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Chapter 20
Liver Tumors: Metastases
Ahsun Riaz and Riad Salem
Clinical Features
• Secondary liver tumors are more common than primary liver tumors.
• Embolization in these cases is performed as an elective procedure.
• Tumors that commonly metastasize to the liver are
◦ Colorectal carcinoma (CRC)
◦ Neuroendocrine tumors (NET)
◦ Other: breast cancer, sarcoma, melanoma
Available Embolic Therapies
• Following are the embolic therapeutic options available in the management of
secondary live tumors
◦ Bland embolization
◦ Transarterial chemoembolization (TACE)
◦ Yttrium-90 radioembolization (Y-90)
◦ Drug-eluting bead-transarterial chemoembolization (DEB-TACE)
Diagnostic Evaluation
• Clinical
• Secondary liver lesions rarely lead to signs and symptoms of liver decompen-
sation (e.g., encephalopathy). However, evidence of liver dysfunction in cases
of metastatic liver lesions indicates a poor prognosis.
Transcatheter Embolization and Therapy,
Techniques in Interventional Radiology, DOI 10.1007/978-1-84800-897-7_20,
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198 A. Riaz and R. Salem
• Laboratory
• The laboratory tests include the following:
◦ Liver function tests (LFT)
◦ Complete blood count (CBC)
◦ Carcinoembryonic agent (for colorectal carcinoma)
• Urinary 5-HIAA (for carcinoid)
• Imaging
• The imaging characteristics of metastatic lesions to the liver are assessed using
contrast-enhanced CT or MRI. Biopsy may be required if the diagnosis is
uncertain.
◦ Colorectal carcinoma: moderately hypervascular lesions
◦ Neuroendocrine tumors: very hypervascular tumors
• Pre-treatment angiography is performed to assess vascular anatomy prior to all
embolic therapies.
• Technetium-99m macroaggregated albumin (Tc-99m MAA) scan is a nuclear
scan that is performed before Y-90 to assess the following:
◦ Lung shunt fraction (LSF)
◦ Splanchnic flow
Indications
• Unresectable metastatic liver lesions.
Relative Contraindications
• Poor performance status (Eastern Cooperative Oncology Group performance
status >1).
• Deranged liver function (bilirubin > 2 mg/dL).
• Y-90: LSF allowing >30 Gy dose delivery to the lungs in one session.
Anatomy
The aorta, iliac arteries, and portal vein are usually assessed on cross-sectional
imaging. Pre-treatment angiography is performed to assess vascular anatomy, in
particular the cystic artery, anatomical variations, extrahepaatic tumor supply, and
communications with the gastrointestinal and systemic circulations. The following
are typically performed.
◦ Superior mesenteric angiogram: for replaced hepatic arteries.
20 Liver Tumors: Metastases 199
◦ Celiac arteriogram: for left gastric supply to liver (replaced left hepatic) and
inferior phrenic arteries.
◦ Common hepatic arteriogram: for communications between hepatic and gas-
trointestinal vasculature (right gastric, dorsal pancreatic, and gastroduodenal
artery).
◦ Gastroduodenal arteriogram: for cystic, superior pancreaticoduodenal, and
accessory hepatic arteries. Parasitization of flow to liver from GDA or its
branches is also assessed.
◦ Proper hepatic arteriogram: for right gastric artery communication between
hepatic and gastrointestinal vasculature.
◦ Right hepatic arteriogram: vascular supply of tumor is assessed. Vessels of
interest include the cystic, supraduodenal, and middle hepatic arteries.
◦ Left hepatic arteriogram: vascular supply of tumor is assessed. Vessels
sought include the accessory left gastric inferior esophageal, right gastric, falciform, and left inferior phrenic arteries. Delayed imaging is recommended
to confirm that the coronary vein does not opacify as this indicates splanchnic
flow.
Patient Preparation
• Coil embolization of arterial communications with non-hepatic tissue is recommended to prevent aberrant flow of embolic particles (the threshold for
coil embolization prior to radioembolization should be low). Arterial communications with non-hepatic tissue are meticulously sought during pre-treatment
angiography and embolized with coils.
Pre-procedure Medications
• The pre-procedure medications include anti-emetics, anti-histamines, proton
pump inhibitors, and antibiotics.
Equipment
• Catheters: once the vascular anatomy has been studied, microcatheters are recommended. The vessels may be fragile due to previous exposure to systemic
chemotherapeutics and are prone to spasm and dissection anyway.
