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Ann Thorac Surg 2003;75:1720-1726
© 2003 The Society of Thoracic Surgeons

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Original article: general thoracic

Factors predictive of complete resection of operable esophageal cancer: a prospective study

^a Service de Chirurgie Digestive et Générale Hôpital Claude Huriez, Lille Cedex, France,
^b Unité INSERM 560–CHRU, Lille, France

Accepted for publication January 14, 2003.

^* Address reprint requests to Dr Triboulet, Service de Chirurgie Digestive et Générale Hôpital, Claude Huriez–CHRU, Place de Verdun, Lille Cedex 59037, France
e-mail: jp-triboulet{at}chru-lille.fr

	Abstract

Top Abstract Introduction Patients and methods Results Comment References

 
BACKGROUND: Esophagectomy remains a standard treatment for patients with resectable esophageal cancer, but the 5-year survival is only 20% to 25%. After complete resection survival is significantly longer than after incomplete resection with microscopic or macroscopic penetration. The purpose of this study was to prospectively identify the factors predictive of complete resection of operable esophageal cancers.

METHODS: Betwen January 1995 and January 2002, 372 patients with esophageal cancer underwent surgery with curative intent. Complete resection was performed in 304 patients (81.7%), incomplete resection with microscopic penetration in 28 (7.5%), and incomplete resection with macroscopic penetration in 40 (10.8%). Univariate and multivariate analysis included 16 preoperative and operative factors.

RESULTS: Factors predictive of complete resection were absence of any modification of the esophageal axis on the barium swallow (p = 0.019) and a partial or complete response to preoperative radiochemotherapy (p = 0.042). Three groups of patients were identified: group 1 had no deviation of the axis on the barium swallow (n = 253); group 2 had deviation of the axis on the barium swallow and partial or complete response to radiochemotherapy (n = 66); and group 3 had deviation of the axis on the barium swallow and no response to radiochemotherapy or no preoperative treatment (n = 53). Rates of complete resection were 90.1%, 74.2%, and 50.9%, and 5-year actuarial survivals were 46%, 37%, and 0%, respectively (p < 0.001).

CONCLUSIONS: Complete resection of esophageal cancer is predictable. Deviation axis on the barium swallow and morphologic response to neoadjuvant radiochemotherapy are variables available for all patients at onset of therapeutic management.

	Introduction

Top Abstract Introduction Patients and methods Results Comment References

 
Invasion of neighboring tissues (that is, trachea, aorta, lung, pericardium) is common in cancer of the esophagus and is caused by anatomic proximity and lack of a protective serosa. Complete surgical resection is one of the most important prognostic factors [1–4]. Therefore it is fundamental to establish a precise assessment of tumor extension to avoid incomplete surgical resection and establish an appropriate therapeutic strategy. Despite recent advances in imaging techniques, the rate of incomplete resection has varied from 19.2% to 64.0% depending on the series [5]. In a retrospective study [6] we showed that complete resection of esophageal cancer was predictable.

The purpose of this study was to prospectively identify factors predictive of complete resection (R0), as defined in the Union Internacional Contra la Cancrum (UICC) 1993 classification of operable esophageal cancer, to determine the appropriate pre-therapeutic workup for defining a population likely to benefit from surgical resection in terms of survival.

	Patients and methods

Top Abstract Introduction Patients and methods Results Comment References

 
Patients
Between January 1995 and January 2002, 372 patients (mean age, 58.1 years; standard deviation [sd], 9.8; range,31 to 78 years) with cancer of the cervical or thoracic esophagus underwent surgery with curative intent in our digestive surgical unit of the Claude Huriez university hospital (Lille, France). The hospital files of these patients were prospectively noted.

Patients were considered to be operable with resectable esophageal cancer after a complete pre-therapeutic workup (including physical examination; standard laboratory tests; ear, nose, and throat examination; panendoscopy under general anesthesia for squamous cell tumors; digestive fibroscopy and esogastroduodenal barium study; bronchial fibroscopy with biopsies; ultrasound exploration of the cervical and abdominal areas; computed tomographic (CT) scan of the thorax, mediastinum and abdomen; and endoscopic ultrasound).

Criteria for nonresecability were adherence to the aorta (> 90°), invasion of the pericardium, diaphragm, pleura, trachea-bronchi, azygos vein, recurrent nerve, tumor diameter (> 4 cm), celiac or subclavian lymph node enlargement, and visceral metastasis. Criteria for nonoperability were cirrhosis (any stage) associated with portal hypertension, respiratory failure, forced expiratory volume (< 1,000 mL/s), weight loss more than 20%, heart failure (New York Heart Association functional class III to IV).

Surgical approach
The detailed resection techniques have been described elsewhere [1]. Surgical resection consisted of a transthoracic esophagectomy for tumor of the middle-third or lower-third of the esophagus, completed with a cervical incision for anastomosis in case of tumor of the upper-third of the thoracic esophagus. The surgical approach included an abdominal lymphadenectomy and an extended en bloc mediastinal lymphadenectomy (two-field lymphadenectomy). No cervical lymphadenectomy was undertaken. Abdominal lymphadenectomy comprised en bloc removal of all lymphatic tissue in the lower posterior mediastinum, in the left and right pericardial regions, along the lesser curve, and along the left gastric artery.

