Background
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive malignancies worldwide. Most patients die within 1 year of diagnosis, and the 5-year overall survival (OS) rate is less than 20%.1,2 According to the NCCN Clinical Practice Guidelines for Oncology (NCCN Guidelines) for Esophageal and Esophagogastric Junction Cancers, treatment options for patients with locoregional cancer (T1b,N+, T2–T4a,N0–N+) include esophagectomy with or without preoperative chemoradiation or definitive chemoradiation (only for patients who decline surgery and recommended for cervical esophagus; to view the most recent version of these guidelines, visit NCCN.org).3 The largest randomized trials concluded that preoperative chemoradiation therapy (CRT) improved survival among patients with potentially curable esophageal cancer. These trials included adenocarcinoma and squamous cell carcinoma (SCC), and therefore only a subset analysis shows that clinical lymph node (LN)-positive SCC benefits from preoperative CRT.4 A recent randomized trial showed that definitive CRT is comparable to preoperative CRT followed by surgery in SCC of the mid to lower esophagus.5 Recent meta-analyses also indicate that the addition of preoperative CRT leads to a survival benefit compared with surgery alone for the treatment of locally advanced esophageal carcinoma.6,7 As the use of preoperative CRT has become more prevalent, the need has emerged to determine the impact of this treatment on the post-CRT pathologic stage and patient outcome.
Accurate staging systems play a critical role in cancer treatment. They also provide clinicians and patients with the means to predict survival and select optimal treatment modalities, tailored to disease stage. The TNM tumor staging system is the most widely used system in the world. This staging system has evolved periodically, due to a better understanding of the advances in cancer prognosis. The latest edition of the AJCC TNM staging system was published in January 2010. This newly published staging system for ESCC relies on the retrospective analysis of pathologic data from 4627 patients treated by esophagectomy alone without induction chemotherapy or radiotherapy. With the increased use of preoperative therapy, the AJCC TNM staging system also includes the prefix “y.” Pathologic reclassification after surgery that has been preceded by chemotherapy and/or radiotherapy is designated by “yp.” Adenocarcinoma and SCC are considered different entities and are staged separately in the esophageal cancer staging system.8
The use of preoperative CRT in treating locally advanced ESCC is becoming increasingly frequent. Surgical specimens resected after induction chemotherapy or radiotherapy must be carefully evaluated. Accurate post-CRT pathologic staging is important because it may provide prognostic information, which can help direct subsequent therapeutic decisions. However, using the post-CRT pathologic stage to predict prognosis is still uncertain and the number of relevant studies is limited.9–17 Furthermore, the reasons for the discrepancy in outcome between the pathologic and the post-CRT pathologic stages in ESCC remain unclear.
Thus, the goal of this study was to investigate the survival outcomes between the pathologic and the post-CRT pathologic stages in a large series of patients with ESCC. The investigators reviewed patients with ESCC who underwent esophagectomy with or without preoperative CRT in Taiwan from 2008 to 2011.
Patients and Methods
The Taiwan Cancer Registry (TCR) prospectively records clinicopathologic parameters in individuals diagnosed with various cancers in Taiwan. The database contains medical information, including age, sex, date of hospitalization, care facilities, date of diagnosis, surgical method, surgical margin, pathologic stage, treatment modality, survival status, and diagnoses coded in the International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3). Patients with cancer confirmed by tissue diagnosis were included in the database. This study uses generalized data from the TCR between 2008 and 2011. The clinical sample was identified from the pooled database by the ICD-O site codes C15.0, C15.1, C15.2, C15.3, C15.4, C15.5, C15.8, and C15.9. SCC was included for analysis (ICD-O codes 8052, 8070, 8071, 8072, 8073, 8074, 8076, 8077, 8083, and 8044). From 2008 to 2011, a total of 6140 patients with ESCC in Taiwan were identified.