• Bland embolization: Gelfoam or PVA particles.
• Y-90: TheraSphere (glass) or SIR-Sphere (resin). Specific equipment is provided
for radioembolization.
• TACE: chemotherapeutic agent mixed with lipiodol. This is followed by injection
of bland embolic particles as above.
• DEB-TACE: chemotherapeutic agent-loaded microspheres.
200 A. Riaz and R. Salem
Procedure
• Access
◦ The femoral artery is used in most cases, but access from the arm may be
necessary in some cases.
• Performing the Procedure
◦ The angiogram is performed on the same day of the procedure in cases of
bland embolization, TACE, and DEB-TACE.
◦ Y-90: The pre-treatment angiography and Tc-99m MAA scan are performed
approximately 1 week prior to the actual procedure.
• Technique
◦ It is recommended to be as selective as possible, as secondary lesions (with
the exception of NET) may not be very hypervascular relative to surrounding
normal tissue.
◦ Whole liver infusions are not recommended (a “bilobar lobar” approach is
recommended if the whole liver is to be treated—separate injection of the left
and right hepatic arteries to minimize aberrant flow of embolic material and
hence incidence of toxicities.)
• Endpoints
◦ Bland embolization: stasis.
◦ Y-90: the particles are minimally embolic; hence flow is maintained post-
radioembolization.
◦ TACE: stasis or sub-stasis of flow.
◦ DEB-TACE: the particles are minimally embolic; so flow is maintained.
• Immediate Post-procedure Care
◦ Access puncture site is closed.
◦ Y-90: radiation safety protocols are followed; catheters and equipment are
disposed appropriately.
Post-procedure Medications
• Supportive management of the post-embolization syndrome (pain, fatigue, nausea, vomiting).
• Patients are discharged on the same day in the case of Y-90.
Follow-Up
• Two week phone call (to assess general patient well being)
• One month follow-up
◦ Cross-sectional Imaging: to assess tumor response to therapy using size
(RECIST)/necrosis (EASL) guidelines
◦ Laboratory work-up: this includes LFTs, CBC, and tumor markers
20 Liver Tumors: Metastases 201
• After the first follow-up visit, radiologic evaluation is recommended every 3
months
Current Data
• Bland Embolization
◦ It has also been used for pain relief and control of symptoms in hepatic
metastases from neuroendocrine tumors and sarcomas [1].
• Y- 90
◦ CRC: the combination of radioembolization with systemic chemotherapy has
been shown to have a significantly better tumor response, a longer time to progression, survival benefit, and an acceptable safety profile than chemotherapy
alone [2]. Dose escalation studies have shown a better response with increasing
doses [3].
◦ NET: radioembolization of metastatic disease to the liver from a neu-
roendocrine neoplasia has been shown to be effective and safe. A prolonged response to treatment, i.e., greater than 2 years has been seen
[4, 5].
◦ Breast cancer: radioembolization is an efficacious treatment for unresectable
reast cancer metastases to the liver [6]. There is a significant radiologic
response after radioembolization, but the survival benefit of this treatment in
these patients has not been established.
• TAC E
◦ CRC: Geschwind et al. demonstrated that TACE can prolong survival of
patients with colorectal metastases even in patients who had not responded
to systemic chemotherapy [7].
◦ NET: Liapi et al. analyzed imaging responses and determined outcomes of
26 patients with neuroendocrine metastases treated with TACE and showed a
mean patient survival of 78 months [8].
◦ Breast cancer: patients with breast metastasis to the liver unresponsive to stan-
dard of care chemotherapy have been treated with TACE and the survival
benefit seen is not impressive as most patients develop extrahepatic metastases
[9, 10].
• DEB-TACE
◦ DEBs loaded with irinotecan are being investigated for the treatment of
patients with colorectal hepatic metastases [11].
Alternative Therapies
• Surgical resection
• Thermal ablation (e.g., radiofrequency ablation)
202 A. Riaz and R. Salem
Complications
• Post-embolization syndrome is managed supportively.
• Biliary complications: biliary strictures, abscesses, etc are seen more often in
non-cirrhotic livers (metastatic) [12]. Cholecystitis due to aberrant deposition of
embolic material into the gall bladder wall may be seen.
• Hepatic dysfunction: whole liver chemoembolization and radioembolization may
lead to liver dysfunction.
• Gastrointestinal (GI) complications: GI ulcers may be seen. The vascular communications of hepatic vasculature with the GI tract should be studied in detail
and prophylactic proximal coil embolization should be performed to prevent
particulate agent bowel embolization.
