The role of radiotherapy in metastatic pancreatic cancer: a narrative review
Review Article

The role of radiotherapy in metastatic pancreatic cancer: a narrative review

Timothy A. Lin, Amol Narang

Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Contributions: (I) Conception and design: Both authors; (II) Administrative support: Both authors; (III) Provision of study materials or patients: Both authors; (IV) Collection and assembly of data: Both authors; (V) Data analysis and interpretation: Both authors; (VI) Manuscript writing: Both authors; (VII) Final approval of manuscript: Both authors.

Correspondence to: Amol Narang, MD. Department of Radiation Oncology & Molecular Radiation Sciences, Johns Hopkins University School of Medicine, 401 N Broadway, Baltimore, MD 21287, USA. Email:

Background and Objective: To describe the current and emerging role of radiotherapy in metastatic pancreatic cancer (MPC), including for palliation of locally invasive primary disease; metastasis-directed therapy in the setting of oligometastatic disease; and for immunomodulation in the setting of immunotherapy.

Methods: A search of the PubMed database was performed using the search terms “metastatic pancreatic cancer”, “oligometastatic pancreatic cancer”, and “radiotherapy” for articles published between January 1, 1980 to July 30, 2022. Articles were included at the discretion of the authors.

Key Content and Findings: This review provides an updated and comprehensive evaluation of the role of radiotherapy in the context of modern radiotherapy techniques [i.e., stereotactic body radiation therapy (SBRT)], as well as a discussion of key considerations regarding the potential role for radiotherapy to enhance the immune response to immune checkpoint inhibition. While palliative radiotherapy for MPC was historically delivered in conventionally fractionated or short-course hypofractionated palliative dose and fractionations, the use of more modern approaches such as SBRT for the palliation of symptoms related to local tumor invasion is being explored due to potential benefits, including reduction in the number of fractions and minimizing time off of systemic therapy, while maintaining good pain response and local tumor control rates. Metastasis-directed radiation therapy for patients with oligometastatic pancreatic cancer (OMPC) is similarly being explored and has been well tolerated in initial studies, with the potential to facilitate systemic therapy treatment breaks and potentially improve survival outcomes, though prospectively designed studies are currently lacking. The addition of SBRT as an immunomodulatory agent to enhance the effect of immunotherapy in pancreatic cancer is an area of continued investigation.

Conclusions: Despite the aggressive course of MPC, radiation therapy can play an important role in palliation of local tumor invasion, with the potential for benefit as metastasis-directed therapy in the setting of oligometastatic disease and as an adjunct to immunotherapy, though further prospective study is required.

Keywords: Pancreatic cancer; metastatic; oligometastatic; radiotherapy; stereotactic body radiation therapy (SBRT)

Received: 01 August 2022; Accepted: 11 October 2022; Published online: 29 November 2022.

doi: 10.21037/dmr-22-54


Pancreatic cancer is the third-leading cause of cancer death among men and women in the United States (1). Just over half of all patients with pancreatic cancer present with metastatic disease, which is associated with a dismal 5-year survival rate of 3.1% (2). Historically, the role of radiation therapy in the setting of unresectable pancreatic cancer was chemoradiotherapy, often to 50.4 Gy in 28 fractions, or short-course hypofractionated radiotherapy (3). In recent years, investigation of the use of stereotactic body radiation therapy (SBRT) to the pancreatic tumor primary has been pursued, given relatively high rates of locally invasive disease even in the setting of metastatic disease (4). Additionally, the role of metastasis-directed radiotherapy in oligometastatic pancreatic cancer (OPMC) is an area of active investigation as a consequence of increased interest in the oligometastatic state in solid tumor malignancies as a whole, given randomized trials demonstrating a survival benefit (5,6) to radiotherapy in patients with a limited number of metastases. The question remains as to whether modern radiotherapy technology is best used to optimize palliative radiotherapy versus as a means to maximize local tumor control. Similarly, the exact role of ablative radiotherapy in the oligometastatic setting has yet to be determined.

In this review, as compared to prior reviews on this subject, we provide an updated presentation of the current evidence for the role of radiotherapy in metastatic pancreatic cancer (MPC). Specifically, we will elucidate the role of modern radiation therapy techniques in MPC as a palliative measure and as a potential tool in the setting of oligometastatic disease. We will also describe ongoing efforts to use SBRT to enhance the effect of immunotherapy in pancreatic cancer. We present this article in accordance with the Narrative Review reporting checklist (available at


A search of the PubMed database was conducted for articles containing the search terms “metastatic pancreatic cancer”, “oligometastatic pancreatic cancer”, and “radiotherapy” published between January 1, 1980 and July 30, 2022 (Table S1). Retrospective and prospective studies available in the English language that reported outcomes for patients with MPC who received radiotherapy were reviewed and included based on the authors’ judgment.

