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Ann Thorac Surg 2004;78:1177-1183
© 2004 The Society of Thoracic Surgeons
a Service de Chirurgie Digestive et Générale, Hôpital Claude Huriez, Lille, France
b Unité INSERM 560, Centre Hospitalier Régional Universitaire, Lille, France
Accepted for publication February 17, 2004.
* Address reprint requests to Dr Mariette, Service de Chirurgie Digestive et Générale, Hôpital Claude Huriez, CHRU, Place de Verdun 59037, Lille Cedex, France
c-mariette{at}chru-lille.fr
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Abstract |
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METHODS: Complete esophageal resection was attempted for middle and lower third esophageal carcinomas in 386 consecutive patients between January 1982 and January 2002. Two study periods were analyzed: 1982 to 1993 and 1994 to 2002. Prognostic factors were identified by multivariate analysis and the two periods compared.
RESULTS: Hospital mortality rate decreased from 5.4% to 2.9% (p = 0.245). Both anastomotic leakage and pulmonary complications rates decreased from 9.8% to 2.2% (p = 0.001) and 24.1% to 19.3% (p = 0.295), respectively. An increased proportion of patients had R0 resection in the latter period, 78.5% versus 67.0%, (p = 0.028). Five-year survival rate after R0 resection increased from 29% to 46% (p = 0.001), with a decreased recurrence rate from 65.8% to 44.3% (p = 0.002). Three favorable prognostic factors were identified: low pT stage, pN0 stage, and operation during the 1994 to 2002 study period.
CONCLUSIONS: Short-term outcome and survival of patients with resected esophageal cancer have improved over time. Advances in perioperative technique, staging methods, and surgical management combined with higher patient selection and use of neoadjuvant chemoradiation may be responsible for this progress.
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Introduction |
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Surgery is traditionally viewed as the most effective way to ensure both locoregional control and long-term survival. Therefore, use of radical surgical procedures, is considered reasonable to improve overall outcome [5]. Transthoracic esophagectomy has been shown to be the best technique allowing extended en bloc esophagectomy with extended lymphadenectomy, complete surgical resection, and long-term survival in patients who are eligible for major thoracic surgery [6].
To have any impact on long-term survival in these patients, it is essential to minimize postoperative mortality and morbidity by optimizing surgical technique and perioperative care [7]. Moreover, patients with high risk of incomplete surgical resection, recurrent disease, or cancer-related death must be identified to propose them nonsurgical treatment [8, 9].
We report a single-center experiment on 386 patients who underwent attempted complete en bloc transthoracic resection for middle and lower third esophageal carcinomas during a 20-year period. It was the objective of the present study to (1) identify factors affecting postoperative course and long-term survival and (2) isolate factors responsible for better surgical results in the last decade.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Preoperative Workup
Patients were considered to be operable with resectable esophageal cancer after a complete pretherapeutic workup which included: physical examination, standard laboratory tests, ear, nose and throat examination, panendoscopy under general anesthesia, and bronchial fibroscopy with biopsies for squamous cell tumors, digestive fibroscopy, and esogastroduodenal barium study, ultrasonography exploration of the cervical and abdominal areas, CT of the thorax, mediastinum and abdomen, and more recently endoscopic ultrasonography.
Criteria for nonresecability were as follows: adherence to the aorta more than 90 degrees, invasion of the tracheobronchi, azygos vein, recurrent nerve, celiac or subclavian lymph node enlargement, and visceral metastasis. Criteria for nonoperability were as follows: cirrhosis (any stage) associated with portal hypertension, respiratory failure, forced expiratory volume less than 1,000 mL/s, weight loss more than 20%, heart failure (New York Heart Association functional class III to IV).
The objective response to neoadjuvant chemoradiotherapy was defined according to the World Health Organization criteria [9]. A complete response was defined as the disappearance of all evidence of disease, for both esophageal wall penetration and lymph node status.
Surgical Approach
The detailed resection techniques have been described elsewhere [10]. Surgical resection consisted of a transthoracic en bloc esophagectomy. The surgical approach included an abdominal lymphadenectomy (left and right paracardial regions, suprapyloric and infrapyloric sites, along the lesser curve, the left gastric artery and celiac axis) and an extended mediastinal lymphadenectomy (left recurrent and right subclavian nodes, paratracheal, subcarinal, left and right bronchial lymph nodes, lower posterior mediastinum, paraaortic, paraesophageal, and thoracic duct; extended two-field lymphadenectomy). No cervical lymphadenectomy was undertaken. The esophagus was replaced by the stomach in all patients. Manual anastomosis was realized in the apex of the chest in all cases.
