1. Introduction
Pancreatic cancer (PC), one of the most lethal cancers, is the seventh leading cause of cancer-related deaths worldwide and the fourteenth most common cancer [
1]. By 2030, PC is predicted to become the second leading cause of cancer mortality in Western countries [
2]. Although radical resection is the only curative treatment for PC, most patients are diagnosed with unresectable or metastatic disease, with resectable tumors reported in only 20% of the cases at diagnosis [
3]. Despite curative resection, most patients develop postoperative recurrence, and the prognosis, including that for unresectable and metastatic stages, remains unsatisfactory, with the 5-year overall survival rate being 6% [
4].
Neoadjuvant chemotherapy (NAC) is an effective strategy for improving R0 resection and prognosis in patients with resectable (R) and borderline resectable (BR) PC. The Prep-02/JSAP-05 study showed that NAC with gemcitabine plus S-1 (GS) afforded a significant survival advantage over upfront surgery for patients with R and BR PC [
5]. After fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine with nab-paclitaxel (GnP) were shown to improve the prognosis of patients with advanced PC, regimens such as NAC were introduced [
6,
7,
8,
9]. Among these regimens, FOLFIRINOX is associated with a high incidence of adverse events (AEs) and therefore has limited indications. In Japan, the modified FOLFIRINOX (mFOLFIRINOX) regimen, in which rapid intravenous 5-FU (bolus 5-FU) is omitted and the irinotecan dose is reduced to 150 mg/m
2 to decrease the toxicity of FOLFIRINOX therapy, is widely used as the standard therapy. However, it is more toxic than GnP and is not administered to patients older than 75 years of age [
10]. Currently, there are no prospective randomized trials to evaluate the efficacy and toxicity of mFOLFIRINOX in patients older than 75 years. Compared with non-elderly patients, elderly patients often have concomitant conditions, including heart disease, hypertension, and diabetes, and are considered to have higher risks associated with chemotherapy. Because the number of elderly patients has been increasing rapidly in recent years, it remains to be determined whether NAC can be performed in both non-elderly and elderly patients. Surgical opportunities should not be missed due to associated AEs during NAC in patients with R and BR PC. Hence, this study was aimed at evaluating the safety and feasibility of neoadjuvant mFOLFIRINOX in elderly patients with PC.
4. Discussion
In this study, we analyzed the outcomes in elderly patients with PC who were treated with neoadjuvant mFOLFIRINOX and compared them with those in non-elderly patients. The safety and feasibility of the treatment in elderly patients were similar to those in non-elderly patients. Therefore, age should not be a limiting factor for NAC application.
Compared with upfront surgery, NAC has been shown to improve survival outcomes in patients with R and BR PC [
5,
16,
17,
18,
19,
20]. However, there are few studies on the efficacy of chemotherapy including mFOLFIRINOX, which is an aggressive multi-agent chemotherapy, in elderly patients aged >75 years with PC. Additionally, the effectiveness of pancreatic surgery in this age group is also not well documented [
17,
21,
22,
23]. Oba et al. compared the outcomes in elderly patients with BR PC and those with locally advanced PC who received neoadjuvant FOLFIRINOX or GnP. The study population was divided into three age groups: <70, 70–74, and >75 years. They concluded that the safety and efficacy of NAC in elderly patients were similar to those in young patients. However, in their study, elderly patients aged >75 years were less likely to receive FOLFIRINOX compared with patients aged 70–74 and <70 years (35% vs. 50% vs. 80%,
p < 0.001). No treatment-related FOLFIRINOX toxicity was observed. FOLFIRINOX may be selected for administration in elderly patients with a good physical status. In our study, an mFOLFIRINOX regimen was used considering the increased toxicity of the FOLFIRINOX regimen. The major grade 3 or 4 AE in our study was neutropenia (prevalence of 46% in the elderly group and 48% in the non-elderly group). These rates were similar to those reported in previous metastatic cohort studies [
9]. Because severe neutropenia was manageable with granulocyte colony-stimulating factor, febrile neutropenia was observed in one patient in each group. Surgical resection following NAC was performed in 87% and 74% of the elderly and non-elderly patients, respectively. These results suggested that neoadjuvant mFOLFIRINOX was tolerable for patients with PC including those aged >75 years. A grade 5 pneumonitis was observed in one non-elderly patient with BR PC. NAC probably should not have been administered to this patient, as he had multiple comorbidities, including an old myocardial infarction, chronic obstructive pulmonary disease, and diabetes mellitus. Patients receiving NAC should be carefully selected considering their comorbidities.