Palliative radiation therapy for metastatic pancreatic adenocarcinoma

Radiation therapy in the setting of MPC historically has been used with palliative intent. Patients with MPC at the time of death frequently have concurrent local tumor invasion, with evidence suggesting that patients with a limited number of metastatic sites of disease frequently die of local tumor invasion (4). Potential symptoms of pancreatic adenocarcinoma include gastric outlet or duodenal obstruction, gastric or duodenal ulceration and associated bleeding, obstructive jaundice, venous obstruction and associated ascites, and abdominal pain (7,8). Palliative radiation therapy to the primary pancreatic tumor has been used to reduce symptoms related to local tumor invasion (9), with pain relief being a common byproduct of palliative radiotherapy (10). The pathophysiology of abdominal pain in the context of pancreatic cancer is thought to be related to tumor invasion of the celiac plexus resulting in celiac plexopathy (11).

Certainly, standard palliative fractionation regimens such as 30 Gy in 10 fractions can be utilized for palliation of primary tumor-related symptoms in the setting of metastatic disease. Tumor-related pain and bleeding can be particularly responsive to palliative radiation. Mass effect related complications can be less predictable in their response to radiation, but intervention in the setting of impending symptoms can be considered. Importantly, in recent years, the advent of SBRT has allowed for significantly more focused delivery of radiation, such that shorter fractionation schedules that deliver high biologically effective dose (BED) can be considered, minimizing time off of systemic therapy while achieving good local tumor control for a tumor type that can often be radio-resistant in the setting of low BED (12). Indeed, SBRT has demonstrated high response rates for pain in the treatment of locally advanced pancreatic cancer (LAPC) (13). A limited number of retrospective studies examining the use of SBRT in the setting of LAPC also included a small number of patients with metastatic disease (14-17), with encouraging rates of pain response. A handful of recent studies have also explored the use of SBRT to the primary tumor specifically for patients with metastatic disease. A few such studies will be discussed (Table 1).

Table 1

Studies assessing SBRT for local palliation of MPC

Author Year Design N Patient Population Intervention RT dose Main findings Toxicity
Koong (18) 2020 RR 27 OMPC SBRT to primary tumor (n=27) Median doses by fractionation: 1 fraction: 25 Gy; 5 fraction: 33 Gy Median OS 7 mos (95% CI: 3–10 mos); 1-yr LF 25% (95% CI: 10–44); reduced mean intensity of pain (SS); 46% reduction in continuous opioid use G3+ late toxicity: 2 pts
Ji (19) 2021 RR 89 OMPC (liver-only) Neoadjuvant ChT + SBRT to primary tumor (n=34); neoadjuvant ChT alone (n=65) Mean 41.4 Gy (range, 25–50 Gy) in 5–7 fractions 1-yr OS 39.4% vs. 21.3%, P=0.059, favoring SBRT; 3-mo local symptomatic palliation rate 87.0% vs. 54.5% in propensity score matched group (SS) No SS difference in G1–2 or G3+ toxicities between the two treatment arms. Notably, 1 pt with history of duodenal ulcer with G3 duodenal ulcer hemorrhage in SBRT arm
Hammer (20) 2022 Phase II 18 Pancreas (n=16); other GI malignancy (n=2) SBRT to the celiac plexus 25 Gy in 1 fraction Baseline median NRS 6/10 (IQR, 5.0–7.5) declined to 3/10 (IQR, 1.0–4.3; P<0.005) at 6 weeks post-treatment G1–2: 39% pts; G3+: 0% pts

SBRT, stereotactic body radiation therapy; MPC, metastatic pancreatic cancer; N, sample size; RT, radiotherapy; RR, retrospective review; OMPC, oligometastatic pancreatic cancer; Gy, Grey; OS, overall survival; mos, months; CI, confidence interval; yr, year; LF, local failure; SS, statistically significant; G, grade; pts, patients; ChT, chemotherapy; NRS, numerical rating score; IQR, interquartile range.

Koong et al. (18) retrospectively analyzed a cohort of 27 patients with OMPC, defined as patients with 1–3 metastatic lesions, treated with SBRT to the primary tumor. The majority (89%) received upfront chemotherapy, most commonly using a gemcitabine-based regimen, while 26% received chemotherapy following radiation. The median radiation dose for single-fraction treatments was 25 Gy (range, 12.5–25 Gy), while the median dose for 5-fraction treatments was 33 Gy (range, 25–40 Gy). Image guidance consisted of gold fiducial placement for target localization, with 4D-CT simulation for motion management. At a median follow-up of 7 months, the median overall survival (OS) was 7 months [95% confidence interval (CI): 3–10]. The 1-year cumulative incidence of local failure was 25% (95% CI: 10–44%). Mean intensity of pain as measured by the Stanford Pain Scale was significantly reduced following SBRT (P=0.01), with a 46% reduction in continuous opioid use. There were two cases of grade 3 or higher late toxicities. One involved grade 3 fatigue; the other was an episode of acute duodenal obstruction treated with duodenal stent placement.

