Stereotactic body radiotherapy in pancreatic ductal adenocarcinoma: interpreting the results of the SPAN-C trial

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor outcomes despite advances in local and systemic therapy (1). In patients with localized disease, radiotherapy has been explored in different clinical contexts, but its role has been debated for many years. Earlier studies failed to demonstrate a clear benefit of conventional radiotherapy or chemoradiation in terms of disease control and survival, which limited its integration into standard treatment strategies (2-4).

With conventional radiotherapy, the safe delivery of higher radiation doses to pancreatic tumors within an acceptable number of fractions was impeded. Limited soft-tissue visualization, respiratory motion, and the close proximity of radiosensitive gastrointestinal organs restricted dose escalation and compromised target coverage. Consequently, outcomes remained modest, and uncertainty persisted regarding the clinical value of radiotherapy in the management of PDAC (4). Image-guided stereotactic body radiotherapy (SBRT) was introduced as a distinct approach with the aim of delivering an effective radiation dose to tumors with greater precision. Improved target visualization, motion management, and tighter margins enabled more reliable and strongly hypofractionated dose delivery while limiting irradiation of surrounding gastrointestinal organs. Early SBRT studies demonstrated that this approach was safe in pancreatic tumors and achieved local tumor control (5,6).

Against this background, the SPAN-C phase II trial by Chan et al. evaluates SBRT in patients with PDAC across several clinically relevant scenarios, including borderline resectable, locally advanced, and oligometastic disease (7). By focusing on feasibility, toxicity, and local control, the study demonstrates what can be achieved with SBRT at the applied dose levels and how these outcomes should be interpreted in the context of evolving radiotherapy practice.

Results of the SPAN-C trial

The SPAN-C trial demonstrates that SBRT can be delivered successfully across a heterogeneous population of patients with PDAC. Treatment was feasible in the majority of patients, indicating that SBRT can be integrated into routine clinical workflows. The observed toxicity profile was favorable, consistent with prior studies demonstrating the feasibility of delivering higher radiation doses in PDAC of approximately 40–45 Gy in 5 fractions over 2 to 3 weeks.

Recruitment of the SPAN-C trial was slow, leading to a smaller sample size. In addition, fiducial markers could not be placed in four patients. A total of 26 patients were treated with SBRT, which is reasonable for a single-center study.

At 12 months, SPAN-C reports high rates of local tumor control (84.6%), indicating that SBRT can achieve effective short-term control of the primary tumor. Importantly, this local control was achieved with limited treatment-related toxicity, reflected by low rates of grade ≥3 adverse events and the absence of unexpected safety signals.

A proportion of patients proceeded to surgical resection following SBRT, with favorable pathological findings reported in some cases. These observations suggest that SBRT may support local disease management prior to surgery in selected patients. However, SPAN-C was not designed to evaluate resection rates, margin status, or survival outcomes, and these findings should therefore be interpreted descriptively. Patient selection, systemic therapy, and surgical decision-making are likely to have contributed substantially to these outcomes.

Interpretation of local tumor control

The local control outcomes reported in SPAN-C are consistent with those observed in prior SBRT studies employing comparable dose levels (8-10). In this regard, SPAN-C provides prospective evidence that SBRT can achieve effective local tumor control.

Local tumor control is a clinically relevant endpoint in PDAC, particularly in patients with unresectable disease, as progressive local tumor growth can lead to pain, biliary obstruction, gastric outlet obstruction, and malnutrition (11). Achieving control of the primary tumor over a 12-month period may therefore contribute meaningfully to patient management, even in the absence of demonstrated survival benefit. From this perspective, the local control outcomes reported in SPAN-C are relevant in appropriate clinical contexts.

At the same time, the outcomes should be interpreted with care. SPAN-C reports local control at 12 months, a clinically relevant time frame given the prognosis of many patients with PDAC. In addition, the trial includes measures of symptom burden that strengthen the clinical interpretation of these findings. However, symptom measures capture only part of patient benefit and do not replace broader assessments of quality of life and functioning. Furthermore, the absence of a comparator arm limits causal interpretation, making it difficult to determine the extent to which observed local control and symptom outcomes can be attributed to SBRT. Many patients also received systemic therapy before or after radiotherapy, further complicating attribution of treatment effects. Accordingly, SPAN-C does not establish comparative effectiveness or superiority over alternative strategies such as chemotherapy alone.

