简介Hepatic artery infusion chemotherapy (HAIC) is a treatment modality for advanced hepatocellular carcinoma (HCC).
肝动脉输注化疗(HAIC)是治疗晚期肝癌(HCC)的一种治疗方式。
HAIC entails infusing chemotherapeutic agents directly into hepatic tumors through the percutaneous catheterization of feeding arteries.
HAIC需要通过经皮供血动脉将化疗药物直接注入肝肿瘤。
Because HCC tumors are primarily supplied by the hepatic arteries, HAIC provides a higher intratumoral concentration of chemotherapeutic agents and avoids the first-pass effect, theoretically yielding greater treatment efficacy and less hepatocellular injury [1].
These chemotherapeutic agents subsequently went through the body by circulation and also offered systemic anti-tumor effect but with less concentration advantage.
这些化疗药物随后通过循环进入体内，也具有全身抗肿瘤作用，但浓度优势较低。
Therefore, HAIC is basically a systemic treatment with more prominent locoregional efficacy.
因此，HAIC基本上是一种全身治疗，局部疗效更突出的方法。
These peculiar features make HAIC distinct from other transarterial therapeutic approaches for HCC, such as transarterial chemoembolization (TACE) and selective internal radiation therapy (SIRT), which yield locoregional efficacy only and failed to provide survival benefit for patients with advanced HCC [2,3,4].
这些特殊的特征使HAIC不同于其他经动脉HCC治疗方法，如经动脉化疗栓塞(TACE)和选择性内放疗(SIRT)，后者仅产生局部疗效，不能为晚期HCC[2,3,4]患者提供生存效益。
Furthermore, TACE is considered as relative contraindicated in patients with portal vein thrombosis (PVT), since reduced blood supply in both portal vein system and hepatic arteries may cause substantial hepatocyte injury, especially for Vp3/4 thrombosis (Figure 1).
此外，TACE被认为是门静脉血栓形成(PVT)患者的相对禁忌症，因为门静脉系统和肝动脉的血供减少可能导致大量的肝细胞损伤，特别是Vp3/4血栓形成（图1）。
In contrast, HAIC can be performed safely in these patients.
相比之下，HAIC可以对这些患者进行安全的治疗。
HAIC has been utilized for advanced HCC more commonly in East Asia than in other regions of the world.
HAIC在东亚被用于晚期HCC，比在世界其他地区更常见。
Because viral hepatitis is endemic in East Asia, the region is among those with the highest disease burden for HCC [5], exhibiting distinct features in terms of epidemiology, etiology, diagnostic modalities, and treatment patterns.
由于病毒性肝炎是东亚流行的，该地区是HCC[5]疾病负担最高的地区之一，在流行病学、病因学、诊断方式和治疗模式方面表现出明显的特征。
Many Asian HCC treatment guidelines adopt a more aggressive strategy for the use of HAIC[6,7,8,9], which is not yet recognized by many international organizations such as the National Comprehensive Cancer Network (NCCN) [10 ] or the European Society for Medical Oncology (ESMO) [11]; the under-recognition of this therapy is due to a lack of proven survival benefits from well-designed, randomized controlled trials in comparison with current standard treatments.
许多亚洲HCC治疗指南采用了更积极的策略来使用HAIC[6,7,8,9]，这尚未得到许多国际组织的认可，如国家综合癌症网络(NCCN)[10]或欧洲医学肿瘤学会(ESMO)[11]；与目前的标准治疗相比，精心设计的随机对照试验缺乏有效的生存效益。
In this review, we revisit current evidence regarding HAIC treatment for advanced HCC and assess its potential role in HCC treatment.
在这篇综述中，我们回顾了目前关于HAIC治疗晚期HCC的证据，并评估了其在HCC治疗中的潜在作用。
HAIC的单药治疗
HAIC has long been reported as a potential therapy for advanced HCC [12].
HAIC长期以来一直被报道为晚期HCC【12】的一种潜在的治疗方法。
Before the advent of sorafenib, advanced HCC was often most effectively treated with supportive care, antiangiogenesis agents such as thalidomide [13], or chemotherapy.
在索拉非尼出现之前，晚期HCC通常通过支持性治疗、抗血管生成药物如沙利度胺（thalidomide）【13】或化疗得到最有效的治疗。
These treatments conferred limited objective response rates (ORR), ranging from 0% to 21%, and were associated with a risk of high rates of hematological toxicity 【13.14,15,16】.
