Secondary liver cancer

See also the separate Malignancy of unknown origin and Carcinomatosis articles.

What is secondary liver cancer?¹

The liver is the most common organ to which malignancies metastasise,² accounting to 25% of all metastases. The most common cancers to metastasise to the liver in the developed world are colorectal followed by pancreas and breast. Nearly 25% of patients with colorectal cancer will develop liver metastases; 25% of these present with concomitant disease. In women under the age of 50, breast cancer is the most common primary resulting in liver metastases. In a worldwide population the most common cancer to metastasise to the liver is lung.³

The vulnerability of the liver for metastatic disease may be related to the fact that it is the largest organ in the body and it filters blood from both the systemic and the portal systems.⁴

Over 70% of cases with metastatic disease remain confined to the liver. Metastatic liver cancer is the most common cause of death in cancer patients. Complete surgical resection is the gold-standard of treatment but chemotherapy is an option for those people for whom surgery is not possible.¹Survival appears to be better when the primary cancer is breast or colorectal; average survival time has been found to be less than 6 months on average. Negative prognostic indicators include: advanced age, male gender, black race, poor differentiation of the tumour , and regional lymph node metastases.³ Liver metastases have a worse prognosis in terms of survival than metastases to other organs.⁵

Secondary liver cancer symptoms

• There are a number of symptoms including distention, early satiety, vague abdominal complaints, changes in bowel habits, hematochezia, weight loss, encephalopathy, jaundice, ascites, and metabolic disturbances which should all raise suspicion for metastatic disease, but there are no pathognomonic findings for liver metastasis.

• Hepatomegaly and ascites are present in about half of patients with liver metastases. Nodularity may be palpable along the enlarged liver edge. Ascites indicate wide dissemination and a poor prognosis.

• Large liver metastases may block bile ducts and cause jaundice, malaise, anorexia and loss of weight.

Investigations

• Abnormal blood results may include anaemia and leukocytosis. Bilirubin, alkaline phosphatase and transaminase levels may be raised but LFTs are not always abnormal.

• A number of liver tumour markers have been identified, including alpha-fetoprotein (AFP), protein induced by vitamin K absence (PIVKA-II) and carcinoembryonic antigen (CEA). None of these should be used as diagnostic tools; they are useful as markers of cancer progression (or treatment) in an oncology setting. They should not be used in general practice.

• Other useful immunohistochemical markers (in an oncology clinic) for the differential diagnosis of metastatic carcinomas in the liver include cytokeratins (CK7, CK19, and CK20), neuroendocrine markers (CD56, synaptophysin, and chromogranin A), and tissue-specific markers (CDX2, SATB2, TTF-1, GCDFP-15, mammaglobin).²

• CT, MRI and positron emission tomography (PET) scanning may all be useful in varying circumstances, but triple-phase CT and MRI scans are the most often used. PET scans can sometimes miss very small metastases; it is possible for benign liver lesions to mimic liver metastases on MRI.¹

• Angiography is essential if vascular intervention is planned.

• Liver biopsy is needed for a histological diagnosis. Over the past few years, liver biopsy has become less common due to the fears of "seeding" during the process. However recent studies suggest that the actual rate of seeding after biopsy of liver lesions is very low (less than 1%), with no impact on overall survival. This seeding risk is even lower in series using modern co-axial biopsy technology.⁶ Biopsy is not recommended if surgery is planned.

Differential diagnosis

See also the separate Benign liver tumours and Primary liver cancer articles. Secondary liver cancer is much more common than primary liver cancer.

Secondary liver cancer treatment and management

Treatment for metastatic liver cancer depends on the location and stage of the liver cancer and how well liver function is preserved. Treatment options include surgical resection, thermal ablation, systemic chemotherapy, transarterial chemoembolisation, selective internal radiation therapy, targeted therapy and immunotherapy.

Liver transplantation may be appropriate for some patients. For most patients with liver metastases, treatment with curative intent is not possible.

Surgery for secondary liver cancer¹

Surgical resection of hepatic metastases with adjuvant chemotherapy is associated with improved survival outcomes and reduced morbidity and mortality. Surgical resection remains the gold standard for anatomically resectable colorectal hepatic metastases (most of the literature focuses on colorectal cancer as the primary). Clinical guidelines have indicated that the future liver remnant should be at least 20% of its original volume in a healthy liver, 30% with mild to moderate hepatic dysfunction, and 40% with hepatic cirrhosis. Strategies to improve the chances of resection include neoadjuvant chemotherapy, portal vein embolization to increase the future liver remnant or a two-stage resection.

If neoadjuvant chemotherapy is being used then this is administered for 4-6 months prior to surgery. Studies vary between showing significant survival benefit and no survival benefit for the use of neoadjuvant chemotherapy with surgery. One study suggested a 3-year disease-free survival of 31.7% compared with 20.4%.⁷

Other secondary liver cancer treatments¹⁴⁸

• Stereotactic Body Radiotherapy (SBRT): Studies suggest overall survival of 84% at one year and 44% at three years.

• Conformal Radiotherapy: This is used where the liver tumour is too large to be treated with SBRT.

• Whole Liver Radiation: This tends to be offered as a palliative measure to patients with painful metastases and a high disease burden.

• Trans-arterial Radioembolization (TARE): This appears to prolong disease-free survival.

• Trans-arterial Chemoembolization (TACE): Disease stabilisation has been shown in 40-60% of patients.

• Hyperthermic Ablation: This heats rely tumour cells, causing denaturation of proteins, destruction of the cell membrane, and coagulative necrosis.

• Chemotherapy: There is mixed data but no clear evidence of improved survival.

• Immunotherapy: Several studies have shown that immunotherapy has poor efficacy in patients with liver metastases though some newer studies have shown promise with combinations of immunotherapy and radiotherapy or immunotherapy and targeted therapy.

• Targeted therapy: Targeted, systemic drugs including atezolizumab, bevacizumab, and durvalumab may be treatment options depending on the primary site.

NICE guidelines and recommendations.

• The National Institute for Health and Care Excellence (NICE) has advocated the use of laparoscopic liver resection for a solitary liver metastasis.⁹

• Image-guided percutaneous laser ablation for primary and secondary liver tumours can be used in the NHS while more evidence is generated. ¹⁰

• Selective internal radiation therapy (SIRT) can be used in specific centres as an option for neuroendocrine tumours that have metastasised to the liver.¹¹

• Radiofrequency-assisted liver resection is supported by NICE.¹²

• NICE recommends that evidence on microwave ablation for treating liver metastases raises no major safety concerns and the evidence on efficacy is adequate in terms of tumour ablation.¹³

• NICE also endorses the use of ex vivo hepatic resection (operation on the liver outside the body followed by re-implantation) in patients who would otherwise die and have tried all other appropriate treatments.¹⁴

• NICE recommends that selective internal radiation therapy (SIRT) should be considered as a treatment option for non-resectable colorectal metastases in the liver.¹⁵

• NICE recommends that the evidence on the safety of melphalan chemosaturation with percutaneous hepatic artery perfusion and hepatic vein isolation for cancer or metastases in the liver shows there are serious, well-recognised complications. For patients with metastases in the liver from ocular melanoma, there is some evidence of short-term tumour response. However, for patients with primary liver cancer or metastases in the liver that are not from ocular melanoma, evidence of efficacy is inadequate in quality and quantity.¹⁶