|Year : 2015 | Volume
| Issue : 5 | Page : 16-23
Factors on prognosis in patients of stage pT3N0M0 thoracic esophageal squamous cell carcinoma after two-field esophagectomy
Yuxiang Wang1, Lili Wang1, Qiong Yang1, Jing Li1, Zhan Qi2, Ming He2, Jifang Yao2, Xueying Qiao1
1 Department of Radiation Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050011, China
2 Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province 050011, China
|Date of Web Publication||31-Aug-2015|
Prof. Yuxiang Wang
The Fourth Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang, Hebei Province 050011
Source of Support: None, Conflict of Interest: None
Aims: To evaluate prognosis and its related factors in patients of pT3N0M0 thoracic esophageal squamous cell carcinoma (ESCC).
Subjects and Methods: From January 2008 to December 2009, 249 patients of stage T3N0M0 thoracic ESCC were treated with two-field esophagectomy. Among them, 171 males and 78 females; the median age was 60 years old (range 33-78 years). Site of lesion: 39 in upper-, 166 in middle-, and 44 patients in lower-thoracic esophagus; the median length of lesion was 5 cm (range 2-12 cm); the degree of adhesion during surgery: No adhesions in 35, mild adhesions in 90, and severe adhesions in 124 patients; the median number of dissected lymph node (LN) was 9 (range 1-27). Ninety-eight patients are treated with surgery alone, 151 patients with postoperative adjuvant treatment (20 with radiotherapy, 110 with chemotherapy, and 21 patients with radiotherapy and chemotherapy). Statistical analysis was performed using SPSS 13.0 statistical software.
Results: Follow-up deadline was July 2013. The 1-, 3-, 5-year overall survival (OS) were 90.0%, 68.7% and 55.2%; Univariate analysis identified gender, location of lesion, differentiation of pathology and hemoglobin (Hb) levels were prognostic factors for OS (P < 0.05); multivariate analysis showed, location of lesion, Hb levels, mediastinal small LN (<1 cm in diameter) in computed tomography (CT) image before surgery, and number of removed LN were independent prognostic factors for OS. The 1-, 3-, 5-year progress-free survival (PFS) were 82.1%, 61.7%, and 53.9%; univariate analysis identified, age, site of lesion and degree of adhesion during surgery were associated with PFS (P < 0.05); multivariate analysis showed, site of lesion was the only independent prognostic factor. Postoperative adjuvant therapy did not effect on OS and PFS.
Conclusion: For patients of pT3N0M0 thoracic ESCC, the independent factors were the site of a lesion for OS and PFS, Hb levels, small LN in CT, and number of removed LN for OS. The value of postoperative adjuvant therapy need be further proved.
Keywords: Adjuvant therapy, esophageal neoplasm/pT3N0M0, esophagectomy, survival
|How to cite this article:|
Wang Y, Wang L, Yang Q, Li J, Qi Z, He M, Yao J, Qiao X. Factors on prognosis in patients of stage pT3N0M0 thoracic esophageal squamous cell carcinoma after two-field esophagectomy. J Can Res Ther 2015;11, Suppl S1:16-23
|How to cite this URL:|
Wang Y, Wang L, Yang Q, Li J, Qi Z, He M, Yao J, Qiao X. Factors on prognosis in patients of stage pT3N0M0 thoracic esophageal squamous cell carcinoma after two-field esophagectomy. J Can Res Ther [serial online] 2015 [cited 2019 Nov 19];11:16-23. Available from: http://www.cancerjournal.net/text.asp?2015/11/5/16/163833
| > Introduction|| |
Esophageal cancer (EC), an aggressive disease with a poor overall outcome, is estimated to be among the 8 th most common malignancies worldwide.  In China, EC is the fourth most common cause of death  and frequently found in the thorax, and more than 90% of EC is pathologically diagnosed as esophageal squamous cell carcinoma (ESCC). ,, Surgery is still a preferred therapeutic strategy for EC patients. However, most of the patients still die of local, regional recurrence or distant metastasis (DM) even in the presence of radical resection and extended lymph node (LN) dissection. Postoperative radiotherapy (PORT) is used in EC patients to reduce local regional recurrence, , but its value is still conflicting. In some prospectively and retrospectively studies, survival benefit with PORT could be observed only in patients of EC with positive node lymph metastasis (N1) or stage III, but not in N0 or stage II. ,,,,,, Similarly, esophagectomy alone or postoperative chemotherapy (POCT) have revealed overall survival (OS) benefit only in N1 but not in N0 or stage II patients. ,,,, The value of postoperative radiochemotherapy in EC patients is controversial also. ,,,, Therefore, in those for whom the primary treatment is surgery, there is no clear indication for adjuvant treatment, especially for stage N0 or II ESCC patients. Two-field esophagectomy was the most common style of operation for thoracic ESCC in our hospital. The aim of the present study was to observe OS, progress free survival (PFS) and its related factors in patients of stage T3N0M0 thoracic ESCC after two-field esophagectomy.
