Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma A Phase 2 Clinical Trial
Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma A Phase 2 Clinical Trial
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DOI：
10.1001/jamaoncol.2019.3718
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发表时间：
2020-01-01
期刊：
影响因子：
28.4
通讯作者：
Jarnagin, William R.
中科院分区：
文献类型：
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作者：
Cercek, Andrea;Boerner, Thomas;Jarnagin, William R.
不可切除的肝内胆管细胞癌（IHC）预后较差，中位总生存期（OS）为11个月。肝动脉灌注（HAI）大剂量化疗可能对这些患者有潜在的益处。目的评价HAI联合全身化疗治疗不能切除的原发性肝癌的临床疗效。设计、设置和参与者2013年5月20日至2019年6月27日，在纪念斯隆-凯特琳癌症中心进行了一项单机构、2期临床试验，包括38例患者，使用HAI尿苷联合全身性吉西他滨和奥沙利铂治疗不可切除的IHC患者。在同一时间段内，在圣刘易斯的华盛顿大学进行了一项使用相同治疗的确证性I/II期研究。组织学证实的、不可切除的IHC患者有资格。允许可切除的区域淋巴结转移性疾病和既往全身治疗。排除了远处转移性疾病患者。介入治疗肝动脉灌注阿托尿苷和全身给予吉西他滨和奥沙利铂。主要结局和测量主要结局是6个月时无进展生存率（PFS）为80%。结果对于Memorial Sloan Kettering癌症中心的2期临床试验，纳入了42例不可切除的IHC患者，其中38例患者接受了治疗（13例[34%]男性;诊断时的中位[范围]年龄为64 [39 - 81]岁）。中位随访时间为30.5个月。22例患者（58%）在6个月时实现了部分放射学缓解，32例患者（84%）实现了疾病控制。4例患者有足够的反应接受切除术，1例患者有一个完整的病理反应。中位PFS为11.8个月（单侧90% CI，11.1），6个月PFS率为84.1%（90% CI，74.8%-无穷大），因此符合主要终点（6个月PFS率，80%）。中位OS为25.0个月（95% CI，20.6-未达到），1年OS率为89.5%（95% CI，80.2%-99.8%）。与淋巴结阴性疾病患者相比，可切除区域淋巴结患者（18例[47%]）的OS无差异（24个月OS：淋巴结阴性：60%; 95% CI，40%-91% vs淋巴结阳性：50%; 95% CI，30%-83%; P = 0.66）。4例患者（11%）发生4级毒性反应，需要从研究中移除（1例门静脉高压，2例胃十二指肠动脉瘤，1例泵囊袋感染）。亚组分析显示，IDH 1/2突变肿瘤患者的生存率（2年OS，90%; 95% CI，73%-99%）与野生型（2年OS，33%; 95% CI，18%-63%）相比有显著改善（P = 0.01）。在华盛顿大学圣刘易斯验证性队列中，9例患者（90%）在6个月时达到疾病控制;最常见的3级毒性反应为肝功能检查结果升高，中位PFS为12.8个月（单侧90% CI，6.4）。结论和相关性肝动脉灌注联合全身化疗对不能切除的肝内胆管癌有高度的疗效，且耐受性好;进一步的评估是必要的。这项2期临床试验评估了在不可切除的肝内胆管癌患者中使用肝动脉输注阿糖胞苷联合全身给药吉西他滨和奥沙利铂。吉西他滨和奥沙利铂与不能切除的肝内胆管癌患者的预后改善相关？结果在这项单臂2期临床试验中，38例不可切除的肝内胆管癌患者接受了肝动脉灌注阿托尿苷联合全身吉西他滨和奥沙利铂治疗，58%的患者达到了客观的放射学反应，84%的患者达到了疾病控制。中位总生存期为25.0个月，4例患者有足够的反应接受切除术;淋巴结状态似乎与临床获益无关。肝动脉灌注尿嘧啶核苷联合全身化疗对不能手术切除的肝内胆管癌患者有较好的临床疗效，值得进一步研究。
Importance Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients. Objective To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC. Design, Setting, and Participants A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded. Interventions Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin. Main Outcomes and Measures The primary outcome was progression-free survival (PFS) of 80% at 6 months. Results For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4). Conclusions and Relevance Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.This phase 2 clinical trial evaluates the use of hepatic arterial infusion of floxuridine plus systemic administration of gemcitabine and oxaliplatin in patients with unresectable intrahepatic cholangiocarcinoma.Question Is hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin associated with improved outcomes in patients with unresectable intrahepatic cholangiocarcinoma? Findings In this single-arm, phase 2 clinical trial, 38 patients with unresectable intrahepatic cholangiocarcinoma were treated with hepatic arterial infusion of floxuridine in combination with systemic gemcitabine and oxaliplatin, with 58% of the patients achieving an objective radiographic response and 84% achieving disease control. Median overall survival was 25.0 months, and 4 patients had sufficient response to undergo resection; lymph node status did not appear to be associated with clinical benefit. Meaning Combination hepatic arterial infusion floxuridine with systemic chemotherapy appears to be clinically active in patients with unresectable intrahepatic cholangiocarcinoma and should be investigated further.