Chemotherapy before or after Chemoradiation Followed by Surgery or Non-operative Management in Treating Patients with Previously Untreated Stage II-III Rectal Cancer

This randomized phase II trial studies how well chemotherapy before or after chemoradiation followed by surgery or non-operative management works in treating patients with previously untreated stage II-III rectal cancer. Drugs used in chemotherapy, such as FOLFOX regimen (leucovorin calcium, fluorouracil, oxaliplatin), and CapeOX (oxaliplatin and capecitabine), work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high energy x rays to kill tumor cells. It is not yet known whether giving chemotherapy before or after chemoradiation is more effective in treating rectal cancer. Additional chemotherapy may reduce the number of patients that require surgery.

Inclusion Criteria

• Histologically confirmed diagnosis of adenocarcinoma of the rectum
• Clinical stage II (T3-4, N-) or stage III (any T, N+) based on magnetic resonance imaging (MRI)
• Rectal tumor at baseline which would be considered to require complete TME
• No evidence of distant metastases
• No prior pelvic radiation therapy
• No prior chemotherapy or surgery for rectal cancer
• No active infections requiring systemic antibiotic treatment (oral antibiotics are acceptable at the discretion of the treating physician)
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Women with childbearing potential (WOCBP) who are negative for pregnancy test (urine or blood) and who agree to use effective contraceptive method; a woman of childbearing potential is defined of one who is biologically capable of becoming pregnant; reliable contraception should be used from trial screening and must be continued throughout the study
• Patients must read, agree to, and sign a statement of informed consent prior to participation in this study; patients who do not read or understand English are eligible and may be consented according to institutional and federal regulations
• Absolute neutrophil count (ANC) > 1.5 cells/mm^3
• Hemoglobin (HGB) > 8.0 gm/dl
• Platelets (PLT) > 150,000/mm^3
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (except in patients with Gilbert‘s syndrome who must have total bilirubin =< 3.0 x ULN)
• Aspartate aminotransferase (AST) =< 3 x ULN
• Alanine aminotransferase (ALT) =< 3 x ULN

Exclusion Criteria

• Recurrent rectal cancer
• Primary unresectable rectal cancer; a tumor is considered unresectable when invading adjacent organs and an en bloc resection will not achieve negative margins
• Creatinine level greater than 1.5 times the upper limit of normal
• Patients who have received prior pelvic radiotherapy
• Patients who are unable to undergo MRI
• Patients with a history of any arterial thrombotic event within the past 6 months; this includes angina (stable or unstable), myocardial infarction (MI), transient ischemic attack (TIA), or cerebrovascular accident (CVA)
• Patients with a history of venous thrombotic episodes such as deep venous thrombosis, pulmonary embolus occurring more than 6 months prior to enrollment may be considered for protocol participation, provided they are on stable doses of anticoagulant therapy; similarly, patients who are anticoagulated for atrial fibrillation or other conditions may participate, provided they are on stable doses of anticoagulant therapy
• Other anticancer or experimental therapy; no other experimental therapies (including chemotherapy, radiation, hormonal treatment, antibody therapy, immunotherapy, gene therapy, vaccine therapy, angiogenesis inhibitors, matrix metalloprotease inhibitors, thalidomide, anti-vascular endothelial growth factor [VEGF]/fetal liver kinase 1 [Flk-1] monoclonal antibody or other experimental drugs) of any kind are permitted while the patient is receiving study treatment
• WOCBP who are unwilling or unable to use an acceptable method of avoiding pregnancy for the entire study period
• Women who are pregnant or breast-feeding
• Patients with any other concurrent medical or psychiatric condition or disease which, in the investigator's judgment, would make them inappropriate candidates for entry into this study
• Patients with a history of a prior malignancy within the past 5 years, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer

PRIMARY OBJECTIVES:

I. To evaluate 3-year disease-free survival (DFS) in patients managed with total neoadjuvant therapy (TNT) and total mesorectal excision (TME) or non-operative management (NOM), compared with standard historical controls managed according to standard of care (chemoradiation therapy [CRT] and TME followed by adjuvant chemotherapy [ACT]).

SECONDARY OBJECTIVES:

I. To compare outcomes between patients in the two study arms, with respect to rates of organ preservation, compliance with the neoadjuvant protocol, and adverse events.

II. To measure patient-reported functional outcomes and quality of life (QoL) in patients with locally advanced rectal cancer (LARC) treated with TNT and NOM, and compare them to patients treated with TNT and TME.

EXPLORATORY OBJECTIVES:

I. To investigate the diagnostic performance of conventional and diffusion-weighted magnetic resonance imaging (DW-MRI) in identifying patients with LARC treated with TNT, who may benefit from NOM.

II. To evaluate the feasibility of using circulating tumor deoxyribonucleic acid (DNA) and micro ribonucleic acid (miRNA) profiles in plasma to monitor tumor response to TNT in rectal cancer patients treated in both protocol arms.

III. Use of genomic analysis by next generation sequencing to profile distal rectal cancer treated with neoadjuvant chemotherapy and radiation.

IV. Investigation of the molecular mechanisms of tumor resistance to neoadjuvant therapy by genomic analysis of rectal cancer before and after treatment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I:

INDUCTION NEOADJUVANT CHEMOTHERAPY (INCT): Patients receive either FOLFOX or CapeOX regimen. Patients administered the FOLFOX regimen receive oxaliplatin intravenously (IV) over 120 minutes on day 1, leucovorin calcium IV over 120 minutes on day 1, and fluorouracil IV push (IVP) and continuously on days 1 and 2. Treatment repeats every 14 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients administered the CapeOX regimen receive oxaliplatin IV over 2 hours on day 1 and capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

CHEMORADIOTHERAPY: Patients undergo intensity modulated radiation therapy (IMRT) once daily (QD) 5 days a week over 5-6 weeks. Beginning the first day of radiation therapy, patients receive fluorouracil IV continuously 7 days a week or capecitabine PO BID 5 days a week on days of radiation therapy.

ARM II:

CHEMORADIOTHERAPY: Patients undergo IMRT QD 5 days a week over 5-6 weeks. Beginning the first day of radiation therapy, patients receive fluorouracil IV continuously 7 days a week or capecitabine PO BID 5 days a week on days of radiation therapy.

CONSOLIDATION NEOADJUVANT CHEMOTHERAPY (CNCT): Patients receive either FOLFOX or CapeOX regimen. Patients administered the FOLFOX regimen receive oxaliplatin IV over 120 minutes on day 1, leucovorin calcium IV over 120 minutes on day 1, and fluorouracil IVP and continuously on days 1 and 2. Treatment repeats every 14 days for 8 courses in the absence of disease progression or unacceptable toxicity. Patients administered the CapeOX regimen receive oxaliplatin IV over 2 hours on day 1 and capecitabine PO BID on days 1-14. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

In both arms, patients are analyzed by endoscopic exam, digital rectal exam, and rectal MRI within 8 weeks. Patients with no clinical response undergo TME within 2 weeks, and patients with complete or near complete clinical response undergo NOM. Patients in the NOM group may cross over to TME at any point during follow up.

After completion of study treatment, patients are followed up every 6 months for up to 5 years.

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Julio E. Garcia-Aguilar