Ji et al. (19) compared the efficacy of chemotherapy with or without SBRT to the primary lesion in patients with liver-only OMPC. Of the 89 patients included in the study with liver-only OMPC, defined as a tumor burden consisting of no more than 5 liver metastases less than 4 cm in size, 34 patients underwent SBRT to the primary site, with chemotherapy delivered in the upfront or consolidative setting; the rest received chemotherapy alone. Mean SBRT dose was 41.1 Gy (range, 25–50 Gy) delivered in 5–7 fractions. The primary outcome, 1-year OS, was numerically higher in the SBRT plus chemotherapy group compared to those receiving chemotherapy alone but did not reach statistical significance in either the unmatched (39.4% vs. 21.3%, P=0.059) or propensity-score-matched cohorts (34.0% vs. 16.5%, P=0.115). In an exploratory subgroup analysis, patients with head of pancreas tumors or good performance status who were treated with SBRT and chemotherapy had improved OS compared to those treated with chemotherapy alone. Furthermore, after propensity score matching, patients treated with SBRT plus chemotherapy were observed to have lower rates of abdominal and back pain compared to those treated with chemotherapy alone (87.0% vs. 54.5%, P=0.016).

Hammer et al. (20), reported the results of a pilot study of stereotactic radiation specifically to the celiac plexus for celiac plexopathy in patients with upper GI malignancies, the majority of whom had pancreatic cancer. In this single-arm phase II trial, 16 patients with pancreatic cancer and 2 with other upper GI malignancies with celiac pain of at least 5 out of 10 on the Numerical Rating Scale (NRS) were treated with SBRT to a dose of 25 Gy in 1 fraction to the celiac plexus, defined for treatment planning purposes as the anterolateral aspect of the T12 to L2 vertebral levels contoured with a 5 mm brush. A 5 mm expansion on the celiac plexus was then prescribed to 20 Gy. Gross tumor in the proximity of these volumes could be included at the treating physician’s discretion. 4D-CT simulation was used for all patients, with abdominal compression added if tolerated. Prophylactic anti-emetics were given on the day of treatment. Concurrent systemic therapy was prohibited. The primary endpoint was change in NRS at 3 weeks post-treatment. The median NRS at 3 weeks decreased to 3 out of 10 [interquartile range (IQR), 1.0–4.3, P<0.005 vs. baseline] from a baseline of 6 out of 10 (IQR, 5.0–7.5); at 6 weeks post-treatment, median NRS declined to 2.8 out of 10 (IQR, 0–3.3, P<0.005 vs. baseline). Four patients experienced complete resolution of their pain. Thirty-nine percent of patients experienced grade 1 to 2 toxicities, most commonly acute GI toxicities; no patients experienced grade 3 or higher toxicity.

These studies underscore the potential for radiotherapy in MPC yet also highlight the current dearth of evidence to guide management, as patients who were selected for treatment for oligometastatic disease may have been enriched for clinical factors that portended a better outcome. Two trials assessing the role of stereotactic radiation for palliation of pain in pancreatic malignancies are currently enrolling. As a follow-up to the study by Jacobson et al., a larger multi-center international single-arm phase II trial (21) is currently open for enrollment, with a target accrual of 125 patients. The treatment will again consist of single-fraction stereotactic radiosurgery to the celiac plexus, with the primary endpoint being the rate of complete or partial pain response at 3 weeks assessed with the Brief Pain Inventory scale. The second, the MASPAC trial (22), is a randomized controlled trial evaluating the benefit of magnetic resonance (MR)-guided SBRT to the primary tumor in patients with MPC. The treatment will consist of standard of care chemotherapy with or without SBRT to a total of 33 Gy in 5 fractions prescribed to the 80% isodose line to the primary tumor. The primary endpoint will be improvement in pain as measured by the “mean cumulative pain index.” These trials will provide further prospective data regarding the impact of RT on quality of life that can be used to guide management decisions in MPC.

Metastasis-directed radiation therapy in oligometastatic pancreatic adenocarcinoma

The current standard of care management of MPC consists of multi-agent chemotherapy, usually composed of folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (23,24). In the metastatic setting, there is increasing consideration towards classifying patients with a limited number of metastatic sites as having oligometastatic disease. It is postulated that local therapy including radiotherapy for OMPC may provide a survival benefit, as suggested by multiple prospective studies in other solid tumor malignancies (5,6). Retrospective studies of local therapy in the setting of OMPC have been conducted, primarily with surgery (i.e., metastatectomy) as the local therapy of choice (25,26), while a prospective study, the HOLIPANC trial (27), is an ongoing single-arm phase II study of patients with liver-only oligometastatic pancreatic adenocarcinoma with stable disease after neoadjuvant chemotherapy who will be treated with synchronous resection of the primary tumor and hepatic metastases. Prospective data specifically evaluating metastasis-directed radiotherapy in OMPC are lacking. However, multiple retrospective studies have evaluated the benefit of radiation therapy in OMPC. Three such studies will now be discussed (Table 2), which suggest SBRT to oligometastatic sites of disease is well-tolerated, provides high rates of local control, may facilitate treatment breaks from systemic therapy, and may improve progression-free and overall survival (28-30).

