Long‐term results of a randomized controlled trial comparing neoadjuvant Adriamycin, cisplatin, and 5‐fluorouracil vs docetaxel, cisplatin, and 5‐fluorouracil followed by surgery for esophageal cancer (OGSG1003)

Abstract Aim The aim is to report the long‐term outcomes of preoperative cisplatin and fluorouracil plus docetaxel (DCF) vs Adriamycin (ACF) for resectable esophageal squamous cell carcinoma (ESCC). Previously, this trial showed that DCF is associated with prolonged recurrence‐free survival (RFS). Methods Patients were randomly assigned to two cycles of ACF (35 mg/m2 of Adriamycin, 70 mg/m2 of cisplatin intravenously on day 1, and 700 mg/m2 of fluorouracil infusion for 7 days) every 4 weeks or DCF (70 mg/m2 of docetaxel, 70 mg/m2 of cisplatin intravenously on day 1, and 700 mg/m2 of fluorouracil infusion for 5 days) every 3 weeks, followed by surgery. The primary endpoint was RFS. The secondary endpoint was overall survival (OS). Results Between October 2011 and October 2013, 162 patients at 10 institutions were enrolled in the study, 162 of whom were eligible and randomly assigned to the two groups. The median follow‐up for surviving patients was 69.8 months. The 5‐year RFS was significantly better in the DCF group than in the ACF group (59.9% vs 40.7%, hazard ratio [HR] 0.55; 95% confidence interval [CI], 0.35‐0.86; P = .009) and the 5‐year OS was significantly better in the DCF group than in the ACF group (63.5% vs 49.4%, HR, 0.61; 95% CI, 0.38‐0.96; P = .03). The benefit of DCF chemotherapy on survival was significantly greater in the subgroups with more advanced clinical T and N stage. Conclusions Cisplatin and fluorouracil plus docetaxel are associated with better RFS and OS than ACF in resectable ESCC patients.


| INTRODUC TI ON
Esophageal cancer is an aggressive disease with a high degree of both distant and regional metastasis at comparatively early stages. 1 Neoadjuvant therapy, or adjuvant therapy followed by surgery, is widely used to improve the prognosis of patients with resectable esophageal squamous cell carcinoma (ESCC). [2][3][4] Neoadjuvant chemoradiotherapy is currently regarded as the standard treatment for patients with resectable esophageal cancer in Western countries. [5][6][7][8] On the other hand, neoadjuvant chemotherapy such as cisplatin and fluorouracil (CF) chemotherapy is also regarded as an alternative treatment in Asia. However, CF regimen has a low response rate and controversial survival benefit. [9][10][11][12][13][14] Triplet regimens with Adriamycin, epirubicin, or docetaxel in addition to CF were recently reported to be more effective in patients with advanced esophageal cancer rather than doublet regimen. [15][16][17][18][19] Thus, we planned a clinical trial of triplet neoadjuvant chemotherapy regimens so that we can select the best chemotherapy regimen in order to compare with chemoradiotherapy in future.
The randomized controlled chemotherapy for esophageal cancer followed by surgery trial (OGSG1003) compared two regimens of neoadjuvant chemotherapy (CF plus Adriamycin (ACF) vs CF plus docetaxel (DCF) plus surgery. 20 A total of 162 patients at 10 institutions were enrolled between November 2010 and October 2012.
The initial results of this trial showed that DCF chemotherapy is associated with prolonged recurrence-free survival (RFS) compared to ACF. 21 Here, we report long-term follow-up results with analysis of the primary endpoint, RFS, as well as secondary endpoints such as overall survival (OS) and recurrence patterns.

