Abstract
PURPOSE
External beam radiation therapy (EBRT) has gained delayed acceptance as a recommended first-line treatment modality for patients with hepatocellular carcinoma (HCC), given limited evidence that it improves overall survival (OS). We analyzed individual patient data (IPD) from an international cohort to assess OS among patients with HCC treated with EBRT.
METHODS
We performed a systematic review of publications that assessed EBRT, met prespecified technical standards for HCC, and reported OS (search date December 15, 2022). Corresponding authors were invited to submit IPD for the study. We performed Kaplan-Meier survival analyses to determine OS and restricted mean survival time (RMST) stratified by Barcelona Clinic Liver Cancer (BCLC) stage and treatment status (ie, treatment-naïve and experienced). We performed random effects Cox proportional hazards modeling to assess clinical characteristics associated with OS.
RESULTS
Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. The median OS was 6.8 years (95% CI, 5.7 to 8.7) for BCLC-0 and 4.6 years (95% CI, 4.1 to 5.1) for BCLC-A. Among treatment-naïve patients, the median OS was not reached (95% CI, 8.6 to not reached) for BCLC-0 and was 5.4 years (95% CI, 4.5 to 6.7) for BCLC-A. In multivariable models, more advanced BCLC stage, higher tumor burden, worse performance status, and Child-Pugh class B or C were associated with a higher risk of mortality. Ablative radiation dose and more recent year of treatment were associated with a reduced risk of death.
CONCLUSION
To our knowledge, this study represents the largest multinational cohort of patients with HCC treated with EBRT. OS outcomes with EBRT for very early- and early-stage HCC appear to be comparable with resection, thermal ablation, and other ablative locoregional therapies. These data support the inclusion of EBRT in the BCLC HCC clinical decision-making process.
INTRODUCTION
Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide.1 Treatment decisions for HCC are guided by factors such as tumor burden, degree of liver dysfunction, and patient Eastern Cooperative Oncology Group performance status (ECOG-PS).2-4
CONTEXT
Key Objective
What is the overall survival (OS) after liver-directed external beam radiation therapy (EBRT) for hepatocellular carcinoma (HCC)?
Knowledge Generated
In this individual patient data meta-analysis, including nearly 5,000 patients from 30 centers across 11 countries, patients with very early- or early-stage HCC treated with EBRT had OS comparable with resection, thermal ablation, or other local ablative therapies. OS outcomes were particularly favorable for treatment-naïve patients with well-preserved liver disease.
Relevance (C. Chung)
External beam radiotherapy is a treatment to be considered as first-line therapy for patients with HCC and should be considered an option in clinical management and further investigated in clinical trials of combinatorial therapy.*
*Relevance section written by JCO Associate Editor Caroline Chung, MD, MSc, FRCPC.
Historically, external beam radiotherapy (EBRT) was used cautiously for primary liver cancers because of the liver's radiosensitivity and technical challenges regarding precise, image-guided, conformal tumor targeting and safe delivery of ablative doses.5 Consequently, EBRT has been slow to hold a central place in widely adopted consensus guidelines until recently,3,4,6 including a major update in the 2025 Barcelona Clinic Liver Cancer (BCLC) treatment algorithm.7 However, advances in imaging and radiation delivery techniques, alongside improved understanding of normal liver tolerance, have led to an increasing volume of clinical data on EBRT for HCC over the past two decades.8-10
Recent prospective randomized studies of EBRT for HCC have provided favorable results in certain scenarios, including proton beam radiotherapy or stereotactic body radiotherapy (SBRT) treating recurrent/residual disease11,12 and inoperable patients,13 SBRT compared with transarterial chemoembolization (TACE),14,15 SBRT combined with systemic therapy,16 and EBRT for palliation of HCC-related capsular pain.17 However, compared with most other therapies for HCC, there are less data defining outcomes after EBRT for HCC across the spectrum of BCLC stages.
To inform clinical practice, we performed an international, multicenter individual patient data (IPD) study to assess overall survival (OS) after liver-directed EBRT for HCC. To assemble an unbiased international cohort to participate in the IPD meta-analysis, we performed a systematic review of the literature to identify institutions based on their published technical standards. These institutions were then invited to contribute IPD data to be pooled for meta-analysis.
METHODS
Data Coordinating Center and Regulatory Approval
The University of North Carolina served as the data coordinating center for this IPD meta-analysis. This study was registered to the PROSPERO database (CRD42023467399).
The study was reviewed by the University of North Carolina institutional review board (IRB# 22-0918) and, given that it was limited to secondary data analysis, was deemed to be exempt from further review under 45 Code of Federal Regulations 46.104. The IRB determined that this project meets the definition of a limited data set under Code of Federal Regulations 45, Part 164.514 (e). Data use agreements were required for the transfer of limited data sets from each participating institution.
Inclusion Criteria
We performed a systematic literature review to objectively and comprehensively identify centers that had demonstrated the ability to deliver ablative radiation for HCC and had published relevant patient outcomes. These centers were then invited to contribute IPD to this multinational meta-analysis. We included manuscripts that (1) were in the English language, (2) published full manuscript or conference abstract, (3) included at least 10 individuals with HCC, (4) assessed the role of EBRT in HCC, (5) reported on OS, and (6) included liver-directed EBRT that met minimum technical requirements to be considered ablative. We excluded reports with (1) <10 patients or (2) combined therapies (eg, a priori plan for EBRT and other locoregional treatment or concurrent systemic therapy). Additional details on included studies and modified Delphi (mDelphi) process to define ablative radiotherapy18 can be found in the Supplementary Materials.
Identification of Eligible Studies
A health sciences librarian searched PubMed, Embase (Elsevier), Scopus (Elsevier), the Cochrane Library, and ClinicalTrials.gov through the last search date of December 15, 2022. The search strategy for all databases is available in the Supplementary Material. All unique references were placed into Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia, available at www.covidence.org). Two reviewers (AM and TY) independently reviewed abstracts and full texts to identify studies that fit inclusion criteria. Discrepancies were resolved by consensus or by a third reviewer (MR), when needed.
Invitations to Corresponding Authors and Transfer of Data
Corresponding authors from identified full texts were contacted via e-mail and invited to participate in the study. A limited data set with identifiers removed was transferred. Additional details of author invitations and data transfer are available in the Supplementary Materials.
Clinical Variables and Outcomes Collected
Corresponding authors provided baseline patient and treatment data, patient outcomes (eg, retreatment, liver transplantation, and death), and dates of events. The primary outcome was OS. To participate, authors were required to submit data on mandatory variables and were requested to submit additional nonmandatory data variables (Supplementary Materials).
Statistical Analysis
Quantitative variables were expressed as mean (and standard deviation) and median (and IQR, 25th-75th percentiles). Categorical variables were presented as absolute frequencies and percentages (%). Poisson models were used to calculate rates and 95% CIs. We performed Kaplan-Meier survival analyses to determine median OS among all patients with HCC treated with liver-directed EBRT. We calculated pooled OS and restricted mean survival time (RMST) at 3 years, by BCLC stage and stratified by prior treatment at the patient level (eg, treatment-naïve and previously treated). RMST, defined as the area under the survival curve up to a specific time, provides some advantages over median OS including consideration of the entire survival curve, statistical stability, and intuitive interpretation.19 The BCLC stage was adjudicated based on the reported tumor burden, the presence of vascular/metastatic spread, ECOG PS, and CP score. Patients with no cirrhosis were categorized as CP-A. Adjudication was performed to minimize center-level variability in BCLC staging. We performed a sensitivity analysis using the investigator-reported BCLC stage. We additionally calculated pooled OS in the following predefined subgroups: CP score, modified Albumin-Bilirubin (mALBI) score, etiology (hepatitis C virus [HCV], hepatitis B virus [HBV], nonviral), and treatment type (protons, photons, carbon ions).
We performed random effects Cox proportional hazards modeling with complete case analysis to assess baseline and tumor characteristics associated with OS in EBRT-treated patients. In all analyses, we accounted for the center of treatment. Covariates for inclusion in these models were determined a priori. Models 1-4 included the BCLC stage (adjudicated) or components of the BCLC stage, alpha fetoprotein (AFP) (ng/mL), ablative radiation dose (BED10 ≥ 80 Gy), year of treatment, and/or etiology of liver disease. While each center was required to provide information on post-EBRT transplantation, given the retrospective design, we were unable to determine if patients were treated with an a priori plan to proceed to transplant (ie, bridging therapy) or if they received salvage liver transplant because of tumor or liver disease progression. Therefore, we performed sensitivity analysis considering liver transplantation a competing risk of death.
Formal tests of the proportional hazard assumption indicated deviations from proportionality for several covariates, for Models 1-4. Because the RMST difference is a robust measure of treatment effect that does not rely on the proportional hazards assumption, we report RMST estimates as our primary measure of effect. While hazard ratios from Cox models are also presented for comparability, they should be interpreted with caution considering these proportional hazards violations.
All statistical analyses were performed using SAS v9.4 software (SAS Institute, Cary, NC).
RESULTS
Systematic Review Results
A PRISMA flow diagram of the systematic review is presented in Figure 1. All 96 centers meeting eligibility criteria were invited, and 30 (31%) groups from 11 countries agreed to participate.
FIG 1.
PRISMA flow diagram of included studies.
Patient Characteristics
Data were provided on 4,913 patients treated with EBRT with a median follow-up time of 5.0 years. Patient and treatment characteristics of the combined cohort and stratified by BCLC stage are presented in Tables 1 and 2. Most patients had BCLC stage C disease (n = 2685, 58%), and this was primarily driven by having vascular invasion (n = 1,129, 42% of BCLC-C) and/or ECOG >0 (n = 1,259, 71% of BCLC-C). In the entire cohort (inclusive of all BCLC stages), 57% had ECOG PS 0. Regarding hepatic tumor burden, the highest proportion of patients had a solitary nodule ≥2 cm (46%) followed by a solitary nodule <2 cm (17%), multifocal HCC (19%), or ≤3 lesions all ≤3 cm (16%). Most patients had HBV (32%) or HCV (30%) etiology, cirrhosis (80%), Child-Pugh A class (73%), and albumin-bilirubin (ALBI) score 1 (48%) or 2 (48%) grades. The median AFP was 14 ng/mL (IQR, 4-165).
TABLE 1.
Patient Characteristics of the Overall Cohort and Stratified by Adjudicated BCLC Stage
| Baseline Characteristicb | Overall (N = 4,913)a | BCLC-0 (n = 484) | BCLC-A (n = 1,123) | BCLC-B (n = 213) | BCLC-C (n = 2685) | BCLC-D (n = 147) |
|---|---|---|---|---|---|---|
| Age, years, mean (SD) | 67 (10) | 66 (10) | 67 (10) | 67 (10) | 67 (11) | 65 (9) |
| Male sex, No. (%) | 3,748 (76) | 322 (67) | 869 (77) | 171 (80) | 2073 (77) | 111 (76) |
| Cirrhosis, No. (%) | 3,690 (75) | 418 (86) | 878 (78) | 141 (66) | 2047 (76) | 127 (86) |
| Etiology, No. (%) | ||||||
| ALD | 521 (11) | 50 (10) | 111 (10) | 34 (16) | 270 (10) | 19 (13) |
| HBV | 1,573 (32) | 243 (50) | 334 (30) | 49 (23) | 895 (33) | 18 (12) |
| HCV | 1,459 (30) | 124 (26) | 346 (31) | 78 (37) | 775 (29) | 47 (32) |
| MASLD | 410 (8) | 15 (3) | 124 (11) | 16 (8) | 22 (8) | 28 (19) |
| Other/unknown | 950 (19) | 52 (11) | 208 (19) | 36 (17) | 523 (19) | 35 (24) |
| ALBI grade, No. (%) | ||||||
| 1 | 1,731 (35) | 264 (55) | 446 (40) | 103 (48) | 887 (33) | 19 (13) |
| 2 | 1,720 (35) | 140 (29) | 374 (33) | 73 (34) | 1,071 (40) | 45 (31) |
| 3 | 148 (3) | 7 (1) | 11 (1) | 1 (0) | 84 (3) | 43 (29) |
| mALBI grade, No. (%) | ||||||
| 1 | 1,731 (35) | 264 (55) | 446 (40) | 103 (48) | 887 (33) | 19 (13) |
| 2a | 646 (13) | 76 (16) | 159 (14) | 27 (13) | 360 (13) | 17 (12) |
| 2b | 1,074 (35) | 64 (13) | 215 (19) | 46 (22) | 711 (26) | 28 (19) |
| 3 | 148 (3) | 7 (1) | 11 (1) | 1 (<1) | 84 (3) | 43 (29) |
| Child-Pugh class, No. (%) | ||||||
| Ac | 3,583 (73) | 437 (90) | 957 (85) | 176 (83) | 1,886 (70) | 8 (5) |
| B | 871 (18) | 40 (8) | 140 (12) | 29 (14) | 601 (22) | 29 (20) |
| C | 96 (2) | — | — | — | — | 17 (12) |
| Unknown/missing | 363 (7) | — | — | — | — | 93 (63) |
| ECOG, No. (%) | ||||||
| 0 | 2675 (57) | 484 (100) | 1,123 (100) | 213 (100) | 774 (29) | 25 (17) |
| 1 | 1,611 (34) | — | — | — | 1,578 (59) | 50 (34) |
| 2 | 344 (7) | — | — | — | 333 (12) | 17 (12) |
| >2 | 55 (1) | — | — | — | — | 67 (46) |
| Total tumor burden, No. (%) | ||||||
| Solitary nodule <2 cm | 766 (17) | 484 (100) | — | — | 250 (10) | 10 (7) |
| Solitary nodule ≥2 cm | 2152 (46) | — | 858 (76) | — | 1,160 (46) | 65 (46) |
| ≤3 lesions all ≤3 cm | 724 (16) | — | 265 (24) | — | 399 (16) | 35 (25) |
| Multifocal | 902 (19) | — | — | 194 (91) | 641 (25) | 30 (21) |
| Unknown | 98 (2) | — | — | 19 (9) | 77 (3) | 2 (1) |
| Vascular invasion, No. (%) | ||||||
| Yes | 1,167 (24) | — | — | — | 1,129 (42) | 28 (19) |
| No | 3,589 (73) | 484 (100) | 1,122 (>99) | 212 (>99) | 1,481 (55) | 114 (78) |
| Unknown/missing | 156 (3) | 0 (0) | 2 (<1) | 1 (<1) | 74 (3) | 5 (3) |
| Extrahepatic spread, No. (%) | ||||||
| Yes | 449 (9) | — | — | — | 423 (16) | 14 (10) |
| No | 4,287 (87) | 484 (100) | 1,122 (>99) | 212 (>99) | 2167 (81) | 128 (87) |
| Unknown/missing | 177 (4) | 0 (0) | 1 (<1) | 1 (<1) | 95 (4) | 5 (3) |
| AFP (ng/mL) (median, IQR) | 14 (4-165) | 7 (4-23) | 8 (4-40) | 17 (5-265) | 28 (5-523) | 17 (5-336) |
| BCLC (investigator reported), No. (%) | ||||||
| 0 | 383 (8) | 224 (46) | 40 (4) | 2 (1) | 100 (4) | 9 (6) |
| A | 1,258 (26) | 105 (22) | 557 (50) | 13 (6) | 486 (18) | 40 (27) |
| B | 542 (11) | 32 (7) | 133 (12) | 99 (46) | 198 (7) | 4 (3) |
| C | 1,006 (20) | 2 (<1) | 23 (2) | 7 (3) | 944 (35) | 12 (8) |
| D | 32 (1) | 0 (0) | 0 (0) | 0 (0) | 4 (<1) | 28 (19) |
| Missing | 483 (10) | 72 (15) | 61 (5) | 20 (9) | 314 (12) | 8 (5) |
Abbreviations: AFP, alpha fetoprotein; ALBI, albumin-bilirubin; ALD, alcohol-associated liver disease; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; mALBI, modified albumin-bilirubin; MASLD, metabolic dysfunction-associated steatotic liver disease; SD, standard deviation.
