Background
Globally, esophageal cancer is one of the most life-threatening diseases and causes approximately 540,000 deaths per year worldwide [
1]. Despite recent developments in perioperative management and surgical techniques, esophageal cancer remains a highly lethal malignancy. Surgical treatment is one of the most important therapeutic modalities for esophageal cancer, but it is difficult to improve the outcome of local treatment by surgery alone, and adjuvant chemotherapy is increasingly utilized. The efficacy of neoadjuvant chemotherapy (NAC) for the treatment of esophageal cancer using 5-fluorouracil (5-FU) and cisplatin (FP therapy) has been proven in a phase III Japan Clinical Oncology Group (JCOG) trial (JCOG9907) [
2]. Based on this result, preoperative FP therapy has been introduced as the standard treatment for patients with stage II or III esophageal cancer in Japan [
3]. The response rate to preoperative FP therapy was only about 38%, however, and the development of a more powerful regimen has been anticipated. In recent years, the results of the JCOG1109 trial confirmed the efficacy of the triple regimen comprising docetaxel, cisplatin, and 5-FU (DCF therapy), and the use of DCF is expected to increase [
4].
Malignant esophageal stenosis (MES) is a common and severe complication in patients with locally advanced or unresectable esophageal cancer. MES can cause difficulty in food intake, dysphagia, and aspiration pneumonia, and it can worsen patients’ nutritional status [
5‐
7]. Furthermore, MES affects several aspects of quality of life such as physical experience and the impact on social life [
8]. MES can therefore be a serious problem in the maintenance of nutritional status and the continuation of various anticancer treatments. In addition, effective treatment should be selected for patients with reduced quality of life associated with oral intake disorder during chemotherapy.
For these reasons, chemotherapy must be selected with the focus on both the antitumor effect and also the improvement in the stricture and dysphagia. Previously, there were no reports on stenosis improvement in which FP and DCF therapies were compared. In this study, we assessed the relationship between the improvement in MES and chemotherapy regimen in patients who received preoperative FP or DCF therapy for the treatment of esophageal squamous cell carcinoma (ESCC).
Discussion
In this study, we investigated the relationship between the chemotherapy regimen and its impact on MES. Our data showed that DCF therapy is effective in the improvement of MES. Recently, the efficacy of DCF therapy for esophageal cancer has been described by Watanabe et al., who reported that the clinical response rate to DCF therapy was 53%, and pathological response rate was 36% for preoperative chemotherapy as NAC [
14]. Other reports showed that the OS of ESCC was significantly longer for DCF therapy than for FP therapy, as well as RFS [
4,
15]. In addition, DCF therapy as induction chemotherapy for initially unresectable, locally advanced esophageal cancer elicits a good response and improves the prognosis. The DCF regimen was superior to the FP regimen with regard to OS, R0 resection rate, and histopathological response rate [
7,
16]. However, the JCOG1109 trial was adapted for patients up to 75 years old, and its high frequency of adverse events raises the question of whether it should be given as NAC to all operable patients with advanced esophageal cancer [
4]. Therefore, it is necessary to consider the benefits and potential adverse effects of DCF therapy in addition to the improvement in prognosis.
The expansion rate in the narrowest width after chemotherapy was significantly increased in the DCF group compared with the FP group. In addition, the SI index, which is thought to represent the severity of MES, was significantly improved in the DCF group compared with the FP group. These results indicate that the DCF regimen is effective not only for its reductive anticancer effect, but also for the improvement of MES. To our knowledge, this is the first study to report the improvement of MES and the type of chemotherapy.
Furthermore, we assessed the dysphagia score before and after chemotherapy as the evaluation of patients’ symptoms. DCF regimen was also found to be effective in the improving of patients’ dysphagia scores. This indicates that DCF therapy improves patients’ intake disorder, and is clinically useful for patients with MES.
Dysphagia resulting from MES leads to malnutrition and difficulty continuing chemotherapy [
17‐
19], so it is important to reduce the dysphagia and improve the nutrition status. Esophageal stent implantation was useful and immediate for the palliative treatment for MES [
20‐
24]. However, esophageal stents can have complications, such as bleeding, migration into the stomach or small bowel, aspiration pneumonia, and fistula formation [
25‐
27]. In addition, the oncologic safety and the effectiveness of the esophageal stent in patients with non-palliative esophageal cancer are not well known. The European Society of Gastrointestinal Endoscopy has not recommended the temporary placement of a self-expandable metallic stent (SEMS) for MES as a bridge to surgery or before preoperative chemoradiotherapy [
28]. The choice of chemotherapy is important because SEMS should not be used for patients with ESCC before surgery.
In the analysis of the two groups with respect to the rate of SI change, a high level of SI change was identified; that is, the improvement of MES, is significantly correlated with patients who only received DCF therapy, though there were no significant changes in other clinicopathological features including tumor stages. There is a possibility that the hardness and degree of stenosis of the primary tumor may be related to the amount of stromal fibrosis in the tumor tissue. DCF therapy may suppress the stromal fibrosis and improve the solidity and degree of stenosis of the primary tumor.
Taxane-based chemotherapy has been commonly used for the treatment of several cancers such as those of the stomach, esophagus, breast, and ovary. Paclitaxel (PTX), one of the major taxane drugs, improves intestinal stenosis related to the cancer-associated fibrosis in patients with gastric cancer and peritoneal metastasis [
29]. In this study, the DCF group using Docetaxel showed a significant improvement in the width of the narrowest portion and SI, suggesting that the tissue softened and expanded better on examination by esophageal fluoroscopy. These results indicate that taxane-containing chemotherapy may be suppressing not only the cancer progression but also the tumor fibrosis and MES. However, there have been a few reports on the inhibition of fibrosis by docetaxel, another taxane anticancer drug.
Docetaxel is a microtubule-stabilizing taxane, and it has increased affinity for tubulin [
30]. This drug suppresses the expression of TGF-β, as does paclitaxel [
31]. Therefore, it is thought that docetaxel may inhibit the function of fibroblasts and fibrocytes that are associated with stromal fibrosis in cancer tissues. The details, however, are not yet known. Further in vitro and in vivo studies on docetaxel are needed.
Though DCF therapy is effective in the improvement of MES, there was no significant change in the prognosis between the FP and DCF groups in our study (data not shown). Patients with more advanced diseases were included in the DCF group, which may have affected the treatment outcomes and prognosis. The results of JCOG 1109 showed a significant survival benefit in the DCF group, making it a highly effective treatment as NAC for the patients with resectable esophageal cancer (median survival time: FP 5.6 years, DCF 6.7 years,
p = 0.006) [
4]. However, adverse events such as neutropenia and anorexia have occurred more frequently in DCF therapy. Therefore, we have to use this regimen in consideration of the patient comorbidities, age, condition, and degree of esophageal cancer. The results of our study suggest that DCF therapy should be recommended for the patients with ESCC and MES.
This study has some limitations. First, this investigation was retrospective in nature and was conducted at a single institution. The number of cases is small and there are differences in patient backgrounds between the FP and the DCF groups. Second, we did not evaluate the degree of fibrosis at the tumor site in either group. The assessment of fibrosis using Azan staining and alpha-smooth muscle actin immunohistochemical staining may provide valuable data, and further the understanding of the mechanism of stenosis improvement in ESCC. These factors should be considered, and further prospective, multicenter studies are needed to confirm our results.
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