Abstract
Background/Aim: To further improve the prognosis of locally advanced esophageal cancer patients, investigating new perioperative treatment strategies is necessary. The current study aimed to retrospectively investigate neoadjuvant radiotherapy with cisplatin and 5-fluorouracil (CF-RT) and radiotherapy with docetaxel and CF (DCF-RT) and compare their treatment outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Patients and Methods: We retrospectively reviewed 95 patients with ESCC who received CF-RT or DCF-RT followed by esophagectomy. The CF-RT group received chemotherapy consisting of two courses of CF repeated every 4 weeks. The DCF-RT group received chemotherapy consisting of two courses of DCF repeated every 2 weeks. A radiotherapy dose of 1.8-2 Gy was administered per session, up to a total of 40-41.4 Gy. Adverse events of neoadjuvant chemoradiotherapy, surgical outcomes, pathological responses, prognosis, and recurrence patterns were evaluated. Results: Both the CF-RT and DCF-RT groups had equivalent pathological complete response rates of the primary tumor at 31.6% and 38.6%, respectively. However, the DCF-RT group had significantly better 5-year disease-free survival and 5-year overall survival than (HR=0.50, 95%CI=0.26-0.97, p=0.0392) than the CF-RT group. Conclusion: DCF-RT may be a candidate neoadjuvant therapy for locally advanced ESCC.
Esophageal cancer, the seventh most common cancer and sixth most common cause of cancer-related mortality worldwide, is an aggressive malignant tumor with poor prognosis (1). There have been various discussions regarding perioperative treatments for locally advanced esophageal cancer. Over the last few decades, neoadjuvant treatment for locally advanced esophageal cancer has consisted of two to three chemotherapeutic drugs with or without radiotherapy (2). In Western countries, several clinical trials have shown that neoadjuvant chemoradiotherapy (NACRT) promotes better survival over surgery alone (3), leading NACRT to be accepted as the standard therapy for locally advanced esophageal cancer. Moreover, a phase III randomized controlled trial (RCT) in China reported that NACRT significantly improved long-term overall survival (OS) and disease-free survival (DFS) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) (4). In Japan, neoadjuvant chemotherapy with cisplatin and 5-fluorouracil (5-FU) followed by surgery has been accepted as the standard regimen for locally advanced ESCC based on results from a Japan Clinical Oncology Group RCT that compared pre- and postoperative cisplatin and 5-FU (CF) regimens in patients with stage II/III ESCC (JCOG9907) (5). To further improve the prognosis of patients with locally advanced ESCC, we conducted a RCT in a single institution that compared neoadjuvant radiotherapy with standard CF regimen (CF-RT) followed by surgery and surgery alone in patients with ESCC, which demonstrated that responders to CF-RT experienced better clinical outcomes compared to non-responders (6).
Recent clinical trials have reported that docetaxel and CF (DCF) offer favorable outcomes as perioperative chemotherapy in patients with locally advanced ESCC (7-12). Furthermore, a phase II study (13) and a single high-volume center retrospective study (14) showed that neoadjuvant radiotherapy with DCF (DCF-RT) promoted high pathological complete response (pCR) rates in locally advanced esophageal cancer. Based on the aforementioned reports, we have concluded that the addition of docetaxel to CF-CRT is beneficial and have subsequently started DCF-RT as NACRT for locally advanced ESCC.
Only a few studies have compared CF-RT and DCF-RT as NACRT in locally advanced esophageal cancer to date. As such, this retrospective study sought to investigate and compare the treatment outcomes of conventional CF-RT and DCF-RT in patients with locally advanced ESCC.
Patients and Methods
This retrospective study was approved by the Institutional Committee of Kagoshima University Hospital (approval no. 200125). The need for informed consent was waived because of the retrospective design of the study.
Patients and data retrieval. We retrospectively examined 95 patients with esophageal cancer who received CF-RT or DCF-RT followed by esophagectomy at the Kagoshima University Hospital between July 2007 and March 2020. All information about esophageal cancer described in the present study was based on the clinicopathological guidelines for esophageal cancer issued by the Japan Esophageal Society (15) and the 8th UICC-TNM classification (16) as evaluated by esophageal endoscopy, barium esophagogram, computed tomography (CT), and positron emission tomography-CT (PET-CT). Exclusion criteria were salvage esophagectomy, total pharyngo-laryngo-esophagectomy, transhiatal esophagectomy, cervical esophagectomy, and synchronous double cancer.
Chemotherapy. In the CF-RT group, chemotherapy consisted of two courses of CF (cisplatin, 70 mg/m2/day, day 1; 5-FU, 700 mg/m2/day, days 1-5) repeated every 4 weeks or low-dose CF (cisplatin, 1-h infusion of 4 mg/m2/day, days 1-5, 8-12, 15-19, and 22-26; 5-FU, continuous infusion of 200 mg/m2/day, days 1-5, 8-12, 15-19, and 22-26).
