Adjuvant stereotactic pancreatic radiotherapy (SPARTA trial): interim safety analysis of an ongoing phase II single center prospective study

Abstract

Aims

This interim safety/toxicity analysis aims to assess toxicity of adjuvant stereotactic body radiation therapy (SBRT) after surgery of pancreatic cancer (PC) with high risk features across an ongoing prospective phase II trial, allowing better integration of chemotherapy and surgery.

Methods

The study started in 2021 and this paper represents an interim safety analysis. Enrollment will last 36 months, followed by 12 months of follow-up for a duration of 4 years and 50 patients. Inclusion criteria are: pT1-T4 adenocarcinoma with or without positive resection margin and/or N1 at lymphadenectomy. Chemotherapy can be administered in neoadjuvant and adjuvant setting. The primary endpoint is local relapse. The secondary endpoints are disease-free survival, overall survival, patterns of failure, acute and late toxicity. Radiation dose is 40 Gy in 5 fractions. Toxicities are recorded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The study protocol was approved by the institutional research ethics committee on May 18th 2021 and registered on ClinicalTrials.gov (NCT05043857).

Results

This preliminary analysis was focused on 50 patients. The median follow-up at the time of the analyses was 16.5 months (range 3–35). Neoadjuvant chemotherapy was administered to 23 patients (46%) and 30 (60%) received adjuvant chemotherapy. No patients experienced ≥ G3 toxicity. The most frequent toxicities during SBRT were: nausea (G1, 18%; G2, 8%), asthenia (G1, 10%), abdominal pain (G1, 12%; G2, 2%) and diarrhea (G1, 6%; G2, 2%). After 3 and 6 months abdominal pain (16%) and diarrhea (12%) remained the most G1-G2 toxicities. At 6 and 12 months, we observed two cases of G2 malabsorption. At 1 year, we recorded G2 abdominal pain (4%) and G1 diarrhea (4%).

Conclusions

In this series, adjuvant SBRT in PC was associated with acceptable tolerability with no ≥G3 toxicity. A longer follow-up is needed to fully characterize late toxicity. The final results are awaited to confirm the safety and efficacy of SBRT as a new therapeutic option for patients with resected PC.

Trial registration

The study protocol was approved by the institutional research ethics committee (Comitato Etico Indipendente IRCCS Humanitas Research Hospital) on May 18th 2021 and registered on ClinicalTrials.gov (NCT05043857) on September 14th 2021.

Background

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related mortality worldwide within the next decade, representing a growing global health burden [1]. Surgical resection remains the corner-stone of the treatment with curative intent. However, long-term survival outcomes following resection remain unsatisfactory, with a 5-year survival rate of approximately 20% [2]. This low survival rate is compounded by the fact that within two years post-surgery, up to 70% of patients will develop distant metastases, with the liver, lungs, and peritoneum being the most common sites of metastatic spread [3]. In addition to distant metastasis, local recurrence frequently occurs in this cohort, with synchronous local failure being commonly observed [4]. However, it is notable that up to 30% of patients may experience isolated local recurrence, which can occur without the presence of distant metastases [5]. Autopsy studies further underscore the importance of local progression, revealing that approximately 30% of deaths in patients with PDAC are due to local disease progression rather than distant metastatic spread [6]. These findings highlight the critical need for improved local control strategies in patients with resectable or borderline resectable PDAC, as enhancing local control could potentially improve patient survival outcomes.

Patients who present with lymph node involvement or those who undergo resection with close or positive surgical margins are at significantly increased risk of local recurrence. These patients also tend to exhibit worse survival outcomes compared to those with node-negative disease and R0 resections, underscoring the importance of achieving clear surgical margins and addressing lymphatic spread in the treatment of PDAC [7]. Although the role of adjuvant multi-agent chemotherapy (CT) has been firmly established in improving survival following surgical resection [8], the role of adjuvant chemoradiation (CRT) remains controversial. Some studies have suggested that adjuvant CRT improves survival outcomes in PDAC patients, particularly in those at high risk of recurrence, by targeting both microscopic residual disease and possible local recurrences [9–11]. Instead, other studies have raised concerns regarding the potential adverse effects of adjuvant CRT, suggesting that the associated toxicity may negate its potential benefits when compared to adjuvant chemotherapy or surgery alone [12–15]. Despite these ongoing debates, it is widely acknowledged that the absence of adjuvant therapies, particularly in patients with resected PDAC, is associated with a significantly worse prognosis and an increased risk of recurrence [9–11]. Current clinical guidelines advocate the use of conventionally fractionated radiotherapy (CFRT) at a dose of 45–50.4 Gy, in conjunction with fluoropyrimidine-based chemotherapy, as a standard adjuvant approach for patients with resected PDAC who do not exhibit progressive disease following surgery, particularly for those deemed high-risk [16].

