TABLE 3.

Palliative treatment options for the patients with colorectal liver metastases, adopted from several current guidelines.

Treatment regimen	Description
First line systemic palliative chemotherapy options
FOLFOX and FOLFIRI +/− bevacizumab or cetuximab [163, 164]	Left-sided wild-type KRAS colorectal cancer (CRC) patients have significant survival benefit from cetuximab, while right-sided CRC patients have survival benefit from bevacizumab [165]. Combining both anti-VEGF and anti-EGFR agents is not recommended due to poorer outcome [166, 167].
FOLFOX or FOLFIRI + panitumumab	For the patients with RAS wild-type tumor [168, 169].
S-1 plus oxaliplatin or irinotecan	S-1 is only used in selected countries, such as Japan and Korea [170, 171].
FOLFIRINOX or FOLFOXIRI	This regimen is used only in selected younger patients with high tumor burden and RAS or BRAF mutation.
HAI with FUDR or in combination with FU/LV, FOLFOX or FOLFIRI	For patients with unresectable liver metastasis [40, 41].
Beyond first line systemic chemotherapy options
Irinotecan-based chemotherapy	For patients received oxaliplatin based initial therapy, irinotecan-based chemotherapy is considered to be the next treatment choice. The following regimens are recommended: FOLFIRI; FOLFIRI + bevacizumab (for patients with tumor bearing RAS mutation); FOLFIRI + cetuximab/ panitumumab (for patients with RAS wild-type tumor); FOLFIRI with intravenous aflibercept [172, 173]; FOLFIRI with ramucirumab [174].
Oxaliplatin-based chemotherapy	For patients received irinotecan-based initial therapy, changing to oxaliplatin-based chemotherapy with or without biological agents depending on RAS mutational status would be reasonable. For RAS wild-type, anti-EGFR therapy would be appropriate, anti-VEGF agent can be also be considered, although only anti-VEGF agent would be indicated if RAS mutations present.
Regorafenib or trifluridine-tipiracil	For the patients who have received and failed both oxaliplatin- and irinotecan-based be offered for additional therapy based on performance status and organ functions, we suggest single agent regorafenib or trifluridine-tipiracil [175] [176].
HAI therapy	HAI therapy remains effective treatment for patients who had prior systemic chemotherapy exposure [40, 41, 177].
Immunotherapy (in selective patients)	Mismatch repair protein (MMR) deficient or MSI-high tumors may benefit from check point inhibitors. Patients with MMR-deficient metastatic CRC had a 50% objective response rate (ORR) and a 89% disease control rate (DCR) when treated with pembrolizumab, while in contrast, the ORR and DCR were 0 and 16% respectively in MMR-proficient mCRC [178, 179]. Similar results were also seen in CheckMate-142, in which patients received nivolumab with or without ipilimumab. Significantly higher ORR and PFS were demonstrated in MMR-deficient mCRC [180].
Reutilizing the regimen initially used in the treatment sequence	During the often lengthy phase of sequential therapy, tumors may regain sensitivity to the previously used agents.
Locoregional treatment options
HAI therapy	For liver-dominant metastatic CRC (early stage multifocal liver-only disease)
Transarterial chemoembolization or radioembolization	For liver-dominant metastatic CRC ( late stages multifocal liver-only disease)