一项关于晚期头颈部鳞状细胞癌患者接受羟基脲持续输注联合超分割加速外照射放疗的I期临床试验。

A phase I clinical trial of prolonged infusion of hydroxyurea in combination with hyperfractionated, accelerated, external radiation therapy in patients with advanced squamous cell cancer of the head and neck.

作者信息

Beitler J J, Smith R V, Haynes H, Silver C E, Quish A, Kotz T, Serrano M, Brook A, Wadler S

机构信息

Department of Radiation Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY 10467-2490, USA.

出版信息

Invest New Drugs. 1998;16(2):161-9. doi: 10.1023/a:1006102716920.

DOI:10.1023/a:1006102716920

PMID:9848580

Abstract

BACKGROUND

Preclinical data suggested that sustained inhibition of the anabolic enzyme, ribonucleotide reductase (RR), by hydroxyurea (HU) may be critical for the anticancer effects of the drug. A phase I trial of continuous infusion HU with concomitant hyperfractionated, accelerated radiation therapy (CHU-CHRT) was initiated to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of HU in patients with locally advanced squamous cell carcinoma (SCC) of the head and neck.

METHODS

Patients were required to have histologically-documented and radiographically-staged locally advanced SCC of the hypopharynx (AJC stages II, III or IV), oropharynx (AJC stage IV), or oral cavity (AJC stage IV) not amenable to reasonable surgical resection. Eligible patients had adequate bone marrow, hepatic, and renal function and had to give informed consent. Concomitant, hyperfractionated, accelerated radiation therapy (CHRT) consisted of 1.2 Gy BID (6 hour minimum interfraction interval) on weekdays and 1.2 Gy delivered daily on the weekends to a total tumor dose of 74.4 Gy. Continuous infusion hydroxyurea (CHU) was administered at 0.25-0.375 mg/m2/min as a continuous intravenous infusion daily for 5 days with weekends days off for the duration of the radiation therapy. The dose of HU was increased by 0.125 mg/m2/min between dose levels until DLT was reached in 2/6 patients. If the primary had a complete clinical response and biopsies were negative, planned neck dissections were performed.

RESULTS

Fifteen patients were enrolled and are evaluable. The initial dose level, 0.25 mg/m2/min was tolerated by 3/3 patients. At 0.375 mg/m2/min, 3/6 patients experienced grade 3-4 infections, with one patient having a non-fatal, subendocardial infarction. At 0.313 mg/m2/min, no patient experienced DLT.

CONCLUSION

The MTD for CHU-CHRT was 0.313 mg/m2/min. The toxicities were primarily mucosal and a phase II study is in progress.

摘要

背景

临床前数据表明，羟基脲（HU）对合成代谢酶核糖核苷酸还原酶（RR）的持续抑制作用可能是该药物抗癌效果的关键。开展了一项羟基脲持续输注联合超分割加速放疗（CHU-CHRT）的I期试验，以确定HU在局部晚期头颈部鳞状细胞癌（SCC）患者中的最大耐受剂量（MTD）和剂量限制毒性（DLT）。

方法

患者需经组织学证实且经影像学分期为下咽（美国癌症联合委员会II、III或IV期）、口咽（美国癌症联合委员会IV期）或口腔（美国癌症联合委员会IV期）局部晚期SCC，且不适合进行合理的手术切除。符合条件的患者骨髓、肝脏和肾功能良好，并需签署知情同意书。联合超分割加速放疗（CHRT）包括工作日每天两次，每次1.2 Gy（两次照射间隔至少6小时），周末每天照射1.2 Gy，总肿瘤剂量达74.4 Gy。持续输注羟基脲（CHU）以0.25 - 0.375 mg/m²/min的速度持续静脉输注，每天5天，放疗期间周末休息。HU剂量在不同剂量水平之间每次增加0.125 mg/m²/min，直至6名患者中有2名出现DLT。如果原发灶出现完全临床缓解且活检结果为阴性，则进行计划性颈部清扫术。