• Vascular injury: Vessels may be fragile due to previous history of exposure
to chemotherapeutic agents. Careful wire/catheter manipulation and use of
microcatheters are recommended.
Keypoints
• Limited options available for unresectable liver metastases.
• Embolization techniques (Bland, Y-90, TACE, DEB-TACE) present safe
and efficacious methods of management for some of these tumors.
• The decision to use a treatment modality should be made after consensus
of a multi-disciplinary team.
• Meticulous assessment of the pre-treatment angiography and the prophylactic coil embolization of vessels prevent the occurrence of serious
complications following these procedures.
Suggested Reading
1. Maluccio MA, Covey AM, Schubert J, et al. Treatment of metastatic sarcoma to the liver with
bland embolization. Cancer 2006; 107:1617–1623.
2. Gray B, Van Hazel G, Hope M, et al. Randomised trial of SIR-spheres plus chemotherapy
vs. chemotherapy alone for treating patients with liver metastases from primary large bowel
cancer. Ann Oncol 2001; 12:1711–1720.
3. Goin JE, Dancey JE, Hermann GA, Sickles CJ, Roberts CA, MacDonald JS. Treatment of
unresectable metastatic colorectal carcinoma to the liver with intrahepatic Y-90 microspheres:
a dose-ranging study. World J Nucl Med 2003; 2:216–225.
4. Rhee TK, Lewandowski RJ, Liu DM, et al. 90Y Radioembolization for metastatic neuroendocrine liver tumors: preliminary results from a multi-institutional experience. Ann Surg
2008; 247:1029–1035.
20 Liver Tumors: Metastases 203
5. Kennedy AS, Dezarn WA, McNeillie P, et al. Radioembolization for unresectable neuroendocrine hepatic metastases using resin 90Y-microspheres: early results in 148 patients. Am J
Clin Oncol 2008; 31:271–279.
6. Coldwell D, Nutting C , Kennedy AK. Treatment of hepatic metastases from breast cancer with
Yttrium-90 SIR-Spheres radioembolization. In: Society of Interventional Radiology Annual
Meeting. New Orleans, LA, 2005.
7. Hong K, McBride JD, Georgiades CS, et al. Salvage therapy for liver-dominant colorectal
metastatic adenocarcinoma: comparison between transcatheter arterial chemoembolization
versus yttrium-90 radioembolization. J Vasc Interv Radiol 2009; 20:360–367.
8. Liapi E, Geschwind J-F, Vossen JA, et al. Functional MRI evaluation of tumor response in
patients with neuroendocrine hepatic metastasis treated with transcatheter arterial chemoembolization. Am J Roentgenol 2008; 190:67–73.
9. Giroux MF, Baum RA, Soulen MC. Chemoembolization of liver metastasis from breast
carcinoma. J Vasc Interv Radiol 2004; 15:289–291.
10. Buijs M, Kamel IR, Vossen JA, Georgiades CS, Hong K, Geschwind JF. Assessment of
metastatic breast cancer response to chemoembolization with contrast agent enhanced and
diffusion-weighted MR imaging. J Vasc Interv Radiol 2007; 18:957–963.
11. Taylor RR, Tang Y, Gonzalez MV, Stratford PW, Lewis AL. Irinotecan drug eluting beads for
use in chemoembolization: in vitro and in vivo evaluation of drug release properties. Eur J
Pharm Sci 2007; 30:7–14.
12. Yu JS, Kim KW, Jeong MG, Lee DH, Park MS, Yoon SW. Predisposing factors of bile
duct injury after transcatheter arterial chemoembolization (TACE) for hepatic malignancy.
Cardiovasc Intervent Radiol 2002; 25:270–274.
Chapter 21
Liver Tumors: Neuroendocrine Hepatic Metastases
Kenneth J. Kolbeck and John A. Kaufman
Clinical Features
• Historically less aggressive than gastrointestinal adenocarcinoma, thus the term
carcinoid.
• Primary tumor can be from many locations: foregut (lungs, bronchi, and stom-
ach), midgut (small intestine, appendix, and proximal colon), or hindgut (distal
colon, rectum).
• Majority of cell types originate from neural crest during fetal development.
• Secretory/functional tumors release physiologically active compounds; non-
secretory/non-functional tumors do not.
• Symptoms frequently related to hormone (peptides, steroids, and neuroamines)
production and release.
