粒子治疗肝细胞癌的长期有效性和安全性的Meta分析

摘要/Abstract

摘要： 目的：系统评价质子、重离子治疗肝细胞癌（hepatocellular carcinoma,HCC）的长期有效性和安全性。
方法：系统检索Medline、Embase、Web of Science、中国生物医学文献数据库、万方数据库和中国知网,检索时间均从建库至2022年7月。由2名研究者独立筛选文献、提取资料并评价纳入研究的方法学质量,并进行Meta分析。
结果：共纳入20篇文献,其中质子治疗13篇,碳离子治疗8篇,其中1篇文献同时包含碳离子和质子治疗HCC结果,共包括1884例患者。Meta分析结果显示,碳离子和质子治疗HCC可获得较高的长期局部控制率[5年局部控制率分别为90%（95%CI：86%~94%）,85%（95%CI：80%~91%）]及可接受的长期生存率[5年总生存率分别为33%（95%CI：23%~43%) 、41%（95%CI：32%~50%）]。亚组分析结果表明,碳离子和质子治疗肿瘤病灶小、肝功能Child-Pugh A级、首次治疗、单发肿瘤的HCC患者可取得更好的生存结果。3级以上严重不良事件的发生率均较低。
结论：质子、重离子治疗HCC具有良好的局部控制率、可接受的总生存率和较低的复发率。但现有研究文献质量较低,报道不全,尤其是毒性反应方面,因此需要开展更多前瞻性、多中心、高质量研究进行深入探讨。

关键词: 肝细胞癌, 碳离子, 质子, Meta分析

Abstract: Objective:To evaluate the efficacy and safety of proton and heavy ion therapy for hepatocellular carcinoma (HCC).
Method:Medline, Embase, Web of Science, China Biology Medicine (CBM), Wanfang Database and China National Knowledge Internet (CNKI) were systematically searched from inception to July 2022. Two researchers independently screened the titles and abstracts, extracted the data, and evaluated the methodological quality of the included studies. STATA 14.0 software was used for meta-analysis.
Result:Totally 13 proton irradiation and 8 carbon ion irradiation which included 1884 patients were included in our final research. The results of meta-analysis showed that carbon ion and proton irradiation could achieve higher long-term local control (LC) rates {5-year LC rate: 90% [95%(confidence interval, CI): 86%-94%], 85% (95%CI: 80%-91%)} and long-term overall survival (OS) rates for HCC [5-year OS rate: 33% (95%CI: 23%-43%), 41% (95%CI: 32%-50%)]. The results of subgroup analysis showed that HCC patients with small tumor diameter, Child-Pugh grade A, primary treatment and single tumor could achieve better survival outcomes, and the incidence of grade 3 or higher adverse events was low.
Conclusion:Proton and heavy ion therapy offer high local control, acceptable overall survival and a low recurrence rate for HCC. However, the existing literature is of low quality and incomplete reporting, especially on toxicity. Therefore, there is a strong need for more prospective, multicenter, and high-quality studies.

Key words: Hepatocellular carcinoma, Carbon ion, Proton, Meta-analysis

刘锐锋, 王丹丹, 张秋宁, 罗宏涛, 董猛, 王小虎. 粒子治疗肝细胞癌的长期有效性和安全性的Meta分析[J]. 肝癌电子杂志, 2022, 9(4): 32-45.

Liu Ruifeng¹, Wang Dandan², Zhang Qiuning¹, Luo Hongtao³, Dong Meng², Wang Xiaohu^1,*. Efficacy and safety of particle therapy for hepatocellular carcinoma: a meta-analysis[J]. Electronic Journal of Liver Tumor, 2022, 9(4): 32-45.