In the DCF-RT group, chemotherapy consisted of two courses of DCF (docetaxel, 30 mg/m2/day, day 1; cisplatin, 7 mg/m2/day, days 1-5 and 8-12; 5-FU, 350 mg/m2/day, days 1-5 and 8-12) repeated every 2 weeks.
Radiotherapy. Radiotherapy with 6- or 10-MV external photons to a total dose of 40-41.4 Gy was performed. The clinical target volume included the primary tumor, metastatic lymph nodes (LNs), and regional LNs. Prophylactic irradiation was performed to the noninvolved regional LNs including bilateral supraclavicular and perigastric LNs.
Surgery. Either open transthoracic, thoracoscopic, or mediastinoscopic esophagectomy was scheduled 8-10 weeks after completing NACRT. The proportion of endoscopic surgeries increased yearly according to the endoscopic proficiency of the surgeons. The indications for mediastinoscopic esophagectomy included elder patients with expected severe thoracic adhesions due to a past history of lobectomy or pleuritis or inflammatory diseases.
Assessment. Adverse events associated with NACRT were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0) (17). Postoperative complications were defined based on the Clavien–Dindo classification (18). The frequency of follow-up was typically once every 3 months after esophagectomy.
Statistical analysis. Continuous variables were analyzed at the median (range). The Chi-squared test and Wilcoxon rank sum test were performed to compare categoric and continuous variables between the two groups, respectively. Survival curves were calculated by the Kaplan–Meier method and compared by the log-rank test. Statistical analyses were performed by JMP® Pro 16 (SAS Institute, Cary, NC, USA). A p-value less than 0.05 was considered to be statistically significant.
Results
Patients’ characteristics. The CF-RT and DCF-RT groups comprised 38 and 57 patients, respectively. Table I summarizes the clinicopathologic characteristics of the patients. The two groups were well balanced regarding baseline characteristics except for sex.
Clinicopathological characteristics of patients.
Compliance and adverse events. Among the 38 and 57 patients who received with CF-RT and DCF-RT, 36 (94.7%) and 53 (93.0%) completed their neoadjuvant treatments, respectively. Reasons for not completing CF-RT included febrile neutropenia (n=1) and patient’s refusal (n=1), whereas those for not completing DCF-RT included leukopenia (n=2), viral infection (n=1), and periodontal disease (n=1). Hematological and nonhematological adverse events that occurred during the NACRT are summarized in Table II. Lymphopenia (p=0.0067), anorexia (p=0.0358), and viral infection (p=0.0403) occurred significantly more frequency in the DCF-RT group. No neoadjuvant treatment-related deaths occurred in both groups.
Adverse events of neoadjuvant chemoradiotherapy.
Surgical findings and postoperative complications. Surgical outcomes, postoperative morbidity, and mortality are shown in Table III. Right thoracotomy (p<0.0001) was more frequent in the CF-RT group. As such, operative time was significantly longer (p=0.0013) and intraoperative blood loss was significantly lesser (p<0.0001) in the DCF-RT than in the CF-RT group. Although both groups had similar incidence rates of postoperative complications, recurrent nerve palsy tended to occur more frequently in the CF-RT group than the DCF-RT group (p=0.0834).
Surgical outcomes and postoperative morbidity and mortality.
Histopathological tumor response rates and pathological staging. Histopathological tumor response rates and pathological staging in both groups are detailed in Table IV. R0 resection rates for the CF-RT and DCF-RT groups were equivalent (92.1% vs. 91.2%, p=0.8797). The histological responses of Grade 3, 2, and 0/1 primary tumors were observed in 12 (31.6%), 6 (15.8%), and 20 (52.6%) patients in the CF-RT group and 22 (38.6%), 6 (10.5%), and 29 (50.9%) patients in the DCF-RT group, respectively, suggesting that the effects of CF-RT and DCF-RT on histological response of the main tumor were equivalent (p=0.6630). No differences in pathological T stage (p=0.2749), N stage (p=0.1143), M stage confined to supraclavicular lymph node metastasis (p=0.3223), and stage (p=0.4718) were observed in both groups.
Pathological effects of neoadjuvant chemoradiotherapy.
Patterns of postoperative recurrence and survival. At the time of analysis, the median follow-up was 63.5 and 40.2 months in the CF-RT and DCF-RT groups, respectively. Patients who received CF-RT had a significantly higher recurrence rate compared to those who received DCF-RT (63.2% vs. 38.6%, p=0.0184), with no significant intergroup differences in recurrence sites having been observed (p=0.1012) (Table V). The 5-year DFS was 37.4% and 59.8% in the CF-RT and DCF-RT groups, respectively (p=0.0401) (Figure 1A). Accordingly, the DCF-RT group had significantly better DFS than the CF-RT group (HR=0.43, 95%CI=0.21-0.85, p=0.0150). The 5-year OS was 48.4% and 66.4% in the CF-RT and DCF-RT groups, respectively (p=0.0354) (Figure 1B). The DCF-RT group had significantly better OS than the CF-RT group (HR=0.50, 95%CI=0.26-0.97, p=0.0392).
Recurrence patterns.
