Definitive Radiochemotherapy With 5-FU / Cisplatin Plus/Minus Cetuximab in Unresectable Locally Advanced Esophageal Cancer: a Phase II Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 74
- 试验地点
- 1
- 主要终点
- Rate of Participants Who Were Alive at 2 Years
研究概览
简要总结
Esophageal cancer is a highly aggressive tumor. Treatment options are various and range from chemotherapy to radiotherapy and several surgical techniques. Nevertheless, the overall survival rates for this disease remain poor.
During the last years the combination of cetuximab with standard chemotherapy or radiotherapy has mainly be investigated in clinical trials focusing on colorectal and/or head and neck cancer.
The results obtained from theses studies were very encouraging and led to the initiation of active clinical research in esophageal cancer patients with antibody inhibition of the epidermal growth factor receptor (EGFR).
The first data in this indication are encouraging showing that cetuximab can safely be added to chemoradiation for esophageal cancer patients with first hints of efficacy.
Based on the experiences with cetuximab in colorectal cancer and in combination with radiotherapy in head and neck cancer, the aim of the present study is to evaluate the feasibility of a combined treatment of cetuximab with continuous infusional 5-FU, cisplatin and radiotherapy in patients with esophageal cancer and to assess if the overall survival rates can be increased by addition of an EGFR-targeted therapy.
详细描述
Esophageal cancer is a highly aggressive neoplasm which is fatal in the great majority of patients. On a global basis, cancer of the esophagus is the sixth leading cause of cancer death worldwide. In fact, gastric and esophageal cancers together accounted for nearly 1.3 million new cases and 980,000 deaths worldwide in 2000 - more than lung, breast, or colorectal cancer. With advances in surgical techniques and treatment, the prognosis of esophageal cancer has slowly improved over the past decades. However, with a 5-year overall survival rate of approximately 14%, at the time of development of the LEOPARD-II protocol, survival was poor, even in comparison with the dismal survival rates (4%) from the 1970s. Underlying reasons for this disappointingly low survival rate are above all the difficulties in cancer detection at an advanced stage, with over 50% of patients with unresectable disease or distant metastasis at presentation and the limited survival achieved with palliative chemotherapy alone for patients with metastatic or unresectable disease.
Clearly, additional strategies are needed to improve the systemic treatment options for esophageal cancer.
The optimal treatment of locally advanced esophageal cancer, a potentially curable disease, is controversial. Through several non-randomized cooperative group trials, concurrent cisplatin-based chemoradiation or surgery alone represent acceptable standards of care for patients with resectable tumors.
Metastatic or unresectable esophageal cancer is found at presentation in more than 50% of patients and is considered incurable. At the time of protocol development, chemotherapy was palliative, improving quality of life and dysphagia in 60%-80% of patients. Typical clinical and radiographic responses lasted for fewer than 4 months, with a median overall survival time of 8-10 months.
Combination chemotherapies have been demonstrated to be superior to best supportive care and chemotherapy given as a single agent, with occasional patients achieving complete responses (0%-11%). However, even with the combination regimens, the median survival time remained less than 10 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Dated and signed written informed consent
- •Male or female patients between 18 years and 75 years; patients > 75 years if their karnofsky performance status is ≥
- •Histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus which is not curatively resectable. Resectability has to be defined by a surgeon before radiochemotherapy. The tumor is considered unresectable due to T-stage, N-stage, performance status, nutritional status, co-morbidity (pulmonal function, other), tumor location upper third or other reasons
- •Karnofsky Performance Status ≥ 70
- •Women of child-bearing potential must have a negative pregnancy test
- •Adequate cardial-, pulmonal- and ear function
- •Adequate bone marrow function:
- •leukocytes ≥ 3.0 x 10^9/L
- •neutrophiles ≥ 1.5 x 10^9/L
- •thrombocytes ≥ 100 x 10^9/L
- •hemoglobin ≥ 10.0 g/dl
- •Adequate liver function:
- •bilirubin ≤ 2.0 mg/dl
- •transaminases (serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOT), gamma-GT) ≤ 3 x upper limit of normal (ULN)
- •Adequate kidney function:
- •serum creatinine ≤ 1.5 mg/dl
- •creatinine clearance ≥ 50 ml/min according to Cockcroft-Gault Formula
- •no known allergies against chimeric antibodies
- •effective contraception for male and female patients if there is a risk of conception
排除标准
- •distant metastasis
- •previous treatment of esophageal cancer
- •previous therapy with monoclonal antibodies and / or EGFR-targeted therapy
- •previous second malignancies with exception of a history of a previous curatively treated basal cell carcinoma of the skin or pre-invasive cervix carcinoma
- •serious concomitant disease or medical condition
- •lung function: forced expiratory volume in one second (FEV1)) < 1.1
- •clinically relevant coronary artery diseases or known myocardial infarction within the last 12 months or ventricular ejection fraction (LVEF) below normal
- •every active dermatological condition > grade 1
- •contraindications to receive cisplatin, 5-FU or cetuximab
- •concurrent treatment with other experimental drugs or participation in another clinical trial within 30 days before study start
- •patient pregnant or breast feeding
- •known drug abuse, medication abuse, alcohol abuse
- •social situations limiting the compliance with the study requirements
研究组 & 干预措施
Cetuximab, Cisplatin, 5-FU, Radiotherapy
Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV
5-fluorouracil (5-FU): 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102
Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102)
radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.
