Journal of Thoracic Oncology:
Lymph Node Ratio May Predict the Benefit of Postoperative Radiotherapy in Non–Small-Cell Lung Cancer
Urban, Damien MBBS, B Med Sc*; Bar, Jair MD, PhD†; Solomon, Benjamin MBBS, PhD*§; Ball, David MBBS, MD, FRANZCR‡§
*Department of Medical Oncology, Peter MacCallum Cancer Centre, Ramat Gan, Israel; †Institute of Oncology, Chaim Sheba Medical Center, Israel; ‡Department of Radiation Oncology, Peter MacCallum Cancer Centre, East Melbourne, Australia; and §Sir Pater MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: Damien Urban, Department of Medical Oncology, Peter MacCallum Cancer Centre, 10 St. Andrews Place, East Melbourne 3002, Australia. E-mail: firstname.lastname@example.org
Introduction: The use of postoperative radiotherapy (PORT) after resection of non–small-cell lung cancer (NSCLC) is controversial, with some evidence suggesting a benefit in patients with N2 disease. We assessed lymph node ratio (LNR) as a predictor of PORT benefit.
Methods: By using the Surveillance, Epidemiology and End Results database, we analyzed resected, node-positive (N1–N2) NSCLC patients diagnosed between 1998 and 2009. LNR, (number of positive nodes/number of resected nodes) was categorized into four groups: LNR less than 12.5%, 12.5 to 24.9%, 25 to 49.9%, and 50% or more.
Results: Of 11,324 node-positive NSCLC patients identified, 6551 (57.9%) had N1 disease. The LNR was prognostic for survival in the entire cohort and within each nodal stage. The median survival in LNR groups 1, 2, 3, and 4 was 43, 40, 30, and 23 months in N1 disease and 40, 32, 27, and 22 months in N2 disease, respectively. PORT was associated with a worse survival on univariate analysis (hazard ratio [HR] =1.09; confidence interval [CI] 1.03–1.15; p = 0.002) but no effect on multivariate analysis (HR = 0.96; CI 0.90–1.02; p = 0.201). When analyzed by nodal stage, the benefit of PORT was limited to N2 disease (HR = 0.9; CI 0.84–0.99; p= 0.026) with no benefit in N1 disease (HR = 1.06; CI 0.97–1.15; p=0.2). After stratifying by LNR, the survival benefit of PORT was limited to those with N2 disease and an LNR of 50% or more.
Conclusion: A high LNR is associated with a poorer survival in resected, node-positive NSCLC. The survival benefit associated with PORT in this disease seems to be limited to those with an LNR of 50% or more. This warrants further investigation in other cohorts and prospective studies.
Lung cancer is the second most common cancer diagnosed and the most common cause of cancer death in both sexes in the United States.1 Non–small-cell lung cancer (NSCLC) accounts for the majority of lung cancer cases. Treatment recommendations and prognosis are largely determined by the stage of cancer at diagnosis, with surgery typically recommended in early stage tumors.
After surgical resection, a finding of involved lymph nodes (LNs) is a significant prognostic factor and provides an indication for adjuvant chemotherapy.2,3 The recommendation for adjuvant radiotherapy is more controversial. A previous meta-analysis suggested a detrimental effect of postoperative radiotherapy (PORT),4 but the relevance of this study is uncertain in light of recent advances in radiation techniques, and other nonrandomized studies have suggested that patients with advanced nodal disease (ie., N2 disease) may benefit from PORT.5,6 The American Joint Committee on Cancer Tumor Node Metastasis (TNM) lung cancer staging system classifies nodal stage based on the anatomical lymph node stations involved, irrespective of the absolute number of involved lymph nodes. Furthermore, it does not account for the number of LNs or LN stations examined, but recommendations that at least 6 to 10 lymph nodes or stations should be sampled have been suggested.7,8
The lymph node ratio (LNR), defined as the number of pathologically positive LNs divided by the number of LNs examined, has been proposed as a useful prognostic metric because it incorporates both the number of pathologically positive LNs and the number of LNs examined. The LNR has been shown to be prognostic in multiple malignancies, including breast cancer,9 colon cancer,10 and melanoma.11 It has been shown to be prognostic in NSCLC,12–15 but the majority of these studies have included patients diagnosed in the era before positron emission tomography (PET) or integrated PET/computer tomography (PET/CT). Furthermore, the LNR has been shown to be predictive of PORT benefit in oral cavity squamous cell carcinoma (SCC).16
The purpose of this study was to further validate the LNR in the modern PET and PET/CT era and to evaluate its ability to predict the survival benefit of PORT in resected NSCLC.
