Radiation Therapy and Fluorouracil With or Without Combination Chemotherapy Followed by Surgery in Treating Patients With Stage II or Stage III Rectal Cancer

Sponsor

Memorial Sloan Kettering Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00335816

Collaborator

National Cancer Institute (NCI) (NIH)

248

Enrollment

Locations

Arms

172

Anticipated Duration (Months)

16.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as fluorouracil, oxaliplatin, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Fluorouracil may also make tumor cells more sensitive to radiation therapy. Leucovorin calcium may protect normal cells from the side effects of chemotherapy, and it may help fluorouracil work better by making tumor cells more sensitive to the drug. Giving radiation therapy together with chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase II trial is studying how well giving radiation therapy together with fluorouracil with or without combination therapy works in treating patients who are undergoing surgery for stage II or stage III rectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: fluorouracil Drug: leucovorin calcium Drug: oxaliplatin Procedure: conventional surgery Radiation: radiation therapy Other: laboratory biomarker analysis Genetic: DNA analysis Genetic: polymerase chain reaction Other: immunohistochemistry staining method	Phase 2

Detailed Description

OBJECTIVES:

To determine the rate of pathologic complete response to chemoradiation (no evidence of residual tumor in the resected specimen) of Stage II and Stage III rectal cancers that are staged preoperatively by endorectal ultrasound (ERUS) or magnetic resonance imaging (MRI), treated according to a standardized chemoradiation and surgery protocol, and evaluated by a systematic pathologic exam of the surgical specimen.
To study the effect of different chemoradiation-to-surgery intervals on the rate of pathologic complete response, on surgical difficulty, and on postoperative complications.
To investigate the feasibility of using sensitive molecular assays to detect tumor cells in the tumor bed and regional lymph nodes of rectal cancer specimens, with or without pathologic complete response to preoperative chemoradiation.

OUTLINE:

Patients are assigned to 1 of 4 treatment groups. All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil intravenously (IV) continuously over 24 hours 7 days a week for 6 weeks.

GROUP I (closed to enrollment): Patients undergo standard surgical resection after completion of chemoradiation therapy.

GROUP II (closed to enrollment): Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1-2. Treatment repeats every 14 days for 2 courses. After the last week of post-radiation chemotherapy, patients undergo standard surgical resection.

GROUP III: Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 4 courses. After the last week of post-radiation chemotherapy, patients undergo standard surgical resection.

GROUP IV: Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 6 courses. After the last week of post- radiation chemotherapy, patients undergo standard surgical resection.

In all groups, treatment continues in the absence of disease progression or unacceptable toxicity. A

fter completion of study treatment, patients are followed up for 5 years.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

248 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Timing of Rectal Cancer Response to Chemoradiation

Actual Study Start Date :

Aug 1, 2008

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1 (Closed to Enrollment) All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil intravenously continuously over 24 hours 7 days a week for 6 weeks. Patients undergo standard surgical resection after completion of chemoradiation therapy..	Drug: fluorouracil Given IV Procedure: conventional surgery Patients undergo surgery Radiation: radiation therapy Patients undergo radiotherapy Other: laboratory biomarker analysis Correlative studies Genetic: DNA analysis Correlative studies Genetic: polymerase chain reaction Correlative studies Other Names: PCR Other: immunohistochemistry staining method Correlative studies Other Names: immunohistochemistry
Experimental: Group 2 (Closed to Enrollment) All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil IV continuously over 24 hours 7 days a week for 6 weeks. Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy comprising oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1-2. Treatment repeats every 14 days for 2 courses. After the last week of post-radiation chemotherapy, patients undergo standard surgical resection.	Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV Procedure: conventional surgery Patients undergo surgery Radiation: radiation therapy Patients undergo radiotherapy Other: laboratory biomarker analysis Correlative studies Genetic: DNA analysis Correlative studies Genetic: polymerase chain reaction Correlative studies Other Names: PCR Other: immunohistochemistry staining method Correlative studies Other Names: immunohistochemistry
Experimental: Group 3 (chemotherapy, FOLFOX, conventional surgery) All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil IV continuously over 24 hours 7 days a week for 6 weeks. Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 4 courses. After the last week of post-radiation chemotherapy, patients undergo standard surgical resection.	Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV Procedure: conventional surgery Patients undergo surgery Radiation: radiation therapy Patients undergo radiotherapy Other: laboratory biomarker analysis Correlative studies Genetic: DNA analysis Correlative studies Genetic: polymerase chain reaction Correlative studies Other Names: PCR Other: immunohistochemistry staining method Correlative studies Other Names: immunohistochemistry
Experimental: Group 4 (chemotherapy, FOLFOX, conventional surgery) All patients undergo chemoradiation therapy comprising radiation therapy once daily 5 days a week for 5 weeks and fluorouracil IV continuously over 24 hours 7 days a week for 6 weeks. Beginning 4 weeks after completion of chemoradiation therapy, patients receive modified FOLFOX-6 chemotherapy as in group II. Treatment repeats every 14 days for 6 courses. After the last week of post- radiation chemotherapy, patients undergo standard surgical resection. Patients then receive 3 additional courses of FOLFOX-6 chemotherapy or other chemotherapy off study as directed by the physician.	Drug: fluorouracil Given IV Drug: leucovorin calcium Given IV Drug: oxaliplatin Given IV Procedure: conventional surgery Patients undergo surgery Radiation: radiation therapy Patients undergo radiotherapy Other: laboratory biomarker analysis Correlative studies Genetic: DNA analysis Correlative studies Genetic: polymerase chain reaction Correlative studies Other Names: PCR Other: immunohistochemistry staining method Correlative studies Other Names: immunohistochemistry

