Med Oncol (2015) 32:417 DOI 10.1007/s12032-014-0417-6

ORIGINAL PAPER

Postoperative adjuvant therapy for resectable thoracic esophageal squamous cell carcinoma: a retrospective analysis of 426 cases Hailu Chen • Zhiyong Wu • Jiexin Chen • Xiaorong Lin Chunpeng Zheng • Yanghang Fan • Zechun Zhang • Xiaodong Yao • Jianyi Wu • Liyan Xu • Enmin Li



Received: 7 October 2014 / Accepted: 27 November 2014 Ó Springer Science+Business Media New York 2014

Abstract The aim of this study was to evaluate the value of postoperative adjuvant therapy for resectable thoracic esophageal squamous cell carcinoma (ESCC) in China. We retrospectively analyzed 426 eligible patients seen between October 2007 and November 2011. Specifically, we assessed clinicopathological characteristics and the disease-free and overall survival rates. Of the 426 patients, 272 cases underwent surgery alone, and 154 cases received postoperative adjuvant therapy (67 cases with radiotherapy, 57 cases with chemotherapy, and 30 cases with simultaneous chemoradiotherapy). The median follow-up time was 48.0 months (23.0–72.0 months), and the median survival time was 48.4 months (1.0–72.0 months). We found a significant difference between the surgery-alone and adjuvant therapy groups in the status of lymph node (LN) metastasis (N stage; P \ 0.01), but there were no differences between the two groups with regard to other clinicopathological characteristics, including age, sex, lesion location, T stage, differentiation grades, surgery approach, or average number of LN dissections. The 5-year disease-free survival (DFS) rates of the surgery-alone and adjuvant therapy groups were 48.9 and 37.1 %, respectively (P \ 0.001); no significant difference was found in 5-year overall survival (OS) rate between the two groups (P [ 0.05). A stratification analysis

H. Chen  Z. Wu (&)  J. Chen  X. Lin  C. Zheng  Y. Fan  Z. Zhang  X. Yao Department of Tumor Surgery, Shantou Central Hospital, Affiliated Shantou Hospital of Sun Yat-sen University, Shantou 515041, China e-mail: [email protected] J. Wu  L. Xu  E. Li The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou 515041, China

based on N stage suggested that the 5-year DFS and OS rates were similar in N0–N3 subgroups (P [ 0.05), except that patients with surgery alone had a higher 5-year DFS than those with postoperative adjuvant therapy in N0 subgroup (P = 0.013). Our data suggest that patients with resectable thoracic ESCC may not benefit from postoperative adjuvant therapy. Further prospective studies are required to elucidate the utility of postoperative adjuvant therapy and to standardize individualized treatments for resectable ESCC. Keywords Esophageal cancer  Operation  Adjuvant therapy  Survival analysis

Introduction Esophageal cancer is one of the most aggressive cancers worldwide, and approximately 70 % of global cases occur in China [1, 2]. The current treatment strategy for locoregional esophageal squamous cell cancer (ESCC) in China is surgical resection with postoperative chemotherapy and/ or radiotherapy [3]. The 5-year overall survival (OS) rate of postoperative patients is approximately 20–50 % [4, 5]. Due to advances in imaging, anesthesia, and surgical techniques in recent years, the rate of surgical resection has increased, and surgical morbidity and mortality rates have both significantly decreased. However, the OS rate for resectable ESCC has not markedly improved; more than half of patients eventually die from tumor recurrence or metastasis [6, 7]. Limited clinical studies have reported controversial results regarding the value of postoperative adjuvant therapy for patients who have undergone esophagectomy [8–15]. It is important to mention that while adenocarcinoma predominates in western countries, the

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Materials and methods

tomography (CT) scans, and upper gastrointestinal endoscopy, with positron emission tomography–CT (PET-CT) or neck ultrasonography performed when necessary. Followups were conducted by telephone, and the last follow-up was between October and December 2013. There were 319 males and 107 females, with a sex ratio of 2.98:1. Ages ranged from 33 to 88, with a mean age of 58.3. Overall, 25, 297, and 104 patients had tumors located in the upper, middle, and lower segments of the esophagus, respectively. There were 29, 69, and 328 cases with T1, T2, and T3 tumors respectively. A total of 242 patients had node negative disease (N0), 115 had 1 or 2 regional LNs metastasized (N1), 52 had 3–6 (N2), and 17 had more than 6 LNs involved (N3). We identified 35, 61, 166, 101, 46, and 17 cases were for stages I, IIa, IIb, IIIa, IIIb, and IIIc, respectively. A total of 272 patients underwent surgery alone, while the other 154 patients received surgery with postoperative adjuvant therapy.

Clinical data

Surgical procedures

From October 2007 to December 2013, 899 patients with EC underwent surgical treatment were admitted to our center, and follow-up information were collected. A total of 473 patients were excluded: 169 patients had not undergone surgery, 211 patients were followed up \2 years, 71 patients were non-squamous cell carcinomas (2 with atypical hyperplasia, 1 with lymphoepithelioma-like carcinoma, 11 with neuroendocrine carcinoma, 2 with undifferentiated carcinoma, 1 with adenocarcinoma, 10 with adenosquamous cancer, 2 with small cell carcinoma, 1 with transitional cell carcinoma, 1 with signet ring cell carcinoma, 2 with carcinoma in situ, 35 with cardia adenocarcinoma, 1 with mucinous gastric carcinoma, and 2 with no carcinoma), 12 cases had palliative surgery, 3 cases only underwent biopsy, 4 cases had simple surgical exploration, 3 cases failed to follow up (1 with thoracic middle segment ESCC, cT3N0M0G1, and postoperative anastomotic leak; 1 with thoracic lower segment ESCC, cT3N0M0G1; and 1 with thoracic middle segment ESCC, cT3N1M0G1). The study enrolled patients with thoracic ESCC who had undergone radical excision surgery without any neoadjuvant therapy and who had been followed up for more than 2 years. Finally, the remaining 426 cases that underwent transthoracic esophagectomy with standard lymphadenectomy were included in our study. Demographic characteristics (sex, age at diagnosis, and primary tumor location), pathologic characteristics (T and N staging), and survival outcomes (OS and disease-free survival [DFS]) were collected. Tumor location and stage were classified according to the seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual [17]. Diagnoses of metastasis were based on clinical examination, computed

A total of 346 patients underwent left-sided thoracotomy for esophagectomy followed by mobilization of the stomach via diaphragmatic incision. The subtotal esophagus, sometimes with a proximal stomach, if necessary, and the adjacent LN-bearing tissue were resected, and an intrathoracic supra-aortic esophagogastric anastomosis was performed. The other 80 patients underwent right-sided thoracotomy and upper midline laparotomy followed by esophagogastric anastomosis at the left or right neck.

most common histological type of esophageal carcinoma in China is squamous cell carcinoma. For this reason, treatment protocols such as the National Comprehensive Cancer Network (NCCN) guidelines may not be appropriate for Chinese patients with ESCC. Therefore, it is necessary to evaluate the impact of current postoperative adjuvant therapy on patients with resectable ESCC in China. The Chaoshan area is located in Min-Yue area, which is a high esophageal cancer (EC) incidence area in south China. Notably, the mortality rate of EC in Nan’ao county of this area is as high as 100.87/100,000 [16]. In the present study, we collected and analyzed the recent data of patients with ESCC from the Chaoshan area in our center, with the goal of evaluating the effect of postoperative adjuvant therapy on resectable thoracic ESCC.

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Radiotherapy All patients were immobilized within a thermoplastic and underwent CT stimulation. A total dose of 40–60 Gy (2 Gy/fraction, 5 fractions a week) was delivered to patients with a 23EX (Varian Medical Systems, Palo Alto, CA) linear accelerator. Chemotherapy The major chemotherapy regimens were 5-fluorouracil (5-FU) or tegafur tablets (oral) or nedaplatin; a combination of cisplatin and docetaxel or a combination of cisplatin and 5-FU; a combination of nedaplatin and docetaxel or a combination of nedaplatin and paclitaxel liposome; and a combination of nedaplatin, docetaxel, and 5-FU. Statistical analysis The OS and DFS rates were determined by the Kaplan– Meier method. Log-rank tests were used for the univariate analysis, and the Cox proportional hazard regression model

Med Oncol (2015) 32:417

was used to evaluate the effect of prognostic factors on survival in multivariate analysis. All the statistical analyses were performed using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA). Statistical significance was assumed when the P value was \0.05.

Results Survival analysis Of the 426 cases, 272 and 154 patients were in the surgeryalone and adjuvant therapy groups, respectively. The latter included 67 patients with radiotherapy, 57 patients with

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chemotherapy, and 30 patients with chemoradiotherapy. After a median follow-up of 48 months, the respective 1, 3, and 5-year survival rates were 88, 79, and 49 % for the entire cohort. The median survival time was 48.4 months (1.0–72.0 months). The 5-year DFS was better in the surgery-alone group than in the adjuvant therapy group (P \ 0.001, Fig. 1). After comparing the characteristics of the two groups, we observed a significant difference for N staging (P \ 0.01, Table 1), but there were no differences with regard to sex, age, tumor location, grade, T staging, surgical approach, or number of LNs dissected. In order to eliminate the Table 1 Clinical characteristics of the surgery-alone and postoperative adjuvant groups Clinical pathology factors

Surgery-alone (n = 272) n (%)

Postoperative adjuvant (n = 154) n (%)

197 (72.4)

122 (79.2)

75 (27.6)

32 (20.8)

\45

10 (3.6)

11 (7.1)

C45

262 (96.4)

143 (92.9)

15 (5.5)

10 (6.5)

Middle

189 (69.5)

108 (70.1)

Lower

68 (25)

P

Sex Male Female

0.12 

Age, years 0.11 

Location Upper

Grade X

4 (1.5)

36 (23.4) 0 (0)

I

53 (19.5)

20 (13.0)

II

189 (69.5)

123 (79.9)

26 (9.6)

11 (7.1)

23 (8.5)

6 (3.9)

III

0.87 

0.08 

T staging T1 T2

47 (17.3)

22 (14.3)

T3

202 (74.3)

126 (81.8)

N0

175 (64.3)

67 (43.5)

N1

64 (23.5)

51 (33.1)

N2

22 (8.1)

30 (19.4)

N3

11 (4.0)

6 (3.9)

226 (83.1) 46 (16.9)

120 (77.9) 34 (22.1)

0.12 

N staging \0.01 

Surgical approach Left Right Average no. LN dissected

13.7

7.7

0.19  0.73à

LN = lymph node  

Fig. 1 DFS and OS. a The 5-year DFS of the surgery-alone and adjuvant groups were 48.9 and 37.1 %, respectively (P \ 0.001). b The 5-year OS of the surgery-alone and adjuvant groups were 53.5 and 43.1 %, respectively (P [ 0.05)

Chi-square test; each P value is two-tailed, and the significance level is 0.05

à

Wilcoxon test; each P value is two-tailed, and the significance level is 0.05

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Fig. 2 The DFS data for the two groups stratified by LN metastasis status. a N0 layer. The 5-year DFS of the surgery-alone and adjuvant groups were 63.6 and 48.9 %, respectively (P = 0.013). b N1 layer. The 5-year DFS of the surgery-alone and adjuvant groups were 26.4

and 40.3 %, respectively (P [ 0.05). c N2 layer. The 5-year DFS of the surgery-alone and adjuvant groups were both 0 (P [ 0.05). d N3 layer. The 5-year DFS of the surgery-alone and adjuvant groups were both 0 (P [ 0.05)

confounding factor, we further stratified the analysis according to the N staging (Figs. 2, 3). As shown in Figs. 2 and 3, after eliminating the confounding factor of N staging, the 5-year DFS was better in the surgery-alone group than in the adjuvant therapy group, but this was only for N0 layer patients (P = 0.013). Otherwise, there were no significant differences between the two groups for 5-year DFS or OS (P [ 0.05).

the status of postoperative adjuvant therapy was not significantly influential (P = 0.74).

