Downstaging of T or N Predicts Long-Term Survival After Preoperative Chemotherapy and Radical Resection for Esophageal Carcinoma

doi:10.1016/j.athoracsur.2006.03.072

The Annals of Thoracic Surgery

Volume 82, Issue 2, August 2006, Pages 480-485

Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.

https://doi.org/10.1016/j.athoracsur.2006.03.072 Get rights and content

Background

The purposes of this study were to determine the frequency of downstaging of T or N after neoadjuvant chemotherapy and radical resection in patients with carcinoma of the esophagus, and to evaluate the effect of tumor downstaging on survival.

Methods

A cohort of patients who underwent neoadjuvant chemotherapy followed by radical surgical resection for carcinoma of the esophagus was identified from a large, prospectively maintained, single-institution database of esophageal cancer patients. Patients were included if they had an accurate pretreatment clinical stage determined by the authors. Data collected included demographic data, the type of staging regimen, the chemotherapy agents used, clinical and pathologic data and stages, and survival data. Downstaging of T or N was determined by comparing the pretreatment, clinical stage to the postresection, pathologic stage. Downstaging was then evaluated in the context of survival.

Results

Seventy-seven patients were identified who had an accurate clinical stage assigned and underwent neoadjuvant chemotherapy followed by radical resection. Patients were clinically staged before treatment using computed tomography, positron emission tomography, and endoscopic ultrasonography. Thirty-seven patients (48%) experienced downstaging of T or N, and this group of patients had a 5-year overall actuarial survival of 63%, compared with 23% for those who were not downstaged (p = 0.002). Three patients had a complete pathologic response to neoadjuvant chemotherapy (3.9%).

Conclusions

Patients who experience downstaging of T or N after neoadjuvant chemotherapy and radical surgical resection for esophageal carcinoma have a significantly higher survival rate compared with those who do not experience downstaging. This enhanced survival is comparable to survival rates reported in complete pathologic responders after neoadjuvant chemoradiation.

Section snippets

Study Design and Data Collection

This study is a retrospective review of a prospectively maintained esophageal cancer database at a single institution. All patients who underwent radical, en bloc esophagectomy for carcinoma were identified from November 1987 to November 2005. Patients were included regardless of whether they had a two-field or three-field lymphadenectomy. This group was then queried to identify patients who received preoperative chemotherapy (without radiation), and had a clinical stage assigned before

Demographics of Study Cohort

Between November 1987 and November 2005, 274 patients underwent a radical, en bloc esophagectomy for carcinoma in the Division of Thoracic Surgery at The New York/Weill-Cornell Medical Center. An additional 105 patients underwent nonradical esophagectomy for carcinoma during the same time period, but are not included in the present analysis to ensure accurate pathologic staging. Of these 274 patients, 174 received no preoperative therapy, 11 underwent neoadjuvant chemoradiotherapy, and 89

Comment

The use of neoadjuvant chemotherapy before surgical resection for carcinoma of the esophagus remains controversial. Although a multi-institutional randomized trial performed in North America comparing this strategy with surgical resection alone did not demonstrate a difference in overall survival [6], a larger randomized trial using the same agents conducted in Europe showed a significant survival advantage for the patients receiving preoperative chemotherapy [11]. Given that the vast majority

