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

PRIMARY OBJECTIVE:

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.

CORRELATIVE STUDIES 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 cycles 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 5 cycles 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 cycles 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 5 cycles 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.