The initial treatment modalities included definite CRT (n=3020); CRT followed by surgery (n=850); surgery alone (n=679); surgery followed by chemotherapy or/and radiotherapy (n=622); radiotherapy alone (n=442); chemotherapy alone (n=333); other treatments (n=34); and unknown treatment (n=160). Data were obtained to analyze the influence of pTNM and ypTNM staging on survival in patients undergoing esophagectomy. Therefore, a total of 2105 patients with ESCC undergoing esophagectomy were included in this study.
Patients were divided into 2 groups. Group A consisted of patients who underwent primary surgery without prior treatments (N=1301), and group B consisted of patients treated with preoperative CRT followed by esophagectomy (N=850). In group A, 679 patients received surgery alone, 92 received postoperative chemotherapy, 416 received postoperative CRT, and 114 received postoperative radiation therapy.
Histology was described according to the WHO classification. All patients were staged according to the 7th edition of the AJCC TNM staging system published in 2010.7 The definition of pathologic complete response (pCR), or stage 0, was having no evidence of viable disease. High-grade dysplasia was considered T0, and T0N+ was assigned when no viable tumor was present in the esophagus and residual cancer cells were present in the LNs. Univariate and multivariate analyses were performed to determine which factors were independently associated with OS.
Statistical Analysis
OS was defined as the period from the date of the initial treatment of malignancy to the date of death or last follow-up, whichever came first. Date and cause of death were confirmed by death certificates from Taiwan. OS was calculated using the Kaplan-Meier method, and the difference in survival was determined by the log-rank test. An observation was censored in December 2012 when the patients were alive or had died of other causes. To investigate the impact of TNM on OS, the following clinicopathologic factors were included in the univariate analyses: age, sex, tumor location, histologic grade, surgical margin, and pathologic T, N, and M stages. All variables were entered in the multivariate analyses to identify independent predictors of survival. Univariate and multivariate analyses were performed with the Cox proportional hazards model using the SPSS software (version 17.0; SPSS Inc., Chicago, IL, USA). Statistical analysis was considered to be significant for a P value less than .05.
Results
The basic demographic and pathologic characteristics and the survival time in these 2151 patients are summarized in Table 1. Of these patients, 1301 underwent primary esophagectomy (group A) and 850 were treated with preoperative CRT followed by esophagectomy (group B). Regarding the location of tumors, in group A, 11.0% were found in the upper one-third, 36.6% in the middle one-third, and 33.4% in the lower one-third. In group B, 13.3% were found in the upper one-third, 39.3% in the middle one-third, and 22.8% in the lower one-third. Group A comprised 1212 men (93.2%) with a mean age of 56.24 years, and group B comprised 813 men (95.6%) with a mean age of 53.64 years. In group B, 222 patients (26.1%) had a pCR and 38 patients (4.5%) had T0N+ disease after preoperative CRT. In group A, the 3-year survival rates by pathologic stage were 82.2% for stage 0, 67.6% for stage I, 50.7% for stage II, 21.5% for stage III, and 14.8% for stage IV (P<.001) (Figure 1A). In group B, the 3-year survival rates for post-CRT pathologic stages 0, I, II, III, and IV were 59.4%, 46.0%, 40.3%, 19.1%, and 8.2%, respectively (P<.001) (Table 2, Figure 1B).
In univariate analysis, clinicopathologic factors were analyzed (Table 2). Age, surgical margin, tumor location, histologic grade, pT, pN, pM, and pathologic stage were found to be statistically associated with OS in group A. Surgical margin, histologic grade, ypT, ypN, ypM, and post-CRT pathologic stage remained significant prognostic factors in group B.
The Kaplan-Meier survival curves for patients with and without preoperative CRT according to the pathologic stage are shown in Figure 1. Survival was significantly better in patients with pCR than in those who had residual tumor.
The survival curve in both groups was stratified by the T status (Figure 2A and B). Survival became worse with increasing T status in both of the groups (P<.0001). The survival curve was also stratified by the N status in both groups (Figure 3A and B). Worse survival was associated with an increased N stage in both groups (P<.0001).
