ESPAC-4 long-term follow-up: shall we choose gemcitabine and capecitabine as adjuvant therapy for elderly and low-risk pancreatic adenocarcinoma following surgical resection?

Pancreatic ductal adenocarcinoma (PDAC) is well known as one of the most aggressive and lethal malignancies, with 5-year overall survival (OS) rates under 20% despite curative-intent surgery (1). It remains the third leading cause of cancer death in the United States, and the persistently high recurrence rates following surgical resection underscore the critical role of adjuvant systemic therapy (2). Over the past decade, the therapeutic landscape of PDAC has evolved substantially, with pivotal trials redefining standards of care. Since the CONKO-001 study demonstrated a clear disease-free survival (DFS) advantage (3,4), several adjuvant studies, including ESPAC-4 (5,6), PRODIGE-24 (7,8), and APACT (9), have been conducted (Table 1). Among these, the ESPAC-4 trial occupies a critical niche by addressing the needs of patients who may not tolerate the most intensive regimen, modified FOLFIRINOX (mFOLFIRINOX; fluorouracil, leucovorin, irinotecan, oxaliplatin).

ESPAC-4 was a large, multicenter, randomized phase III trial that enrolled patients with resected PDAC to receive either gemcitabine monotherapy or gemcitabine in combination with capecitabine (GemCap) for 6 months in the adjuvant setting. Patients were randomized in a 1:1 fashion to receive either gemcitabine (1,000 mg/m² on days 1, 8, and 15 of a 28-day cycle) or GemCap (gemcitabine 1,000 mg/m² on days 1, 8, and 15 of a 28-day cycle plus capecitabine 830 mg/m² twice daily on days 1–21 of each 28-day cycle) for up to six cycles. The trial’s primary endpoint was OS, with DFS and safety serving as key secondary endpoints. At the time of initial publication in 2017, adjuvant GemCap was shown to improve median OS when compared to gemcitabine alone [28.0 vs. 25.5 months; hazard ratio (HR) =0.83; P=0.032] (5). The mature 5-year follow-up data were recently published and demonstrated that this modest but statistically significant survival benefit was durable (median OS: 31.6 vs. 28.4 months; HR =0.83; P=0.31) (6). The most common grade 2–4 toxicities experienced by patients included neutropenia (38%), hand-foot syndrome (7%), and diarrhea (5%), and these high-grade toxicities were observed more frequently with GemCap than gemcitabine monotherapy (5). Overall, the regimen was generally well tolerated in this postoperative population. When comparing the results of ESPAC-4 to other contemporary trials, it is important to consider the different patient populations being represented. PRODIGE 24 was intentionally designed to evaluate adjuvant mFOLFIRINOX in a highly selected, fit population. PRODIGE 24 excluded patients over the age of 80 years, and those with Eastern Cooperative Oncology Group performance status (ECOG PS) >1. Notably, the trial also excluded any patient with post-operative carbohydrate antigen 19-9 (CA19-9) ≥180 U/mL (7). While intended to minimize the inclusion of patients with occult metastatic disease, this decision potentially introduced selection bias into the study, as patients with higher post-operative CA19-9 represent a substantial proportion of real-world PDAC patients. In contrast to PRODIGE 24, ESPAC-4 was designed with broader eligibility criteria; there was no upper age limit, no exclusion based on post-operative CA19-9, and patients with ECOG 1–2 were included (5). By including older patients and those with higher risk features, ESPAC-4 boasted a heterogeneous cohort more representative of routine clinical practice.

