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Non colorectal liver metastases

Factors associated with improved long term outcomes

  • Long disease-free interval between treatment of primary and development of liver metastases
  • Little or no extrahepatic disease
  • Projected FLR
  • Well to moderately differentiated cancer

Pathophysiology

Metastatic cascade - clonal selection model

  • Clonal expansion, growth, diversification, angiogenesis
  • Subclone randomly acquires the necessary traits to disseminate successfully
  • Adhesion to and invasion of basement membrane
  • Passage through ECM
  • Intravasation
  • Tumor cell embolus
  • Adhesion to basement membrane
  • Extravasation
  • Metastatic deposit
  • Angiogenesis and growth

Clinical approach

  • Investigations guided by type of tumour and ability of potential treatments to alter outcomes
  • Important to determine extent of metastatic spread with anatomical areas targeted dependent on known metastatic pattern of primary.
  • Tumour markers specific to primary may be useful, e.g. chromogranin A for NET
  • Laparoscopy and laparoscopic ultrasound useful.

Treatment strategies

  • RFA useful for breast, ovarian and NETs
    • Limited by size > 3 cm and if close to major vascular or biliary structures
  • Transarterial embolization and TACE useful for unresectable hepatocellular carcinoma and symptomatic relief of NET.
  • Immunotherapy

Management by primary tumour

Neuro-endocrine tumours

Multimodal approach

  • Medical therapy:
    • Somatostatin analogues e.g. octretide, can achieve symptomatic relief for functional tumours and improvement in progression-free survival
    • Tyrosine kinase receptor inhibitors and anti-VEGF promising
    • Cytotoxic therapy has unclear benefit
  • Metastatic pattern of spread:
    • I – restricted metastases involving one lobe or two adjacent segments
    • II – dominant lesion with bilobar metastases – single major focus with multiple contralateral satellite lesions
    • III – diffuse, multifocal liver mets (non-curative)
  • Hepatic resection associated with improved survival
    • R1 and R2 resections have 5-year survival of 70% & 60%.
      • challenging the dogma that surgery for R0
    • Cytoreduction aims to reduce tumour volume by at least 90% - improved survival
  • RFA
    • Can achieve symptomatic relief and local control.
    • Useful for bilobar disease with up to 14 lesions of < 7 cm in diameter, involving up to 20% liver volume.
  • TAE or TACE
    • Indicated for more extensive hepatic disease or close proximity to biliary structures precluding RFA.
    • Often short duration of response, tumour forms collaterals and repeat treatments often required.
    • Contraindicated if 50-75% liver involvement – risk of liver failure.
  • Liver transplant
    • Possible. Concerns for tumour recurrence in context of immunosuppression. Careful selection of patients.

Gastrointestinal stromal tumor

  • Primary classified into four prognostic categories from very low risk to high risk. Based on:
    • Site of primary
    • Size of primary
    • Number of mitotic figures
  • Imatinib – selective tyrosine kinase inhibitor
    • First line in metastatic disease
    • Useful for adjuvant therapy, metastatic and recurrence.
    • In combination with surgery, good 5-year survival rates (>70%)
  • Resection
    • R0 was significant predictor of survival
    • 6–9 months from the initiation of imatinib for maximal treatment response
    • Usually appropriate for patients with response to preoperative imatinib treatment.
  • Disease progression
    • Imatinib dose escalation followed by second- and third-line agents.
    • If tumour rupture or haemorrhage – emergency surgery or hepatic artery embolization

Advanced breast cancer

  • Liver is 3rd most common site after bone and lungs.
  • Rare for isolated met
  • Selected patients may benefit from resection – improves survival
    • Limited disease in the liver
    • Long disease-free interval between primary diagnosis of breast cancer and liver metastasis,
    • HER2 positive and triple-negative disease that responded to systemic chemotherapy

Ovarian cancer

  • As part of cytoreductive surgery
    • Survival following primary surgical debulking is inversely correlated with volume of residual disease
  • TACE and RFA potential options for local control if contraindication to resection.
  • Stage III – peritoneal lesion on liver surface
  • Stage IV – intraparenchymal mets

Renal cell carcinoma

  • Limited data on liver resection
  • Poor prognosis in metastatic RCC
  • Tyrosine kinase inhibitors are effective.
    • Can also be used to downsize unresectable RCC liver mets to facilitate safe resection.

Melanoma

  • Limited data on liver resection
    • May be reasonable in some highly selected patients
  • Checkpoint inhibitor (BRAF and MEK inhibitors - vemurafenib and trametinib, respectively)
    • Are used for patients with tumour mutations in the BRAF gene
  • Immunomodulators targeting CTLA-4 (e.g. ipilimumab) and PD-1 (e.g. nivolumab, pembrolizumab) are used increasingly in all patients with advanced melanoma.
    • widespread use of these agents may lead to an increased number of patients referred for consideration for resection of isolated hepatic metastases

Non-colorectal gastrointestinal adenocarcinoma

  • Generally been considered to be contraindicated
  • Gastric cancer maybe the exception

Oesophagus

  • Rarely feasible
  • Hepatectomy may provide a limited survival benefit in chemosensitive oesophageal cancer with isolated liver metastases. Stomach
  • The 5-year OS in patients with liver metastases ranges 0–10% and surgery has historically been contraindicated.
  • There is some emerging literature that liver resection or ablation may provide a therapeutic benefit in the rare situation when of a solitary hepatic metastasis.
  • Highly selected subset of patients with gastric cancer liver metastases can achieve long-term survival with an aggressive surgical approach. Small bowel
  • Minimal evidence given rarity
  • The National Comprehensive Cancer Network Practice dismal prognosisGuidelines for treatment of small bowel adenocarcinoma recommends that certain patients with small bowel adenocarcinoma and limited metastases to visceral organs may be candidates for metastasectomy. Pancreatic ductal adenocarcinoma
  • Dismal prognosis

Testicular tumours

  • Seminomas
  • Non-seminomas
    • more aggressive biology.
    • Metastasectomy is well established in the management of disseminated non-seminomatous germ cell testicular carcinoma that does not completely respond to chemotherapy
    • Isolated liver metastases are rare

Urothelial cancer

  • Data limited

Lung cancer

  • Data limited

Adrenocortical tumors

  • Limited data

Endometrial cancer

  • Complete cytoreduction of visible disease is associated with improved OS
  • Maybe role

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