Abstract
Background
To determine accuracy of clinical staging of T2N0 esophageal cancer from the National Cancer Database (NCDB).
Methods
The NCDB was accessed to identify patients with T2N0M0 esophageal cancer (adenocarcinoma or squamous cell carcinoma) treated between 2004–2013 that underwent esophagectomy. Pathologic staging was compared to clinical stage. Univariate (UVA) and multivariate analysis (MVA) was performed to identify factors related to pathologic upstaging using Cox proportional hazard ratio.
Results
We identified 1,840 patients with T2N0 esophageal cancer who underwent esophagectomy as first line therapy. The median age was 67 years. The vast majority of patients were male and had distal adenocarcinomas. Clinical staging in was accurate pathologically in 30.7% of patients. While there was a trend for worse accuracy with increasing year of diagnosis, there rate of pT0–2N0 was stable. Tumor length >3 cm was significantly associated with tumor upstaging, while poor differentiation was significantly associated with nodal upstaging. UVA and MVA identified younger age, tumor length >3 cm, and poor differentiation were significantly associated with overall upstaging. Gender, tumor location, and tumor histology were not prognostic.
Conclusions
Clinical staging for T2N0M0 esophageal cancer continues to remain highly inaccurate, however, rates of pT0–2N0 have steadily remained over 50%. Tumor length >3 cm and poor differentiation are strongly associated with pathologic upstaging.
Keywords: Esophageal cancer, T2N0, staging, National Cancer Database (NCDB)
Introduction
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].
Methods
Patients
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.
Statistics
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.
Results
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.
Table 1. Patient characteristics.
| Variable | N (%) [1,840] |
|---|---|
| Median age, years [range], | 67 [22–90] |
| Gender | |
| M | 1,479 (80.4) |
| F | 361 (19.6) |
| Location | |
| Middle | 156 (8.5) |
| Lower | 760 (41.3) |
| GEJ | 885 (48.1) |
| Overlap | 39 (2.1) |
| Histology | |
| Adenocarcinoma | 1,610 (87.5) |
| Squamous cell | 230 (12.5) |
| Median tumor length, cm (range) | 3.0 (2.0–4.2) |
| Path T stage | |
| T0 | 24 (1.3) |
| T1 | 538 (29.2) |
| T2 | 802 (43.6) |
| T3 | 461 (25.1) |
| T4 | 15 (0.8) |
| Path N stage | |
| N0 | 1,209 (65.7) |
| N1 | 478 (26.0) |
| N2 | 101 (5.5) |
| N3 | 52 (2.8) |
| Median lymph nodes removed [range] | 14 [8–21] |
| Grade | |
| Well | 149 (8.1) |
| Moderate | 777 (42.2) |
| Poor | 914 (49.7) |
| Surgical margins | |
| No residual | 1,677 (91.1) |
| Microscopic | 160 (8.7) |
| Macroscopic | 3 (0.2) |
| Facility volume | |
| Low (<10/year) | 1,081 (58.8) |
| Medium (10–20/year) | 401 (21.8) |
| High (>20/year) | 358 (19.5) |
GEJ, gastroesophageal junction.
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 2. Accuracy by year of surgery.
| Year | % correct | % tumor downstage | % tumor upstage | % nodal upstage | % pT0–2N+/pT3–4 (upstage) | % pT0–1N0 (downstage) | % pT0–2N0 (correct/downstage) |
|---|---|---|---|---|---|---|---|
| 2004 | 39.3 | 19.6 | 21.4 | 19.6 | 41.1 | 19.6 | 58.9 |
| 2005 | 42.8 | 15.1 | 26.1 | 16.0 | 42.0 | 15.1 | 57.9 |
| 2006 | 34.1 | 24.6 | 23.9 | 17.4 | 41.3 | 24.6 | 58.7 |
| 2007 | 37.5 | 21.3 | 20.6 | 20.6 | 41.3 | 21.3 | 58.8 |
| 2008 | 34.2 | 21.5 | 24.2 | 20.1 | 44.3 | 21.5 | 55.7 |
| 2009 | 35.9 | 21.8 | 22.2 | 20.1 | 42.3 | 21.8 | 57.7 |
| 2010 | 26.2 | 28.3 | 29.5 | 16.0 | 45.6 | 28.3 | 54.5 |
| 2011 | 19.6 | 31.5 | 30.6 | 18.3 | 48.9 | 31.5 | 51.1 |
| 2012 | 20.2 | 30.9 | 34.6 | 14.4 | 48.9 | 30.9 | 51.1 |
| 2013 | 28.5 | 32.2 | 22.4 | 16.8 | 39.3 | 32.2 | 60.7 |
| Overall | 30.7 | 25.5 | 25.9 | 17.9 | 43.8 | 25.5 | 56.2 |
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.