By contrast, HAIC conferred higher ORRs, ranging from 5% to 71% (Table 1), and lower systemic toxicity [1].
相比之下，HAIC赋予了更高的ORR，从5%到71%（表1），以及较低的全身毒性【1】。
aHCC: advanced hepatocellular carcinoma; CP: Child–Pugh classification; EHS: extrahepatic spread; HAIC: hepatic arterial infusion chemotherapy; HBV: hepatitis B virus; IFN-α: interferon-alpha; MVI: macrovascular invasion; NR: not reported; ORR: overall response rate; OS: overall survival; PVT: portal vein thrombosis; TACE: transcatheter arterial chemoembolization; VP3: right/left portal vein; VP4: main portal vein; 5-FU: 5-fluorouracil. * 57% patients received 5-FU plus IFNα.
A nationwide registry study in Japan compared HAIC treatment with no active treatment for patients with advanced HCC; the study revealed that HAIC was associated with improved overall survival (OS) compared with the most effective supportive care (median survival, 14.0 vs.5.0 months; hazard ratio [HR], 0.48; p < 0.001) [17]. Other retrospective studies have also reported higher efficacy of HAIC compared with transcatheter arterial chemoembolization (TACE) or systemic chemotherapy for advanced HCC [18,19].
日本的一项全国性注册研究比较了晚期HCC患者的HAIC治疗和没有积极治疗；该研究显示，与最有效的支持性治疗，中位生存期为14.0 vs5.0个月；风险比[HR]，0.48；p＜0.001【17】相比，HAIC与总生存期(OS)的改善相关。其他回顾性研究也报道了HAIC比经导管动脉化疗栓塞(TACE)或全身化疗治疗晚期HCC【18,19】的疗效更高。
As a result of the SHARP clinical trial [20] and associated Asia-Pacific trials [21], sorafenib became the first standard systemic treatment with improved OS for advanced HCC compared with placebos.
由于SHARP的临床试验[20]和相关的亚太试验[21]，索拉非尼成为第一个与安慰剂相比，改善晚期HCCOS的标准全身治疗。
Several small-scale studies have subsequently investigated whether HAIC can yield superior benefits over sorafenib for patients with advanced HCC. 随后，一些小规模研究调查了HAIC对晚期HCC患者是否优于索拉非尼。
Such studies have generally reported that HAIC demonstrated higher ORRs than sorafenib did, but they could not draw definite conclusions regarding OS (Table 1)[22,23,24,25,26,27,28]
In the prospective SCOOP-2 Phase 2 trial comparing HAIC with sorafenib, HAIC was even associated with a numerically shorter OS compared with sorafenib (median survival, 10.0 vs.15.7 months, p = 0.78).
在比较HAIC和索拉非尼的前瞻性scoop-22期试验中，与索拉非尼相比，HAIC甚至与数值上更短的OS相关 (中位生存期，10.0 vs.7个月，p=0.78).
Additionally, HAIC antitumor effects on extrahepatic spread (EHS) were not specifically reported, but it was considered theoretically attenuated.
此外，HAIC对肝外扩散(EHS)的抗肿瘤作用尚未被明确报道，但理论上被认为是减弱的。
Thus, HAIC monotherapy lacks sufficient evidence as a standard first-line therapy for advanced HCC.
因此，HAIC单药治疗作为晚期HCC的标准一线治疗方法缺乏足够的证据。
Regarding second-line treatments and beyond, HAIC has not been directly compared with other second-line systemic therapeutic agents such as regorafenib, cabozantinib, and ramucirumab.
关于二线治疗和其他治疗，HAIC尚未直接与其他二线全身治疗药物如雷格拉非尼、卡博赞替尼和拉穆珠单抗进行比较。
HAIC after failure of sorafenib or other first-line treatments was reported to be effective and well tolerated, with a remarkable ORRs of approximately 30%, even in patients unsuitable for regorafenib treatment [29,30,31].
据报道，索拉非尼或其他一线治疗失败后的HAIC有效且耐受性良好，即使在不适合瑞格拉非尼治疗[29,30,31]的患者中，其orr约为30%。
Selected patient populations may, however, gain greater benefit from HAIC.
然而，选定的患者群体可能会从HAIC中获得更大的好处。
Many investigators have administered HAIC to patients with macrovascular invasion (MVI), a subgroup with inferior prognosis and required prompt treatment response.
