Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial

IF 9.5 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

JHEP Reports Pub Date : 2024-03-11 DOI:10.1016/j.jhepr.2024.101063

Philipp Hoegen-Saßmannshausen , Patrick Naumann , Paula Hoffmeister-Wittmann , Semi Ben Harrabi , Katharina Seidensaal , Fabian Weykamp , Thomas Mielke , Malte Ellerbrock , Daniel Habermehl , Christoph Springfeld , Michael T. Dill , Thomas Longerich , Peter Schirmacher , Arianeb Mehrabi , De-Hua Chang , Juliane Hörner-Rieber , Oliver Jäkel , Thomas Haberer , Stephanie E. Combs , Jürgen Debus , Jakob Liermann

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引用次数: 0

Abstract

Background & Aims

Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I.

Methods

CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1–10.5 Gy (total doses 32.4–42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks.

Results

Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression.

Conclusions

CIRT of HCC yields excellent local control without dose-limiting toxicity.

Impact and implications

To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials.

Clinical Trials Registration

The study is registered at ClinicalTrials.gov (NCT01167374).

Abstract Image

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肝细胞癌的碳离子放射治疗可提供出色的局部控制：前瞻性 I 期 PROMETHEUS 试验

背景& 目的无法手术的肝细胞癌（HCC）可采用立体定向体放射治疗。然而，碳离子放射治疗（CIRT）在保护非肿瘤肝脏方面更为有效。高线性能量传递可提高疗效。日本和中国的低分次碳离子放疗研究取得了很好的效果。由于不同的放射生物学模型和 HCC 病因谱不同，这些结果是否适用于欧洲队列和中心仍存在疑问。这项前瞻性研究旨在评估安全性和有效性，并根据局部效应模型（LEM）I确定主动光栅扫描CIRT的最佳剂量。方法CIRT每隔一天进行一次，分四次进行，相对生物效应（RBE）加权的分次剂量为8.1-10.5 Gy（总剂量为32.4-42.0 Gy [RBE]）。剂量升级分为五个剂量水平，每个剂量水平至少有三名患者接受治疗。结果20名患者接受了CIRT治疗（中位年龄74.7岁，肝硬化患者16人，Child-Pugh评分[CP] A5 [n = 10]、A6 [n = 4]、B8 [n = 1]和B9 [n = 1]）。中位随访时间为 23 个月。除了 CIRT 12 个月后出现一次 III 级γ-谷氨酰转移酶升高（与场外肝功能进展同步）外，未出现剂量限制性毒性反应和超过 II 级的毒性反应。在 CIRT 后的 12 个月内，CP 没有升高。可以安全地使用最高剂量。随访期间未出现局部复发。客观反应率为 80%。中位总生存期为30.8个月（1/2/3年：75%/64%/22%）。无进展生存期中位数为20.9个月（1/2/3年：59%/43%/43%）。结论CIRT治疗HCC可获得良好的局部控制效果，且无剂量限制性毒性。影响和意义迄今为止，只有日本和中国的研究对碳离子放疗治疗肝细胞癌的安全性和有效性进行了前瞻性评估。使用局部效应模型制定放疗计划时的最佳剂量和分次尚不清楚。我们的研究结果不仅对欧美粒子治疗中心具有重要意义，而且对所有参与肝细胞癌治疗和护理的专家也具有重要意义，因为我们首次在亚洲以外地区展示了碳离子放疗治疗肝细胞癌的前瞻性数据。出色的局部控制效果应鼓励进一步使用碳离子放射疗法治疗肝细胞癌，并鼓励设计随机对照试验。临床试验注册该研究已在ClinicalTrials.gov（NCT01167374）上注册。

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来源期刊

JHEP Reports GASTROENTEROLOGY & HEPATOLOGY-

CiteScore

12.40

自引率

2.40%

发文量

161

审稿时长

36 days

期刊介绍： JHEP Reports is an open access journal that is affiliated with the European Association for the Study of the Liver (EASL). It serves as a companion journal to the highly respected Journal of Hepatology. The primary objective of JHEP Reports is to publish original papers and reviews that contribute to the advancement of knowledge in the field of liver diseases. The journal covers a wide range of topics, including basic, translational, and clinical research. It also focuses on global issues in hepatology, with particular emphasis on areas such as clinical trials, novel diagnostics, precision medicine and therapeutics, cancer research, cellular and molecular studies, artificial intelligence, microbiome research, epidemiology, and cutting-edge technologies. In summary, JHEP Reports is dedicated to promoting scientific discoveries and innovations in liver diseases through the publication of high-quality research papers and reviews covering various aspects of hepatology.