In an attempt to increase the R0 resection rate of patients with locally advanced PDAC, our institution has used preoperative gemcitabine-based chemoradiation therapy (GEM-CRT ) since February 2005 [5–7]. Although the benefits of preoperative CRT in this clinical scenario have been suggested by others [8–10], the extent to which histopathologic response to CRT is associated with survival in this setting has historically been unclear. We therefore explored the relationship between histopathologic response (as determined by evaluation of UICC-T3 and T4 PDAC tumors resected following GEM-CRT) and prognosis and found that in T3 tumors, histological response was a significant prognostic indicator, whereas in T4 tumors, GEM-CRT did not lead to a beneficial histological response [5]. Furthermore, we examined the relationship between the intratumoral expression of human equilibrative nucleoside transporter (hENT1, the main GEM transporter into cells) in the resected specimens and the outcome of GEM-CRT in patients with T3 and T4 PDAC [6]. We showed that the hENT1 expression in PDAC cells was strongly associated with the outcome of preoperative GEM-CRT treatment, suggesting that this biomarker might represent a useful predictor of the effect of gemcitabine-based therapies. From these studies, we concluded that GEM-CRT, even when used for patients with advanced PDAC, allowed for the identification of candidates for aggressive resection at the time of reassessment, facilitated an increase in the R0 resection rate, and improved the prognosis of patients with positive hENT1 expression [7].

Our treatment protocol for preoperative GEM-CRT was used to treat 124 PDAC patients from February 2005 to October 2011, and thereafter we switched our protocol to S-1/GEM-based CRT (S-1/GEM-CRT) which was used to treat 96 patients from November 2011 to September 2014 (Fig. 17.6). Although we initially referred to our protocol as neoadjuvant or preoperative CRT [5, 6], we subsequently adopted the term “CRT followed by surgery (CRT-S)” because approximately half of the patients registered in the protocol were staged as having unresectable PDAC—for these patients, the term “preoperative treatment” was not appropriate [7]. S-1 is an oral agent that contains tegafur, gimeracil, and oteracil [11], and the agent appears at least equivalent to or even more active than 5-FU when combined with radiotherapy for locally advanced PDAC [12, 13]. Recently, a randomized phase III study of GEM plus S-1, S-1 alone, or GEM alone in patients with locally advanced and metastatic PDAC (GEST Study) showed that monotherapy with S-1 demonstrated noninferiority to GEM in overall survival with good tolerability and that GEM plus S-1 significantly improved progression-free survival as compared with GEM [14].

The surgical outcomes of all 220 patients enrolled in our CRT-S protocol are shown in Table 17.2. Staged using NCCN criteria [3], there were 18 patients (8.2 %) with resectable tumors, 106 (48.2 %) with borderline resectable tumors and 96 (43.6 %) with unresectable tumors. The resection rate was significantly lower in patients with unresectable tumors (44.8 %) as compared to those with BR tumors (76.4 %). Combined resection of PV was aggressively performed in BR and in LUR: 90.1 % and 88.4 %, respectively. The R0 resection rate was also significantly lower in LUR (58.1 %) as compared to R (100 %) and BR (86.4 %). Survival curves according to the three resectability groups (R, BR, and LUR) in the total 220 patients and in the 135 patients who underwent curative-intent resection after CRT are shown in Figs. 17.7 and 17.8, respectively. Survival was significantly different among the three resectability groups: 5-year survival rates of 41.0 % (R), 24.2 % (BR), and 4.4 % (LUR) were observed in all treated patients, and 5-year survival rates of 68.6 % (R), 29.3 % (BR), and 9.5 % (LUR) were observed among patients who underwent resection.

CA19-9 has been accepted as a measure of PDAC burden; however, the role of CA19-9 in the evaluation of patients with preoperative CRT prior to planned surgical resection has not been well evaluated. Previously, we explored whether serum CA19-9 levels could be used as an index of response to GEM-CRT, especially in BR-PDAC patients [7]. By comparing the level of pre-CA19-9 with that measured at the time of reassessment (post-CA19-9), the reduction rate was calculated as follows: (pre-CA19-9–post-CA19-9)/(pre-CA19-9) (%). When the reduction rate was greater than 50 % regardless of the pre-CA19-9 level, GEM-CRT was defined as being effective. Survival curves for the 43 BR-PDAC patients were analyzed according to the CA19-9 reduction rate. The 3-year survival rate was significantly higher in 23 patients who had a CA19-9 reduction rate of 50 % or more than in 20 patients who had a CA19-9 reduction rate less than 50 % (36.6 % vs. 7.9 %, P = 0.0003). In the present cohort study using 102 BR-PDAC patients in whom serum levels of CA19-9 could be reassessed after GEM-CRT or S1/GEM-CRT, the 3-year survival rate was significantly higher in 60 patients who had a CA19-9 reduction rate of 50 % or more than in 42 patients who had a CA19-9 reduction rate less than 50 % (37.0 % vs. 21.0 %, P = 0.011) (Fig. 17.9). As compared to the previous study, the 3-year survival rate in patients who had a CA19-9 reduction rate less than 50 % improved from 7.9 % to 21.0 %, while in patients with a CA19-9 reduction rate of 50 % or more, it did not change (36.6 % vs. 37.0 %).