干预措施: Cetuximab (Drug)
Cetuximab, Cisplatin, 5-FU, Radiotherapy
Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV
5-fluorouracil (5-FU): 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102
Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102)
radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.
干预措施: Cisplatin, 5-FU (Drug)
Cetuximab, Cisplatin, 5-FU, Radiotherapy
Cetuximab: Initial doses 400mg/m2 (day 1), followed by weekly doses of 250mg/m2 for 14 weeks in total, IV
5-fluorouracil (5-FU): 1000mg/m2 per day as continuous infusion on day 8-11 and 36-39, 750mg/m2/day as continuous infusion on day 71-74 and 99-102
Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 8-11, 36-39, 71-74 and 99-102)
radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.
干预措施: Radiotherapy (Radiation)
Cisplatin, 5-FU, Radiotherapy
5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95
Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95)
radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.
干预措施: Cisplatin, 5-FU (Drug)
Cisplatin, 5-FU, Radiotherapy
5-FU: 1000mg/m2 per day as continuous infusion on day 1-4 and 29-32, 750mg/m2/day as continuous infusion on day 64-67 and 92-95
Cisplatin 20mg/m2/day as intravenous bolus over 60 min on day 1-4 of every cycle (day 1-4, 29-32, 64-67 and 92-95)
radiotherapy: 59.4 Gy (33 fractions of 1.8 Gy) over 6.5-7 weeks (5 x 1.8 Gy per week)on primary tumor. 50.4 Gy on locoregional lymphnodes. If resectability is reached after 4-4.5 weeks (36-41.4 Gy) the radiotherapy stops after 45 Gy and the patient undergoes surgery.
干预措施: Radiotherapy (Radiation)
结局指标
主要结局
Rate of Participants Who Were Alive at 2 Years
时间窗: 2 years
Overall Survival (OS) was defined as freedom from death of any cause. Time to death was calculated from the day of randomization, and the patients were followed for a maximum of 24 months (2 years).
次要结局
- Rate of Participants Who Were Alive at 1 Year(1 year)
- Rate of Participants Who Were Alive Without Progression of Disease at 1 Year(1 year)
- Rate of Participants Who Were Alive Without Progression of Disease at 2 Years(2 years)
- Number of Participants Experiencing at Least One Grade >=3 Toxicity(up to 2 years)
- Rate of Participants Who Were Alive Without Distant Metastases at 1 Year(1 year)
- Rate of Participants Who Were Alive Without Loco-regional Failure at 2 Years(2 years)
- Rate of Participants Who Were Alive Without Distant Metastases at 2 Years(2 years)
- Number of Participants Who Achieved at Least Partial Response (Responders)(up to 2 years)
- Rate of Participants Who Were Alive Without Loco-regional Failure at 1 Year(1 year)
- Change in Quality of Life Between Baseline and End of Treatment (After 5 to 13 Weeks)(end of treatment (after 5 to 13 weeks))
研究者
Prof. Dirk Rades, MD
Professor Dr. med.
University Hospital Schleswig-Holstein