A Phase I Dose Escalation Trial of Conformal Hypofractionated Radiation Therapy for Patients With Hepatitis B Virus-Related Child A Cirrhosis and Hepatocellular Carcinoma
试验速览
- 阶段
- 1 期
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Maximally tolerated dose of RT
研究概览
简要总结
Hepatocellular carcinoma (HCC) is one of the leading malignancies in Taiwan. Surgery and local ablative therapy remain the treatment of choice for curative purpose. Transarterial chemoembolization has been the mainstay of intrahepatic control for patients not being candidates for local modalities of treatment. Sorafenib is recently integrated into the treatment options, mainly for intrahepatic or extrahepatic wide spread disease contraindicated for the other modalities. External radiotherapy (RT) has been selectively used for patients with the localized hepatic tumor(s) refractory to the above treatment options. The data from the retrospective studies were biased by the patient selection and uncontrolled comparison with patients not receiving RT. The obstacles for RT to HCC remain unanswered with heterogeneity in dose of radiation and lower tolerance of liver to RT in viral hepatitis carriers. Such a sublethal dose might be associated with unsatisfactory tumor control, intra-/extra-hepatic metastasis, and radiation-induced liver disease in a significant proportion of HCC patients.
The purposes of this phase I study are primarily to determine the maximally tolerated dose of RT, and secondarily to evaluate the tumor control, to assess patterns of failure and survival, to analyze the characteristics of radiation-induced liver disease, as well as to collect blood samples for translational research. HCC patients who are hepatitis B virus carriers and graded as Child-Pugh A cirrhosis are enrolled. This dose escalation trial is conducted with the 7-Gy increase in 2 fractions (3.5 Gy per fraction) for a total of four levels, from 42 Gy up to 63 Gy. Conformal RT with three-dimensional design, intensity modulated RT, or volumetric modulated arc therapy is used with the defined dose-volume threshold for normal liver and the other structures. Five patients are treated for each dose level, with dose limiting toxicity in less than 2 patients judged to be acceptable. A minimum of 15 patients are required for the starting dose level of 49 Gy if the treated tumor diameter is less than 10 cm. Imaging modalities are used for estimating treatment response and detecting metastasis. Serum analyses are done for evaluating hepatic function, viral load, hematological toxicity, and translational research for angiogenic and inflammatory studies.
详细描述
Synopsis
All enrolled patients will receive 3.5 Gy per fraction (five fractions per week) at the following levels;
Dose escalation by 7 Gy in 2 fractions to maximum of 63 Gy, as follows:
Dose Level I: 3.5 Gy for 12 fractions (42 Gy total) Dose Level II*: 3.5 Gy for 14 fractions (49 Gy total) Dose Level III: 3.5 Gy for 16 fractions (56 Gy total) Dose Level VI: 3.5 Gy for 18 fractions (63 Gy total) *Protocol treatment begins at level 2 for patients with the sum of the diameters of irradiated tumor(s) less than 10 cm.
Patient population:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Eligible patients include those with HCC based on the diagnostic criteria of European Association for the Study of the Liver (EASL), either confirmed cyto-histologically or confirmed non-invasively (restricted to cirrhotic patients) by radiological criteria (two coincident imaging techniques and focal lesion > 2 cm with arterial hypervascularization) or combined criteria (one imaging technique associated with AFP, focal lesion > 2 cm with arterial hypervascularization, and AFP levels > 400 ng/ml).
- •They have Child-Pugh grade A cirrhosis and are HBsAg-positive for more than 6 months.
- •These patients are not feasible for other conventional treatment modalities of treatment including surgery, transarterial embolization, ethanol injection, and radiofrequency ablation.
- •No systemic anti-cancer therapy with high priority is available.
- •All of the above 3 criteria should be judged by the caring physician.
- •All intrahepatic disease must be encompassed within the radiation fields, except intrahepatic diseases outside the radiation field(s) have been controlled by other treatment modalities before radiotherapy.
- •Karnofsky Performance Scale ≧
- •Adequate bone marrow function, defined as follows:
- •Absolute neutrophil count (ANC) > 1,000 cells/mm3 based upon CBC/differential obtained within 2 weeks prior to registration on study
- •Platelets > 20,000 cells/mm3 based upon CBC/differential obtained within 2 weeks prior to registration on study
- •Hemoglobin > 8.0 g/dl based upon CBC/differential obtained within 2 weeks prior to registration on study (Note: The use of blood transfusion or other intervention to achieve Hgb > 8.0 g/dl is acceptable.)
- •Previous liver resection, embolization, or ablative therapy is permitted.
- •Chemotherapy and/or targeted agent therapy must be completed at least 2 weeks prior to radiation.
- •Women of childbearing potential and male participants must practice adequate contraception.
- •Patient must sign informed consent prior to study entry.
- •Pretreatment evaluations for eligibility include:
- •A complete history and general physical examination
- •For women of childbearing potential, a serum or urine pregnancy test must be performed within 72 hours prior to registration INR, total bilirubin, albumin, alkaline phosphatase, AST, ALT within 1 week prior to study entry
- •At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR at least 10 mm by spiral CT scan
排除标准
- •Prior invasive malignancy, other than HCC, (except nonmelanomatous skin cancer) unless disease free for a minimum of 3 years (For example, carcinoma in situ of the breast, oral cavity, or cervix are all permissible).
- •Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
- •Tumor thrombosis in the main trunk of portal vein, hepatic vein, or inferior vena cava.
- •Child-Pugh grade B or C cirrhosis.
- •Extrahepatic metastasis.
- •Clinical ascites that requires diuretic treatment or paracentesis for symptom relief.
- •Serum alanine aminotransferase (ALT) level > 5X normal upper limits or total bilirubin level > 3.
- •Active hepatitis (serum ALT level > 5X normal upper limits) or clinically significant liver failure.
- •Positivity of anti-HCV, pregnancy, nursing women, or women of childbearing potential, and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
结局指标
主要结局
Maximally tolerated dose of RT
时间窗: weekly during radiotherapy
次要结局
- Tumor control, patterns of failure and survival(Monthly after radiotherapy)