The Many Controversies of Stage IIIA/IIIB Lung Cancer

Drs. Balmanoukian and Ettinger present a comprehensive overview of the current state of management of stage IIIA/IIIB lung cancer. This is a very controversial topic, encompassing a number of different treatment strategies that have been advocated, all with limited data.

Disease Heterogeneity

The first issue deserving comment is the heterogeneity of stage III disease. Stage IIIA N₂ non–small-cell lung cancer (NSCLC) includes patients with at least one “incidental” N₂ node detected at the time of surgical resection in patients who had a negative mediastinal evaluation (including mediastinoscopy) preoperatively. It also includes patients whose initial computed tomography (CT) and positron-emission tomography (PET) scans show multiple bulky (> 2 cm) nodes that are confirmed by either mediastinoscopy or endobronchial ultrasound-guided bronchoscopy. These are very distinct groups of patients clinically; in the former, surgical resection is indicated, whereas in the latter, there is no role for surgical resection and these patients are best approached with concurrent chemoradiation. Likewise, stage IIIB disease includes patients with contralateral adenopathy, supraclavicular adenopathy, or T₄ primary lesions. We would contend that the multidisciplinary approach differs in these distinct subsets of stage III NSCLC, but these differences are not necessarily accounted for in the former or current revision of the staging system.[1]

Given the lack of definitive evidence of one strategy over another and the clinical judgment required to treat patients with stage IIIA as well as IIIB lung cancer, we would emphasize the need for a multidisciplinary approach to these patients. At our center, all of these patients are discussed at our multidisciplinary conference incorporating the opinions of radiation oncologists, medical oncologists, and thoracic surgeons in determining the optimal treatment strategies in a prospective manner for these patients.

Patient Selection

We would also like to highlight some of the more controversial areas presented in the Balmanoukian/Ettinger review. First, regarding selection criteria for patients who benefit from surgery, we agree with the authors that patients with bulky stage IIIA and IIIB disease are usually considered inoperable. The available surgical literature suggests that patients who may benefit most from surgical resection are those with either single-station N2 disease or N2 disease that is incidentally found-ie, there is microscopic evidence of disease but no macroscopic or radiographic evidence of bulky tumor or disease found at the time of resection.[2-4] We would emphasize that other descriptors of advanced T stage require a surgeon to carefully assess the patient to determine operability. For example, it is tempting to label a patient as inoperable due to mediastinal invasion when, in fact, all that is involved is the pericardial fat. This again reinforces the concept of requiring multidisciplinary evaluation and careful mediastinal staging prior to formulating a definitive treatment strategy.

The role of combined-modality neoadjuvant therapy prior to resection of IIIA lung cancer is perhaps the most controversial issue in this setting. In this review, the authors recommend that for bulky nodal disease, neoadjuvant chemoradiation followed by restaging should be considered. If the patient is deemed unresectable after neoadjuvant therapy, the authors recommend continuing the patient’s definitive concurrent chemoradiation. We would contend that there are no data to support this strategy.

In the recently published Intergroup trial evaluating the role of surgical resection in N₂-positive stage IIIA NSCLC,[5] patients were carefully selected before neoadjuvant therapy was initiated and only those who were thought to be candidates for surgical resection were enrolled. Unlike in other disease processes, such as breast cancer, no data support the contention that preoperative chemotherapy or chemoradiation improves resectability rates or allows lesser surgical procedures to be done. The authors of the Intergroup trial demonstrated that if mortality is minimized, there may be a role for surgical resection in patients with limited N2 disease, although this was based on an unplanned, retrospective subset analysis. The analysis-which suggested that if lobectomy is possible, survival may be improved with surgery-may be misleading since data regarding downstaging were not presented but may have been influential in the lobectomy vs pneumonectomy decision.

We do not believe it is prudent to attempt a neoadjuvant strategy for every patient in anticipation that some may become resectable. The criteria upon which this decision should be made are unclear and not universally agreed upon. The information obtained from CT or PET scans is not necessarily reliable, and the modality or role of restaging remains controversial. The decision regarding resectability should be made initially by the multidisciplinary team, and the prescribed course of therapy should be defined prospectively.

