Exploring the role of immunotherapy and radiotherapy in the adjuvant landscape of resected pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is notoriously associated with poor survival outcomes. Even amongst the 15–20% of patients who present with resectable disease, long-term survival remains dismal, with 5-year survival rates of approximately 10–12% (1). The current standard of care following curative resection of PDAC is adjuvant systemic chemotherapy, which has been shown to improve survival (2). While multiagent chemotherapeutic regimes have achieved incremental survival benefit when compared to conventional regimes, a significant proportion of patients continue to experience disease recurrence, particularly amongst those with high-risk features such as close or involved surgical margins and nodal involvement (2). In a bid to improve outcomes following PDAC resection, additional adjuvant strategies, such as immunotherapy and radiotherapy, have been investigated (3,4).

We read with interest a recently published phase 1 study by Hill et al. investigating the use of the adjuvant allogeneic granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced pancreatic tumor cell vaccine (GVAX), low-dose cyclophosphamide, and stereotactic body radiation therapy (SBRT) followed by FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin) in high-risk resected PDAC (5). This carefully designed trial primarily sought to establish the safety and feasibility of an intensified multimodality adjuvant strategy, with exploratory analyses of survival outcomes. Key inclusion criteria were adult patients who underwent curative resection (R0/R1) of PDAC in the head or uncinate process, with pathological staging [per the American Joint Committee on Cancer (AJCC), 7th edition]: I–IIB, T1–2, N0–1, M0. Patients were enrolled sequentially into three treatment cohorts using a mechanistic decision rule modeled on a 3+3 design to determine treatment escalation from one cohort to the next. Cohort 1 evaluated the safety of combining SBRT with FOLFIRINOX. Cohort 2 evaluated the safety of SBRT with modified FOLFIRINOX (mFOLFIRINOX), given that the standard of care shifted from FOLFIRINOX to mFOLFIRINOX at the time of the study. Cohort 3 evaluated the addition of low-dose cyclophosphamide and GVAX to SBRT and mFOLFIRINOX.

A total of 19 patients were enrolled in this study, with 3, 4, and 12 in cohorts 1, 2, and 3, respectively. All 3 patients in cohort 1 experienced grade 3–4 neutropenia, and 2 had grade 3–4 thrombocytopenia during the first two cycles of FOLFIRINOX. Following the protocol-mandated switch to mFOLFIRINOX in cohort 2, no grade 3–4 adverse events were observed, allowing the study to proceed to cohort 3. Of the 12 patients in cohort 3, the number of patients with grade 3–4 neutropenia (1/12, 8%), thrombocytopenia (0/12, 0%), and diarrhea (2/12, 17%) during the first two cycles of mFOLFIRINOX was well below pre-defined safety limits (<40% diarrhea and thrombocytopenia, <60% neutropenia). With a median follow-up of 36 months, secondary exploratory analyses of treatment efficacy showed median overall survival (OS) and disease-free survival (DFS) of 36.2 and 18.2 months, respectively, across the entire cohort. Notably, patients in cohort 3 achieved a median OS of 61.3 months and DFS of 24.1 months, outcomes that compare favorably with those of contemporary adjuvant chemotherapy trials. Taken together, these findings concluded that the studied multimodality treatment regimen of SBRT, immunotherapy, and mFOLFIRINOX was safe and showed favorable survival outcomes compared with contemporaneous trials investigating adjuvant multiagent chemotherapy alone (6,7).

The role of radiotherapy in PDAC treatment has been controversial owing to conflicting results from earlier trials (3). In the context of adjuvant therapy following resection of PDAC, the first trial conducted by the Gastrointestinal Tumor Study Group (GITSG) comparing adjuvant 5-fluorouracil-based chemoradiation followed by maintenance chemotherapy to surgery alone demonstrated a 9-month median OS benefit (20 vs. 11 months) in the former group (8). However, subsequent trials—including the European Organization for Research and Treatment of Cancer (EORTC), European Study Group for Pancreatic Cancer-1 (ESPAC-1), Radiation Therapy Oncology Group (RTOG) 9704, and Capecitabine-based chemoradiotherapy (CapRI) trials—failed to reproduce a survival benefit with adjuvant radiotherapy (9-12). While these trials primarily explored the use of conventional long-course chemoradiation, newer methods of radiation delivery, such as SBRT, offer a shorter treatment duration (1 as opposed to 4–6 weeks), which facilitates inter-digitation with systemic chemotherapy while allowing for a higher biologically effective dose and a more focused treatment field (13). However, gastrointestinal toxicity remains a significant issue in the use of SBRT following pancreatoduodenectomy, particularly with larger target volumes, which can be partially mitigated by high-precision SBRT delivery techniques such as the breath-hold technique [computed tomography (CT)-based] or magnetic resonance imaging-linear accelerator (MRI-LINAC) (14). The results of ongoing trials evaluating the role of adjuvant SBRT for resected PDAC will help shed light on its incremental value beyond adjuvant chemotherapy.

