What is the recommended first-line treatment for patients with colorectal cancer and bilobar multiple liver metastases?

Management of Colorectal Bilobar Multiple Liver Metastases

First-Line Treatment Strategy

For patients with colorectal cancer and bilobar multiple liver metastases, systemic chemotherapy should be initiated upfront in the vast majority of cases (approximately 90% of patients), regardless of whether the metastases appear technically resectable, with the specific regimen determined by molecular tumor characteristics and primary tumor sidedness. 1, 2

Treatment Algorithm Based on Molecular Profile and Resectability

For Initially Unresectable Bilobar Disease

The treatment selection depends critically on molecular testing results:

MSI-H/dMMR tumors:

• Pembrolizumab immunotherapy is the recommended first-line treatment 1
• This represents a distinct pathway from chemotherapy-based approaches

MSS/pMMR, RAS/BRAF wild-type, LEFT-sided tumors:

• Chemotherapy (doublet regimen: FOLFOX or FOLFIRI) plus anti-EGFR monoclonal antibody (cetuximab or panitumumab) is the preferred first-line treatment 1
• This combination achieves the highest response rates and conversion to resectability in this molecular subgroup 1

MSS/pMMR, RAS/BRAF wild-type, RIGHT-sided tumors:

• Triplet chemotherapy (FOLFOXIRI or FOLFIRINOX) is the preferred backbone 1
• Bevacizumab is favored over anti-EGFR agents when adding targeted therapy to triplet chemotherapy in right-sided disease 1

MSS/pMMR, RAS or BRAF mutant tumors:

• Triplet chemotherapy (FOLFOXIRI or FOLFIRINOX) plus bevacizumab is the preferred first-line treatment 1
• This represents the most intensive systemic approach for this molecular subgroup 1

For Initially Resectable Bilobar Disease

Even when bilobar metastases appear technically resectable, perioperative chemotherapy should be administered in most cases rather than proceeding directly to surgery 1, 2:

• Only patients with a solitary metastasis ≤2 cm with favorable prognostic features should proceed directly to surgery (representing <10% of patients) 1
• All other patients should receive neoadjuvant chemotherapy first 1

The perioperative chemotherapy approach:

• Administer 3 months of preoperative chemotherapy (typically FOLFOX) 2
• Perform surgical resection if response is adequate and R0 resection remains feasible 1, 2
• Complete with 3 months of postoperative chemotherapy (total perioperative duration: 6 months) 1, 2
• This strategy improves progression-free survival compared to surgery alone 2

Surgical Considerations for Bilobar Disease

Either one-stage or two-stage hepatectomy can be performed for bilobar metastases, with one-stage resection preferred whenever technically feasible 1:

• Two-stage hepatectomy combined with portal vein embolization and systemic chemotherapy can achieve 5-year survival of 50% in selected patients with complex bilobar disease 3
• The decision depends on tumor size, location, number of lesions, and local surgical expertise 1
• Combination of resection and ablation techniques can be used to achieve complete hepatic clearance 1, 4

Critical surgical principles:

• R0 resection (negative margins) of all visible disease is mandatory 2
• Sufficient functional liver remnant must be preserved (approximately one-third of standard liver volume or minimum of two segments) 2
• Complete hepatic clearance is the strongest predictor of survival; incomplete clearance dramatically worsens prognosis (3-year survival 91.7% vs 12.1%) 4

Common Pitfalls and How to Avoid Them

Never allow complete radiological disappearance before resection:

• Complete metabolic response on imaging does not mean absence of disease; viable microscopic tumor cells typically remain 2, 5
• If lesions disappear during chemotherapy, perform anatomical resection of the liver segments where disease was originally located 5
• Close imaging surveillance is mandatory when approaching complete response to enable timely surgery 5

Do not exceed 6 months total perioperative chemotherapy:

• Prolonged preoperative chemotherapy (>3-4 months) can cause chemotherapy-associated liver injury and compromise surgical outcomes 1, 6
• In initially resectable disease, 20% of tumors will progress during chemotherapy, potentially eliminating the chance for cure 2

Avoid biopsy of liver metastases when possible:

• Biopsy carries significant risk of tumor dissemination and may compromise resectability and long-term survival 2
• Diagnosis can typically be established based on imaging characteristics in patients with known colorectal primary

Do not proceed with surgery if R0 resection is not achievable:

• Incomplete hepatic clearance is the strongest independent risk factor for mortality (HR 5.86) 4
• If adequate response is not achieved with first-line chemotherapy, consider changing regimen or reassessing resectability with multidisciplinary team 1

Postoperative Management

For patients who undergo curative-intent resection after downsizing chemotherapy:

• Continue the same chemotherapy backbone postoperatively to complete 6 months total perioperative treatment 1
• For patients with positive surgical margins (R1 resection), postoperative systemic chemotherapy is strongly recommended 1

Surveillance after resection:

• Up to 60% of patients develop recurrence after hepatic resection, with liver being the most common site 2
• Approximately 90% of recurrences occur within the first 2 years 2
• About 20% of patients with liver-only recurrence may be candidates for repeat resection 2

Role of Multidisciplinary Management

All treatment decisions must be made by a multidisciplinary team including hepatobiliary surgeons, medical oncologists, and radiologists 1:

• Resectability assessment should be performed by specialized hepatobiliary units 2
• The definition of resectability is subjective and varies significantly between centers 1
• Shared decision-making with patients is essential given the complexity of treatment options 1