Histopathologic Assessment
All nodal material was separately dissected from the specimen at the end of the procedure by the surgeon and analyzed according to the guidelines of the Japanese Society for Esophageal Diseases [11]. The histologic staging was based on the pTNM classification [12]. The resection was designated R0 when it was considered that both macroscopic and microscopic complete clearance had been achieved, R1 when microscopically incomplete with histologic evidence of invasion of the longitudinal or lateral margins, and R2 when macroscopically incomplete with macroscopic residual tumor after surgery, according to the 1993 Union Internacional Contra la Cancrum (UICC) criteria [13].
Follow-up
All patients surviving operation were followed up until death or the time of writing, at the end of the first month, every 6 months for years 1 and 2, and annually thereafter. Clinical review consisted in history and abdominal examination. Abdominal ultrasonography was realized twice a year, chest roentgenogram, thoracoabdominal CT, endoscopy with biopsies, and indirect laryngoscopy once a year. Histologic, cytologic, or unequivocal radiologic proof was required before a diagnosis of recurrence was made. Recurrent disease was classified as locoregional (occurring in the upper abdomen or mediastinum) or distant (including cervical recurrences). The survival status of patients was ascertained in January 2003. Follow-up was complete for all patients. The mean (SD) follow-up was 48.3 (36.1) months.
Variables Analyzed
In this retrospective observational study, the collected data included demographic variables, histomorphologic tumor characteristics, postoperative mortality and morbidity rates, and recurrent disease. Factors predictive of postoperative mortality, morbidity, R0 resection, and recurrence were identified by multivariate analysis. Overall survival and prognostic factors were also studied.
Statistical Analysis
Data are shown as prevalence, means (SD), or median (range). Continuous data were compared by means of the Mann-Whitney U test and ordinal data by the 
2 test or Fisher's exact test as appropriate. Survival was estimated by the actuarial method, including postoperative deaths, using SPSS software (SPSS, Chicago, IL). The log-rank test was used for comparison of survival curves. Prognostic factors were analyzed by Cox's proportional hazard regression analysis, using a stepwise procedure; the 0.2 level was defined for entry into the model. Multivariate 2 and p values were used to characterize the independence of these factors; the relative risk (RR) and the 95% confidence interval (CI) were used to quantify the relationship between survival time and each independent factor. To determine predictors of complete resection, postoperative mortality, morbidity or recurrence, a stepwise logistic regression model was used, in which all the covariables were adjusted simultaneously. Differences were considered to be significant at 5% alpha risk.
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Results |
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2 = 12.8, RR = 13.4, 95% CI: 3.2 to 55.6, p < 0.001), ASA 3 score (2 = 9.1, RR = 5.3, 95% CI: 1.8 to 15.8, p = 0.003), anastomotic leak (2 = 6.4, RR = 8.6, 95% CI: 1.6 to 45.2, p = 0.011), and palliative resection (2 = 3.9, RR = 4.3, 95% CI: 1.1 to 18.4, p = 0.049).
Postoperative Morbidity
Significant postoperative complications (defined as enhanced hospital stay) occurred in 140 patients (36.3%). Seventeen (4.4%) anastomotic leaks were observed clinically or radiologically. A neoadjuvant treatment had no impact on postoperative leakage (p = 0.821). The leakage rates were 9.8% and 2.2% in the 1982 to 1993 and 1994 to 2002 study period, respectively (p = 0.001). The only factor predictive of anastomotic leak was operation performed before 1994 (2 = 9.1, RR = 5.0, 95% CI: 1.8 to 14.1, p = 0.026).
Significant pulmonary complications were observed in 80 patients (20.7%) with aspiration atelectasis (n = 10), bronchopneumonia (n = 44), and respiratory insufficiency (n = 26), including 17 patients with primary acute respiratory distress syndrome. Thirty-five patients (9.1%) presented significant pleural complication (defined as required drainage). The pulmonary complication rates were 24.1% and 19.3% in the 1982 to 1993 and 1994 to 2002 study period, respectively (p = 0.295). Anastomotic leakage significantly enhanced pulmonary complication rate from 3.3% to 8.8% (p = 0.030). The only predictor of pulmonary complications was ASA 3 score (2 = 5.1, RR = 1.6, 95% CI: 1.1 to 2.5, p = 0.024). A neoadjuvant treatment did not significantly improve postoperative pulmonary complications (p = 0.291). Other postoperative complications were represented by cardiac, neurologic, or other complications with 0.8%, 1.3%, and 4.4% rates, respectively. The median time of resumption for oral feeding was 9.0 days (range, 6 to 255) after operation. The median hospital stay for the whole population was 13.0 days (range, 7 to 150).
Histopathologic Staging
Resection was macroscopically complete (R0) in 290 patients (75.1%), microscopically incomplete (R1) in 36 patients, and macroscopically incomplete (R2) in 60 patients. The percentage of R0 resection significantly increased during the 1994 to 2002 study period (78.5%) compared with the 1982 to 1993 period (67.0%; p = 0.028). Squamous cell carcinoma was the predominant histologic subtype compared with adenocarcinoma with a ratio of 3.3:1. Tumors were well or moderately differentiated in 269 patients, and poorly or undifferentiated in 117 patients. Histologic response to neoadjuvant treatment was observed in 107 patients (55.2%). On histopathologic assessment of the resected specimens, the lesion was pT0 in 45 cases (11.7%), pT1 in 69 cases (17.9%), pT2 in 59 cases (15.3%), pT3 in 180 cases (46.6%), and pT4 in 33 cases (8.5%). Lymph node metastases were found in 221 patients (57.3%). Tumoral stages were as follows: esophageal cancer stage 0 (pT0N0, complete response after neoadjuvant chemoradiotherapy), n = 33; stage I, n = 51; stage IIA, n = 74; stage IIB, n = 59; stage III, n = 169. A mean (SD) of 19.0 (10.8) lymph nodes was dissected from each specimen, 21.3 (11.7) after surgery alone and 16.6 (9.3) after neoadjuvant treatment (p < 0.001). The mean (SD) number of histologically positive lymph nodes was 2.2 (3.2), 2.8 (3.8) after surgery alone and 1.6 (2.4) after neoadjuvant treatment (p = 0.003). Predictors of R0 resection were pT1 and pT2 stages (2 = 15.7, RR = 2.3, 95% CI: 1.5 to 3.6, p < 0.001), morphologic response to neoadjuvant treatment (2 = 4.7, RR = 1.6, 95% CI: 1.1 to 2.5, p = 0.030), and pN0 stage (2 = 3.9, RR = 2.3, 95% CI: 1.1 to 5.3, p = 0.047).
Recurrence
After excluding postoperative deaths and patients with incomplete resection (R1 and R2), 141 of 283 patients (49.8%) experienced recurrent disease. Recurrence rate decreased from 65.8% to 44.3% (p = 0.002) between the 1982 to 1993 and the 1994 to 2002 study periods. Distant metastasis were found in 69 patients (24.4%), locoregional recurrences in 32 (11.3%), and both distant and locoregional recurrences in 40 (14.1%). Median time to recurrence after operation was 14.0 months (range, 6 to 92), with 42.5% of all recurrences developing within 12 months of operation. Recurrence within 12 months was also recognized in 4 of 51 cases for stage I, in 9 of 74 cases for stage IIA, in 11 of 59 cases for stage IIB, in 33 of 169 cases for stage III and in 3 of 33 cases for stage 0, respectively. A neoadjuvant treatment had no impact on recurrent disease (p = 0.258). The only predictor of recurrent disease was a pT3 or pT4 stage (2 = 28.5, RR = 2.6, 95% CI: 1.7 to 3.0, p < 0.001).
Survival Analysis
The overall 1-, 3-, and 5-year survival rates for the entire population were 80%, 45%, 31%, respectively, and for the R0 population, 96%, 59%, 41%, respectively. The median survivals for overall population and R0 patients was 28.9 months and 43.4 months, respectively. The overall 1- and 3-year survival rates for the R1 and R2 patients were 37% and 4%, respectively. None of these patients was alive beyond 3 years of follow-up. After R0 resection median survival was 28.6 months and 53.2 months for the 1982 to 1993 and the 1994 to 2002 study periods, respectively (p = 0.001). The clinical variables related to poor prognosis (Table 2) were male sex (p = 0.049), operation in the 1982 to 1993 study period (p = 0.001), weight loss (p = 0.048), and dysphagia (p = 0.028). Neither postoperative complication nor neoadjuvant treatment had any influence on the long-term survival in this study (p = 0.327 and p = 0.408, respectively). Histologic variables related to survival in univariate analysis (Table 3) were pT category (p < 0.001; Fig 1), pN category (p < 0.001; Fig 2), tumoral stage (p < 0.001), and histologic response to neoadjuvant chemoradiotherapy (p = 0.010). After R0 resection, the prominent independent factors of poor prognosis in multivariate analysis were pT3 and pT4 stages, pN1 stage, and operation in the 1982 to 1993 study period (Table 4).
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Comment |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Our study is in agreement with previous studies in which it was shown that the short-term outcomes after esophageal resection have improved [1, 3], with operative mortality dropping from 5.4% to 2.9%, between the 1982 to 1993 and the 1994 to 2002 study periods. Both anastomotic leakage and pulmonary complications rates decreased in the latter study period, 9.8% versus 2.2% (p = 0.001) and 24.1% versus 19.3% (p = 0.295), respectively. Predictors of postoperative mortality were palliative resection and ASA 3 score, anastomotic leak, and pulmonary complications. Consequently, improvement in short-term outcomes should include improved patient selection, refinements in surgical techniques, and intensive perioperative care, respectively. An other factor could be surgical expertise of the center related to the volume. Several authors have noted that increasing esophagectomy volume is directly correlated with decreased operative mortality, morbidity, and hospital costs [14, 15].
Long-term survival of patients with esophageal carcinoma a priori suitable for radical esophagectomy depends on the completeness of the resection. Indeed, although 41% of patients may anticipate long-term survival when R0 resection has been possible, patient prognosis for those who had part of the neoplastic process left in the dissection field (R1, R2 resections) is very poor [9]. None of these patients was alive beyond 3 years of follow-up.
In this study, we have documented three favorable prognostic factors after R0 resection: pT0 to T1-T2 stages, pN0 category, and 1994 to 2002 study period. Of the three prognostic factors identified, pT and pN category are widely accepted and are not debated.
Several reasons could explain better long-term prognosis with time. First, although not significant, hospital mortality rate was lowered from 5.4% to 2.9%.
Second, the improvement in long-term prognosis was related to an increase in number of R0 resections. The R0 resection rate was 67.0% in the 1982 to 1993 and 78.5% in the 1994 to 2002 study periods (p = 0.028). Recent reports after complete en bloc esophagectomy also showed survival rates ranging from 38% to 48% [6, 16, 17]. Failure to complete the procedure in approximately 25% of patients for whom radical resection is attempted is mainly due to the CT scanning to predict the existence of nonresectable extraesophageal neoplastic tissue with total accuracy. Identified in the present study, a pT1 or pT2 stage, a pN0 stage, and a morphologic response to neoadjuvant treatment as predictor of R0 resection should help choose patients who could benefit from exclusive radical surgery. Although CT scan was available throughout the study, endoscopic ultrasonography was only introduced in 1990. We have found it very useful in altering clinical decisions after a few years, and we have shown recently it was a predictor of R0 resection and a prognostic factor of survival [18]. Moreover, we introduced during the latter period a preoperative score, published recently, predictable of R0 resection [9].
Third, dramatic increase in overall survival with time was probably related with lowering of tumor stage by neoadjuvant chemoradiation. Neoadjuvant chemotherapy or chemoradiotherapy in patients with locally advanced esophageal carcinoma is still experimental and there is no consensus about an optimal treatment regimen. Nevertheless, neoadjuvant treatment was associated with a better prognosis in patients who responded to treatment by the way of increasing the rate of R0 resection [19, 20]. Significant downstaging by chemoradiation probably selects the favorable ones for surgical resection. In this study, neoadjuvant therapy had no global impact on recurrent disease and survival, probably because of absence of selection of responding patients.
Fourth, it is difficult to completely dissociate the relative contributions of more stringent patient selection and downstaging by chemoradiation to produce more R0 resections and lower stage tumors in the latter study period. The ability to perform R0 resections correlated with the pT stage, however, and that 15% of patients in the second period had pT0 disease compared with only 4.5% in the first period suggests that tumor downstaging by chemoradiation played a significant role. However, the proportion of pT4 tumors in the latter period was more than half compared with the earlier period (14.3% versus 6.2%). No patient with pT4 tumor underwent R0 resection and consequently was alive at 5 years. Therefore, palliative resection of T4 tumor is not warranted based on long-term survival or improved quality of life. Therefore, the R1-R2 resection rate, which was 33.0% in the earlier period, decreased significantly to 21.5% in the latter period. Our philosophy is to avoid palliative esophagectomy since chemoradiation has been shown to be an alternative to surgery in patients with locally advanced esophageal cancers responding to induction treatment [21]. Consequently, patient selection may play an important role in improving short- and long- term results after esophageal resection.
The reason for the improved survival is difficult to determine, however, because of the retrospective nature of this review. It is likely multifactorial, reflecting improved patient selection, changing epidemiology, refinements in staging methods, neoadjuvant treatments, and surgical techniques. In the present study we have attempted to limit these possible confounding factors. All patients underwent transthoracic approach with attempted en bloc resection. Indications and proportions of neoadjuvant treatment were similar between the two study periods (p = 0.132). Moreover, we observed a trend toward changing in epidemiology, but proportion of squamous cell and adenocarcinoma did not differ significantly (p = 0.069).
In summary, significant improvements in short-term outcome have occurred after esophageal resection, despite the use of preoperative chemoradiation. These improvements may be due to advances in perioperative and surgical management. Advances in long-term survival, in contrast, are mainly attributable to higher patient selection suitable for R0 resection with better preoperative staging, and to a lesser degree, to neoadjuvant chemoradiation. Further progress should be made to identify reliable predictors of good response to chemoradiation therapy in order to tailor the most appropriate approach for each individual patient.
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