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Page 12 of 23 Koukourakis et al. J Cancer Metastasis Treat 2022;8:38 https://dx.doi.org/10.20517/2394-4722.2022.43

median survival was 31 months.

More recent phase II studies continue to provide encouraging results from neoadjuvant chemo-RT. A study
[85]
from Japan recruited 57 patients (33 resectable tumors) , treated with hypofractionated RT (total dose 30
Gy and 3 Gy/fraction) and S-1 chemotherapy. The two-year OS was 83% in resectable tumors and 58% in
tumors with borderline resectability. In 2015, the first ever randomized phase II trial (University of
[93]
Erlangen) was published . Although this was terminated prematurely due to low recruitment rates, 66
patients were analyzed. Patients were randomized to receive primary surgery or neoadjuvant chemo-RT
(total dose 50.4 Gy and 1.8 Gy/fraction) with four weekly cycles of gemcitabine and cisplatin. The study
confirmed good tolerance, but there was no difference in terms of efficacy.

NEOADJUVANT TARGETED THERAPIES FOR PDAC
PDAC is a tumor with extensive activation of multiple growth and metastasis-related molecular pathways.
Overall, four major pathways are active. The KRAS gene is frequently mutated, which leads to the
overactivation of the RAF-MEK-ERK and PI3K-AKT/mTOR pathways . Furthermore, mutations of the
[94]
EGFR gene are common in PDAC. The EGFR pathway also intersects with the insulin growth factor IFG-1
pathway, both promoting growth and migration properties of the cancer cells [95,96] . Angiogenic pathways
involving VEGF secretion and VEGF-receptor overexpression by the neo-vasculature also characterize a
subgroup of PDACs . In addition, the hepatocyte growth factor receptor (Met) pathway regulates cancer
[97]
cell interactions with the tumor stroma and cancer-associated fibroblasts, promoting stromatogenesis,
[98]
invasion, and metastasis . Finally, a subgroup of patients with BRCA1/2 mutations suffer from DNA repair
deficiency, which is a potential target for the development of molecular therapy .
[99]

Targeting agents against KRAS and downstream pathways have mainly focused on RAF and MEK
[100]
inhibitors. Direct inhibition of KRAS with pharmacological agents is problematic for several reasons .
Trametinib, a MEK inhibitor, has some potential in the treatment of PDAC, as a randomized phase II study
showed benefit in combination with gemcitabine, with a longer duration of response . Promising results
[101]
have also been published regarding the concurrent administration of trametinib with pembrolizumab and
RT in locally recurrent PDAC . Moreover, the combination of trametinib with the autophagy inhibitor
[102]
chloroquine is being assessed in an ongoing trial for advanced PDAC (NCT03825289), but there are no
trials in the neoadjuvant setting. AKT inhibition with the MK-2206 agent has shown activity in PDAC, and
two clinical studies have been completed in advanced and metastatic disease (NCT01658943,
NCT01783171).

Anti-EGFR therapies have been tested against PDAC. Randomized phase III trials on the combination of
cetuximab monoclonal antibody (MoAb) with different gemcitabine, irinotecan, and cisplatin combinations
failed to improve the survival of patients with metastatic disease . A phase III trial comparing gemcitabine
[103]
with or without erlotinib showed prolongation of the PFS . The GEMCAD 10-03 phase II trial published
[29]
in 2018 combining neoadjuvant gemcitabine and erlotinib with RT in R-PDAC provided encouraging
results, suggesting further trials should be conducted with neoadjuvant erlotinib . Moreover, a recent
[104]
phase I/II trial showed benefit in terms of OS when combining the IGF-1R antagonist with gemcitabine and
[105]
erlotinib in advanced disease, suggesting a potential value in the neoadjuvant setting .

Specific anti-VEGF or anti-VEGF-receptor agents, e.g., bevacizumab and ramucirumab, respectively, have
not shown any efficacy in combination with chemotherapy for PDAC . Broad spectrum multitarget
[106]
tyrosine kinase inhibitors (MTKIs), e.g., sunitinib, sorafenib, imatinib, and axitinib, have displayed limited
activity in PDAC [107,108] . In a phase III trial, axitinib failed to show a benefit in combination with gemcitabine