Postoperative adjuvant chemotherapy versus chemoradiotherapy for node-positive esophageal squamous cell carcinoma: a propensity score-matched analysis

Esophageal cancer is associated with a poor prognosis and substantial mortality rate [1, 2]. Although esophagectomy is the main treatment option for patients with localized advanced esophageal cancer, the 5-year overall survival (OS) rate remains < 20% after surgery alone [3‐7]. Furthermore, patients with pathologic lymph node LN metastasis have a significantly lower survival rate than patients without LN metastasis [4, 5, 8, 9]. Several studies have indicated that, relative to surgery alone, multimodality treatment significantly improves OS among patients with locally advanced esophageal cancer [5, 8, 10‐13]. The main additional treatment for locally advanced esophageal squamous cell carcinoma and adenocarcinoma is neoadjuvant chemoradiotherapy (NCRT), based on the results from the CROSS study [11] and the NEOCRTEC5010 study [10]. Recently some researchers reported persistent pathologic LN metastasis with or without NCRT is a strong poor prognostic factor in ESCC [14, 15]. Therefore, an effective preoperative or postoperative treatment (e.g., radiotherapy and/or chemotherapy) is needed to improve outcomes, especially for patients with pathologically node-positive (pN+) esophageal cancer. Postoperative chemotherapy and/or radiotherapy provide significantly better long-term survival, relative to surgery alone, for patients with pN+ esophageal cancer [3, 5, 7, 13]. However, to the best of our knowledge, no studies have directly compared S + CT and S + CRT for pN+ esophageal squamous cell carcinoma (ESCC). Therefore, this retrospective study examined whether S + CT or S + CRT were associated with improved survival among patients with pN+ ESCC.

The current National Comprehensive Cancer Network guidelines [17] recommend no additional treatment for squamous esophageal cancer unless the surgical margins are positive, although even patients with complete resection have a poor prognosis. The present study evaluated patients with pN+ ESCC and found that S + CRT was associated with a survival advantage in terms of OS and DFS, relative to S + CT. Furthermore, this advantage was still observed when we compared the propensity score-matched groups. Moreover, the independent predictors of OS and DFS were S + CRT, KPS score, and pathological T/N status. Finally, S + CRT was associated with a significantly lower LRR (relative to S + CT), although S + CRT did not appear to affect the rate of distant metastasis.

Surgical techniques for esophageal cancer have improved dramatically over the last decade, from two-field dissection to three-field dissection and from open surgery to video-assisted thoracoscopic minimally invasive surgery [16‐18]. These advances have led to improvements in survival. However, local recurrence remains the main cause of treatment failure among patients with locally advanced tumors (41.5-49% of cases) [17, 19, 20]. A few studies reported that additional preoperative and postoperative therapy is necessary for patients with pN+ disease [3, 4, 8, 22–24]. Hsu et al. also reported that, among pN+ patients, S + CRT provided better outcomes than surgery alone in terms of 3-year OS (45.8% vs. 14.1%, p < 0.001) and 3-year DFS (24.1% vs. 11.5%, p = 0.0002) [25]. Furthermore, Lee et al. reported that S + CT was associated with a significantly better 3-year DFS rate than surgery alone (47.6% vs. 35.6%, p = 0.049) [4]. Thus, these studies have consistently indicated that adding postoperative chemotherapy and/or radiotherapy was able to improve OS among patients with pN+ disease, relative to surgery alone [3,4,6,8,16,25]. However, no studies have directly attempted to determine whether S + CT or S + CRT is preferable in this setting, and the present study aimed to address this issue. The results from before and after the propensity score-matching indicate that S + CRT provided better long-term OS and DFS, relative to S + CT.

Interestingly, Bedard et al. [21] have reported that S + CRT can cause biological changes in the tumor and reduce the possibility of subclinical or local recurrence. For patients underwent NCRT in CROSS study [11], the local regional recurrence have decrease significant (Anastomosis: 2.8% vs 8.7%, P = 0.008, Mediastinum: 7.0% vs 20.5%, P<0.001). Only 9 patients have recurrence in RT field. The results showed that local radiotherapy plus surgery could significantly reduce the LRR, and the LRR in the irradiated field was even lower. The present study also revealed that S + CRT was associated with a significantly lower LRR, especially for mediastinal recurrences, relative to S + CT. Thus, it is possible that ESCC may be sensitive to CRT, which might explain why S + CRT was more effective at improving the long-term OS and DFS outcomes. Furthermore, many studies have indicated that preoperative chemoradiotherapy significantly increases the pCR, relative to preoperative chemotherapy [10‐12, 22, 23]. Moreover, improvements in radiotherapy techniques have helped improve OS outcomes for locally advanced esophageal cancer, and improved surgical techniques have resulted in smaller postoperative radiotherapy targets [9, 24]. Unfortunately, a radiation field limited to the mediastinal region is associated with a high supraclavicular and abdominal recurrence rate [13]. Thus, more precise treatments need to balance efficacy and treatment-related side effects, which suggest that further studies are needed to clarify the most appropriate chemotherapy regimens and radiation doses and target volumes.

The present study has several limitations. First, the retrospective data collection over a 10-year period is prone to bias and confounding, although we attempted to minimize the effects by using propensity score matching to create two relatively comparable groups. For example, patients with KPS 90-100 can benefit from the S + CRT. Second, there have been various improvements in radiotherapy, chemotherapy, and surgical techniques during the 10-year period, which might have influenced our findings. Third, we only considered patients who were treated at a single institution. Fourth, the retrospective design precluded any analysis of patients who were not considered eligible for postoperative therapy because of their performance status.

In conclusion, we retrospectively evaluated patients with pN+ ESCC who underwent surgery followed by adjuvant chemotherapy or chemoradiotherapy. The results indicate that S + CRT was associated with a substantial survival advantage in this setting. Therefore, further work is needed to better understand the role of adjuvant chemoradiotherapy for patients who have undergone esophagectomy for pN+ ESCC.