Objective: This randomized phase II/III study evaluated the superiority of neoadjuvant therapy with gemcitabine plus S-1 over upfront surgery for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Background: PDAC is a leading cause of cancer mortality that urgently requires better treatment. Methods: Patients with resectable PDAC (without arterial abutment) were randomly assigned to upfront surgery or neoadjuvant chemotherapy with gemcitabine (1000 mg/m ² days 1 and 8) and S-1 (40–60 mg orally twice daily, days 1–14 every 3 wk for 2 cycles). Phase II and III primary endpoints were resection rate and overall survival, respectively. UMIN Clinical Trials Registry number: UMIN000009634. Results: Patients (n=364) were enrolled and randomly allocated to upfront surgery (UPS; n=182) or neoadjuvant gemcitabine plus S-1 (NAC-GS; n=182). Patient demographics and tumor characteristics were balanced between groups. Median overall survival in the UPS and NAC-GS groups was 26.6 (95% CI: 21.5, 31.5) and 37.0 (95% CI: 28.6, 43.3) months, respectively. The hazard ratio for mortality in the NAC-GS group compared with the UPS group was 0.73 (95% CI: 0.56, 0.95; P =0.018). Median relapse-free survival in the UPS and NAC-GS groups was 11.3 (95% CI: 9.41, 13.5) and 14.3 (95% CI: 11.7, 17.0) months, respectively. The hazard ratio for relapse in the NAC-GS group compared with the UPS group was 0.77 (95% CI: 0.61, 0.98; P =0.030). Conclusions: The Prep-02/JSAP05 trial results showed that neoadjuvant chemotherapy with gemcitabine plus S-1 significantly extends survival compared with upfront surgery in patients with resectable PDAC.

Carbohydrate antigen (CA) 19–9 levels after resection are considered to predict prognosis; however, the significance of decreased CA19–9 levels after neoadjuvant therapy has not been clarified. This study aimed to define the prognostic significance of decreased CA19–9 levels after neoadjuvant therapy in patients with pancreatic adenocarcinoma. Between 2001 and 2012, 240 consecutive patients received neoadjuvant therapy and subsequent resection at seven high-volume institutions in Japan. These patients were divided into three groups: Normal group (no elevation [≤37 U/ml] before and after neoadjuvant therapy), Responder group (elevated levels [> 37 U/ml] before neoadjuvant therapy but decreased levels [≤37 U/ml] afterwards), and Non-responder group (elevated levels [> 37 U/ml] after neoadjuvant therapy). Analyses of overall survival and recurrence patterns were performed. Uni- and multivariate analyses were performed to clarify the clinicopathological factors influencing overall survival. The initial metastasis sites were also evaluated in these groups. The Responder group received a better prognosis than the Non-responder group (3-year overall survival: 50.6 and 41.6%, respectively, P = 0.026), but the prognosis was comparable to the Normal group (3-year overall survival: 54.2%, P = 0.934). According to the analysis of the receiver operating characteristic curve, the CA19–9 cut-off level defined as no elevation after neoadjuvant therapy was ≤103 U/ml. The multivariate analysis revealed that a CA19–9 level ≤ 103 U/ml, (P = 0.010, hazard ratio: 1.711; 95% confidence interval: 1.133–2.639), tumor size ≤27 mm (P = 0.040, 1.517; (1.018–2.278)), a lack of lymph node metastasis (P = 0.002, 1.905; (1.276–2.875)), and R0 status (P = 0.045, 1.659; 1.012–2.627) were significant predictors of overall survival. Moreover, the Responder group showed a lower risk of hepatic recurrence (18%) compared to the Non-responder group (31%), though no significant difference in loco-regional, peritoneal or other distant recurrence were observed between groups (P = 0.058, P = 0.700 and P = 0.350, respectively). Decreased CA19–9 levels after neoadjuvant therapy predicts a better prognosis, with low incidence of hepatic recurrence after surgery.

The prognosis of pancreatic adenocarcinoma is dismal. Hence, advances in multidisciplinary treatment strategies, including surgery, are urgently needed. Early recurrence of distant organ metastases suggests that there are occult metastases even in cases with resectable disease. Several randomized controlled trials on adjuvant chemotherapy have been conducted to prolong survival after resection. CONKO-001 study was the first to demonstrate significant improvement in disease-free survival after surgery with gemcitabine administration. The JASPAC-01 study showed the superiority of adjuvant S1 over gemcitabine in survival after resection. Based on the results, adjuvant S1 therapy is the prescribed standard of care in Japan. Recently, the PRODIGE 24/CCTG PA.6 study showed that survival of patients treated with a modified FOLFIRINOX regimen as adjuvant therapy was significantly longer than those treated with adjuvant gemcitabine therapy. Although the evidence from these trials on adjuvant chemotherapy have been the gold-standard treatment for curatively resected and fully recovered patients, resectable disease at diagnosis is not the status, resected disease after curative resection. Currently, neoadjuvant therapy is considered to be a promising alternative to surgery for pancreatic cancer. Although there are many reports regarding neoadjuvant chemoradiotherapy, so far there has been no solid evidence proving the advantage of this strategy versus standard up-front surgery. Newly obtained results from the Prep-02/JSAP05 randomized phase II/III study, comparing neoadjuvant therapy with up-front surgery, revealed significant improvement in overall survival with neoadjuvant chemotherapy by intention-to-treat analysis. Thus, neoadjuvant intervention might become a new standard strategy in cases undergoing planned resection for pancreatic cancer.

Although upfront surgery has been the gold standard for pancreatic adenocarcinoma that is planned for resection, it should be compared with the alternative strategy of neoadjuvant therapy. Despite the many reports of the efficacy of neoadjuvant therapy, most of them were not comparative. Recently Prep‐02/JSAP05 study clearly demonstrated the significant survival benefit of neoadjuvant chemotherapy over upfront surgery for pancreatic adenocarcinoma that is planned for resection. These findings opened a new chapter of neoadjuvant therapy. Ongoing trials are expected to confirm the evidence. This review summarizes the past, present, and future perspectives of neoadjuvant therapy and its optimization.