In 2017, there will be 16,940 new cases of esophageal cancer diagnosed, with 15,690 dying from the disease in the United States (1). The majority of esophageal cancers are either adenocarcinoma or squamous cell carcinoma. Trimodality therapy of neoadjuvant chemoradiation followed by surgical resection has been established as the standard of care for advanced disease (2,3). However, the role of multimodality therapy in the management of clinical T2N0 esophageal cancer remains controversial. The NCCN recommends upfront surgery for T2N0 esophageal cancers if lesions are low-risk (well differentiated, <2 cm), but recommends either preoperative chemotherapy, preoperative chemoradiation, or definitive chemoradiation for all others (4).
Several issues arise when considering management of clinical T2N0 esophageal cancers including mostly retrospective studies with small sample size and earlier time periods, inclusion of both squamous cell carcinoma of adenocarcinoma patients, inclusion of patients treated with multiple types of induction therapy with either chemotherapy, chemoradiation, or radiation therapy, and no reporting of outcomes of patients treated with definitive chemoradiation (5-10). A recent randomized study failed to show a survival benefit of neoadjuvant therapy in stages I and II esophageal cancer patient, however, 70% of patients had squamous cell carcinomas (11).
While clinical T2N0 esophageal cancer is considered early stage, several reports have documented significant tumor and nodal understaging in >50% of patients not receiving induction therapy (6,12-16). Given the risk of nodal involvement, some have suggested that multimodality therapy is highly recommended in the management of clinical T2N0 esophageal cancer (6,10), while other groups recommend upfront surgery (5,7-9,17). The purpose of our study was to determine accuracy of clinical staging of T2N0 esophageal cancer identified from the National Cancer Database (NCDB) in a modern time period [2004–2013].
The NCDB is a dataset maintained by the American College of Surgeons and the American Cancer Society and collects patient data from >1,500 centers across the United States. Patients were eligible for analysis if they had clinical T2N0M0 esophageal cancer treated between 2004 and 2013 with upfront esophagectomy.
To estimate the accuracy of clinical staging among the cT2N0 patient population, pathologic staging data were used to calculate the respective rates of T and N upstaging and downstaging after resection for the upfront surgery group. Univariate and multivariable Cox proportional hazard models were developed to determine predictors of upstaging. Included in the models were age, sex, tumor location, tumor grade, tumor length, and tumor histology. All statistical tests were two-sided and α (type I) error <0.05 was considered statistically significant. Statistical analysis was performed using SPSS® version 23.0 (IBM®, Chicago, IL, USA). This study was approved as exempt by the Institutional Review Board.
Patient characteristics are presented in Table 1. We identified 1,840 patients with clinical T2N0 esophageal cancer treated from 2004–2013. The median age was 67 years. The median tumor length was 3 cm. The majority of patients were male, had distal tumors, pT2N0 disease, node negative, margin negative, and had adenocarcinomas.
Clinical staging in US patients was accurate pathologically in 30.7% of patients (Table 2). Overall accuracy decreased with time. In 2004, accuracy was 39.3% versus 28.5% in 2013. However, rates of pT0–2N0 patients, remained stable. Overall rates of pT0–2N0 staging was 56.2%, 58.9% in 2003, and 60.7% in 2013. Tumor downstaging was seen in 25.9%, tumor upstaging was seen in 25.5%, and nodal upstaging was seen in 17.9%.
Table 3 illustrates the impact of tumor length and grade on accuracy of staging. For patients with accurate pathologic staging or pathologic downstaging, there was a significant association with tumor length ≤3 cm and well to moderately differentiated tumors. In patients with pT0–2N0 staging, 62.7% and 59.7% had tumor length ≤3 cm (P<0.001) and well/moderately differentiated tumors (P<0.001), respectively. In addition, tumor length >3 cm (P<0.001) and poorly differentiated tumors (P<0.001) significantly correlated to tumor and nodal upstaging. Table 4 shows the impact of esophagectomy facility volume on accuracy of staging. Interestingly, low volume institutions had higher accuracy compared to medium and high-volume centers. Univariate and multivariate analysis of factors prognostic for predicting pT0–2N0 are presented in Table 5. Younger age, tumor length >3 cm, and poorly differentiated tumors, and high esophagectomy volume were prognostic for upstaging, while gender, tumor location, and tumor histology were not prognostic.
