PROSPECT: Chemotherapy Alone or Chemotherapy Plus Radiation Therapy in Treating Patients With Locally Advanced Rectal Cancer Undergoing Surgery

OUTLINE: This is a multicenter, phase II/III study. Patients are stratified according to ECOG
performance status (0 or 1 vs 2) and randomized to 1 of 2 treatment regimens. Patients will
receive full supportive care while on this study.

OBJECTIVES:

Primary

1. Phase II component: To assure that neoadjuvant FOLFOX followed by selective use of
5FUCMT group (Group 1) maintains the current high rate of pelvic R0 resection and is
consistent with non-inferiority for time to local recurrence (TLR).

2. Phase III component: To compare neoadjuvant FOLFOX followed by selective use of 5FUCMT
(Group 1) to standard 5FUCMT (Group 2) with respect to the co-primary endpoints of the
Time to Local Recurrence (TLR) and Disease-Free Survival (DFS).

Secondary

1. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is
non-inferior to the standard group 5FUCMT (Group 2) with respect to the proportion of
patients who achieve a pathologic complete response (pCR) at the time of surgical
resection.

2. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is
non-inferior to the standard 5FUCMT (Group 2) with respect to overall survival.

3. To evaluate and compare the adverse event profile and surgery complications between two
groups.

4. To estimate the proportion of patients in the selective group (Group 1) who receive: 1)
pre-operative 5FUCMT; 2) post-operative 5FUCMT; 3) either pre- or post-operative 5FUCMT.

Event monitoring of patients will continue up to 8 years post randomization.

Registration Inclusion Criteria:

1. Age ≥ 18 years at diagnosis

2. Diagnosis of rectal adenocarcinoma

3. Radiologically measurable or clinically evaluable disease as defined in the protocol

4. ECOG Performance Status (PS): 0, 1 or 2

5. For this patient, the standard treatment recommendation in the absence of a clinical
trial would be combined modality neoadjuvant chemoradiation followed by curative
intent surgical resection

6. Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy
according to the primary surgeon

7. Primary surgeon is credentialed or is willing to be credentialed in Total Mesorectal
Excision (TME), which entails submission of photos of a single TME specimen either
before enrolling the first patient or by using the surgeon's 1st accrued case.

8. Clinical Stage: T2N1, T3N0, T3N1.

- N2 disease is to be estimated as four or more lymph nodes that are ≥ 10 mm.

- Clinical staging should be estimated based on the combination of the following
assessments: physical exam by the primary surgeon, CT or PET/CT scan of the
chest/abdomen/pelvis and either a pelvic MRI or an ultrasound (ERUS). If a pelvic
MRI is peformed, it is acceptable to perform CT of the chest/abdomen, ommitting
CT imaging of the pelvis.

9. The following laboratory values obtained ≤ 28 days prior to registration:

- Absolute neutrophil count (ANC) ≥ 1500/mm^3

- Platelet count ≥ 100,000/mm^3

- Hemoglobin > 8.0 g/dL

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

- SGOT (AST) ≤ 3 x ULN

- SGPT (ALT) ≤ 3 x ULN

- Creatinine ≤1.5 x ULN

10. Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing
potential only

11. Patient of child-bearing potential is willing to employ adequate contraception

12. Provide informed written consent

13. Willing to return to enrolling medical site for all study assessments

Registration Exclusion Criteria:

1. Clinical T4 tumors

2. Primary surgeon indicates need for abdominoperineal (APR) at baseline

3. Evidence that the tumor is adherent to or invading the mesorectal fascia on imaging
studies such that the surgeon would not be able to perform an R0 resection (one with
negative margins)

4. Tumor is causing symptomatic bowel obstruction (patients who have had a temporary
diverting ostomy are eligible).

5. Chemotherapy within 5 years prior to registration. Hormonal therapy is allowable if
the disease free interval is ≥ 5 years.

6. Any prior pelvic radiation

7. Other invasive malignancy ≤ 5 years prior to registration. Exceptions are colonic
polyps, non-melanoma skin cancer, ductal carcinoma in situ, bladder carcinoma in situ,
or carcinoma-in-situ of the cervix.

8. Any of the following because this study involves an agent that has known genotoxic,
mutagenic and teratogenic effects.

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

9. Co-morbid illnesses or other concurrent disease which, in the judgment of the
clinician obtaining informed consent, would make the patient inappropriate for entry
into this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens.