Neoadjuvant FOLFOX6 Chemotherapy With or Without Radiation in Rectal Cancer

A Phase II/III Randomized Controlled Study of Neoadjuvant FOLFOX6 Treatment With or Without Radiation Compared to 5-Fu Based Chemoradiation in Treating Patients With Resectable Rectal Cancer

RATIONALE: Preoperative 5-Fu based chemoradiation has become standard treatment for stage 2/3 rectal cancer. However whether these patients, especially T3N0-1M0 patients, really need radiation for local control after total mesentery excision being applied in routine practice is still unknown. And whether new drugs adding in can achieve better local and distant control is worth investigating.

PURPOSE: This randomized phase II trial is studying 5Fu based radiation therapy or FOLFOX based radiation or FOLFOX alone, comparing them to see how well they work when given before surgery in treating patients with intermediate risk resectable rectal cancer. It is not yet known whether 5-Fu based or FOLFOX based radiation therapy or even FOLFOX alone is more effective in treating rectal cancer.

OBJECTIVES:

Primary Compare the objective response rate and the rate of local-regional relapse in patients with resectable rectal cancer treated with either 5-Fu or FOLFOX based chemoradiotherapy or FOLFOX alone without radiation.

Secondary

1. Compare the rate of pathologic complete response in patients treated with these regimens.
2. Compare the local recurrence rate

2.Determine the increase in the number of patients who are able to undergo sphincter-saving surgery after treatment with these regimens.

3.Correlate genetic patterns and the presence or absence of specific tissue biomarkers with response and prognosis in patients treated with these regimens.

4.Compare preoperative quality of life (QOL) of patients treated with oral capecitabine versus continuous infusion with fluorouracil. pelvic auto-nerve function 5.Determine the impact of oxaliplatin on neurotoxicity in patients treated with these regimens.

6.Compare the toxic effects of these regimens in these patients. 7.Compare the convenience of care in patients treated with these regimens. 8.Determine the impact of the type of surgical management on QOL at 1 year postoperatively in these patients.

OUTLINE: This is a randomized, multi-center study. Patients are stratified according to participating center, gender, clinical tumor stage (stage II vs. stage III), and surgical intent (sphincter saving vs. non-sphincter saving). Patients are randomized to 1 of 4 treatment arms.

• Arm A: Patients receive fluorouracil IV continuously and undergo radiotherapy once daily 5 days a week for 5-6 weeks.
• Arm B: Patients receive FOLFOX for 4 cycles and undergo radiotherapy as in arm I from the second cycle of FOLFOX.
• Arm C: Patients receive FOLFOX for 4 cycles Within 4-6 weeks after the completion of chemo radiotherapy, patients with responding or stable disease undergo surgery. Patients with progressive disease are treated at the discretion of the investigator and continue to be followed. Patients with progressive disease in arm III should received radiation.

Quality of life is assessed at baseline, at completion of chemo radiotherapy, and at 1 year after surgery.

After completion of study treatment, patients are followed every 3 months for 2 years, and then every 6 months for 3years.

PROJECTED ACCRUAL: A total of 495 patients will be accrued for this study within 5 years.

Eligibility Ages Eligible for Study: 18-75 Years old Genders Eligible for Study: Both Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosis of adenocarcinoma of the rectum

2. Age: 18-75 years old

3. Stage of the primary tumor may be determined by ultrasound or MRI

4. Stage II (T_3-4, N_0 [N_0 is defined as all imaged lymph nodes < 1.0 cm]) OR stage III (T_1-4, N_1-2 [with the definition of a clinically positive lymph node being any node ≥ 1.0 cm]

5. Tumor palpable by digital rectal exam OR accessible by proctoscope or sigmoidoscope

6. Distal border of the tumor must be located < 12 cm from the anal verge

7. Tumor amenable to curative resection

8. 15 days prior recruit, meet the following criteria: Hematopoietic

   • Absolute neutrophil count ≥ 1,200/mm^3
   • Platelet count ≥ 100,000/mm^3 Hepatic
   • Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
   • Alkaline phosphatase ≤ 2 times ULN
   • AST ≤ 2 times ULN*
   • No hepatic disease that would preclude study treatment or follow-up
   • No uncontrolled coagulopathy Renal
   • Creatinine clearance > 50 mL/min
   • No renal disease that would preclude study treatment or follow-up

9. ECOG status: 0～1

Exclusion Criteria:

1. Hypersensitivity to fluorouracil, or oxaliplatin
2. No More than 4 weeks since prior participation in any investigational drug study
3. More than 4 weeks since prior participation in any investigational drug study
4. Clear indication of involvement of the pelvic side walls by imaging
5. With distant metastasis
6. History of invasive rectal malignancy, regardless of disease-free interval
7. Fertile patients must use effective contraception
8. Uncontrolled hypertension
9. Cardiovascular disease that would preclude study treatment or follow-up
10. Lack of upper gastrointestinal tract integrity or malabsorption syndrome，active upper gastrointestinal tract bleeding
11. Synchronous colon cancer
12. Pregnant or nursing, Fertile patients do not use effective contraception
13. Other malignancy within the past 5 years except effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum
14. No psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation