Neoadjuvant FOLFOX6 Chemotherapy With or Without Radiation in 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.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

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

• DERIVEDZhang T, Shi L, Jian L, Jiang J, Qiu Y, Xie F, Zhang J, Peng H, Zhong L, Chen Y, Zhong Y, Deng Y; FOWARC Group. Clinical Benefit and Cost-Effectiveness of FOLFOX Versus LCCRT in Neoadjuvant Treatment for Patients with Locally Advanced Rectal Cancer: An Economic Analysis of the FOWARC and PROSPECT Trial. Ann Surg Oncol. 2026 May;33(5):3814-3826. doi: 10.1245/s10434-025-18802-8. Epub 2025 Dec 11. PMID 41379261
• DERIVEDWan H, Weng J, Cai J, Chen Z, Li P, Han J, Li Z, Wan Z, Yuan Z, Gan Y, Huang M, Li X, Li T, Liu X, Wang X, Yu H, Liu B, Lin J, Luo Y. Nodal Downstaging in Patients With Rectal Cancer: Survival Is Promising if YpN0 Is Achieved. Dis Colon Rectum. 2025 Oct 1;68(10):1162-1171. doi: 10.1097/DCR.0000000000003846. Epub 2025 Jul 8. PMID 40626521
• DERIVEDShi L, Zhang J, Deng Y. Associations of pretreatment emotional distress with adherence to therapy for patients with locally advanced rectal cancer: a post hoc analysis of the Chinese FOWARC phase 3 randomized clinical trial. BMC Med. 2025 May 21;23(1):293. doi: 10.1186/s12916-025-04128-5. PMID 40399932
• DERIVEDZhang J, Chi P, Shi L, Cui L, Gao J, Li W, Wei H, Cheng L, Huang Z, Cai G, Zhao R, Huang Z, Zhou H, Wei Y, Zhang H, Zheng J, Huang Y, Cai Y, Zhou Z, Kang L, Huang M, Wu X, Peng J, Ren D, Lan P, Wang J, Deng Y. Neoadjuvant Modified Infusional Fluorouracil, Leucovorin, and Oxaliplatin With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Updated Results of the FOWARC Study After a Median Follow-Up of 10 Years. J Clin Oncol. 2025 Feb 20;43(6):633-640. doi: 10.1200/JCO-24-01676. Epub 2024 Dec 13. PMID 39671537
• DERIVEDLi L, Xu B, Zhuang Z, Li J, Hu Y, Yang H, Wang X, Lin J, Zhou R, Chen W, Ran D, Huang M, Wang D, Luo Y, Yu H. Accurate tumor segmentation and treatment outcome prediction with DeepTOP. Radiother Oncol. 2023 Jun;183:109550. doi: 10.1016/j.radonc.2023.109550. Epub 2023 Feb 21. PMID 36813177
• DERIVEDXie Y, Lin J, Wang X, Wang P, Zhuang Z, Zou Q, Cai D, Huang Z, Bai L, Tang G, Huang M, Wang J, Yu H, Luo Y. The Addition of Preoperative Radiation Is Insufficient for Lateral Pelvic Control in a Subgroup of Patients With Low Locally Advanced Rectal Cancer: A Post Hoc Study of a Randomized Controlled Trial. Dis Colon Rectum. 2021 Nov 1;64(11):1321-1330. doi: 10.1097/DCR.0000000000001935.