The impact of adjuvant therapy on survival for node-negative esophageal squamous cell carcinoma: a propensity score-matched analysis

Introduction

The prognosis of esophageal cancer is poor, with the 5-year overall survival (OS) being lower than 40% (1,2). The most common pathological type of esophageal cancer in China is esophageal squamous cell carcinoma (ESCC) (3), and the dominant treatment for esophageal cancer is comprehensive treatment based on surgery. The National Comprehensive Cancer Network (NCCN) guidelines suggest that pathologically node-negative (pN0) patients with R0 resection require only follow-up and not adjuvant therapy. However, in clinical practice, postoperative adjuvant therapies are selectively applied to patients with pN0 ESCC. Indeed, for some time now, postoperative adjuvant therapy has been performed on the basis of doctors; judgment, and thus adjuvant therapy strategies for ESCC are diverse. Some studies have discussed the relationship between postoperative adjuvant therapy and the survival status of patients with pN0 ESCC, but the conclusions remain controversial (4-9); overall the number of studies focusing on this issue is insufficient, and so the value of postoperative adjuvant treatment for pN0 ESCC remains unclear. Previous related studies have mostly concentrated on the relationship between the prognosis of patients with lymph node-positive esophageal cancer and adjuvant therapy. This study focuses on lymph node-negative ESCC. Different treatment methods are included in the analysis. The case data is closer to the current time, the follow-up survival data is complete, and the application of propensity-score matching eliminates bias as much as possible. Consequently, exploring therapies to improve the prognosis of patients with pN0 ESCC might be considerably beneficially, and thus this study was performed to evaluate the value of postoperative adjuvant therapies for patients with pN0 ESCC. We present the following article in accordance with the STROBE reporting checklist (available at https://dx.doi.org/10.21037/atm-21-2539).

Methods

Study population

The initial data consisted of 387 patients in total, and patients who underwent radical esophagectomy in Sichuan Cancer Hospital from January 2008 to December 2013 were involved. Inclusion criteria were as follows: (I) patients with pN0 ESCC according to the postoperative pathology reports; (II) no neoadjuvant therapy or molecular targeted therapy before esophagectomy; and (III) Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. The exclusion criteria were as follows: (I) pathologically positive margin; (II) death related to the surgery in 3 months; (III) diagnosis of any other malignancy simultaneously; and (IV) refusal of follow-up. Data collection and the last follow-up were completed in December 2013, and the data were collected from telephone follow-ups, the hospital information center, and local household registration management departments. All patients were divided among two groups: a surgery alone (Group S) group or a surgery + adjuvant therapy (Group S + A) group, the flow chart is shown in Figure 1. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Sichuan Cancer Hospital, and all patients were informed of the study and consented to participate.

Figure 1 Flow chart of the study. pN0, pathologically node-negative; ESCC, esophageal squamous cell carcinoma.

Surgery

All patients underwent radical esophagectomy and two (mediastinal and perigastric) or three (cervical, mediastinal, and perigastric) fields of regional lymphadenectomy. Surgical methods included right thoracotomy with or without thoracoscopy but with transhiatal esophagectomy. The anastomotic site was related to tumor location. In general, cervical anastomosis was performed in patients with upper esophageal tumors. A supra-aortic arch esophagogastric anastomosis was performed for patients with middle or lower esophageal lesions. Reconstruction of the alimentary tract was performed using the stomach or jejunum after esophageal resection for carcinoma.

Adjuvant therapy

The general postoperative adjuvant treatment procedure at our institution is pathological T1a-3N1-3 and T4a-4bNx, R1 resection, and nerve or vascular invasion. However, when we provide postoperative adjuvant treatment for pN0 patients, the surgeon not only takes into account the patient’s pathological results and intraoperative conditions but also the patient’s wishes. The following adjuvant chemotherapy regimens were applied: paclitaxel (a dose of 135–175 mg/m²) combined with cisplatin (a dose of 80–100 mg/m²) or carboplatin (a dose of 300 mg/m²) for 2–4 courses; each course of chemotherapy lasted 28 days (4 weeks). A subsequent or concurrent radiotherapy course of a total dose of 50–60 Gy in 25–30 fractions 5 days a week was given 2–4 weeks after or during chemotherapy administration. According to the results of the computed tomography (CT) scan, the radiation field was delineated using conformal intensity-modulated radiation therapy, including mediastinal, bilateral supraclavicular, and epigastric radiation.

Outcomes

The primary outcomes were 5-year OS and disease-free survival (DFS) after the operation. OS was assessed as the interval between the date of surgery and the date of death from any cause, loss to follow-up, or last follow-up. DFS was assessed as the interval between the date of surgery and the date of first recurrence, death from any cause, loss to follow-up, or last follow-up. Recurrence was defined as local regional recurrence, lymph node metastasis, or distant metastasis.