• Hormones produced include insulin, glucagon, gastrin, vasoactive intestinal
peptide, pancreatic polypeptide, somatostatin, calcitonin, neurotensin, ACTH,
growth hormone releasing factor, corticotrophin, histamine, dopamine, substance
P, neurotensin, prostaglandins, kallikrein, as well as serotonin and its precursor
5-hydroxytryptophan and metabolite 5-hydroxyindoleacetic acid (5-HIAA).
• Carcinoid lesions (primarily neuroamine producers) present with carcinoid syn-
drome in approximately 10% of cases. Pancreatic endocrine tumors (primarily
peptide producers) secrete functioning peptides in approximately 75% of cases
and present with symptoms related to the specific peptide.
• Carcinoid syndrome is a constellation of symptoms including diarrhea, fre-
quent bowel movements, weight changes, heart palpitations, hypotension, hypertension, wheezing/asthma, intermittent skin flushing, acromegaly, Cushing’s
syndrome, and right heart valvular disease/heart failure.
• Carcinoid crisis (sudden release of active agents and abrupt onset of severe
symptoms) can be induced with surgery, chemotherapy, emotional stressors, and
iodinated contrast injection (can be confused with contrast allergy).
• Patients with secretory lesions present with symptoms related to the agent
released, while those with non-secretory lesions present late with bulk symptoms.
• Many neuroendocrine lesions over-express somatostatin receptors on the cell
surface (which can assist in diagnosis and monitoring response to therapy).
• Non-specific symptoms frequently delay an accurate diagnosis.
• The majority of patients present with hepatic metastases; the primary lesion may
never be identified.
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Techniques in Interventional Radiology, DOI 10.1007/978-1-84800-897-7_21,
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206 K.J. Kolbeck and J.A. Kaufman
Diagnostic Evaluation
Laboratory
• Several secreted neuroamines and peptides have specific serum/urine tests that
assist in diagnosis and evaluation of response to therapy.
• Twenty four hour urine serotonin/5-HIAA results in false negatives in up to 50%
of cases.
• Serum serotonin, tryptophan, and Chromogranin A commonly assist in the
diagnosis in the appropriate patient population.
Fig. 21.1 An axial image
from a contrast-enhanced CT
scan in a patient with
symptomatic metastatic
neuroendocrine tumor
demonstrates multiple, large,
hypervascular lesions within
the liver
Fig. 21.2 An Octreoscan from the same patient demonstrates the high concentration of somato-
statin receptors within the hepatic metastases. The primary lesion was not identified in this patient;
however, an isolated bone metastases was also identified
21 Liver Tumors: Neuroendocrine Hepatic Metastases 207
Imaging
• Ultrasound, CT, and MRI are used frequently in diagnosis of hepatic metastases
(lesions are primarily hypervascular compared to adjacent liver parenchyma).
• Endoscopy and colonoscopy may assist in identifying the primary lesion.
• An Octreoscan (radiolabeled somatostatin analog) may assist in identifying
primary and metastatic lesions.
Indications for Embolization
• Uncontrolled symptoms of hormone release in spite of adequate subcutaneous
octreotide therapy.
• Tumor bulk with mass effect symptoms (i.e. early satiety and weight loss)
• Clinical concern for residual liver function being overwhelmed by hepatic
metastases
Alternative Therapies
• Observation: for asymptomatic patients with small metastatic liver tumor burden.
• Systemic administration of octreotide (long acting ± short acting): can lead to
tumor regression and sympton control in some cases.
• Resection of primary and/or dominant metastases: goal of reducing the overall
number of metastases and tumor bulk.
• Chemoinfusion liver metastases: 5 day infusion from intra-arterial delivery of
5-fluorouracil.
• Ablation of liver metastases: radiofrequency ablation and cryoablation have been
utilized.
• Bland embolization: usually particle embolization.
• Routine chemoembolization: frequently with three drug combination (cisplatin,
doxorubicin, and mitomycin C).
• Drug-eluting bead chemoembolization: primarily doxorubicin.
• Y-90 radiotherapy with arterial delivery of glass/resin microspheres: increasing
in popularity, less overall embolic effect per treatment. Expensive.
• Intravenous delivery of Y-90 radiotherapy-labeled octreotide peptide analog.
Contraindications
• Contraindications to arteriography: bleeding/coagulopathy, poor arterial access,
unstable catheter position, diminished renal function.
• Contraindications to chemotherapy: agent/dose specific, rare cardiac and renal
toxicity with doxorubicin/cisplatin.