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

• Rate of pathologic complete response [ Time Frame: Determined at the time of surgery ] [ Designated as safety issue: No ]
• Effect of different chemoradiation-to-surgery intervals on rate of pathologic complete response and surgical difficulty. [ Time Frame: Measured at the time of surgery ] [ Designated as safety issue: No ]
• Effect of different chemoradiation-to-surgery intervals on postoperative complications [ Time Frame: 30 days after surgery ] [ Designated as safety issue: No ]

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.

OBJECTIVES:

I. 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.

II. To study the effect of different chemoradiation-to-surgery intervals on the rate of pathologic complete response, on surgical difficulty, and on postoperative complications.

III. 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.

• 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 Name: PCR
• Other: immunohistochemistry staining method
  Correlative studies
  Other Name: immunohistochemistry

• 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..
  Interventions:

  • Drug: fluorouracil
  • Procedure: conventional surgery
  • Radiation: radiation therapy
  • Other: laboratory biomarker analysis
  • Genetic: DNA analysis
  • Genetic: polymerase chain reaction
  • Other: immunohistochemistry staining method
• 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.
  Interventions:

  • 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
• 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.
  Interventions:

  • 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
• 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.
  Interventions:

  • 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

• Duldulao MP, Lee W, Streja L, Chu P, Li W, Chen Z, Kim J, Garcia-Aguilar J. Distribution of residual cancer cells in the bowel wall after neoadjuvant chemoradiation in patients with rectal cancer. Dis Colon Rectum. 2013 Feb;56(2):142-9. doi: 10.1097/DCR.0b013e31827541e2.
• Duldulao MP, Lee W, Nelson RA, Ho J, Le M, Chen Z, Li W, Kim J, Garcia-Aguilar J. Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer. Cancer. 2013 Mar 1;119(5):1106-12. doi: 10.1002/cncr.27862. Epub 2012 Oct 23.
• Chen Z, Liu Z, Deng X, Warden C, Li W, Garcia-Aguilar J. Chromosomal copy number alterations are associated with persistent lymph node metastasis after chemoradiation in locally advanced rectal cancer. Dis Colon Rectum. 2012 Jun;55(6):677-85.
• Duldulao MP, Lee W, Le M, Wiatrek R, Nelson RA, Chen Z, Li W, Kim J, Garcia-Aguilar J. Surgical complications and pathologic complete response after neoadjuvant chemoradiation in locally advanced rectal cancer. Am Surg. 2011 Oct;77(10):1281-5.
• Garcia-Aguilar J, Chen Z, Smith DD, Li W, Madoff RD, Cataldo P, Marcet J, Pastor C. Identification of a biomarker profile associated with resistance to neoadjuvant chemoradiation therapy in rectal cancer. Ann Surg. 2011 Sep;254(3):486-92; discussion 492-3.
• Duldulao MP, Lee W, Le M, Chen Z, Li W, Wang J, Gao H, Li H, Kim J, Garcia-Aguilar J. Gene expression variations in microsatellite stable and unstable colon cancer cells. J Surg Res. 2012 May 1;174(1):1-6. Epub 2011 Jul 7.
• Chen Z, Liu Z, Li W, Qu K, Deng X, Varma MG, Fichera A, Pigazzi A, Garcia-Aguilar J. Chromosomal copy number alterations are associated with tumor response to chemoradiation in locally advanced rectal cancer. Genes Chromosomes Cancer. 2011 Sep;50(9):689-99. Epub 2011 May 16.
• Garcia-Aguilar J, Smith DD, Avila K, Bergsland EK, Chu P, Krieg RM; Timing of Rectal Cancer Response to Chemoradiation Consortium. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann Surg. 2011 Jul;254(1):97-102.
• Chen Z, Duldulao MP, Li W, Lee W, Kim J, Garcia-Aguilar J. Molecular diagnosis of response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer. J Am Coll Surg. 2011 Jun;212(6):1008-1017.e1. Epub 2011 Mar 31.

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