Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy in Treating Patients Who Are Undergoing Surgical Resection for Locally Advanced Rectal Cancer

Randomized Phase II Trial Of Neoadjuvant Combined Modality Therapy For Locally Advanced Rectal Cancer

RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Chemoradiotherapy (combining chemotherapy with radiation therapy) before surgery may shrink the tumor so that it can be removed. Giving chemotherapy after surgery may kill any remaining tumor cells.

PURPOSE: This randomized phase II trial is studying two different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy and comparing how well they work in treating patients who are undergoing surgical resection for locally advanced rectal cancer.

OBJECTIVES:

• Evaluate the pathologic complete response rate in patients with locally advanced rectal cancer undergoing surgical resection treated with 2 different regimens of neoadjuvant chemoradiotherapy and adjuvant chemotherapy.
• Evaluate the time to treatment failure and patterns of failure in patients treated with these regimens.
• Evaluate the incidence of hematologic and non-hematologic grade 3-4 toxicity (preoperatively, postoperatively, and overall) in patients treated with these regimens.
• Evaluate the quality of life of patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to clinical stage of tumor (T3 vs T4). Patients are randomized to 1 of 2 treatment arms.

Quality of life is assessed at baseline, within 1 week after completion of radiotherapy, within 1 week after completion of adjuvant chemotherapy (12 months), and then at 24 months.

Patients are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Inclusion Criteria:

1. Adenocarcinoma of the rectum originating at or below 12 cm from the anal verge without evidence of distant metastases

2. Patient must be 18 years of age or greater.

3. Potentially resectable en bloc based upon surgeon evaluation

4. Clinical stages T3 or T4, based upon endorectal ultrasound, or physical examination (only acceptable for T4 lesions).

5. Absolute neutrophil count of > 1500 per microliter and platelet count > 100,000 per microliter; aspartate aminotransferase (AST) and alkaline phosphatase < 2.5 X upper limit of normal (ULN), bilirubin < = 1.5 ULN, calculated creatinine clearance > 50 ml/min using Cockcroft-Gault formula:

   • CrCl male = (140 - age) x (wt. in kg) / (Serum Cr) x 72
   • CrCl female = 0.85 x (CrCl male)

6. Zubrod performance status 0-2

7. No history of other malignancies within 5 years, except non-melanoma skin cancer, in situ carcinoma of the cervix, or ductal carcinoma in situ of the breast. Previous invasive cancer permitted if disease free at least 5 years.

8. Signed study-specific informed consent prior to randomization

Exclusion Criteria:

1. Any evidence of distant metastasis
2. Synchronous primary colon carcinomas, except T1 lesions (full colonoscopy not required for enrollment)
3. Extension of malignant disease to the anal canal
4. Prior radiation therapy to the pelvis
5. Prior chemotherapy for malignancies
6. Pregnancy or lactation, (exclusion due to potential adverse effects of therapy). Women of childbearing potential with either a positive or no pregnancy test (serum or urine) at baseline. Women/men of childbearing potential not using a reliable and appropriate contraceptive method. (Postmenopausal women must have been amenorrheic for at least 12 months to be considered to be of non-childbearing potential.) Patients will agree to continue contraception for 30 days from the date of the last study drug administration.
7. Serious, uncontrolled, concurrent infection(s).
8. Participation in any investigational drug study within 4 weeks preceding the start of study treatment.
9. Clinically significant cardiac disease (e.g. congestive heart failure, symptomatic coronary artery disease and cardiac arrhythmias not well controlled with medication) or myocardial infarction within the last 12 months.
10. Evidence of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
11. Other serious uncontrolled medical conditions that the investigator feels might compromise study participation.
12. Major surgery within 4 weeks of the study treatment.
13. Lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome.
14. Known, existing uncontrolled coagulopathy.
15. No concurrent cimetidine allowed.