Pancreatic surgery is one of the most challenging and complex types of abdominal surgery. Although improvements in surgical techniques and perioperative management have reduced hospital mortality, the rates of postoperative complications such as pancreatic fistula, bile leakage, and delayed gastric emptying remain high (up to 50%) [
24,
25,
26]. Compared with non-elderly patients, elderly patients often have concomitant conditions and are considered to have higher risks associated with surgery. Some studies reported that the rates of complications and mortality in elderly patients were higher than the corresponding rates in younger patients, while others reported that they were comparable [
24,
27,
28,
29,
30,
31]. Our study showed no difference in the occurrence of POPF and major postoperative complications (C-D > IIIA) between the elderly and non-elderly groups. Furthermore, there was no postoperative mortality and the duration of postoperative hospital stay was similar between the two groups. Pancreatectomy following NAC can be safely performed, even in elderly patients.
In the intention-to-treat-based analysis, PFS and OS rates in the elderly group treated with NAC were similar to those in the non-elderly group. Among the 49 patients who underwent pancreatectomy, no differences in either RFS or OS were observed between different age groups. Previous studies have reported poor OS in elderly patients who underwent pancreatectomy for PC, although the postoperative complication rates were similar between elderly and non-elderly patients [
31,
32]. The authors demonstrated that the rate of adjuvant chemotherapy (AC), a prognostic factor for PC, was significantly lower in elderly patients than in young patients. S-1 monotherapy, which is the standard AC in Japan, was used in our study [
33]. Our study showed no difference in the rate of AC between the elderly and non-elderly groups. Therefore, elderly patients may have comparable prognoses in terms of OS and RFS. In Western countries, AC with mFOLFIRINOX has been considered the standard therapy based on the results of the PRODIGE-24 trial [
34,
35]. However, grade 3 and 4 AEs developed in 75.9% of patients who received mFOLFIRINOX. Therefore, this regimen should be limited to patients with good performance status. Indeed, some elderly patients may not complete AC because of postoperative complications, impaired organ function, or poor tolerance. In contrast, NAC offers some advantages such as (1) downstaging of the size of the primary tumors, (2) early administration and high tolerance of systemic therapy, (3) treatment of clinically undetectable microscopic metastatic disease, and (4) avoidance of unnecessary surgery in patients with progressive disease. In a recent large cohort study using the National Cancer Database, 5086 patients with PC aged >70 years were allocated to upfront surgery and AC (51.7%), upfront surgery only (29.9%), and NAC (18.4%) groups [
36]. One-third of patients treated with NAC received AC. NAC was associated with a higher R0 resection rate and better OS than upfront surgery with or without AC. NAC may be an effective strategy for improving R0 resection and prognosis in elderly patients.
This study had several limitations. First, this was a retrospective study conducted at a single institution, resulting in a limited number of patients and selection bias. The elderly patients in this study might have had a good general condition because 65% of the elderly patients had a 0–1 CCI and 78% had a G8 of ≤14. Therefore, it is necessary to conduct comprehensive geriatric assessments rather than performing age-based analyses alone. Prehabilitation programs should be considered according to physical and psychological status. Second, NAC dose reduction or discontinuation had no specific criteria. Third, the follow-up period was short, and long-term follow-up is needed to reveal clinically relevant survival differences. To overcome these limitations, further large-scale prospective studies are required.