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Journal of Clinical Oncology, Vol 24, No 21 (July 20), 2006: pp. 3317-3318 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.06.5235
Selection of Patients for Surgery After Induction Chemotherapy for N2 Non–Small-Cell Lung CancerRoyal Brompton Hospital, Imperial College, London, United Kingdom Stage IIIA non–small-cell lung cancer with mediastinal node metastases (N2 non–small-cell lung cancer) is actually a spectrum of diseases with widely divergent prognoses. Each subset has been traditionally defined by the tests that are necessary to detect the N2 disease, which in itself is an indication of the extent and bulk of the nodal deposits. The subset with the worst prognosis has such gross N2 disease that it could be detected clinically as the patient enters the clinic. Survival in such patients is usually measured in months. The subset with the best prognosis has such subtle nodal disease that it eludes clinical examination, chest radiology, CT scanning, and even mediastinoscopy, and it is ultimately called unexpected N2 disease when found at thoracotomy. According to several authors, patients in this subset have a 20% survival at 5 years if, despite the mediastinal nodal disease, complete resection proves feasible.1 Even this subset is an amalgam of cases. Some unexpected N2 disease is not so much unexpected as unconfirmed; others might have small deposits, even widespread involvement, in nodes below the size threshold that would normally trigger a mediastinoscopy. Some cases are the result of a falsely negative mediastinoscopy, and others involve nodes beyond the reach of the mediastinoscope. The realization that N2 disease might elude even the most diligent preoperative evaluation led surgeons to undertake an increasingly detailed intrathoracic re-evaluation at thoracotomy. A central part of this has become the removal of apparently normal lymph nodes in the mediastinum and hilum for subsequent histologic examination.2 Such techniques have improved staging and have often discovered N2 disease that was not visualized by naked-eye assessment of the sliced nodal tissue but was discovered on subsequent histologic–even immunohistologic–examination after surgery. All of the component groups within the unexpected N2 subset had one unifying and comforting characteristic: in patients whose disease could not be confirmed before thoracotomy, complete resection was feasible in the majority of cases, and the survival rates justified the added risks of continuing with resection. The widespread use of positron emission tomography (PET) scanning with fluorodeoxyglucose has reshuffled the pack. The greater accuracy with which this technique detects N2 disease compared with computed tomography (CT) scanning and even with mediastinoscopy has resulted in some patients with "unexpected" N2 disease being identified before surgery. These patients, if their disease is confirmed histologically, now join the proven N2 cases, for which the current standard of care is induction therapy. Presumably, those cases of N2 disease that elude PET scanning and are discovered at thoracotomy will have even more subtle nodal disease. The principles of stage migration suggest that both groups should have an improved survival when compared with the older subsets. However, PET scanning has spawned two new problems. The specificity with which PET scanning identifies nodal disease is less than perfect, with around 10% false-positive rates in studies. How do we ensure that these patients proceed appropriately with surgical treatment? In those patients whose PET scan suggestion of N2 disease is confirmed histologically, how do we select patients who should then proceed with resection? The simple answer to the first question is to undertake mediastinoscopy in all PET-positive cases without extrathoracic disease. Studies have shown that the answer to the second question lies in selecting patients in whom induction therapy has downstaged the patients and eradicated the mediastinal nodal deposits. This favorable response in the mediastinal lymph nodes is presumably a surrogate for the eradication of occult distant metastases by induction therapy. Those with persistent N2 disease have low survival chances with surgery and are probably better served by consolidation therapy with chemoradiotherapy. The article by De Leyn et al3 from the Leuven Lung Cancer Group in Belgium seeks to answer the resulting dilemma. How, after induction chemotherapy, do we identify which patients have persistent N2 disease and should go on to chemoradiotherapy and which have been downstaged and should proceed with second-line surgery? Can further PET scanning undertake this reliably, or do we have to accept the problems inherent in repeat mediastinoscopy? They conclude that the sensitivity and accuracy of PET are sufficiently superior to those of repeat mediastinoscopy to justify its use as the technique of choice in these circumstances. This conclusion, and the magnitude of the difference between the results with these investigations, will surprise many. The sensitivity with which PET scanning after induction therapy identifies residual disease in the mediastinal lymph nodes, summarized in the De Leyn et al Table 6, is around 50% to 60%. This is considerably worse than the 83% sensitivity reported for PET scanning in the primary staging of lung cancer.4 However, the sensitivity of repeat PET in the study by De Leyn et al is 77%—within the range reported in the primary setting. Is