Outcome Measures

Primary Outcome Measures

Rate of pathologic complete response [Determined at the time of surgery]
Effect of different chemoradiation-to-surgery intervals on rate of pathologic complete response and surgical difficulty. [Measured at the time of surgery]
Effect of different chemoradiation-to-surgery intervals on postoperative complications [30 days after surgery]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have an Eastern Cooperative Oncology Group (ECOG) Status of 0 or 1, or comparable Karnofsky performance status
Patients must have histologically confirmed invasive adenocarcinoma of the rectum Distal border of the tumor must be within 12 cm from the anal verge as measured on rigid proctoscopic exam
Patients must have Stage II (uT3-4, uN0) or Stage III (any T, uN1-2) tumors, as confirmed by ERUS or MRI; females with anterior tumors invading the posterior vaginal wall (uT4) and males with anterior tumors that invade the seminal vesicles or adjacent organs (uT4) will also be eligible provided they undergo an extended resection including the organs involved
Patients with high grade obstruction that impedes the ERUS exam are eligible for the study provided they can be staged by MRI
Patients with synchronous or metachronous colorectal cancer are eligible for the study on condition that they are treated for rectal cancer in accordance with the protocol
Patients with the following are NOT allowed on study:
Metastatic disease or other primaries
Locally recurrent rectal cancer
Previously documented history of Familial Adenomatous Polyposis
History of Inflammatory Bowel Disease
History of prior radiation treatments to pelvis
History of clinically significant cardiac disease (i.e., Class 3-4 congestive heart failure, symptomatic coronary artery disease, uncontrolled arrhythmia, and/or myocardial infarction within the previous 6 months
History of uncontrolled seizures or clinically significant central nervous system disorders
History of psychiatric conditions or diminished capacity that could compromise the giving of informed consent, or interfere with study compliance
History of allergy and/or hypersensitivity to 5-fluorouracil (fluorouracil), leucovorin (leucovorin calcium), and/or oxaliplatin
History of difficulty or inability to take or absorb oral medications
Patients must have adequate bone marrow, hepatic and renal function within 7 days prior to registration
White blood cells (WBC) >= 3,000 mm^3
Absolute neutrophil count (ANC) > 1,500 mm^3
Hemoglobin > 9.5 mg/dl
Platelet count >= 100,000 mm^3
Total bilirubin =< 1.5 mg/dl
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.0 times institutional upper limit of normal (ULN)
Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.0 times ULN
Alkaline phosphatase =< 2.0 times ULN
Serum creatinine =< 1.5 times ULN
Patients with hereditary non-polyposis colorectal cancer are eligible for the study provided they meet the rest of the eligibility criteria
Patients who have experienced a prior malignancy should have received potentially curative therapy for that malignancy, and should be cancer-free for at least five years from the date of initial diagnosis (Exceptions: patients treated for basal cell carcinoma, or carcinoma in-situ of the cervix)
Patients of reproductive potential should agree to use an effective method of birth control when undergoing treatments with known or possible mutagenic or teratogenic effects; all female participants of childbearing potential must have a negative urine or serum pregnancy test within two weeks prior to study registration
Patients or the patient's legally acceptable representative must provide written authorization to allow the use and disclosure of protected health information; NOTE: this may be obtained in either the study-specific informed consent or in a separate authorization form and must be obtained from the patient prior to study registration or the initiation of any study-specific procedures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cancer Care Center at John Muir Health - Concord Campus	Concord	California	United States	94524-4110
2	City of Hope Medical Center	Duarte	California	United States	91010-3000
3	St. Joseph Hospital Regional Cancer Center - Orange	Orange	California	United States	92868-3849
4	Chao Family Comprehensive Cancer Center at University of California Irvine Medical Center	Orange	California	United States	92868
5	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
6	Washington Cancer Institute at Washington Hospital Center	Washington	District of Columbia	United States	20010
7	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida	United States	33612-9497
8	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
9	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455
10	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
11	Colon and Rectal Surgery, Incorporated	Omaha	Nebraska	United States	68114
12	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
13	Knight Cancer Institute at Oregon Health and Science University	Portland	Oregon	United States	97239-3098
14	Vermont Cancer Center at University of Vermont	Burlington	Vermont	United States	05405-0110
15	Tom Baker Cancer Centre - Calgary	Calgary	Alberta	Canada	T2N 4N2