The total number is higher than BCLC categories summed given missing component variables used to determine the BCLC stage.
Because of missingness in some variables, percentages may not total 100%.
Inclusive of patients with no cirrhosis.
TABLE 2.
Treatment Characteristics of the Overall Cohort and Stratified by Adjudicated BCLC Stage
| Characteristica | Overall (N = 4,913) | BCLC-0 (n = 484) | BCLC-A (n = 1,123) | BCLC-B (n = 213) | BCLC-C (n = 2685) | BCLC-D (n = 147) |
|---|---|---|---|---|---|---|
| Pretreatment characteristics | ||||||
| Treatment-naïve patient | 1,983 (40) | 134 (28) | 468 (42) | 89 (42) | 1,085 (40) | 79 (54) |
| Prior LRT | 2827 (58) | 350 (72) | 650 (58) | 121 (57) | 1,522 (57) | 65 (44) |
| Prior systemic therapy | 221 (4) | 1 (<1) | 20 (2) | 12 (6) | 151 (6) | 3 (2) |
| EBRT treatment characteristics | ||||||
| No. of liver lesions treated | 1 (1-1) | 1 (1-1) | 1 (1-1) | 1 (1-3) | 1 (1-1) | 1 (1-1) |
| Size of the largest lesion (cm) | 3.1 (1.9-5.6) | 1.4 (1.1-1.6) | 2.8 (2.1-4.3) | 4.1 (3.0-6.2) | 4.0 (2.3-7.4) | 3.2 (2.2-4.7) |
| Treatment modality | ||||||
| Photons | 2176 (44) | 158 (33) | 407 (36) | 101 (47) | 1,446 (54) | 62 (42) |
| Protons | 1,778 (36) | 299 (62) | 527 (47) | 50 (23) | 833 (31) | 54 (37) |
| Days of treatment | 11 (7-14) | 11 (6-14) | 11 (7-14) | 10 (4-14) | 11 (8-14) | 9 (4-13) |
| EBRT prescription dose (GyE) | 45 (36-58) | 60 (42-66) | 48 (40-66) | 45 (40-52) | 42 (33-50) | 40 (30-50) |
| Fractions | 6 (5-10) | 6 (5-10) | 5 (5-10) | 5 (4-10) | 6 (5-10) | 5 (3-5) |
| Adaptive treatment | 1,069 (22) | 118 (24) | 316 (28) | 61 (29) | 530 (20) | 42 (29) |
| Post-treatment characteristics | ||||||
| Planned, not salvage, sequential treatment | 401 (8) | 4 (1) | 52 (5) | 24 (11) | 309 (12) | 8 (5) |
| Salvage treatment for recurrence or progression | 191 (4) | 15 (3) | 57 (5) | 16 (8) | 100 (4) | 2 (1) |
| Liver transplant | 289 (6) | 25 (5) | 104 (9) | 15 (7) | 111 (4) | 20 (14) |
| Time to LT, years | 0.8 (0.5-1.5) | 1.5 (0.9-2.8) | 0.9 (0.6-1.6) | 1.4 (0.9-2.1) | 0.9 (0.5-1.3) | 0.4 (0.2-0.7) |
NOTE. Data are presented as No. (%) or median (IQR).
Abbreviations: BCLC, Barcelona Clinic Liver Cancer; EBRT, external beam radiation therapy; GyE, Gray Equivalent; LT, liver transplantation; LRT, locoregional therapy.
Because of missingness in some variables, percentages may not total 100%.
Treatment Characteristics
Among the entire cohort, 1,983 (40%) were treatment-naïve, and among previously treated patients (n = 2930, 60%), 2827 (96%) received prior locoregional therapies and 221 (8%) received prior systemic therapy. The most common EBRT treatment modality was photons (n = 2176, 54%), followed by protons (n = 1,778, 44%) and carbon ions (n = 78, 2%). Among those receiving photon therapy, the median dose delivered was 40 Gy (IQR, 32-48) and the median number of fractions was 6 (IQR, 5-10). For protons, the median dose delivered was 60 GyE (IQR, 40-66) and the median number of fractions was 10 (IQR, 5-10). Among patients with available data on post-EBRT treatments (94.5%), 401 (9%) patients received planned sequential treatment. Among 1,523 (31%) patients with available data on salvage treatment, 13% (191 of 1,523) received salvage treatment for recurrence or progression at the lesion level. Liver transplant was provided to 289 (6%) patients at a median time from EBRT to transplant of 10 months (IQR, 6-18).
Survival by BCLC Stage
The median OS and RMST over 3 years by BCLC stage are included in Table 3. Kaplan-Meier curves for all EBRT-treated patients and treatment-naïve EBRT-treated patients by BCLC stage are included in Figure 2. For patients with BCLC-0 HCC, the median OS was 6.8 years (95% CI, 5.7 to 8.7) and not reached (95% CI, 8.6 to NA) for treatment-naïve BCLC-0 patients. The median OS for patients with BCLC-0 HCC and no cirrhosis/CP-A was 8.6 years (95% CI, 3.3 to not reached), and median OS was not reached for patients who had BCLC-0 disease, had no cirrhosis/CP-A, and were treatment-naïve.
TABLE 3.
