Testing Chemotherapy versus Chemotherapy plus Radiotherapy Prior to Limited Surgery for Early Rectal Cancer

Summary

Objectives

PRIMARY OBJECTIVE:
I. To compare the complete clinical response (cCR) rate and primary quality of life (QOL) endpoint defined as the rate of major low anterior resection syndrome (LARS) at 12 months after restaging between a strategy of induction chemotherapy and chemoradiotherapy followed by TES for patients with cT1-3ab (T3a: < 1mm depth invasion, T3b: 1-5mm depth of invasion) N0 rectal adenocarcinoma.

SECONDARY OBJECTIVES:
I. To compare total mesorectal excision (TME) free survival among patients treated with induction chemotherapy versus chemoradiotherapy.
II. To compare disease free survival among patients treated with induction chemotherapy versus chemoradiotherapy.
III. To compare overall survival among patients treated with induction chemotherapy versus chemoradiotherapy.
IV. To compare rate of downstaging to ypT0/1N0/X among patients treated with induction chemotherapy versus chemoradiation.
V. To compare bowel, bladder, sexual function and QOL in patients treated with induction chemotherapy versus chemoradiation.
VI. To evaluate the toxicity and safety of induction chemotherapy and chemoradiation.
VII. To validate the magnetic resonance tumor regression grade (MR-TRG) in patients with T1-T3ab (T3a: < 1mm depth invasion, T3b: 1-5mm depth of invasion) rectal adenocarcinoma.

TERTIARY OBJECTIVES:
I. To describe the circulating tumor DNA dynamics of patients treated with organ sparing therapy.
II. To describe the sensitivity and specificity of circulating tumor DNA to detect locoregional and distant recurrence in patients treated with organ-preserving intent for cT1-3abN0 rectal cancer.
III. To explore relationships between tumor response, adverse events, and quality of life with radiotherapy planning technique (3-dimensional conformal radiation therapy [3DCRT] vs intensity-modulated radiation therapy [IMRT]), plan minor and major deviations, and doses to organs at risk.
IV. To explore relationship between MR-TRG regression grade and circulating tumor DNA dynamics.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients may receive fluorouracil intravenously (IV) over 46-48 hours on days 1 and 2, leucovorin IV over 2 hours on day 1, and oxaliplatin IV over 2 hours on day 1 of each cycle. Treatment repeats every 14 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may alternatively receive capecitabine orally (PO) twice daily (BID) for 14 days and oxaliplatin IV over 2 hours on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo TES followed by observation. Patients undergo magnetic resonance imaging (MRI), computed tomography (CT), and colonoscopy throughout the trial. Patients also undergo rectal endoscopy and digital rectal exams (DRE) on the trial. Additionally, patients undergo blood sample collection and may undergo tissue biopsy throughout the trial.

ARM II: Patients undergo radiation therapy daily 5-7 days a week for up to 6 weeks. Patients also receive capecitabine PO BID or fluorouracil IV on the same days as radiation therapy. Patients then undergo TES followed by observation. Patients undergo MRI, CT, and colonoscopy throughout the trial. Patients also undergo rectal endoscopy and DRE on the trial. Additionally, patients undergo blood sample collection and may undergo tissue biopsy throughout the trial.

After completion of study treatment, patients are followed up at every 4 months for 2 years, then every 6 months for 1 year, and every year for 2 years.