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Other chemotherapy regimens have been applied in phase II trials for BR/LA-PDAC. A randomized phase
II study on a four-drug combination (gemcitabine, nab-paclitaxel, cisplatin and capecitabine) vs. sequential
[48]
nab-paclitaxel and gemcitabine suggested improved OS in the multidrug arm . Two additional phase II
studies [49,50] on gemcitabine with capecitabine or S-1 are also mentioned in Table 1, which summarizes
published phase II/III trials on neoadjuvant chemotherapy for PDAC.

R-PDAC
Although R-PDAC has not been clearly defined, it is commonly accepted that it should not abut or encase
the regional vascular structures, namely SMA, CHA, and CA. It is undetermined whether the involvement
of SMV and PV contributes to the resectability of this tumor; in the event of contact between tumor and
[6]
SMV, it should be limited to less than 180° without disrupting the venous contour in all respects .
Due to the lack of sufficient evidence from clinical trials and studies supporting the superiority of
neoadjuvant therapy over upfront surgery, the latter is considered as a standard-of-care treatment in
resectable tumors despite the high postoperative morbidity rates. Nevertheless, neoadjuvant treatment has
gradually gained ground recently, thanks to some favorable results from completed trials. In a pilot study,
no benefit in OS and disease-free survival (DFS) was demonstrated in patients who received neoadjuvant
chemotherapy with gemcitabine and oral S-1 over patients who underwent surgical resection .
[51]
Heinrich et al. conducted a prospective phase II trial comparing neoadjuvant chemotherapy with
gemcitabine and cisplatin to the resection-first option and reported an OS of 26.5 vs. 19.1 months,
[52]
respectively, and a similar DFS between the two arms (9.2 vs. 9 months) . O’Reilly et al. proved in a phase
II, single-arm trial that neoadjuvant gemcitabine and oxaliplatin may offer surprisingly long OS (27.2
[53]
months) and DFS (30.6 months) . Similarly, neoadjuvant gemcitabine and S-1 offered a median OS of 34.7
in R0 patients . The most promising results were published in the PREP-02/JSAP05 phase II/III
[54]
randomized trial, which showed that neoadjuvant chemotherapy (gemcitabine and S-1) has a statistically
significant superiority in OS (36.7 vs. 26.6 months in the upfront surgery group) . Al-Batran et al. reported
[55]
a phase II/III randomized study (NEPAFOX trial) comparing upfront surgery with adjuvant gemcitabine-
based chemotherapy (Arm A) to perioperative FFX (Arm B). The results, however, were disappointing;
median OS was 25.68 (Arm A) vs. 10.03 (Arm B) months, respectively, while median PFS was also lower
[56]
among patients who received neoadjuvant chemotherapy . In 2020, the SWOG S1505 phase II trial
demonstrated that neither neoadjuvant FFX nor GnP for R-PDAC was associated with a statistically
significant improvement in two-year OS when compared to the a priori threshold of 40% (41.6% and 48.8%
[57]
with FFX and GnP, respectively) . Surgical results from the same trial display an 85% R0 resection rate in
patients who underwent surgery (95%), while complete or significant pathologic response with systemic
treatment was achieved in 33% of patients . The final results of the NEONAX randomized phase II trial
[58]
comparing neoadjuvant GnP (followed by surgery and adjuvant GnP) with upfront surgery followed by
[59]
adjuvant GnP for patients with R-PDAC were published . Perioperative GnP was associated with a longer
median OS (25.2 vs. 16.7 months). The authors suggested that this difference in OS could be attributed to
more patients receiving chemotherapy preoperatively and fewer patients proceeding to adjuvant
chemotherapy in the upfront surgery arm. Similar to the NEONAX trial, the efficacy of neoadjuvant
FOLFIRINOX for patients with R-PDAC was investigated in the PANACHE01-PRODIGE48 randomized
[60]
phase II study ; one-year OS rates were 84.1% and 80.8% for patients who received neoadjuvant
chemotherapy with FOLFIRINOX and upfront surgery, respectively, indicating that preoperative treatment
for R-PDAC is a sound option and demands further investigation. The above trials are summarized in
Table 1.