Another chapter in the tale of FOLFIRINOX in the management of pancreatic ductal adenocarcinoma: do the results in the locally advanced setting fall short of expectations?

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies in humans. With a growing epidemiological burden, it is expected to become the second leading cause of cancer-related death in developed countries by the end of the decade (1). Despite recent developments in patient care, the 5-year overall survival (OS) rate of patients with PDAC is only 13% (2), highlighting the need for innovative therapies to tackle this disease.

Despite minor variations in its definition across classifications, locally advanced PDAC (LAPC) is characterized by major (≥180°) arterial involvement and/or venous invasion in which venous resection and reconstruction is not feasible (3). It represents roughly 30% of all patients with newly diagnosed PDAC (4). In the dawn of randomized clinical trials (RCTs) assessing the role of systemic therapy in the management of LAPC, chemotherapy and early chemoradiation followed by maintenance chemotherapy were compared in the 2000-01 FFCD/SFRO and ECOG trials (5,6). These studies showed controversial findings and further analyses showed 30% of patients with LAPC experience systemic disease progression within three months of radiotherapy (7), indicating that upfront systemic therapy should be the standard-of-care. Indeed, a few retrospective studies suggested induction chemotherapy was associated with improved survival (8,9). Henceforth, induction chemotherapy became standard-of-care in the management of LAPC.

Given the propensity of PDAC to disseminate systemically, the improved efficacy of systemic therapy, and the benefits associated with induction chemotherapy in retrospective studies, the role of chemoradiation in the management of LAPC started to be challenged. In the LAP07, 269 patients with LAPC were randomized to either capecitabine-based chemoradiation or two further cycles of gemcitabine (with or without erlotinib) (10). There were no differences in OS and chemoradiation was associated with a non-statistically significant benefit in progression-free survival (PFS) and an increased treatment-free interval. Accordingly, in the CONKO-007, which used FOLFIRINOX as the induction regimen for most patients, chemoradiation did not lead to improved OS when compared to continuation of chemotherapy (11).

Altogether, these studies not only show that many patients with LAPC can be spared from the side effects of upper abdominal chemoradiation, but also suggest that the choice of the induction regimen is important. In this sense, only recently have RCTs designed to establish the optimal induction chemotherapy regimen been conducted (Table 1). In the GAP trial, induction treatment with gemcitabine plus nab-paclitaxel (GnP) was associated with a superior overall response rate (ORR) and PFS (but not OS) when compared to single-agent gemcitabine (12). In turn, in the Japanese JCOG 1407 phase II RCT, 126 patients were randomized to receive mFOLFIRINOX or GnP as induction chemotherapy (13). There were no differences in ORR, PFS, or OS between arms, despite a slightly higher depth of response for patients treated with GnP (14).

When compared to single-agent gemcitabine, FOLFIRINOX has been proven to confer improved outcomes for patients with PDAC both in the adjuvant and metastatic settings, based on the findings of the PRODIGE 24/CCTG PA.6 and PRODIGE 4/ACCORD 11 studies, respectively (15,16). However, a direct comparison between FOLFIRINOX and gemcitabine in the upfront treatment of patients with LAPC was lacking. Nonetheless, in June’s edition of the Journal of Clinical Oncology, Ducreux et al. published the data on the PRODIGE 29-UCGI 26 (NEOPAN) study, which randomized patients with pathologically-proven LAPC [according to National Comprehensive Cancer Network (NCCN) 2012 guidelines] to receive either modified FOLFIRINOX [no 5-fluorouracil (5FU) bolus] or single-agent gemcitabine for six months as upfront therapy (17). After this period, patients could have treatment stopped, continue to receive either maintenance 5FU (in the FOLFIRINOX arm) or gemcitabine, or close treatment with conventional or stereotactic radiotherapy. The primary outcome of the study was PFS. Thirty French centers enrolled 171 patients from March 2015 to January 2022. After a median follow-up of 59.6 months, treatment with FOLFIRINOX was associated with improved median PFS [9.7 vs. 7.7 months; hazard ratio (HR) =0.66; P=0.02]. However, there was no difference in median OS between groups (15.7 vs. 15.4 months; HR =1.00; P=0.99). As expected, ORR favored FOLFIRINOX (42.4% vs. 15.1%); yet, resection rates were low in both treatment arms, with 6% and 5% of patients submitted to resection in the FOLFIRINOX and gemcitabine arms, respectively. The toxicity profile in both arms was reassuring and consistent with that observed in other clinical trials evaluating these regimens. Finally, the authors observed no differences in quality-of-life metrics between arms.