This is the largest and most modern report of accuracy clinical T2N0 esophageal cancer from the NCDB. The overall accuracy of clinical staging pathologically was only 30.7% and decreased with time, however, rates of pT0–2N0 were stable (overall 56.2%). Tumor and nodal upstaging were found in 25.9% and 17.9% of patients, respectively, while tumor downstaging was found in 25.5% of patients. Factors related to pathologic upstaging included younger age, tumor length >3 cm, high grade tumors, and high esophagectomy volume centers.
The accuracy of staging for clinical T2N0 esophageal cancer is one of the most important factors when considering treatment recommendations for preoperative therapy. In a NCBD analysis of clinical T2N0 esophageal cancer from 2006–2012, 932 patients underwent upfront esophagectomy (18). Of the 713 patients with complete pathologic data, 326 (45.7%) were upstaged, 26.7% tumor upstaging, 30.1% nodal upstaging, 43.3% with both. Upstaged patients were more likely to have high grade tumors. Age and tumor size was not predictive of upstaging. In an analysis of 482 patients with clinical T2N0 esophageal cancer who underwent esophagectomy, 46.7% were pathologically upstaged. Factors identified as prognostic for upstaging on MVA included male gender, higher Zubrod score, and absence of prior thoracic surgery (12). Grade was not included in the MVA. Age and tumor size were not prognostic. This study is the first to show that younger age and tumor length strongly correlated with pathologic upstaging.
Interestingly, we also found a direct correlation with esophagectomy volume and lower accuracy. NCDB does not provide information on gastroenterology staging volume. We hypothesize that this finding maybe related to more aggressive surgeons in high volume centers and the controversy of neoadjuvant therapy prior to publication on recent randomized trials and meta-analyses (2,3).
Several published studies have shown very poor accuracy for staging clinical T2N0 esophageal cancer (6,9,10,12,14-17,19) (Table 6). Accuracy ranged from 6% to 28.6% as compared to 30.7% in this study. Tumor upstaging ranged from 17% to 40%, compared to 25.9% in this study. Nodal upstaging was notably lower in this study (17.9%) compared 30% to 55% in the other reported studies. This is likely due to the large number of patients included in this analysis. Given the risk of nodal involvement, some have suggested that multimodality therapy is highly recommended in the management of clinical T2N0 esophageal cancer (6,10), while other groups recommend upfront surgery (5,7-9,17). Despite the increased risk of pathologically involved lymph nodes at the time of surgery, no study has reported any OS benefit associated with NCR (5-10,15,17). Speicher et al. reported on a NCDB analysis of clinical T2N0 esophageal cancer of patients treated between 1999 and 2011 (9). There was no difference in OS associated with neoadjuvant therapy. More recently, Markar et al. reported on long-term outcomes of 355 clinical T2N0 esophageal patients of which 70 (19.7%) received neoadjuvant therapy (17). Data was collected from 30 European Centers between 2000 and 2010. They reported no difference in survival.
We present the largest and most modern report of accuracy clinical T2N0 esophageal cancer from the NCDB. The overall accuracy of clinical staging pathologically was only 30.7% and decreased with time, however, rates of pT0–2N0 were stable (overall 56.2%). Factors related to pathologic upstaging included younger age, tumor length >3 cm, high grade tumors, and high volume esophagectomy centers.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: This study was reviewed by the Sarasota Memorial Hospital Institutional Review Board (#16-ONC-03) and determined exempt because it does not meet the definition of human subject research.
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