Herrmann Evelyn, Naehrig Diana, Sassowsky Manfred, Bigler Martin, Buijsen Jeroen, Ciernik Ilja, Zwahlen Daniel, Pellanda Alessandra Franzetti, Meister Andreas, Brauchli Peter, Berardi Simona, Kuettel Erika, Dufour Jean-François, Aebersold Daniel M
Department of Radiation Oncology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Division of Radiation Oncology, Basel University Hospital, Basel, Switzerland.
Radiat Oncol. 2017 Jan 13;12(1):12. doi: 10.1186/s13014-016-0745-0.
To assess feasibility and safety of conventionally fractionated radiotherapy (cfRT) in patients with hepatocellular carcinoma (HCC).
Patients with histologically confirmed stage cT1-4, cN0-1 HCC and Child-Pugh Score (CPS) A or B disease were included in a phase I multicenter trial. Metastatic HCC were allowed if ≥90% of total tumor volume was located within the liver. Patients were enrolled onto five dose-escalation levels (54-70Gy in 2Gy fractions) based on a modified 3 + 3 design, with cohorts of five patients instead of three patients in dose levels 4 and 5. Primary trial endpoint was dose-limiting toxicity (DLT), as specifically defined for 17 clinical and nine laboratory parameters as grade ≥3 or ≥4 toxicity (CTCAE vs. 3). The threshold to declare a dose level as maximum tolerated dose (MTD) was defined as a DLT rate of ≤16.7% in dose levels 1-3, and ≤10% in dose levels 4-5. Best objective response of target liver lesions and adverse events (AE's) were assessed as secondary endpoints.
The trial was terminated early in DL 3 due to low accrual. Nineteen patients were recruited. Fifteen patients were evaluable for the primary and 18 for the secondary endpoints. Maximum tolerated dose was not reached. One patient in dose level 1, and one patient in dose level 2 experienced DLT (lipase > 5xULN, and neutrophils <500/μL respectively). However, dose level 3 (62Gy) was completed, with no DLTs in 3 patients. Overall, 56% of patients had a partial response and 28% showed stable disease according to RECIST. No signs of radiation induced liver disease (RILD). Two patients in dose level 3 experienced lymphocytopenia grade 4, with no clinical impact.
Conventionally fractionated radiotherapy of 58Gy to even large HCC was safe for patients with CPS A and B. 62Gy was delivered to three patients without any sign of clinically relevant increased toxicity. The maximum tolerated dose could not be determined.
ClinicalTrials.gov identifier NCT00777894 , registered October 21st, 2008.
评估常规分割放疗（cfRT）用于肝细胞癌（HCC）患者的可行性和安全性。
组织学确诊为cT1 - 4期、cN0 - 1期HCC且Child - Pugh评分（CPS）为A或B级疾病的患者纳入一项I期多中心试验。如果≥90%的肿瘤总体积位于肝脏内，则允许转移性HCC患者入组。根据改良的3 + 3设计，将患者分为五个剂量递增水平（2Gy分割，总剂量54 - 70Gy），在剂量水平4和5中每组有5名患者而非3名患者。主要试验终点为剂量限制性毒性（DLT），具体针对17项临床和9项实验室参数定义为≥3级或≥4级毒性（依据CTCAE v3标准）。将剂量水平定义为最大耐受剂量（MTD）的阈值为：在剂量水平1 - 3中DLT发生率≤16.7%，在剂量水平4 - 5中≤10%。目标肝病灶的最佳客观缓解率和不良事件（AE）作为次要终点进行评估。
由于入组率低，试验在剂量水平3提前终止。共招募了19名患者。15名患者可评估主要终点，18名可评估次要终点。未达到最大耐受剂量。剂量水平1中有1名患者、剂量水平2中有1名患者发生DLT（分别为脂肪酶>5倍ULN和中性粒细胞<500/μL）。然而，剂量水平3（62Gy）完成，3名患者均未发生DLT。总体而言，根据RECIST标准，56%的患者有部分缓解，28%显示病情稳定。无放射性肝病（RILD）迹象。剂量水平3中有2名患者发生4级淋巴细胞减少，对临床无影响。
对于CPS A和B级的患者，即使是大的HCC，58Gy的常规分割放疗也是安全的。62Gy给予了3名患者，未出现任何临床相关毒性增加的迹象。无法确定最大耐受剂量。
ClinicalTrials.gov标识符NCT00777894，于2008年10月21日注册。