A multivariate Cox regression model was constructed incorporating age, sex, tumor location, histologic grade, surgical margins, and pathologic T, N, and M stages (Table 3). Age, surgical margins, pT, pN, and pM were independent prognostic factors in group A. Tumor location, surgical margins, ypT, ypN, and ypM remained independent prognostic factors in group B. In summary, the pathologic TNM was a significant independent prognostic factor in both groups.
Discussion
The TNM cancer staging system, the most widely used system, is based on tumor extent (T), LN invasion (N), and the presence of distant metastasis (M). With regard to the esophageal cancer staging system,the Worldwide Esophageal Cancer Collaborationanalyzed 4627 patients who underwent surgery alone for adenocarcinoma, SCC, or undifferentiated cancer to form the 7th edition of the AJCC TNM staging system. In the 7th edition, adenocarcinoma and SCC are considered different entities in the esophageal cancer classification. Therefore, this analysis only included ESCC. The investigators identified 2151 patients undergoing esophagectomy with or without
Patient Demographic Data for 2151 Patients Who Underwent Esophagectomy With or Without Neoadjuvant Chemoradiotherapy
The influence of preoperative CRT on pathologic stage ESCC staging system remains undefined and the results from the relevant studies are controversial.9–17 Swisher et al9 included 593 patients with esophageal cancer in their analysis
Univariate Analyses for Overall Survival in Patients With Resected Esophageal Squamous Cell Carcinoma With or Without Neoadjuvant Chemoradiotherapy
(A) Kaplan-Meier survival curves stratified by the pathologic stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Abbreviations: pCR, pathologic complete response.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
(A) Kaplan-Meier survival curves stratified by the pathologic stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Abbreviations: pCR, pathologic complete response.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
(A) Kaplan-Meier survival curves stratified by the pathologic stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Abbreviations: pCR, pathologic complete response.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
Law et al12 studied 279 patients with ESCC, and indicated that the ypT and the ypTNM stages did not have as clear a prognostic value compared with patients who did not undergo prior therapy. Barbour
(A) Kaplan-Meier survival curves stratified by the pathologic T stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic T stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
(A) Kaplan-Meier survival curves stratified by the pathologic T stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic T stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
(A) Kaplan-Meier survival curves stratified by the pathologic T stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic T stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
The patient numbers included in previous studies were small, and these studies did not differentiate between adenocarcinoma and SCC, which explains the inconsistent results. The present study’s large population-based database enrolled 2151 patients with uniform histology. All of the patients were staged according to the 7th edition of the TNM staging system. In multivariate analysis, the pathologic T, N, and M stages were all independent prognostic factors in both groups A (surgery alone) and B (CRT plus esophagectomy). According to the analysis, the post-CRT pathologic stage could accurately predict survival in patients with ESCC treated with preoperative CRT followed by esophagectomy.
The effect of preoperative CRT on the pathologic staging of ESCC has not been well defined. Swisher et al9 performed stage-specific survival comparisons between patients with and without preoperative therapy and found that the stage-specific survival rates were similar, except for those with stage I disease. Patients with advanced esophageal cancer are often treated with preoperative CRT, and pathologic downstaging has been suggested. In the present study, similar results regarding the effect of preoperative CRT for downstaging patients with ESCC were obtained. Although both pTNM and ypTNM could predict survival, the survival curves were not the same. For example, the 3-year survival
(A) Kaplan-Meier survival curves stratified by the pathologic N stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic N stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
(A) Kaplan-Meier survival curves stratified by the pathologic N stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic N stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
(A) Kaplan-Meier survival curves stratified by the pathologic N stage for 1301 patients with esophageal squamous cell carcinoma treated with surgery alone. (B) Kaplan-Meier survival curves stratified by the pathologic N stage for 850 patients with esophageal squamous cell carcinoma treated with preoperative CRT followed by surgery.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0171
After CRT, scattered residual tumor cells would exist within the esophageal wall and regional LNs, and therefore the accurate assignment of the deepest layers of tumor involvement may be questionable.6–14 Several proposals have been suggested with respect to tumor response.7,12 In the population database, the pathologic regression grade was not recorded.