Cox regression analysis To identify potential prognostic factors for ESCC patients, the effects of possibly relevant clinicopathological characteristics on survival were analyzed using a multivariable Cox regression model. The results showed that T and N staging were the independent prognostic factors (Table 2);

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Discussion and Conclusion In our study, all 426 patients with ESCC underwent esophagectomy. A total of 154 patients (36.2 %) received postoperative adjuvant therapies, and 272 patients underwent surgery alone. The overall survival rates were not significantly different between the two groups (P [ 0.05), which is consistent with the results of several studies. [8, 12, 15] However, it was quite different with these studies reporting that the DFS rate of the adjuvant group was significantly lower than that in the surgery-alone group (P \ 0.05). To explore this discrepancy, we assessed

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Fig. 3 The OS data for the two groups stratified by LN metastasis status. a N0 layer. The 5-year OS of the surgery-alone and adjuvant groups were 68.3 and 61.0 %, respectively (P [ 0.05). b N1 layer. The 5-year OS of the surgery-alone and adjuvant groups were 31.3

and 43.9 %, respectively (P [ 0.05). c N2 layer. The 5-year OS of the surgery-alone and adjuvant groups were both 0 (P [ 0.05). d N3 layer. The 5-year OS of the surgery-alone and adjuvant groups were both 0 (P [ 0.05)

whether there were baseline heterogeneities between the two groups. No significant differences were found with regard to sex, age, tumor location, grade classification, invasive depth, or the total number of LNs. However, the proportion of metastatic LNs varied from 56.5 % in the adjuvant group to 35.7 % in the surgery-alone group (P \ 0.05), indicating that doctors tended to administer adjuvant therapies according to the patients’ N staging. A further subgroup analysis of the different N stages revealed that postoperative adjuvant therapy had no impact on 5-year DFS and OS rates except in patients staged as N0. Moreover, we obtained the same result from the Cox regression analysis, which indicated that adjuvant therapy treatment was not an independent prognostic factor for patients with ESCC who underwent esophagectomy (P = 0.74). Potential explanations for these results are as follows: (1) Digestion and absorption were decreased in postoperative patients, and their immunity was also

weakened. Adjuvant therapy may exacerbate these factors, which can lead to adverse effects. (2) The patterns of adjuvant therapy in our study were varied, and the different chemotherapy regimens may have made the results difficult to interpret. The effects of postoperative adjuvant chemoradiotherapy in patients with ESCC are not clear due to the following factors: (1) the absence of large case–control and prospective clinical studies; (2) vague statements about the indication for adjuvant therapy in the guidelines, leading to varying applications and assessments by different physicians; and (3) research into the mechanisms of local or distant metastasis of EC lag behind that for many other solid tumors, such as breast and lung cancers. The indications of postoperative adjuvant treatment for EC are mainly based on clinical histopathological staging, which may not be the best way to determine which subgroups can benefit from adjuvant treatment.

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Table 2 Univariate and multivariate Cox regression analyses Clinical pathology factors

Wald (univariate)

P (univariate)

P (multivariate)

Sex Male

0.46

0.5



3.23

0.07



0.01

0.94



3.69

0.06



6.16

0.01

0.01

56.63

\0.01

0.03

0.85



0.74



Female Age, years \45 C45 Location Upper Middle Lower Grade X I II III T staging T1 T2 T3 N staging N0

\0.01

N1 N2 N3 Surgical approach Left Right Postoperative adjuvant therapy Yes

0.11

No

In summary, postoperative adjuvant therapy did not improve the prognosis of resectable thoracic ESCC in the patients in our study. Physicians should be cautious when determining treatment for ESCC, especially for N0 patients. We look forward to a prospective, multicenter, cooperative clinical study to offer new insight into the best course of treatment for ESCC. Acknowledgments This work was supported by grants from the National Natural Science Foundation of China (No. 81071737), the National Research Program (973 Program No. 2012CB526600), the National High Technology Research and Development Program of China (Nos. 2012AA02A503 and 2012AA02A209), and the Natural Science Foundation of China-GuangDong Joint Fund (No. U1301227). Conflict of interest None of the authors have any potential financial conflict of interest related to this manuscript.

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Postoperative adjuvant therapy for resectable thoracic esophageal squamous cell carcinoma: a retrospective analysis of 426 cases.

The aim of this study was to evaluate the value of postoperative adjuvant therapy for resectable thoracic esophageal squamous cell carcinoma (ESCC) in...
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