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Koukourakis et al. J Cancer Metastasis Treat 2022;8:38 https://dx.doi.org/10.20517/2394-4722.2022.43 Page 9 of 23

suggested that induction chemotherapy followed by chemo-RT (total dose 50.4 Gy and 1.8 Gy/fraction with
[73]
gemcitabine or capecitabine) results in 70% resectability with negative margins in 98% of cases . The study
comprised 39 patients with borderline resectability and 30 resectable cases. The local failure at two years was
impressively low (9%), and 23% of operated patients were alive without disease at the time of analysis
(median follow-up of 47 months). Another retrospective study by Katz et al. included 129 patients with BR-
[74]
PDAC treated with gemcitabine-based chemo-RT . Resectability was obtained in 66% of patients (95% R0
resection), and the median OS reached 33 months. In 2022, a report by Hill et al. analyzed 198 patients , 76
[75]
of whom had received neoadjuvant chemotherapy and 122 chemo-RT with stereotactic body radiation
therapy (SBRT) technique. SBRT offered significantly higher complete resectability rates (92% vs. 70%) and
negative node histopathology (59% vs. 42%). Of interest, a pathologic complete response (pCR) rate of 7%
was recorded. However, there was no survival benefit from SBRT (two-year OS rate of 50.4%).

Nevertheless, phase II and a small number of phase III trials have provided encouraging results in LA/BR-
PDAC [46,73-85] , as shown in Table 2. In 2018, a phase II study from the Massachusetts General Hospital
reported 48 patients with BR-PDAC who were treated with eight cycles of FFX . Patients who achieved
[82]
resolution of the vascular involvement (56%) were further treated with hypofractionated accelerated proton
radiotherapy (5 Gy × 5 fractions) with capecitabine, while the rest of the patients received long course
chemo-RT (total dose 50.4 Gy and 1.8 Gy/fraction) with capecitabine or 5-FU. Tumor resection was feasible
in 32/48 patients, with R0 resection obtained in 97% of cases. The overall two-year PFS rate was 43%, while
the median PFS for operated patients reached 48.6 months. The two-year OS rate for this latter group of
patients was 72%.

A Korean study published in the same year enrolled 50 patients with BR-PDAC to receive preoperative
chemo-RT with gemcitabine vs. upfront surgery and adjuvant chemo-RT . The resectability rates were
[83]
significantly higher in patients receiving neoadjuvant chemo-RT (51.8% vs. 26.1%) and the two-year OS rate
was significantly better in the neoadjuvant arm (40.7% vs. 26.1%).

Early results of the ESPAC-5F multicenter randomized phase II trial were reported at the 2020 ASCO
[46]
congress . Patients with BR-PDAC were recruited in a four-arm study (upfront surgery vs. neoadjuvant
gemcitabine/capecitabine vs. neoadjuvant FFX vs. neoadjuvant chemo-RT). An early analysis of 88 patients
showed a benefit in the neoadjuvant arms in terms of one-year survival rate (77% vs. 40%). There are no
data available on the role of RT yet. In contrast, the A021501 randomized phase II trial did not demonstrate
a survival benefit in patients with BR-PDAC who received SBRT or hypofractionated RT after neoadjuvant
mFOLFIRINOX when compared to patients that received mFOLFIRINOX alone (median OS 29.8 vs. 17.1
months for the chemotherapy alone and chemotherapy plus RT arms, respectively) .
[84]
The PREOPANC randomized trial, published in 2020, included 246 patients who were treated with
preoperative chemo-RT vs.upfront surgery . Patients had BR/R-PDAC and were randomized to receive
[86]
upfront surgery vs. neoadjuvant chemo-RT with gemcitabine, followed by surgery and postoperative
gemcitabine chemotherapy. The R0 resection rates were better in the RT group (71% vs. 40%). The DFS and
locoregional control were also improved in the RT arm, while a benefit in survival was also noted (median
OS 35.2 vs. 19.8 months). Long-term results of the PREOPANC study were published in 2022, and the five-
year OS rate was significantly better in the chemo-RT arm (20.5% vs. 6.5%), despite the rather small 1.4
months difference in median survival (15.7 vs. 14.3 months in the chemo-RT and upfront surgery arms,
respectively) . Moreover, the first results of a randomized phase III trial (CONKO-007) comparing
[87]
induction chemotherapy (GnP or FOLFIRINOX) followed by additional chemotherapy cycles or chemo-RT
(RT + gemcitabine) for patients with advanced PDAC were reported in the 2022 ASCO Annual Meeting I.