参考文献

[1] GALLE P R, DUFOUR J F, PECK-RADOSAVLJEVIC M, et al.Systemic therapy of advanced hepatocellular carcinoma[J]. Future Oncol, 2021, 17(10): 1237-1251.
[2] MOHAN R, GROSSHANS D.Proton therapy-Present and future[J]. Adv Drug Deliv Rev, 2017, 109: 26-44.
[3] KOMATSU S, FUKUMOTO T, DEMIZU Y, et al.Clinical results and risk factors of proton and carbon ion therapy for hepatocellular carcinoma[J]. Cancer, 2011, 117(21): 4890-4904.
[4] SHIBUYA K, OHNO T, KATOH H, et al.A feasibility study of high-dose hypofractionated carbon ion radiation therapy using four fractions for localized hepatocellular carcinoma measuring 3cm or larger[J]. Radiother Oncol, 2019, 132: 230-235.
[5] SHIBUYA K, KATOH H, KOYAMA Y, et al.Efficacy and Safety of 4 Fractions of Carbon-Ion Radiation Therapy for Hepatocellular Carcinoma: A Prospective Study[J]. Liver Cancer, 2022, 11(1): 61-74.
[6] YASUDA S, KATO H, IMADA H, et al.Long-Term Results of High-Dose 2-Fraction Carbon Ion Radiation Therapy for Hepatocellular Carcinoma[J]. Adv Radiat Oncol, 2020, 5(2): 196-203.
[7] KASUYA G, KATO H, YASUDA S, et al.Progressive hypofractionated carbon-ion radiotherapy for hepatocellular carcinoma: Combined analyses of 2 prospective trials[J]. Cancer, 2017, 123(20): 3955-3965.
[8] SHIBA S, SHIBUYA K, KATOH H, et al.No Deterioration in Clinical Outcomes of Carbon Ion Radiotherapy for Sarcopenia Patients with Hepatocellular Carcinoma[J]. Anticancer Res, 2018, 38(6): 3579-3586.
[9] KATO H, TSUJII H, MIYAMOTO T, et al.Results of the first prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis[J]. Int J Radiat Oncol Biol Phys, 2004, 59(5): 1468-1476.
[10] KIM T H, PARK J W, KIM B H, et al.Does risk-adapted proton beam therapy have a role as a complementary or alternative therapeutic option for hepatocellular carcinoma?[J]. Cancers, 2019, 11(2): 230.
[11] LIN S Y, CHEN C M, HUANG B S, et al.A preliminary study of hepatocellular carcinoma post proton beam therapy using MRI as an early prediction of treatment effectiveness[J]. PLoS One, 2021, 16(3): e0249003.
[12] KIM T H, PARK J W, KIM B H, et al.Phase Ⅱ Study of Hypofractionated Proton Beam Therapy for Hepatocellular Carcinoma[J]. Front Oncol, 2020, 10: 542.
[13] HOJO H, RATURI V, NAKAMURA N, et al.Impact of Proton Beam Irradiation of an Anatomic Subsegment of the Liver for Hepatocellular Carcinoma[J]. Pract Radiat Oncol, 2020, 10(4): e264-e271.
[14] IIZUMI T, OKUMURA T, SEKINO Y, et al.Long-term clinical outcomes of patients receiving proton beam therapy for caudate lobe hepatocellular carcinoma[J]. J Radiat Res, 2021, 62(4): 682-687.
[15] SHIBATA S, TAKAMATSU S, YAMAMOTO K, et al.Proton Beam Therapy without Fiducial Markers Using Four-Dimensional CT Planning for Large Hepatocellular Carcinomas[J]. Cancers (Basel), 2018, 10(3): 71.
[16] CHIBA T, TOKUUYE K, MATSUZAKI Y, et al.Proton beam therapy for hepatocellular carcinoma: a retrospective review of 162 patients[J]. Clin Cancer Res, 2005, 11(10): 3799-3805.
[17] FUKUMITSU N, SUGAHARA S, NAKAYAMA H, et al.A prospective study of hypofractionated proton beam therapy for patients with hepatocellular carcinoma[J]. Int J Radiat Oncol Biol Phys, 2009, 74(3): 831-836.
[18] KIM T H, PARK J W, KIM Y J, et al.Phase I dose-escalation study of proton beam therapy for inoperable hepatocellular carcinoma[J]. Cancer Res Treat, 2015, 47(1): 34-45.
[19] IWATA H, OGINO H, HATTORI Y, et al.Image-Guided Proton Therapy for Elderly Patients with Hepatocellular Carcinoma: High Local Control and Quality of Life Preservation[J]. Cancers, 2021, 13(2): 219.
[20] KAWASHIMA M, KOHNO R, NAKACHI K, et al.Dose-volume histogram analysis of the safety of proton beam therapy for unresectable hepatocellular carcinoma[J]. Int J Radiat Oncol Biol Phys, 2011, 79(5): 1479-1486.
[21] MIZUMOTO M, OKUMURA T, HASHIMOTO T, et al.Proton beam therapy for hepatocellular carcinoma: a comparison of three treatment protocols[J]. Int J Radiat Oncol Biol Phys, 2011, 81(4): 1039-1045.
[22] 李家敏, 刘素文, 黄术林, 等. 质子束治疗肝细胞癌的临床价值及预后因素分析[J]. 中华放射肿瘤学杂志, 2012, 21(1): 27-28.
[23] EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[J]. J Hepatol, 2018, 69(1): 182-236.
[24] SPYCHALSKI P, KOBIELA J, ANTOSZEWSKA M, et al.Patient specific outcomes of charged particle therapy for hepatocellular carcinoma-A systematic review and quantitative analysis[J]. Radiother Oncol, 2019, 132: 127-134.
[25] SHIBA S, SHIBUYA K, KAWASHIMA M, et al.Comparison of dose distributions when using carbon ion radiotherapy versus intensity-modulated radiotherapy for hepatocellular carcinoma with macroscopic vascular invasion: a retrospective analysis[J]. Anticancer Res, 2020, 40(1): 459-464.
[26] YU Q, LIU C, NAVULURI R, et al.Percutaneous microwave ablation versus radiofrequency ablation of hepatocellular carcinoma: a meta-analysis of randomized controlled trials[J]. Abdom Radiol (NY), 2021, 46(9): 4467-4475.
[27] TAMURA S, OKAMURA Y, SUGIURA T, et al.A comparison of the outcomes between surgical resection and proton beam therapy for single primary hepatocellular carcinoma[J]. Surg Today, 2020, 50(4): 369-378.
[28] SANFORD N N, PURSLEY J, NOE B, et al.Protons versus Photons for Unresectable Hepatocellular Carcinoma: Liver Decompensation and Overall Survival[J]. Int J Radiat Oncol Biol Phys, 2019, 105(1): 64-72.
[29] HASAN S, ABEL S, VERMA V, et al.2nd: Proton beam therapy versus stereotactic body radiotherapy for hepatocellular carcinoma: practice patterns, outcomes, and the effect of biologically effective dose escalation[J]. J Gastrointest Oncol, 2019, 10(5): 999-1009.
[30] SHIBA S, SHIBUYA K, KATOH H, et al.A comparison of carbon ion radiotherapy and transarterial chemoembolization treatment outcomes for single hepatocellular carcinoma: a propensity score matching study[J]. Radiat Oncol, 2019, 14(1): 137.
[31] KOMATSU S, KIDO M, ASARI S, et al.Particle radiotherapy, a novel external radiation therapy, versus liver resection for hepatocellular carcinoma accompanied with inferior vena cava tumor thrombus: A matched-pair analysis[J]. Surgery, 2017, 162(6): 1241-1249.
[32] LEUNG H W C, CHAN A L F. Cost-utility of stereotactic radiation therapy versus proton beam therapy for inoperable advanced hepatocellular carcinoma[J]. Oncotarget, 2017, 8(43): 75568-75576.
[33] SCORSETTI M, COMITO T, COZZI L, et al.The challenge of inoperable hepatocellular carcinoma (HCC): results of a single-institutional experience on stereotactic body radiation therapy (SBRT)[J]. J Cancer Res Clin Oncol, 2015, 141(7): 1301-1309.
[34] YAMASHITA H, ONISHI H, MATSUMOTO Y, et al.Local effect of stereotactic body radiotherapy for primary and metastatic liver tumors in 130 Japanese patients[J]. Radiat Oncol, 2014, 9: 112.
[35] QI W X, FU S, ZHANG Q, et al.Charged particle therapy versus photon therapy for patients with hepatocellular carcinoma: a systematic review and meta-analysis[J]. Radiother Oncol, 2015, 114(3): 289-295.