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A Single-Center Retrospective Study to Compare the Efficacy and Safety of Modified FOLFIRINOX with S-1 as Adjuvant Chemotherapy in 71 Patients with Resected Pancreatic Carcinoma

Background Studies are ongoing to determine the optimal adjuvant chemotherapy (ACT) for resected pancreatic carcinoma (PC). FOLFIRINOX is a chemotherapy regimen including oxaliplatin, irinotecan, leucovorin, and 5-fluorouracil (5-FU). S-1 is a fluoropyrimidine derivative widely used as ACT for gastrointestinal malignancy. This single-center retrospective study aimed to compare the efficacy and safety of modified FOLFIRINOX (mFOLFIRINOX) with S-1 as ACT for resected PC. Material/Methods A total of 71 patients with PC who accepted ACT after R0 resection between February 2016 and January 2019 were enrolled in this retrospective study. Among these patients, 34 received mFOLFIRINOX regimen chemotherapy (mFFX group), while 37 received S-1 monochemotherapy (S-1 group). The mFOLFIRINOX regimen included oxaliplatin 65 mg/m2, leucovorin 400 mg/m2, irinotecan 150 mg/m2, 5-FU 400 mg/m2, and continuous 5-FU 2400 mg/m2 (for 46 h), in a 2-week schedule. The S-1 monochemotherapy (80–120 mg/day according to body surface area [BSA], in 2 divided doses for 2 week) was administrated every 3 weeks. We followed up these patients and analyzed the relapse-free survival (RFS), overall survival (OS), and chemotherapy-induced adverse events (AEs). Results The mFFX group demonstrated a markedly higher 3-year RFS (P=0.0332) and OS (P=0.0346) than the S-1 group. Patients in the mFFX group experienced significantly more common and severe thrombocytopenia (P=0.0372), fatigue (P=0.0226), nausea/vomiting (P=0.0337), and diarrhea (P=0.0018). No chemotherapy-induced death was documented. Conclusions This retrospective study indicated that if dose adjustment and adverse events management are properly administrated, mFOLFIRINOX regimen chemotherapy could result in an improved survival compared with S-1 monochemotherapy for resected PC.


Background
Pancreatic carcinoma (PC) causes 466 000 deaths yearly because of its dismal prognosis and is the seventh most lethal malignancy globally [1]. Despite advances in diagnostic and management of PC, both incidence and mortality rates of PC have gradually risen through the last few decades [2]. Radical surgery provides the only opportunity for cure, whereas over 90% of the patients relapse postoperatively [3].
Adjuvant chemotherapy (ACT) has been proven to effectively improve prognosis and is recommended as a necessary postoperative treatment for PC [4]. Gemcitabine and gemcitabinebased regimens are used as first-line regimens of ACT and lead to remarkable survival improvement among patients with resected PC [5,6]. Recently, regimens with promising clinical efficacy were reported. The JASPAC-01 trial revealed the superiority of S-1 over gemcitabine in the Asian population [7].
Therefore, this single-center retrospective study aimed to compare the efficacy and safety of mFOLFIRINOX with S-1 as ACT for patients with resected PC.

Patients
This study was conducted following the Helsinki Declaration principles and Good Clinical Practice recommendations and was approved by the Medical Research Ethics Committee of First People's Hospital affiliated to Huzhou Normal College. Patient informed consent was waived.
We enrolled 71 patients with PC who underwent ACT after R0 resection between February 2016 and January 2019. Eligibility criteria were: ages 18-75 years; histologically confirmed pancreatic adenocarcinoma; no neoadjuvant chemotherapy; World Health Organization (WHO) performance-status score of 0 or 1; and sufficient organ function. Patients were not eligible if they were lost to follow-up or had a history of other malignancies. Among these patients, 34 received mFOLFIRINOX regimen chemotherapy (mFFX group), while 37 received S-1 monochemotherapy (S-1 group).
Chemotherapy-induced adverse events (AEs) were graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. A 25% dose reduction was applied subsequently in the event of grade 2 or 3 handfoot syndrome, grade 4 neutropenia, grade 3 or 4 thrombocytopenia or anemia, or another grade 3 or 4 acute non-hematologic AEs. ACT was terminated in case of overwhelming chemotherapy-induced AEs, relapse, or the patients' request for discontinuation. Patients accepting fewer than 4 cycles of ACT were not eligible for analysis.

Patient Assessment and Follow-up
All patients received routine health assessment and disease monitoring at the start of each treatment cycle. We followed up these patients monthly during the first postoperative year, and then quarterly until the last follow-up or death. Relapse was confirmed based on imaging and histological examination. Once relapse was diagnosed, chemotherapy of alternative regimen, radiofrequency ablation, or palliative treatment was implemented.

Statistical Analysis
MedCalc software (version 15.2.2, MedCalc Software, Ltd) was used for statistical analysis and visualization. Quantitative data were shown as mean±SD and compared using the t test. Count data were analyzed using c 2 or Fisher's exact test. Chemotherapy-induced AEs, TNM stage, WHO performancestatus score, and tumor differentiation were compared using Ridit analysis. RFS was the interval time from the initiation of ACT to (i) the last follow-up, (ii) death, or (iii) first relapse. OS was the interval time from the initiation of ACT to death or the last follow-up. RFS and OS curves were created by the Kaplan-Meier method and compared by the log-rank test. Results with P<0.05 were considered statistically significant.

Patient Characteristics
Patient characteristics, including sex, comorbidities, operative procedure, postoperative CA19-9 level, age, tumor differentiation, histological type, TNM stage (on the basis of the 8 th edition of AJCC/UICC staging system) [11], and time from surgery to initiation of ACT did not differ significantly between the 2 groups ( Table 1).

Chemotherapy-Induced Adverse Events and Treatment Outcomes
The severity and incidence of chemotherapy-induced AEs are summarized in Table 2. Patients in the mFFX group experienced significantly more common and severe thrombocytopenia (P=0.0372), fatigue (P=0.0226), nausea/vomiting (P=0.0337), and diarrhea (P=0.0018). Most of the AEs were properly managed by symptomatic therapy and dose adjustment. No chemotherapy-induced death was documented.
The incidence of dose reduction was markedly greater in the mFFX group (14/34 vs 6/37, P=0.0195). Chemotherapy was discontinued in 5 patients of the mFFX group (2 for relapse, 2 for refractory diarrhea, and 1 for grade 4 thrombocytopenia), and 4 patients in the S-1 group (2 for relapse and 2 for refractory hand-foot syndrome). All patients underwent more than 4 cycles of ACT.

Relapse-free Survival
Relapse was confirmed in 23 patients of the mFFX group and 26 patients of the S-1 group, respectively, within 3 years postoperatively. The mFFX group demonstrated a markedly higher 3-year RFS (P=0.0332) and lower hazard ratio (HR) for relapse (0.5577, 95% confidence interval [CI], 0.3138 to 0.9910) than the S-1 group (Figure 1). Sites of first relapse are shown in Table 3.

Overall Survival
A total of 46 patients died within 3 years postoperatively (22 from the mFFX group and 24 from the S-1 group). Compared with the S-1 group, the mFFX group obtained a significantly improved 3-year OS (P=0.0346) and lower HR for death (0.5501, 95% CI 0.3029 to 0.9993) (Figure 2).

Discussion
In this study, we retrospectively analyzed 71 patients with resected pancreatic carcinoma, among whom 34 received the mFOLFIRINOX regimen chemotherapy and 37 received S-1 monochemotherapy. The results indicated that the     mFOLFIRINOX regimen resulted in a markedly improved 3-year RFS and lower HR for relapse compared to the S-1 group in patients with resected PC. The mFOLFIRINOX regimen achieved a significantly improved 3-year overall survival with a lower HR for death.
Pancreatic carcinoma remains a major medical dilemma, with an extremely poor prognosis worldwide [12]. Surgical resection improves survival outcomes. However, 80-85% of the patients were diagnosed at an advanced inoperable stage [13].
Despite the development of surgical techniques, relapse often occurs within 2 years after surgery, most of which are local recurrence and hepatic metastases [14]. Therefore, 5-year survival probabilities after surgical resection alone are unsatisfactory (under 10%) [15].
S-1 is an innovative oral chemotherapeutic agent used for resected gastric cancer in Asian countries [19]. According to recent studies, S-1 conferred a higher response and improved overall survival than gemcitabine in metastatic and resected PC [7,20,21]. Therefore, S-1 monochemotherapy was recognized as a new standard adjuvant chemotherapy regimen for PC. The mFOLFIRINOX regimen is another competitive chemotherapy regimen with superior long-term survival to gemcitabine for resected PC. The MPACA-3 trial compared the efficacy of mFOLFIRINOX with S-1 as second-line chemotherapy in metastatic PC patients who were failed after gemcitabine chemotherapy, and demonstrated an increased overall survival compared to S-1 [22]. However, the efficacy of these 2 regimens as first-line chemotherapy in resected PC has not been compared. So far as we know, this single-center retrospective study was the first to directly compare the efficacy of mFOL-FIRINOX with S-1 as ACT for patients with resected PC.
The safety of these 2 regimens was also compared. Patients who accepted mFOLFIRINOX regimen chemotherapy experienced e937136-5 significantly more common and severe thrombocytopenia, fatigue, nausea/vomiting, and diarrhea. Therefore, the incidence of dose reduction was significantly greater in the mFFX group. Eventually, most of the patients finished treatment, and no chemotherapy-induced death occurred.
The limitations of this study are non-negligible. As a retrospective cohort study, bias in patient enrollment was unavoidable.
Due to the scale of our hospital, the sample size was relatively limited. Hence, we are considering performing a multicentre, prospective, randomized trial.

Conclusions
This retrospective study indicates that if dose adjustment and adverse events management are properly administered, the mFOLFIRINOX regimen chemotherapy can result in better survival than S-1 monochemotherapy for patients with resected PC.

Declaration of Figures' Authenticity
All figures submitted have been created by the authors, who confirm that the images are original with no duplication and have not been previously published in whole or in part.