selectively perform this examination for the evaluation of the mediastinum, especially in individuals with enlarged lymph node with documented fluorodeoxyglucose uptake. But what procedure should be used for the second assessment? The gold standard for initially assessing the mediastinum in 2008 is probably first-time video mediastinoscopy with a sensitivity of 90%, specificity of 100%, false positive rate of 0%, and false negative rate of 7%.¹² These data are remarkably similar to those seen with the use of EBUS for the first-time assessment of the mediastinum. On the basis of the data from Herth, it would be perfectly reasonable to use the repeat PET as a roadmap again (possibly targeting residual lesions better for aspiration) for a repeat EBUS exam. Rapid on-site evaluation (ROSE) of cytology and multiple aspirations of the nodes should be encouraged because the number of aspirations increases the accuracy of the examination. If all of the EBUS aspirations are ROSE negative in the treated mediastinum, then bring out the gold standard—mediastinoscopy—which should be less difficult than the repeat mediastinoscopy situation. One could ask, Why not just do a mediastinoscopy at the postinduction evaluation in the first place? Because it is going to be in only the minority of cases that you really have a truly negative mediastinum after induction therapy, so why not find the positive with EBUS, a less invasive, less complication-prone procedure and reserve mediastinoscopy for the final search-and-find mission?

It really comes down to a matter of the right timing. It looks like thoracic surgeons and pulmonologists are finding this the right time to adapt real-time EBUS in their everyday practice. The timing for PET scanning after induction therapy is closer to a reality (at least after chemotherapy), and the time is right for EBUS to use PET-CT to guide the biopsies, and for having the cytologists evaluate our biopsies on a just-in-time basis. But most important is deciding on the timing for the mediastinoscopy so that we will have the most accurate documentation of lymph node status after induction by repeating the EBUS and using mediastinoscopy only to confirm true sterilization. Moreover, EBUS in the restaging scenario might even be able to allow for a kindler, gentler method for the longitudinal aspiration of material for guiding therapy on the basis of molecular signatures.¹³

But that's another story, along with the management of the individual after you get your results.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: Harvey I. Pass, Olympus Medical Inc Research Funding: None Expert Testimony: None Other Remuneration: None

NOTES

published online ahead of print at www.jco.org on June 2, 2008.

REFERENCES

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2. Albain KS: SRRVTASFSCeal: Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for Stage IIIA (pN2) non-small cell lung cancer (NSCLC):Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol 23:624s, 2005 (suppl; abstr 7014)

3. Betticher DC, Hsu Schmitz SF, Totsch M, et al: Prognostic factors affecting long-term outcomes in patients with resected stage IIIA pN2 non-small-cell lung cancer: 5-year follow-up of a phase II study. Br J Cancer 94:1099-1106, 2006[CrossRef][Medline]

4. De Leyn P, Stroobants S, De Wever W, et al: Prospective comparative study of integrated positron emission tomography-computed tomography scan compared with remediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy-proven stage IIIA-N2 Non-small-cell lung cancer: A Leuven Lung Cancer Group Study. J Clin Oncol 24:3333-3339, 2006[Abstract/Free Full Text]

5. Rami-Porta R, Mateu-Navarro M, Serra-Mitjans M, et al: Remediastinoscopy: Comments and updated results. Lung Cancer 42:363-364, 2003[CrossRef][Medline]

6. De Leyn P, Lardinois D, Van Schil PE, et al: ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg 32:1-8, 2007[Abstract/Free Full Text]

7. Van Schil PE, De Waele M: A second mediastinoscopy: How to decide and how to do it? Eur J Cardiothorac Surg 33:703-706, 2008[Abstract/Free Full Text]

8. Herth FJF, Annema JT, Eberhardt R, et al: Endobronchial ultrasound with transbronchial needle aspiration for restaging the mediastinum in lung cancer. J Clin Oncol 26:3346-3350, 2008[Abstract/Free Full Text]

9. Herth FJ, Eberhardt R, Vilmann P, et al: Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax 61:795-798, 2006[Abstract/Free Full Text]

10. Herth FJ, Eberhardt R, Krasnik M, et al: Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and PET normal mediastinum in patients with lung cancer. Chest 133:887-891, 2008[CrossRef][Medline]

11. Herth FJ, Eberhardt R: Actual role of endobronchial ultrasound (EBUS). Eur Radiol 17:1806-1812, 2007[CrossRef][Medline]

12. Venissac N, Alifano M, Mouroux J: Video-assisted mediastinoscopy: Experience from 240 consecutive cases. Ann Thorac Surg 76:208-212, 2003[Abstract/Free Full Text]

13. Nakajima T, Yasufuku K, Suzuki M, et al: Assessment of epidermal growth factor receptor mutation by endobronchial ultrasound-guided transbronchial needle aspiration. Chest 132:597-602, 2007[Abstract/Free Full Text]

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