Neoadjuvant FOLFIRINOX in resectable pancreatic cancer: impact of the NORPACT-1 trial

Prior to the area of neoadjuvant treatment in pancreatic cancer, surgery was the treatment of choice in patients with resectable and borderline resectable pancreatic ductal adenocarcinomas (PDAC). In the recently published randomized multicenter phase II NORPACT-1 trial, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX while 63 patients were randomized to upfront surgery and adjuvant FOLFIRINOX (2017–2021) (1). All patients had a resectable PDAC of the pancreatic head and were evaluated in one of the 12 study centers, and chemotherapy was delivered in an additional 26 local hospitals. Only in the neoadjuvant FOLFIRINOX group, cytological or histological confirmation was required, and if the second attempt of pathology did not confirm malignancy, patients were offered upfront surgery. Adjuvant chemotherapy, which had to be started within 12 weeks after resection, was for the first 21 patients gemcitabine plus capecitabine, and it was advised to change it into modified FOLFIRINOX after the results of the PRODIGE-24 trial (2). However, the chosen adjuvant chemotherapy regimen was according to the discretion of the medical oncologist. The authors of the NORPACT-1 trial should be commended for being one of the first on completing a phase II trial of neoadjuvant FOLFIRINOX in patients with resectable PDAC. No survival benefit could be demonstrated in patients who received neoadjuvant FOLFIRINOX [hazard ratio (HR) 1.52, 95% CI: 1.00–2.33]. On the contrary, the primary endpoint (18 months survival by intention to treat) was even better in the upfront surgery arm (1). These results question the role of neoadjuvant FOLFIRINOX in resectable pancreatic cancer.

Over the past decade, an increasing number of randomized controlled trials (RCT) investigating the role of neoadjuvant treatment in (borderline) resectable PDAC have been conducted. Most studies found superior overall survival (OS) in patients who underwent a neoadjuvant approach (3). Neoadjuvant treatment presents various potential advantages, including early control of systemic disease, enhanced delivery of chemotherapy, and improved histopathologic results. Yet, though neoadjuvant treatment is generally considered standard treatment for borderline resectable PDAC, controversy remains about its role in the subgroup of patients with resectable PDAC (4).

A recent meta-analysis by van Dam et al. of seven RCTs found that neoadjuvant treatment improves OS in patients with borderline resectable PDAC (HR 0.61, 95% CI: 0.44–0.85) (3). Consequently, international guidelines recommend a neoadjuvant approach for patients with borderline resectable PDAC (5). Further evidence was required for patients with resectable PDAC (HR 0.77, 95% CI: 0.53–1.12) (3). A more recent meta-analysis, however, showed superior OS of neoadjuvant treatment in patients with resectable PDAC (HR 0.75; 95% CI: 0.58–0.98) (6).

Meanwhile, FOLFIRINOX was shown to be superior in the adjuvant and metastatic settings, and many believe that it may also be the optimal neoadjuvant treatment (2,7). The role of neoadjuvant FOLFIRINOX has been investigated only in large reviews and some phase II trials (Table 1). Most retrospective studies only included patients who had a surgical resection and recovered from surgery. Consequently, these studies suffer from selection bias. In 2018, a pilot study was conducted to assess the tolerability and effectiveness of four cycles of mFOLFIRINOX in resectable PDAC (8). Twenty-one patients participated, with 95% completing the prescribed four cycles of neoadjuvant mFOLFIRINOX. Of these patients, 81% underwent a resection, and 94% had an R0 resection (8). The PANACHE01-PRODIGE48 prospective, multicenter, phase II trial randomized 153 patients with resectable PDAC to 4 cycles of mFOLFIRINOX, FOLFOX or upfront surgery. Only the abstract has been published, showing a 1-year OS rate of 84.1% in the mFOLFIRINOX group, versus 71.8% in the FOLFOX group, and 80.8% in the upfront surgery group (9). More recently, the multicenter phase II NEPAFOX trial randomizing patients with resectable or borderline resectable PDAC into upfront surgery plus adjuvant gemcitabine, or perioperative FOLFIRINOX, was presented. Due to poor accrual, recruitment was prematurely stopped after randomization of 40 patients, of whom 75% were patients with resectable PDAC. The median OS of patients receiving neoadjuvant FOLFIRINOX (10.03 months; 95% CI: 6.25–27.95) was shorter compared to patients in the upfront surgery group (25.68 months; 95% CI: 11.74–not reached) (10).

Recently, the abstract of the PREOPANC-2 trial was presented, encompassing patients with both resectable and borderline resectable PDAC. No difference in OS could be demonstrated between patients treated with neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy (HR 0.87; 95% CI: 0.68–1.12) (11). In 2021, the results of the phase II SWOG S1505 were presented in which 102 eligible patients with resectable PDAC were enrolled and randomized between neoadjuvant FOLFIRINOX and neoadjuvant gemcitabine/NabPaclitaxel. No difference was found in 2-year OS between both groups (12).

To summarize, existing data suggests that for borderline resectable PDAC neoadjuvant approach with gemcitabine or gemcitabine-based radiotherapy is superior to upfront resection (3), and for resectable PDAC neoadjuvant treatment appears to be superior as well (6). In the few RCTs performed so far, neoadjuvant FOLFIRINOX has similar results to neoadjuvant gemcitabine/nab-paclitaxel of gemcitabine-based radiotherapy (9,11). The NORPACT-1 trial is one of the first published RCT comparing neoadjuvant FOLFIRINOX with upfront surgery in resectable PDAC. Below, we will discuss several aspects of the study design and results of the NORPACT study to provide insights for future studies concerning patients with resectable PDAC.

Primary endpoint

The primary endpoint in the NORPACT-1 trial focused on OS at 18 months. The 18-month OS was 60% in the neoadjuvant FOLFIRINOX group versus 73% in the upfront surgery group (P=0.032). In the PREOPANC trial, there was no difference in OS between the neoadjuvant treatment group and the upfront surgery group at the 18-month mark (13). The survival curves demonstrated an initial steep decline that began to diverge only 18 months after randomization, suggesting that long-term survival data may provide a more robust assessment of treatment efficacy. Apparently, it takes time for a superior perioperative approach to impact OS. Only after long-term follow-up, the PREOPANC trial show a statistically significant and clinically relevant difference in OS at 5 years of 20.5% (95% CI: 14.2–29.8%) with neoadjuvant chemoradiotherapy versus 6.5% (95% CI: 3.1–13.7%) with upfront surgery (13,14). The majority of the trials investigating the role of neoadjuvant treatment in pancreatic cancer use OS as primary outcome, with a sufficient needed median follow up for events. The statistical power of NORPACT-1 to distinguish a clinically relevant difference in OS was inadequate due to limited sample size and a median follow up of less than 2 years.

In the NORPACT-1 trial, the median OS was 25.1 months in the neoadjuvant FOLFIRINOX group, compared to 38.5 months in the upfront surgery group (1). The median OS of upfront surgery was far superior to the median OS of other neoadjuvant arms of RCTs. This could be attributed to superiority of adjuvant FOLFIRINOX compared to gemcitabine-based adjuvant regimens. However, both SWOG S1505 and PREOPANC-2 found no improved OS of adjuvant FOLFIRINOX compared to gemcitabine-based regimens (9,11). Moreover, only 19 out of 63 patients (30%) started adjuvant FOLFIRINOX; so it is dubious to attribute the favorable median OS to the effectiveness of adjuvant FOLFIRINOX. Finally, the lower limit of the 95% confidence interval for the median OS was 27.6 months, reflecting uncertainty about this estimate.

Number of cycles of neoadjuvant chemotherapy

In the NORPACT-1 trial, nearly one quarter (22%) of patients in the neoadjuvant group did not receive any neoadjuvant FOLFIRINOX, and only about half (46%) of the patients completed all four cycles of neoadjuvant FOLFIRINOX (1). In the SWOG1505 trial, 75% of patients completed the neoadjuvant treatment (9). The completion of the neoadjuvant treatment proved challenging. This could be explained by the high number of centers (n=38) and by the full dose regimen that was used. The optimal duration of neoadjuvant treatment varies across trials; in most trials neoadjuvant chemotherapy is administered for 2–4 months, followed by adjuvant chemotherapy for another 2–4 months. The 2-month duration of neoadjuvant FOLFIRINOX in this study may be considered too short by some. In the research by Kim et al., it was proposed that patients capable of tolerating chemotherapy would likely benefit from a comprehensive neoadjuvant regimen comprising a minimum of 4 months of neoadjuvant chemotherapy (15). An important finding in this study was that this extensive neoadjuvant regimen did not lose the window of resection. The resection rate reported in this study was 82%, comparable to the resection rate between 55–85% in the meta-analysis of van Dam et al. (3). This is also reported for other primary tumors, in which there is general consensus that 4–6 months of neoadjuvant therapy is optimal (16-18). In the PREOPANC-2 trial, but also the PREOPANC-3 and the ALLIANCE-021806 trial, patients received 4 months of neoadjuvant treatment (11,19,20). In the PREOPANC-3 trial, a CT scan is conducted after 2 months of chemotherapy to assess for progression of disease (19).