The interest in immunotherapy for PDAC treatment has, in part, been fuelled by successes seen in other conventionally chemotherapy-resistant tumors, such as melanomas and hepatocellular carcinomas (15,16). The evidence supporting the use of immunotherapy in PDAC remains scarce to date, with only pembrolizumab approved for use in microsatellite instability-high (MSI-H) tumors (17). Cancer vaccines represent one of the approaches in immunotherapy that has been studied in PDAC in various phase I/II trials with mixed results to date (18). Cancer vaccines aim to trigger and strengthen patients’ anti-tumoral immune responses, which can be achieved through a multitude of mechanisms. For instance, whole-tumor-cell vaccines contain multiple T-cell epitopes to induce T-cell responses against tumor antigens. Of these, GVAX is one of the most extensively studied vaccines in PDAC treatment, previously shown to improve response rates to immunomodulatory blockade agents, with immune responses further potentiated by the addition of low-dose cyclophosphamide (19-21). Preclinical and translational studies have also demonstrated the synergistic effect of immunotherapy and radiotherapy, establishing the rationale for the multimodality adjuvant regimen evaluated in the present trial (22). Another promising approach is the use of personalized messenger RNA (mRNA) vaccines that encode specific tumor antigens, which are taken up by the patient’s antigen-presenting cells and displayed, thereby triggering anti-tumor T-cell responses (18). One example is cevumeran, which is synthesized in real time from surgically resected pancreatic cancers for use in the adjuvant setting. A phase I study utilising cevumeran with atezolizumab and mFOLFIRINOX as adjuvant treatment after surgically resected PDAC found that patients who mounted a T-cell response to the vaccine had a longer median recurrence-free survival compared to those who did not, setting the basis for further studies examining the role of mRNA vaccines in the multimodality adjuvant treatment setting for PDAC (23).

While the initial exploratory efficacy results from this study appear promising, they should be interpreted cautiously given the trial’s limitations and against the backdrop of ongoing developments in PDAC treatment. Apart from this study’s limited sample size, designed primarily to assess safety rather than efficacy, the specific adjuvant treatments used in this study, viz., those in contemporaneous PDAC cohorts, vary not only in the modalities used but also in the specific chemotherapeutic regimens (6,7). Hence, whether observed differences in survival outcomes are attributable to the addition of radiotherapy and immunotherapy or primarily to differences in chemotherapeutic regimens is unclear.

Moreover, the novel multimodality adjuvant treatment regime evaluated in this study represents one of the many fronts on which treatment of resectable PDAC is being investigated. The reference standard for systemic chemotherapy in PDAC is ever-evolving (as it was during the time frame of this study), and potential shifts in chemotherapeutic paradigms may blunt the additive value of multimodality treatments. While mFOLFIRINOX had previously been the standard of care for systemic chemotherapy across various settings of PDAC treatment, the recently published PACT-21 CASSANDRA trial reported improved event-free survival with PAXG (cisplatin, nab-paclitaxel, capecitabine, and gemcitabine) compared with mFOLFIRINOX in a neoadjuvant setting for resectable and borderline resectable PDAC (24). On another front, the role of neoadjuvant therapy (as opposed to upfront surgery followed by adjuvant therapy) for resectable PDAC has been a topic of considerable interest. While existing trial data have affirmed improved event-free survival with a neoadjuvant approach, the OS benefit remains uncertain. This will be clarified by accrual of further data from ongoing trials.

All in all, this trial affirms the safety profile of a multimodality adjuvant regimen comprising SBRT, immunotherapy, and mFOLFIRINOX, setting the stage for subsequent phase II/III studies to explore its relative efficacy compared with existing standard treatment regimens for resected PDAC.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Gastroenterology and Hepatology. The article has undergone external peer review.

Peer Review File: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0026/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0026/coif). The 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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