Pancreatic ductal adenocarcinoma (PDAC), the incidence of which appears to be increasing worldwide, is associated with a high mortality rate due to its aggressive biological behavior [1]. PDAC was rated as the third leading cause of cancer-related mortality in the USA in 2023 [2]. In Japan, about 39,000 deaths were attributed to PDAC in 2022, and pancreatic cancer was estimated to be the fourth most common cause of cancer death in men and the third in women [3]. While surgical resection is the only hope for cure in patients with PDAC, the resection rate has remained at approximately 20% in recent years [4,5]. In addition, surgery, as the lone treatment strategy, has reportedly been associated with a high recurrence rate and early cancer death. As such, multidisciplinary approaches, including R0 surgical resection combined with neoadjuvant and adjuvant therapies, have been proposed.

With recent advances in chemotherapeutic and chemoradiotherapeutic regimens, evidence of the benefits of neoadjuvant/adjuvant therapies using these novel regimens has been accumulating. Recent prospective studies have suggested that all patients with resectable or borderline resectable (BR) PDAC are candidates for adjuvant treatments (ATs) [6,7]. However, AT cannot be applied in all patients undergoing surgical resection, mainly due to postoperative complications and/or the frailty of patients, or early recurrence. In addition, dose reduction during AT is frequently needed in postoperative patients, resulting in a weakened efficacy of the treatment. From this standpoint, neoadjuvant therapies (NATs) might be more reasonable, because NATs can be applied to more patients scheduled for curative resections, with more reliable treatment intensity [8]. On the other hand, complications associated with NATs may also preclude curative resection in potentially resectable patients, and, at present, there are no measures to predict the benefits/disadvantages of NATs. A number of excellent reviews and meta-analyses have traced the development of NAT/AT for PDAC and discussed its significance [8,9,10,11]. Herein, we discuss some unresolved issues associated with NAT/AT for PDAC. We also provide a review of our experience with neoadjuvant chemotherapy (NAC) using gemcitabine plus S-1 for PDAC.

Evidence for the benefit of adjuvant chemotherapy (AC) for PDAC is well established, and virtually all patients with resectable and BR disease are considered as candidates for AC [6,7]. Various regimens have been utilized for AC, including gemcitabine monotherapy, S-1 monotherapy, combined therapy with gemcitabine plus capecitabine, and modified FOLFIRINOX [12,13,14,15]; evidence of the benefit of gemcitabine plus nab-paclitaxel is, however, still limited [16]. In the SWOG-S1505 study, although the survival outcomes of patients who received adjuvant gemcitabine plus nab-paclitaxel therapy were similar to those of patients who received adjuvant mFOLFIRINOX therapy, the primary endpoints were not met statistically. Therefore, the National Comprehensive Cancer Network (NCCN) guidelines and the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines recommend modified FOLFIRINOX or gemcitabine plus capecitabine as the preferred regimens for AC for patients with PDAC [6,17]. Meanwhile, in Japan, S-1 monotherapy is the mainstay of AC for PDAC [13], mainly due to concerns about the adverse events associated with more powerful and toxic regimens. Regarding AC, completion of the scheduled regimen (usually lasting six months) with a maintained dose intensity is considered to be of critical importance to prevent recurrence and prolong patient survival. Therefore, the selection of the regimen should be patient-based, and meticulous management of the patient during AC is important.

On the other hand, the significance of adjuvant chemoradiotherapy (CRT) has not yet been established. The ESPAC-1 and EORTIC trial 40,891 showed no additional benefit of adjuvant CRT in patients with PDAC [18]; however, in one retrospective cohort study, some patients benefited more from adjuvant CRT than from adjuvant CT [19].

It should be noted that in an AT setting, the response to or effectiveness of the selected regimens cannot be monitored or evaluated, as the tumor has already been removed. In other words, many patients who undergo up-front resection may receive ineffective ATs with significant toxicity without biological information about the tumor. It is from this viewpoint that the concept of neoadjuvant therapy was conceived, as the effect of the selected chemotherapy regimens can be evaluated, at least in part, by the radiological or biological responses.

The necessity of NAT in patients with BR disease has come to be well recognized, and several clinical guidelines recommend NAT for patients with BR PDAC [6,7,17]. Recent meta-analyses have shown the survival benefit of NAT (NAC or NACRT) for BR PDAC [20,21], while any additional benefit of one over the other of NACRT versus NAC remains unclear. In a retrospective analysis of 884 Japanese patients with BR PDAC, NACRT was associated with a lower resection rate, but also a lower rate of lymph node metastasis and lower rate of local recurrence; however, the overall survival was comparable between the NACRT and NAC groups [22].

Recently, the application of NAC has been expanded to resectable PDAC [11,23]. The Prep-02/JSAP05 study showed that NAC using gemcitabine plus S-1 provided significant survival benefit, while the PREOPANC study showed that NACRT using gemcitabine-based NAC and radiotherapy was associated with an improved median survival period [24,25]. Unno et al. conducted a randomized controlled trial of Neoadjuvant Chemotherapy Using Gemcitabine Plus S-1 (NAC-GS) in 362 patients with resectable or BR PDAC with portal vein involvement. Those authors demonstrated a significantly higher median OS in the NAC-GS arm than in the up-front surgery arm and concluded that NAC-GS could be a new standard treatment strategy for potentially resectable PDAC [24]. The PREOPANIC trial assigned patients with resectable or BR PDAC in a randomized manner to treatment with adjuvant chemotherapy (control arm) or perioperative NACRT (test arm). The patients in the control arm received up-front surgery followed by adjuvant gemcitabine-based chemotherapy, while the patients in the test arm received neoadjuvant gemcitabine-based conformal radiation therapy followed by surgery, followed again by another four months of adjuvant gemcitabine-based chemotherapy. The five-year overall survival rates were 20.5% in the test arm and 6.5% in the control arm [25]. However, the results of meta-analyses have been conflicting [8,11]. More recently, the effectiveness of modified FOLFIRINOX in a neoadjuvant setting has been examined [26]. Based on these observations, the current NCCN guidelines recommend up-front surgery followed by AT for patients with resectable PDAC, but they also advise considering NAT in PDAC patients with high-risk features, e.g., equivocal or indeterminate imaging findings, markedly elevated serum CA19-9, large primary tumors, large regional lymph nodes, excessive weight loss, and extreme pain. Recently, BR PDAC has been re-defined using anatomical (A), biological (B), and conditional (C) factors [27]. Biological factors include elevated serum CA19-9 levels, i.e., exceeding 500 U/mL, and/or regional lymph node metastasis, as diagnosed by biopsy or PET-CT. Based on these circumstances, PDAC patients with elevated serum CA19-9 levels are, even if their tumors are anatomically resectable, candidates for NAT and re-assessment of the expected outcome prior to surgery.

Monitoring of the trends of tumor markers, especially the serum levels of CA19-9, is of great importance in patients receiving NAT. The monitoring of serological markers is simple and provides important information regarding the tumor biology. It has been reported that normalization of serum CA19-9 is not achieved in 30% of patients undergoing up-front surgery, and that the beneficial effect of surgery was reduced in these patients. Another retrospective study showed that patients with a normalized serum CA19-9 level during NAT showed better long-term survival than those with persistently elevated serum CA19-9 levels [28]. Thus, normalizing of the CA19-9 level during NAT could be a potential and ideal goal in patients receiving NAT in order to extract the maximum benefit from surgery and to improve survival outcomes. In cases of CA19-9 non-producing tumors, serum DUPAN-2 can be an alternative target for monitoring.