Table 3. Accuracy by tumor length and grade.
| cT2N0 | All | Tumor length | Tumor grade | |||||
|---|---|---|---|---|---|---|---|---|
| ≤3 cm | >3 cm | P | Well/mod | Poor | P | |||
| pT2N0 | 565 | 308 (54.5) | 257 (45.5) | 0.66 | 309 (54.7) | 256 (45.3) | 0.01 | |
| pT0–1N0 | 469 | 340 (72.5) | 129 (27.5) | <0.001 | 308 (65.7) | 161 (34.3) | <0.001 | |
| pT0–2N0 | 1034 | 648 (62.7) | 386 (37.3) | <0.001 | 617 (59.7) | 417 (40.3) | <0.001 | |
| pT3–4N0 | 175 | 78 (44.6) | 97 (55.4) | 0.01 | 73 (41.7) | 102 (58.3) | 0.02 | |
| pT1–2N+ | 327 | 166 (50.8) | 161 (49.2) | 0.23 | 141 (43.1) | 186 (56.9) | 0.004 | |
| pT3–4N+ | 301 | 95 (31.6) | 206 (68.4) | <0.001 | 95 (31.6) | 206 (68.4) | <0.001 | |
Table 4. Accuracy by facility volume.
| Variable | Low (<10/year) | Medium (10–20/year) | High (>20/year) | P |
|---|---|---|---|---|
| 30-day mortality | 48 (5.1) | 8 (2.3) | 7 (2.1) | 0.01 |
| 90-day mortality | 85 (9.1) | 15 (4.2) | 16 (4.8) | 0.002 |
| pT2N0 | 366 (33.9) | 124 (30.9) | 75 (20.9) | <0.001 |
| pT0–2N0 | 606 (56.1) | 246 (61.3) | 182 (50.8) | 0.01 |
Table 5. Univariate and multivariate analysis for predicting pT0–2N0.
| Variable | Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|---|
| OR | 95% CI | P | OR | 95% CI | P | ||
| Age | 0.99 | 0.98–0.99 | 0.03 | 0.99 | 0.98–0.99 | 0.02 | |
| Gender | |||||||
| Male | Ref | Ref | Ref | Ref | Ref | Ref | |
| Female | 0.76 | 0.60–0.96 | 0.02 | 0.81 | 0.63–1.05 | 0.11 | |
| Location | |||||||
| Middle | Ref | Ref | Ref | Ref | Ref | Ref | |
| Lower | 1.42 | 0.99–2.04 | 0.06 | 1.33 | 0.88–2.00 | 0.17 | |
| GEJ | 1.73 | 1.21–2.47 | 0.003 | 1.66 | 1.10–2.52 | 0.02 | |
| Overlap | 1.21 | 0.59–2.51 | 0.6 | 1.16 | 0.54–2.50 | 0.7 | |
| Tumor length | |||||||
| ≤3 cm | Ref | Ref | Ref | Ref | Ref | Ref | |
| >3 cm | 2.29 | 1.90–2.76 | <0.001 | 2.17 | 1.78–2.63 | <0.001 | |
| Grade | |||||||
| Well/moderate | Ref | Ref | Ref | Ref | Ref | Ref | |
| Poor | 2.38 | 1.97–2.87 | <0.001 | 2.21 | 1.82–2.69 | <0.001 | |
| Histology | |||||||
| Adenocarcinoma | Ref | Ref | Ref | Ref | Ref | Ref | |
| Squamous cell | 0.91 | 0.69–1.20 | 0.5 | 1.2 | 0.85–1.67 | 0.3 | |
| Facility volume | |||||||
| Low (<10/year) | Ref | Ref | Ref | Ref | Ref | Ref | |
| Medium (10–20/year) | 0.8 | 0.64–1.02 | 0.07 | 0.87 | 0.68–1.12 | 0.28 | |
| High (>20/year) | 1.23 | 0.97–1.57 | 0.08 | 1.3 | 1.01–1.68 | 0.04 | |
GEJ, gastroesophageal junction.
Discussion
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.
Table 6. Previous published studies.
| Study | N | % accuracy | % T-downstage | % T-upstage | % N-upstage |
|---|---|---|---|---|---|
| Stiles 2011 | 40 | 12.5 | 30 | 40 | 55 |
| Zhang 2012 | 14 | 28.6 | 42.9 | 21.4 | 21.4 |
| Crabtree 2013 | 482 | 27.4 | 25.9 | 18 | 44.5 |
| Hardacker 2014 | 35 | 8.5 | 42.8 | 48.5 | 40 |
| Shin 2014 | 66 | 15 | 60.6 | 16.7 | 39 |
| Tekola 2014 | 38 | 21 | 45 | 17 | 50 |
| Speicher 2014 | 786 | 26.7 | 30 | 27.7 | 30.2 |
| Dolan 2016 | 16 | 6 | 38 | 56 | 52 |
| Markar 2016 | 285 | 26 | 35.7 | 34.8 | 50 |
| Current study | 1,840 | 30.7 | 25.5 | 25.9 | 17.9 |
Conclusions
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.
Acknowledgements
None.
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.
Footnotes
Conflicts of Interest: The authors have no conflicts of interest to declare.
