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Page 4 of 23 Koukourakis et al. J Cancer Metastasis Treat 2022;8:38 https://dx.doi.org/10.20517/2394-4722.2022.43

The current establishment of FFX and GnP (gemcitabine/nab-paclitaxel) as preferred regimens for
neoadjuvant treatment of LA-PDAC was preceded by a long period of clinical experimentation with older
drugs and schedules. In 1997, a randomized trial by Burris et al. demonstrated moderately increased
[25]
survival and improved pain palliation, achieved by gemcitabine alone over 5-FU . The addition of cisplatin
to gemcitabine has also been explored with conflicting results. Colucci et al. reported longer median time to
disease progression when gemcitabine and cisplatin were combined vs. gemcitabine alone in patients with
LA-PDAC or metastatic PDAC, while non-statistically significant better overall survival (OS) was
[26]
observed . On the contrary, 10 years later, the randomized phase III GIP-1 study showed that the
combination of cisplatin and gemcitabine conferred no benefit . A subset of LA-PDAC patients with
[27]
[28]
BRCA mutations appear to be more sensitive to platinum drugs and, as per the NCCN guidelines,
gemcitabine-cisplatin is one of the two preferred first-line regimens for locally advanced disease alongside
FFX for patients with known BRCA1/2 mutations . An alternative regimen for advanced pancreatic cancer
[6]
is erlotinib plus gemcitabine. Moore et al. reported that a statistically longer one-year OS can be achieved
through these two drugs combined vs. gemcitabine monotherapy, although the benefit is small . Another
[29]
phase III trial published in 2009 compared gemcitabine monotherapy to gemcitabine plus capecitabine for
the treatment of LA-PDAC and demonstrated significantly better response rates and progression-free
[30]
survival (PFS), as well as a trend towards longer OS with the latter regimen . Finally, a meta-analysis by
Li et al. suggested that gemcitabine plus fluoropyrimidine drugs lead to improved OS in comparison to
gemcitabine alone .
[31]

Towards neoadjuvant FFX and GnP for LA-PDAC
A phase II study by Conroy et al. introduced FFX in 2005 as an effective drug combination for the treatment
[32]
of advanced pancreatic disease , further prompting the PRODIGE phase III trial that cemented the
superiority of this regimen over gemcitabine monotherapy for metastatic PDAC as far as median OS (11.1
vs. 6.8 months), median PFS (6.4 vs. 3.3 months), and objective response rate (31.6% vs. 9.4%) are
concerned . These results have also been supported by a meta-analysis of 13 studies assessing the efficacy
[33]
of FFX over gemcitabine alone with or without subsequent radiation or chemoradiation in LA-PDAC,
which reported a median OS of 24.2 months when FFX was utilized vs. a 6-13 months OS achieved with
[34]
gemcitabine . In addition, FFX rendered LA-PDAC resectable in 76 out of 125 patients (60%) when
analyzed retrospectively , thus exhibiting another potential benefit from its use. The effectiveness of GnP
[35]
was originally addressed in a phase I/II study by Von Hoff et al. . Two years later, the MPACT phase III
[36]
trial, assigning patients with metastatic PDAC to either GnP or gemcitabine monotherapy, displayed longer
median OS (8.5 vs. 6.7 months) and PFS (5.5 vs. 3.7 months) with the combined regimen and expanded the
[37]
available and efficient chemotherapy drugs for this disease .

Following the favorable results obtained in advanced and metastatic PDAC, FFX and GnP were evaluated in
the neoadjuvant setting. A retrospective study comparing FFX and GnP as a preoperative regimen in LA-
and BR-PDAC showed a survival benefit in patients who achieved pathological response and biochemical
marker regression patterns. Both regimens, however, were equally effective, although a better tolerance of
[38]
GnP should be considered when treating frail patients . Another smaller retrospective study confirmed the
equivalence of the two regimens . Neoadjuvant GnP examined in the LAPACT phase II study provided a
[39]
median OS of 18.8 months . The NEOLAP-AIO-PAK-0113 randomized phase II trial, published in 2021,
[40]
investigated whether induction chemotherapy with GnP followed by FFX could yield better outcomes than
GnP alone . Sequential induction chemotherapy was proven to confer similar results to the GnP regimen.
[41]
Overall, applying multidrug induction chemotherapy could be a potential means to overcome the inherent
chemoresistance of this malignancy [Table 1].