Histotripsy Plus Chemotherapy vs Chemotherapy Alone for Advanced Colorectal Liver Metastasis

The goal of this clinical trial is to learn if histotripsy plus chemotherapy works to treat unresectable, bilobar liver- confined colorectal cancer liver metastasis (CRLM). The main question this clinical trial aims to answer is: • Does the management of this condition with uninterrupted palliative chemotherapy and histotripsy demonstrate improved progression-free survival? Participants will: * Receive chemotherapy treatment per standard procedure. * Undergo histotripsy treatment according to current standard procedures at Cleveland Clinic. * Occasionally receive Computerized Tomography (CT) scan with and without contrast, give biopsy of treated and untreated liver lesions, and participate in a blood draw of up to 3 teaspoons at each in-person visit. * Participate in genetic testing, as a part of the standard of care for the treatment.

Inclusion Criteria: * Participants with liver-confined colorectal cancer liver metastasis (CRLM) or participants who have low-volume pulmonary disease along with CRLM * Participants receiving first line therapy with base of 5-FU with either oxaliplatin or irinotecan, or who are within 3 months of beginning chemotherapy, or participants who have completed chemotherapy treatment within 1 month of the histotripsy evaluation * Participants who have undergone other liver-directed therapy, such as ablation, embolization * Participants with multiple unresectable metastases that cannot be completely treated with resection and/or ablation * Participants aged ≥18 years Exclusion Criteria: * Participants with resectable disease * Participants with non-pulmonary extra-hepatic disease including but not limited to bone or peritoneal metastasis. * Participants who are not able to tolerate general anesthesia * Participants who have Childs C Cirrhosis * Other non-skin malignancy within 2 years of study * WBC count \< 3,000 /uL * Absolute Neutrophil Count \< 1,500 /uL * History of Non-malignant serious concurrent illness that would increase the risk of histotripsy * Participants with MSI-High * Participants aged \< 18 years * Pregnant participants