| > Subjects and Methods|| |
From January, 2008 to December, 2009, 249 patients with stage T3N0M0 (UICC, 2002) thoracic ESCC who had esophagectomy were recruited for this study. Patients who had received preoperative chemotherapy and/or radiotherapy were excluded. In addition, only patients who survived for >3 months after surgery were included in this study. Thus, patients treated with an esophagectomy with or without adjuvant POCT and/or PORT were enrolled. The study was approved by the Ethics Committee of the 4 th Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China. Informed consent was obtained from the patients.
All patients were treated with radical resection. The standard surgical approach consisted of a limited thoracotomy on the left side and intrathoracic gastric tube reconstruction for lesions at the middle/lower third of the esophagus. Upper third lesions were treated anastomosed in cervical or above aortic arch. The majority of patients underwent two-field lymphadenectomy. The number of LNs harvested per case ranged from 1 to 27 (median 9). A nasogastric tube was inserted for each patient until the anastomotic wound had closed on postoperative day 7-14.
As the role of postoperative adjuvant therapy in EC patients was controversial, the utilization of postoperative adjuvant radiotherapy and/or chemotherapy was according to the physician's preference and the general physical condition of the patient. Cisplatin and 5-fluorouracil were the most frequently used agents in POCT, the median cycles of chemotherapy was 2 (range from 1 to 6). The dimension conformal radiotherapy was used in most of the patients with PORT, the total dose for PORT was 50-54 Gy, the daily fraction dose was 1.8-2.0 Gy.
Actual survival was calculated according to Kaplan-Meyer and statistically evaluated by the log-rank test. The Cox proportional hazards regression model was used to analyze the simultaneous influence of prognostic factors. A confidence value of 95% (P < 0.05) was considered significant for all the tests run. For the statistical analysis, we used the SPSS 13.0 software for Windows was used to statistical analysis.
| > Results|| |
The patient characteristics of this study were summarized in [Table 1]. All tumors were histologically confirmed to be ESCC. A total of 249 patients were included in this study. The gender was biased toward males (male/female, 2.2:1). The median age was 60 years old (range 33-78). Median length of lesions was 5 cm (range 2-12 cm). Fifty patients has mediastinal small LN (<1 cm in diameter) in computed tomography (CT) image before surgery (defined as "small LN in CT" below). Anastomotic location: Cervical in 25, pleural top in 17, above the aortic arch in 184, under the aortic arch in 23 patients. The median number of dissected LNs during surgery were 9 per case (range 1-27). The degree of adhesion during surgery was no adhesions in 35, mild adhesions in 90, and severe adhesions in 124 cases. 98 (39.4%) patients received with surgery alone, 20 (8.0%) with PORT, 110 (44.2%) with POCT and 21 (8.4%) with PORT and POCT.
All patients were followed-up with an interval of 3 months for the first 2 years, 6 months for 2-5 years. The end date of follow-up was July 31, 2013. The time of follow-up was more than 3 years for all and was more than 5 years for 71 patients. The median follow-up time was 48 months (5-66 months). Up to the end date of follow-up, 108 out of 249 patients occurred recurrence. Among them, 61 with local, regional recurrence, 24 with DM, and 23 patients with local-regional and distant recurrence; die in 105 and alive in 144 patients.
