Clinical trial NCT00081289: Neoadjuvant Chemoradiotherapy and Adjuvant Chemotherapy in Treating Patients Who Are Undergoing Surgical Resection for Locally Advanced Rectal Cancer
Official title: Randomized Phase II Trial Of Neoadjuvant Combined Modality Therapy For Locally Advanced Rectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: stage III rectal cancer
adenocarcinoma of the rectum
stage II rectal cancer
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-04-08
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Pathologic Complete Response Rate
timeFrame: After protocol surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation
Secondary outcomes:
measure: Survival Rate at 4 Years
timeFrame: From randomization to four years
measure: Local-regional Failure Rate at 4 Years
timeFrame: From randomization to four years
measure: Distant Failure Rate at 4 Years
timeFrame: From randomization to four years
measure: Second Primary Rate at 4 Years
timeFrame: From randomization to four years
measure: Disease-free Survival Rate at 4 Years
timeFrame: From randomization to four years
measure: Number of Participants With Grade 3+ Treatment-related Adverse Events
timeFrame: From start of treatment to end of follow-up. Maximum follow-up is 5.2 years.
measure: Number of Participants With Grade 3+ Treatment-related Adverse Events Preoperatively
timeFrame: From start of treatment to surgery, approximately 10-16 weeks from randomization based on surgery occurring 4-8 weeks after chemoradiation. If no surgery, then <= 90 days from start of treatment.
measure: Number of Participants With Grade 3+ Treatment-related Adverse Events Postoperatively
timeFrame: From post-surgery to before chemotherapy (CT), or within 60 days of surgery if no postoperative CT. Approximately 10-16 weeks to 14-22 weeks from randomization based on CT starting 4-6 weeks after surgery.
measure: Tumor Marker Evaluation Using Preoperative Tissue Biopsy Specimens and Surgically Resected Tissue Specimens
timeFrame: End of study
measure: Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Chemoradiation
timeFrame: Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization
measure: Change From Baseline in QLQ-C30 Global Health Status Score at Completion of Post-operative Chemotherapy
timeFrame: Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy
measure: Change From Baseline in QLQ-C30 Global Health Status Score at Two Years
timeFrame: Baseline and two years
measure: Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Chemoradiation
timeFrame: Baseline and completion of chemoradiation approximately 6-8 weeks from randomization
measure: Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Completion of Post-operative Chemotherapy
timeFrame: Baseline and completion of post-operative chemotherapy approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy
measure: Change From Baseline in EORTC QLQ-CR38 Gastro-intestinal Symptom Score at Two Years
timeFrame: Baseline and two years
measure: Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Completion of Chemoradiation
timeFrame: Baseline and completion of chemoradiation, approximately 6-8 weeks from randomization
measure: Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Post-operative Chemotherapy
timeFrame: Baseline and completion of post-operative chemotherapy, approximately 32 to 40 weeks from randomization based on 18 weeks of post-operative chemotherapy
measure: Change From Baseline in EORTC QLQ-CR38 Defecation Symptom Score at Two Years
timeFrame: Baseline and two years
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: University of California Davis Cancer Center
state: California
city: Miami
country: United States
facility: Baptist-South Miami Regional Cancer Program
state: Florida
city: Harvey
country: United States
facility: Ingalls Cancer Care Center at Ingalls Memorial Hospital
state: Illinois
city: Marlton
country: United States
facility: Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
state: New Jersey
city: Dunmore
country: United States
facility: Northeast Radiation Oncology Center
state: Pennsylvania
Study officials:
affiliation: Fox Chase Cancer Center
name: Neal J. Meropol, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wong SJ, Winter K, Meropol NJ, Anne PR, Kachnic L, Rashid A, Watson JC, Mitchell E, Pollock J, Lee RJ, Haddock M, Erickson BA, Willett CG. Radiation Therapy Oncology Group 0247: a randomized Phase II study of neoadjuvant capecitabine and irinotecan or capecitabine and oxaliplatin with concurrent radiotherapy for patients with locally advanced rectal cancer. Int J Radiat Oncol Biol Phys. 2012 Mar 15;82(4):1367-75. doi: 10.1016/j.ijrobp.2011.05.027. Epub 2011 Jul 19.
citation: Wong SJ, Moughan J, Meropol NJ, et al.: Efficacy endpoints of RTOG 0247: A randomized phase II study of neoadjuvant capecitabine (C) and irinotecan (I) or C and oxaliplatin (O) with concurrent radiation therapy (RT) for locally advanced rectal cancer. [Abstract] J Clin Oncol 29 (Suppl 15): A-3517, 2011.