许多研究者将HAIC应用于大血管侵犯(MVI)患者，这是一个预后较差的亚组，需要及时的治疗反应。
Retrospective studies focusing on patients with PVT have revealed that patients receiving HAIC had a longer OS compared with those receiving sorafenib treatment [22,28].
针对PVT患者的回顾性研究显示，接受HAIC治疗的患者比接受索拉非尼[22,28]治疗的患者生存期更长。
HAIC also provided survival benefits for large HCC as shown in retrospective studies [32,33], and also in a randomized Phase 3 study comparing HAIC and TACE in large (>7 cm) intermediate HCC [34].
HAIC在回顾性研究[32,33]中显示，在大HCC中，在一项随机3期研究中比较HAIC和TACE。
Adverse events of HAIC in these studies were relatively low [32,34].
这些研究中HAIC的不良事件为[32,34]相对较低。
At the 2021 American Society of Clinical Oncology conference, Lyu et al.
在2021年美国临床肿瘤学会会议上，Lyu等人。
presented the results of FOHAIC trial comparing first-line HAIC with sorafenib in advanced HCC mainly with MVI and high tumor burden; they reported, for the first time in a prospective Phase 3 study, that HAIC could lead to a longer OS than sorafenib could (median survival, 13.9 vs.8.2 month months p < 0.001) [35].
介绍了FOHAIC比较一线HAIC和索拉非尼主要用于MVI和高肿瘤负荷的晚期HCC的试验结果；他们首次在前瞻性3期研究中报道，HAIC可能导致比索拉非尼更长的OS(中位生存期，13.9 vs..8.2个月，p＜0.001) [35].
These study results support the efficacy of HAIC in patients with MVI or with large intrahepatic tumor burden.
这些研究结果支持HAIC对MVI或肝内肿瘤负荷患者的疗效。
Another area for HAIC monotherapy is in patients with poor liver function reserve, such as those with Child–Pugh (CP) Class B or C cirrhosis [6].
HAIC单药治疗的另一个领域是肝功能储备较差的患者，如Child-Pugh(CP)B级或C级肝硬化[6]患者。
For such patients, systemic treatment choice is still very limited because most therapeutic modalities for advanced HCC were developed for patients with adequate liver function.
对于这类患者，全身治疗的选择仍然非常有限，因为大多数晚期HCC的治疗方式都是为肝功能充足的患者开发的。
The CP-B cohort in the CheckMate-040 trial [36] exhibited an attenuated ORR (10%) for nivolumab monotherapy, which was only half that observed for the CP-A cohort.
在CheckMate-040试验[36]中，CP-B队列显示尼鲁单抗单药治疗的ORR减弱（10%），这仅为CP-A队列的一半。
Two retrospective studies have revealed survival benefits of HAIC over sorafenib treatment for CP-A and selected CP-B group [26,37], although such benefits were not consistently observed in other retrospective studies [28,38].
两项回顾性研究显示，HAIC比索拉非尼治疗CP-A和选择的CP-B[26,37]组的生存益处，尽管这种益处在其他回顾性研究[28,38]中观察到并不一致。
Terashima et al. [39] published a notable retrospective study of patients receiving sorafenib or HAIC and discovered that more patients receiving HAIC exhibited sustained or improved liver function after four weeks of treatment compared with patients receiving sorafenib (72% vs.50%, p = 0.006).
Terashima等人[39]发表了一项对接受索拉非尼或HAIC的患者进行的显著的回顾性研究，发现与接受索拉非尼的患者相比，接受HAIC的患者在治疗4周后表现出持续或改善的肝功能(72% vs.50%, p = 0.006)。
This result further indicates that HAIC may minimize injury to normal hepatocytes and possibly improves liver function by reducing tumor burden.
这一结果进一步表明，HAIC可以减少对正常肝细胞的损伤，并可能通过降低肿瘤负荷来改善肝功能。
Correspondingly, Liu et al.[40] reported a patient of advanced HCC with CP-C who received HAIC treatment.
相应的，刘等人[40]报告了一例晚期HCC合并CP-C的患者，他接受了HAIC治疗。
The patient had a good partial response and his liver function reserve also improved to CP-A gradually.
患者部分反应良好，肝功能储备也逐渐改善至CP-A。
Therefore, HAIC may be considered as a potential first-line treatment for patients withpoor liver function reserve.
因此，HAIC可被认为是治疗肝功能储备不良的患者的一种潜在的一线治疗方法
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