Nevertheless, CFRT protocols present several notable drawbacks. These include prolonged overall treatment duration, a high number of treatment fractions, and relatively low biologically equivalent doses (BED), which may not provide sufficient therapeutic effect. The extended treatment time—often spanning 5 to 6 weeks—presents the theoretical risk of tumor repopulation, which may, in turn, facilitate the development of distant metastases. Additionally, the need to deliver a lower dose to the treatment target in order to reduce toxicity to adjacent healthy tissues may result in suboptimal local control rates. Although some studies have suggested that increasing the radiation dose might improve clinical outcomes in PDAC patients [17], there is also evidence suggesting that escalating the dose beyond 55Gy in Equivalent Dose in 2Gy fractions (EQD2) may have a detrimental effect on survival due to the increase in treatment-related toxicity [18].

Stereotactic body radiotherapy (SBRT) is a technique that offers a potential alternative to CFRT, as it delivers highly focused radiation with a steep dose gradient, using a significantly reduced number of fractions. By delivering ablative doses of radiation to the tumor target in a shorter treatment period, SBRT minimizes exposure to surrounding healthy tissues and critical structures. This characteristic makes SBRT an attractive option for improving the therapeutic ratio, as it could potentially provide better local control while reducing the risk of toxicity. Furthermore, the ability to deliver a higher, more concentrated dose of radiation in fewer fractions may facilitate better integration with systemic therapies, improving the overall therapeutic outcome compared to conventional CFRT.

Given these considerations, we designed a prospective, single-arm, phase II clinical trial aimed at evaluating the impact of adjuvant SBRT in patients with resected PDAC who exhibit high-risk features, such as lymph node involvement or positive surgical margins. In this preliminary analysis, we present data on the feasibility of this approach, with a specific focus on both acute and late toxicity profiles. Our findings may contribute to the development of more effective, tailored adjuvant treatment strategies for this challenging and often fatal disease.

Materials and methods

Study design and patient selection

A prospective, single-arm, phase 2 trial assessing the impact of adjuvant SBRT for PDAC was conducted at the Humanitas Research Hospital in Milan, Italy. The study protocol was approved by the institutional research ethics committee (Comitato Etico Indipendente IRCCS Humanitas Research Hospital) on May 18th 2021 and registered on ClinicalTrials.gov (NCT05043857). The investigation was performed in accordance with the Helsinki Declaration and informed consent was obtained from all patients before enrollment. This work was supported by an institutional research grant to the Radiotherapy and Radiosurgery Department, Humanitas Research Hospital IRCCS, Rozzano, Milano, Italy, from Varian Medical Systems. The funding source was not involved in the initiation or design of the study, data collection and analysis or preparation of the manuscript.

The indication, timing and sequence of systemic and local therapies was determined for all patients by a multidisciplinary tumor board comprising radiation-oncologists, medical oncologist, biliary-pancreatic surgeons, radiologists, gastroenterologists, and pathologists. Following screening, patients meeting the inclusion criteria were offered either standard adjuvant CFRT (with or without concomitant CT) or participation in the SPARTA protocol to receive adjuvant SBRT. Eligibility criteria included all of the following:

The inclusion criteria were:

• Surgically treated T1-T4 adenocarcinoma with or without prior chemotherapy.

AND

• Close (< 2.5 mm)/positive resection margin.

AND/OR

• N1 staging at lymphadenectomy.

• ECOG performance status < 2.

• Age > 18.

• Estimated life expectancy > 6 months.

• Ability to provide written informed consent.

