Complete Neoadjuvant Treatment for REctal Cancer (CONTRE)

The goals of treatment of locally advanced (T3-4 or N1-2) rectal cancer are to eliminate the
primary tumor and any involved adjacent lymph nodes, minimize the risk of distant recurrence,
and, when possible, preserve anal sphincter function. Standard treatment consists of surgery,
concurrent chemotherapy and radiation (RT) and adjuvant chemotherapy. As the present time,
the chemoradiation portion of the treatment is often administered before, as opposed to
following, surgical resection. This approach has been associated with tumor down-staging,
leading to higher rates of tumor resectability and an increase in the ability to perform
sphincter-saving surgeries. (1). However, while advances in treatment of the primary tumor
and regional nodes, specifically administration of preoperative chemoradiation and more
aggressive surgical approaches, such as total mesorectal excision (TME), have been shown to
improve locoregional disease control, toxicities and complications of these treatments may
result in delay or omission of adjuvant chemotherapy, which could increase the risk of
distant recurrence. In this pilot study, standard adjuvant chemotherapy (8 cycles of modified
FOLFOX6) will be administered prior to chemoradiation and definitive surgery, eliminating the
need for post-operative systemic therapy. The investigators will evaluate the ability of
patients to tolerate this treatment and its impact on achievement of pathologic complete
responses (pCRs), negative surgical margins and sphincter preservation.

Inclusion Criteria

- Patients must have histologically proven adenocarcinoma of the rectum with no evidence
of distant metastases.

- The tumor must be clinically Stage II (T3-4 N0 with N0 being defined as all imaged
lymph nodes are < 1.0cm) or III (T1-4 N1-2 with the definition of a clinically
positive node being any node > 1.0cm). Stage of the tumor may be determined by CT
scan, endorectal ultrasound or MRI.

- Patients must have no evidence of distant metastases including liver metastases,
peritoneal seeding, or inguinal lymphadenopathy.

- Patients must not have received prior chemotherapy or pelvic radiation for rectal
cancer, or prior pelvic radiation for any other malignancy that would prevent the
patient from receiving the required radiation treatments for this study.

- Patients must have a life expectancy of 5 years, excluding their diagnosis of cancer
(as determined by the investigator).

- Patients must not have an active concurrent invasive malignancy. Patients with prior
malignancies, including invasive colon cancer, are eligible if they are deemed by
their physician to be at low risk for recurrence. Patients with squamous or basal cell
carcinoma of the skin, melanoma in situ, carcinoma of the cervix, or carcinoma in situ
of the colon or rectum that have been effectively treated are eligible, even if these
conditions were diagnosed within 5 years prior to randomization.

- Patients must be > 18 years of age, ECOG performance status 0-1.

- ANC > 1,500/µl, platelets > 100,000/µl, total bilirubin < 2.0 mg/dl or direct
bilirubin < 1.0 mg/dl, alkaline phosphatase < 3xULN, ALT < 3xULN, creatinine <
1.5xULN.

- The patient must have been evaluated by a surgeon, radiation oncologist and medical
oncologist and all must concur that the patient is appropriate for this study.

- Signed informed consent; able to comply with study and/or follow- up procedures

- Peripheral neuropathy < grade 1

Exclusion Criteria:

- Evidence of metastatic disease.

- Rectal cancers other than adenocarcinoma, i.e., sarcoma, lymphoma, carcinoid, squamous
cell carcinoma, cloacogenic carcinoma, etc.

- Pregnancy or lactation at the time of proposed randomization. Eligible patients of
reproductive potential (both sexes) must agree to use adequate contraception.

- Any therapy for this cancer prior to randomization.

- Synchronous invasive colon cancer.

- Nonmalignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
preclude the patient from receiving any chemotherapy treatment option or would prevent
required follow-up.

- Patients with active inflammatory bowel disease, abdominal fistula, gastrointestinal
perforation, or intraabdominal abscess within 6 months prior to Day 0 or other serious
medical illness which might limit the ability of the patient to receive protocol
therapy.

- Prior pelvic irradiation for any indication.

- Known hypersensitivity to 5-fluorouracil or oxaliplatin

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements.