This pilot trial studies how well active surveillance and chemotherapy before surgery work in treating participants with stage II-III rectal cancer. Active surveillance involves monitoring participants for additional tumor growth after receiving cancer treatment. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether deferring surgery after active surveillance and chemotherapy will work better in treating participants with stage II-III rectal cancer.

PRIMARY OBJECTIVES:

I. To quantify the rates of organ preservation and tumor regrowth with non-operative management of locally advanced rectal cancer in patients achieving a clinical complete response (cCR).

SECONDARY OBJECTIVES:

I. To correlate clinical, radiographic, and pathologic findings after neoadjuvant therapy for rectal cancer.

II. To determine the impact of active surveillance with deferral of surgery on oncologic outcomes.

III. To assess decision quality for patients with rectal cancer facing multiple treatment options.

IV. To explore the impact of patient-provider communication on patient decisions for surgical versus nonsurgical treatment decision for rectal cancer.

V. To assess safety of deferral of surgery in distal rectal cancer patients with possibility of cohort expansion to more proximal locally advanced rectal cancer patients.

CORRELATIVE OBJECTIVES:

I. Obtain tissue to monitor treatment response and any future biomarker analyses

OUTLINE: Participants are assigned to 1 of 2 groups.

GROUP I: Participants who have achieved clinical complete response undergo standard surgical resection.

GROUP II: Participants who have achieved clinical complete response receive active surveillance and consolidated chemotherapy for up to 4 months in the absence of disease progression or unacceptable toxicity. Participants with incomplete response or regrowth of tumor, undergo surgical resection as in Group I.

After the completion of study treatment, participants in Group I are followed up at 6 and 12 months, and then once a year for up to 3 years. Participants in Group II are followed up every 3 months for 18 months, every 6 months for 2 years, and then every year for up to 3 years.

Inclusion Criteria:

• Histologically confirmed diagnosis of rectal adenocarcinoma
• Eligible for curative resection of rectal adenocarcinoma
• Rectal tumor location =< 12 cm from the anal verge as determined by endoscopy or magnetic resonance imaging (MRI) (if endoscopy report is not available or deemed inadequate my treating oncologist)
• Nodal involvement confined to the radiation field
• Radiologically measurable or clinically evaluable disease as defined in the protocol
• Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, 1 or 2
• Clinical Stage: Stage II and III. N2 disease is to be estimated as four or more lymph nodes that are >= 10 mm. Clinical staging should be estimated based on the combination of the following assessments: physical exam by the primary surgeon including digital rectal exam (DRE), computed tomography (CT) or positron emission tomography (PET)/CT scan of the chest/abdomen/pelvis and a pelvic MRI. If a pelvic MRI is performed, it is acceptable to perform CT of the chest/abdomen, omitting CT imaging of the pelvis. PET/CT is optional.
• No known contraindication to standard (fluoropyrimidine-based) pelvic chemoradiation (e.g. dihydropyrimidine dehydrogenase [DPD] deficiency)
• Patient of child-bearing potential is willing to employ adequate contraception during treatment and after treatment, as directed by treating clinical team
• Willing to provide written informed consent
• Willing to return to enrolling medical site for all study assessments

Exclusion Criteria:

• Diagnosis of inflammatory bowel disease (IBD)
• Diagnosis of MSI-H colorectal cancer at time of consent
• Recurrent rectal cancer
• Tumor is causing symptomatic bowel obstruction (patients who have diverting ostomy are eligible)
• Any prior pelvic radiation
• Other invasive malignancy undergoing active treatment. Patients receiving prior treatment that precludes standard chemoradiation or ability to receive consolidation/adjuvant chemotherapy will be excluded from survival analyses
• Patients unwilling or unable to undergo pelvic MRI