Effect of Short-duration Preoperative Neoadjuvant Therapy With FOLFOX Based Therapy on Morbidity After Liver Resection for Colorectal Cancer Metastases
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 9
- 试验地点
- 1
- 主要终点
- Postoperative Complication Rate
研究概览
简要总结
The purpose of this study is to determine the effect of short-duration pre-operative FOLFOX based therapy on postoperative problems after liver surgery for patients with metastatic colorectal cancer.
详细描述
Although early stage, localized colon and rectal cancers are associated with 5 year survival rates of nearly 90%, only a minority of patients present with localized disease. Unfortunately, at the time of their initial presentation, approximately 35% of patients with colon or rectal cancer have metastatic disease. Nearly two thirds of these patients with stage IV disease have evidence of extrahepatic spread and have a median overall survival rate of 8-10 months in the absence of further treatment. Even with the most intensive chemotherapeutic regimens, the median overall survival for these patients ranges from 12 months to 20 months. However, a small subset of patients with stage IV disease has isolated hepatic metastatic disease and can undergo resection. The patients with completely resected liver metastases enjoy a significantly higher overall five-year survival, which is as high as 58% in carefully selected patients. Ten-year overall survival has been reported in 22% of patients. Despite this improvement, the five-year disease-free survival for these patients is at best 35%, with hepatic recurrences occurring in 46%.
The fact that adjuvant chemotherapy improves the three-year survival rate for stage II disease and five-year survival rates for stage III disease implies that it can treat micrometastatic disease in some fraction of patients. Because micrometastatic disease is likely the cause of the high recurrence rate in patients who undergo liver resection, there is a clear biologic rationale for using postoperative adjuvant chemotherapy after liver resection. Although this strategy is a common practice in many centers, no convincing data that this improves survival have been reported. A large randomized phase III trial (EORTC 40983) examining this question is currently ongoing and effect on survival has not yet been reported. Given that systemic chemotherapy after liver resection remains of unproven benefit at the present time, many have wondered if preoperative treatment might have more promise in improving recurrence rates.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Synchronous or metachronous colorectal metastases
- •Technically resectable liver metastases
- •Four or fewer metastases
- •No tumors in porta hepatis
- •Resection of no more than 70% of liver needed
- •Medically suitable candidate for major liver resection
- •FDG-PET scan without metastatic disease outside the liver
排除标准
- •Near-obstructing or obstructing colon lesions in patients in whom combined resection is planned (as delay for preoperative chemotherapy would be medially impossible)
- •Treatment with FOLFOX or cetuximab within 12 months
- •Treatment with irinotecan within 12 months
- •Abnormal liver function (ALT or AST > 5x ULN, bilirubin > 3x ULN)
- •Body mass index >/= 35 kg/m² (as the risk for steatohepatitis is increased)
- •Renal insufficiency (Cr > 2.5mg/dL)
- •Interstitial lung disease (because cetuximab has been rarely associated with development of interstitial lung disease)
- •ECOG performance score >/= 3
- •Patients unable to give informed consent
- •Pregnant patient (as cetuximab is a Class C drug)
- •Peripheral neuropathy >/= grade II (as oxaliplatin causes neuropathy to worsen)
研究组 & 干预措施
Arm 1 - Wildtype
Neoadjuvant therapy
Week 1
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8 *Cetuximab 250 mg/m^2 IV weekly
Weeks 3, 5, 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Week 1, 3, 5, 7, 9, 11, 13, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8, 10, 12, 16
*Cetuximab 250 mg/m^2 IV weekly
干预措施: Cetuximab (Drug)
Arm 1 - Wildtype
Neoadjuvant therapy
Week 1
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8 *Cetuximab 250 mg/m^2 IV weekly
Weeks 3, 5, 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Week 1, 3, 5, 7, 9, 11, 13, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8, 10, 12, 16
*Cetuximab 250 mg/m^2 IV weekly
干预措施: Leucovorin (Drug)
Arm 1 - Wildtype
Neoadjuvant therapy
Week 1
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8 *Cetuximab 250 mg/m^2 IV weekly
Weeks 3, 5, 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Week 1, 3, 5, 7, 9, 11, 13, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8, 10, 12, 16
*Cetuximab 250 mg/m^2 IV weekly
干预措施: Oxaliplatin (Drug)
Arm 1 - Wildtype
Neoadjuvant therapy
Week 1
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8 *Cetuximab 250 mg/m^2 IV weekly
Weeks 3, 5, 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Week 1, 3, 5, 7, 9, 11, 13, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV Cetuximab 400 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2/day over 46 hours
Weeks 2, 4, 6, 8, 10, 12, 16
*Cetuximab 250 mg/m^2 IV weekly
干预措施: Fluorouracil (Drug)
Arm 2 K-Ras 12/13 codon mutation
Neoadjuvant Therapy
Weeks 1, 3, 5
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Weeks 1, 3, 5, 9, 11, 13
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
干预措施: Bevacizumab (Drug)
Arm 2 K-Ras 12/13 codon mutation
Neoadjuvant Therapy
Weeks 1, 3, 5
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Weeks 1, 3, 5, 9, 11, 13
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
干预措施: Leucovorin (Drug)
Arm 2 K-Ras 12/13 codon mutation
Neoadjuvant Therapy
Weeks 1, 3, 5
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Weeks 1, 3, 5, 9, 11, 13
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
干预措施: Oxaliplatin (Drug)
Arm 2 K-Ras 12/13 codon mutation
Neoadjuvant Therapy
Weeks 1, 3, 5
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Wait 3-8 weeks after completion of therapy
Liver resection
Wait 4 weeks or until clinical status allows
Adjuvant Therapy
Weeks 1, 3, 5, 9, 11, 13
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- Bevacizumab 5 mg/kg IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
Week 7, 15
- Leucovorin 400 mg/m^2 IV
- Oxaliplatin 85 mg/m^2 IV
- 5FU bolus 400 mg/m^2
- 5FU CIVI 1200 mg/m^2
干预措施: Fluorouracil (Drug)
结局指标
主要结局
Postoperative Complication Rate
时间窗: 30 days following surgery
Fraction of patients with any grade of complication I-V
Major Postoperative Complication Rate
时间窗: 30 days following surgery
Fraction of patients with any complication grades IV and V
All-cause Mortality
时间窗: 30 days following surgery
次要结局
- Postoperative Recurrence Patterns(Up to 5 years)
- Change in Tumor Size From Pretreatment to Preoperative CT Scan(Completion of neoadjuvant therapy (approximately 8 weeks))
- Liver Injury Scale Score (0-27)(Time of surgery (approximately 11-16 weeks))
- Histologic Hepatic Toxicity at Surgery(Time of surgery (approximately 11-16 weeks))
- Nonalcoholic Steatohepatitis Score (0-3)(Time of surgery (approximately 11-16 weeks))
- Effect of Preoperative Chemotherapy on Tumor Size(Upon completion of neoadjuvant chemotherapy (approximately 2 months))