Survival by Adjudicated BCLC Stage
| Group | BCLC-0 | BCLC-A | BCLC-B | BCLC-C | BCLC-D | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Median OS (IQR) | RMST, 3 Years (95% CI) | Median OS (IQR) | RMST, 3 Years (95% CI) | Median OS (IQR) | RMST, 3 Years (95% CI) | Median OS (IQR) | RMST, 3 Years (95% CI) | Median OS (IQR) | RMST, 3 Years (95% CI) | |
| All patients | 6.8 (3.0-NA) | 2.7 (2.6 to 2.8) | 4.6 (2.1-11.9) | 2.5 (2.4 to 2.5) | 3.6 (1.7-7.1) | 2.3 (2.2 to 2.5) | 1.7 (0.7-4.4) | 1.8 (1.7 to 1.8) | 0.8 (0.3-2.9) | 1.3 (1.2 to 1.5) |
| Treatment status | ||||||||||
| Naïve | NA (4.9-NA) | 2.7 (2.6 to 2.8) | 5.4 (2.3-9.6) | 2.5 (2.5 to 2.6) | 6.3 (2.4-9.8) | 2.5 (2.3 to 2.7) | 1.5 (0.6-3.9) | 1.7 (1.6 to 1.7) | 0.6 (0.2-2.8) | 1.2 (0.9 to 1.4) |
| Previously treated | 6.0 (2.8-NA) | 2.6 (2.5 to 2.7) | 4.3 (1.8-11.9) | 2.5 (2.4 to 2.6) | 3.0 (1.3-5.1) | 2.2 (2.1 to 2.4) | 1.8 (0.8-4.7) | 1.9 (1.8 to 1.9) | 1.2 (0.5-1.5) | 1.5 (1.2 to 1.6) |
| Child-Pugh class | ||||||||||
| A | 8.6 (3.3-NA) | 2.7 (2.6 to 2.8) | 4.8 (2.3-11.9) | 2.6 (2.5 to 2.6) | 4.0 (2.2-7.4) | 2.5 (2.3 to 2.6) | 2.0 (0.8-4.8) | 1.9 (1.8 to 1.9) | 1.7 (0.7-3.2) | 1.7 (1.3 to 2.1) |
| B7 | 2.9 (1.4-8.1) | 2.2 (1.9 to 2.6) | 2.6 (1.0-6.2) | 2.1 (1.9 to 2.3) | 0.8 (0.6-3.0) | 1.4 (0.8 to 2.0) | 1.2 (0.5-2.4) | 1.5 (1.3 to 1.6) | 0.7 (0.7-1.0) | 1.0 (0.3 to 1.6) |
| B8 | 1.6 (1.2-4.7) | 1.9 (1.0 to 2.8) | 4.2 (1.5-NA) | 2.2 (1.9 to 2.5) | 0.8 (0.5-2.3) | 1.4 (0.6 to 2.2) | 0.8 (0.4-2.2) | 1.2 (1.1 to 1.3) | 0.2 (0.1-0.7) | 0.6 (0.0 to 1.2) |
| B9 | 0.7 (0.2-1.2) | 0.7 (0.0 to 1.4) | 1.0 (0.5-5.0) | 1.7 (0.8 to 2.6) | 1.8 (1.0-2.7) | 1.8 (0.6 to 3.1) | 0.7 (0.3-1.2) | 1.2 (1.0 to 1.4) | 0.7 (0.3-3.3) | — |
| C | — | — | — | — | — | — | — | — | 0.8 (0.3-3.3) | 1.3 (1.1 to 1.6) |
| mALBI grade | ||||||||||
| 1 | 8.8 (4.4-NA) | 2.8 (2.7 to 2.8) | 5.9 (3.0-12.1) | 2.7 (2.6 to 2.7) | 4.5 (2.3-7.1) | 2.5 (2.3 to 2.7) | 2.4 (0.9-5.8) | 2.0 (1.9 to 2.1) | 0.8 (0.5-2.2) | 1.3 (0.8 to 1.8) |
| 2a | 6.7 (2.3-NA) | 2.5 (2.3 to 2.7) | 4.3 (2.1-9.5) | 2.5 (2.4 to 2.6) | 3.7 (3.2-NA) | 2.7 (2.5 to 2.9) | 1.5 (0.7-3.9) | 1.7 (1.6 to 1.8) | 1.6 (0.3-1.8) | 1.4 (0.8 to 2.0) |
| 2b | 3.0 (1.5-8.2) | 2.3 (2.0 to 2.5) | 2.9 (1.1-6.7) | 2.2 (2.0 to 2.3) | 2.3 (0.7-6.3) | 1.9 (1.6 to 2.3) | 1.1 (0.5-2.5) | 1.4 (1.3 to 1.5) | 1.1 (0.2-2.1) | 1.2 (0.8 to 1.6) |
| 3 | 2.0 (0.2-NA) | 1.7 (0.8 to 2.6) | 1.0 (1.0-4.3) | 1.7 (1.0 to 2.4) | 2.7 (2.7-2.7) | 2.7 (2.7 to 2.7) | 0.7 (0.4-2.3) | 1.2 (1.0 to 1.4) | 0.6 (0.2-2.7) | 1.2 (0.8 to 1.6) |
| Etiology | ||||||||||
| ALD | 6.4 (3.0-8.2) | 2.6 (2.4 to 2.8) | 4.3 (1.6-6.2) | 2.3 (2.1 to 2.5) | 3.0 (0.6-6.3) | 2.2 (1.7 to 2.6) | 2.0 (0.8-4.9) | 1.9 (1.8 to 1.9) | 1.5 (0.3-3.9) | 1.6 (1.0 to 2.1) |
| HBV | 8.7 (3.8-NA) | 2.8 (2.7 to 2.9) | 5.5 (2.6-NA) | 2.6 (2.5 to 2.7) | 3.7 (2.1-5.4) | 2.5 (2.3 to 2.7) | 1.7 (0.7-4.4) | 1.8 (1.7 to 1.8) | 0.5 (0.1-1.1) | 1.1 (0.5 to 1.6) |
| HCV | 5.7 (2.3-NA) | 2.6 (2.4 to 2.7) | 4.3 (1.9-9.5) | 2.4 (2.3 to 2.5) | 3.0 (1.1-7.7) | 2.2 (2.0 to 2.4) | 1.6 (0.7-4.5) | 1.7 (1.7 to 1.8) | 0.8 (0.3-1.5) | 1.2 (1.1 to 1.3) |
| MASLD | 5.7 (4.0-NA) | 2.9 (2.6 to 3.1) | 3.3 (2.2-6.7) | 2.5 (2.4 to 2.6) | 2.4 (1.1-NA) | 2.2 (1.7 to 2.7) | 1.7 (0.7-3.8) | 1.7 (1.6 to 1.8) | 2.1 (0.8-3.4) | 1.9 (1.4 to 2.3) |
| Treatment type | ||||||||||
| Photons | 6.4 (3.2-NA) | 2.7 (2.6 to 2.8) | 4.3 (2.0-8.3) | 2.5 (2.4 to 2.6) | 2.4 (1.0-5.4) | 2.1 (1.9 to 2.3) | 1.6 (0.6-3.9) | 1.7 (1.6 to 1.8) | 0.7 (0.1-1.6) | 1.0 (0.7 to 1.3) |
| Protons | 8.6 (2.9-NA) | 2.6 (2.5 to 2.7) | 4.9 (2.1-11.9) | 2.5 (2.4 to 2.6) | 3.5 (2.4-5.0) | 2.5 (2.3 to 2.8) | 1.9 (0.8-4.7) | 1.9 (1.8 to 1.9) | 1.2 (0.3-3.6) | 1.5 (1.2 to 1.8) |
Abbreviations: ALD, alcohol-associated liver disease; BCLC, Barcelona Clinic Liver Cancer; HBV, hepatitis B virus; HCV, hepatitis C virus; mALBI, modified albumin-bilirubin; MASLD, metabolic dysfunction-associated steatotic liver disease; NA, median not reached; RMST, restricted mean survival time.
FIG 2.
OS by BCLC stage in (A) all EBRT-treated patients with HCC and (B) previously treatment-naïve EBRT-treated patients with HCC. BCLC, Barcelona Clinic Liver Cancer; EBRT, external beam radiation therapy; HCC, hepatocellular carcinoma; OS, overall survival.
For patients with BCLC-A HCC, the median OS was 4.6 years (95% CI, 4.1 to 5.1) for all patients and 5.4 years (95% CI, 4.5 to 6.7) for those who were treatment-naïve. For BCLC-A with a solitary lesion, the median OS was 4.6 years (95% CI, 4.2 to 5.4) overall and 5.5 years (95% CI, 4.3 to 6.7) for treatment-naïve. For BCLC-A with multiple lesions (ie, multifocal within Milan criteria), the median OS was 4.3 years (95% CI, 3.5 to 5.5) overall and 4.8 years (95% CI, 2.1 to 6.7) for treatment-naïve. The median OS for patients who had BCLC-A disease and no cirrhosis/CP-A and CP-B was 4.8 years (95% CI, 4.4 to 5.5) and 2.7 years (95% CI, 2.0 to 4.2), respectively.