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Oesophageal cancers, including oesophageal adenocarcinoma (OAC) and oesophageal gastric junction cancer (OGJ), are one of the leading causes of cancer mortality worldwide. Curative therapy consists of surgery, either alone or in combination with adjuvant or neoadjuvant chemotherapy or radiation, or combination chemoradiotherapy regimens. There are currently no clinico-pathological means of predicting which patients will benefit from chemotherapeutic treatments. There is therefore an urgent need to improve oesophageal cancer disease management and treatment strategies. This work compared proteomic differences in OAC patients who responded well to chemotherapy as compared to those who did not, using quantitative proteomics prior to treatment commencement. SWATH-MS analysis of plasma (with and without albumin/IgG-depletion) from OAC patients prior to chemotherapy was performed. This approach was adopted to determine whether depletion offered a significant improvement in peptide coverage. Resultant datasets demonstrated that depletion increased peptide coverage significantly. Additionally, there was good quantitative agreement between commonly observed peptides. Data analysis was performed by adopting both univariate as well as multivariate analysis strategies. Differentially abundant proteins were identified between treatment response groups based on tumour regression grade. Such proteins included complement C1q sub-components and GSTP1. This study provides a platform for further work, utilising larger sample sets across different treatment regimens for oesophageal cancer, that will aid the development of ‘treatment response prediction assays’ for stratification of OAC patients prior to chemotherapy.
Low- vs. High-Dose Neoadjuvant Radiation in Trimodality Treatment of Locally Advanced Esophageal Cancer
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The optimal dose of neoadjuvant radiation for locally advanced, resectable esophageal cancer remains controversial in the absence of randomized clinical trials, with conventional practice favoring the use of 50.4 vs. 41.4 Gy.
Retrospective analysis of adults with non-metastatic esophageal cancer in the National Cancer Database (2004–2015) treated with neoadjuvant chemoradiotherapy. Outcomes were compared between patients undergoing 41.4, 45, or 50.4 Gy. Primary outcome was overall survival. Secondary outcomes included T and N downstaging and perioperative mortality adjusted for demographics, clinicopathologic factors, and facility volume.
Eight thousand eight hundred eighty-one patients were included: 439 (4.9%) received low-dose (41.4 Gy), 2194 (24.7%) received moderate-dose (45 Gy), and 6248 (70.4%) received high-dose (50.4 Gy) neoadjuvant radiation. Compared to high-dose, low-dose radiation was associated with superior median overall survival (52.6 vs. 40.7 months) and 5-year survival (48.3% vs. 40.2%), and lower unadjusted 90-day mortality (2.3% vs. 6.5%, all p ≤ 0.01). Multivariable proportional hazards models confirmed an increased hazard of death associated with high-dose radiation therapy (HR = 1.38, 95% CI 1.10–1.72, p = 0.005). There was no significant difference in T and/or N downstaging between low-dose vs. high-dose therapy (p > 0.1 for both). Patients receiving 45 Gy exhibited the lowest median overall survival (37.2 months) and 5-year survival (38.7%, log-rank p = 0.04).
Compared to 50.4 Gy, 41.4 Gy is associated with reduced perioperative mortality and superior overall survival with similar downstaging in locally advanced esophageal cancer. In the absence of randomized clinical data, our findings support the use of 41.4 Gy in patients with chemoradiation followed by esophagectomy. Prospective trials are warranted to further validate these results.
Prognostic differences in 8th edition TNM staging of esophagogastric adenocarcinoma after neoadjuvant treatment
2018, European Journal of Surgical Oncology
Citation Excerpt :
So the benefit of NT shows, when comparing outcome of ypT0-2 tumors with prognosis of pT3-tumors, which was clearly worse. Downstaging of T- and N-category after NT has been previously shown to be associated with improved survival [26–28]. Complete pathologic responders (ypT0) showed no prognostic advantage compared to those with ypT1-and even ypT2-tumors.
Prognostic differences between pTN- and ypTN-categories and the prognostic accuracy of the 8th edition UICC-pTNM- and AJCC-ypTNM-staging-system for esophageal and gastric adenocarcinoma are unclear.
We retrospectively analyzed data of 740 patients with esophagogastric adenocarcinoma, who underwent curative surgery (344 after neoadjuvant treatment [NT]) at our institution. Survival analyses were performed according to Kaplan-Meier (log-rank test). Multivariate analyses were performed using the Cox proportional hazard model.
Low ypT-categories did not discriminate overall survival (ypT0: reference; ypT1: HR1.0/p = 0.909; ypT2: HR0.9/p = 0.845; ypT3: HR1.5/p = 0.184; ypT4: HR2.8/p = 0.004) and no difference was found between ypN1- and ypN2-disease (ypN0: HR0.4/p < 0.001; ypN1: reference; ypN2: HR1.1/p = 0.653; ypN3: HR1.7/p = 0.014). In esophageal adenocarcinoma the UICC-TNM- and AJCC-ypTNM-staging-system was able to predict survival for patients after NT, while in gastric cancer it failed to provide sufficient prognostic information. A simplified staging system provided better stratification after NT and was an independent prognosticator for both esophageal and gastric adenocarcinoma (stage I: reference; stage II: HR2.2/p = 0.005; stage III: HR4.1/p < 0.001).
Prognostic value of ypTN-categories seems limited. After NT the current UICC/AJCC-staging-system is able to predict survival in esophageal adenocarcinoma, but needs to be reevaluated in gastric cancer patients and modified if needed. A novel simplified staging system might be more practicable for patients after NT.