OS of all patients is summarized in [Figure 1]. The estimated 1-, 2-, 3- and 5-year survival rates were 90.0%, 77.9%, 68.7%, and 55.2%, respectively. Univariate analysis identified gender, location of lesion, differentiation of pathology and hemoglobin (Hb) level as prognostic factors for OS (P < 0.05); but age, history of smoking or drinking, family history of cancer, length of lesion, small LN in CT, degree of adhesion during surgery, number of removed LNs and postoperative adjuvant therapy were not associated with OS (P > 0.05), as shown in [Table 2]. With multivariate analysis, the location of the lesion, Hb levels and small LN in CT, number of removed LNs were independent prognostic factors, as shown in [Table 3]. Further analysis show, OS were different in patients of upper- versus middle-thoracic ESCC (χ2 = 11.551, P = 0.001), upper- versus low-thoracic ESCC (χ2 = 13.056, P = 0.000) and <6 removed LNs (defined as "LNs" below) versus ≥12 LNs (χ2 = 5.219, P = 0.022); but OS was not different in middle- versus low-thoracic ESCC (χ2 = 2.696, P = 0.101); <6 LNs versus 6-11 LNs (χ2 = 2.153, P = 0.142), 6-11 LNs versus ≥12 LNs (χ2 = 1.430, P = 0.232).
|Figure 1: Overall survival of T3N0M0 thoracic esophageal squamous cell carcinoma|
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|Table 2: Univariate analysis of factors effected on survival in patients of T3N0M0 thoracic ESCC after surgery |
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|Table 3: Multivariate analysis of factors effected on survival in patients of T3N0M0 thoracic ESCC after surgery |
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41 of 249 patients were treated with adjuvant PORT. The estimated 1-, 3- and 5-year survival rates for without- or with PORT were 89.4%, 70.2%, 58.5% and 92.7%, 61.0%, and 35.8%, respectively (χ2 = 2.038, P = 0.153). Further analysis showed, for middle-throacic-ESCC, the estimated 1-, 3- and 5-year survival rates for without- or with-PORT were 94.0%, 73.9%, 62.5% and 90.6%, 59.4%, 24.9%, respectively (χ2 = 5.474, P = 0.019). 131 of 249 patients were treated with adjuvant POCT after surgery. The survival rate was no different between without- or with-POCT (P > 0.05). Further analysis, for patients of more than 60 years old, the estimated 1-, 3- and 5-year survival rates for without- or with-POCT were 90.2%, 62.3%, 47.7% and 93.4%, 78.7%, 69.6%, respectively (χ2 = 4.247, P = 0. 039); for patients of no adhesion during surgery, 1-, 3- and 5-year survival rates for without- or with-POCT were 78.6%, 50%, 50% and 100%, 90.5%, 80.0% (χ2 = 4.590, P = 0. 032).
PFS in all patients is shown in [Figure 2]. The estimated 1-, 2-, 3- and 5-year PFS in stage T3N0M0 ESCC were 82.1%, 70.8%, 61.7% and 53.9%, respectively. Univariate analysis identified age, location of lesion and degree of adhesion during surgery were associated with PFS (P < 0.05); but gender, type of pathology, length of lesion, Hb levels and small LN in CT before surgery, number of dissected LN and postoperative adjuvant therapy were not associated with PFS (P > 0.05) [Table 4]. With multivariate analysis, location of lesion was the only independent prognostic factor for PFS (χ2 = 9.573, P = 0.002); age and small LN in CT before surgery were also important factors for PFS (χ2 = 3.765, 2.994, P = 0.052, 0.084, respectively).
