The Role of Multimodality Management In Risk-Stratified Patients With Lung-Limited Metastatic Colorectal Cancer (H-48032)

Primary objectives:

1. To compare recurrence-free survival in patients with "low risk" lung-limited mCRC undergoing pulmonary metastasectomy with or without perioperativechemotherapy.
2. To compare overall survival in patients with "high risk" lung-limited mCRC receiving systemic chemotherapy with or without surgical resection.

Design: 

Patients with low risk CRC are randomized to either have surgical resection or chemotherapy, then surgical resection, then chemotherapy. Patients with high risk CRC will receive chemotherapy, then once resectable, randomized to either chemotherapy or surgical resection. 

Inclusion Criteria:

1.  Histological confirmation of colorectal adenocarcinoma.
2.  Metastatic colorectal cancer involving the lung classified as determined by the treating clinical team. Patients with a history of prior resected colorectal cancer must have had a disease-free interval no greater than three years prior to study consent.
3.  Diagnosis of colorectal metastasis to lung made either histologically with trans-thoracic needle biopsy or clinically based on radiographic imaging.
4.  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 FEV1 > 40% predicted, post-operative predicted FEV1 > 30% predicted, 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, and absent severe chronic heart disease.
   • Ability to tolerate surgical resection and acceptable operative risk as deemed by thoracic surgeon based on performance status and medicalcomorbidities
5. Identification as a medically appropriate candidate for systemic chemotherapy at the discretion of the evaluating medical oncologist.
6. Resection/definitive therapy of primary colorectal tumor with no suspicion of recurrence. Prior radiation to a rectal adenocarcinoma is permitted.
7. Age ≥ 18 years.
8. ECOG performance status (Appendix A) of 0 or 1.
9. Ability to provide informed consent for participation.
10. Patients must have normal organ and marrow function as defined below:
    • − Leukocytes ≥2,000/mcL
    • − absolute neutrophil count ≥1,000/mcL
    • − hemoglobin ≥ 9.0 gm/dL
    • − platelet count ≥100,000/mcL
    • − total bilirubin = 1.5× institutional upper limit of normal (ULN) (except patients with Gilbert Syndrome, who can have total bilirubin <3.0mg/dL)
    • − AST(SGOT)/ALT(SGPT) ≤ 2.5× ULN
    • − Serum creatinine ≤1.5× ULN OR creatinine clearance (CrCl ≥50 mL/min
    • (if using the Cockcroft-Gault formula below):
    • Female CrCl = (140 - age in years) x weight in kg x 0.85
    • 72 x serum creatinine in mg/dL
    • Male CrCl = (140 - age in years) x weight in kg x 1.00
    • 72 x serum creatinine in mg/dL
11. Patients (men and women) of child bearing potential should use an effective(for them) method of birth control throughout their participation in thisstudy.

Exclusion Criteria:

1. 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, provided that there is no history of more than two extrapulmonary sites of metastatic disease and a history of no more than 5 extrapulmonary lesions.
2. Presence of intact primary colorectal adenocarcinoma (or of an anastomotic recurrence).
3. Previous radiotherapy to a lung metastasis that is still detectableradiographically.
4. Known DPD deficiency that would preclude the patient from tolerating 5-fluorouracil chemotherapy.
5. 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, ramicirumab), or anti-EGFR therapies (e.g., cetuximab, panitumumab, for patients with RAS wild-type colorectal tumors).
6. Two or more different prior lines of systemic chemotherapy for the treatment of metastatic/unresectable colorectal cancer. For patients with “high risk” disease, adjuvant chemotherapy is considered a prior line of chemotherapy only if this treatment was completed within 6 months of study consent. Hepatic arterial infusion is not to be considered a separate line of therapy. Prior therapy with regorafenib or TAS-102 for metastatic/unresectable colorectalcancer is not permitted.
7. Synchronous primary or prior malignancy in the past 5 years other than nonmelanomatous skin cancer or in situ cancer.
8. Pregnant or lactating women, as treatment involves unforeseeable risks to the embryo or fetus.
9. History of peritoneal metastasis.