Table 2

Studies of metastasis-directed therapy in MPC

Author Year Design N Patient population Inclusion criteria Intervention RT dose Main findings
Scorscetti (28) 2020 RR 41 OMPC ≤5 metastases,
≤2 sites
SBRT to metastases (12.2% with additional metastases not treated) Most common dose/fx by location: lung: 48 Gy/4 fx; liver: 54–75 Gy/3 fx, 45–63 Gy/6 fx 2-yr LC 73.9%; 2-yr PFS 10.9%; 2-yr OS 46.7%; extra-target disease associated with PFS
Lee (29) 2021 RR 76 MPC All with liver metastases; 14% with extra-hepatic metastases SBRT to liver metastases Median 50 Gy/5 fx 12-mo LC 66%; 12-mo PFS 7%; 12-mo OS 38%; ChT break >6 mos after RT: 32% of pts
Elamir (30) 2022 RR 41 OMPC (<5 metastases) in de novo pts or <3 mos after surgical resection of primary; CA19-9 <1,000 U/mL; pts included ChT alone arm required to have no progression on ChT for >5 mos ChT + SBRT (n=20); ChT alone (n=21) Median BED10 =100, IQR, 100–132 Gy; most commonly treated with 1–5 fx 2-yr LC 82.5%; median poly-PFS 40 vs. 14 mos (HR =0.2, 95% CI: 0.07–0.54, P<0.01) favoring SBRT; median OS 42 vs. 18 mos, HR =0.21, 95% CI: 0.08–0.53, P<0.01) favoring SBRT; ChT break of 6+ mos in 85% of SBRT cohort vs. 33.3% in ChT cohort

MPC, metastatic pancreatic cancer; N, sample size; RT, radiotherapy; RR, retrospective review; OMPC, oligometastatic pancreatic cancer; SBRT, stereotactic body radiation therapy; fx, fractions; Gy, Grey; yr, year; LC, local control; mo, month; PFS, progression-free survival; OS, overall survival; mos, months; pts, patients; ChT, chemotherapy; CA19-9, carbohydrate antigen 19-9; BED10, biologically effective dose assuming alpha/beta of 10; IQR, interquartile range; HR, hazard ratio; CI, confidence interval.

Scorsetti et al. (28) reported outcomes from a single-institution retrospective analysis of 41 patients with OMPC, defined as 5 or fewer metastases across 2 or fewer sites, treated to a total of 64 metastases with SBRT. The majority had metachronous disease (95.1%). The most commonly treated sites of metastases were in the lung (29.3%) and liver (56.1%). Five patients (12.2%) had additional metastatic lesions not treated with SBRT. The dose of SBRT varied, with most lung lesions treated to 48 Gy in 4 fractions. There was greater heterogeneity in the dose and fractionation to liver metastases, with patients treated from 54–75 Gy in 3 fractions, or 45–63 Gy in 6 fractions. Abdominal compression was used for the treatment of liver metastases, while four-dimensional-computed tomography (4D-CT) simulation was used for liver or lung lesions. The majority of patients (78.1%) did not receive further planned systemic therapy after SBRT. Local control (LC) at 1 and 2 years were 88.9% and 73.9%, respectively. Progression-free survival (PFS) at 1 and 2 years were 21.9% and 10.9%, respectively, while overall survival at 1 and 2 years were 79.9% and 46.7%, respectively. On multivariable analysis of PFS, sex [hazard ratio (HR) =4.59, 95% CI: 1.90–11, P=0.0001], time to metastases (HR =0.96, 95% CI: 0.93–0.99; P=0.031), and extra target disease (HR =7.36, 95% CI: 2.24–24.15; P=0.001) were significantly associated with PFS.

Lee et al. (29) reported on outcomes from a multi-institutional retrospective analysis of 76 patients with MPC treated with SBRT to liver metastases. Sixty-eight percent of patients presented with metachronous liver metastases. A minority of patients (14%) had sites of extrahepatic metastases at time of treatment, most commonly in the lungs. Median SBRT dose and fractionation was 50 Gy in 5 fractions. With a median follow-up of 10.9 months, 12-month LC was 66%, 12-month PFS was 7%, and 12-month OS was 38%. Thirty-two percent of patients had a chemotherapy treatment break of 6 or more months following completion of radiation. Multivariable analysis showed ECOG performance status of 2–3, progressive liver metastases while on chemotherapy, and a higher carbohydrate antigen 19-9 (CA19-9) at the time of radiotherapy were associated with inferior overall survival.

Elamir et al. (30) conducted a retrospective analysis of patients with OMPC, defined as patients with five or fewer metastatic sites of disease in either the de novo setting or diagnosed 3 or more months after surgical resection of their primary disease, with CA19-9 <1,000 U/mL, treated with chemotherapy with or without SBRT to all metastatic lesions. Twenty patients received SBRT, while the 21 patients included for comparison who received chemotherapy only were required to have had no progression for at least 5 months. SBRT consisted of 1–5 fractions of treatment to a minimum dose of 7.65 Gy per fraction [median biologically effective dose assuming alpha/beta of 10 (BED10) =100, IQR: 100–132 Gy], while one patient was treated with 67.5 Gy in 15 fractions. At a median follow-up of 16 months, 1- and 2-year local control rates of lesions treated with SBRT were 91.6% and 82.5%, respectively. The study measured the rate of polyprogression-free survival, defined as progression of greater than five metastatic tumors, and found that patients in the SBRT cohort had a median polyprogression free survival of 40 vs. 14 months (HR =0.2, 95% CI: 0.07–0.54, P=0.0009) compared to the chemotherapy cohort. Similarly, OS was improved in the SBRT cohort (median OS 42 vs. 18 months, HR =0.21, 95% CI: 0.08–0.53, P=0.0003). Seventeen out of 20 (85%) patients in the SBRT cohort had a chemotherapy treatment break of 6 or more months, compared to 7/21 (33.3%) in the chemotherapy cohort.