Dose level and technical considerations

An important aspect of interpreting SPAN-C relates to the radiation dose delivered and the treatment technique used. In SPAN-C, SBRT was delivered using computed tomography (CT)-guidance with fiducial marker–based tumor localization, with total prescribed doses of approximately 40–45 Gy. These dose levels represent a meaningful escalation compared with conventionally fractionated radiotherapy and were appropriate within the technical constraints of the applied approach. One patient was treated with 45 Gy and 25 patients with 40 Gy in 5 fractions; however, it remains unclear why different doses were chosen.

Importantly, SPAN-C does not report to what extent the prescribed dose covered the entire tumor on a patient-level basis. The prescribed dose alone does not guarantee that the full tumor volume receives that dose, particularly when tumors are close to sensitive gastrointestinal organs. In pancreatic SBRT, the prevalence of these dose-limiting anatomies is common but highly variable between patients. This makes it difficult to fully interpret the relationship between dose, local control, and toxicity.

Furthermore, the dose levels used in SPAN-C are lower than those currently being explored in several ongoing SBRT studies (12,13). With total doses of approximately 40–45 Gy in five fractions, the corresponding biologically effective dose (BED₁₀) falls below the levels increasingly targeted in current pancreatic SBRT, where BED₁₀ values of 100 Gy or higher are often pursued. This growing interest in dose escalation is driven by the hypothesis that higher doses may improve local tumor control, facilitated by advances in image guidance, motion management, and treatment adaptation. These technical advances better account for the day-to-day anatomical variation of the pancreas and surrounding gastrointestinal organs. Considering this, the study clarifies the balance between local control and toxicity achievable with CT-based SBRT. At the same time, SPAN-C does not address whether higher dose regimens lead to improved clinical outcomes or whether such escalation can be achieved without increased toxicity.

The treatment technique used in SPAN-C reflects established CT-based SBRT practice, including motion management strategies and daily setup verification, without continuous soft-tissue visualization or online adaptive replanning. This context is relevant when interpreting the dose levels used in SPAN-C and when comparing its results with more recent SBRT approaches that rely on advanced image guidance.

Methodological considerations

The phase II design of SPAN-C is appropriate for its stated objectives. By focusing on feasibility, toxicity, and local control, the study avoids reliance on survival endpoints that are strongly influenced by systemic disease progression and subsequent treatments. The statistical analyses used are appropriate for a single-arm phase II study and are well aligned with the descriptive objectives of SPAN-C. The described approach allows for a focused evaluation of SBRT as a local treatment modality in PDAC.

The selection of local control as a primary outcome is methodologically defensible in this context. In PDAC, survival outcomes are largely driven by distant disease, which can limit the ability to detect the effects of local interventions. Evaluating local control, therefore, provides a more direct assessment of the technical and biological effectiveness of SBRT, particularly in a phase II setting. At the same time, local control should be interpreted as a measure of local disease management rather than as a surrogate for overall treatment benefit.

The heterogeneous patient population included in SPAN-C strengthens the external validity of the feasibility and safety findings, despite the single-centre nature of the study. SBRT was delivered across different disease stages and clinical contexts, reflecting how this treatment is applied in clinical practice. However, the heterogeneity complicates the interpretation of outcomes such as resection and survival, which are influenced by disease characteristics, systemic therapy, and surgical decision-making. Differences in treatment intent across subgroups further limit the ability to draw definite conclusions beyond feasibility and local tumor control.

The study appropriately limits causal interpretation of outcomes. Observations regarding surgical resection and pathological findings are reported descriptively and are not framed as evidence of treatment effect. This restraint is appropriate given the non-randomized design, the absence of a comparator arm, and the modest sample size. Without accounting for selection effects and time-dependent treatment strategies, stronger causal claims would not be justified.

While comparative effectiveness cannot be assessed, SPAN-C provides internally consistent prospective data that define what can be achieved with SBRT under the applied conditions. These data are valuable for contextualizing results from ongoing studies and for informing the design and interpretation of future evaluations that aim to address comparative and patient-centered outcomes.

Positioning SPAN-C in evolving practice

SPAN-C was conducted during a period of active development in pancreatic SBRT. Since its design, treatment approaches have continued to evolve, with increasing emphasis on dose escalation and more advanced image guidance. In this context, SPAN-C does not reflect the most recent technical developments in SBRT delivery, but rather represents an important stage in the clinical implementation of SBRT as a local treatment strategy for PDAC.