By the end of the six-month period, 33% of patients in the FOLFIRINOX arms and 24% in the gemcitabine arm had received some form of radiotherapy. Importantly, a higher proportion of patients in the FOLFIRINOX arm received subsequent lines of chemotherapy after progression (77% vs. 64%), a factor that could have biased results in favor of this regimen. A similar proportion of patients in both groups were treated with FOLFIRINOX at progression (15% each). Given the activity of FOLFIRINOX in metastatic PDAC, the finding that only 15% of patients in the gemcitabine arm eventually received FOLFIRINOX is particularly intriguing. This may reflect the lack of evidence supporting FOLFIRINOX in the advanced setting after gemcitabine-based chemotherapy in Western populations, the older median age of patients compared with other trials, or a worsened performance status after progression, despite the relatively short scan interval (8 weeks).

Given these results, the PRODIGE 29-UCGI 26 (NEOPAN) study is considered positive, meeting its primary end-point of increasing PFS with FOLFIRINOX over gemcitabine. However, the magnitude of benefit appears less pronounced in locally advanced disease than in the adjuvant (HR =0.58) and metastatic (HR =0.47) settings (15,16). Moreover, PFS curves begin to diverge only after the 6-month landmark, indicating therapies given after this period might have affected the outcome. Indeed, before tumor progression, 53% of patients in the FOLFIRINOX arm received additional therapies (including 33% treated with radiotherapy), while only 42% in the gemcitabine arm received such treatments (including 24% treated with radiotherapy). Therefore, regardless of the negative results of the LAP07 and CONKO-007 trials, radiotherapy is frequently used as a consolidation therapy in patients with LAPC. Indeed, the use of radiotherapy in this setting might be motivated by multiple factors, including symptom control, the goal of improving tumor response and resectability, or providing a chemotherapy-free interval. However, one cannot rule out that the use of radiotherapy after six months contributed to the lack of OS benefit in the PRODIGE 29-UCGI 26 (NEOPAN) study. In this study, the majority of patients received conventional chemoradiation instead of stereotactic body radiation therapy (SBRT). In this sense, retrospective studies using SBRT have demonstrated improved OS compared with conventional radiotherapy, especially when higher doses of radiotherapy [biologically effective dose (BED) ≥70 Gy] are used (18), and prospective studies evaluating the role of modern radiotherapy techniques such as stereotactic magnetic resonance (MR)-guided on-table radiotherapy (SMART) and ablative radiotherapy (A-RT) are ongoing.

