Selection of Patients for Surgery After Induction Chemotherapy for N2 Non–Small-Cell Lung Cancer
Authors: Peter Goldstraw
Journal: Journal of Clinical Oncology (2006)

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. 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. 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 al 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. 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 study 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 JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 21 JULY 2