Introduction
Biliary tract cancer is relatively rare but increasing in occurrence; additionally, it is characterized by aggressive malignancy with generally poor prognosis1. For this cancer, surgical resection is the standard of care for curative intention.; however, most patients present locally advanced and/or unresectable disease at diagnosis. Effective treatments for these patients are being investigated, and systemic therapy has contributed significantly to unresectable disease, with a median survival of a year2, 3–4.
In unresectable non-metastatic biliary cancer, radiotherapy with or without chemotherapy has been employed to control local disease5, which is a major cause of disease failure. Recently, advanced techniques have been introduced, such as stereotactic radiotherapy (SBRT)6,7, intensity-modulated radiotherapy (IMRT)8, and particle beam therapy9,10. These techniques have the potential to escalate the irradiation dose to tumors compared with conventional radiotherapy. Among them, proton beam therapy (PBT) presents a unique physical characteristic of the Bragg peak that allows increased dose delivery to the tumor without increasing the dose to healthy tissue9,10. In Japan, all proton-beam facilities began registration in 2016 to evaluate the efficacy and safety of PBT for malignant carcinoma prospectively, including extrahepatic cholangiocarcinoma (EHC).
At first, we reported outcomes for EHC and gallbladder cancer11. To perform a more comprehensive analysis, we updated the data of outcomes after PBT for EHC with larger number of patients, excluding those with gallbladder cancer. In addition, we report the outcome for elderly patients because our population included older patients than those included in previous important randomized trials12, 13–14, some of whom could not receive standard systemic therapy.
Results
A total of 201 patients who underwent PBT for EHC between May 2016 and June 2021 were enrolled. Among them, 124 with initial definitive PBT were included in the analysis. The male-to-female ratio was 81:43, and the median age was 76 years old (44–91 years old).
Diagnoses were based on pathology (n = 92, 74.2%) or imaging/tumor markers (n = 32, 25.8%). The perihilar group included younger patients who received higher prescribed doses. The median tumor diameter was 30.00 mm (range: 3.00–90.00). The median prescribed dose was 67.5 Gy (RBE) (range: 50–72.6 Gy (RBE)) in 25 fractions (range: 22–30 fractions). Three major types of prescribed dose were (1) 50–60 Gy (RBE)/25–30 fraction, n = 41; used for tumors located near the gastrointestinal tract, (2) 67.5 Gy (RBE)/25 fraction, n = 34; using simultaneous integrated boost, and (3) 70.2–72.6 Gy (RBE)/22–26 fraction, n = 48; used for perihilar type. The detailed background data of the patients are summarized in Table 1.
Table 1. Patients characteristics in total population and each location of tumor.
Variables | Strata | Total (n = 124) | Distal (n = 21) | Perihilar (n = 103) | p—value |
|---|---|---|---|---|---|
No. (%) or Median [range] | No. (%) or Median [range] | No. (%) or Median [range] | |||
Age | 76.00 [44.00, 91.00] | 81.00 [58.00, 91.00] | 74.00 [44.00, 89.00] | 0.007 | |
Gender | Female | 43 (34.7) | 5 (23.8) | 38 (36.9) | 0.319 |
Male | 81 (65.3) | 16 (76.2) | 65 (63.1) | ||
