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

NEOADJUVANT CHEMO-RT FOR PDAC
Experience from definitive chemo-RT for LA-PDAC
Several randomized trials provided evidence that the addition of chemo-RT to chemotherapy is beneficial
for patients with LA-PDAC. In 2011, a randomized trial conducted by ECOG reported 74 patients with LA-
PDAC who received gemcitabine with or without local radiotherapy (total dose 50.4 Gy and 1.8
Gy/fraction) . The quality of life achieved was similar in both groups, while a significantly improved OS
[61]
(median 11.1 vs. 9.2 months) in the chemo-RT arm was noted. Five years later, the LAP07 randomized trial
[62]
on 442 patients was published . Patients were randomized to receive gemcitabine with or without
erlotinib, followed by a second randomization of patients without disease progression at four months. In
this latter phase of the trial, 133 patients received chemo-RT (54 Gy conventionally fractionated RT with
capecitabine). After a median follow-up of 36.7 months, the median OS was similar in all groups. However,
the rate of locoregional progression in the chemo-RT group was significantly lower than the one recorded
for the chemotherapy group (32% vs. 46%). Chemo-RT was well tolerated, as no increase of grade 3-4
toxicities was recorded. Only 6% of the patients recruited in the trial had surgery after chemo-RT.

Low total dose conventionally fractionated photon RT, which applies a low dose per fraction, seems to be
ineffective at suppressing the growth or eradicating PDAC, which is well-known to be radio- and
chemoresistant [63,64] . Large radiotherapy fractions, the application of which has become feasible with modern
radiotherapy techniques including stereotactic approaches, may be more potent against radioresistant
PDAC cells. A study from the MD Anderson Cancer Center recruited a total of 200 patients in a dose
escalation radiotherapy protocol using intensity modulated radiotherapy (IMRT) with simultaneous
[65]
integrated boost (SIB) to deliver a biologically effective dose of 50-70 Gy concurrently with capecitabine .
Patients receiving a dose above 70 Gy had a significantly better OS (median 17.8 vs. 15 months) and
estimated two-year survival rates (36% vs. 19%). The locoregional relapse-free survival was almost doubled
(10.2 vs. 6.2 months). Using biomarkers, the isolation of the group of patients with a high tendency to
develop metastasis could exclude them from radiotherapy and eventually help to identify a subgroup that
[66]
would benefit from the locoregional control offered by RT .
Densely ionizing radiation, produced by proton and heavy-ion linear accelerators, also has potential
advantages. However, these rely on the superior dose distribution and the consequent sparing of normal
tissues, as well as on the specific radiobiology of this type of radiation that kills cancer cells ignoring the
[67]
hypoxic tumor microenvironment and the repair capacity of single DNA strand breaks . Although
randomized trials are not available, phase II trials have provided encouraging results, with a two-year
survival of around 50% [68-70] .

Neoadjuvant chemo-RT for LA/BR-PDAC
[46]
Upfront surgery of presumed operable PDACs results in high rates (up to 60%) of incomplete excisions .
The postoperative survival of patients with involved surgical margins is significantly worse . Based on the
[71]
favorable outcome of patients with rectal cancer receiving neoadjuvant chemo-RT, the hypothesis that
neoadjuvant chemo-RT could also be beneficial in pancreatic cancer is sound. An analysis of 6936 patients
with PDAC, collected from the National Cancer Database, identified 3185 patients who were treated with
[72]
neoadjuvant chemo-RT and 3751 with neoadjuvant chemotherapy . Negative resection margins were
more frequent in the chemo-RT group (86.1% vs. 80%), but postoperative mortality rates were higher (6.4%
vs. 3.6%). There was no survival benefit detected between the two groups.

Several retrospective studies with a relatively low number of patients have reported high resectability rates
[8]
in LA/BR-PDAC treated with FFX with or without radiotherapy . In 2014, a study by Kharofa et al.