One limitation of all three studies is a lack of reporting on toxicity data from SBRT (28-30), though increased toxicity from metastasis-directed therapy in other disease sites has been documented, such as in the SABR-COMET trial in which the rate of grade 2 or higher treatment-related toxicity was 20 percentage points higher in the SABR arm than in the control arm (6). Nevertheless, these studies demonstrate the potential benefit of metastasis-directed radiation therapy in patients with a limited number of metastatic sites of disease. There exists inter-study variability in the criteria for oligometastatic disease in the pancreatic cancer setting. A number of clinical characteristics have been used to define a clinically relevant oligometastatic subtype in MPC, including the number of organs with metastases, the total number and specific sites of metastatic deposits, CA19-9 levels, as well as a favorable response to first-line chemotherapy (30,31). Further study of optimal inclusion criteria is needed, including the potential value of incorporating novel biomarkers such as circulating tumor DNA (32) and molecular alterations that may predict differential response to therapy (33). Prospective studies are required to further elucidate the selection criteria and outcomes of patients with OMPC.

SBRT and immunotherapy in metastatic PDAC

The rapidly accumulating body of evidence demonstrating the benefit of immunotherapy in an array of cancer types stands in contrast to the limited success of immunotherapy in pancreatic cancer (34), though case reports suggest the potential efficacy of immune-mediated therapy in appropriately selected patients with MPC (35,36). The reasons for this lack of efficacy may relate to the immunosuppressive tumor microenvironment in pancreatic cancer (37,38). Radiation therapy can promote an immunologic response via multiple mechanisms, including induction of immunogenic cell death (39), tumor antigen presentation via increased expression (40,41), and promotion of T-cell homing to the tumor bed (42-44). The immunomodulatory effects of radiotherapy may result in a more favorable response to immunotherapy when used in tandem (45). Current clinical studies specifically in MPC have evaluated the safety and efficacy of SBRT in addition to immune checkpoint inhibition. In a phase I study by Xie and colleagues, the safety of durvalumab and/or tremelimumab in combination with SBRT to 8 Gy in 1 fraction or 25 Gy in 5 fractions to the primary pancreatic tumor or post-operative recurrence was evaluated in 59 patients. There were no dose-limiting toxicities observed, and 2/39 (5.5%) patients with evaluable disease had a partial response to treatment (46), which the authors note was higher than the 3.1% response rate observed in patients on a separate study of patients with MPC treated with combination durvalumab and tremelimumab (47). The CheckPAC trial evaluated a cohort of patients with refractory MPC treated with a combination of SBRT to 15 Gy in 1 fraction to a single primary or metastatic lesion with nivolumab, ipilimumab, or both in tandem. A partial response lasting 4.6 months was observed in 1 patient receiving SBRT/nivolumab, while 6 patients who received SBRT and nivolumab/ipilimumab achieved a partial response with a median duration of 5.4 months, including 1 patient still alive at the time of reporting with a continued response of 55 months. Grade 3 or higher treatment-related toxicity was observed in 24.4% and 30.2% of patients in the SBRT/nivolumab and SBRT/nivolumab/ipilimumab groups, respectively (48). In a single-arm phase II study by Parikh and colleagues (49), patients with metastatic microsatellite stable colorectal (n=40) and pancreatic (n=25) cancer were treated with 3 cycles of ipilimumab and nivolumab, with radiotherapy administered on day 1 of cycle 2 as 24 Gy in 3 fractions every other day or every two days. In patients with MPC, the disease control rate was 20% (5/25 patients, 95% CI: 7–41%); in those patients who received radiotherapy per protocol, the disease control rate was 29% (5/17 patients; 95% CI: 10–45%). As Parikh and colleagues note, these response rates compare favorably to those in patients with advanced/MPC who received FOLFIRINOX followed by gemcitabine monotherapy as second-line therapy (50).

While cross-trial comparisons are imperfect, the favorable response rates compared to that seen in trials of systemic therapy alone, including immunotherapy alone trials, suggest the continued study of SBRT in combination with immunotherapy in MPC is warranted. Mismatch repair deficiency, which is a positive predictor of response to immune checkpoint inhibition (51,52), is estimated to occur in a mere 1% of patients with pancreatic cancer (53). Thus there is a need to develop predictive biomarkers of response to immunotherapy in pancreatic cancer, and, as demonstrated by the study by Parikh and colleagues (49), SBRT may represent an opportunity to enhance the response to immunotherapy in patients with MPC. Questions also remain regarding the optimal dose/fractionation (54-56), target (57), and timing (58,59) of radiotherapy to generate maximal antitumor immune response while mitigating concomitant immunosuppressive effects of radiotherapy. In particular, the timing or sequencing of radiotherapy with immunotherapy may impact the receipt of radiotherapy as a result of immune-related adverse events, as observed in the study by Parikh and colleagues in which radiotherapy was delivered after an initial cycle of immune checkpoint inhibition rather than concurrently with cycle 1; thirty-two percent of patients in the overall cohort discontinued immunotherapy prior to receipt of radiotherapy due to immune-related adverse events (49). The optimal timing of radiotherapy may also depend on the mechanism of action of the immunotherapy being used in conjunction with radiotherapy (59). These factors must be carefully considered in the design of future trials testing radiation therapy and immunotherapy combinations for MPC as in other disease sites.


