Abstract
Background/Aim: In Japan, proton beam therapy (PBT) for locally advanced pancreatic cancer was administered under an advanced medical treatment system until 2022; since then, it has been covered by national insurance. Our hospital initiated PBT for pancreatic cancer in July 2022. This study evaluated the clinical outcomes of PBT for pancreatic cancer after the initiation of national insurance coverage and assessed whether our initial experience at our hospital reproduced previously reported results.
Patients and Methods: This study included 10 patients with pancreatic cancer confirmed as inoperable due to locally advanced stage, comorbidity, or refusal to undergo surgery, without distant metastasis. All patients received a total PBT dose of 67.5 Gy (relative biological effectiveness) delivered in 25 fractions.
Results: The median follow-up durations for all and surviving patients were 13.9 months (range=3.9-24.6 months) and 19.5 months (range=8.1-24.6 months), respectively. The 1- and 2-year overall survival and local control rates were 70% and 35%, and 89% and 89%, respectively. No grade 3 or higher acute or late non-hematological toxicities associated with PBT were observed.
Conclusion: The clinical outcomes at the newly established PBT facility were comparable and reproducible to those observed in patients treated under the previous advanced medical treatment system.
Introduction
Proton beam therapy (PBT) offers advantages over conventional X-ray radiotherapy because of its physical characteristics, including distal tail-off and a sharp lateral penumbra, which enable a favorable dose distribution by allowing higher doses to be delivered to the tumors while minimizing exposure to surrounding healthy tissues (1-3). These advantages have led to favorable clinical outcomes, contributing to widespread adoption of PBT (4-6). Among the cancer types shown to benefit from PBT is pancreatic cancer, with reported 1- and 2-year overall survival (OS) rates of 78% and 35-51%, respectively, and 1- and 2-year local control (LC) rates of 83-90% and 75-79%, respectively, without severe toxicity (7, 8).
In Japan, PBT for locally advanced pancreatic cancer has been covered by national insurance since 2022. Shonan Kamakura General Hospital (SKGH) initiated abdominal PBT in July 2022, becoming the first facility to begin treating pancreatic cancer with PBT following the introduction of national insurance coverage for the disease. Although favorable clinical outcomes have been reported in Japan (7, 8), the studies were conducted under the advanced medical treatment system, in which medical expenses were not covered by national insurance and may have included a relatively wealthy and health-conscious patient population, potentially introducing bias in patient background. To date, as far as we are aware, no studies have exclusively analyzed patient groups treated after the implementation of national insurance coverage.
This study reports the clinical outcomes of PBT for pancreatic cancer following the initiation of national insurance coverage and evaluates whether the initial experience at our hospital reproduces previously reported clinical results.
Patients and Methods
Patient eligibility. This retrospective study reviewed the medical records of patients with pancreatic cancer who were treated with PBT at SKGH between July 2022 and December 2023. A total of 10 consecutive patients met the following eligibility criteria: (i) Inoperable pancreatic cancer due to locally advanced stage, comorbidity, or refusal to undergo surgery; (ii) absence of distant metastasis; (iii) a prescribed dose of 67.5 Gy [relative biological effectiveness (RBE)]; and (iv) Eastern Cooperative Oncology Group performance status ≤2. Patients were excluded if they had direct invasion of the gastrointestinal tract, intractable infection in the target area, or other active malignancies. Clinical stage was determined based on the eighth edition of the Union for International Cancer Control/American Joint Committee on Cancer TNM staging system (9). The study protocol was reviewed and approved by the SKGH Institutional Review Board (approval number: TGE02564-024) and written informed consent was obtained from all patients prior to treatment initiation.
Proton beam therapy. Before undergoing PBT, patients were immobilized using fixation cushions and thermoplastic shells to capture treatment-planning computed tomography (CT) images. Both respiratory-gated and four-dimensional CT scans were performed. The movement of the tumor was tracked using four-dimensional CT images to ensure that PBT was administered within a 3 mm range of the tumor’s peak expiratory movement. PBT was administered once daily, five days per week (Monday to Friday). Treatment-planning CT images were combined with contrast-enhanced CT images to accurately outline the gross tumor volume. The clinical target volume for the primary tumor (CTVPri) was defined as the gross tumor volume with a minimum margin of 5-mm in all directions. The clinical target volume for the prophylactic area (CTVPro) encompassed the regional lymph nodes and associated neuroplexus. Areas that overlapped with the gastrointestinal tract were excluded from the CTVPri and CTVPro. The planning target volumes for the primary tumor and prophylactic area (PTVPri and PTVPro) included the CTVPri and CTVPro with a 3-mm margin for possible positioning errors. The planning organ-at-risk volume was obtained by adding a 7-mm margin to the gastrointestinal tract. When the PTVPri or PTVPro overlapped with this, the margin was reduced accordingly.