Surrogate Marker

The literature has repeatedly demonstrated that patients who benefit most from neoadjuvant chemoradiation or chemotherapy are those in whom the mediastinal nodes are clear of disease at the time of surgical resection.[6] We advocate mediastinal restaging prior to considering resection after neoadjuvant therapy. The significance of mediastinal downstaging is in the identification of patients whose disease is relatively treatment-sensitive. Clearance of mediastinal disease is likely a surrogate marker for sensitivity of occult micrometastatic disease since multiple studies have repeatedly identified this finding as a positive prognostic factor with regard to survival.

Recent advances in surgical technique have changed our ability to stage and restage these patients. In patients who we suspect preoperatively to have significant N2 disease, we often employ endobronchial ultrasound to stage the patient followed by definitive mediastinoscopy after the patient has received neoadjuvant therapy. Patients who then proceed to surgery are those who have demonstrated clearance of the mediastinal nodes with neoadjuvant therapy. Although the Intergroup trial demonstrated increased morbidity and mortality associated with pneumonectomy-especially right-side pneumonectomy-other single-center experience has demonstrated that with careful patient selection and an experienced surgical team, even pneumonectomies can be performed after the neoadjuvant setting in a safe manner with minimal morbidity and mortality and a demonstrated survival advantage.[7] Techniques to mitigate mortality include judicious fluid management, as well as tissue flaps to prevent complications of bronchopleural fistula and dehiscence of the bronchial stem.

Standard of Care

We believe that the standard of care for stage III NSCLC remains chemoradiation, based on the trials and data discussed by Drs. Balmanoukian and Ettinger. Although surgery may be useful in selected patients, it is uncertain whether this approach uniformly improves survival in this heterogeneous population of patients. Hopefully the next version of the staging system will include sufficient information on regional nodal disease, such that we can begin to subclassify this very complicated group of patients, allowing the role of surgery to be much better understood.

Our current inclination is that surgery is (or may be) useful in patients with nonbulky, minimal, or incidentially identified N2 disease. While that principle may be true, the possibility exists that aggressive chemoradiotherapy may be equally effective in this more favorable group of patients. Undoubtedly, there are patients in whom chemoradiotherapy may be effective in eradicating regional nodal disease as well as occult micrometastatic disease but fails to sterilize bulky primary disease. Surgical resection in these patients may be very important, and the challenge is to identify them and use surgical resection only in those who are likely to truly benefit.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Detterbeck FC, Boffa DJ, Tanoue LT: The new lung cancer staging system. Chest 136:260-271, 2009.

2. Decaluwé H, De Leyn P, Vansteenkiste J, et al: Surgical multimodality treatment for baseline resectable stage IIIA-N2 non-small cell lung cancer. Degree of mediastinal lymph node involvement and impact on survival. Eur J Cardiothorac Surg 36:433-439, 2009.

3. Sawabata N, Keller SM, Matsumura A: The impact of residual multi-level N2 disease after induction therapy for non-small cell lung cancer. Lung Cancer 42:69-77, 2003.

4. Keller SM, Vangel MG, Wagner H: Prolonged survival in patients with resected non-small cell lung cancer and single-level N2 disease. J Thorac Cardiovasc Surg 128:130-137, 2004.

5. Albain KS, Swann RS, Rusch VW, et al: Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: A phase III randomised controlled trial. Lancet 374:379-386, 2009.

6. Bueno R, Richards WG, Swanson SJ: Nodal stage after induction therapy for stage IIIA lung cancer determines patient survival. Ann Thorac Surg 70:1826-1831, 2000.

7. Krasna MJ, Gamliel Z, Burrows WM, et al: Pneumonectomy for lung cancer after preoperative concurrent chemotherapy and high-dose radiation. Ann Thorac Surg 89:200-206 (incl discussion), 2010.