The median OS was 3.6 years (95% CI, 3.0 to 4.9) for BCLC-B patients and 6.3 years (95% CI, 3.9 to NA) for BCLC-B patients who were treatment-naïve. The median OS was 1.7 years (95% CI, 1.6 to 1.8) for all BCLC-C patients and 1.5 years (95% CI, 1.4 to 1.7) for treatment-naïve patients. Finally, the median OS was 0.8 years (95% CI, 0.7 to 1.4) for BCLC-D patients and 0.6 years (95% CI, 0.3 to 1.4) for BCLC-D, treatment-naïve patients.
In the sensitivity analysis using the investigator-reported BCLC category, patients with BCLC-0 had a median OS of 5.2 years (95% CI, 2.0 to 11.2) and an RMST of 2.5 years (95% CI, 2.4 to 2.6), BCLC-A patients had a median OS of 4.0 years (95% CI, 1.4 to 8.6) and an RMST of 2.3 years (95% CI, 2.2 to 2.3), BCLC-B patients had a median OS of 2.6 years (95% CI, 1.1 to 5.0) and an RMST of 2.1 years (95% CI, 2.0 to 2.2), BCLC-C patients had a median OS of 1.4 years (95% CI, 0.6 to 3.5) and an RMST of 1.6 years (95% CI, 1.5 to 1.7), and BCLC-D patients had a median OS 0.5 years (95% CI, 0.1 to 2.2) and an RMST of 1.0 year (95% CI, 0.6 to 1.4).
Subgroup Analyses
Table 3 demonstrates median OS and RMST at 3 years stratified by BCLC stage and by CP score, mALBI grade, etiology, and treatment type. There were stepwise decreases in OS with more advanced CP score and mALBI grade. In addition, numerically higher OS was observed for patients who had BCLC-0, BCLC-A, or BCLC-B disease. Finally, there appeared to be slightly higher OS for patients treated with protons compared with photons.
Multivariable Models of Factors Associated With OS
Table 4 demonstrates results of unadjusted and multivariable Cox proportional hazards models of patient factors associated with mortality. The Data Supplement (Table S1, online only) displays these models with consideration of liver transplant as a competing risk of death. In multivariable Model 1, a more advanced BCLC stage was associated with increased hazard of death, whereas ablative radiation dose and more recent year of treatment were associated with a decreased risk of death. In multivariable Model 2, factors associated with increased hazard of death included higher ECOG PS, CP class, multifocal HCC, vascular invasion, extrahepatic spread, and increased AFP levels. In this model, factors associated with a reduced risk of death included solitary HCC <2 cm, ablative radiation dose, and more recent year of EBRT treatment. In multivariable Model 3, there was no statistically significant association between any liver disease etiology and mortality in the unadjusted analysis or when accounting for BCLC stage, ablative radiation dose, and year of treatment. Model 4 demonstrated similar results with positive and statistically significant associations between ECOG PS, CP class, tumor burden, and AFP with increased mortality. Results were consistent when considering liver transplant a competing risk of death (Data Supplement, Table S1).
TABLE 4.
Factors Associated With Mortality Among Patients With HCC Treated With EBRT
| Model | Variable | Unadjusted HR | Adjusted HR |
|---|---|---|---|
| Model 1 | BCLC stage (ref = BCLC-0) | ||
| BCLC-A | 1.35 (1.14-1.61) | 1.29 (1.09-1.54) | |
| BCLC-B | 1.80 (1.40-2.32) | 1.73 (1.34-2.22) | |
| BCLC-C | 2.62 (2.23-3.07) | 2.33 (1.98-2.75) | |
| BCLC-D | 4.02 (3.14-5.15) | 3.41 (2.65-4.39) | |
| Ablative radiation dose (yes/no)a | 0.55 (0.51-0.61) | 0.62 (0.56-0.68) | |
| Year of treatment (ref = 2000-2014) | |||
| 2015-2016 | 0.83 (0.74-0.92) | 0.82 (0.74-0.92) | |
| 2017-2018 | 0.82 (0.72-0.03) | 0.85 (0.75-0.97) | |
| 2019-2024 | 0.77 (0.68-0.87) | 0.76 (0.67-0.87) | |
| Model 2 | ECOG PS (ref = 0) | ||
| 1 | 1.42 (1.30-1.54) | 1.27 (1.15-1.40) | |
| 2 | 1.87 (1.62-2.16) | 1.76 (1.48-2.08) | |
| 3 | 2.56 (1.85-3.54) | 2.28 (1.58-3.28) | |
| 4 | 5.10 (1.62-16.06) | 4.49 (1.42-14.22) | |
| Child-Pugh class (ref = CP-A) | |||
| B | 1.79 (1.63-1.97) | 1.61 (1.44-1.80) | |
| C | 2.13 (1.66-2.72) | 2.39 (1.77-3.23) | |
| Tumor burden (ref = Solitary <2 cm) | |||
| Solitary >2 cm | 1.69 (1.49-1.92) | 1.43 (1.24-1.64) | |
| <3 lesions all <3 cm | 1.65 (1.42-1.90) | 1.46 (1.25-1.71) | |
| Multifocal | 2.71 (2.33-3.16) | 2.00 (1.69-2.38) | |
| Vascular invasion | 2.07 (1.88-2.28) | 1.51 (1.35-1.69) | |
| Extrahepatic spread | 2.07 (1.84-2.33) | 1.62 (1.42-1.86) | |
| AFP (ref = 0-4.2) | |||
| >4.2-13.5 | 1.14 (1.01-1.29) | 1.14 (1.01-1.30) | |
| >13.5-165.5 | 1.43 (1.26-1.61) | 1.32 (1.16-1.49) | |
| >165.5 | 2.00 (1.77-2.25) | 1.57 (1.38-1.78) | |
| Ablative radiation dosea | 0.55 (0.51-0.61) | 0.72 (0.65-0.80) | |
| Year of treatment (ref = 2000-2014) | |||
| 2015-2016 | 0.83 (0.74-0.92) | 0.84 (0.74-0.95) | |
| 2017-2018 | 0.82 (0.72-0.03) | 0.88 (0.77-1.01) | |
| 2019-2024 | 0.77 (0.68-0.87) | 0.85 (0.74-0.98) | |
| Model 3 | BCLC stage (ref = BCLC-0) | ||
| BCLC-A | 1.35 (1.14-1.61) | 1.26 (1.06-1.51) | |
| BCLC-B | 1.80 (1.40-2.32) | 1.69 (1.32-2.18) | |
| BCLC-C | 2.62 (2.23-3.07) | 2.28 (1.94-2.69) | |
| BCLC-D | 4.02 (3.14-5.15) | 3.29 (2.55-4.24) | |
| Etiology of liver disease (ref = ALD) | |||
| HBV | 0.86 (0.74-1.00) | 0.92 (0.79-1.07) | |
| HCV | 1.03 (0.90-1.19) | 1.08 (0.94-1.25) | |
| MASLD | 1.12 (0.93-1.34) | 1.16 (0.97-1.40) | |
| Other | 1.02 (0.88-1.18) | 1.04 (0.89-1.21) | |
| Ablative radiation dose (yes/no)a | 0.55 (0.51-0.61) | 0.61 (0.56-0.67) | |
| Year of treatment (ref = 2000-2014) | |||
| 2015-2016 | 0.83 (0.74-0.92) | 0.82 (0.73-0.91) | |
| 2017-2018 | 0.82 (0.72-0.03) | 0.84 (0.74-0.96) | |
| 2019-2024 | 0.77 (0.68-0.87) | 0.75 (0.66-0.85) | |
| Model 4 | ECOG PS (ref = 0) | ||
| 1 | 1.42 (1.30-1.54) | 1.29 (1.17-1.42) | |
| 2 | 1.87 (1.62-2.16) | 1.77 (1.49-2.10) | |
| 3 | 2.56 (1.85-3.54) | 2.27 (1.58-3.27) | |
| 4 | 5.10 (1.62-16.06) | 5.23 (1.66-16.53) | |
| Child-Pugh class (ref = CP-A) | |||
| B | 1.79 (1.63-1.97) | 1.70 (1.53-1.89) | |
| C | 2.13 (1.66-2.72) | 2.70 (2.02-3.62) | |
| Tumor burden (ref = Solitary <2 cm) | |||
| Solitary >2 cm | 1.69 (1.49-1.92) | 1.49 (1.30-1.70) | |
| <3 lesions all <3 cm | 1.65 (1.42-1.90) | 1.49 (1.27-1.74) | |
| Multifocal | 2.71 (2.33-3.16) | 2.09 (1.76-2.48) | |
| Vascular invasion | 2.07 (1.88-2.28) | 1.64 (1.47-1.83) | |
| Extrahepatic spread | 2.07 (1.84-2.33) | 1.68 (1.47-1.93) | |
| AFP (ref = 0-4.2) | |||
| >4.2-13.5 | 1.14 (1.01-1.29) | 1.15 (1.01-1.31) | |
| >13.5-165.5 | 1.43 (1.26-1.61) | 1.33 (1.17-1.50) | |
| >165.5 | 2.00 (1.77-2.25) | 1.60 (1.41-1. 28) | |
Abbreviations: AFP, alpha fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; HR, hazard ratio; MASLD, metabolic dysfunction-associated steatotic liver disease; PS, performance status.
