Neoadjuvant mFOLFIRINOX for resectable pancreatic cancer: increasing evidence, ongoing challenges

Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the deadliest malignancies, with an improved though still dismal 5-year overall survival (OS) rate of only 12% (1). Surgical resection remains the best chance for long-term survival, but most patients are diagnosed with unresectable cancers, and the majority of patients who undergo successful resection still experience disease recurrence (2). While adjuvant chemotherapy leads to improved OS, a significant proportion of patients are unable to receive it due to declining performance status or rapid recurrence after surgery. These realities have prompted a recent paradigm shift toward the use of neoadjuvant therapy (NT) for patients with localized PDAC, even though strong prospective data have not yet necessarily been accrued (3). While NT has clearly become the standard of care for locally advanced (LA) and borderline resectable (BR) PDAC, its use for potentially resectable (PR) disease remains more controversial due to conflicting evidence of its efficacy (4,5).

In this context, the study by Cecchini et al. provides constructive data regarding the safety and efficacy of NT for PR PDAC. In this single-arm, non-randomized trial at a single institution between 2014–2021, patients with resectable PDAC according to National Comprehensive Cancer Network (NCCN) criteria were prospectively enrolled to receive 6 cycles of neoadjuvant modified FOLFIRINOX (mFOLFIRINOX) followed by surgical resection and 6 cycles of adjuvant mFOLFIRINOX. The primary endpoint was 12-month progression-free survival (PFS), which, in an intention-to-treat fashion, was 67% and exceeded the pre-specified threshold of 50%. The study highlighted a median OS of 37.2 months for all patients, 46.2 months for those who completed NT, and not reached for patients who received all 12 intended cycles of perioperative mFOLFIRINOX and resection. Additionally, the investigators reported compelling data on circulating tumor DNA (ctDNA) and K17 levels, which correlated with patient outcomes, underscoring the potential of these biomarkers as prognostic tools (6).

While the study by Cecchini et al. is intriguing, it must be considered within the context of its limitations and within the broader literature on NT for PDAC. First, its single-arm, non-randomized design limits the ability to draw definitive conclusions about the superiority of NT compared to an upfront surgical approach. Furthermore, the study was conducted at a single institution with a small cohort of 46 patients over 7 years recomend deleting, which limits its generalizability. This small sample size may be partially related to statistical calculations made for its sample size using an alpha of 0.1 and a single-sided P value. Lastly, the protocol did not allow for interim assessments during NT to allow for treatment modification for those not responding.

While the challenges of delivering adjuvant chemotherapy after pancreatic surgery are well known (7), the barriers to delivering NT have only recently been recognized, many of which are highlighted in the trial by Cecchini et al. For example, SWOG S1505 randomized patients with PR PDAC to either neoadjuvant mFOLFIRINOX or gemcitabine/nab-paclitaxel and found that regardless of chemotherapy received, nearly 30% were unable to complete NT and undergo surgical resection (8). More recently, the NORPACT-1 trial randomized patients with PR PDAC to either four cycles of FOLFIRINOX followed by surgery and eight adjuvant cycles, or upfront surgery and adjuvant mFOLFIRINOX for 12 cycles (9). Strikingly, only 60% of patients were able to complete all cycles of NT (9). These results are important as a recent meta-analysis demonstrated pooled resection rates after initiating NT for PR, BR, and LA PDAC of only 77.4%, 60.6%, and 22.2%, respectively (10). The reasons for attrition are incompletely understood but often related to disease progression, therapy-related toxicities, or both (8,11). Addressing attrition is important as failure to undergo resection is significantly associated with worse OS, and surgery remains a key endpoint reflecting patient preferences (12). Future research is needed to further understand and mitigate the factors contributing to attrition, such as chemotoxicity and malnutrition, during NT, with the goal of increasing completion rates, optimizing patient outcomes, and ensuring more patients receive potentially curative surgical resection.

In the era of precision oncology, an improved understanding of individual tumor genomics and molecular profiling of PDAC will become increasingly important to help guide not only targeted therapeutics but also the optimal treatment sequencing. Indeed, emerging evidence suggests that certain molecular subtypes of PDAC exhibit divergent responses to mFOLFIRINOX (13). Early clinical trials of biomarker-driven NTs have recently been conducted for PDAC and others are ongoing (14). Cecchini et al. found that undetectable ctDNA was associated with improved PFS and that higher keratin 17 (K17) expression levels were associated with shorter survival for PDAC patients (6). In clinical practice, carbohydrate antigen 19-9 (CA 19-9) remains the only prognostic and potentially predictive biomarker for patients with PDAC (15). While interesting and hypothesis generating, the prognostic and predictive influence of these specific biomarkers, and others, should be further explored in prospective clinical trials.

In conclusion, we congratulate the authors on completing a well-designed and well-conducted prospective clinical trial of perioperative NT with mFOLFIRINOX and generating compelling biomarker correlates. Nevertheless, the role of NT in patients with PDAC, particularly PR disease, will continue to remain undefined until the completion of the ongoing PREOPANC-III (16) and Alliance A021806 trials (17). Both are large multi-center, randomized controlled trials evaluating neoadjuvant mFOLFIRINOX in PR PDAC. Until then, identifying novel methods of personalizing NT as well as understanding and addressing the challenges to completing NT will hopefully improve outcomes for patients with PDAC. Indeed, recently published consensus best practices for delivering NT may help standardize care delivery and help accomplish this goal (18). Overall, the study by Cecchini et al. represents a positive step forward; however, despite the valuable evidence it provides several challenges for NT administration in PDAC remain unresolved.

Acknowledgments

None.

Footnote

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-135/coif). The authors have no conflicts of interest to declare.

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