• Cardiovascular comorbidities limiting life expectancy or other comorbidities jeopardizing the safety of the experimental procedure (Crohn Disease, active fistula).

The exclusion criteria were:

• Metastatic disease.

• Biliary tract or neuroendocrine tumors.

• Diagnosis of other infiltrative malignancies within 5 years except for non-melanoma skin tumors.

Treatment characteristics

All patients underwent standard oncological resection of the pancreatic tumor plus lymphadenectomy with insertion of surgical clips in the operative bed. Systemic therapy was allowed in the neoadjuvant and/or in the post-operative setting according to the multidisciplinary team recommendation. SBRT started within 4–12 weeks from surgery or at the end of adjuvant chemotherapy. All patients underwent thoracoabdominal computed tomography (CT) with and without contrast enhancement prior to radiotherapy. The treatment was administered in 5 consecutive daily fractions using volumetric modulated arc therapy (VMAT) with RapidArc (Varian Medical Systems). All patients underwent CT-simulation in supine position with arms above the head and a thermoplastic body mask for immobilization. The patients observed a fasting period of approximately four-six hours. Non-contrast and triphasic contrast-enhanced CT scans with a 3 mm slice thickness, along with a four-dimensional CT (4D-CT) imaging, were acquired. This approach is consistent with practices adopted in several SBRT workflows, where 3 mm slice thickness represents a balance between image quality, noise, and manageable dataset size, particularly when combined with 4D imaging.

Co-registration with diagnostic preoperative contrast-enhanced CT and magnetic resonance imaging (MRI) was done to guide target volume definition.

Target volume and organ a risk definition

We reviewed the surgical, pathologic and preoperative axial imaging information at the time of treatment planning.

Our delineation approach has now been explicitly aligned with published consensus recommendations, including the ESTRO-ACROP target volume guidelines and the Radiation Therapy Oncology Group postoperative pancreas atlas [19]. Using the surgical clips at the tumor-surgical bed interface and all available diagnostic and simulation imaging, two clinical target volumes (CTV) were delineated on the non-contrast planning CT.

CTV1 encompassed the surgical clips with a 5 mm isotropic expansion, edited at anatomical barriers (bones and muscles). This volume represents the tumor bed volume, which encompasses the postoperative anatomical region at highest risk of residual microscopic disease.

CTV2 was defined as an additional 10–15 mm anisotropic around CTV1, edited at anatomical boundaries, to include the superior mesenteric vein, superior mesenteric artery and the celiac axis, along with the retroperitoneal space located posteriorly to the corresponding vessel. These are the at-risk regions, including relevant vascular and retroperitoneal structures (e.g., perivascular spaces around major vessels).

A simultaneous integrated boost (SIB) technique was used, with CTV1 receiving a total dose of 40 Gy in 8 Gy fractions and CTV2 30 Gy in 6 Gy fractions. Both dose levels were delivered within the same treatment course, consisting of five fractions, with differential dose prescriptions to distinct target volumes, an internal target volume (ITV) for CTV2 was delineated based on respiratory motion information obtained from the 4D-CT. Subsequently, a planning target volume (PTV) was created using a 5 mm expansion around ITV.

In our study nodal involvement does not lead to routine elective nodal irradiation. Target definition remains focused on the tumor bed and regions at highest risk of microscopic disease, including selected perivascular and retroperitoneal areas. Pathologically or radiologically involved lymph nodes are included when identifiable; however, uninvolved nodal stations are not electively encompassed.

This strategy support a risk-adapted approach rather than systematic elective nodal coverage, particularly in the context of highly conformal techniques such as SBRT.

The rationale for omitting elective nodal irradiation is threefold:

• Patterns-of-failure data indicate that the predominant sites of recurrence in pancreatic cancer are local (tumor bed and perivascular regions) and distant [3, 5].

• Dosimetric constraints, especially in SBRT, limit the feasibility of safely treating large elective nodal volumes due to proximity of critical organs at risk (e.g., duodenum, stomach, small bowel).

• Treatment intent, which prioritizes escalation of dose to high-risk regions while minimizing toxicity.

The critical surrounding organs at risk (OAR) were contoured: stomach, duodenum, small bowel loops and large bowel loops, liver, spinal cord, large vessels and kidneys.

