Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy With 5-Fluorouracil and Oxaliplatin Versus 5-Fluorouracil Alone in Rectal Cancer

Official Title: “Prospective Randomised Multicenter Phase-III-study: Preoperative Radiochemotherapy and Adjuvant Chemotherapy With 5-Fluorouracil Plus Oxaliplatin Versus Preoperative Radiochemotherapy and Adjuvant Chemotherapy With 5-Fluorouracil for Locally Advanced Rectal Cancer”

Standard treatment for locally advanced cancer of the rectum is preoperative chemoradiotherapy with 5-Fluorouracil (5-FU) plus 4 cycles of postoperative chemotherapy with 5-FU. According to our previous study (CAO/ARO/AIO-94, published in the New England Journal of Medicine 2004; 351:1731-40) this treatment results in only 6% of local failures, yet, still 36% of all patients develop distant metastasis. Therefore, our new study (CAO/ARO/AIO-04) incorporates new drugs, i.e. 5-FU + oxaliplatin, in an effort to improve the control of distant metastases. It is our hypothesis that the rate of disease free survival will improve by 5 to 8% after 3 years of follow-up.

Intervention(s) in this Clinical Trial

• Drug: 5-FU and oxaliplatin
  • Preoperative radiochemotherapy: Oxaliplatin: 50 mg/m² i.v., days 1, 8, 22 und 29; 5-Fluorouracil: 250 mg/m²/d continuous infusion, days 1-14 and 22-35 Adjuvant Chemotherapy: Oxaliplatin: 100 mg/m² i.v. on day 1; Calciumfolinat:400 mg/m² on day 1; 5-Fluorouracil: 2400 mg/m² continuous infusion for 46 hours repeat day 15, 8 cycles
• Drug: 5-FU
  • Preoperative radiochemotherapy: 5-Fluorouracil: Days 1-5 and 29-33: 120h-continuous infusion 1000 mg/m²/d Adjuvant Chemotherapy: 5-Fluorouracil: 500 mg/m² on 5 consecutive days (day 1-5) i.v. bolus fot 2-5 minutes; repeat day 29, 4 cycles

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Preoperative simultaneous radiochemotherapy: 5-Fluorouracil und Oxaliplatin: Radiotherapy starts on day 1 of chemotherapy; 28 fractions; single dose: 1,8 Gy once per day, monday through friday; Total dose: 50,4 Gy; Oxaliplatin: 50 mg/m² i.v., days 1, 8, 22 und 29; 5-Fluorouracil: 250 mg/m²/d continuous infusion, days 1-14 and 22-35 Adjuvant Chemotherapy: Oxaliplatin: 100 mg/m² i.v. on day 1; Calciumfolinat: 400 mg/m² on day 1; 5-Fluorouracil: 2400 mg/m² continuous infusion for 46 hours; repeat day 15, 8 cycles
• Active Comparator: 2
  • Preoperative simultaneous radiochemotherapy: 5-Fluorouracil Radiotherapy starts on day 1 of chemotherapy; 28 fractions; single dose: 1,8 Gy once per day, monday through friday; Total dose: 50,4 Gy; 5-Fluorouracil: Days 1-5 and 29-33: 120h-continuous infusion 1000 mg/m²/d Adjuvant Chemotherapy: 5-Fluorouracil: 500 mg/m² on 5 consecutive days (day 1-5) i.v. bolus fot 2-5 minutes; repeat day 29, 4 cycles

Primary Measures

• Disease free survival at 3 years defined as the interval from randomization to locoregional or metastatic recurrence or the appearance or a secondary colorectal cancer or death, whichever occurs first.
  • Time Frame: 3 years
    Safety Issue?: No

Secondary Measures

• Resection rate, rate of sphincter preservation, tumor regression, cumulative incidence of local and distant recurrences, overall survival, toxicity, quality of life
  • Time Frame: 5-year follow up
    Safety Issue?: No

Inclusion Criteria:

• Minimum age: 18 years
• Histologically proven, advanced primary carcinoma of the rectum (tumor ? 12cm from the anal verge, with clinically staged T3/4 or any node-positive disease
• No prior therapy except a diverting stoma
• ECOG PS less than or equal 2
• Adequate bone marrow function: Leukocytes > 3,5 x 10^9/L Absolute neutrophil count >
• 1,5 x 10^9/L Platelet count > 100 x 10^9/L Hemoglobin > 10 g/dl
• Adequate hepatic function: Total bilirubin < 2,0 mg/dl ALAT, ASAT, alkaline phosphatase, gamma-GT < 3 x ULN 7. Serum creatinine < 1,5 mg/dl, creatinine-clearance
• > 50 ml/min
• Written informed consent before randomization

Exclusion Criteria:

• Pregnant or breast feeding women
• Fertile patients without adequate contraception during therapy
• Past or ongoing drug abuse or alcoholic excess
• Prior chemotherapy
• Prior radiotherapy to the pelvis
• Prior (within 4 weeks) or concurrent treatment with any other investigational agent
• Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
• History of severe somatic or psychological diseases: - instable cardiac disease not well controlled with medication, myocardial infarction within the last 6 months:*
• Central nervous system disorders or psychiatric disability including dementia or epileptic disease; * active uncontrolled intercurrent infections or sepsis
• Peripheral neuropathy > 2 (NCI CTC AE grading)
• Previous or concurrent malignancies, with the exception of adequately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix. The inclusion of patients with other adequately treated tumors within the last 5 years has to be discussed with the principal investigator
• Chronic diarrhea (> NCI CTC AE-Grad 1)
• Known allergy to substances containing platinum compounds
• Concurrent use of the antiviral agent sorivudine or chemically related analogues
• Known deficiency of dehydropyrimidindehydrogenase (DPD)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: University of Erlangen-Nürnberg Medical School Other

Overall Clinical Trial Officials and Contacts

Rolf Sauer, M.D. Principal Investigator Dept. of Radiation Therapy, University of Erlangen, Germany  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00349076

Study ID Number: CAO/ARO/AIO-04

ClinicalTrials.gov Identifier: NCT00349076

Health Authority: Germany: Federal Institute for Drugs and Medical Devices