|Figure 2: Progress-free survival of T3N0M0 thoracic Esophageal squamous cell carcinoma|
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|Table 4: Univariate analysis of PFS in patients of T3N0M0 ESCC after surgery |
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| > Discussion|| |
EC is the fourth most common cause of death in China.  Surgical resection remains the primary treatment for thoracic EC as it offers the best chance of cure. In this study, the estimated, 3-, 5-year OS were 68.7% and 55.2% respectively for 249 patients of stage T3N0M0 thoracic ESCC after radical resection at the single cancer center. Our center's another report, the 5-year OS and median were 53.9% and 48.8 months for 512 patients of T3N0M0 thoracic EC after surgery.  Xiao et al.  reported, the 5-year OS was 52.3% for 119 patients of stage I-IIa thoracic EC. Zhu et al.  reported, the 3-, 5-year OS were 64.8% and 44.9% for 389 patients of stage I-II thoracic EC. Zhang et al.  reported, the 3-, 5-year OS were 58.5% and 43.2% for 125 patients of stage IIa middle-thoracic EC. Zhang et al.  reports, the 1-, 3-, 5-year OS were 89.6%, 62.6%, and 51.0% for 349 patients of stage IIa EC. In brief, the 5-year OS for stage IIa esophageal carcinoma was about 50%, and prognosis of surgery for these patients was better.
In the present study, site of lesion was one of the independent prognostic factors for stage T3N0M0 thoracic ESCC after surgery. 5-year OS and PFS for upper-, middle- and low-thoracic ESCC were 35.7% and 35.9%, 56.1% and 53.4%, 67.8% and 73.9%, respectively (P = 0.000). Zhang et al.  and An et al.  also reported site of the primary tumor was associated with OS of EC, and its results were consistent with ours. However Zhu et al.  and Zhang  reported, site of lesion was not associated with OS of EC. Small LN in CT image before surgery was also an independent prognostic factor for OS, most of small LN in CT located in upper-mediastinum (especially above the arch of the aorta). The main reason is two-field esophagectomy is the routine operation style in our hospital for thoracic EC, three-field esophagectomy was rarely used; lymphadenectomy was seldom used for cervical, LN in upper-mediastinum (especially above arch of aorta) was usually dissected incompletely; so potential metastasis of LN in cervical and upper-mediastinum could not be removed during operation; metastasis of LNs in supraclavicular and upper-mediastinum was common in upper-thoracic ESCC, recurrence rate was more higher in upper-thoracic than in modulate- and low-throacic ESCC (data not shown). Site of the lesion could no influence OS in patients of thoracic ESCC after three-field esophagectomy.  Postoperative adjuvant therapy should be considered in these ESCC patients after two-field esophagectomy.
The number of dissected LN was also one of the independent prognostic factors for OS in T3N0M0 thoracic ESCC patients after surgery. The 5-year OS for <6, 6-11 and ≥12 dissected LNs were 39.1%, 56.9% and 66.2%, respectively; the survival time was lower in patients of dissected <6 LNs than in ≥12 LNs (P = 0.022). Chen et al. report, OS for patients of stage IIa thoracic EC was lower in <6 LNs than ≥6 LNs (χ2 = 7.99, P = 0.005). Groth et al.  reported surveillance, epidemiology, and end results (SEER) data included of 4882 EC patients after surgery, 5-year OS for 0, 1-11, 12-29 and ≥30 LNs were 27.7%, 28.5%, 30.9% and 47.4%, respectively (P < 0.0001). Schwarz and Smith  results showed, a relative increase in OS at 5 years for every 10 LNs identified of about 10% for N0 and ESCC patients. Bollschweiler et al.  found it is significantly worse prognosis for patients with fewer than 16 LNs examined when compared to patients with 16-30 or more than 30 examined LNs for pN0 EC patients (P < 0.01). Fraunberger et al.  result showed, at least 6 LNs should be dissected during surgery, and it should be proved pathology negative, LN metastasis could be excluded. Dutkowski et al.  reported a maximum increase of the sensitivity in classifying pN occurred from 0 to 6 examined LNs; an over 90% sensitivity of a correct LN classification was reached when more than 12 LNs were examined; the author suggested a new threshold for number of examined LN at least 12. NCCN guideline recommend numbers of LN removal was more than 15 during esophagectomy.  But in our hospital, there were about 75% (825/1098) thoracic EC patients dissected <6 LNs, only 25% (273/1098) patients dissected ≥6 LNs during 1984-1989.  In the present study, among 249 patients of thoracic ESCC, there were 22% (55/249) of patients dissected <6 LNs, 54% (133/249) dissected 6-11 LNs, and 24% (61/249) dissected ≥ 12 LNs. Above all, removal of at least 6 LN for each EC patients during esophagectomy should be recommended in our hospital.