The PBT dose was calculated using the VQA system (Hitachi, Tokyo, Japan). The radiation dose calculation for the target volume and surrounding normal structures was expressed in Gy (RBE), defined as the physical dose multiplied by the RBE of PBT (10). The prescribed PBT dose was 67.5 Gy (RBE) for PTVPri and 50 Gy (RBE) for PTVPro, delivered in 25 fractions using a simultaneously integrated boost technique. Dose constraints were defined as a maximum dose to the gastrointestinal tract of <50 Gy (RBE) and to the spinal cord of <40 Gy (RBE). Figure 1 illustrates the dose distribution of PBT.
Axial computed tomography image showing the dose distribution for an 80-year-old female patient with pancreatic body cancer treated with proton beam therapy. The gross tumor volume is shaded in red. Isodose curves are displayed as follows: Red: 95%, orange: 90%, yellow: 80%, green: 65%, light blue: 50%, and purple: 20%, with 100% corresponding to 67.5 Gy relative biological effectiveness.
Statistical analysis. All statistical analyses were performed using JMP Pro 12.2.0 software (SAS Institute, Inc., Cary, NC, USA). OS was measured from the date of PBT initiation and initial treatment to the date of death or the most recent follow-up. LC was defined as no evidence of tumor regrowth on CT, magnetic resonance imaging, or positron-emission tomography in the irradiated tumor bed, with or without continuous elevation of blood levels of tumor markers, including carbohydrate antigen 19-9 (CA19-9). LC was measured from the date of PBT initiation to the date of local failure or the most recent follow-up. Progression-free survival (PFS) was defined as the absence of progression of both local and distant metastases. PFS was measured from the date of PBT initiation to the date of tumor progression or death from any cause. The probabilities of OS, LC, and PFS were estimated using the Kaplan–Meier method. Variable risk was expressed as a hazard ratio with a corresponding 95% confidence interval (CI). Patients were followed up every 3 months after PBT completion. Acute and late toxicities were graded using the Common Terminology Criteria for Adverse Events (version 5.0) of the National Cancer Institute (11). Acute and late toxicities were evaluated as the highest grades of toxicity that occurred immediately following and up to 3 months after, respectively, the initiation of PBT.
Results
Patient characteristics. Ten consecutive patients were enrolled in the study. Patient characteristics are summarized in Table I. The median duration of follow-up from the initial treatment considering all patients was 27.6 months (range=3.8-52.2 months). The median follow-up durations from the start of PBT initiation and for all surviving patients were 13.9 months (range=3.9-24.6 months) and 19.5 months (range= 8.1-24.6 months), respectively. The median age at PBT initiation was 81 years (range=48-87 years). Three patients received concurrent chemotherapy with PBT: two with S-1 and one with gemcitabine. Prior to treatment with PBT, one patient received gemcitabine plus nab-paclitaxel (GnP) and liposomal irinotecan in combination with fluorouracil (5-FU)/leucovorin; two patients received GnP, two patients underwent surgery followed by adjuvant S-1; one patient received neoadjuvant GnP, underwent surgery, and then received adjuvant S-1; one patient received GnP and radiofrequency ablation for liver metastases; and three patients were treatment-naïve. All patients received 67.5 Gy (RBE) in 25 fractions and completed the PBT regimen as scheduled.
Characteristics of patients with pancreatic cancer treated with proton beam therapy of 67.6 Gy (relative biological effectiveness) (n=10).
Clinical results. The median OS, LC, and PFS after PBT were 14.3 months, not reached, and 10.0 months, respectively. The median OS from initial treatment was 31.2 months. The 1- and 2-year OS, LC, and PFS rates after PBT were 70% and 35% (95% CI=38-90% and 12-68%), 89% and 89% (95% CI=50-98%), and 48% and 36% (95% CI=20-77% and 14-70%), respectively (Figure 2). Additionally, the 2- and 3-year OS rates from initial treatment were 70% and 38% (95% CI=38-90% and 12-68%), respectively. Six patients died during the follow-up period, five due to pancreatic cancer and one from ischemic heart disease. One patient developed both local recurrence and peritoneal dissemination. Four patients developed distant organ metastasis without local recurrence: Two developed liver metastasis, one developed lung metastasis, and one developed peritoneal dissemination along with bone and liver metastases.
Kaplan–Meier curves for survival of patients with pancreatic cancer treated with proton beam therapy (n=10). (A) Overall survival, (B) local control, (C) progression-free survival, and (D) overall survival from initial treatment.
No grade 3 or higher acute or late non-hematological toxicities were associated with PBT. All recorded acute and late toxicities are presented in Table II. One patient developed a grade 3 hepatic abscess as a late toxicity, and another developed grade 2 pyelonephritis as an acute toxicity; both events were deemed unrelated to PBT.