In daily practice, this evolution has been driven by advances in image guidance and treatment adaptation, with current SBRT workflows no longer routinely relying on implanted fiducial markers. The introduction of magnetic resonance imaging (MRI)-guided radiotherapy (MRgRT) has enabled daily soft-tissue visualization and online adaptive replanning, allowing more precise visualization of anatomical variation of the pancreas and surrounding gastrointestinal organs, which represent key dose-limiting factors in pancreatic SBRT. Several prospective and large single-institution studies have demonstrated the feasibility of MRgRT, with the capacity to safely deliver higher biologically effective doses while maintaining acceptable toxicity profiles (13-15). In parallel, substantial progress has been made in CT-based SBRT through improved motion management, refined target margins, and adaptive or iterative replanning strategies (12,16).

As a consequence, SPAN-C reflects CT-based SBRT practice at a time when higher dose delivery was constrained by available image guidance and adaptation capabilities. Its results therefore provide an important reference for outcomes achievable without continuous soft-tissue visualization or routine online adaptive replanning, and help contextualize the reported benefits of more advanced SBRT platforms.

At the same time, SPAN-C highlights several unresolved questions that remain relevant despite technical advances. The optimal radiation dose for pancreatic SBRT remains undefined, as does the extent to which higher dose delivery translates into clinically meaningful benefit. It also remains unclear which patient subgroups are most likely to benefit from local dose intensification and how SBRT, whether CT- or magnetic resonance (MR)-guided, should be optimally integrated with systemic therapy and surgery. Addressing these questions will require study designs that extend beyond feasibility and local control.

Clinical implications and remaining questions

The primary contribution of SPAN-C lies in demonstrating that SBRT can be delivered safely in PDAC and can achieve effective short-term local tumor control. From a clinical perspective, these results support implementation of SBRT in clinical workflows and consideration of SBRT as a local treatment option in selected patients.

At the same time, SPAN-C does not establish SBRT as a standard component of care for all patients with PDAC. Decisions regarding the use of SBRT should remain individualized and be made within a multidisciplinary setting, taking into account disease stage, treatment intent, systemic therapy options, and patient-specific factors. The role of SBRT relative to systemic therapy and surgery, therefore, remains an area of active investigation.

Future studies will need to address whether delivery of higher radiation doses translates into clinically meaningful benefit, how toxicity can be managed as dose levels increase, and which endpoints best capture patient-relevant outcomes. The incorporation of patient-reported outcomes, alongside longer and more structured follow-up, will be important to more fully define the clinical value of SBRT in PDAC.

Several clinical trials are currently ongoing investigating the effect of ablative SBRT in different settings for pancreatic cancer. The ARCADE (NCT04881487) is a randomized trial evaluating 5 fractions of 8 Gy in patients with isolated local pancreatic carcinoma recurrence (17). The PANCOSAR trial (NCT05265663) is a randomized study assessing five fractions of 8 Gy in patients with localized pancreatic carcinoma who, due to comorbidities or age, are not candidates for surgical tumor resection and/or chemotherapy (18). Several randomized studies, LAPSTAR (NCT06272162), LAP100 (NCT06958328) and TORPEDO (NCT06691425), randomized patients with locally advanced pancreatic cancer without distant metastases after initial chemotherapy, to evaluate ablative SBRT. These trials aim to address several key knowledge gaps regarding the role of ablative SBRT in patients diagnosed with pancreatic cancer.

Conclusions

SPAN-C is a well-conducted phase II study that provides prospective data on the feasibility, safety, and local efficacy of SBRT in PDAC. The study demonstrates that SBRT at the investigated dose levels is associated with effective local tumor control with acceptable toxicity across a range of clinical scenarios. While the dose levels and delivery techniques used may not reflect the most recent technical developments, SPAN-C defines an important benchmark in the evolution of pancreatic SBRT.

When interpreted in the context of ongoing advances in radiotherapy, the results of SPAN-C help clarify both what has been achieved and what questions remain unanswered. As such, the study makes a meaningful contribution to the ongoing discussion on the role of SBRT within multimodality treatment strategies for PDAC.

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-26-0018/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-26-0018/coif). The authors have no conflicts of interest to declare.

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