In the present study, gender was also a prognostic factor for OS. Five-year OS was 50.7% in male and 65.3% in female. Zhang et al.  also report, the 1-, 3-, 5-year OS were 87.6%, 52.6%, 39.9% in male and 90.4%, 59.2%, 50.7% in female for patients of stage II thoracic ESCC (P = 0.001). Several other authors ,,,,, indicated gender was the independent prognostic factor for EC after surgery, OS was higher in female than in male (P < 0.05). But, Zhu et al.  and Zhang et al.  reported gender, was not associated with OS of EC. But Chen et al.  reported, 5-year OS was 57.7% for male and 46.4% for female (P = 0.000). It needs further study to prove the relationship between gender and OS in esophageal carcinoma after surgery.
The value of PORT in patients of EC was controversial. Prospective studies and meta-analysis showed no obvious survival benefit in EC patients with PORT compared with surgery alone. , In the present retrospective study, 41 patients of thoracic ESCC were treated with PORT, OS and PFS were similar with or without PORT. Xiao et al. , reported, PORT could improve OS only in patients of stage III or ≥3 positive LNs metastasis. Shridhar R  retrospective analyzed of SEER data included 2109 EC patients from 2004 to 2008, its results showed, PORT could improve OS only in stage III but not in stage II or negative LN patients. Schreiber et al.  results showed, OS was not different with or without PORT in stage IIa and IIB patients. Xu et al. , reported, PORT could improve OS in stage III but not in stage IIb patients of EC. Zhu et al.  reports, OS was similar to radical surgery alone or PORT for patients of stage T2-3N0M0 ESCC. Liu et al.  reported, 581 patients of T2-3N0M0 ESCC treated with radical surgery, 5-year OS for surgery alone or PORT were 59.2% and 72.3%, respectively (P = 0.157). Zhang et al.  and Zhu et al.  reported, PORT did not improve OS in thoracic EC. Zhang et al. reported, the 5-year OS for 125 patients of stage IIa middle-thoracic ESCC with postoperative adjuvant radiotherapy, chemotherapy, chemoradiotherapy (CRT) and no adjuvant therapy were 52.2%, 40.6%, 55.6% and 24.1%, respectively; postoperative adjuvant therapy could be improved survival compared with no-adjuvant therapy (P = 0.04). In brief, until now, whether PORT affects the therapeutic outcomes in stage II EC has remained controversial.
The value of adjuvant POCT in EC patients is controversial also. In previous several retrospectively reports, the benefit of OS was not observed. Ando et al. reported results of Japan Clinical Oncology Group, 5-year OS in ESCC was 48.1% for POCT and 44.9% for surgery alone (P = 0.26); for N1 ESCC patients, 5-year OS was 43.7% in patients of POCT and 35.5% in surgery alone (P = 0.15). Ando et al.  another study included 242 patients of ESCC, 5-year disease free-survival (DFS) was 55% in patients of POCT and 45% in surgery alone (P = 0.037); but, 5-year OS was 61% in patients of POCT and 52% in surgery alone (P > 0.05). Lee et al.  reported, for pN+ thoracic ESCC, 3-year DFS were 47.6% for POCT and 35.6% for surgery alone (P = 0.049), but OS did not different with or without POCT (P = 0.228). Study of Heroor et al.,  Zhang et al.,  Xu et al. , did not observe benefit of OS with POCT. Hsu et al.  retrospectively study, PFS and OS were not different with or without POCT for N0 ESCC; but POCT could be improved PFS and OS for N1 ESCC. Zhang et al.  reported, POCT could be improved OS in patients of stage IIa ESCC. Zhu et al.  reported, 1-, 3-, 5-year OS were 77.4%, 44.7%, 31.6% for surgery alone and 90.9%, 66.0%, 43.9% for POCT in stage II-III EC patients (P < 0.001). In our study, OS and PFS for stage T3N0M0 ESCC patients of were not different with or without POCT. Its results were similar with the previous study. ,,,,,, For stage T3N0M0 ESCC, the value of POCT needs to be also proved.