For OARs the applied dose constraints were derived from an internal review of the available literature [20–22]. These constraints were further refined and consolidated based on the institutional experience with SBRT for locally advanced pancreatic cancer (Table 1) [23, 24].

Table 1.

Constraints of organ at risk

CONSTRAINTS OAR
Spinal cord and medulla	D1cc< 27 Gy
Kidneys	V15 Gy< 30%
Duodenum	V36Gy < 1 cc
Stomach	V36 Gy < 1 cc
Jejunum/ileumy	V36 Gy< 3 cc
Liver	(Vliver –V21 Gy ) > 700 cc

A minimum target coverage objective of D98% > 98% was set for the CTV, while for the PTV, dose heterogeneity was constrained to D98% > 95% and D2% < 107%. Figure 1 illustrates a representative target volume and typical dose distribution. Before each fraction, a cone-beam CT (CBCT) was performed and matched to the surrounding bony, with adjustments made to the treatment area as needed, to verify the target’s positioning and assess the critical structures. Patients were assessed the first and last day of SBRT, and on a necessity-basis during treatment.

Fig. 1.

Example of target volumes and dose distribution

Definition of margin status

In resected pancreatic cancer, the definition of a “close” margin (< 2.5 mm) derives from histopathological criteria based on microscopic analysis of the surgical specimen, not from clinical or radiological data. We acknowledge that no universally accepted cut-off exists beyond the standard R0/R1 classification. However, margin clearance has been shown to behave as a continuous prognostic variable. The study by Chang et al. (2009) [25] demonstrated progressively improved survival with increasing margin distance, identifying a threshold of approximately 1.5 mm. This concept was further supported by Strobel et al. (2017) [26], who confirmed a survival benefit for margins > 1 mm and suggested incremental improvement with wider clearance. Based on these findings, the term “close margin” (≈ 1–2/2.5 mm) has been introduced in the literature as a pragmatic, non-standard category to identify patients at intermediate risk.

Histopathological assessment of surgical margins was performed according to the standardized protocol adopted at our institution. The following resection margins, as reported in the pathology records, were systematically evaluated: pancreatic transection margin, bile duct margin, cystic duct margin, posterior pancreatic margin, anterior pancreatic surface, proximal duodenal margin, distal intestinal margin and the retroperitoneal (vascular groove) margin.

Follow-up

Patients were assessed 3 months after completion of SBRT and subsequently every 3 months. At each visit, clinical evaluation, blood tests (including CEA and CA 19 − 9) and a contrast-enhanced CT scan were performed. Data on recurrence status and toxicity were systematically collected at each follow-up visit. 18F-FDG PET/CT was obtained if clinically indicated, but no earlier than 6 months after completion of radiation therapy.

Outcomes

The primary endpoint was local recurrence (LR). Secondary endpoints included disease-free survival (DFS), overall survival (OS), patterns of failure, acute and late toxicities, and clinical-pathological factors associated with disease recurrence for future prognostic stratification. Hematologic and non-hematologic toxicities were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 [27]. Acute and late toxicities were defined as any treatment-related adverse event occurring within 90 days after completion of SBRT or beyond that period, respectively.

Statistical analysis

The primary endpoint of LR will be analysed using the Brookmeyer and Crowley method to test the null hypothesis that the true 1-year LR rate is ≤ 20%, against a one-sided alternative. Enrolment is planned for 36 months, with 12 months of follow-up, for a total study duration of 4 years and a target accrual of 50 patients. Clinical data was prospectively recorded in a study-specific institutional database. This report presents an initial analysis focused on treatment-related toxicity, baseline patient characteristics and treatment details. Descriptive statistics were used to summarize all collected data, without performing any formal statistical comparisons. Given the exploratory nature of the analysis, toxicity outcomes were summarized descriptively and were not subjected to inferential statistical testing.

Results

Between 2021 and 2023, 50 patients were enrolled at the Radiotherapy and Radiosurgery Department of Humanitas Research Hospital. Baseline patient and treatment characteristics are summarized in Table 2. The median follow-up at the time of the analyses was 16.5 months (range 3–35) and the median age was 67 years (range 46–84), with a balanced sex distribution. Most patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–1.

Table 2.