Key limitations of this review include its use of a single database (PubMed) which yielded mainly small retrospective reviews. However, in summary, the role of radiotherapy in MPC, historically delivered with standard palliative dose and fraction, is evolving. The advent of modern radiotherapy techniques that allow for greater dose escalation may allow higher-dose stereotactic radiotherapy to play an increasingly prominent role in MPC, whether as a palliative measure in the setting of celiac plexopathy, or as a potential modality to improve oncologic outcomes in the oligometastatic setting or in combination with immunotherapy. A limited number of retrospective studies suggest that SBRT to the primary tumor particularly in the setting of oligometastatic disease is well tolerated and provides effective pain relief. Furthermore, metastasis-directed therapy using SBRT in the oligometastatic setting is being explored, with initial retrospective reports suggesting it is safe and well tolerated, with high local control rates and the potential to facilitate systemic therapy treatment breaks. The role of radiotherapy as a supplement to immunotherapy in MPC is an area of active investigation. Randomized trials assessing quality of life and cost-effectiveness of radiotherapy would be beneficial to further understand the value of radiotherapy in the context of MPC. In the interim, clinicians considering the use of SBRT as a palliative measure for the primary tumor as well as in the setting of metastasis-directed therapy should continue to practice shared decision-making with a thorough discussion of the risks and benefits as well as a communication regarding the limitations of the current evidence base. Similarly, radiotherapy delivered specifically as a means to induce an antitumor immune response should be provided on prospective studies at this time.


Funding: None.


Provenance and Peer Review: This article was commissioned by the Guest Editor (Michael D. Chuong) for the series “Novel Therapies for Pancreas Cancer” published in Digestive Medicine Research. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at

Peer Review File: Available at

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at The series “Novel Therapies for Pancreas Cancer” was commissioned by the editorial office without any funding or sponsorship. The authors have no other 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See:


  1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33. [Crossref] [PubMed]
  2. Pancreatic Cancer — Cancer Stat Facts [Internet]. [cited 2022 Jul 18]. Available online:
  3. Wong AA, Delclos ME, Wolff RA, et al. Radiation dose considerations in the palliative treatment of locally advanced adenocarcinoma of the pancreas. Am J Clin Oncol 2005;28:227-33. [Crossref] [PubMed]
  4. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806-13. [Crossref] [PubMed]
  5. Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol 2019;37:1558-65. [Crossref] [PubMed]
  6. Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol 2020;38:2830-8. [Crossref] [PubMed]
  7. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with unresectable pancreatic cancer. A prospective randomized trial. Ann Surg 1993;217:447-55; discussion 456-7. [Crossref] [PubMed]
  8. Crippa S, Domínguez I, Rodríguez JR, et al. Quality of life in pancreatic cancer: analysis by stage and treatment. J Gastrointest Surg 2008;12:783-93; discussion 793-4. [Crossref] [PubMed]
  9. Hudgins PT, Meoz RT. Radiation therapy for obstructive jaundice secondary to tumor malignancy. Int J Radiat Oncol Biol Phys 1976;1:1195-8. [Crossref] [PubMed]
  10. Wolny-Rokicka E, Sutkowski K, Grządziel A, et al. Tolerance and efficacy of palliative radiotherapy for advanced pancreatic cancer: A retrospective analysis of single-institutional experiences. Mol Clin Oncol 2016;4:1088-92. [Crossref] [PubMed]
  11. Lahoud MJ, Kourie HR, Antoun J, et al. Road map for pain management in pancreatic cancer: A review. World J Gastrointest Oncol 2016;8:599-606. [Crossref] [PubMed]
  12. Herman JM, Hoffman JP, Thayer SP, et al. Management of the Primary Tumor and Limited Metastases in Patients With Metastatic Pancreatic Cancer. J Natl Compr Canc Netw 2015;13:e29-36. [Crossref] [PubMed]
  13. Buwenge M, Macchia G, Arcelli A, et al. Stereotactic radiotherapy of pancreatic cancer: a systematic review on pain relief. J Pain Res 2018;11:2169-78. [Crossref] [PubMed]
  14. Rwigema JC, Parikh SD, Heron DE, et al. Stereotactic body radiotherapy in the treatment of advanced adenocarcinoma of the pancreas. Am J Clin Oncol 2011;34:63-9. [Crossref] [PubMed]
  15. Didolkar MS, Coleman CW, Brenner MJ, et al. Image-guided stereotactic radiosurgery for locally advanced pancreatic adenocarcinoma results of first 85 patients. J Gastrointest Surg 2010;14:1547-59. [Crossref] [PubMed]
  16. Su TS, Liang P, Lu HZ, et al. Stereotactic body radiotherapy using CyberKnife for locally advanced unresectable and metastatic pancreatic cancer. World J Gastroenterol 2015;21:8156-62. [Crossref] [PubMed]
  17. Ebrahimi G, Rasch CRN, van Tienhoven G. Pain relief after a short course of palliative radiotherapy in pancreatic cancer, the Academic Medical Center (AMC) experience. Acta Oncol 2018;57:697-700. [Crossref] [PubMed]
  18. Koong AJ, Toesca DAS, Baclay JRM, et al. The Utility of Stereotactic Ablative Radiation Therapy for Palliation of Metastatic Pancreatic Adenocarcinoma. Pract Radiat Oncol 2020;10:274-81. [Crossref] [PubMed]
  19. Ji X, Zhao Y, He C, et al. Clinical Effects of Stereotactic Body Radiation Therapy Targeting the Primary Tumor of Liver-Only Oligometastatic Pancreatic Cancer. Front Oncol 2021;11:659987. [Crossref] [PubMed]
  20. Hammer L, Hausner D, Ben-Ayun M, et al. Single-Fraction Celiac Plexus Radiosurgery: A Preliminary Proof-of-Concept Phase 2 Clinical Trial. Int J Radiat Oncol Biol Phys 2022;113:588-93. [Crossref] [PubMed]
  21. Jacobson G, Fluss R, Dany-BenShushan A, et al. Coeliac plexus radiosurgery for pain management in patients with advanced cancer: study protocol for a phase II clinical trial. BMJ Open 2022;12:e050169. [Crossref] [PubMed]
  22. Pavic M, Niyazi M, Wilke L, et al. MR-guided adaptive stereotactic body radiotherapy (SBRT) of primary tumor for pain control in metastatic pancreatic ductal adenocarcinoma (mPDAC): an open randomized, multicentric, parallel group clinical trial (MASPAC). Radiat Oncol 2022;17:18. [Crossref] [PubMed]
  23. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-703. [Crossref] [PubMed]
  24. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-25. [Crossref] [PubMed]
  25. Hackert T, Niesen W, Hinz U, et al. Radical surgery of oligometastatic pancreatic cancer. Eur J Surg Oncol 2017;43:358-63. [Crossref] [PubMed]
  26. Breton C, Meyer A, Malka D, et al. Local treatment of pancreatic cancer metastases: A multicenter French study of the AGEO group. Clin Res Hepatol Gastroenterol 2021;45:101607. [Crossref] [PubMed]
  27. Gebauer F, Damanakis AI, Popp F, et al. Study protocol of an open-label, single arm phase II trial investigating the efficacy, safety and quality of life of neoadjuvant chemotherapy with liposomal irinotecan combined with Oxaliplatin and 5-fluorouracil/Folinic acid followed by curative surgical resection in patients with hepatic Oligometastatic adenocarcinoma of the pancreas (HOLIPANC). BMC Cancer 2021;21:1239. [Crossref] [PubMed]
  28. Scorsetti M, Comito T, Franceschini D, et al. Is there an oligometastatic state in pancreatic cancer? Practical clinical considerations raise the question. Br J Radiol 2020;93:20190627. [Crossref] [PubMed]
  29. Lee G, Kim DW, Oladeru OT, et al. Liver Metastasis-Directed Ablative Radiotherapy in Pancreatic Cancer Offers Prolonged Time Off Systemic Therapy in Selected Patients: Data From a Multi-institutional Retrospective Study. Pancreas 2021;50:736-43. [Crossref] [PubMed]
  30. Elamir AM, Karalis JD, Sanford NN, et al. Ablative Radiation Therapy in Oligometastatic Pancreatic Cancer to Delay Polyprogression, Limit Chemotherapy, and Improve Outcomes. Int J Radiat Oncol Biol Phys 2022;114:792-802. [Crossref] [PubMed]
