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Objective: The aim of this study was to evaluate outcomes for patients with unresectable intrahepatic cholangiocarcinoma (ICC) treated with hypofractionated proton or photon radiation therapy (HF-RT)., Methods: We retrospectively identified 66 patients with ICC who were treated with HF-RT from 2008 to 2018. Median age at RT was 76 years (range 30-92), including 27 patients (41%) aged ≥ 80 years. Median RT dose was 58.05 Gy (range 37.5-67.5), all delivered in 15 daily fractions. Thirty-two patients received proton RT and 34 patients received photon RT., Results: Median follow-up times from diagnosis and RT start were 21 months and 14 months, respectively. In total, five patients (7.6%) developed local failure. The 2-year outcomes were 84% local control (LC) and 58% OS. Among the 51 patients treated with definitive intent, the 2-year LC rate was 93% and the OS rate was 62%. On multivariate analysis for LC, older age was associated with a lower risk of local failure [hazard ratio (HR) 0.91; p = 0.02], while prior surgery (HR 16.5; p = 0.04) and macrovascular invasion (HR 123.93; p = 0.02) were independently associated with an increased risk of local failure. On multivariate analysis for OS, female sex (HR 0.33; p = 0.001) and prior chemotherapy (HR 0.38; p = 0.003) remained significantly associated with OS. On multivariate analysis for OS, compared with photon RT, there was a trend towards improved survival with proton RT (HR 0.50; p = 0.05). The rate of overall grade 3 + toxicity was 11%. One patient developed radiation-induced liver disease and was treated with corticosteroids., Conclusions: HF-RT yields high rates of local control and is an effective modality to optimize biliary control for unresectable/locally recurrent ICC.

Purpose: Ablative radiation therapy is increasingly being used for hepatocellular carcinoma (HCC) resulting in excellent local control rates; however, patients without evidence of disease progression often die from liver failure. The clinical benefit of proton- over photon-based radiation therapy is unclear. We therefore sought to compare clinical outcomes of proton versus photon ablative radiation therapy in patients with unresectable HCC., Methods and Materials: This is a single-institution retrospective study of patients treated during 2008 to 2017 with nonmetastatic, unresectable HCC not previously treated with liver-directed radiation therapy and who did not receive further liver-directed radiation therapy within 12 months after completion of index treatment. The primary outcome, overall survival (OS), was assessed using Cox regression. Secondary endpoints included incidence of non-classic radiation-induced liver disease (defined as increase in baseline Child-Pugh score by ≥2 points at 3 months posttreatment), assessed using logistic regression, and locoregional recurrence, assessed using Fine-Gray regression for competing risks. All outcomes were measured from radiation start date., Results: The median follow-up was 14 months. Of 133 patients with median age 68 years and 75% male, 49 (37%) were treated with proton radiation therapy. Proton radiation therapy was associated with improved OS (adjusted hazard ratio, 0.47; P = .008; 95% confidence interval [CI], 0.27-0.82). The median OS for proton and photon patients was 31 and 14 months, respectively, and the 24-month OS for proton and photon patients was 59.1% and 28.6%, respectively. Proton radiation therapy was also associated with a decreased risk of non-classic radiation-induced liver disease (odds ratio, 0.26; P = .03; 95% CI, 0.08-0.86). Development of nonclassic RILD at 3 months was associated with worse OS (adjusted hazard ratio, 3.83; P < .001; 95% CI, 2.12-6.92). There was no difference in locoregional recurrence, including local failure, between protons and photons., Conclusions: Proton radiation therapy was associated with improved survival, which may be driven by decreased incidence of posttreatment liver decompensation. Our findings support prospective investigations comparing proton versus photon ablative radiation therapy for HCC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: We evaluated the efficacy and safety of risk-adapted, proton-based stereotactic body radiation therapy (SBRT) for liver metastases from solid tumors., Methods: This single-arm phase II single institutional study (NCT01239381) included patients with limited extrahepatic disease, 800 mL or greater of uninvolved liver, and no cirrhosis or Child-Pugh A, who had received proton-based SBRT to one to four liver metastases from solid tumors. Treatment comprised 30 to 50 Gray equivalent (GyE) in five fractions based on the effective volume of liver irradiated. Sample size was calculated to determine if local control (LC) at one year was greater than 70%. The cumulative incidence of local failure was used to estimate LC. The association of tumor characteristics, including genetic alterations in common cancer genes such as BRAF, EGFR, HER2, KRAS, NRAS, PIK3CA, and TP53 with local tumor control, was assessed. All statistical tests were two-sided., Results: Eighty-nine patients were evaluable (colorectal, n = 34; pancreatic, n = 13; esophagogastric, n = 12; other, n = 30). Median tumor size was 2.5 cm (range = 0.5-11.9 cm). Median dose was 40 GyE (range = 30-50 GyE), and median follow-up was 30.1 months (range = 14.7-53.8 months). There was no grade 3 to 5 toxicity. Median survival time was 18.1 months. The one- and three-year LC rates were 71.9% (95% confidence limit [CL] = 62.3% to 80.9%) and 61.2% (95% CL = 50.8% to 71.8%), respectively. For large tumors (≥6 cm), one-year LC remained high at 73.9% (95% CL = 54.6% to 89.8%). Mutation in the KRAS oncogene was the strongest predictor of poor LC (P = .02). Tumor with both mutant KRAS and TP53 were particularly radioresistant, with a one-year LC rate of only 20.0%, compared with 69.2% for all others (P = .001)., Conclusions: We report the largest prospective evaluation to date of liver SBRT for hepatic metastases, and the first with protons. Protons were remarkably well tolerated and effective even for metastases that were 6 cm or larger. KRAS mutation is a strong predictor of poor LC, stressing the need for tumor genotyping prior to SBRT and treatment intensification in this patient subset., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To evaluate the efficacy and safety of high-dose, hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC)., Materials and Methods: In this single-arm, phase II, multi-institutional study, 92 patients with biopsy-confirmed HCC or ICC, determined to be unresectable by multidisciplinary review, with a Child-Turcotte-Pugh score (CTP) of A or B, ECOG performance status of 0 to 2, no extrahepatic disease, and no prior radiation received 15 fractions of proton therapy to a maximum total dose of 67.5 Gy equivalent. Sample size was calculated to demonstrate > 80% local control (LC) defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria at 2 years for HCC patients, with the parallel goal of obtaining acceptable precision for estimating outcomes for ICC., Results: Eighty-three patients were evaluable: 44 with HCC, 37 with ICC, and two with mixed HCC/ICC. The CTP score was A for 79.5% of patients and B for 15.7%; 4.8% of patients had no cirrhosis. Prior treatment had been given to 31.8% of HCC patients and 61.5% of ICC patients. The median maximum dimension was 5.0 cm (range, 1.9 to 12.0 cm) for HCC patients and 6.0 cm (range, 2.2 to 10.9 cm) for ICC patients. Multiple tumors were present in 27.3% of HCC patients and in 12.8% of ICC patients. Tumor vascular thrombosis was present in 29.5% of HCC patients and in 28.2% of ICC patients. The median dose delivered to both HCC and ICC patients was 58.0 Gy. With a median follow-up among survivors of 19.5 months, the LC rate at 2 years was 94.8% for HCC and 94.1% for ICC. The overall survival rate at 2 years was 63.2% for HCC and 46.5% ICC., Conclusion: High-dose hypofractionated proton therapy demonstrated high LC rates for HCC and ICC safely, supporting ongoing phase III trials of radiation in HCC and ICC., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2015 by American Society of Clinical Oncology.)

To report the long-term outcomes of a prospective, multi-institutional phase II trial of hypofractionated proton beam therapy for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). This single-arm, phase II, multi-institutional study enrolled 92 patients with localized, unresectable, biopsy-confirmed HCC or ICC with a Child-Turcotte-Pugh score (CTP) of A or B, and ECOG performance status of 0 to 2, to receive proton radiotherapy to a maximum dose of 67.5 GyRBE in 15 fractions. Overall survival (OS) and progression-free survival (PFS) rates were estimated using the Kaplan-Meier method. The patient characteristics, treatment techniques, and two-year outcomes have been previously reported on the 83 evaluable patients in this trial, including 44 with HCC and 39 with ICC who at that time had a median follow-up of 19.5 months. This updated analysis includes a median follow-up of 60.8 months (range 10.3–121.5) and 45.9 months (range 31.1–49.5) among the survivors with HCC and ICC, respectively. For those with HCC, the 5-year OS rate was 25.9% (95% CI 0.13-0.40), with a median OS of 29.2 months. For those with ICC, the 5-year OS rate was 12.3% (95% CI 0.03–0.27), with a median OS of 20.8 months. The 5-year PFS rate was 23.4% (95% CI 0.092-0.41) in HCC and 11.0% (95% CI 0.030-0.25) in ICC. As previously reported, two patients (6.8%) with HCC recurred locally, both within 2 years of treatment, and there were no further local failures. Among the patients with ICC, only one additional local failure occurred, for a total of 7/39 patients (17.9%), with a median time to recurrence of 26.1 months (range 5.5–42.3 months). All patients with local failure had CTP A scores, with a median tumor size of 5.8 cm (range 3.5–7.6 cm). The median radiation dose received by those who had a local recurrence was 58.0 GyRBE (range 45.0–67.5). Local failures occurred in 12.3% (7/57) of patients who received a BED less than 80.5 Gy and in 7.7% (2/26) of those who received a BED greater than 80.5 Gy. Distant failures, including intrahepatic non-local failures, occurred in 56.8% (25/44) of patients with HCC with a median time to progression of 10.2 months (range 2.7–63.6). In those with ICC, distant failures occurred in 61.5% of patients (24/39), with a median time to progression of 5.8 months (range 0.4–68.4). There were no grade 3 or greater late toxicities, including no late biliary toxicity. Hypofractionated proton beam therapy is associated with durable, high rates of local control for both HCC and ICC, however, distant failures are common and remain a challenge. There were no significant late adverse effects, including no late biliary obstruction. Future strategies to incorporate radiation and systemic therapies, including immunotherapy, should be explored to further improve the long-term outcomes of HCC and ICC. [ABSTRACT FROM AUTHOR]