Based on this analysis, ypT and ypN remained independent prognostic factors on multivariate analysis. The hazard ratio for OS increased with advanced ypT and ypN. The ypT and ypN could stratify the survival course even without data on the tumor regression grade. The current ypTNM system could maintain the prognostic significance in the 7th edition of the esophageal staging system.
In the 7th edition of the AJCC TNM staging system, the N stage is classified based on the number of positive LNs in patients undergoing surgery alone (N0: no regional LN metastasis; N1: metastases in 1–2 regional LNs; N2: metastases in 3–6 regional LNs; N3: metastases in ≥7 regional LNs). However, the clinical impact of the number of LNs with metastasis in patients after preoperative CRT plus esophagectomy is still being investigated.18–21 Mariette et al18 indicated that the number of LNs
Multivariate Analyses for Overall Survival in Patients With Resected Esophageal Squamous Cell Carcinoma With or Without Neoadjuvant Chemoradiotherapy
The pCR rate after preoperative CRT has been reported to be 25% to 30% in the literature. Patients with pCR had better survival than those with residual tumors.23–26 Similar results were obtained in the present study. In the TCR database, the pCR rate was 26.1%. In the remaining 73.9% of patients with residual tumors, the posttherapy pathologic stage remained a predictor of survival. The present data found that the current staging system could provide adequate survival estimates for patients with ESCC who underwent preoperative CRT followed by esophagectomy.
T0N+ was defined as the absence of viable tumor in the esophagus but the persistent presence of metastatic LNs. Kim et al27 reviewed 336 patients with esophageal cancer and identified 20 with T0N1. They indicated that the survival was similar to that of patients with stage II esophageal cancer with a pathologic partial response. In the present database, 38 patients had T0N+ esophageal cancer. The 3-year survival rate (32.6%) was also similar to that in patients with post-CRT pathologic stage II disease.
The present study has several strengths compared with other published series. This series consists of a large number of patients (n=2151) with uniform histology (SCC). The investigators also performed stage-specific, T-specific, and N-specific survival comparisons to explore the discrepancy between the pTNM and the ypTNM systems. This study had several limitations, including its retrospective nature; the lack of data on chemotherapy regimens, response to CRT, and disease recurrence patterns; and the heterogeneous radiation dose.
Conclusions
This study showed that the 7th edition of the esophageal TNM staging system could adequately stratify prognostic groups in patients with SCC who underwent preoperative CRT and esophagectomy. However, the pCR and T0N+ stage are not included in the current 7th edition staging system. With the widespread use of preoperative therapy, these new therapies must be incorporated into future revised TNM staging systems.
This work is supported by Health Promotion Administration, Ministry of Health and Welfare, Taiwan (R.O.C.). Sources of funding are from the tobacco control and health care funds.
References
- 2↑
Chen MF, Yang YH, Lai CH et al.. Outcome of patients with esophageal cancer: a nationwide analysis. Ann Surg Oncol 2013;20:3023–3030.
- 4↑
Van Hagen P, Hulshof MC, Van Lanschot JJ et al.. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012;366:2074–2084.
- 5↑
Teoh AY, Chiu PW, Yeung WK et al.. Long-term survival outcomes after definitive chemoradiation versus surgery in patients with resectable squamous carcinoma of the esophagus: results from a randomized controlled trial. Ann Oncol 2013;24:165–171.
- 6↑
Sjoquist KM, Burmeister BH, Smithers BM et al.. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable esophageal carcinoma: an updated meta-analysis. Lancet Oncol 2011;12:681–692.
- 7↑
Courrech Staal EF, Aleman BM, Boot H et al.. Systematic review of the benefits and risks of neoadjuvant chemoradiation for oesophageal cancer. Br J Surg 2010;97:1482–1496.