ECOG.PS | 0 | 88 (71.5) | 11 (57.9) | 77 (74.7) | 0.075 |
1 | 29 (23.6) | 6 (31.6) | 23 (22.5) | ||
2 | 5 ( 4.1) | 2 (10.5) | 2 (2.0) | ||
3 | 1 ( 0.8) | 0 (0.0) | 1 (1.0) | ||
Liver function (Child Pugh category) | Normal—A | 109 (87.9) | 20 (95.2) | 89 (86.4) | 0.551 |
B | 14 (12.1) | 1 (4.8) | 13 (12.6) | ||
C | 1 ( 0.8) | 0 (0.0) | 1 (1.0) | ||
Diagnosis | Pathological | 92 (74.2) | 19 (90.5) | 73 (70.9) | 0.098 |
Imaging + tumor markers | 32 (25.8) | 2 ( 9.5) | 30 (29.1) | ||
Tumor diameter | mm | 30.00 [3.00, 90.00] | 24.00 [9.00, 77.00] | 31.00 [3.00, 90.00] | 0.019 |
T | 1 | (-) | 6 ( 31.6) | 7 ( 7.4) | NA |
2 | (-) | 8 ( 42.1) | 24 ( 25.5) | ||
3 | (-) | 4 ( 21.1) | 12 ( 12.8) | ||
4 | (-) | 1 ( 5.3) | 51 ( 54.3) | ||
NA | 5 (25.0) | 3 (4.6) | |||
N | 0 | 90 (78.9) | 11 (57.9) | 79 (83.2) | 0.027 |
1 | 24 (21.1) | 8 (42.1) | 16 (16.8) | ||
NA | 10 ( 8.0) | 2 ( 9.5) | 8 ( 6.8) | ||
Stage | 1 | (-) | 7 (33.3) | 10 ( 9.7) | NA |
2 | (-) | 10 (47.6) | 25 (24.3) | ||
3 | (-) | 2 ( 9.5) | 15 (14.6) | ||
4 | (-) | 2 ( 9.5) | 52 (50.5) | ||
NA | 2 ( 9.5) | 8 ( 7.8) | 0.095 | ||
Chemotherapy | Yes | 64 (51.6) | 7 (33.3) | 57 (55.3) | 0.093 |
Concurrent | 51 (41.1) | 6 (28.6) | 45 (43.7) | ||
Neoadjuvant | 37 (29.8) | 2 (9.5) | 35 (34.0) | ||
Adjuvant | 28 (22.6) | 3 (14.3) | 25 (24.3) | ||
No | 60 (48.4) | 14 (66.7) | 46 (44.7) | < 0.001 | |
Prescribed dose (type of treatment schedules) | 70.2–72.6 Gy (RBE) / 22—26 fr | 48 (38.7) | 1 ( 4.8) | 47 (45.6) | < 0.001 |
67.5 Gy (RBE)/ 25–30 fr | 34 (27.4) | 3 (14.3) | 31 (30.1) | ||
50–60 Gy (RBE)/ 25–30 fr | 41 (33.1) | 17 (81.0) | 24 (23.3) | ||
Other | 1 ( 0.8) | 0 ( 0.0) | 1 ( 1.0) | ||
[BED10: Gy10] | 85.7 [60.00, 96.56] | 72.00 [60.00, 96.56] | 85.7 [60.00, 96.56] | < 0.001 | |
Distance between tumor and gastrointestinal tract | < 1 cm | 91 (73.4) | 19 ( 90.5) | 72 (69.9) | 0.105 |
1—2 cm | 17 (13.7) | 2 ( 9.5) | 15 (14.6) | ||
2 cm ≤ | 16 (12.9) | 0 ( 0.0) | 16 (15.5) |
BED10 Biological equivalent dose = n*d*(α/β + d)/(a/b + 2), α/β = 10, n number of fractionation, d single dose.
p—value was calculated between perihilar and distal groups, and calculated excluding NA.
Bold values indicate statistically significance, NA not available.
T and stage classification was cited only in subgroup because of different definition of classification among primary site.
Based on a median follow-up of 17.0 months (18.3 months for surviving patients), the median survival time (MST) was 20.0 months (95% CI: 17.3–22.8 months), and the 1- and 2-year OS rates were 73.8% (95% confidence interval [CI]: 64.6–81.0% and 36.9% (95% CI: 27.3–46.4%) (Fig. 1), respectively.
[See PDF for image]
Fig. 1
Survival analysis. Overall survival rate (OS), progression free survival rate (PFS) and local control (LC) in total population.
Recurrence was observ7ed in 57 cases; the initial site of progression was local (n = 26), lymph node (n = 4), and distant metastases (n = 27). The pattern of failure during follow-up period was shown in supplemental Fig. 1. The Median PFS was 13.9 months (95% CI: 11.5–16.6 months), and the 1- and 2-year PFS were 56.1% (95% CI: 46.6–64.0%) and 23.5% (95% CI: 15.8–32.1%) (Fig. 1), respectively. The 1- and 2-year LCs were 85.3% (75.7%–91.3%) and 65.2% (95% CI: 50.0%–76.8%) (Fig. 1).
