Induction Chemotherapy Before or After Preoperative Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer: A Randomized Phase II Trial of the German Rectal Cancer Study Group
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 311
- 试验地点
- 10
- 主要终点
- Number of patients with pathological complete response (pCR), i.e. ypT0N0.
研究概览
简要总结
Preoperative 5-FU-based (5-fluorouracil) chemoradiotherapy (CRT), total mesorectal excision surgery, and 4 cycles of adjuvant 5-FU - as established by CAO/ARO/AIO-94 - is at present a standard of care for patients with locally advanced rectal cancer (UICC stage II and III). The phase III German CAO/ARO/AIO-04 trial showed, that the addition of oxaliplatin increased treatment efficacy in terms of early secondary efficacy endpoints (e.g. the pCR-rate). With a median follow-up of 50 months, the primary endpoint of this trial - disease free survival - was significantly improved in the oxaliplatin-containing treatment arm (3-year disease-free survival (DFS) 71.2% versus 75.9%, hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.64-0.98, p=0.03). The hereby proposed randomized phase II trial CAO/ARO/AIO-12 aims at finding novel and innovative aspects of rectal cancer treatment, and will thus provide important information for defining the experimental arm in the upcoming large scale trial of the group. Compared to the current standard, in both study arms, the sequence of the three treatment modalities is modified, placing the chemotherapy block before surgery. The pre-operative sequence of chemotherapy -> chemoradiotherapy (arm A) has been shown to be feasible with no early tumor progression prior to definitive surgical resection in a small randomized phase II study from Spain. The sequence chemoradiotherapy -> chemotherapy (arm B) may be beneficial according to response kinetics considerations, and by maintaining a highly effective local treatment in the first place. Both approaches could avoid the problem of major compliance problems with post-operative adjuvant chemotherapy. CAO/ARO/AIO: German Rectal Cancer Study Group
研究设计
- 研究类型
- Interventional
- 分配方式
- 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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male and female patients with histologically confirmed diagnosis of rectal cancer localised 0 - 12 cm from the anocutaneous line as measured by rigid rectoscopy (i.e. lower and middle third of the rectum)
- •Staging requirements: High-resolution, thin-sliced (i.e. 3mm) magnetic resonance imaging (MRI) of the pelvis is the mandatory local staging procedure.
- •MRI-defined inclusion criteria: presence of at least one of the following high risk conditions: any cT3 (clinical stage tumor-3) if the distal extent of the tumor is < 6 cm from anocutaneous line or cT3 in the middle third of the rectum (≥ 6-12 cm) with MRI evidence of extramural tumor spread into the mesorectal fat of more than 5 mm (>cT3b), or resectable cT4 tumors, or any clear cN+ (clinical staging nodes) based on MRI-criteria
- •Trans-rectal endoscopic ultrasound (EUS) is additionally used when MRI is not definitive to exclude early cT1/T2 disease in the lower third of the rectum or early cT3a/b tumors in the middle third of the rectum.
- •Spiral-CT of the abdomen and chest to exclude distant metastases.
- •Aged at least 18 years. No upper age limit.
- •WHO/ECOG (World Health Organisation/Eastern Cooperative Oncology Group) Performance Status ≤ 1
- •Adequate haematological, hepatic, renal and metabolic function parameters: Leukocytes ≥ 3.000/mm^3, absolute neutrophil count (ANC) ≥ 1.500/mm^3, platelets ≥100.000/mm^3, Hb > 9 g/dl; Serum creatinine ≤ 1.5 x upper limit of normal; Bilirubin ≤ 2.0 mg/dl, serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT), and alkaline phosphatase (AP) ≤ 3 x upper limit of normal
- •Informed consent of the patient
排除标准
- •Lower border of the tumor localised more than 12 cm from the anocutaneous line as measured by rigid rectoscopy
- •Distant metastases (to be excluded by CT scan of the thorax and abdomen)
- •Prior antineoplastic therapy for rectal cancer
- •Prior radiotherapy of the pelvic region
- •Major surgery within the last 4 weeks prior to inclusion
- •Subject pregnant or breast feeding, or planning to become pregnant within 6 months after the end of treatment.
- •Subject (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 6 months (male or female) after the end of treatment (adequate: oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
- •On-treatment participation in a clinical study in the period 30 days prior to inclusion
- •Previous or current drug abuse
- •Concomitant other antineoplastic therapy
- •Serious concurrent diseases, including neurologic or psychiatric disorders (incl. dementia and uncontrolled seizures), active, uncontrolled infections, active, disseminated coagulation disorder
- •Clinically significant cardiovascular disease in (incl. myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 6 months before enrolment
- •Chronic diarrhea (> grade 1 according NCI CTCAE)
- •Prior or concurrent malignancy ≤ 3 years prior to enrolment in study (Exception: non-melanoma skin cancer or cervical carcinoma FIGO (International Federation of Gynecology and Obstetrics) stage 0-1), if the patient is continuously disease-free
- •Known allergic reactions on study medication
- •Known dihydropyrimidine dehydrogenase deficiency
- •Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule (these conditions should be discussed with the patient before registration in the trial)
研究组 & 干预措施
Arm A: Chemotherapy -> Chemoradiotherapy
Induction chemotherapy followed by chemoradiotherapy before surgery
干预措施: Induction Chemotherapy arm A (Drug)
Arm A: Chemotherapy -> Chemoradiotherapy
Induction chemotherapy followed by chemoradiotherapy before surgery
干预措施: Radiation arm A (Radiation)
Arm A: Chemotherapy -> Chemoradiotherapy
Induction chemotherapy followed by chemoradiotherapy before surgery
干预措施: Surgery (Procedure)
Arm B: Chemoradiotherapy -> Chemotherapy
Combined chemoradiotherapy followed by three cycles chemotherapy before surgery
干预措施: Radiation arm B (Radiation)
Arm B: Chemoradiotherapy -> Chemotherapy
Combined chemoradiotherapy followed by three cycles chemotherapy before surgery
干预措施: Chemotherapy arm B (Drug)
Arm B: Chemoradiotherapy -> Chemotherapy
Combined chemoradiotherapy followed by three cycles chemotherapy before surgery
干预措施: Surgery (Procedure)
结局指标
主要结局
Number of patients with pathological complete response (pCR), i.e. ypT0N0.
时间窗: 123 +30 days
Efficacy (pCR) of induction chemotherapy followed by chemoradiotherapy, or the other way round, before surgery in patients with locally advanced rectal cancer.
次要结局
- Pathological staging(123 +14 days)
- Safety of the respective combination sequences by Toxicity assessment according to NCI CTCAE V.4.0(5 years)
- Surgical morbidity(123 +30 days)
- Surgical complications(123 +30 days)
- Tumor downstaging assessed by ypTNM (neoadjuvant pathological staging tumor nodes metastasis) findings in relation to initial cTNM (clinical stage tumor nodes metastasis)(123 +14 days)
- Relapse-free survival (local / distant / overall)(5 years)
- Tumor regression grading according to Dworak(123 +14 days)
- R0 resection rate; negative circumferential resection rate(123 +14 days)
- Rate of sphincter-sparing surgery(123 +14 days)
- Overall survival(5 years)
研究者
Prof. Dr. med. Claus Rödel
Prof. MD
Goethe University