| Patients
Full details of the eligibility criteria and pre-treatment evaluation were reported previously. 14

| Treatment
The randomization scheme was described previously. 14 Patients were stratified by institution and clinical N stage. They were then randomly assigned to either ACF chemotherapy followed by surgery (ACF group) or DCF chemotherapy followed by surgery (DCF group). ACF chemotherapy consisted of two cycles of Adriamycin

| Follow-up
Patients were seen every 3 months during the first 2 years after the date of random assignment, every 6 months for the next 3 years, and annually thereafter. Disease recurrence was defined as locoregional (at the primary site including the anastomosis, regional lymph nodes, and supraclavicular lymph nodes) or distant (including non-regional lymph nodes except for the supraclavicular lymph nodes or distant organs). The study protocol stipulated that postoperative adjuvant chemotherapy or chemoradiotherapy was not performed.

| Statistical analysis
Data were analyzed according to the intention-to-treat principle. OS was measured from the date of randomization to the date of death due to any cause or last follow-up. RFS was measured from the date of randomization to the date of first evidence of recurrence, death due to any cause, or last follow-up in patients without recurrence.
We used the Kaplan-Meier method to estimate OS and RFS and the log-rank test to compare differences across groups. Univariate Cox regression modeling was used to analyze differences in recurrencefree interval between treatment groups. Deaths from non-diseaserelated causes were censored. Recurrence was defined as recurrence K E Y W O R D S esophageal cancer, neoadjuvant chemotherapy, squamous cell carcinoma in patients with R0 resection and either locoregional residual disease after protocol treatment or distant residual disease during or after protocol treatment in patients with R0 resection or patients who did not undergo resection.
Hazard ratios (HRs) for DCF and ACF and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression for each subgroup. Differences in OS between the two treatment groups were tested. Subgroups were predefined according to baseline patient characteristics such as age, sex, performance status, location of the primary tumor, clinical T stage, and clinical N stage. Statistical analyses were performed with JMP 13.0.1 (SAS).

| Patient characteristics
From November 2010 to October 2012, a total of 162 patients with resectable esophageal squamous cell carcinoma were randomly allocated to the two treatment groups in a 1:1 ratio ( Figure 1) and included in the intention-to-treat analysis. Since the initial reporting of this study, no additional information became available regarding baseline characteristics, which were well-balanced between the two treatment groups (Table 1). Histological tumor stage and response evaluation are summarized in Table 2.
The final day of follow-up was January 2018, guaranteeing a minimum follow-up of 5 years for all patients included in the analysis except for one patient in the DCF group who was lost to follow-up after moving at 26 months after randomization. The median follow-up for surviving patients was 69.8 months.  had radiotherapy, and two (4%) had surgery in the ACF group. On the other hand, 10 patients (34%) had chemoradiotherapy, nine (31%) had chemotherapy, four (14%) had radiotherapy, and two (7%) had surgery in the DCF group. The difference in the first treatment after recurrence difference was not seen between two groups (P = .934). We found no differences in OS between patients receiving ACF vs DCF by age, sex, performance status, and tumor location ( Figure 3). On the other hand, the OS of patients with advanced clinical T (cT3 or cT4) stage and N (cN2 or cN3) stage who underwent DCF was significantly better than those who underwent ACF.

| Survival
However, we found no differences in OS between the two groups among those with early clinical T (cT1 or cT2) stage and N (cN0 or cN1) stage.

| D ISCUSS I ON
These long-term results confirm the initial report that preoperative DCF chemotherapy followed by surgery is associated with pro-

ACK N OWLED G M ENT
The authors thank the staff from all the centers that participated in data collection.

D I SCLOS U R E
Funding: The authors report no funding sources for any products mentioned or concepts discussed in this article.

E TH I C S A PPROVA L A N D CO N CE NT TO PA RTI CI PATE
The Human Ethics Review Committee of each institute approved the study protocol. Subjects have provided written informed consent.
This study was performed in accordance with the Declarations of Helsinki.

CO N S E NT FO R PU B LI C ATI O N
All the authors declare consent for publication.

DATA AVA I L A B I L I T Y S TAT E M E N T
The authors declare that the data supporting the findings of this study are available within the article.