Additionally, patients receiving total neoadjuvant treatment showed enhanced pathological response compared to those receiving shorter neoadjuvant treatment (15). Although OS was worse with neoadjuvant treatment in the NORPACT-1 trail, the pathological nodal and margin status were better (1). This could be considered as inconsistent, or pathological response is not an adequate surrogate endpoint.

Adjuvant treatment

Initially, all patients who underwent resection received adjuvant gemcitabine plus capecitabine, four cycles in the neoadjuvant FOLFIRINOX group versus six cycles in the upfront surgery group. Gemcitabine monotherapy could also be administered. Following the results of the PRODIGE-24 trial it was recommended to use modified FOLFIRINOX as adjuvant chemotherapy in the NORPACT-1 trial. Only a minority of patients received adjuvant FOLFIRINOX. In total, only 8 patients (10.4%) in the FOLFIRINOX arm completed all cycles of neoadjuvant and adjuvant chemotherapy. In the FOLFIRINOX group, modified FOLFIRINOX was given to 13 (17%) of 77 patients versus 19 (30%) of 63 patients in the upfront surgery (1). However, adjuvant trials have demonstrated the superiority in OS of adjuvant FOLFIRINOX over the use of gemcitabine alone (HR: 0.64; 95% CI: 0.48–0.86) (2). Regarding the changes in adjuvant chemotherapy protocols after the 2018 amendment, it is important to emphasize that the shift from gemcitabine-capecitabine to FOLFIRINOX likely resulted in variations in treatment intensity, which could confound the interpretation of the trial’s results. In addition, the role of adjuvant chemotherapy following neoadjuvant treatment is also under investigation. In a retrospective cohort study by van Roessel et al., adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection was associated with improved survival, specifically in patients with positive lymph node involvement (21).

Neoadjuvant FOLFIRINOX or chemoradiotherapy?

The majority of existing evidence concerning neoadjuvant treatment in patients with resectable PDAC has focused on neoadjuvant gemcitabine-based chemoradiotherapy. In two meta-analyses published, the HR for neoadjuvant treatment in resectable PDAC were 0.77 (95% CI: 0.53–1.12) (3) and 0.75 (95% CI: 0.58–0.98) (6). Given the dense stromal component characteristic of PDAC, radiotherapy has the potential to disrupt this tumor stroma, thereby facilitating improved chemotherapy delivery to the tumor site. This synergistic effect may enhance chemotherapy efficacy and reduce local recurrence rates. The PREOPANC-2 trial could not demonstrate a difference in OS between neoadjuvant chemoradiotherapy and neoadjuvant FOLFIRINOX (13). Ablative radiotherapy (biologically effective dose ≥100 Gy) in just a few fractions can minimize interference with systemic therapy (22,23) and should be further investigated in RCTs.

In conclusion, the NORPACT-1 trial found no superiority in 18 months survival in patients with resectable PDAC who underwent neoadjuvant FOLFIRINOX compared to upfront surgery. In contrast, upfront surgery provided superior outcomes compared to neoadjuvant treatment. The key concerns regarding the interpretation of the results are the limited number of patients that received all neoadjuvant and adjuvant cycles of chemotherapy and the low number of neoadjuvant cycles (4 instead of the more frequently used 8 cycles). Two RCTs are currently accruing patients. In the PREOPANC-3 trial, 378 patients with resectable PDAC will be randomized in 24 centers (20 Dutch, three Norway and one Sweden center) to 8 cycles of neoadjuvant FOLFIRINOX (and 4 adjuvant cycles) or to surgery followed by 12 cycles of adjuvant FOLFIRINOX. In the ALLIANCE-021806 trail, 352 patients with resectable PDAC from the US and Canada are randomized between 8 cycles of neoadjuvant mFOLFIRINOX followed by 4 cycles of adjuvant mFOLFIRINOX or upfront surgery followed by 12 cycles of adjuvant mFOLFIRINOX. The PREOPANC-3 and ALLIANCE-021806 trials are both at two-thirds of accrual and will together provide a more definitive answer regarding the role of a neoadjuvant FOLFIRINOX in resectable PDAC.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-51/coif). J.W.W. reports research funding from Servier, MSD, Nordic and consulting fees from AstraZeneca, MSD and Servier. The other authors have no conflicts of interest to declare.

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