Concurrent Versus Sequential Chemoradiation Therapy in Completely Resected Pathologic N2 Non-Small Cell Lung Cancer: Propensity-Matched Analysis of the National Cancer Data Base
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The optimal treatment of patients with locally advanced non-small cell lung cancer remains unclear. While multimodality therapy is essential, which modalities and in what order remains controversial. Although much of the focus of surgical patients with N2 disease looks at neoadjuvant therapies, a large portion of patients are not identified as N2 before surgery and therefore receive adjuvant treatment. Often, the adjuvant regimen delivered is merely adopted from similar neoadjuvant regimens or from regimens developed for nonsurgical patients. In the excellent paper, “Concurrent versus Sequential Chemoradiation Therapy in Completely Resected Pathologic N2 Non-Small Cell Lung Cancer: Propensity-Matched Analysis of the National Cancer Data Base,” Moreno et al. address this significant knowledge gap by examining the impact of the sequence of adjuvant chemotherapy and radiation therapy in patients with completely resected non-small cell lung cancer with N2 positive disease.1 In a very large retrospective, propensity matched analysis they showed that giving chemotherapy and radiation sequentially (sCRT), rather than concurrently (cCRT) is associated with significantly improved overall survival. In their analysis of nearly 2,000 patients within the National Cancer Database (NCDB), they found a difference in median overall survival of 16 months (53 months for sCRT vs. 37 months for cCRT). Patients receiving cCRT compared with sCRT had a 35% increase risk of death. This is indeed a dramatic difference.
Much of the research focused on radiation in the adjuvant setting compares adjuvant chemotherapy alone to adjuvant chemotherapy plus either concurrent or sequential radiation.2, 3, 4, 5 This study represents an important addition to the field in that it focuses not on merely the use of postoperative radiation therapy (PORT) but rather the timing. One similar paper looked at the timing of therapy but included only 68 patients in total (25 patients who underwent concurrent treatment and 43 patients who received it sequentially).6 In multivariable analysis, they found that concurrent therapy showed better locoregional control but had no difference in distant recurrence or overall survival. This stands in contrast to the current paper, which shows significantly worse outcomes for patients receiving concurrent therapy.
The data on the use of PORT more broadly supports it is use. Both large database retrospective trials and several phase II trials have demonstrated superior long-term survival with the addition of PORT to adjuvant chemotherapy. In the majority of the studies, PORT was given sequentially. A single phase III trial compared PORT alone to PORT followed by chemotherapy (radiation first) and confirmed that dual modality therapy is superior to radiation alone. Importantly, they demonstrated that a radiation first approach was feasible and did not compromise subsequent chemotherapy.7
Much of the impetus for concurrent over sequential therapy comes from patients not deemed candidates for surgical resection. In this patient population, dual modality therapy with concurrent chemotherapy and radiation remains the standard of care. As the authors highlight in their paper, several primary papers and meta-analyses show a small but consistent 5% absolute survival benefit for concurrent therapy versus sequential.8,9 For patients fit for surgery, the optimal treatment strategy, with respect to dual modality versus trimodality, and the timing of those treatments, is uncertain. The use of concurrent chemotherapy and radiation in a neoadjuvant setting derives largely from the intergroup 0139 trial, which confirmed the benefit of surgical resection after neoadjuvant chemotherapy and radiation, given concurrently, in patients with N2 disease.10 However, recent evidence suggests that in the neoadjuvant setting, concurrent neoadjuvant therapy may not be necessary. Within NCCN member institutions, there is an increased trend towards neoadjuvant chemotherapy alone followed by surgery with optional postoperative radiation. Several recent studies have demonstrated improved overall survival by with upfront chemotherapy alone, with radiation used as an adjuvant treatment, after complete resection.11,12 All of these studies are in patients identified preoperatively; yet despite improvements in identifying N2 patients before surgery, a significant percentage (51% in this study) are still identified only after resection. Therefore, a regimen that may be beneficial for a patient who is not receiving surgical resection may have excessive toxicity when combined with surgical resection, especially in an adjuvant setting.
This paper is not without limitations. It is retrospective in nature and based on a large national database. While the numbers are large, the NCDB lacks the granularity to look at issues of single station versus multistation disease, bulky disease, clinical staging modality, and outcomes other than readmission, perioperative mortality, and overall survival. The authors address some of these limitations. For example, they looked at the total number of nodes resected, total number of positive nodes, and lymph node ratio—all surrogates for more advanced mediastinal disease; none were significantly associated with differences in overall survival. The authors also compared patients who were clinical stage III with those who were clinical stage I–II. While the sequential group had more clinical N0-1 patients than the concurrent group, the survival was similar between cN0-1 and cN2 patients.
Despite these limitations, this is an important paper that adds to a growing body of work suggesting that the benefit of concurrent therapy may be the exception, rather than the rule. The additional toxicity associated with concurrent therapy, when combined with surgical resection, may outweigh the benefit of concurrent over sequential seen in patients who do not undergo surgical resection. As our systemic therapy continues to improve and radiation technology evolves, surgical resection may begin to play a larger role in patients with advanced disease who are living long enough to receive the benefit of additional local therapy. If that is the case, then this paper and others like it highlight the need for prospective trials to determine the optimal treatment strategy with respect not only to the types of therapy utilized, but the timing of such therapies as well.
The authors declare no conflicts of interest.
- 1.Moreno AC, Haque W, Verma V, Fang P, Lin SH. Concurrent versus sequential chemoradiation therapy in completely resected pathologic N2 non-small cell lung cancer: propensity-matched analysis of the National Cancer Data Base. Ann Surg Oncol. 2018. https://doi.org/10.1245/s10434-018-6399-4.PubMedGoogle Scholar