For ESPAC-4, subgroup analyses indicated that the greatest benefit was observed in patients with margin-negative (R0) resections and lymph node-negative (N0) disease, where median OS approached 50 months (6). Conversely, although PRODIGE 24 demonstrated a robust overall benefit favoring mFOLFIRINOX, subgroup analyses revealed that survival advantage was not statistically significant in patients who were elderly (≥70 years), had small primary tumors (T1/T2), had N0 disease, or who had R0 resections (8). These findings suggest that for patients with lower-risk pathological features or borderline fitness, the absolute benefit of mFOLFIRINOX over gemcitabine may be modest at best. This further underscores the particular value of GemCap in patients with favorable pathologic features. However, it is worth noting that nodal status in ESPAC-4, and age and T-staging in PRODIGE 24 were not stratification factors during randomization.

The therapeutic landscape for adjuvant treatment of resected PDAC continues to evolve, with recent trials integrating novel immunologic and molecularly targeted strategies (Table 2). APOLLO is a phase II clinical trial evaluating the efficacy of olaparib as adjuvant therapy in patients with PDAC harboring pathogenic mutations in BRCA1, BRCA2, or PALB2 (10). APOLLO is ongoing, and its outcome will help to determine olaparib’s role in the adjuvant treatment of genetically selected PDAC patients.

AMPLIFY-201 was a phase I trial that investigated a lymph node-targeted KRAS-specific amphiphile vaccine (ELI-002 2P) in patients with KRAS G12D or KRAS G12R mutated PDAC or CRC with minimal residual disease following surgical resection and adjuvant therapy (11). ELI-002 2P vaccine induced robust KRAS mutant-specific T-cell responses and led to significant reductions in tumor biomarkers [circulating tumor DNA (ctDNA) or tumor antigen] in 21 patients (84%). In addition, complete biomarker clearance was observed in 6 patients (24%), supporting the potential for ELI-002 2P as an adjuvant therapy for KRAS-mutated cancers, including PDAC.

Autogene cevumeran is an individualized messenger RNA (mRNA)-lipoplex vaccine targeting tumor-specific neoantigens, meaning the vaccine is personalized for each patient based on the mutational profile of their tumor. A phase 1 study investigated autogene cevumeran in the adjuvant setting for PDAC and showed promising early results. Following surgery, patients received anti-PD-L1 immunotherapy, autogene cevumeran, and adjuvant mFOLFIRINOX. The investigational vaccine produced a T-cell response in 50% of the patients (responders), and at a median follow-up of 3.2 years, responders demonstrated prolonged recurrence-free survival compared to non-responders (P=0.007) (12). This emphasizes the potential for personalized mRNA vaccines to take a more prominent role in the adjuvant treatment of PDAC. As research in the field continues, immunologic and molecularly targeted therapies may become a potential complement or perhaps even an alternative to traditional adjuvant cytotoxic chemotherapy.

Until such platforms are validated in larger trials, optimized chemotherapy remains the backbone of treatment in resected PDAC. PRODIGE 24 and ESPAC-4 represent complementary trials that have helped shape the modern landscape of adjuvant therapy in pancreatic cancer. While PRODIGE 24 demonstrated the impressive efficacy of modified FOLFIRINOX, it did so in a highly selected, fit population. As a result, it set the benchmark for survival outcomes at the cost of greater toxicity and limited generalizability to the broader PDAC population. In contrast, ESPAC-4 enrolled a more inclusive cohort, reflecting the heterogeneity seen in clinical practice. Although the survival benefit of GemCap over Gemcitabine was modest compared to mFOLFIRINOX, ESPAC-4 validated GemCap as an evidence-based alternative for patients less suited to aggressive chemotherapy. This dual framework should aid clinicians to develop individualized treatment strategies for patients with resected PDAC. Considering its more tolerable side effect profile and the favorable long-term data in patients with R0 resections and N0 disease, GemCap should be a true consideration in patients with lower-risk pathological features not fit enough for mFOLFIRINOX. In conclusion, ESPAC-4 has served to refine our stratified approach to adjuvant therapy in PDAC. Its long-term data support a durable, clinically meaningful benefit for GemCap in a representative population.

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-25-24/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-25-24/coif). D.W.K. received honoraria from Ipsen. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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