Kaplan–Meier curves showing disease-free survival and overall survival in each group. The DCF-RT group had significantly better disease-free survival than the CF-RT group (p=0.0401) (A). The DCF-RT group had significantly better overall survival than the CF-RT group (p=0.0354) (B). CF-RT: Radiotherapy with cisplatin and 5-fluorouracil; DCF-RT: radiotherapy with CF and docetaxel.
Discussion
CRT has become more common as a neoadjuvant treatment of patients with locally advanced esophageal cancer compared to chemotherapy alone, especially in Western countries (19, 20). A phase II study of neoadjuvant DCF-RT for locally advanced esophageal cancer showed a 47.3% pCR and a 59% 3-year OS (13). Moreover, a single institution retrospective study found a 49.6% pCR and a 43% 5-year OS (14). Based on the aforementioned reports, we concluded that the addition of docetaxel to CF-CRT was beneficial. Notably, our findings showed that the DCF-RT group had a significantly better 5-year DFS (37.4% vs. 59.6%) and OS (48.4% vs. 64.7%) compared to the CF-RT group, although the pCR rate of CF-RT and DCF-RT on the main tumor (31.6% vs. 35.9%) was equivalent. These discrepancies in pathological response and prognosis probably resulted from the eradication of subclinical systemic micrometastases outside the irradiated area and surgical field by DCF chemotherapy alone. While local control is, of course, important, control of subclinical systemic micrometastases through combined powerful chemotherapies might also be important to improve prognosis after esophagectomy.
The present study found further improvements in OS and DFS in the DCF-RT group, with values better than those previously reported for NAC (5, 7-12) and NACRT (4, 13, 14, 21). CF therapy had been established as the standard regimen in Japan by the JCOG 9907 trial, in which the pCR rate and the 5-year OS rate were 5% and 55%, respectively (5). Two phase III RCTs, namely Chemoradiotherapy for Esophageal Cancer followed by Surgery Study (CROSS) and Neoadjuvant Chemoradiotherapy for Esophageal Cancer 5010 (NEOCRTEC5010), revealed a pCR rate of 49% and 43% and a 5-year OS of 47% and 60% among patients with squamous cell carcinoma (SCC) (4, 21, 22). Meanwhile, a recent phase II RCT that compared NACRT with neoadjuvant chemotherapy (NAC) for the treatment of locally advanced cancer of the esophagus or gastroesophageal junction (NeoRes trial) showed that NACRT promoted a 28% pCR rate and a 42.2% 5-year OS rate (23). As such, the 5-year OS rate of 64.7% obtained in the present study is one of the highest OS rates reported thus far.
Several trials on NAC or NACRT for esophageal cancer have shown that neoadjuvant therapy offers better prognosis than surgery alone. However, the optimal neoadjuvant strategy still remains to be identified. A recent meta-analysis indirectly comparing NAC and NACRT reported that NACRT could promote higher R0 resection and pCR rates, lower local recurrence rates, and better 3-year survival compared to NAC among those with the SCC subtype. Overall, the meta-analysis concluded that NACRT may be the standard preoperative treatment for ESCC (24). The NeoRes trial, which directly compared NAC and NACRT, reported no evidence of survival advantage from the addition of radiotherapy, despite the better tumor response (23). Notably, a three-arm phase III RCT, namely the JCOG 1109 NExT trial, comparing doublet NAC (two courses of CF) with triplet NAC (three courses of DCF) and CF-RT (41.4 Gy with two courses of CF) in locally advanced ESCC in Japan is currently ongoing to confirm the optimal neoadjuvant therapy (25). Two phase III RCTs comparing perioperative chemotherapy with NACRT for adenocarcinoma of the esophagus and esophagogastric junction have also been initiated in other countries. One such study is the ESOPEC trial in Germany comparing the CROSS protocol (41.4 Gy with carboplatin/paclitaxel) with FLOT protocol (5-FU/leucovorin/oxaliplatin/docetaxel) (26), whereas the other is the Neo-AEGIS trial conducted in Ireland comparing the CROSS protocol with modified MAGIC protocol (epirubicin/cisplatin or oxaliplatin/5-FU) (27). The optimal neoadjuvant strategy for esophageal and esophagogastric junction cancer is expected to be derived from these RCTs.
The current study has several limitations worth noting. Selection bias cannot be overlooked given the retrospective, single-center design of the present study. Hence, a multicenter RCT is required to clarify the feasibility of neoadjuvant DCF-RT for locally advanced esophageal cancer.
In conclusion, DCF-RT may be a reliable candidate neoadjuvant therapy for locally advanced ESCC.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number JP21K16479.
Footnotes
Authors’ Contributions
Substantial contributions to the conception or design of the work, or acquisition, analysis, or interpretation of data for the work: KS, YT, MS, MN, YU, TA, DM, SM, HK and AN. Drafting the work: KS. Final approval of the version to be published: TO.
Conflicts of Interest
The Authors declare that they have no conflict of interest relative to this study.
- Received June 14, 2022.
- Revision received June 29, 2022.
- Accepted June 29, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