this, as the authors claim, the result of coregistering PET and CT images in the newer generation of scanners? One study5 suggests that, in the primary setting, integrated PET-CT is superior to the visual correlation of images from separate PET and CT studies. However, in this study, the accuracy with which nodal disease was identified with the integrated equipment was only as good as that reported in many studies using visual correlation. It seems unlikely that the use of such a scanner alone can account for the improved sensitivity found by De Leyn et al. These investigators reduced the threshold for the PET identification of abnormal nodes to levels of tracer uptake that could be physiologic. Such a change would increase sensitivity at the expense of an unacceptable fall in the study specificity. The authors acknowledge that they used the CT images on the fusion study to identify areas where such low-level, possibly physiologic PET uptake is located in anatomic positions where nodal tissue would be not be expected, and they dismissed these from their analysis of the specificity of the integrated PET-CT studies. More studies are necessary to assess whether this is a valid change in practice that remains reliable in larger series. The competing assessment, repeat mediastinoscopy, is known to be technically demanding and not without its drawbacks. It should be entertained only by those with extensive experience. Small studies have shown that repeat mediastinoscopy after induction therapy has a sensitivity of 70% to 75%. De Leyn et al, who are certainly experienced in such an examination, found a sensitivity of only 29% for repeat mediastinoscopy. Was this poor result, as they suggest, the result of the extensive examination that they undertook at first-time mediastinoscopy? All first-time mediastinoscopies in their study were conducted by the same surgical group, and an average of 3.8 nodal levels were sampled in each patient. Comparative data is not available in many studies using repeat mediastinoscopy. However, one large series6 reports experience with 165 consecutive repeat mediastinoscopies after induction chemoradiotherapy for mediastinoscopy-proven N2 or N3 disease. All first-time mediastinoscopies had been performed in the same department, and an average of 4.2 nodal stations were sampled per patient. Sensitivity of repeat mediastinoscopy in this study was 74%. This does suggest that the previous extensive nodal evaluation at mediastinoscopy cannot completely explain the poor sensitivity of repeat mediastinoscopy reported by De Leyn et al. Clearly, we have not heard the final word in this debate, and we are left with the problem of selecting patients for surgery after induction therapy. Much will depend on the expertise that is available locally and on the attitude of patients and their advisors. Faced with the reality that the perfect test has yet to be identified, should we emphasize specificity, to ensure that the patient is not deprived of surgery inappropriately, or sensitivity, to avoid risky and damaging surgery unless assured of downstaging? Such difficult decisions should only be made in multimodality discussions that include specialist thoracic surgeons and before a decision on induction therapy has been made. We should consider an alternative approach, making greater use of less invasive techniques, such as mediastinal nodal biopsy by endoscopic ultrasound and endobronchial ultrasound,7 as the primary means of confirming N2 disease in PET-positive cases. This may result in some patients undergoing induction therapy without a realistic chance of proceeding with surgery. However, for those who will be considered for postinduction surgery, we will have available first-time mediastinoscopy as the final assessment. We cannot expect this investigation to completely exclude all residual mediastinal nodal disease, but it does allow us to reliably assess resectability. The 100% specificity of this examination will ensure that no patient is denied such surgery inappropriately. Authors' Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Goldstraw P, Mannam GC, Kaplan DK, et al: Surgical management of non-small-cell lung cancer with ipsilateral mediastinal node metastasis (N2 disease). J Thorac Cardiovasc Surg 107(1):19-27, 1994 2. Graham ANJ, Chan KJM, Pastorino U, et al: Systematic nodal dissection in the intrathoracic staging of patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 117:246-251, 1999 3. De Leyn P, Stroobants SG, de Wever WF, et al: Prospective comparative study of integrated PET-CT scan versus re-mediastinoscopy in the assessment of residual mediastinal lymph node disease after induction chemotherapy for mediastinoscopy proven IIIA-N2 non-small cell lung cancer: A Leuven Lung Cancer Group study. J Clin Oncol 24:3333-3339, 2006 4. Birim O, Kappetein AP, Stijnen T, et al: Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer. Ann Thorac Surg 79:375-381, 2005 5. Lardinois D, Weder W, Hany TF, et al: Staging of non-small-cell lung cancer with integrated Positron-Emission tomography and computed tomography. N Engl J Med 348:2500-2507, 2003 6. Stamatis G, Fechner S, Hillejan L, et al Repeat mediastinoscopy as a restaging procedure. Pneumologie 59:862-866, 2005[CrossRef][Medline] 7. Okamoto H, Watanabe K, Nagamoto A, et al: Endobronchial ultrasonography for mediastinal and hilar lymph node metastases of lung cancer. Chest 121:1498-1506, 2002
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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