MATERIALS AND METHODS
The Surveillance, Epidemiology and End Results (SEER) program is a comprehensive source of population-based data in the United States, which includes patient demographics, primary tumor site and histology, stage of cancer at the time of diagnosis, and surgical and/or radiation treatment as part of the first treatment. In 2001, the database was expanded to include new regions of the United States, covering approximately 26% of the population. Inclusion criteria were patients registered within the SEER 18 database between 1998 and 2009, with a single cancer diagnosis of NSCLC who underwent surgical resection (defined as at least a lobectomy), with at least one lymph node involved, and a TNM nodal stage of N1 or N2. The stage of these patients recorded in SEER is the pathological TNM stage. The histologic subtypes included were: NSCLC, NOS; large-cell carcinoma (large-cell carcinoma, NOS, large-cell neuroendocrine carcinoma, giant cell carcinoma); SCC (papillary squamous cell, SCC NOS, SCC keratinizing NOS, SCC large-cell nonkeratinizing, SCC small-cell nonkeratinizing); adenocarcinoma (AC) (AC NOS); AC with mixed subtypes (AC with mixed subtype, papillary AC NOS, clear-cell AC NOS, mucinous producing AC, signet ring cell carcinoma, adenosquamous); and bronchoalveolar carcinoma (BAC, BAC nonmucinous, BAC mucinous, BAC mucinous and nonmucinous).
LNR categories were divided into four similar-sized groups based on quartiles: group 1 was defined as LNR less than 12.5%, group 2 as LNR 12.5 to 24.9%, group 3 as LNR 25 to 49.9% and group 4 as LNR 50% or more. Staging was based on the American Joint Committee of Cancer 6th edition TNM staging as extracted from the SEER database. The number of LNs examined was divided into two groups: less than 10 LNs and 10 LNs or more because the removal of 10 LNs has been associated with the highest median survival.8
Statistical analyses were performed using the Stata Statistical package (version IC 11.1; Statacorp, College Station, TX). Correlations between categorical variables were analyzed with χ2tests. Overall survival (OS) from date of diagnosis was calculated using the Kaplan–Meier method. Patients with missing data were excluded from the multivariate analysis. A two-sided p value less than 0.05 was considered statistically significant. (survival months changed from 0 to 0.5)
A total of 11,324 NSCLC patients were identified. The median age at diagnosis was 66 years among the entire cohort and in each LNR group. Demographics, tumor characteristics, and the use of PORT are summarized in Table 1, for all patients and according to LNR. The distribution of LNR is illustrated in Figure 1.
Factors associated with a higher LNR included women, diagnosis in earlier years, nonwhites, AC compared with SCC, right-sided tumors, lobectomy, a higher T-stage, a higher N-stage, and examination of less than 10 LNs. The use of PORT was more common in patients with a high LNR.
The median follow-up of all patients was 21 months (range, 0.5–124) and of those alive was 33 months (range, 0.5–143). Variables associated with OS on univariate and multivariate analysis are summarized in Table 2. The TNM N-stage was significantly associated with OS. The median survival of N1 and N2 disease was 33 and 27 months, respectively, and the 5-year survival of N1 and N2 disease was 33 and 27%, respectively. LNR was able to provide further prognostic value within each nodal stage, both for OS (Fig. 2) and cancer-specific survival (Supplementary Fig. 1, Supplementary Digital Content 1, http://links.lww.com/JTO/A411). The median survival in LNR groups 1, 2, 3, and 4 was 43, 40, 30, and 23 months in N1 disease and 40, 32, 27, and 22 months in N2 disease, respectively.
Among all patients PORT was associated with a worse survival outcome on univariate analysis (hazard ratio [HR] = 1.09; confidence interval [CI] 1.03–1.15; p = 0.002) but no effect on multivariate analysis (HR = 0.96; CI 0.90–1.02; p = 0.201). When analysed by nodal stage, the benefit of PORT was limited to N2 disease (HR = 0.91; CI 0.84–0.99; p = 0.026), with no benefit in N1 disease (HR = 1.06; CI 0.97–1.15; p = 0.2). After stratifying by LNR, the benefit of RT was limited to those with N2 disease and an LNR of 50% or more for OS (Table 3) and cancer-specific survival (Supplementary Table 1, Supplementary Digital Content 2, http://links.lww.com/JTO/A412).