Multivariate analyses were performed to evaluate factors with possible relationships with OS, PFS, and LC (Table 2). Poor liver function (Child B–C; hazard ratio [HR] = 2.889, 95% CI: 1.52–5.477, p = 0.001), tumor diameter > 3 cm (HR = 1.753, 95% CI: 1.112–2.761, p = 0.015), and distance from the gastrointestinal (GI) tract ≤ 2 cm (HR = 0.3426, 95% CI: 0.154–0.759, p = 0.008) significantly affected the OS. Patients with normal liver function or Child–Pugh class A was 39.7% at 2-year OS, whereas that of Child–Pugh class B or C patients was 14.3% (Fig. 2a , p= 0.0357). Patients with a tumor diameter > 3 cm showed a 32.6% 2-year OS, whereas patients with a tumor diameter ≤ 3 cm indicated 41.6% (Fig. 2b , p= 0.0739). Patients with a tumor distance from the GI tract ≥ 2 cm showed a 52.8% 2-year OS, whereas those with < 2 cm showed 33.9% (Fig. 2c , p= 0.0253).
Table 2. Multi-variate analysis of potential predictive factors for overall survival, and local control.
Variable | Strata | PT No | 2-year (%) | HR | 95% CI | p—value |
|---|---|---|---|---|---|---|
Overall survival | ||||||
Liver function (Child-Pugh category) | Normal-A | 109 | 39.7 | – | ||
B/C | 15 | 14.3 | 2.889 | 1.52—5.477 | 0.001 | |
Tumor diameter | ≤ 3 cm | 50 | 41.6 | – | ||
3 cm < | 74 | 32.6 | 1.753 | 1.112—2.761 | 0.015 | |
Distance from GI | < 2 cm | 108 | 33.9 | – | ||
2 cm ≤ | 16 | 52.8 | 0.3426 | 0.154—0.759 | 0.008 | |
Local control | ||||||
Prescribed dose: BED10 | ≤89Gy10 | 75 | 47.1 | – | ||
89 Gy10 < | 49 | 83.7 | 0.3061 | 0.119—0.787 | 0.014 | |
Bold values indicate statistically significance.
CI confidence interval, HR hazard ratio, BED Biological equivalent dose.
[See PDF for image]
Fig. 2
Survival analysis according to predisposing factors. (a) OS according to liver function. (b) OS according to tumor diameter. (c) OS according to distance tumor from gastrointestinal tract (GI distance). (d) LC according to prescribed dose. (e) OS according to age.
The prescribed dose significantly affected the LC. Higher prescribed doses (˃ 89 Gy10; HR = 0.3061, 95% CI: 0.119–0.787, p = 0.014) significantly affected the LC. The 2-year LC of patients with higher prescribed doses (˃ 89 Gy10), i.e., 83.7%, was higher than that of patients with lower prescribed doses (≤ 89 Gy10), i.e., 47.1% (Fig. 2d, p= 0.00982).
The background of patient characteristics and outcomes between elderly and young patients is shown in Supplementary Table 1. Elderly patients had more distal tumor and received a similar treatment schedule except for less frequent administration of chemotherapy compared to younger counterparts. The 2-year OS was 41.3% in those aged 75 years and older, similar to the 2-year OS of 32.0% in those younger than 75 years (MST 20.1 and 20.0 months, Fig. 2e, p= 0.927). The local control, progression free survival and toxicity results for older patients were also comparable to those observed in younger patients (Supplementary Table 1).
The MST for patients with distal bile duct was 19.1 months (95% CI: 8.8–31.6 months), whereas it was 20.0 months (95% CI: 16.7–22.8 months) for patients with perihilar lesions (Supplemental Fig. 1a, p= 0.707). For the patients with distal and perihilar lesions, their 2-year OS, PFS, and LC rates were (41.7% and 35.7%, Supplemental Fig. 2a), (22.8% and 32.4%), and (29.2% and 71.7%, Supplemental Fig. 2b), respectively.
At the final follow-up, grade 3 adverse reactions occurred in 18 patients (18/124, 14.5%), and a relationship with PBT could not be excluded (Table 3). Five (4.0%) patients experienced acute toxicities during or within 90 d of PBT completion, whereas fifteen patients (12.1%) experienced late toxicity (Table 3).
Table 3. PBT related toxicity grade 3.
