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Lo et al. J Cancer Metastasis Treat 2022;8:30 https://dx.doi.org/10.20517/2394-4722.2022.48 Page 7 of 12

Ongoing systemic therapy trials in BR-PDAC
There are a multitude of ongoing trials to further study neoadjuvant therapy for BR-PDAC. As mentioned
above, the PREOPANC-2 study (NTR7292) is a randomized phase III trial comparing OS (by ITT) between
neoadjuvant FFX vs. neoadjuvant chemoradiation with gemcitabine in resectable and BR-PDAC. Another
randomized phase II trial called PANDAS-PRODIGE 44 (NCT02676349) aims to compare neoadjuvant
mFFX with or without chemoradiation with capecitabine for patients with BR-PDAC, with a primary
outcome of R0 resection rate .
[34]

With numerous phase II and recent phase III RCT studies published in the last few years, data supporting
neoadjuvant therapies is starting to emerge for BR-PDAC. At present, it is difficult to recommend a
definitive strategy due to the significant heterogeneity amongst the studies, including the definition of BR-
PDAC used, the inclusion of other risk groups of PDAC in the same study (i.e., resectable, locally
advanced), the surgical skill of the cancer center, variations in the neoadjuvant chemotherapy regimen, the
use of concurrent chemoradiation or radiation alone, and the outcome measures assessed (i.e., OS by ITT,
per protocol, or other proxy measures such as R0 resection rates, relapse rates, and PFS). Accrual to high-
quality prospective trials is encouraged to determine the most effective strategy for this population.

LOCALLY ADVANCED DISEASE (LA-PDAC)
Locally advanced PDAC is considered to be surgically unresectable. It is defined in the NCCN guidelines as
follows [Table 4].

Systemic therapy in LA-PDAC
As discussed earlier in the BR-PDAC section, a phase II trial by Reni et al. randomized 54 patients at a
[17]
single centre with either BR-PDAC or LA-PDAC to GnP with and without cisplatin and capecitabine .
This study was not powered sufficiently to draw conclusions about the superiority of either treatment arm
with respect to the primary outcome of R0/R1 resection rates. Furthermore, this study did not analyze
patients by resectability classification (ex. BR-PDAC or LA-PDAC), choosing to group both populations
together in their analysis. While these two entities exist on a spectrum, they arose due to differences in
resectability at the time of diagnosis, have different baseline risks for poor outcomes, and should be
examined separately.

A systematic review and patient-level meta-analysis on neoadjuvant FFX for patients with LA-PDAC was
published in 2016 . This review included studies up to July 2015, with a primary outcome of OS.
[35]
Secondary endpoints included PFS, proportion of patients receiving radiation/chemoradiation, rates of
grade 3 or 4 AEs, rates of surgical resection, and R0 resection rates. A total of 13 studies were included (689
patients), but only 315 patients had LA-PDAC and were eligible for patient-level meta-analysis of survival.
The pooled mOS was 24.2 months, with a mPFS of 15 months. The grade 3 and 4 AE rate was
approximately 60%, though no deaths were attributable to FFX toxicity. Radiotherapy was given after
neoadjuvant FFX in 63.5% of patients, but there was no significant association found between radiotherapy
and OS. The resection rate was approximately 26%, with an R0 resection rate of 78%. Criticisms of this
meta-analysis include the fact that none of the included studies had randomization and the vast majority
(11/13) were retrospective in nature, thus leading to potentially significant selection and sampling bias.
Nonetheless, this study provided some evidence that neoadjuvant chemotherapy was able to convert a
subset of patients with unresectable disease due to vessel involvement, to a state where an R0 resection was
achievable. Unfortunately, the contributory role of radiotherapy to resectability was not determined.
Achieving an R0 resection is important because it represents the only chance for long-term survival and
cure, but high-level evidence of whether neoadjuvant systemic therapy followed by resection leads to