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Page 6 of 12 Lo et al. J Cancer Metastasis Treat 2022;8:30 https://dx.doi.org/10.20517/2394-4722.2022.48

[29]
FFX . Thus neoadjuvant trials in patients with BR-PDAC using more active regimens should be studied,
and indeed neoadjuvant FFX is being studied in the currently active PREOPANC-2 trial (NTR7292).

In support of multi-agent chemotherapy, a single-arm phase II trial by Murphy et al. assessed the role of
neoadjuvant FFX for 8 cycles in 48 patients with BR-PDAC, with subsequent chemoradiation with
capecitabine (either short course or long course, if there is persistent vascular involvement after
[15]
chemotherapy) . They found an R0 resection rate of 65% (31/48), with a mPFS of 14.7 months and mOS of
37.7 months . The authors concluded that these outcomes were substantially better than historical controls
[15]
when only adjuvant therapy was used. Furthermore, this strategy appears safe as there were no grade 3
toxicities exceeding 10% and no deaths from toxic effects. However, replication of these impressive results
in a larger RCT will be necessary.

Yet another phase II trial by Reni et al. published in 2018 randomized 54 patients at a single center with
either BR-PDAC or LA-PDAC to GnP with and without cisplatin and capecitabine . The primary
[17]
endpoint was the rate of R0 and R1 resection, though notably only 8/26 patients (31%) in the quadruple-
agent arm and 9/28 (32%) in the GnP only arm actually underwent resection. The R0 rate was 5/8 and 4/9
patients respectively making it difficult to draw definitive conclusions. Furthermore, randomization
between the two arms was uneven as the GnP only treatment arm had a higher proportion of Karnofsky
performance status (KPS) in 90-100 patients (86% vs. 73%) and a higher proportion of BR-PDAC (54% vs.
38%). This uneven distribution of important prognostic factors would likely bias outcomes more favorably
towards the GnP only arm. Interestingly, there were more grade 3-4 adverse events in the GnP only arm,
suggesting that the addition of capecitabine and cisplatin did not significantly increase toxicity. Nonetheless,
the authors conclude that further testing in a phase III trial is needed to determine if there is a benefit to
adding cisplatin and capecitabine to GnP in the neoadjuvant setting. This study also highlights the difficulty
and complexity of conducting and completing neoadjuvant studies in pancreatic cancer, as it requires the
participation of multiple disciplines and stakeholders.

ESPAC-5F was a prospective phase II trial designed to compare upfront resection to neoadjuvant treatment
with GnP, FFX, or chemoradiation with capecitabine (50.4 Gy/28 fr) in patients with BR-PDAC . A total
[16]
of 88 patients were randomized to the four arms and analyzed. The primary outcome was resection rate and
R0/R1 (R1: microscopic margin-positive resection) resection rate by ITT, whereas OS and toxicity were
secondary endpoints. While there was no significant difference in resection or R0 rate between upfront
resections compared to neoadjuvant treatment, the one-year survival rate was significantly improved with
neoadjuvant treatment (77% vs. 40%; HR = 0.27). It is important to note the low sample size and phase II
nature of this study, and also that it has yet to be published in full article format.

In the Alliance for Clinical Trials in Oncology randomized phase II trial A021501 (NCT02839343)
presented as an abstract at ASCO 2021, patients with BR-PDAC of the pancreatic head were randomized to
neoadjuvant FFX without the 5FU bolus [Table 3] with or without subsequent stereotactic body radiation
therapy (SBRT), prior to resection and adjuvant FFX. The primary endpoint was 18-month OS, and was
found to be 67.9% without SBRT and 47.3% with SBRT [32,33] . Amongst those who underwent
pancreatectomy, the 18-month OS was 93.1% and 78.9% respectively. While both treatment arms
outperformed historical controls of 50% 18-month OS, these results suggest that the addition of SBRT did
not improve survival. However, this was only a small study of 126 patients between both arms. This study
has also yet to be published in full article format.