Location | Toxicity | Acute toxicity | Late toxicity | ||
|---|---|---|---|---|---|
PT NO | (%) | PT NO | (%) | ||
Gastrointestinal | Stomach bleeding | 1 | (0.8%) | ||
Duodenal bleeding | 2 | (1.6%) | |||
Duodenal perforation | 1 | (0.8%) | |||
Bile duct | Cholangitis | 3 | (2.4%) | 4 | (3.2%) |
Bile duct stenosis | 1 | (0.8%) | 3 | (2.4%) | |
Cholecystitis | 1 | (0.8%) | |||
Liver | Liver dysfunction | 3 | (2.4%) | 2 | (1.6%) |
Absces | 1 | (0.8%) | |||
Other | Hematological toxicity | 1* | (0.8%) | 1* | (0.8%) |
Ascites | 2 | (1.6%) | |||
Total | 5 | (4.0%) | 15 | (12.1%) | |
*Hematological toxicity included neutropenia and leukopenia in acute toxicity and anemia in late toxicity.
Total number of patients did not always equal to summation of each toxicity because several patients showed multiple toxicities.
Discussion
This study aims to update the outcomes of PBT efficacy and toxicity in unresectable EHC based on a multicenter prospective registry study in Japan. In particular, this study reconfirmed that tumor diameter, liver function, and distance between the tumor and gastrointestinal tract were associated with the OS after PBT11. Additionally, an escalated prescribed dose of EHC resulted in improved local control and PFS but was not associated with OS. To date, this is the largest outcome study of EHC treated with PBT. Furthermore, our report provides useful data for treating elderly patients not suitable for standard systemic therapy.
Recently, several advanced radiotherapy techniques, such as SBRT, IMRT, and PBT, have been introduced for the treatment of biliary tract carcinoma6, 7, 8, 9, 10–11. SBRT can escalate the radiation dose with a shallow dose gradient and has been investigated as a potentially curative radiotherapy strategy for patients with biliary cancer6,7. Lee et al. conducted a systematic review of SBRT and reported survival outcomes (MST of 13 months) with 0%–20% late toxicity15. IMRT allows a lower irradiation dose to normal tissues even if they are located near a tumor and has been reported to increase safety profiles in upper abdominal malignancies8,16. PBT can provide superior dose distributions owing to the physical characteristics of the Bragg peak and affords 12–23 months of MST for EHC9,10,17,18. Our data are consistent with those of previous studies, and an MST exceeding 20 months is encouraging.
In several studies, Child–Pugh class and tumor diameter have been suggested as prognostic factors for OS after treatment2,10,18. Additionally, we have discovered that the distance to the GI tract was a significant factor for survival11. A distance greater than 2 cm from the GI tract was associated with better OS, which may improve the dose distribution in PBT and allow the safe irradiation of tumors using higher doses without excessive doses to the GI tract.
Radiation-dose escalation has been shown to improve the outcomes of several hepatobiliary cancers19, 20, 21–22. In liver cancer, LC and OS improved by increasing the irradiation dose in SBRT and PBT19. For intrahepatic cholangiocarcinoma, dose escalation has been associated with improved LC and OS20, 21–22. This correlation was confirmed in a prospective multicenter study involving PBT, and a 2-year survival rate of 46.5% was reported23. However, a different scenario was observed for EHC16,24. Because EHC is located near the bowel, tone cannot easily administer a higher radiation dose while maintaining the dose constraints for the bowel20,25. Nonetheless, several studies reported improvement to the LC10,26, but not to the PFS and OS26, by administering higher doses including our study. Elganainy et al. did not observe any improvement in the OS or LC after administering higher irradiated doses16. In this cohort, we observed a statistically significant relationship between local tumor control and prescribed dose (< 89 Gy10); however, higher prescribed doses did not translate into improved survival in this study. Based on previous data obtained from a retrospective multi-institutional study, we discovered that an escalated prescribed dose was associated with better OS in EHC (MSTs of 25 and 15 months for high- and low-dose groups, respectively)27. This was not reproduced in previous initial prospective data accumulation11 but was confirmed in this cohort. This discrepancy may be caused by failures outside the irradiated area, particularly distant metastases, thus highlighting the importance of systemic therapy.