An ablative dose of radiation was defined by a prior study based on expert consensus16 as a BED10 ≥ 80 Gy; AFP and years divided by quartiles; all models accounted for the center of treatment.
DISCUSSION
To our knowledge, this international IPD meta-analysis represents the largest effort to date evaluating outcomes after EBRT for HCC. Drawing from nearly 5,000 patients treated at 30 centers across 11 countries and five continents, this collaborative analysis provides real-world outcomes after EBRT, across all BCLC groups. While retrospective in nature, the scope and depth of this study afford unique insights into the evolving role of EBRT in the management of HCC and provide a critical complement to prospective data.
In this cohort, OS appears to be favorable and stratification by BCLC stage aligns with expectations from the existing literature.2 The BCLC strategy proposes an expected survival for BCLC-0 and A patients of >5 years.2 In our study, the median OS for BCLC-0 patients was 6.8 years, in line with the >5-year survival expectation from the 2022 BCLC update for patients with early-stage (BCLC 0/A) disease. Similarly, the median OS for treatment-naïve BCLC-A patients was 5.4 years and 4.6 years for the entire BCLC-A subgroup. For BCLC-B patients, the median OS was 3.6 years (estimated at >2.5 years in the BCLC strategy),2 and for patients in the subgroup who were treatment-naïve, the survival was 6.3 years. Even in BCLC-C and BCLC-D stages, where survival is generally poor (estimated >2 years and 3 months, respectively)2 and patients may often be treated with systemic therapy alone or supportive care, EBRT was associated with outcomes that compared favorably with expectations. While these patients with advanced stage were a selected subgroup of patients most suitable for EBRT (ie, with liver-dominant rather than extrahepatic-dominant HCC), these findings suggest that EBRT may offer meaningful disease control across the HCC spectrum.
Our findings add to a growing body of prospective randomized trials supporting EBRT as a viable alternative to traditional locoregional therapies. Recent trials comparing EBRT with radiofrequency ablation (RFA) for small recurrent HCC have demonstrated similar OS in EBRT- and RFA-treated groups.12,20 Randomized comparisons of EBRT with TACE have consistently demonstrated superior local control but no significant differences in OS for patients treated with EBRT.13-15 Results from our study provide an important benchmark for ongoing and future randomized trials, which are expected to further elucidate the role of photon and proton EBRT and immunotherapy combinations (eg, NCT03186898, NCT03895359). Our study demonstrates promising OS for patients with HCC treated with EBRT regardless of liver disease etiology, hepatic function (including the added granularity provided by ALBI score), prior treatments, or tumor burden, supporting the need for further prospective evaluation of EBRT for HCC. These data are comparable with the stage-by-stage expected OS outcomes proposed by BCLC guidelines.2
Favorable OS data in our data for treatment-naïve BCLC-0 and BCLC-A patients are especially relevant given the frequent use of EBRT as salvage therapy, which may underestimate its potential benefit. For instance, in the RCT comparing proton EBRT with thermal ablation, the included patients were heavily pretreated (45% receiving prior TACE).11 The excellent outcomes for treatment-naïve patients in our cohort and a small phase 2 study21 suggest that EBRT should be evaluated as a potential frontline therapy.
Multivariable analyses confirmed the prognostic significance of known clinical variables, including tumor burden, liver disease severity, and ECOG PS. In addition, analyses suggested that the EBRT technique and radiation dose may influence outcomes. Specifically, delivery of an ablative radiation dose (BED10 ≥ 80 Gy) was associated with a lower risk of mortality in adjusted models (hazard ratios, 0.61-0.72). Improvements in outcomes over more recent treatment years further suggest that evolving radiotherapy technologies and strategies (eg, improved imaging, image guidance, motion management, computer optimized radiation dose planning, and adaptive treatment), more careful patient selection, and improvements in HCC therapies more generally may contribute to improved survival. Future analyses are planned to more precisely evaluate the role of radiation dose and technique in optimizing patient outcomes, including survival and treatment toxicities.
Our data also demonstrated a numerically higher OS in patients treated with proton therapy relative to photons in several BCLC stage groups (Table 3 and Data Supplement, Fig S1), a finding that has previously been identified in other retrospective data.22 However, these results are subject to confounding bias and further study is needed to investigate the effectiveness of proton compared with photon therapy with careful adjustment for relevant confounders. Of note, the population of patients treated with these two techniques seem to be inherently distinct because of differences in geographical availability, socioeconomic access, insurance status, and other baseline patient characteristics.23,24 Furthermore, the use of protons may be associated with other technical variables, such as tumor volume, radiation dose and fractionation, and dosimetric planning goals. Our study did not have an a priori hypothesis about proton versus photon treatment and therefore did not require submission of these pertinent covariates.
Despite the strengths of our study, including its international reach, granular individual-level data, large sample size, and evaluation of survival using both median OS and RMST, we acknowledge several limitations. As a retrospective analysis, treatment assignment was not randomly assigned, and institutional differences in treatment protocols, radiation technique, and supportive care likely introduced heterogeneity. However, the inclusion of IPD in this analysis allowed us to adjust for key confounders. In addition, we accounted for centers in all multivariable models. Furthermore, there might have been discrepancies in the reporting of clinical factors. Of note, there was a difference between investigator-reported and adjudicated BCLC stages. This occurred for several reasons including the misclassification of patients with a single lesion ≤2 cm as BCLC-A, misclassification of patients with ≤3 lesions ≤3 cm as BCLC-B, and failure to classify patients with ECOG PS > 0 as BCLC-C. We chose to perform our primary analysis using adjudicated BCLC to improve consistency and minimize missing data (since its components were required variables). However, the potential for misclassification remains. For instance, it remains possible that this resulted in patients with CP-C cirrhosis who were transplant candidates being misclassified as BCLC-D. Nonetheless, similar results in the sensitivity analysis using investigator-reported BCLC stages are reassuring. Finally, ECOG >0 was excluded from the BCLC-0/BCLC-A/BCLC-B categories in accordance with the BCLC algorithm. However, it remains possible that patients were classified to have ECOG 1 because of underlying cirrhosis or other comorbidities, which may lead to an overestimate of OS in these groups.