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Citation Excerpt :
Although no completed randomized controlled trial has compared induction chemotherapy with chemoradiation therapy directly, the results from studies comparing each modality with surgery alone have demonstrated substantial differences in pathologic complete response (pCR) rates. Although trials of induction chemotherapy and surgery reported pCR rates of 3% to 13%, those studies evaluating induction chemoradiation and surgery achieved pCR rates of 29% (from the CROSS trial) and 40% (CALGB 9781).2,7-10 Although our analysis examined patients with persistent positive nodes, it is not surprising that even among this population there was overall less disease burden seen among those patients who received induction chemoradiation therapy.
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Treatment data for patients with esophageal cancer receiving induction chemotherapy ± radiotherapy and esophagectomy were abstracted from the National Cancer Data Base. Pathologic node-positive patients were dichotomized by whether they received 2 or more cycles of adjuvant chemotherapy or none. Kaplan–Meier survival curves were generated, and a Cox proportional hazards model was done to identify factors associated with overall survival.
From 2006 to 2012, 3100 patients had pathologic positive nodes after induction therapy and esophagectomy. A total of 2625 patients (84.7%) did not receive adjuvant chemotherapy, and 475 patients (15.3%) did. N3 nodal stage was associated with an increased likelihood of receiving adjuvant chemotherapy (reference: N1, odds ratio, 1.82, 95% confidence interval, 1.15-2.97, P = .01), whereas increasing age (by year, odds ratio, 0.97, confidence interval, 0.96-0.98, P < .001), induction chemoradiation therapy (reference: induction chemotherapy, odds ratio, 0.39, confidence interval, 0.30-0.52, P < .001), and increasing inpatient length of stay after esophagectomy (per day: odds ratio, 0.98, confidence interval, 0.97-0.99, P = .007) were associated with a decreased likelihood. Patients receiving adjuvant chemotherapy had improved overall survival at each pathologic nodal stage: 31.6 months versus 22.7 months for N1 disease (P < .001), 32.4 months versus 19.2 months for N2 disease (P = .035), and 19.5 months versus 10.4 months for N3 disease (P < .001). Adjuvant therapy was independently associated with decreased mortality hazard (hazard ratio, 0.69, 95% confidence interval, 0.57-0.83, P < .001).
Patients receiving adjuvant chemotherapy after induction therapy and esophagectomy show a survival benefit at all positive nodal stages. Prospective studies may help further delineate this benefit.
Neoadjuvant Chemotherapy versus Chemoradiation Prior to Esophagectomy: Impact on Rate of Complete Pathologic Response and Survival in Esophageal Cancer Patients
2016, Journal of Thoracic Oncology
The aim of this study was to evaluate differences in pathologic complete response (pCR) rates and overall survival among patients receiving either neoadjuvant chemotherapy or chemoradiation before esophagectomy for locally advanced esophageal cancer.
Patients with esophageal cancer receiving either neoadjuvant chemotherapy or chemoradiation before esophagectomy were identified using the National Cancer Database. Univariate analysis compared patient, tumor, and postoperative outcome characteristics. Logistic regression was performed to identify variables associated with achieving pCR. Kaplan-Meier analysis was performed to compare overall median survival by neoadjuvant therapy type and pCR status. Finally, a Cox proportional hazards model was fitted to identify variables associated with increased mortality hazard.
From 2006 to 2012, a total of 916 of 7338 of patients (12.5%) received neoadjuvant chemotherapy whereas 6422 (87.5%) received neoadjuvant chemoradiation. Patients who received neoadjuvant chemoradiation were more likely to achieve a pCR (17.2% versus 6.4%, p < 0.001) and less likely to have positive margins (5.6% versus 11.5%, p < 0.001) than were patients who received neoadjuvant chemotherapy, with no difference in 30- or 90-day mortality. Achieving a pCR was associated with improved overall median survival (59.5 ± 4.0 months versus 30.1 ± 0.76 months for those with persistent disease, p < 0.001). On logistic regression, neoadjuvant chemoradiation therapy was independently associated with achieving a pCR (OR = 2.75, 95% confidence interval: 2.01–3.77, p < 0.001). Despite improvement in the pCR rate with neoadjuvant chemoradiation, neoadjuvant therapy type was not independently associated with long-term survival (hazard ratio = 1.12; 95% confidence interval: 0.97–1.30, p = 0.12).
Although neoadjuvant chemoradiation is more successful in downstaging esophageal cancer before esophagectomy, it was not independently prognostic for improved long-term survival. Other factors affecting long-term survival among pathologic complete responders and among patients with persistent disease should be investigated to clarify this association.
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Original ArticleDownstaging of T or N Predicts Long-Term Survival After Preoperative Chemotherapy and Radical Resection for Esophageal Carcinoma

Background

Methods

Results

Conclusions

Section snippets

Study Design and Data Collection

Demographics of Study Cohort

Comment

Ann Thorac Surg

J Thorac Cardiovasc Surg

Surg Clin North Am

Am J Gastroenterol

Ann Thorac Surg

Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma

J Clin Oncol

Use of concurrent chemotherapy, accelerated fractional radiation, and surgery for patients with esophageal carcinoma

Cancer

Combined therapies for squamous cell carcinoma of the esophagus, a Southwest Oncology Group study (SWOG 8037)

J Clin Oncol

Original Article
Downstaging of T or N Predicts Long-Term Survival After Preoperative Chemotherapy and Radical Resection for Esophageal Carcinoma