References
- 1.Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin 2017;67:7-30. 10.3322/caac.21387 [DOI] [PubMed] [Google Scholar]
- 2.Sjoquist KM, Burmeister BH, Smithers BM, et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011;12:681-92. 10.1016/S1470-2045(11)70142-5 [DOI] [PubMed] [Google Scholar]
- 3.van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074-84. 10.1056/NEJMoa1112088 [DOI] [PubMed] [Google Scholar]
- 4.Ajani JA, D'Amico TA, Almhanna K, et al. Esophageal and esophagogastric junction cancers, version 1.2015. J Natl Compr Canc Netw 2015;13:194-227. 10.6004/jnccn.2015.0028 [DOI] [PubMed] [Google Scholar]
- 5.Chen WH, Chao YK, Chang HK, et al. Long-term outcomes following neoadjuvant chemoradiotherapy in patients with clinical T2N0 esophageal squamous cell carcinoma. Dis Esophagus 2012;25:250-5. 10.1111/j.1442-2050.2011.01243.x [DOI] [PubMed] [Google Scholar]
- 6.Dolan JP, Kaur T, Diggs BS, et al. Significant understaging is seen in clinically staged T2N0 esophageal cancer patients undergoing esophagectomy. Dis Esophagus 2016;29:320-5. 10.1111/dote.12334 [DOI] [PubMed] [Google Scholar]
- 7.Martin JT, Worni M, Zwischenberger JB, et al. The role of radiation therapy in resected T2 N0 esophageal cancer: a population-based analysis. Ann Thorac Surg 2013;95:453-8. 10.1016/j.athoracsur.2012.08.049 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Rice TW, Mason DP, Murthy SC, et al. T2N0M0 esophageal cancer. J Thorac Cardiovasc Surg 2007;133:317-24. 10.1016/j.jtcvs.2006.09.023 [DOI] [PubMed] [Google Scholar]
- 9.Speicher PJ, Ganapathi AM, Englum BR, et al. Induction therapy does not improve survival for clinical stage T2N0 esophageal cancer. J Thorac Oncol 2014;9:1195-201. 10.1097/JTO.0000000000000228 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zhang JQ, Hooker CM, Brock MV, et al. Neoadjuvant chemoradiation therapy is beneficial for clinical stage T2 N0 esophageal cancer patients due to inaccurate preoperative staging. Ann Thorac Surg 2012;93:429-35; discussion 436-7. 10.1016/j.athoracsur.2011.10.061 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mariette C, Dahan L, Mornex F, et al. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901. J Clin Oncol 2014;32:2416-22. 10.1200/JCO.2013.53.6532 [DOI] [PubMed] [Google Scholar]
- 12.Crabtree TD, Kosinski AS, Puri V, et al. Evaluation of the reliability of clinical staging of T2 N0 esophageal cancer: a review of the Society of Thoracic Surgeons database. Ann Thorac Surg 2013;96:382-90. 10.1016/j.athoracsur.2013.03.093 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Crabtree TD, Yacoub WN, Puri V, et al. Endoscopic ultrasound for early stage esophageal adenocarcinoma: implications for staging and survival. Ann Thorac Surg 2011;91:1509-15; discussion 1515-6. 10.1016/j.athoracsur.2011.01.063 [DOI] [PubMed] [Google Scholar]
- 14.Shin S, Kim HK, Choi YS, et al. Clinical stage T1-T2N0M0 oesophageal cancer: accuracy of clinical staging and predictive factors for lymph node metastasis. Eur J Cardiothorac Surg 2014;46:274-9; discussion 279. 10.1093/ejcts/ezt607 [DOI] [PubMed] [Google Scholar]
- 15.Stiles BM, Mirza F, Coppolino A, et al. Clinical T2-T3N0M0 esophageal cancer: the risk of node positive disease. Ann Thorac Surg 2011;92:491-6; discussion 496-8. 10.1016/j.athoracsur.2011.04.004 [DOI] [PubMed] [Google Scholar]
- 16.Tekola BD, Sauer BG, Wang AY, et al. Accuracy of endoscopic ultrasound in the diagnosis of T2N0 esophageal cancer. J Gastrointest Cancer 2014;45:342-6. 10.1007/s12029-014-9616-9 [DOI] [PubMed] [Google Scholar]
- 17.Markar SR, Gronnier C, Pasquer A, et al. Role of neoadjuvant treatment in clinical T2N0M0 oesophageal cancer: results from a retrospective multi-center European study. Eur J Cancer 2016;56:59-68. 10.1016/j.ejca.2015.11.024 [DOI] [PubMed] [Google Scholar]
- 18.Samson P, Puri V, Robinson C, et al. Clinical T2N0 Esophageal Cancer: Identifying Pretreatment Characteristics Associated With Pathologic Upstaging and the Potential Role for Induction Therapy. Ann Thorac Surg 2016;101:2102-11. 10.1016/j.athoracsur.2016.01.033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Hardacker TJ, Ceppa D, Okereke I, et al. Treatment of clinical T2N0M0 esophageal cancer. Ann Surg Oncol 2014;21:3739-43. 10.1245/s10434-014-3929-6 [DOI] [PubMed] [Google Scholar]