Acute and late toxicities experienced by patients with pancreatic cancer treated with proton beam therapy graded by Common Terminology Criteria for Adverse Events, version 5.0 (n=10).
Management post-PBT. Four out of the five patients without recurrence received chemotherapy: Two received GnP; one received gemcitabine followed by liposomal irinotecan plus 5-FU/leucovorin; and one received 5-FU/leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Among the five patients with recurrence, three received chemotherapy; one received gemcitabine; one received liposomal irinotecan plus 5-FU/leucovorin after PBT, followed by GnP and palliative radiotherapy; and one received liposomal irinotecan plus 5-FU/leucovorin, followed by gemcitabine.
Discussion
This study evaluated the clinical outcomes of PBT for pancreatic cancer after the initiation of national insurance coverage and assessed whether the initial experience reproduced previously reported clinical results.
Previous reports of PBT for pancreatic cancer have demonstrated 1- and 2-year OS rates of 78% and 35-51%, and 1- and 2-year LC rates of 83-90% and 75-79%, respectively (7, 8). Furthermore, studies on carbon-ion radiotherapy (C-ion RT) have reported 2-year OS and LC rates of 53-57% and 76-82%, respectively (12, 13). In the present study, the 1- and 2-year OS rates were 70% and 35%, respectively, whereas the 1- and 2-year LC rates were 89% and 89%, respectively. Although the follow-up period was relatively short and the sample size limited, these outcomes are comparable to those of previous studies on particle therapy, demonstrating that clinical outcomes similar to those achieved under the advanced medical treatment system can be reproduced at newly established PBT facilities following the introduction of national insurance coverage. With regard to the prescribed PBT dose, prior studies have reported favorable LC outcomes with 67.5 Gy (RBE) (7), which is the standard dose administered at our hospital. This likely contributed to the favorable LC observed in this study. Taken together, the clinical outcomes of PBT in the present study, along with previous clinical results from particle therapy, appear comparable.
Recent chemotherapy studies for locally advanced pancreatic cancer conducted by Japan Clinical Oncology Group have reported median OS from the initiation of treatment of 21.3 and 23.0 months in patients treated with GnP and FOLFIRINOX, respectively (14). Although our study may be biased towards chemotherapy responders, the median OS was 31.2 months from the initiation of treatment, despite the inclusion of elderly patients, suggesting a potential life-prolonging effect of PBT. In C-ion RT, the median OS for locally advanced pancreatic cancer in patients who received adequate chemotherapy was reported as 29.6 months from C-ion RT and 34.5 months from the initial treatment (12), which is longer than that reported by Japan Clinical Oncology Group. These findings support the notion that the addition of local therapy may be beneficial for patients with locally advanced pancreatic cancer.
Most patients diagnosed with locally advanced pancreatic cancer may already have microscopic distant metastases at the time of RT and are therefore likely to benefit from systemic therapy. A previous study reported that there were no limitations regarding the timing of RT before or after chemotherapy, and that RT could be effectively administered at any point during the course of chemotherapy (12). In the present study, patient backgrounds, such as the duration of chemotherapy prior to proton therapy and the presence or absence of surgery, varied. Due to the small sample size in the present study, prognosis was not analyzed based on these factors. However, considering the survival duration after initial treatment or PBT, it is suggested that PBT contributed to prolonged survival, regardless of surgical history or prior duration of chemotherapy.
Study limitations. Firstly, it was a single-center retrospective study with a small sample size. Secondly, the study included patients with various backgrounds and postoperative recurrences. However, previous reports have indicated that postoperative treatment with C-ion RT yielded outcomes comparable to those of initial treatment with C-ion RT, despite slightly inferior LC (15). Given the limited number of cases, analyzing all cases simultaneously is considered acceptable in the context of reporting the initial experience with PBT at a newly established facility.
In conclusion, the clinical outcomes at the newly established PBT facility were comparable and reproducible to those of patients treated under the previous advanced medical treatment system.
Acknowledgements
The Authors would like to thank all the patients who participated in this study, the staff of the Department of Radiation Oncology at Shonan Kamakura General Hospital, and Editage (www.editage.com) for English language editing.
Footnotes
Authors’ Contributions
Conceptualization, S. Shiba; investigation, S. Shiba; resources, S. Shiba and K.T.; patient treatment, S. Shiba, S. Shiraishi, K.K., and K.T.; writing-original draft preparation, S. Shiba; writing-review and editing, S. Shiba, S. Shiraishi, K.K., Y.F., N.I., K.T., and M.O.; visualization, S. Shiba; supervision, K.T.; project administration, S. Shiba and K.T.
Conflicts of Interest
All Authors declare that they have no conflicts of interest.
Funding
This research received no external funding.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine-learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received April 14, 2025.
- Revision received May 14, 2025.
- Accepted May 20, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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