Chemotherapy and/or Metastasectomy in Treating Patients With Metastatic Colorectal Adenocarcinoma With Lung Metastases

PRIMARY OBJECTIVES:

I. To compare recurrence-free survival in patients with "low risk" lung-limited metastatic colorectal cancer (mCRC) undergoing pulmonary metastasectomy with or without perioperative chemotherapy.

II. To compare overall survival in patients with "high risk" lung-limited mCRC receiving systemic chemotherapy with or without surgical resection.

SECONDARY OBJECTIVES:

I. To compare grade 3 and 4 adverse events in patients receiving surgical resection and/or chemotherapy in the management of lung-limited mCRC.

EXPLORATORY OBJECTIVES:

I. To evaluate for changes in circulating tumor deoxyribonucleic acid (DNA) following surgical resection and/or systemic chemotherapy in patients with lung-limited mCRC.

OUTLINE: Patients are assigned to 1 of 2 risk groups (low or high).

GROUP 1 (LOW RISK): Patients are randomized to 1 of 2 groups.

GROUP 1A: Patients receive standard of care chemotherapy for 3 months prior to and 3 months after undergoing metastasectomy in the absence of disease progression or unacceptable toxicity.

GROUP 1B: Patients undergo metastasectomy.

GROUP 2 (HIGH RISK): All high risk patients receive standard of care chemotherapy for 3 months in the absence of disease progression or unacceptable toxicity. Patients without progressive disease after 3 months are then randomized to 1 of 2 groups.

GROUP 2A: Patients undergo metastasectomy.

GROUP 2B: Patients continue standard of care chemotherapy for 6 months in the absence of disease progression or unacceptable toxicity. Patients with stable disease or radiographic response after 6 months may then cross over to Group 2A.

After completion of study treatment, patients are followed up periodically for up to 5 years.

Inclusion criteria

• Histological confirmation of colorectal adenocarcinoma
• Metastatic colorectal cancer involving the lung classified as determined by the treating clinical team
• Diagnosis of colorectal metastasis to lung made either histologically with trans-thoracic needle biopsy or clinically based on radiographic imaging
• Identification as a medically appropriate candidate for surgical resection of the lung metastasis (metastases) according to the evaluating cardiothoracic surgeon. Standard justification for deeming a patient medically operable based on:

• Pulmonary reserve adequate to tolerate complete resection of all intrathoracic disease, as deemed by thoracic surgeon, which may be determined by:

• Baseline forced expiratory volume in one second (FEV1) > 40% predicted
• Post-operative predicted FEV1 > 30% predicted
• Diffusion capacity of the lung for carbon monoxide (DLCO) > 40% predicted
• Absent baseline hypoxemia and/or hypercapnia
• Exercise oxygen consumption > 50% predicted
• Absent severe pulmonary hypertension
• Absent severe cerebral, cardiac, or peripheral vascular disease
• Absent severe chronic heart disease
• Ability to tolerate surgical resection and acceptable operative risk as deemed by thoracic surgeon based on performance status and medical comorbidities
• Identification as a medically appropriate candidate for systemic chemotherapy at the discretion of the evaluating medical oncologist
• Resection/definitive therapy of primary colorectal tumor with no suspicion of recurrence. Prior radiation to a rectal adenocarcinoma is permitted
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Ability to provide informed consent for participation
• Leukocytes >= 2,000/mcL
• Absolute neutrophil count >= 1,000/mcL
• Hemoglobin >= 9.0 gm/dL
• Platelet count >= 100,000/mcL
• Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN
• Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl >= 50 mL/min (if using the Cockcroft-Gault formula)
• Patients (men and women) of child bearing potential should use an effective (for them) method of birth control throughout their participation in this study

Exclusion criteria

• Tumor involvement at other metastatic sites (e.g., liver, distant lymph nodes) that has not been definitively treated. Prior surgical resection for metastatic disease at other (non-pulmonary) sites is permitted
• Presence of intact primary colorectal adenocarcinoma (or of an anastomotic recurrence)
• Previous radiotherapy to a lung metastasis that is still detectable radiographically
• Known dihydropyrimidine dehydrogenase (DPD) deficiency that would preclude the patient from tolerating 5- fluorouracil chemotherapy
• Prior intolerance of systemic therapies used as standard regimens in the treatment of metastatic CRC that would prohibit further receipt of systemic chemotherapy and/or biologic agents -e.g.,5-fluorouracil, oxaliplatin, irinotecan, anti-VEGF therapies (e.g., bevacizumab, ramucirumab), or anti-EGFR therapies (e.g., cetuximab, panitumumab, for patients with RAS wild-type colorectal tumors)
• Prior therapy with regorafenib or trifluridine/tipiracil (TAS-102) for metastatic/unresectable colorectal cancer
• Synchronous primary or prior malignancy in the past 5 years other than non-melanomatous skin cancer or in situ cancer
• Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo or fetus