Combination Chemotherapy and Intensity-Modulated Radiation Therapy in Treating Patients Undergoing Surgery for Locally Advanced Rectal Cancer

OBJECTIVES:

Primary

• To determine whether the incidence of neoadjuvant acute gastrointestinal toxicity (grade ≥ 2) associated with neoadjuvant chemoradiotherapy is reduced by inverse-planned intensity-modulated radiotherapy (IMRT)-based radiation treatment when compared with conventionally delivered radiotherapy, as was utilized in the capecitabine and oxaliplatin arm of RTOG-0247 (NCT00081289).

Secondary

• To evaluate the feasibility of performing IMRT in a cooperative group setting for the treatment of rectal cancer.
• To estimate the incidence of all toxicity (hematologic and non-hematologic) associated with protocol treatment in the neoadjuvant period, the adjuvant period, and overall.
• To estimate the pathologic complete response rate following neoadjuvant IMRT-based chemoradiotherapy.
• To estimate the time to treatment failure and patterns of failure.
• To correlate pre- and post-treatment levels of serum cytokines with symptoms during and pathological outcomes following neoadjuvant chemoradiotherapy for rectal cancer.
• To evaluate the rate of abdominoperineal resections.

OUTLINE: This is a multicenter study.

• Chemoradiotherapy: Patients undergo inverse-planned intensity-modulated radiotherapy to the pelvis once daily, 5 days a week, for 5 weeks (total of 45 Gy) and a 3-dimensional conformal radiotherapy boost to gross disease once daily for 3 days (total of 45 Gy). Beginning on the first day of radiotherapy and continuing through completion of radiotherapy, patients receive oral capecitabine twice daily, 5 days a week, for 5 weeks and oxaliplatin IV over 2 hours on days 1, 8, 15, 22, 29.
• Surgery: Within 4-8 weeks after completion of chemoradiotherapy, patients undergo resection of the rectal tumor.
• Adjuvant chemotherapy: Beginning 4-8 weeks after surgery, patients with completely resected disease and negative surgical margins receive leucovorin calcium IV over 2 hours and oxaliplatin IV over 2 hours on day 1 and fluorouracil IV bolus on day 1 and fluorouracil IV infusion continuously over 46 hours beginning on day 1 . Treatment repeats every 14 days for up to 9 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months after the start of treatment for 2 years, every 6 months for years 3-5, and then annually thereafter.

DISEASE CHARACTERISTICS:

• Pathologically confirmed diagnosis of adenocarcinoma of the rectum by biopsy technique that does not completely excise the lesion (e.g., fine needle aspiration, core needle biopsy)

• Located up to 12 cm from the anal verge with no extension of malignant disease into the anal canal
• Clinically determined to be stage T3 or T4,N0-N2, and M0 tumor as determined by the following assessments:

• Colonoscopy and biopsy within 56 days prior to registration
• History/physical examination (including medication history screen for contraindications) within 56 days prior to registration
• Contrast-enhanced imaging of the abdomen and pelvis either by computed tomography(CT), MRI, or Positron-emission tomography(PET)-CT (whole body preferred) within 56 days prior to registration
• Chest x-ray (or CT) of the chest within within 56 days prior to registration to exclude distant metastases (except for patients who have had whole body PET-CT)
• Transrectal ultrasound (TRUS) within 56 days prior to registration required to establish tumor stage

• TRUS not required if clinical exam, CT of the pelvis, and/or MRI demonstrates T4 lesion
• No synchronous primary colon carcinoma
• No evidence of distant metastases (M1)

PATIENT CHARACTERISTICS:

Inclusion criteria

• Zubrod performance status 0-2
• Absolute neutrophil count (ANC) ≥ 1,800/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 8.0 g/dL (transfusion or other intervention to achieve hemoglobin ≥ 8.0 g/dL allowed)
• Aspartate aminotransferase (AST) < 2.5 times upper limit of normal (ULN)
• Alkaline phosphatase < 2.5 times ULN
• Bilirubin ≤ 1.5 times ULN
• Creatinine clearance > 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior invasive malignancy except nonmelanoma skin cancer unless disease free for a minimum of 3 years

Exclusion criteria

• Severe, active comorbidity, defined as follows:

• Unstable angina and/or congestive heart failure requiring hospitalization within the past 12 months
• Transmural myocardial infarction within the past 6 months
• Acute bacterial or fungal infection requiring intravenous antibiotics
• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within the past 30 days
• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects
• AIDS
• 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
• Known, existing uncontrolled coagulopathy, unless clinically stable on anticoagulation therapy for ≥ 2 weeks
• Evidence of peripheral neuropathy ≥ grade 2
• Prior allergic reaction to oxaliplatin or capecitabine
• Lack of physical integrity of the gastrointestinal tract (i.e., severe Crohn disease that results in malabsorption; significant bowel resection that would make one concerned about the absorption of capecitabine) or malabsorption syndrome that would preclude feasibility of oral chemotherapy (i.e., capecitabine)
• Prior systemic chemotherapy for colorectal cancer (prior chemotherapy allowed provided it was for a cancer other than colorectal cancer)
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields
• Major surgery within 28 days of study enrollment(other than diverting colostomy without tumor resection)
• Participation in any investigational drug study within 28 days of study enrollment.
• Concurrent cimetidine, amifostine, and/or depot Sandostatin