Patient and treatment characteristics

Characteristics	No. of patients (%)
Median age [range], years	67 [46–84]
Male Female	24 (48%) 26 (52%)
Primary tumor location Head Body Uncinate Tail	32 (64%) 14 (28%) 3 (6%) 1 (2%)
Margin status Positive Close (< 2.5 mm)	45 (90%) 4 (9.5%)0
Grade G1 G2 G3 Not evaluable due to changes by chemotherapy	0 28 (56%) 17 (34%) 5 (10%)

The most frequent tumour location was the pancreatic head.

Surgery consisted of pancreatoduodenectomy in 27 patients (54%), distal pancreatectomy in 15 patients (30%) and total pancreatectomy in 8 patients (16%). Most of patients (45, 90%) had positive margins, five patients (10%) had close margins. All enrolled patients presented with tumors exhibiting adenocarcinoma histology.

Of the 50 enrolled patients, 23 (46%) had no lymph node involvement, 19 (38%) were classified as N1, and 8 (16%) as N2.

Systemic therapy was frequently used, with 23 (46%) and 30 (60%) patients receiving neoadjuvant CT and adjuvant CT, respectively. In both settings, FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) was the most commonly administered regimen. The duration of neoadjuvant CT and adjuvant CT ranged from 3 to 6 months depending on ECOG PS, age, comorbidities, patient compliance and treatment-related toxicity. Nine patients (18%) did not receive CT.

Neoadjuvant chemotherapy was administered to 23 patients (46%), consisting of folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) in 14 patients (60.8%), gemcitabine and nab-paclitaxel in 6 patients (26.1%), cisplatin, epirubicin, 5-fluorouracil, gemcitabine (PEX-G) in 2 patients (8.7%) and fluorouracil, folinic acid and oxaliplatin (FOLFOX) in one patient (4.4%).

Thirty patients (60%) received adjuvant chemotherapy, which consisted of capecitabine in 4 patients (13.3%), FOLFIRINOX in 17 patients (56.6%), gemcitabine in 7 patients (23.3%) and gemcitabine and nab-paclitaxel in 2 patients (6.6%).

Table 3 summarizes toxicity outcomes during SBRT and at 3-, 6- and 12-month follow-up. Overall, SBRT was well tolerated, with no ≥ G3 acute or late toxicities observed. During SBRT, most patients presented at least one treatment-related symptom, with nausea being the most frequent (G1 in 18% and G2 in 8%). At 3- and 6-month follow-up, the most frequently reported toxicities were G1 abdominal pain and diarrhea (8% each). remained the most frequent reported toxicities at 8% and 8%, respectively. Two cases of G2 malabsorption were recorded at 6 and 12 months, both of which resolved with pancrealipase supplementation. At 12 months, G2 abdominal pain was present in two patients (4%), one of whom had abdominal disease progression, while G1 diarrhea persisted in two cases (4%).

Table 3.

Treatment-related toxicities

	Grade 1 N° of patients (%)	Grade 2 N° of patients (%)
During radiotherapy
Nausea	9 (18%)	4 (8%)
Abdominal pain	6 (12%)	1 (2%)
Diarrhea	3 (6%)	1 (2%)
Asthenia	5 (10%)	0
Vomiting	1 (2%)	0
Dyspepsia	2 (4%)	0
Bloating	1 (2%)	0
Total
3-month follow-up
Abdominal pain	4 (8%)	0
Diarrhea	2 (4%)	0
Bloating	1 (2%)	0
Asthenia	0	1 (2%)
Nausea	0	0
Vomiting	0	0
Dyspepsia	0	0
Total
6-month follow-up
Abdominal pain	3 (6%)	1 (2%)
Diarrhea	4 (8%)	0
Malabsorption	0	1 (2%)
Asthenia	0	0
Nausea	0	0
Vomiting	0	0
Dyspepsia	0	0
Bloating	0	0
Total
12-month follow-up
Diarrhea	2 (4%)	0
Abdominal pain	0	2 (4%)
Malabsorption	0	1 (2%)
Asthenia	0	0
Nausea	0	0
Vomiting	0	0
Dyspepsia	0	0
Bloating	0	0
Total

Discussion

In our experience, adjuvant SBRT in PC appeared to be feasible and generally well tolerated, as no ≥G3 toxicity was observed; however, these findings should be interpreted in light of the study’s limitations. The initial findings suggest that the integration of SBRT into the adjuvant therapy regimen for high-risk PDAC patients is well-tolerated, with manageable toxicity, thereby supporting its potential as a feasible therapeutic option for this patient population. These results warrant further investigation in larger cohorts to validate the long-term safety and efficacy of SBRT in this clinical context.