This study offers several important implications for clinical practice and future research. First, our findings validate that EBRT is associated with favorable long-term outcomes compared with existing BCLC outcomes and should be considered a primary treatment option in select patients, including those who are treatment-naïve and have BCLC-0 or BCLC-A HCC. Second, this supports the investigation of EBRT through prospective, comparative clinical trials. Third, it presents evidence that achieving ablative radiation dose might have a positive effect on OS. Finally, it emphasizes the need for further research and consensus to define the optimal dose and fractionation schema, as well as most appropriate liver constraints, to guide safe treatment across the spectrum of liver dysfunction.
In conclusion, this study demonstrates that EBRT for HCC is associated with post-treatment OS that is comparable with well-established first-line therapies in early stages. These data support the inclusion of EBRT in the HCC clinical decision-making process.
ACKNOWLEDGMENT
We would like to thank Ariel Sanderford, Andrew Wallace, Nuria Perez, Jamie Lynne Conklin, and Jillian Plochoki-Smallwood for their invaluable contributions to this work. The EBRT Collaboration Group is listed in Appendix Table A1 (online only).
APPENDIX
TABLE A1.
EBRT Collaboration Group
| Name | Institution |
|---|---|
| Alanah M Bergman | Department of Medical Physics, BC Cancer—Vancouver, Vancouver, British Columbia, Canada |
| Christopher Crane | Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA |
| Kyle C Cuneo | Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA |
| Natalie Grindrod | Schulich Faculty of Medicine & Dentistry, Western University, London, Ontario, Canada |
| Anca-Ligia Grosu | Department of Radiation Oncology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany |
| Rodrigo El Far | Radiation Oncology Unit, Department of Hematology—Oncology, Pontificia Universidad Catolica de Chile, Santiago, Chile |
| Ciro Franzese | Radiotherapy and Radiosurgery Department, IRCCS Humanitas Research Hospital, Milan, Italy |
| Akihiro Funaoka | Department of Gastroenterology, Yokohama City University Medical Center, Yokohama, Japan |
| Marissa Gilbert | Department of Radiation Oncology, Henry Ford Health, Detroit, Michigan, USA |
| Satoshi Itasaka | Department of Radiation Oncology, Kurashiki Central Hospital, Okayama, Japan |
| Sung Uk Lee | Center for Proton Therapy, National Cancer Center, Goyang, Republic of Korea |
| Yoo Young Dominique Lee | Department of Radiation Oncology, Princess Alexandra Hospital, Brisbane, Queensland, Australia |
| Joel Mases | Radiation Oncology Department, Hospital Clínic Barcelona, Spain |
| Hiroyuki Ogino | Department of Radiation Oncology, Nagoya Proton Therapy Center, Nagoya City University West Medical Center, Nagoya, Japan |
| Vera Qu | Department of Radiation Oncology, Stanford University School of Medicine, Stanford, California, USA |
| Hee Chul Park | Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea |
| Ramtin Rahmani | Department of Radiation Medicine, School of Medicine, Oregon Health & Science University, Portland, OR, USA |
| Lee Ann Shing | Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong |
| Tomotake Shirono | Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan |
| Teodor Stanescu | Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Department of radiation Oncology, University of Toronto, Ontario, Canada |
| Kanokphorn Thonglert | Division of Radiation Oncology, Department of Radiology, Faculty of Medicine. Chulalongkorn University, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand |
| Wilhelm den Toom | Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands |
| Yusuke Uchinami | Department of Radiation Oncology, Hokkaido University Faculty of Medicine, Sapporo, Japan |
| Zhaochong Zeng | Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai, China |
Andrew M. Moon
Consulting or Advisory Role: Intercept Pharmaceuticals, Sirtex Medical, IDEOlogy Health, Eisai, AstraZeneca
Research Funding: DCN Diagnostics (Inst), Madrigal Pharmaceuticals (Inst)
Ted K. Yanagihara
Research Funding: Medtronic (Inst)
Travel, Accommodations, Expenses: Histosonics
Laura A. Dawson
Consulting or Advisory Role: Elekta
Research Funding: Merck (Inst), Elekta (Inst), Varian Medical Systems (Inst)
Michael Yan
Consulting or Advisory Role: Need
Research Funding: Varian Medical Systems (Inst)
Nima Nabavizadeh
Honoraria: GRAIL, Roche, MJH Life Sciences
Consulting or Advisory Role: GRAIL
Michael I. Lock
Stock and Other Ownership Interests: Myovant Sciences, Lilly
Consulting or Advisory Role: Tersera, Bayer
Speakers' Bureau: Knight Therapeutics
Research Funding: Urgo Medical (Inst), Knight Pharmaceuticals (Inst)
Uncompensated Relationships: Oncoinnovations
Michael D. Chuong
Employment: Baptist Health South FL, Fertility Center of Miami (I)
Consulting or Advisory Role: Elekta, Novocure
Research Funding: Novocure (Inst), Stratpharma (Inst)
Travel, Accommodations, Expenses: Novocure
Chi Leung Chiang
Honoraria: AstraZeneca, Taiho Pharmaceutical, Roche, Eisai, Varian Medical Systems
Consulting or Advisory Role: MSD, AstraZeneca, Eisai, Taiho Pharmaceutical
Research Funding: AstraZeneca, Merck KGaA, Taiho Oncology
Travel, Accommodations, Expenses: AstraZeneca, Taiho Oncology, Roche, Eisai
Norio Katoh
Speakers' Bureau: Shimadzu
Erqi L. Pollom
Honoraria: Varian Medical Systems
Consulting or Advisory Role: Vysioneer, GT Medical Technologies, AstraZeneca, AstraZeneca
Research Funding: Genentech, ViewRay
Eleni Gkika
Consulting or Advisory Role: AstraZeneca
Research Funding: AstraZeneca
Travel, Accommodations, Expenses: AstraZeneca, Novocure
Salma K. Jabbour
Consulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Radialogica, Advarra, Johnson & Johnson/Janssen
Research Funding: Merck Sharp & Dohme (Inst), NCI (Inst), Beigene (Inst), Guardant Health (Inst), Haystack Oncology (Inst)
Expert Testimony: deichert
Travel, Accommodations, Expenses: Merck, AstraZeneca
Aharon M. Feldman
Employment: Henry Ford Health System, Corazon Imaging, Carease Health
Leadership: Carease Health, Corazon Imaging
Honoraria: MSHO
Uncompensated Relationships: Kare Center LLC
Joel E. Tepper
Employment: UNC School of Medicine
Consulting or Advisory Role: EMD Serono
Other Relationship: Elsevier
Ferran Torres
Consulting or Advisory Role: Archivel, LEO Pharma, FAES, Ferrer and Boehringer Ingelheim
Other Relationship: DSMB for Argenx BV, Archivel, Connecta and RemAb Therapeutics
Maria Reig
Consulting or Advisory Role: AstraZeneca, Bayer, BMS GmbH & Co. KG, Lilly, Geneos, Ipsen, Merck, Roche, Universal Diagnostics, Boston Scientific, Engitix, Parabilis Medicines
Speakers' Bureau: AstraZeneca, Bayer, BMS GmbH & Co. KG, Lilly, Gilead Sciences, Roche, Biotoscana Farma, GKL
Research Funding: Bayer (Inst), Ipsen (Inst)
Travel, Accommodations, Expenses: AstraZeneca, Roche, Bayer, BMS GmbH & Co. KG, Lilly, Ipsen
No other potential conflicts of interest were reported.