Systemic chemotherapy is the standard care for patients with unresectable EHC2. However, the benefits combining radiotherapy and chemotherapy remain unclear. Several retrospective studies reported that chemoradiotherapy provided greater efficacy compared with chemotherapy or radiotherapy alone28, 29–30. However, one of the standard treatment regimens, i.e., the combination of gemcitabine plus oxaliplatin (GC), appeared to be at least as efficient as conventional chemoradiotherapy (50 Gy + 5 FU and cisplatin, MST 19.9 months and 13.5 months)24. In this cohort, the addition of chemotherapy did not translate into greater treatment efficacy, in part because elderly patients could not receive standard intensive chemotherapy. In other words, although we treated older patients (median age: 76 years) than previous major randomized control trials (ABC-2; median age 63 years, ABC-06; 65, JCOG13; 67)12, 13–14, they showed good outcomes comparable to younger patients even without systemic therapy. Furthermore, the outcomes observed in elderly patients were comparable to those reported in younger patients who could receive more intensive chemoradiotherapy or systemic therapy2,12, 13–14,21. Therefore, our data provided useful information for elderly patients even when they could not receive standard systemic therapy.
Recent studies may provide insights into the use of immune checkpoint inhibitors (ICIs) in oncology, including biliary cancer. In particular, ICI combinations of GC + Durvalumab31 and GC + Pembrolizumab32 showed superior outcomes compared with conventional standard GC therapy. Therefore, as shown in non-small-cell lung cancer33, chemoradiotherapy following ICI therapy may be a promising strategy for enhancing the immune response in EHC. Charged particle radiotherapy has gained interest as it may enhance tumor immunogenicity compared to conventional radiotherapy due to more lethal unrepaired damage, higher ionization density and thus more complex clustered DNA lesions34. However, whether charged particle in combination with immune therapy will elicit superior antitumor effects both locally and systemically needs to be further investigated.
This prospective data-accumulation study presents some limitations. First, although the study was prospective, the inherent weaknesses of a registry study remained. For example, patient selection criteria were not rigorous. The protocol stipulated only dose fractionation, whereas the target-volume definitions, dose constraints for normal tissues, and follow-up methods were determined at each facility. Additionally, the chemotherapeutic regimens were heterogeneous. Therefore, patients with various backgrounds were included in this study. Despite these limitations, this study included a relatively large sample size for the rare tumor type investigated and provides a comprehensive description of EHC.
In conclusion, these updated multicenter prospective registry data demonstrate that PBT is an effective treatment for unresectable EHC, including in elderly patients.
Methods
Patients who received PBT from May 2016 to June 2021 were registered in a database managed by the Biliary Cancer (excluding intrahepatic cholangiocarcinoma) Working Group of the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology (JASTRO). After obtaining prior approval from ethics committees and written informed consent from all patients, 13 centers participated in the study. The study protocol was reviewed and approved by the Ethical Review Board for Life Science and Medical Research at Hokkaido University Hospital (approval no. 016-0106). This research was performed in accordance with the Declaration of Helsinki.
Eligibility for the study was defined as unresectable EHC, including patients who refused surgery. Irradiation was performed using a respiratory-gated system or a motion tracking system. The initial registration items were name of the center, sex, age, PBT (initial treatment, second or more), localized (localized, with metastasis), surgical indication (operable, inoperable), initial treatment (initial, recurrence), tumor location (hilar, distal, gallbladder), clinical stage (T, N, M; based on the Union for International Cancer Control, version 7), diagnostic method (histologic diagnosis, clinical diagnosis), duplicate cancer (yes, no), radiation-treatment history (yes, no), performance status, treatment policy (radical, nonradical), chemotherapy (neoadjuvant, concurrent, adjuvant) , surgery (pre-, post-), gastrointestinal (GI) tract proximity, PBT method (broad beam, spot scanning), PBT start/end date, total dose, number of fractions, treatment period, irradiation-completion status (complete, complete with break ≥ 8 days, discontinuation at ≥ 50% of schedule, discontinuation at ≤ 50% of schedule), liver function, i.e., Child–Pugh class (A, B, C), maximum tumor diameter (cm), and starting date of PBT. Surgical indication (operable, inoperable) was determined by the cancer board at each facility, with the participation of radiation oncologists, gastroenterologists, and surgeons.
The registration items were late adverse events (yes, no), date of confirmation of late adverse events, classification of late adverse events, grade of late adverse events, version 4 (Common Terminology Criteria for Adverse Events version 4, grade 3 or higher), status (death from EHC, survival with recurrence, survival without recurrence, unknown), confirmation date of survival status, recurrence (yes, no), confirmation date of recurrence, site of recurrence (inside irradiated field, outside irradiated field and in side liver, affiliated lymph nodes, distant metastasis, unknown), secondary cancer (yes, no), confirmation date of secondary cancer, and registered at least once a year.
Details of the treatment at each institution have been described elsewhere10, 11, 12–13. Briefly, PBT planning was performed using a 3-dimensional treatment planning system with CT simulation. Locoregional irradiation was performed in areas with obvious lesions, and prophylactic irradiation of lymphatic areas was generally not performed. Daily irradiation was delivered using a respiratory-guided system or a motion-tracking system11.
We analyzed the overall survival (OS) as the primary endpoint and progression-free survival (PFS), local control rate (LC), and toxicity as second endpoints. The study protocol was performed by the principles of the Declaration of Helsinki. This study was performed by the Biliary Tract Cancer (excluding intrahepatic cholangiocarcinoma) Working Group of the Particle Beam Therapy Committee and Subcommittee at the JASTRO.
Statistical analyses
StatView 5.0 and the EZR stat package were used for statistical analysis35. Percentages were analyzed using Fishers exact test, and Student’s t-tests were performed for normally distributed data. The Mann–Whitney U-test for skewed data was performed for comparison. The Kaplan–Meier method was used to analyze the OS, PFS, and LC, all of which were calculated beginning from the first day of PBT. Multivariate Cox regression models were applied for OS, PFS, and local control. The candidate covariates in these models were age, sex, performance status (0–1 vs. 2–3), liver function (Child–Pugh class, normal A vs. B, C), tumor location (hilar or distal), tumor size (< 3 vs. 3 ≤ cm), nodal status, use of chemotherapy, distance between tumor and gastrointestinal tract (< 2 vs. 2 ≤ cm), and prescribed dose (Biologically Effective Dose: BED < 89 Gy10 vs. 89 Gy10 ≤). Variable selection for multivariate models was conducted using the stepwise method with the AIC, and p < 0.05 was considered statistically significant. When not specified, cut-off values were set at the median or mean value.
Acknowledgements
This work was supported by Hokkaido University (Functional enhancement promotion expenses by the Ministry of Education, Culture, Sports, Science and Technology) and AMED under Grant Number JP16lm0103004.
Author contributions
Authorship contribution: H. Y.: Formal analysis, Investigation, Methodology, Writing—original draft. T. K.: Data curation, Writing—review & editing. Kei Shibuya: Data curation, Investigation, review & editing. M. S.: Data curation, Investigation, review & editing. K. T.: Data curation, Investigation review & editing. T. I.: Data curation, Investigation review & editing. M. W.: Data curation, Investigation review & editing. Takayuki Hashimoto: Resources, Software. T. F.: Writing—review & editing. Validation. M. O.: Writing—review & editing. Validation. M. M.: Data curation, Investigation. T. O.: Data curation, Investigation. H. S.: Data curation, Investigation, Supervision, T. O.: Data curation, Investigation. T. A.: Data curation, Investigation. M. T.: Data curation, Investigation. M. A. Data curation, Investigation. T. W.: Data curation, Investigation. S. M.: Data curation, Investigation. H. O.: Data curation, Investigation. N. K.: Data curation, Investigation, Funding acquisition. T. H.: Data curation, Investigation, Funding acquisition. H. H.: Data curation, Investigation. N. F.: Data curation, Investigation. All authors reviewed the manuscript. Informed consent forms were obtained through the ethics committee application, and the study received approval from the ethics committee. Informed consent (including for publication) was obtained from all individual participants.
Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1038/s41598-025-06575-9.
Publisher’s note
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Abstract
This study aimed to analyze the efficacy and safety of a prospective, multicenter registry study of proton beam therapy (PBT) for extrahepatic cholangiocarcinoma (EHC) in Japan. Patients who underwent PBT for EHC between May 2016 and June 2021 were registered in the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology. We updated the overall survival (OS), progression-free survival (PFS), local control rate (LC), and toxicity. Among 201 registered cases, 124 cases including elder population (median age 76 years old, range; 44–91) with initial definitive PBT were evaluated. The follow-up period for survivors was 18.3 months, the median OS time was 20.0 months (95% CI: 17.3–22.8 months), and the 2-year OS rate was 36.9% (27.3–46.4%). The 2-year LC and PFS were 65.2% and 23.0%. The OS was significantly higher for tumor size < 3 cm vs. ≥ 3 cm (p = 0.015); liver function Child–Pugh score normal/A vs. B/C (p < 0.001); and distance of the tumor from the gastrointestinal tract > 2 cm vs. ≤ 2 cm (p = 0.008) in multivariate analysis. Elderly patients age > 75 years underwent less chemotherapy and showed a 2-year OS of 41.3%, whereas young patients with age ≤ 75 years showed a 2-year OS of 32.0%. A higher prescribed dose (biologically effective dose: BED) > 89 Gy10 was associated with better LC and PFS but not OS. PBT-related grade 3 acute and late adverse events occurred in 4.0 and 12.1% of the patients, respectively. These updated multicenter prospective registry data demonstrate that PBT is an effective treatment for unresectable EHC, including in elderly patients.
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Details
1 Kyoto Prefectural University of Medicine, Department of Radiology, Graduate School of Medical Science, Kyoto, Japan (GRID:grid.272458.e) (ISNI:0000 0001 0667 4960); Kyoto Prefectural University of Medicine, Department of Radiology, Kyoto, Japan (GRID:grid.272458.e) (ISNI:0000 0001 0667 4960)
2 Gunma University Heavy Ion Medical Center, Maebashi, Japan (GRID:grid.256642.1) (ISNI:0000 0000 9269 4097)
3 Kyoto Prefectural University of Medicine, Department of Radiology, Graduate School of Medical Science, Kyoto, Japan (GRID:grid.272458.e) (ISNI:0000 0001 0667 4960)
4 Department of Radiation Oncology, Southern TOHOKU Proton Therapy Center, Koriyama, Japan (GRID:grid.508290.6)
5 Hyogo Ion Beam Medical Center, Department of Radiology, Hyogo, Japan (GRID:grid.413699.0) (ISNI:0000 0004 1773 7754)
6 University of Tsukuba Hospital, Department of Radiation Oncology, Proton Medical Research Center, Tsukuba, Japan (GRID:grid.412814.a) (ISNI:0000 0004 0619 0044)
7 QST Hospital, National Institutes for Quantum Science and Technology, Chiba, Japan (GRID:grid.482503.8) (ISNI:0000 0004 5900 003X)
8 Medipolis Proton Therapy and Research Center, Ibusuki, Kagoshima, Japan (GRID:grid.486811.2)
9 Sapporo Teishinkai Hospital, Proton Therapy Center, Sapporo, Japan (GRID:grid.486811.2)
10 Aizawa Hospital, Proton Therapy Center, Matsumoto, Nagano, Japan (GRID:grid.413462.6) (ISNI:0000 0004 0640 5738)
11 Tsuyama Chuo Hospital, Department of Radiology, Tsuyama, Japan (GRID:grid.417325.6) (ISNI:0000 0004 1772 403X)
12 Fukui Prefectural Hospital, Proton Therapy Center, Fukui, Japan (GRID:grid.415124.7) (ISNI:0000 0001 0115 304X)
13 Nagoya City University West Medical Center, Department of Radiation Oncology, Nagoya Proton Therapy Center, Nagoya, Japan (GRID:grid.260433.0) (ISNI:0000 0001 0728 1069)
14 Hokkaido University Faculty of Medicine, Department of Radiation Oncology, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691)
15 Hokkaido University, Global Center for Biomedical Science and Engineering, Faculty of Medicine, Sapporo, Japan (GRID:grid.39158.36) (ISNI:0000 0001 2173 7691)
16 National Cancer Center Hospital East, Department of Radiation Oncology and Particle Therapy, Kashiwa, Japan (GRID:grid.497282.2)
17 Kobe Proton Center, Department of Radiation Oncology, Kobe, Japan (GRID:grid.497282.2)
18 Kobe University Graduate School of Medicine, Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe, Japan (GRID:grid.31432.37) (ISNI:0000 0001 1092 3077)
19 Chiba University, Department of General Surgery, Graduate School of Medicine, Chiba, Japan (GRID:grid.136304.3) (ISNI:0000 0004 0370 1101)