Historically, the role of adjuvant CRT for resected PDAC has been controversial given the inconsistent results in literature regarding survival and treatment-related toxicity. In particular, the concern of a detrimental effect of chemoradiation on overall survival has led to a significant debate regarding the recommendation of adjuvant radiotherapy [12, 28]. The GITSG 9173 [28] was a randomized trial that evaluated surgery with or without postoperative CRT for PDAC. Chemoradiation was administered in a split course, consisting of 2 courses of 20 Gy separated by 2 weeks. The results showed that 14% of patients had hematologic toxicity and 20% had severe leukopenia. Another study assessing the role of adjuvant CRT was ESPAC-1 [14]. In this phase III trial, 289 patients were randomized into four treatment arms, using a two-by-two factorial design. After resection of the pancreatic ductal adenocarcinoma, each patient was randomly assigned to receive chemoradiotherapy or chemotherapy, neither treatment, or both treatments. Among patients receiving CRT, no local control benefits were seen and a detrimental effect in OS was reported.

Nonetheless, the negative findings of these two studies may be partially attributed to the use of outdated radiotherapy techniques, as both trials employed methods that may not reflect the current advancements in radiation therapy. Over time, radiotherapy techniques have significantly evolved, with improvements in precision, treatment planning including motion management and image guidance and dose delivery that enhance tumor targeting while minimizing damage to surrounding healthy tissues. The utilization of older radiotherapy modalities in these studies could have led to suboptimal outcomes, potentially confounding the evaluation of the treatment’s efficacy.

Adjuvant SBRT presents several potential advantages over CFRT. One key benefit is its superior conformality, which enables more precise delivery of radiation to the tumor while minimizing exposure to surrounding healthy tissues. This enhanced precision may contribute to a reduction in treatment-related toxicity, a critical consideration in the management of cancer patients, particularly those with adjacent organs. Additionally, SBRT typically requires a shorter overall treatment duration compared to CFRT. This time-efficient aspect of SBRT not only improves patient convenience but also facilitates better integration with other therapeutic modalities, such as chemotherapy. The ability to deliver more focused radiation over a reduced number of sessions allows for optimized scheduling and potentially more effective multimodal treatment strategies. These factors make SBRT an attractive option in the adjuvant setting.

Currently, there is limited evidence regarding SBRT in the adjuvant setting for PDAC. A retrospective study from the University of Pittsburgh [29] collected data on 24 patients treated with adjuvant SBRT for operated pancreatic cancer. Most patients received a single-fraction treatment (20–24 Gy), while only one case received 30 Gy in 3 fractions. SBRT delivery was done using the CyberKnife Robotic Radiosurgery System in 18 patients and via Trilogy intensity-modulated radiosurgery in 6 cases. Three patients (12.5%) experienced G1-2 acute gastrointestinal toxicities while 2 (8.3%) had G1-2 late toxicities including weight loss and pain. No patients experienced ≥G3 toxicities or bowel perforation. The authors concluded that adjuvant SBRT was a safe and feasible option for patients with resected high-risk pancreatic adenocarcinoma.

In 2019, Bernard et al. [30] reported the initial results of a prospective observational study evaluating the safety and efficacy of SBRT following resection for PDAC with close or positive margins. A total of 49 patients received 36 Gy in 3 fractions to the close or positive margin site. Severe acute ≥ G3 toxicity was recorded in 4.1% of patients and consisted in abdominal pain and hyperglycemia requiring hospitalization within one week after treatment. No patients experienced late ≥ G3 toxicity.