Statistical analyses

Survival data were analyzed by the Kaplan-Meier method, while the log-rank method was applied to compare survival curves between groups. Univariate and multivariate analyses of OS and DFS were conducted by Cox regression models with stepwise selection. Fisher’s exact test or chi-square test for categorical variables and Student’s t-test or Wilcoxon-Mann-Whitney test for continuous variables were applied as appropriate. To balance covariates (10), 1:1 propensity score matching (PSM) was performed, with age, gender, tumor location, differentiation, and lymph node dissection being the covariates considered, and the matching tolerance set to 0.1. A two-tailed P value <0.05 was defined as statistically significant. Statistical analysis was performed using the SPSS 26.0 (IBM Corp., Armonk, NY, USA).

Results

Patients’ demographics

From 2008 to 2013 in a total of 387 patients at Sichuan Cancer Hospital with postoperative pathology of pN0 ESCC were included in the overall cohort (Table 1). Of the total cohort, 157 patients were in Group S, and 230 patients were in Group S + A. In Group S + A, 196 patients received postoperative chemotherapy and 34 patients received chemoradiotherapy. The covariates of age, sex, and tumor location were unbalanced in the two groups. After PSM, 87 patients were excluded, and the matched cohort included 150 patients in Group S and 150 patients in Group S + A (Table 1).

Table 1 Patients’ characteristics before and after PSM
Full table

OS and DFS

Across the whole study population, the median follow-up was 75.60 [95% confidence interval (CI): 73.17–78.03] months. The median follow-up was 76.27 (95% CI: 65.44–87.09) months in Group S and 75.6 (95% CI: 73.89–77.31) months in Group S + A. In the overall cohort, 74 patients died in Group S, and 79 in Group S + A; the 3- and 5-year OS rates were 69% and 53.6% in Group S, respectively, which were significantly lower than the OS rates in Group S + A (3-year: 77.9%; 5-year: 70.2%; log-rank χ²=8.222; P=0.004; Figure 2). The 3- and 5-year DFS rates in Group S were 58% and 48.2%, respectively, which were lower than the DFS rates in Group S + A (3-year: 72.2%; 5-year: 64.9%; log-rank χ²=8.684; P=0.003; Figure 3).

Figure 2 OS between surgery alone and surgery + adjuvant therapy groups before PSM. OS, overall survival; PSM, propensity score matching.

Figure 3 DFS between surgery alone and surgery + adjuvant therapy groups before PSM. DFS, disease-free survival; PSM, propensity score matching.

In the matched cohort, the 3- and 5-year OS rates were 69.6% and 53.6% in Group S, respectively, which were significantly lower than the OS rates in Group S + A (3-year: 76.7%; 5-year: 67.6%; log-rank χ²=4.614; P=0.032; Figure 4). In Group S, the 3- and 5-year DFS rates were 58.2% and 48%, respectively, which were significantly lower than the DFS rates in Group S + A (3-year: 70.6%; 5-year: 62.6%; log-rank χ²=6.083; P=0.014; Figure 5). In hierarchical analysis, postoperative chemotherapy prolonged OS in patients with tumors in the middle thoracic segment (P=0.041) and T3 stage tumors (P=0.008) compared with surgery alone (Figure 6), but differences were not found between postoperative chemoradiotherapy and surgery alone or postoperative chemotherapy. Compared with surgery alone, postoperative chemotherapy improved DFS in patients with moderate differentiation (P=0.023), tumors in the middle thoracic segment (P=0.028), T3 stage tumors (P=0.004), and <15 lymph node dissections (P=0.038; Figure 7), and no significant differences were observed between postoperative and other therapies (surgery alone and postoperative chemotherapy).

Figure 4 OS between surgery alone and surgery + adjuvant therapy groups after PSM. OS, overall survival; PSM, propensity score matching.

Figure 5 DFS between surgery alone and surgery + adjuvant therapy groups after PSM. DFS, disease-free survival; PSM, propensity score matching.

Figure 6 Surgery + adjuvant chemotherapy improved OS in patients with tumor in the middle thoracic segment (P=0.041, A) and T3 stage (P=0.008, B). OS, overall survival.

Figure 7 Surgery + adjuvant chemotherapy improved DFS in patients with moderate differentiation (P=0.023, A), tumor in the middle thoracic segment (P=0.028, B), T3 stage tumor (P=0.004, C), and <15 lymph node dissections (P=0.038, D). DFS, disease-free survival.

Multivariate analysis of DFS

Multivariate analysis was performed in a matched cohort. Time, sex, age, T stage, tumor location, vascular invasion, nerve invasion, histologic differentiation, type of treatment, and lymph node dissection were included in the Cox regression analysis to evaluate the prognostic factors for DFS through calculation of hazard ratios (HRs) and their 95% CIs (Table 2). The results showed that postoperative adjuvant chemotherapy was an independent protective factor (HR: 0.571; 95% CI: 0.390–0.836; P=0.004; Figure 8), and T3 stage tumors (HR: 1.953; 95% CI: 1.238–3.082; P=0.004) and <15 lymph node dissections (HR: 1.81; 95% CI: 1.238–2.648; P=0.002) were independent risk factors for prognosis.

Table 2 Univariate and multivariate Cox analysis of patients after PSM
Full table

Figure 8 Multivariate analysis of postoperative treatment in the matched cohort across Cox regression. HR, hazard ratio; CI, confidence interval.

Discussion

We assessed the value of postoperative adjuvant therapy in patients with pN0 ESCC. The results suggested that postoperative adjuvant therapy prolonged OS and DFS in patients with pN0 ESCC, which is converse to results reported for esophageal adenocarcinoma (11). Univariate analysis of the two groups in the PSM cohort revealed that T3 stage, moderate and poor differentiation, and <15 lymph node dissections were risk factors for prognosis. Moreover, Cox multivariate regression analysis indicated that postoperative adjuvant chemotherapy was an independent protective factor, and T3 tumors and <15 lymph node dissections were independent risk factors for prognosis. We chose DFS as the primary outcome in this study because, after recurrence, patients could be treated with any therapy considered useful. In the comparison of postoperative adjuvant therapy and surgery alone, Yang et al. reported that postoperative modified conformal radiotherapy was associated with improvements in both OS and DFS in patients with pT3N0M0 ESCC (12). Another study indicated that radiotherapy and postoperative chemoradiation did not significantly improve DFS and OS (P=0.692; P=0.368) (13), but the study focused on patients with ESCC with positive lymph node(s). Chen et al. examined 426 patients and found that postoperative adjuvant chemotherapy did not improve OS, regardless of lymph node metastasis (14), but the authors pointed out the problem of inconsistent chemotherapy regimens. We also found that postoperative adjuvant treatment affected the patient’s nutritional status, which in turn affected immune function. A meta-analysis of surgery + adjuvant chemotherapy and surgery alone for patients with resectable thoracic ESCC revealed that postoperative chemotherapy did not improve the patient’s OS but did extend 1-year DFS (15). A Japanese multicenter randomized controlled trial (JCOG9204) found that postoperative adjuvant therapy alone prolonged 5-year DFS compared with the surgery alone (55% vs. 45%; P=0.037) in patients with pN0 ESCC (5). A more remarkable difference was found in patients with pN1 ESCC (P=0.041). The regimen of JCOG9204 was cisplatin and fluorouracil, but the treatment applied to patients was complicated due to individual discrepancies after recurrence. Some study results have supported the JCOG9204 conclusion and indicated that patients with stage III–IV disease can obtain a long-term survival benefit from postoperative chemotherapy (8,9), but this may be a dependent on invasion depth. In a study focusing on patients with stage III disease, Yang et al. found that adjuvant therapy improved the OS and DFS of patients with ESCC (16). Further analysis indicated that lesions of the middle thorax and well-differentiated tumors had a longer OS (P<0.05). Additionally, Zhang et al. observed that concurrent chemoradiotherapy improved the OS of patients with resectable stage III–IV ESCC (17), but did not examine N0 patients. In Zhang et al.’s analysis of patients with pT3N0M0 thoracic ESCC with surgery alone versus those with postoperative adjuvant therapy (chemotherapy/radiotherapy/radiochemotherapy), the results suggested that postoperative adjuvant therapy improves the DFS of these patients; furthermore, postoperative radiotherapy was found to improve DFS in the mid-segment, moderately differentiated, and <15 lymph node dissections subgroups, while multivariate analysis demonstrated that adjuvant radiochemotherapy and female sex can improve survival (7).

There were several limitations to our study that should be noted. First, our study had a retrospective design. Although the PSM procedure can avoid potential biases, unlike in randomized controlled trials, these biases still may not be completely eliminated. Second, this was a single-institution study, and the rate of administration of chemoradiation (n=22) in our cohort was much lower than that of surgery alone (n=150) and postoperative chemotherapy (n=122). Nonetheless, our findings may provide some guidance for clinical work, but more cases and studies are needed to draw more convincing conclusions.

Conclusions

Postoperative chemotherapy significantly improved the OS and PFS of patients with thoracic pN0 ESCC. A future multicenter, randomized controlled clinical trial is warranted to confirm our findings.

Acknowledgments

The authors also appreciate the academic support from AME Esophageal Cancer Collaborative Group.

Funding: This work was supported by Bethune Charitable Foundation (HZB-20190528-19) and Nanchong City School Science and Technology Strategic Cooperation Project (NSMC20170209).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://dx.doi.org/10.21037/atm-21-2539

Data Sharing Statement: Available at https://dx.doi.org/10.21037/atm-21-2539

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-2539). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study involving human participants were in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Sichuan Cancer Hospital. Informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Gray)