A meticulous lymphadenectomy of the peritracheal, carinal, and left and right bronchial nodes was performed followed by en bloc resection of the thoracic duct together with the periaortic nodes. The nodes in the aortopulmonary window were removed but routinely a full dissection of the left recurrent laryngeal nerve chain was not carried out. For patients with respiratory insufficiency and limited tumor of the esophagus, a subtotal esophagectomy without thoracotomy was realized, with only an abdominal and mediastinal inferior lymphadenectomy. The esophagus was replaced by the stomach in 96.8% of patients, excepting patients with a history of gastric surgery or who required composite plasty for cancer of the remaining esophagus.

Histopathological analysis assessment of the removed specimen and lymph nodes
All nodal material was dissected separately from the specimen at the end of the procedure by the surgeon, and the resection specimen was assessed by an experienced pathologist according to the pTNM classification [7].

Squamous cell carcinoma (SCC) was found in 283 patients, adenocarcinoma in 79, and other tumoral types in 10. Tumors were well or moderately differentiated in 251 patients and poorly or undifferentiated in 121 patients. On histopathologic assessment of the 372 resected specimens, the distribution of pT and pN categories was as follows: the lesion was restricted to mucosa in 58 patients, submucosa in 88 patients, and muscularis propria in 51 patients; the lesion had invaded the adventitia in 152 patients (57% of these were adenocarcinoma) and the neighboring structures in 23 patients; and lymph node metastases were found in 180 patients. Tumoral stages were as follows: esophageal cancer stage I (pTis-pT1N0M0), n = 109; stage IIA (pT2-T3N0M0), n = 76; stage IIB (pT1-T2N1M0), n = 60; stage III (pT3N1 or pT4NxM0], n = 127. A mean (sd) of 19.8 lymph nodes (10.9) (range, 2 to 56) was dissected from each specimen by the surgeon and pathologist. The mean (sd) number of histopathologically positive lymph nodes was 1.9 (3.2) (range, 0 to 25).

Variables studied
The preoperative and operative variables presented in Table 1 were used to search for factors predictive of complete resection. Tumor localization was determined by endoscopy and expressed as the distance from the upper pole of the tumor to the mandibular arcade (distance T-MA). A threshold distance of 25 cm was retained because this stratification level has been identified as a prognostic factor in esophageal cancer [6]. Siewert type 1 cancers of the cardia were included in the analysis. Patients with tumors of the hypopharynx or of the esophagus involving the upper esophageal sphincter were excluded. Deviation of the esophageal axis corresponded to a deviation from a virtual axis drawn through the middle of the esophageal lumen over its entire height (Fig 1).

View larger version (94K): [in this window] [in a new window]   Fig 1. Deviation of the esophagus on the barium swallow. Deviation of the virtual axis representing the middle of the esophageal canal.

Neoadjuvant radiochemotherapy was proposed for locally advanced tumors or within the framework of therapeutic protocols. The following morphologic criteria were used to assess response to neoadjuvant radiochemotherapy:

Complete response: absence of identifiable tumor on plain roentgenograms or CT scan. Endoscopy was not performed routinely in all patients as negative biopsies can not rule out residual tumor fragments.

Partial response: greater than or equal to 50% reduction in tumor size determined as the product of the largest dimensions of formations with two measurable dimensions or less than or equal to 30% reduction of the dimension measured for formations with one measurable dimension, without development of a new formation during treatment.

Stability: less than 50% reduction or less than 25% progression of tumors with two measurable dimensions.

Progression: more than 25% progression of measurable tumors or development of a new tumor.

Among the 174 patients who had preoperative radiochemotherapy, 104 (59.8%) exhibited morphologic partial response and 45 (25.9%) exhibited complete response. Postoperative radiochemotherapy or chemotherapy, or both, were proposed in all patients with incomplete resection with microscopic penetration (R1) or incomplete resection with macroscopic penetration (R2).

Statistical analysis
The survival status of patients was ascertained in July 2002. Follow-up was complete for all 372 patients. Data are shown as prevalence or mean (standard deviation). Comparison of continuous data between groups was determined by the Student’s t test and for ordinal data by the ² test or Fischer’s exact test when appropriate. In analyzing survival time, we used the Statistical Package for Social Sciences (SPSS, Chicago, IL). The survival function has been estimated by the actuarial method without excluding the postoperative deaths. The log rank test was used for comparison of survival curves. To determine which of many covariates was the most significant risk factor regarding quality of surgical resection, we used the stepwise logistic regression model, adjusting all the covariates simultaneously. The 0.1 level was defined for entry into the model.

Groups with different risks were identified using a stepwise procedure starting with the two most significant variables from the multivariate analysis. The model retained included two variables known at the time of diagnosis that would be potentially useful for determining resectability. Survival curves were compared between the different subgroups thus defined to establish sets of groups with significantly different risk patterns. Differences in the rate of R0 resection between the defined groups were analyzed with the ² test. Differences were considered to be significant at 5% alpha risk.

	Results

Top Abstract Introduction Patients and methods Results Comment References

 
Postoperative mortality and morbidity
The in-hospital mortality rate was 4.3% (n = 16). Significant complications occurred in 142 patients (38.2%). Thirty-three patients (8.9%) had anastomotic leaks that were observed clinically or by radiology. Respiratory complications were observed in 95 patients (25.5%).

Type of resection
According to the 1993 UICC criteria, macroscopically and microscopically R0 resection was achieved in 304 patients (81.7%), R1 resection (histologic evidence of invasion of the section margin or lateral clearance) was achieved in 28 patients (7.5%), and R2 resection (macroscopic residual tumor after surgery) was achieved in 40 patients (10.8%). We assigned patients to two groups for analysis of factors predictive of complete resection: R0, patients who had complete R0 resection (n = 304; 81.7%); R1-R2, patients who had incomplete R1 or R2 resection (n = 68; 18.3%).

Actuarial survival
The actuarial survival is shown in Figure 2. Follow-up was complete for all patients. The mean (sd) follow-up interval was 27.9 months (20.8) (range, 6 to 91 months), with a median follow-up of 22 months. Median survival for the overall population was 40 months. Overall survival at 1, 3, and 5 years was 84%, 56%, and 40%, respectively. Median survival was 54.9 months in the R0 group and 10.8 months in the R1 and R2 group. The 1, 3, and 5-year survival rates were 93%, 65%, and 47% in the R0 group and 42%, 12%, and 4% in the R1 and R2 group, respectively (p < 0.001).

View larger version (21K): [in this window] [in a new window]   Fig 2. Actuarial survival for the entire population and of group R0 and group R1 and R2 (p < 0.001). The number of subjects at risk at each interval is shown in the table at the bottom of the graph.

View larger version (17K): [in this window] [in a new window]   Fig 3. Group constitution according to the two factors predictive of complete resection: esophageal axis deviation on barium swallow and morphologic response to preoperative radiochemotherapy (RCT).

View larger version (20K): [in this window] [in a new window]   Fig 4. Survival by the two factors predictive of complete resection. Group 1:no deviation of the esophagus on barium swallow; group 2: deviation of the esophagus on barium swallow and partial or complete response to preoperative radiochemotherapy; group 3: deviation of the esophagus on barium swallow and either no response to radiochemotherapy or no preoperative treatment (p less than 0.001 between all groups and p less than 0.013 when compared individually). The number of subjects at risk at each interval is shown in the table at the bottom of the graph.

	Comment

Top Abstract Introduction Patients and methods Results Comment References

In order to establish what elements of the pre-therapeutic workup enable identifying a population of patients who can benefit from surgical resection, we identified two preoperative variables predictive of R0 resection: (1) complete or partial response to preoperative radiochemotherapy and (2) absence of esophageal deviation on the barium swallow.

Objective response to neoadjuvant radiochemotherapy [14, 15] or chemotherapy [16, 17] has been associated with better survival for patients with resectable esophageal carcinoma. Inversely, others have not demonstrated better survival with neoadjuvant radiochemotherapy [18, 19] or chemotherapy [20, 21]. Phase II trials have demonstrated that 20% to 40% of patients given preoperative radiochemotherapy achieve complete histologic response [22, 23]. Patients treated with surgery alone were more likely to have an esophageal resection, but those treated with chemotherapy and surgery were more likely to have R0 resection [16, 20]. Work by the French Federation of Digestive Tract Cancerology [15] demonstrated that clinical response, assessed by the World Health Organization radioendoscopic criteria, is overestimated in 10% of patients and underestimated in 29% compared with histologic response. This discordance between clinical and histologic response is well known, the predictive value of negative endoscopic biopsy for diagnosis of complete response is 21% to 47% [24]. Thus, new tools are necessary to assess the efficacy of nonsurgical treatments for esophageal cancers.

Deviation of the esophageal axis on the barium swallow is associated with noncurative resection [5, 6], and it is also predictive of extension to neighboring organs [5]. The deviation of the esophageal axis is usually a typical sign of advanced squamous cell carcinoma and is rare in Barrett cancer. In our study, axis deviation was equally allocated among both histologic subtypes and only a few specimens showed Barrett mucosa. An explanation could be the importance of pT3 stage patients (57%) with adenocarcinoma.

Surgical resection of esophageal cancer should only be undertaken to attempt curative treatment. The limitations of preoperative explorations to predict tumor resectability require considering other factors predictive of R0 resection. Using two variables predictive of R0 resection (ie, deviation of the esophageal axis on barium swallow and response to neoadjuvant radiochemotherapy), enabled us to identify three groups of patients with significantly different rates of R0 resection. These two variables are available for all patients at the onset of therapeutic management allowing easy classification of the patients into three groups. For patients with 50% risk of R1 or R2 resection (group 3), we recommend preoperative radiochemotherapy for those with axis deviation on barium swallow, and in patients with no response, only palliation. Further oncology research are necessary to refine the patient selection.

	References

Top Abstract Introduction Patients and methods Results Comment References

 

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