The CROSS study published in 2012 established neoadjuvant chemoradiotherapy plus surgery as the standard treatment for locally advanced esophageal cancer. [14] However, the long-term survival is still very disappointing, with a 10-year OS of only 38% for patients treated with the CROSS strategy. [15] Recently, the CheckMate 577 trial showed that adjuvant nivolumab therapy could improve DFS for patients with residual disease after neoadjuvant chemoradiotherapy plus surgery. [16] However, because of the different tumor prevalence and surgery preferences, the optimal treatment strategies for locally advanced ESCC remain unclear. [17]
Over 80% of the patients with ESCC chose surgical resection as their primary therapy in China. [3] However, no optimal postoperative adjuvant therapy for these patients was recommended in the NCCN guidelines. Due to the high recurrence rate and poor prognosis for patients with ESCC who underwent surgery alone, postoperative adjuvant therapy has been used to improve the likelihood of survival. However, the efficacy of adjuvant chemotherapy on ESCC is still controversial. Few randomized trials have evaluated the effect of adjuvant chemotherapy on patients with ESCC after radical surgery. The JCOG8806 study revealed that no survival benefit was obtained from adjuvant chemotherapy using a combination of cisplatin and vindesine. [8] In the JCOG9204 study, the 5-year DFS was significantly better when patients with positive LNs received adjuvant chemotherapy with cisplatin plus fluorouracil (52.0% vs. 38.0%; p = 0.041); however, the difference for OS was not significant. [9] Both of these clinical trials were conducted in an early period. Recently, some retrospective studies and meta-analyses found that adjuvant chemotherapy could improve survival in certain subgroups for patients with ESCC after radical resection, especially for patients with positive LNs,[10, 11, 13,18, 19] indicating that the efficacy of adjuvant chemotherapy should be further determined.
Our current retrospective study enrolled one of the largest patient cohorts to date. We also used PSM to minimize baseline differences between the S group and the S + C group. Our results confirmed that adjuvant chemotherapy not only improved DFS for patients with ESCC who underwent radical resection but also improved OS, and adjuvant chemotherapy was an independent prognostic factor. These results were similar to some of the other retrospective studies. [10, 11, 18] In a recent meta-analysis by Zhao et al.[19] that enrolled 9 studies and a total of 1684 cases, the authors also found that adjuvant chemotherapy could improve OS (HR 0.78, P = 0.002) and DFS (HR 0.72, P < 0.001) for patients with ESCC. There may be three reasons for the positive results in our study. First, all of the surgeries were performed or closely supervised by two senior surgeons (J. S Yang and Y. P Chen). The homogeneity of the surgical treatment will reduce the methodological biases. Second, the mean dissected LN number in this study was 26.2, which was higher than that in most previous studies. The insufficiency of lymphadenectomy would lead to higher locoregional LN recurrence, which might not be very well controlled by adjuvant chemotherapy. Third, most of the patients in our study received sufficient cycles of chemotherapy (88.2% with more than 3 cycles). Patients who undergo esophagectomy always have a slow recovery process, and the lower tolerance to adjuvant chemotherapy would impact the effect of this therapy. [20]
Subgroup analyses in our study showed that not all patients benefited from adjuvant chemotherapy. Our findings that patients with pN1-pN3 diseases and pTNM stage III - IVA diseases, but not pN0 diseases and pTNM stage I - II diseases, were more likely to benefit from adjuvant chemotherapy were consistent with previous studies. [13, 21] Patients with positive LNs and advanced TNM stage are known to have a high risk of tumor recurrence and should be more likely to have systemic disease, so systemic chemotherapy might improve the survival of these patients. [12] Accordingly, patients with moderately and poorly differentiated tumors and tumor lengths >4 cm were also found to benefit from adjuvant chemotherapy, as previous studies showed that these patients might have a higher rate of tumor recurrence and worse survival. [22, 23] However, Pasquer et al.[24] found that adjuvant chemotherapy did not improve the OS and DFS for esophageal cancer patients with positive LNs. Ando et al.[8] also found that adjuvant chemotherapy did not improve 5-year survival for LN-positive ESCC patients (43.7% vs. 35.5%, P = 0.13). The differences in surgical approach, lymphadenectomy, chemotherapy agents, and chemotherapy cycles might contribute to these different results.
Our subgroup analyses also showed that patients who underwent right thoracotomy were more likely to benefit from adjuvant chemotherapy than patients who underwent left thoracotomy. Bilateral recurrent laryngeal nerve LNs, with nearly 40% involvement, were the most frequent metastatic nodes in thoracic ESCC. [25, 26] However, these LNs could not be removed through a left thoracotomy. This means that nearly 40% of ESCC patients who undergo left thoracotomy may not receive radical surgery, resulting in a high rate of locoregional recurrence. For these patients, postoperative chemoradiotherapy but not chemotherapy may be a better adjuvant therapy to reduce locoregional recurrence and improve survival. [27, 28]
Surprisingly, we found that older patients (>60 years) might benefit from adjuvant chemotherapy but not younger patients (≤60 years) in our subgroup analyses, which was different from the result by Zhu et al.[21] There may be several reasons for this result. First, the cutoff point of age was different in these two studies (60 years vs. 65 years). Second, the chemotherapy cycles were similar between younger and older patients in our study; however, younger patients received more chemotherapy cycles in the study by Zhu et al.[21] (although the P value was 0.081). Most previous studies have shown that age is a factor that influences treatment choices but not necessarily outcomes. [29, 30] Both younger patients and older patients could benefit comparably from chemotherapy. [29, 30] According to our results, we think that adjuvant chemotherapy should not be withheld based on age alone in ESCC patients after surgery. Although we also found that adjuvant chemotherapy might not benefit female patients or patients with tumors located in the upper third of the thorax, the sample sizes in these subgroups were too small to draw a conclusion. We think that more data should be collected to evaluate these results.
There are some limitations to this study. First, it was a retrospective study, and we could not analyze the toxicity of adjuvant chemotherapy in this study, as most of these data were missing. Second, different chemotherapy agents, such as 5-fluorouracil, cisplatin, and docetaxel, were used, and we could not define the optimal chemotherapy regimens in this study. Third, although PSM was used to balance the baseline differences, some of the other factors that may impact the prognosis, such as performance status, were not included in this study. With the development of new drugs, such as taxanes, increasing data have shown that adjuvant chemotherapy may improve survival in patients with ESCC. We think that a multicenter, randomized clinical trial should be conducted to explore the role of adjuvant chemotherapy in patients with ESCC after radical surgery.
In conclusion, postoperative adjuvant chemotherapy improves the OS and DFS of ESCC patients after radical resection but may only work for patients in certain subgroups. Further multicenter, randomized clinical trials should be conducted to evaluate our findings.