While the PRODIGE 29-UCGI 26 (NEOPAN) study was not powered to demonstrate improvement in OS, previous trials comparing these two regimens demonstrated large differences in this outcome. Similar results regarding PFS and OS were seen in the GAP trial, suggesting that FOLFIRINOX and GnP lead to similar outcomes for patients with LAPC, as shown in the JCOG 1407 trial. Furthermore, given the lack of OS difference and relatively small benefit in PFS in favor of FOLFIRINOX, single-agent gemcitabine could still be considered a valid option for older patients or those with compromised performance status, especially in the absence of significant tumor-related symptoms. Also, despite higher response rates than usually reported in the localized setting, very few patients in both arms underwent surgery, suggesting these patients had very advanced local diseases not amenable to resection. These data strongly deviate from those of other studies evaluating resection rates for patients with LAPC. A previous meta-analysis demonstrated that one quarter of patients with LAPC treated with induction FOLFIRINOX are submitted to resection, most of them with negative microscopic margins (R0 resection) (19). LAPC has been shown to be a heterogeneous entity, with attempts at subclassification by some groups (20-22). It is probable that the anatomical heterogeneity across studies might explain the differences in resection rates. However, these classifications are based on anatomical grounds only. In this sense, the recent Trans-Atlantic Pancreatic Surgery (TAPS) Consortium classification is considered an improvement in prognostication for patients with localized PDAC (23); however, it also does not take into consideration the molecular mechanisms underpinning tumor progression. In this sense, further efforts should try to generate models that add the tumor molecular features to the currently available prognostic variables in an attempt to better comprehend the clinical behavior of these tumors.

It is important to highlight that, in the PRODIGE 29-UCGI 26 (NEOPAN) study, advanced staging techniques were not mandatory. In a recent Italian study, the combination of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET-CT) and staging laparoscopy identified occult metastases in one third of the patients with borderline resectable and locally advanced PDAC (24). Moreover, diffusion-weighted imaging (DWI) with magnetic resonance imaging (MRI) might identify additional patients with hepatic metastases (25). That said, it is possible that many patients indeed presented metastatic disease and probably should be better treated with FOLFIRINOX given the results of the PRODIGE 4/ACCORD 11 trial. Also, for these patients, maintenance chemotherapy after the 6-month induction period sounds more reasonable than local therapies and some of them could be spared from radiotherapy should their true staging be known at the time of treatment initiation.

While the PRODIGE 29-UCGI 26 (NEOPAN) study answers important questions, the field has moved to evaluate the activity of combinations of chemotherapy and additional local or systemic therapies (Table 2). The recent LAPIS trial compared the activity and safety of chemotherapy (GnP or FOLFIRINOX) with either the monoclonal antibody pamrevlumab [directed against the connective tissue growth factor (CTGF)] or placebo in the setting of LAPC (26). There were no differences in OS (the study’s primary outcome) and PFS. Surprisingly, the ORR was higher in the placebo arm. Despite these disappointing results, other studies using innovative techniques have shown promising results. In the PANOVA-3 trial (27), patients with LAPC were randomized to receive GnP with or without tumor-treating fields (TTF), a local therapy that uses electric fields to disrupt critical processes involved in cancer viability and progression (28). The addition of TTF was associated with improved median OS (16.2 vs. 14.2 months; HR =0.82; P=0.04)—the study’s primary outcome—and, in a post-hoc analysis, benefits in distant metastasis-free survival (13.9 vs. 11.5 months; HR =0.74; P=0.02). Despite the lack of gains in PFS or local disease PFS, the PANOVA-3 is the first study demonstrating improved OS in LAPC, and the addition of TTF to GnP can be considered an option in this setting. Additionally, preliminary data from the TIGeR-PaC study suggest improved OS and PFS of intra-arterial gemcitabine as maintenance therapy after induction chemotherapy and radiotherapy when compared with maintenance GnP (29).

In summary, the PRODIGE 29-UCGI 26 (NEOPAN) trial adds another important chapter to the evolving role of FOLFIRINOX in LAPC. While the study met its primary endpoint with an improvement in PFS, the absence of OS benefit and the low resection rates underscore the limitations of systemic therapy alone in this setting. These findings highlight both the progress achieved with intensified chemotherapy and the unmet need for more effective multimodal strategies that incorporate modern radiotherapy techniques, innovative systemic agents, and refined patient selection tools, including molecular profiling and advanced staging modalities. Future research should aim to integrate these elements in order to move beyond disease stabilization and toward meaningful survival gains for patients with LAPC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Pancreatic Cancer. The article has undergone external peer review.

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-25-23/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-25-23/coif). The author has no conflicts of interest to declare.

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