- 8↑
Edge SB, Byrd DR, Compton CC et al., eds. AJCC Cancer Staging Manual.7th ed. New York, NY: Springer; 2010.
- 9↑
Swisher SG, Hofstetter W, Wu TT et al.. Proposed revision of the esophageal cancer staging system to accommodate pathologic response (pP) following preoperative chemoradiation (CRT). Ann Surg 2005;241:810–817.
- 10↑
Chirieac LR, Swisher SG, Ajani JA et al.. Posttherapy pathologic stage predicts survival in patients with esophageal carcinoma receiving preoperative chemoradiation. Cancer 2005;103:1347–1355.
- 11↑
Rizk NP, Venkatraman E, Bains MS et al.. American Joint Committee on Cancer staging system does not accurately predict survival in patients receiving multimodality therapy for esophageal adenocarcinoma. J Clin Oncol 2007;25:507–512.
- 12↑
Law S, Kwong DL, Wong KH et al.. The effects of neoadjuvant chemoradiation on pTNM staging and its prognostic significance in esophageal cancer. J Gastrointest Surg 2006;10:1301–1311.
- 13↑
Barbour AP, Jones M, Gonen M et al.. Refining esophageal cancer staging after neoadjuvant therapy: importance of treatment response. Ann Surg Oncol 2008;15:2894–2902.
- 14↑
Schneider PM, Baldus SE, Metzger R et al.. Histomorphologic tumor regression and lymph node metastases determine prognosis following neoadjuvant radiochemotherapy for esophageal cancer: implications for response classification. Ann Surg 2005;242:684–692.
- 15
Mandard AM, Dalibard F, Mandard JC et al.. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994;73:2680–2686.
- 16
Ancona E, Ruol A, Santi S et al.. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer 2001;91:2165–2174.
- 17↑
Stiles BM, Christos P, Port JL et al.. Predictors of survival in patients with persistent nodal metastases after preoperative chemotherapy for esophageal cancer. J Thorac Cardiovasc Surg 2010;139:387–394.
- 18↑
Mariette C, Piessen G, Briez N et al.. The number of metastatic lymph nodes and the ratio between metastatic and examined lymph nodes are independent prognostic factors in esophageal cancer regardless of neoadjuvant chemoradiation or lymphadenectomy extent. Ann Surg 2008;247:365–371.
- 19↑
Gu Y, Swisher SG, Ajani JA et al.. The number of lymph nodes with metastasis predicts survival in patients with esophageal or esophagogastric junction adenocarcinoma who receive preoperative chemoradiation. Cancer 2006;106:1017–1025.
- 20
Gaca JG, Petersen RP, Peterson BL et al.. Pathologic nodal status predicts disease-free survival after neoadjuvant chemoradiation for gastroesophageal junction carcinoma. Ann Surg Oncol 2006;13:340–346.
- 21↑
Akutsu Y, Shuto K, Kono T et al.. The number of pathologic lymph nodes involved is still a significant prognostic factor even after neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma. J Surg Oncol 2012;105:756–760.
- 22↑
Reynolds JV, Muldoon C, Hollywood D et al.. Long-term outcomes following neoadjuvant chemoradiotherapy for esophageal cancer. Ann Surg 2007;245:707–716.
- 23↑
Bosset JF, Gignoux M, Triboulet JP et al.. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 1997;337:161–167.
- 24
Walsh TN, Noonan N, Hollywood D et al.. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462–467.
- 25
Urba SG, Orringer MB, Turrisi A et al.. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 2001;19:305–313.
- 26↑
Le Prise E, Etienne PL, Meunier B et al.. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer 1994;73:1779–1178.
- 27↑
Kim MP, Correa AM, Lee J et al.. Pathologic T0N1 esophageal cancer after neoadjuvant therapy and surgery: an orphan status. Ann Thorac Surg 2010;90:884–890.