  31. Damanakis AI, Ostertag L, Waldschmidt D, et al. Proposal for a definition of "Oligometastatic disease in pancreatic cancer". BMC Cancer 2019;19:1261. [Crossref] [PubMed]
  32. Lee JS, Rhee TM, Pietrasz D, et al. Circulating tumor DNA as a prognostic indicator in resectable pancreatic ductal adenocarcinoma: A systematic review and meta-analysis. Sci Rep 2019;9:16971. [Crossref] [PubMed]
  33. Lee MS, Pant S. Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities. Am Soc Clin Oncol Educ Book 2021;41:1-13. [Crossref] [PubMed]
  34. Marabelle A, Le DT, Ascierto PA, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 2020;38:1-10. [Crossref] [PubMed]
  35. Leidner R, Sanjuan Silva N, Huang H, et al. Neoantigen T-Cell Receptor Gene Therapy in Pancreatic Cancer. N Engl J Med 2022;386:2112-9. [Crossref] [PubMed]
  36. Lundy J, McKay O, Croagh D, et al. Exceptional Response to Olaparib and Pembrolizumab for Pancreatic Adenocarcinoma With Germline BRCA1 Mutation and High Tumor Mutation Burden: Case Report and Literature Review. JCO Precis Oncol 2022;6:e2100437. [Crossref] [PubMed]
  37. Danilova L, Ho WJ, Zhu Q, et al. Programmed Cell Death Ligand-1 (PD-L1) and CD8 Expression Profiling Identify an Immunologic Subtype of Pancreatic Ductal Adenocarcinomas with Favorable Survival. Cancer Immunol Res 2019;7:886-95. [Crossref] [PubMed]
  38. Sideras K, Biermann K, Yap K, et al. Tumor cell expression of immune inhibitory molecules and tumor-infiltrating lymphocyte count predict cancer-specific survival in pancreatic and ampullary cancer. Int J Cancer 2017;141:572-82. [Crossref] [PubMed]
  39. Golden EB, Frances D, Pellicciotta I, et al. Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death. Oncoimmunology 2014;3:e28518. [Crossref] [PubMed]
  40. Wan S, Pestka S, Jubin RG, et al. Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. PLoS One 2012;7:e32542. [Crossref] [PubMed]
  41. Reits EA, Hodge JW, Herberts CA, et al. Radiation modulates the peptide repertoire, enhances MHC class I expression, and induces successful antitumor immunotherapy. J Exp Med 2006;203:1259-71. [Crossref] [PubMed]
  42. Menon H, Ramapriyan R, Cushman TR, et al. Role of Radiation Therapy in Modulation of the Tumor Stroma and Microenvironment. Front Immunol 2019;10:193. [Crossref] [PubMed]
  43. Lugade AA, Moran JP, Gerber SA, et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector cells that traffic to the tumor. J Immunol 2005;174:7516-23. [Crossref] [PubMed]
  44. Dovedi SJ, Cheadle EJ, Popple AL, et al. Fractionated Radiation Therapy Stimulates Antitumor Immunity Mediated by Both Resident and Infiltrating Polyclonal T-cell Populations when Combined with PD-1 Blockade. Clin Cancer Res 2017;23:5514-26. [Crossref] [PubMed]
  45. Azad A, Yin Lim S, D'Costa Z, et al. PD-L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy. EMBO Mol Med 2017;9:167-80. [Crossref] [PubMed]
  46. Xie C, Duffy AG, Brar G, et al. Immune Checkpoint Blockade in Combination with Stereotactic Body Radiotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma. Clin Cancer Res 2020;26:2318-26. [Crossref] [PubMed]
  47. O'Reilly EM, Oh DY, Dhani N, et al. Durvalumab With or Without Tremelimumab for Patients With Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2019;5:1431-8. [Crossref] [PubMed]
  48. Chen IM, Johansen JS, Theile S, et al. Randomized Phase II Study of Nivolumab With or Without Ipilimumab Combined With Stereotactic Body Radiotherapy for Refractory Metastatic Pancreatic Cancer (CheckPAC). J Clin Oncol 2022;40:3180-9. [Crossref] [PubMed]
  49. Parikh AR, Szabolcs A, Allen JN, et al. Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial. Nat Cancer 2021;2:1124-35. [Crossref] [PubMed]
  50. Gilabert M, Chanez B, Rho YS, et al. Evaluation of gemcitabine efficacy after the FOLFIRINOX regimen in patients with advanced pancreatic adenocarcinoma. Medicine (Baltimore) 2017;96:e6544. [Crossref] [PubMed]
  51. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-13. [Crossref] [PubMed]
  52. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 2015;372:2509-20. [Crossref] [PubMed]
  53. Hu ZI, Shia J, Stadler ZK, et al. Evaluating Mismatch Repair Deficiency in Pancreatic Adenocarcinoma: Challenges and Recommendations. Clin Cancer Res 2018;24:1326-36. [Crossref] [PubMed]
  54. Dewan MZ, Galloway AE, Kawashima N, et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 2009;15:5379-88. [Crossref] [PubMed]
  55. Schaue D, Ratikan JA, Iwamoto KS, et al. Maximizing tumor immunity with fractionated radiation. Int J Radiat Oncol Biol Phys 2012;83:1306-10. [Crossref] [PubMed]
  56. Tsai MH, Cook JA, Chandramouli GV, et al. Gene expression profiling of breast, prostate, and glioma cells following single versus fractionated doses of radiation. Cancer Res 2007;67:3845-52. [Crossref] [PubMed]
  57. Brooks ED, Chang JY. Time to abandon single-site irradiation for inducing abscopal effects. Nat Rev Clin Oncol 2019;16:123-35. [Crossref] [PubMed]
  58. Dovedi SJ, Adlard AL, Lipowska-Bhalla G, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res 2014;74:5458-68. [Crossref] [PubMed]
  59. Young KH, Baird JR, Savage T, et al. Optimizing Timing of Immunotherapy Improves Control of Tumors by Hypofractionated Radiation Therapy. PLoS One 2016;11:e0157164. [Crossref] [PubMed]
doi: 10.21037/dmr-22-54
Cite this article as: Lin TA, Narang A. The role of radiotherapy in metastatic pancreatic cancer: a narrative review. Dig Med Res 2023;6:15.

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