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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 9 of 12

rate of 33.6%. A criticism of this study includes the lack of a central review of imaging, and it was up to
investigators to make determinations about whether patients’ disease met protocol-defined criteria for LA-
PDAC.

The more recent NEOLAP randomized phase II trial compared the conversion rate by ITT (from
unresectable to R0/R1 resection status) of GnP vs. GnP followed by FFX as neoadjuvant treatment for LA-
[21]
PDAC . Patients were planned to receive two cycles of GnP, and those without progressive disease were
then randomized to either continuing GnP for two more cycles or switching to four cycles of FFX as
neoadjuvant chemotherapy (GnP-FFX). Of 168 patients, 38 (22.6%) did not meet the criteria for
randomization, with 22 (13%) patients having disease progression. The disease control and surgical
exploration rate for the remaining 130 randomized patients was 78% and 63% respectively in the GnP group
(n = 64), and 68% and 64% in the GnP-FFX (n = 66) group respectively, though these differences between
the groups were not statistically significant. The conversion rate from unresectable to R0/R1 resectable
disease was 35.9% (23/64) in the GnP group and 43.9% (29/64) in the GnP-FFX group, but the difference
was also not statistically significant. The mOS for the overall population was 17.1 months after a median
follow-up of 24.9 months, and there was no statistically significant difference in mOS between the GnP and
GnP-FFX groups (18.5 months vs. 20.7 months respectively). However, there was a significant difference in
survival between those who underwent resection compared to those that did not (27.5 months vs. 13.9
months). The rate of grade 3 or higher AEs were similar between the two treatment groups at approximately
54%, with neutropenia, nausea/vomiting, and biliary obstruction as the most common AEs. The NEOLAP
authors conclude that there is no added benefit of switching from GnP induction chemotherapy to FFX for
LA-PDAC, but that resection is important and associated with long-term survival. This study does not
answer the question of which GnP or FFX induction chemotherapy is superior for LA-PDAC, and further
trials are required to answer this question. However, the resection rate of 36%-44% is significantly higher
than the 4% reported in the LAP07 trial, consistent with the understanding that GnP and FFX are more
active than gemcitabine alone in pancreatic cancer. This is significant as the criteria for LA-PDAC in
NEOLAP allow some CA or SMA involvement in contrast to the criteria used in LAP07, which would make
resection even more challenging. However, it is important to note that NEOLAP planned surgical
exploration after chemotherapy, and is a phase II trial with a smaller sample size.

Another phase II study by Murphy et al. examined total neoadjuvant therapy in patients with LA-PDAC,
mirroring the approach currently used in rectal cancer with both induction chemotherapy and
[19]
chemoradiation therapy prior to planned resection . A total of 49 patients who met NCCN guidelines for
LA-PDAC were given FFX for up to 8 cycles with losartan (25 mg up-titrated to 50 mg daily), an
angiotensin-receptor blocker (ARB), followed by either short-course chemoradiotherapy with capecitabine
(25 Gy/5 fr; 825 mg/m ) if they had resectable disease on re-evaluation, or long-course chemoradiotherapy
2
with capecitabine or fluorouracil (50.4 Gy/28 fr with a vascular boost to 58.8 Gy; capecitabine 825 mg/m ; 5-
2
FU 225 mg/m /day) if they had persistent vascular involvement, with a primary outcome of R0 resection
2
rate. The authors used losartan as anti-cancer therapy based on pre-clinical data demonstrating that ARB
may enhance the delivery of chemotherapy to the tumor. Of 49 patients, 34 (69%) underwent resection. The
R0 resection rate was 61% (30/49 patients). The mOS was 31 months and mPFS was 17.5 months. The
authors conclude that neoadjuvant FFX and losartan combined with personalized chemoradiation can lead
to high rates of R0 resection in patients with LA-PDAC and can prolong survival compared to historical
controls. Criticisms of this study include lack of randomization, personalized treatment delivery (short vs.
long course chemoradiation), and relatively small sample size. Thus, it is difficult to determine how much of
the benefit seen is attributable to the FFX regimen itself, radiation therapy, and losartan.