The present study showed that S-1 therapy was safe as an adjuvant chemotherapy regimen for patients with esophageal cancer regardless of whether NAC was administered.
Esophagectomy plays a pivotal role in the treatment of esophageal cancer. Despite advances in surgical techniques, long-term survival after surgery for advanced esophageal cancer has remained unacceptable owing to poor survival. Hence, there is a need for more effective perioperative chemotherapy regimens [1, 2]. However, whether or not to add adjuvant chemotherapy to esophageal cancer surgery remains controversial because treatment toxicity is an important concern for the application of postoperative adjuvant chemotherapy [6, 7]. The main purpose of adjuvant chemotherapy is to eradicate micrometastatic tumor cells. Therefore, it is essential to continue chemotherapy with minimal duration and dose to ensure that these tumor cells are eradicated [17, 18]. A regimen involving 2-week S-1 administration followed by a 1-week rest (3-week regimen) was devised with an expectation to reduce toxicity and improve drug adherence while maintaining the same dose of S-1 as the standard 6-week regimen (4-week S-1 administration followed by a 2-week rest). This regimen was established based on the knowledge that the median time required for marrow suppression and the onset of non-hematological toxicity were 22 days and 15 days, respectively, and that a drug-free interval of 3 weeks after the start of S-1 treatment may reduce the incidence of adverse events. Previous reports of patients with gastric cancer have reported that a 3-week regimen improves medication adherence and reduces adverse events while maintaining the same dose of S-1 as the standard 6-week regimen [19, 20]. Based on the above findings, we provided a 3-week regimen of postoperative adjuvant therapy with S-1 for patients after surgery for advanced esophageal cancer at our institution.
The treatment completion rate of S1 was as high as 80% in the NAC-treated group and 80% in the NAC-non-treated group, which was almost the same as the result of the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC), which examined the efficacy of adjuvant therapy with S1 in patients with gastric cancer [11]. The quality of life of patients is affected more by non-hematological toxicity such as loss of appetite, malaise, and nausea than by hematological toxicity [21]. In this study, S-1 treatment could be continued owing to the low incidence of grade 1–2 non-hematological toxicity. In addition, according to ACTS-GC studies, the incidence of grade 3/4 neutropenia was approximately 5%. In this study, grade 3 neutropenia was observed equally in 18% and 18% of patients in the NAC-treated and non-NAC-treated groups, respectively, and was transient and manageable. To the best of our knowledge, this is the first study to demonstrate that the feasibility and toxicity profile of adjuvant chemotherapy with S-1 was similar in patients who received and did not receive NAC.
The 3-week regimen was considered equally acceptable in terms of RDI, completion rate, and frequency of adverse events, demonstrating better feasibility in both groups. Our results suggested that S-1 adjuvant chemotherapy was safe and feasible for patients with esophageal cancer who underwent esophagectomy regardless of NAC administration. Therefore, it is unnecessary to avoid chemotherapy or to reduce the dose of S-1 in patients who received NAC. If future studies reveal that the 3-week regimen has a detectable preventive effect on long-term prognosis, then this regimen will be established as a safe postoperative adjuvant chemotherapy regimen.
Although detailed data on the nutritional status of patients were not evaluated in this study, several studies have shown a significant reduction in nutrition-related parameters, such as the obesity index, serum albumin, and hemoglobin in patients with esophageal cancer [22, 23]. Chemotherapy can cause both deterioration of nutritional status due to toxicity and, conversely, improvement of nutritional status due to tumor shrinkage. Therefore, it is difficult to determine whether nutritional status changes are due to chemotherapy or the detrimental effects of surgery. For patients with gastric cancer, a decrease in nutritional indicators such as body weight and lean body mass has been reported to reduce compliance with anticancer drug treatment [24, 25]. Thus, maintaining the nutritional status during adjuvant chemotherapy is important, given that drug compliance can lead to improved survival. A decline in health-related quality of life may last from 6 months to 3 years until after the surgery [26]. Fortunately, in this study, only two patients (9.1%) experienced grade 3 or higher toxicity in the non-NAC group, and only two patients (10.0%) experienced grade 3 or higher toxicity in the NAC group. In addition, S-1 may not have had a serious impact on nutritional status (due to adverse events), as most patients did not develop severe anorexia requiring discontinuation of adjuvant chemotherapy. Detailed nutritional assessments and studies of perioperative nutritional interventions during adjuvant therapy in patients undergoing esophagectomy are required.
Esophagectomy is a highly invasive surgery requiring three-field lymph node dissection and reconstruction with a gastric conduit, despite advances in minimally invasive esophagectomy [27, 28]. Therefore, during the early postoperative period, patients would have not yet recovered from surgical stress and are more likely to experience adverse events such as loss of appetite and nausea. To resolve these issues, it is necessary to determine the appropriate initiation time and criteria for adjuvant therapy, as well as the factors that are likely to cause adverse events.
The present study has some limitations, which must be considered when interpreting the results. First, this was a retrospective single-center study with a small sample size, which may account for the lack of meaningful statistical data. Thus, larger sample sizes are needed to draw well-founded conclusions. However, because the toxicity profile in this study was recorded using a check sheet in most patients at the time of consultation during S-1 adjuvant treatment, sufficient information on adverse events was collected, and the results of this study can be reliable. Second, the patients’ follow-up period was too short to assess the therapeutic effect of the S-1 adjuvant therapy on long-term outcomes. The main purpose of the present study was to assess the toxicity profile, not the efficacy of the adjuvant S-1 treatment. Long-term survival outcomes are a topic for future research, and our data support the administration of adjuvant chemotherapy for patients who have undergone curative esophagectomy after preoperative chemotherapy. Third, selection bias was likely among patients treated with S-1. Although there was no significant difference, patients who received NAC were younger, had fewer postoperative complications, and the time from surgery to the initiation of S-1 administration was shorter than that in the non-NAC group. Among patients of the same stage, some received postoperative adjuvant chemotherapy and some did not. Even the first-stage patients received postoperative adjuvant therapy on request, resulting in a potential selection bias. Patients with esophageal cancer often have comorbidities such as chronic obstructive pulmonary disease and liver dysfunction as well as physiological problems that can cause greater drug toxicity than that in patients with other cancers [29, 30]. Therefore, it is important to determine the clinical predictors of serious adverse events and early discontinuation of S-1 adjuvant therapy.
In conclusion, S-1 could be safely and continuously administered as adjuvant chemotherapy in patients with esophageal cancer regardless of the administration of NAC. Although S-1 has a very high antitumor effect on many carcinomas, its long-term prognosis needs to be evaluated in a prospective study to become the standard treatment for postoperative patients with esophageal cancer. Furthermore, to improve the therapeutic outcomes, it is also important to develop individual treatment strategies in the future.