Inclusion Criteria:

• Male or female, 18 years of age, any ethnic or racial group
• Unresectable primary tumor must be stable or asymptomatic
• Patients with unresectable metastatic disease to the liver (unresectable unilobar or bilobar disease) who have disease progression with oxaliplatin or irinotecan based first line chemotherapy
• Eligible to receive second-line standard-of-care chemotherapy with either an oxaliplatin-based or an irinotecan-based chemotherapy regimen
• Must have baseline efficacy images with measurable target tumors in the liver according to RECIST 1.1 using standard imaging techniques taken within 28 days prior to randomization. Images must be taken after or at the time of completion of first-line chemotherapy
• Tumor replacement ≤ 50% of total liver volume
• ECOG of 0-1 through screening to first treatment
• First line chemotherapy regimen completed at least 14 days prior to initiation of 2nd line chemotherapy under the protocol
• Patient willing to participate and has signed informed consent
• Serum creatinine ≤2.0 mg/dL
• Serum bilirubin 1.2 x upper limit of normal
• Albumin ≥ 2.0 g/dL
• Neutrophil count >1200/mm³ (1.2x10⁹/L)

Exclusion Criteria:

• History of hepatic encephalopathy
• Contraindications to angiography and selective visceral catheterization such as bleeding diathesis or coagulopathy that is not correctable by usual therapy of hemostatic agents
• History of severe peripheral allergy or intolerance to contrast agents, narcotics, sedatives or atropine that cannot be managed medically
• Presentation of pulmonary insufficiency or clinically evident chronic obstructive pulmonary disease
• Cirrhosis or portal hypertension
• Prior external beam radiation treatment to the liver
• Prior intra-arterial liver directed therapy, including TACE or Y-90 microsphere therapy
• VEGF inhibitors within 28 days prior to receiving TheraSphere (may resume after Y-90 treatment or immediately if in control arm)
• Clinically evident ascites (trace ascites on imaging is acceptable)
• Planned liver-directed therapy or radiation therapy
• Intervention for, or compromise of, the Ampulla of Vater
• Toxicities due to prior cancer therapy that have not resolved before initiation of study treatment, if the investigator determines that the continuing complication will compromise safe treatment of the patient
• Significant life-threatening extra-hepatic disease, including patients who are on dialysis, have unresolved diarrhea, have serious unresolved infections, including patients known to be HIV positive or have acute HBV or HCV
• Must not have any significant extra-hepatic metastases. Limited extra-hepatic metastases in the lung and/or lymph nodes are permitted (up to 5 lesions in the lung, with each individual lesion <1 cm; any number of lymph lesions with each individual lesion <1.5 cm)
• Contraindications to planned second line standard-of-care chemotherapy
• Women of child-bearing potential must have negative serum pregnancy test within 14 days prior to randomization and must not be breast feeding
• Participation in a clinical trial with an investigational therapy within 30 days prior to randomization
• Co-morbid disease or condition that would place the patient at undue risk and preclude safe use of TheraSphere treatment, in the investigator's judgement