See accompanying Bridging the Gap, p. 1757
SUPPORT
Supported in part by an International Travel Grant from the American College of Gastroenterology (AMM) and an AASLD Clinical, Translational and Outcomes Award from the AASLD Foundation (AMM).
EQUAL CONTRIBUTION
A.M.M. and T. K.Y. contributed equally to this work.
Contributor Information
for the EBRT Collaboration Group:
EBRT Collaboration Group, Alanah M. Bergman, Christopher Crane, Kyle C. Cuneo, Natalie Grindrod, Anca-Ligia Grosu, Rodrigo El Far, Ciro Franzese, Akihiro Funaoka, Marissa Gilbert, Satoshi Itasaka, Sung Uk Lee, Yoo Young Dominique Lee, Joel Mases, Hiroyuki Ogino, Vera Qu, Hee Chul Park, Ramtin Rahmani, Lee Ann Shing, Tomotake Shirono, Teodor Stanescu, Kanokphorn Thonglert, Wilhelm den Toom, Yusuke Uchinami, and Zhaochong Zeng
Supplementary Materials
DATA SHARING STATEMENT
Given restrictions of individual data use agreements and national laws, individual patient data will be unavailable to others. A data dictionary can be made available upon request.
AUTHOR CONTRIBUTIONS
Conception and design: Andrew M. Moon, Ted K. Yanagihara, Theodore S. Lawrence, Nima Nabavizadeh, Michael I. Lock, Erqi L. Pollom, Meritxell Molla, Joel E. Tepper, Ferran Torres, Maria Reig
Administrative support: Carla Hajj
Provision of study materials or patients: Theodore S. Lawrence, Hiromitsu Iwata, Michael I. Lock, Norio Katoh, Kazushi Numata, Howard Yu-hao Liu, Masaru Wakatsuki, Yixing Chen, Salma K. Jabbour, Pablo Munoz-Schuffenegger, Debnarayan Dutta, Carla Hajj, Alejandra Méndèz Romero
Collection and assembly of data: Andrew M. Moon, Ted K. Yanagihara, Laura A. Dawson, Jeong Il Yu, Theodore S. Lawrence, Tae Hyun Kim, Hiromitsu Iwata, Nima Nabavizadeh, Smith Apisarnthanarax, Emma M Dunne, Michael I. Lock, Michael D. Chuong, Chi Leung Chiang, Marta Scorsetti, Norio Katoh, Shirin Sioshansi, Kazushi Numata, Howard Yu-hao Liu, Hideki Iwamoto, Masaru Wakatsuki, Yixing Chen, Erqi L. Pollom, Eleni Gkika, Salma K. Jabbour, Pablo Munoz-Schuffenegger, Debnarayan Dutta, Carla Hajj, Masayuki Ueno, Christopher L. Hallemeier, Aharon M. Feldman, Alejandra Méndèz Romero, Maria Reig
Data analysis and interpretation: Andrew M. Moon, Ted K. Yanagihara, Laura A Dawson, Theodore S. Lawrence, Tae Hyun Kim, Michael Yan, Nima Nabavizadeh, Michael I. Lock, Marta Scorsetti, Shirin Sioshansi, Howard Yu-hao Liu, Erqi L. Pollom, Salma K. Jabbour, Pablo Munoz-Schuffenegger, Carla Hajj, Christopher L. Hallemeier, Alejandra Méndèz Romero, Xianming Tan, Meritxell Molla, Joel E. Tepper, Ferran Torres, Maria Reig
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Overall Survival Among Patients With Hepatocellular Carcinoma Treated With External Beam Radiation Therapy: Individual Patient Data Outcomes From a Multinational Cohort
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
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Andrew M. Moon
Consulting or Advisory Role: Intercept Pharmaceuticals, Sirtex Medical, IDEOlogy Health, Eisai, AstraZeneca
Research Funding: DCN Diagnostics (Inst), Madrigal Pharmaceuticals (Inst)
Ted K. Yanagihara
Research Funding: Medtronic (Inst)
Travel, Accommodations, Expenses: Histosonics
Laura A. Dawson
Consulting or Advisory Role: Elekta
Research Funding: Merck (Inst), Elekta (Inst), Varian Medical Systems (Inst)
Michael Yan
Consulting or Advisory Role: Need
Research Funding: Varian Medical Systems (Inst)
Nima Nabavizadeh
Honoraria: GRAIL, Roche, MJH Life Sciences
Consulting or Advisory Role: GRAIL
Michael I. Lock
Stock and Other Ownership Interests: Myovant Sciences, Lilly
Consulting or Advisory Role: Tersera, Bayer
Speakers' Bureau: Knight Therapeutics
Research Funding: Urgo Medical (Inst), Knight Pharmaceuticals (Inst)
Uncompensated Relationships: Oncoinnovations
Michael D. Chuong
Employment: Baptist Health South FL, Fertility Center of Miami (I)
Consulting or Advisory Role: Elekta, Novocure
Research Funding: Novocure (Inst), Stratpharma (Inst)
Travel, Accommodations, Expenses: Novocure
Chi Leung Chiang
Honoraria: AstraZeneca, Taiho Pharmaceutical, Roche, Eisai, Varian Medical Systems
Consulting or Advisory Role: MSD, AstraZeneca, Eisai, Taiho Pharmaceutical
Research Funding: AstraZeneca, Merck KGaA, Taiho Oncology
Travel, Accommodations, Expenses: AstraZeneca, Taiho Oncology, Roche, Eisai
Norio Katoh
Speakers' Bureau: Shimadzu
Erqi L. Pollom
Honoraria: Varian Medical Systems
Consulting or Advisory Role: Vysioneer, GT Medical Technologies, AstraZeneca, AstraZeneca
Research Funding: Genentech, ViewRay
Eleni Gkika
Consulting or Advisory Role: AstraZeneca
Research Funding: AstraZeneca
Travel, Accommodations, Expenses: AstraZeneca, Novocure
Salma K. Jabbour
Consulting or Advisory Role: Merck Sharp & Dohme, AstraZeneca, Radialogica, Advarra, Johnson & Johnson/Janssen
Research Funding: Merck Sharp & Dohme (Inst), NCI (Inst), Beigene (Inst), Guardant Health (Inst), Haystack Oncology (Inst)
Expert Testimony: deichert
Travel, Accommodations, Expenses: Merck, AstraZeneca
Aharon M. Feldman
Employment: Henry Ford Health System, Corazon Imaging, Carease Health
Leadership: Carease Health, Corazon Imaging
Honoraria: MSHO
Uncompensated Relationships: Kare Center LLC
Joel E. Tepper
Employment: UNC School of Medicine
Consulting or Advisory Role: EMD Serono
Other Relationship: Elsevier
Ferran Torres
Consulting or Advisory Role: Archivel, LEO Pharma, FAES, Ferrer and Boehringer Ingelheim
Other Relationship: DSMB for Argenx BV, Archivel, Connecta and RemAb Therapeutics
Maria Reig
Consulting or Advisory Role: AstraZeneca, Bayer, BMS GmbH & Co. KG, Lilly, Geneos, Ipsen, Merck, Roche, Universal Diagnostics, Boston Scientific, Engitix, Parabilis Medicines
Speakers' Bureau: AstraZeneca, Bayer, BMS GmbH & Co. KG, Lilly, Gilead Sciences, Roche, Biotoscana Farma, GKL
Research Funding: Bayer (Inst), Ipsen (Inst)
Travel, Accommodations, Expenses: AstraZeneca, Roche, Bayer, BMS GmbH & Co. KG, Lilly, Ipsen
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Given restrictions of individual data use agreements and national laws, individual patient data will be unavailable to others. A data dictionary can be made available upon request.