The effectiveness and influence of adjuvant postoperative CRT on the survival of EC patients are still under debate. There have been far fewer studies that have evaluated the effectiveness of CRT for patients with esophageal carcinoma. ,,,, Many of EC patients could not tolerate CRT because of the related complications. Most complications due to CRT are chemotherapy-related. Zheng et al.  meta-analysis indicated that EC patients had greater OS treated with CRT than without. Chen et al.  reported the 5-year OS with or without CRT were 57.4% and 38.6% for pN+ thoracic ESCC patients (P = 0.030). Hsu et al. also reported,  the median and 3-year OS rate and median in ESCC patients with or without CRT were 48.6% and 16.8%, 29 and 16 months (P = 0.003); 3-year DFS and median rate were 21.3% and 12.5%, 11 and 8 months, respectively. But in our retrospective study, for stage T3N0M0 thoracic ESCC, the survival rates were not different with or without CRT. The probable reason is that postoperative CRT could improve survival mainly in N1 or stage III but not in N0 or stage II EC patients.
Differentiation of pathology was also effected prognosis of thoracic T3N0M0 ESCC in the present study. OS in patients of well or middle-differentiated was longer than in poor-differentiated ESCC, our result is consistent with the previous study. ,, This is probably related to more high recurrence rates in poor-differentiated EC. But Xu et al.  reported differentiation in pathology was not related with OS of ESCC.
In our study, Hb levels were one of the independent factors for OS, the 5-year OS were 62.1% in patients of Hb < 140 g/L and 47.4% in Hb ≥ 140 g/L. Rades et al.  reported, for patients of ESCC with radiotherapy, Hb levels of 12.1-14.0 g/dL were associated with the best OS, low DM and local failure (LF), followed by ≥14.1 g/dL and ≤12.0 g/Dl (OS: 35%, 9%12% (P = 0.001); DM: 58%, 78%, 70% (P = 0.08); LF: 46%, 81%, 75% (P = 0.001). Our result was consistent with the previous study. , Zhang et al.  reports, the level of Hb in ESCC patients was the independent factor for OS, the 1, 3, 5-year OS in patients of Hb levels ≥120 (female110) g/L or <120 (female110) g/L were 72.9%, 44.1%, 23.7%, and 59.3%, 18.5%, 5.6%, respectively (P = 0.003). Hamai et al.  reviewed data from 123 patients with ESCC who underwent neoadjuvant CRT that comprised concurrent radiation (40 Gy) and chemotherapy, followed by esophagectomy; these found that 48.8% and 17.1% of patients with Hb level ≤13 and >13 g/dL, respectively, were poor responders (P = 0.0002), with 5-year OS rates of 40.9% and 58.9% (P = 0.048). The existence of such an optimal Hb level for tumor oxygenation resulting in a better prognosis was suggested for uterine, cervical, and vulva carcinoma; at Hb levels >14 g/dL, the worsening of the tumor oxygenation status occurs most likely due to a decrease in nutritive perfusion after a drastic increase in viscous resistance to flow; at Hb levels <12 g/dL, a worsening of the tumor oxygenation can be explained by the reduced oxygen-carrying capacity of the blood. 
In briefly, for patients of stage T3N0M0 thoracic ESCC, site of lesion, Hb level and small LN in CT and number of removed LN were independent factors for OS, site of lesion was also the independent factors for PFS; but the value of postoperative adjuvant therapy need to be further prove.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]