The use of PORT has decreased over time, with 43% of patients receiving PORT between 1998 and 2000 compared with 21% receiving PORT between 2007 and 2009, including in N2 disease (54 versus 33%, respectively). Furthermore, the use of PORT has significantly decreased, in patients with N2 disease and an LNR of 50% or more, from 54%, between 1998 and 2000, to 41% between 2007 and 2009 (p < 0.001), respectively.
A repeat analysis limited to patients diagnosed since 2003, when PET was performed among the majority of early stage NSCLC,17 confirmed a similar prognostic and predictive value of LNR (data not shown).
In this large population-based study, we demonstrate that LNR has prognostic significance, in addition to the standard TNM nodal staging in resected NSCLC. Furthermore, these data indicate that the benefit of PORT in resected NSCLC may be limited to N2 disease with an LNR of 50% or more.
Accurate staging of lung cancer is essential. It impacts on selecting the appropriate treatment, allows prognostic information to be conveyed to patients and their families, and facilitates communication between health care professionals, including the appropriate stratification in clinical trials. We have confirmed that the LNR provides additional, and possibly even more accurate, prognostic information than the current nodal staging. This is consistent with previous reports in NSCLC.12–15
In contrast to most previous reports, we limited our study to patients diagnosed since 1998, after PET and integrated PET/CT was introduced into clinical practice.18 The use of PET, and particularly integrated PET/CT, is known to result in more accurate nodal staging of NSCLC19,20 and reduces the number of thoracotomies and futile thoracotomies.21 It has been shown that the majority of early stage NSCLC patients, who are Medicare beneficiaries in the United States have had a PET since 2003.17 Our results are therefore, relevant with current modern staging investigations. Furthermore, a repeat analysis of patients diagnosed since 2003 confirmed the prognostic and predictive value of LNR.
There is no consensus regarding the benefit of PORT in resected NSCLC. The risk of local recurrence is generally lower with PORT,22 but studies reporting a detrimental effect on survival have discouraged the use of PORT. This is reflected in our study with the decrease in use of PORT over time, even in those patients who potentially stand to benefit from PORT, such as N2 disease and a high LNR. Currently, the Lung Adjuvant Radiotherapy (Lung ART) trial is prospectively evaluating the benefit of PORT in resected N2 disease (NCT00410683).
Why is a high LNR predictive of the benefit of PORT? One plausible explanation is that the risk of locoregional recurrence may be higher in those with a high LNR and may define a group in whom the benefit of PORT outweighs the toxicity. There are data supporting this relationship between LNR and locoregional recurrence in breast23 and rectal cancer,24 but this has not been reported in NSCLC.
Another possible explanation is that the LNR may reflect the body’s immune system and the tumor-host interaction. It is well documented that infiltration of lymphocytes occurs within tumors and has been associated with prognosis in many tumor types,25 including NSCLC.26 Furthermore, the presence of CD8+ tumor-infiltrating lymphocytes is associated with the absence of lymph node metastases in cervical cancer.27 The LNR may, therefore, serve as a marker of the tumor-host interaction and provide prognostic information. Furthermore, the value of the LNR as a predictor of radiotherapy (RT) benefit may also be a result of the interaction between the immune system and RT.28
An additional explanation may be that PORT may compensate for a suboptimal or inadequate surgical resection, as has been suggested in gastric cancer.29 A definition of a complete resection in lung cancer surgery has been developed,30 and it is known that microscopic positive margins are associated with a significantly poorer prognosis.31 However, the optimal extent of lymph node resection is unclear as is its effect on survival. Given the LNR is intrinsically affected by the number of LNs removed, the adequacy of lymph node dissection or sampling will affect the LNR. The SEER data do not record the quality and/or completeness of resection. To minimize this confounder, we included the number of LNs removed in our multivariate analysis and found this to be nonsignificant. This finding suggests the LNR may have a prognostic and predictive value beyond being a surrogate marker for adequate surgery.
Limitations of this study include the retrospective nature and the lack of information regarding the indications for and techniques of RT used. Other confounding factors lacking in SEER include patients’ comorbidities, performance status, the use of chemotherapy, and as mentioned, the completeness of surgical resection and lymph node dissection. There are also data suggesting that there are some inaccuracies in the reporting of RT use in the SEER database in breast cancer patients,32 though whether this is true for lung cancer patients is unknown. The large size of the study’s population and the fact that a CT-based RT planning was common after 1998 minimizes some of these limitations.
In conclusion, our study validates LNR as a significant prognostic factor in resected NSCLC. Importantly, these data indicate that LNR may predict which one of the patients benefit from PORT. The predictive value of LNR requires validation in a prospective study.
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Non–small-cell lung cancer; Postoperative radiotherapy; Lymph node ratio
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