Finally, preliminary data from the NRG Oncology/RTOG 0848 (NCT01013649) showed promising results. In this two-step trial, patients with resected periampullar pancreatic adenocarcinoma randomized to receive 5 cycles of adjuvant gemcitabine +/- Erlotinib, followed by a second randomization to a 6th cycle of the same initial CT, with or without subsequent CRT. Adjuvant CRT consisted of CFRT to a dose of 50.4 Gy in 28 fractions with concomitant 5FU/Capecitabine. Overall, the addition of CRT improved DFS without an impact in OS. However, in the node-negative subgroup, CRT was associated to improvements in both DFS and OS. Moreover, the CT plus CRT approach did not increase grade 4 or 5 toxicity compared to chemotherapy alone [31].

Our preliminary results are consistent with prior reports in the literature, reinforcing the notion of an acceptable toxicity profile for adjuvant SBRT. These findings contribute to the growing body of evidence suggesting that SBRT, when used in the adjuvant setting, demonstrates a manageable safety profile. However, we recognize several limitations in our analysis that should be considered when interpreting these results. These include a relatively short follow-up period, which may not fully capture long-term toxicity and efficacy outcomes. Additionally, the heterogeneity in chemotherapy schedules and sequences employed across patients introduces variability that could impact the interpretation of SBRT’s effectiveness and its interaction with systemic therapy. A further aspect that should be considered when interpreting these findings is the potential for selection bias. Eligible patients were offered either conventionally fractionated radiotherapy or participation in the SBRT protocol, which may have introduced a degree of selection in treatment allocation. Despite these limitations, the prospective design of our study, the use of a homogeneous SBRT protocol and the consistent delivery of treatment across participants provide a strong foundation for the validity of our preliminary results.

Conclusions

The preliminary analysis of this prospective, single-arm Phase II trial suggests that adjuvant SBRT may be a feasible and generally well-tolerated treatment strategy for patients with resected PDAC, as no severe acute or early-late toxicities were observed at this early stage of the study. These initial findings may indicate a potentially favorable safety profile of SBRT in the adjuvant setting; however, they should be interpreted with caution given the limited follow-up and the early nature of the analysis. Accordingly, longer follow-up and final results are required to more comprehensively assess the long-term safety of this approach, particularly with regard to late toxicity. In addition, further investigation is warranted to clarify its impact on efficacy outcomes, including local control and survival. These endpoints will be essential to determine whether the observed tolerability is associated with meaningful and sustained clinical benefit in patients with resected PDAC.

Abbreviations

PDAC

Pancreatic ductal adenocarcinoma

CT

Chemotherapy

CRT

Chemoradiation

CFRT

Conventionally fractionated radiotherapy

BED

Biologically equivalent doses

EQD2

Equivalent Dose in 2 Gy fractions

SBRT

Stereotactic body radiotherapy

VMAT

Volumetric modulated arch therapy

CT

Computed tomography

4D-CT

Four-dimensional

MRI

Magnetic resonance imaging

CTV

Clinical target volumes

SIB

Simultaneous integrated boost

ITV

Internal target volume

PTV

Planning target volume

OAR

Organs at risk

CBCT

Cone-beam CT

LR

Local recurrence

DFS

Disease-free survival

OS

Overall survival

CTCAE

Common Terminology Criteria for Adverse Events

ECOG PS

Eastern Cooperative Oncology Group Performance Status

Author contributions

Marta Scorsetti and Tiziana Comito contributed to the study conception. Material preparation, data collection and analysis were performed by Maria Massaro and Tiziana Comito. The first draft of the manuscript was written by Maria Massaro and Tiziana Comito and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by an institutional research grant to the Radiotherapy and Radiosurgery Department, Humanitas Research Hospital IRCCS, Rozzano, Milano, Italy, from Varian Medical Systems. The funding source was not involved in the initiation or design of the study, data collection and analysis or preparation of the manuscript.

Data availability

The data were extracted from the patient’s medical records, and no materials were utilized.

Declarations

Ethics approval and consent to participate

The study protocol was approved by the institutional research ethics committee (Comitato Etico Indipendente IRCCS Humanitas Research Hospital) on May 18th 2021 and registered on ClinicalTrials.gov (NCT05043857). The investigation was performed in accordance with the Helsinki Declaration and informed consent was obtained from all patients before enrollment.

Competing interests

L.R. reports consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, Eisai, Gilead, Incyte, Ipsen, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.