Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with an overall 5-year survival rate of 8% (1). Radical resection is currently the only treatment that can increase the 5-year rate of survival to 10-25% (2-5). However, only around 20% of patients suffering from PDAC are suitable candidates for radical resection at the time of diagnosis due to the lack of early symptoms or to its aggressive nature (4,6).

Because of the poor prognosis even in the patients with resectable PDAC (rPDAC), adjuvant chemotherapy has commonly been performed. Its introduction has improved prognosis and is one of the factors mainly associated with long-term survival. Despite the use of the most effective regimens, such as modified FOLFIRINOX, the recurrence rate of the disease still remains high, with a disease-free survival rate at 5 years of only 26.1% (7). This poor outcome can be caused by early recurrence and the significantly higher rate of an incomplete resection compared to resection for other gastrointestinal cancers. Therefore, effective neoadjuvant chemotherapy (NAC) is being sought for patients with rPDAC. The results of various randomized controlled trials of NAC for rPDAC such as NEONAX (8), SWOG S1505(9), and the NORPACT-1 study (10) have been reported. In Japan, the Prep-02/JSAP05 trial was the first to show a survival benefit of NAC with gemcitabine plus S-1 (GS) in patients with resectable PDAC, and NAC-GS is now the standard regimen for rPDAC in Japan (11,12). Nevertheless, as it remains controversial whether NAC is actually required for rPDAC (13), the importance of NAC and whether NAC-GS is appropriate therapy for rPDAC require examination.

Staging laparoscopy (SL) has been shown to identify small peritoneal or liver metastases not observed in preoperative imaging (14,15). For patients with distant occult metastases, SL is more beneficial than exploratory laparotomy due not only to its lower invasiveness but also rapid patient recovery, which consequently leads to early induction of chemotherapy (15,16). Therefore, it is meaningful to identify the patients at possible risk of distant metastasis from PDAC.

Therefore, the aim of this study was to investigate the benefits of NAC for patients with rPDAC.

The survival benefits of UpS and adjuvant therapy for rPDAC remain limited, but NAC may result in an improved outcome. NAC offers the following advantages over UpS: elimination of micro-metastases before surgery and a high tolerance rate among patients. These advantages can contribute to improvement in the rate of negative margin resection, reduced nodal involvement, and better survival. However, there are two concerns regarding this approach: risk of tumor progression and toxicities during NAC. Furthermore, NAC-related adverse events could worsen the patient's condition, thereby delaying surgery and potentially depriving them of a chance for a cure.

In this patient series, NAC-GS was started from 2020 for all patients diagnosed as having rPDAC preoperatively, and all patients were treated with GS. We compared UpS and NAC and found that the NAC group showed early delivery of the therapy and no unresectable conditions after NAC. All 12 patients in whom SL revealed occult distant metastases were treated with UpS. Furthermore, NAC did not appear to reduce the complexity of the surgery and showed a high rate of R0 resection. Compared with UpS, NAC was not inferior in terms of perioperative factors, and importantly, the rate of recurrence-free survival at 6 months was significantly lower with NAC. These results suggest that NAC-GS may be a suitable regimen for rPDAC, although the response rate of NAC-GS was relatively low.

Some randomized controlled trials for NAC have been reported. The NEONAX study (8) showed an R0 resection rate of 88% and median OS of 25.5 months in the patients who were treated with GnP, whereas NAC could not be shown to prolong RFS, which was the primary endpoint. SWOG S1505(9) reported the short-term outcome of patients who were treated with modified FOLFIRINOX or GnP. This report showed a high tolerance to these systemic therapies by the patients, successful surgical resection without prohibitive perioperative complications, and a major pathologic response rate of 33%. Immunotherapy using pembrolizumab in NAC has also been reported, and no additive effects were shown (20). Randomized ongoing trials are eagerly awaited with more active combined regimens including modified FOLFIRINOX (21).

Our study showed that occult distant metastases were still found in 7% of the patients with PDAC when performing SL. It is difficult to predict unresectable cases preoperatively, and we reconfirmed the benefit of SL for the patients potentially having rPDAC. SL has a precise effect in identifying patients with unsuspected unresectable lesions and, therefore, in decreasing the number of unnecessary laparotomies. Stefanidis et al reported that SL could identify unsuspected metastases in a significant proportion of patients (15-51%) (22). Karabicak et al also reported that occult distant metastases could be detected by SL in 20% of patients with PDAC although the diagnostic accuracy of CT has improved (23). Therefore, SL is a valuable option for PDAC staging. Nevertheless, some reports noted that SL was not recommended in all cases for two reasons: the number of occult cancers detected by SL has decreased due to the increased sensitivity of CT, and the cost-effectiveness of SL (24,25). However, some papers supported the cost-effectiveness of SL (26,27). In their recent guidelines, the Japan Pancreas Society also recommended performing SL when distant metastasis cannot be ruled out in patients with resectable or locally advanced pancreatic cancer (28). De Rosa et al reviewed 24 studies to try to identify indications for SL (29) and concluded that patients with rPDAC identified by CT and who have a CA19-9 level ≥150 U/ml or tumor size >3 cm should be considered for SL.

The limitations of this study include its retrospective study design and small number of patients. Thus, it will be necessary to examine long-term outcomes to further clarify the significance of NAC-GS administration.

In conclusion, surgery after NAC can be performed safely, and NAC for rPDAC is useful in terms of rapid induction of the treatment, fewer occult distant metastases, and lower rate of early recurrence.