Page 20 - Read Online

Lo et al. J Cancer Metastasis Treat 2022;8:30 https://dx.doi.org/10.20517/2394-4722.2022.48 Page 5 of 12

Table 3. FOLFIRINOX and gemcitabine plus nab-Paclitaxel chemotherapy regimens for locally advanced unresectable or metastatic
pancreatic adenocarcinoma
FOLFIRINOX (FFX) a Gemcitabine plus nab-Paclitaxel (GnP)
2 2
• Oxaliplatin 85 mg/m IV (over 2 h) on Day 1, then • Nab-Paclitaxel 125 mg/m IV on Days 1, 8, and 15
2
2
• Leucovorin 400 mg/m IV (over 2 h) on Day 1, then after 30 min • Gemcitabine 1000 mg/m IV on Days 1, 8, and 15
2
• Irinotecan 180 mg/m IV concurrently with leucovorin (over 90 min), then
2
• 5-Fluorouracil 400 mg/m IV bolus on Day 1, then
2
• 5-Fluorouracil 2400 mg/m infusion (over 46 h) on Day 1
To be repeated every 14 days (one cycle) until disease progression or toxicity; 12 cycles To be repeated every 28 days (one cycle) until
are recommended for patients who are responding disease progression or toxicity
a 2
A modified FFX regimen (mFFX) uses a lower dose of irinotecan at 150 mg/m and also omits the 5-fluorouracil bolus; FOLFIRINOX (5-
fluorouracil, leucovorin, irinotecan, oxaliplatin). IV: Intravenous.
Since the meta-analysis, a number of subsequent trials have been published to further investigate the role of
neoadjuvant systemic therapy for BR-PDAC, especially given the lack of RCT data. A Korean phase II/III
RCT by Jang et al. of neoadjuvant chemoradiation with gemcitabine (n = 27) vs. upfront resection (n = 23)
followed by adjuvant chemoradiation in patients with BR-PDAC was published in 2018 . Both treatment
[14]
arms also received four cycles of adjuvant gemcitabine. The primary outcome was 2-year OS by ITT
analysis, and this trial is one of the first RCTs that demonstrated a survival benefit for a neoadjuvant
approach for BR-PDAC. In the overall population of 50 patients, the mOS was 16mo, with a 2-year OS of
34%. However, patients who received neoadjuvant treatment had superior 2-year OS and mOS of 40.7% and
21 months, compared to those who underwent upfront resection (26.1% and 12 months). The R0 rate was
also higher at 51.8% vs. 26.1%. These results were found at an interim analysis after 50% enrollment, and the
study was terminated early due to the definite difference in mortality rate between the neoadjuvant and
upfront resection groups.

Subsequently, a similar but larger phase III Dutch RCT named PREOPANC studied neoadjuvant
chemoradiation therapy with gemcitabine (n = 120) vs. upfront resection (n = 128) in patients with either
resectable PDAC (54%) or BR-PDAC (46%). Both treatment arms also included adjuvant gemcitabine after
resection. The primary outcome was OS by ITT analysis. The initial report did not demonstrate a survival
benefit with neoadjuvant chemoradiation , however, with a longer median follow-up of 59 months, a
[31]
modest median survival advantage with neoadjuvant chemoradiation was found (15.7 vs. 14.3 months; HR =
0.73) . This survival advantage was maintained in the subgroup of patients with BR-PDAC only (HR =
[13]
0.67). The 5-year OS in the overall population was 20.5% vs. 6.5%, suggesting that a subgroup of patients
may have significantly longer-term responses to neoadjuvant treatment than the average patient. It is also
notable that only 55/120 patients in the investigational arm, and 65/128 patients in the control arm
completed their assigned treatment (at least one cycle of adjuvant gemcitabine), again highlighting the
importance of ITT analyses in this population. Thirteen patients (11%) in the investigational arm also did
not proceed to surgery after chemoradiation due to progression or unresectable/metastatic disease at the
time of response evaluation. A significantly higher proportion of patients in the investigational arm also
achieved an R0 resection compared to the group that had upfront resection (41% vs. 28%). A criticism of the
study includes a higher proportion of ECOG 0 in the interventional arm (58% vs. 39%) suggestive of
unequal randomization. Like the Jang et al. study, it remains to be determined how much of the benefit of
neoadjuvant therapy can be attributed to chemotherapy vs. radiation, or if the benefit is the result of the
[14]
combination as gemcitabine is a potent radiosensitizer . Although both studies demonstrated a survival
benefit, a significant difference was observed as early as one year in the Jang et al. study, whereas no survival
[14]
benefit was seen up to 27 months of follow-up in PREOPANC . This may be a result of the differences in
sample size of the two trials. As mentioned previously, since the conception of these two trials, multi-agent
[28]
chemotherapy has established superiority over gemcitabine alone in metastatic PDAC, such as GnP and