Probably no other topic in thoracic oncology has resulted in more controversy than that of the management of locally advanced non–small-cell lung cancer (NSCLC). Although recent large randomized studies have yielded more reliable and objective data on which to base treatment decisions than were available a decade ago, management of these patients is still influenced by specialty bias and philosophical beliefs. In this issue of ONCOLOGY, Balmanoukian and Ettinger summarize the management options for patients with stage IIIA and IIIB NSCLC, and provide a framework to guide the treatment of patients with what they refer to as “borderline resectable” lung cancer, a term usually applied to resectability issues pertaining to patient performance status or lung function rather than tumor extent.[1]
Historically, stage IIIA N2 NSCLC was treated non-operatively until two randomized trials published in 1994 showed a significant improvement in survival for patients who received induction chemotherapy followed by surgery, compared to surgery alone.[2,3] Though the trials have been criticized because of their small size (60 patients each), lack of pretreatment histologic confirmation of N2 metastases in all patients, and inclusion of more favorable stage IIIA subsets (T3, N0/N1), they created a paradigm shift in the management of stage IIIA disease. Induction chemotherapy followed by surgical resection became a widely accepted management strategy, despite several other studies that showed no significant improvement in overall survival with induction chemotherapy.[4] The results of two recently published multicenter randomized trials have in some ways clarified management of patients with stage IIIA N2 lung cancer.
Key Studies
The European Organisation for Research and Treatment of Cancer (EORTC) sponsored a multicenter prospective randomized trial that compared induction chemotherapy and surgery to induction chemotherapy and definitive radiation in patients with histologically proven stage IIIA N2 lung cancer that was considered to be unresectable.[5] Only patients who showed at least a minor response to induction chemotherapy were randomized to go on to either surgery or radiation. A total of 332 patients were randomized, and neither overall nor progression-free survival was different between the surgery and radiation arms. The study concluded that since radiation therapy was associated with lower morbidity than surgery and was no worse in terms of survival, it should be the preferred locoregional treatment for patients with stage IIIA NSCLC.
The other recently published randomized trial was the North American Intergoup study (INT0139), which compared induction chemoradiation (45 Gy) and surgery to definitive chemoradiation (61 Gy) in patients with histologically confirmed and potentially resectable N2 disease.[6] There were 396 patients randomized and, like the EORTC study, there was no significant difference in overall survival between groups.
Taking only the primary endpoint of each trial (survival) into account, neither showed an advantage to surgery over radiation. However, closer examination of both studies makes this conclusion less clear-cut. In both trials there was a higher rate of local recurrence in the nonsurgical arm. In the EORTC study, this was offset by a higher rate of distant relapse in the surgical group and so did not impact progression-free survival. However, in the Intergroup study progression-free survival was significantly longer in patients who had surgery. Local tumor recurrence after definitive radiation treatment is usually highly morbid and generally not amenable to surgery or further radiation. Both studies defined subgroups of patients with improved survival. In the EORTC trial, patients who underwent lobectomy or bilobectomy, had complete resection, or were staged ypN0 or ypN1 after induction therapy had improved survival. Similarly, pretreatment single-station N2 involvement, surgery limited to lobectomy or bilobectomy, and postinduction stage ypN0 were predictors of better survival in the Intergroup study.
The extent of surgery required in both studies clearly impacted results in both trials. The unusually high pneumonectomy rate (47%) in the EORTC study likely reflected not only the advanced nature of the tumors included in the study—which enrolled patients who were considered to have “unresectable” N2 disease—but also a philosophy among many surgeons at the time that pneumonectomy was an oncologically superior operation for stage IIIA patients. Pneumonectomy is well known to be associated with increased early and late mortality, compared to parenchymal-conserving procedures such as lobectomy or sleeve-lobectomy. In fact, 5 of the 6 early deaths in the EORTC study occurred in patients who had undergone pneumonectomy.
In the Intergroup study, 30-day mortality after pneumonectomy was 27%. Subgroup analysis of this study compared outcomes of patients who had lobectomy or pneumonectomy with patients in the radiation arm matched for age, gender, performance status, and T stage. The analysis revealed that patients who had pneumonectomy after induction chemoradiation experienced far worse survival than those treated with definitive chemoradiation. The converse, however, was true for patients who had lobectomy following induction chemoradiation, where the survival was twice that of matched controls who received chemoradiation only (36% vs 18%, P = .0002).
Prognostic Variables
That there is heterogeneity among patients with stage IIIA N2 disease has been long known. Numerous studies have shown that patients with single-station disease do better than patients with metastases to multiple nodal stations. This has perhaps been most convincingly demonstrated by the recent International Association for the Study of Lung Cancer (IASLC) staging project, which found that patients with metastases to a single N2 zone had survival similar to patients with multiple N1 zones involved, and that patients with metastases to multiple N2 zones had significantly worse survival.[7] Other retrospective studies have shown that extracapsular invasion, bulky nodes, or nodes fixed to surrounding structures confer a worse prognosis.[8,9]
Lastly, many phase II and III trials (including the two described above) have shown that biologic response to induction therapy impacts prognosis. Though patients staged ypN0 following induction therapy are known to have better survival, recent studies suggest that the degree of response may also be important. A recent review of 45 patients with persistent N2 disease after induction chemoradiation found that patients who had < 10% viable tumor cells in mediastinal nodes after induction treatment had survival similar to ypN0 patients (46% vs 39%, P = NS).[10]
With regards to the conclusion of Balmanoukian and Ettinger, that patients with bulky nodal disease should be treated with induction chemoradiation followed by restaging, there appears to be little data in the literature to support this statement. If there is a population of patients who might be considered for surgical resection rather than definitive radiation, it would likely include patients with single-level, non-bulky nodal disease, patients who do not require pneumonectomy, or patients who have been downstaged to minimal or no mediastinal nodal involvement. Though individual experienced centers have published excellent outcomes of pneumonectomy following induction treatment, these results may not be applicable to the thoracic surgical community as a whole. Thus, in patients with stage IIIA N2 disease the requirement to perform a pneumonectomy should probably be a relative contraindication to resection.
Nodal Assessment
Since the number of positive N2 stations impacts survival and therapeutic decisions, it argues for thorough mediastinal nodal assessment before commencing definitive therapy. The advent of minimally invasive staging methods such as endobronchial ultrasound (EBUS) and esophageal ultrasound (EUS) offers the capability to sample more nodal stations than can be accessed by mediastinoscopy alone; however, staging should be detailed and meticulous. It is insufficient to merely biopsy the most prominent node visible on positron-emission tomography or computed tomography scan, but rather, as many different nodal stations as possible ought to be sampled, whether radiographically suspicious or not. Finally, since EBUS and EUS are inaccurate at restaging the mediastinum after induction treatment, and repeat mediastinoscopy is not only inaccurate but also technically challenging, an argument can be made for initial mediastinal staging using EBUS and/or EUS for patients with suspected N2 metastases, followed by thorough post-induction restaging with mediastinoscopy.
Conclusion
The management of patients with stage IIIA N2 lung cancer remains controversial. Though the accumulation of data from recent prospective phase II and III studies has refined our clinical decision-making, the limitations of these studies when applied to the individual patient must also be appreciated. Most importantly, the clinician must recognize that patients with N2 disease represent a very heterogenous group and that therapeutic decisions should be made only after careful initial staging, consideration of potential treatment risks and patient performance, and multidisciplinary input.
—David C. Rice, MB, BCh, BAO
