eMedicine Specialties > Radiology > Gastrointestinal
Liver, Metastases: Follow-up
Updated: Feb 10, 2009
Intervention
Interventions may include liver biopsy, tumor resection, or both. Six minimally invasive techniques are available for the treatment of primary and metastatic hepatic neoplasms:
- Transcatheter arterial chemoembolization (TACE)
- Cryoablation
- Microwave ablation
- Ethanol ablation, or percutaneous ethanol injection (PEI)
- Radiofrequency ablation (RFA)
- Laser ablation
Liver biopsy
A common saying is, "Think first, then don't do it," because the procedure converts local-regional disease to systemic disease (see Image 7).
Liver, metastases. A case against liver biopsy. This 68-year-old woman was referred for resection of an isolated liver metastases found at the time of colectomy. The patient underwent laparoscopy and laparoscopically guided liver biopsy. A surface lesion was examined at biopsy. At 6 weeks, the patient underwent laparotomy. At laparotomy, several surface metastatic deposits were identified in the liver around the biopsy site, and numerous small peritoneal metastases were present.
Liver biopsy should be performed only if the tumor is inoperable (eg, with pulmonary spread or lymph node involvement) or if the results of tumor marker testing are negative. Hepatomas and hemangiomas should never be evaluated by means of biopsy. Biopsy of FNH and adenomas is useless.
If the lesion is operable, laparoscopy and IOUS should be performed. If biopsy is performed, the liver remnant is the most important consideration.
Tumor resection
Depending on the primary site, 30-70% of patients who die of cancer have liver metastasis at autopsy. The most common cause of death from colorectal cancer is liver metastasis. Some success has been achieved in the resection of liver metastases in cases of limited disease (see Image 3).
Liver, metastases. Graph showing results from resection of a colorectal liver metastasis.
Treatment with systemic chemotherapy and radiation therapy is relatively ineffective. The response rate to 5-fluorouracil, the single agent most commonly used in the treatment of hepatic colorectal metastases, is only 20%. Several minimally invasive therapies have been found to be effective in both primary and metastatic tumors. These therapies may replace surgical resection in the near future.63,64,65
The criteria used to select patients for tumor resection include the following 10 points:
- Age: All patients with the physical potential to survive 5 years are candidates.
- Histology: No exclusions are noted.
- Timing of surgery: The timing has no influence; that is, the benefit is the same when surgery is performed between 1 and 12 months.
- CEA test: The level has no influence. (However, a limited amount of benefit may occur in cases in which the CEA level is >30 ng/L.)
- Thoracic CT: Patients must have no evidence of pulmonary disease.
- Bone scans: Symptomatic patients must have no evidence of bone metastases.
- Abdominal CT: No extrahepatic disease should be present.
- Liver CT: No size restriction is imposed (although benefit may be reduced if lesions are >8 cm). Fewer than 4 (or possibly 7) nodules should be present. The lesions must be within a single respectable zone (better if >10 mm).
- Laparotomy: No extrahepatic disease should be seen or palpated, with histologic correlation.
- IOUS: No unexpected tumor should be present in the liver remnant. Results should confirm anatomic resectability.
Transcatheter arterial chemoembolization
As a treatment, TACE has been used the longest, since the mid 1970s. Although the prognosis in liver metastatic disease is usually poor, the use of more aggressive treatment regimens in certain patients, such as those with neuroendocrine tumors and colorectal metastasis, may result in a favorable outcome.66,67
Effective chemoembolization of the liver is possible because of 3 circumstances.
First, the liver has a unique blood supply. The portal vein supplies 75% of the hepatic blood supply, whereas 25% of the blood supply is derived from the hepatic artery. This backup blood supply allows occlusion of either vessel without resultant liver infarction.
Second, 95% of the blood of both primary and metastatic hepatic tumors is derived from the hepatic artery.
Third, the development of catheter technology allows superselective placement of catheters for safe and effective delivery of therapeutic agents to hepatic tumors. Microcatheters allow safe placement, even in the face of aberrant vessels or collateral blood supply. In the early 1980s, it was discovered that when iodized poppy seed oil is injected into the hepatic artery, it preferentially remains in the neovascularity of HCC. Therefore, a vehicle exists for delivering cytotoxic agents to tumor sites within the liver.
Chemotherapeutic agents
A series of animal experiments conducted in Japan, Sweden, and the United States have shown that arterioportal shunting is the only way iodized oil is distributed within the normal liver parenchyma. This is in contrast to the situation with water-soluble contrast agents, in which arterioportal shunting occurs only in pathologic states. In addition, it has been demonstrated unequivocally that iodized oil is retained by portal venules and not by arteries at relatively low doses. The accumulation of iodized oil within hypervascular hepatic tumors is believed to be a direct consequence of the specific hemodynamic characteristics of the tumor.
The most frequently used cytotoxic drugs for chemoembolization include fluorodeoxyuridine, doxorubicin, cisplatin, and mitomycin. These drugs have been used in the systemic treatment of liver tumors since the 1960s, and they form an important component of the chemoembolization arsenal.
Chemotherapeutic drugs used for chemoembolization all share 2 characteristics. First, when the drug is delivered into the hepatic artery, it is rapidly cleared by the liver; such clearance accounts for the 100- to 400-fold difference in concentrations between the liver and systemic circulation. Second, the drug must be effective at high doses. If the agent is effective at the low doses with systemic administration, there is little point in delivering the drug intra-arterially. A further benefit is gained with regional arterial treatment, which results in lower systemic drug levels that reduce toxicity.
Chemotherapeutic agents are usually combined with embolic particles to achieve chemoembolization of hepatic tumors. The aim is to cause ischemia and prolonged contact of the chemotherapeutic agent with the tumor. Such mixtures can dramatically increase the local concentration of the chemotherapeutic agent.
Embolic agents
A variety of embolic agents have been used to treat hepatic tumors. The agents most widely used include Gelfoam (Pharmacia, Peapack, NJ), polyvinyl alcohol, and lipiodol. Used as pledgets or slurry, Gelfoam is a temporary embolic agent, with recanalization occurring within 2-6 weeks. Polyvinyl alcohol is a permanent embolic agent used alone (carcinoid metastases) or in combination with a chemotherapeutic agent. Lipiodol is an oily contrast agent with an affinity for HCC that is exploited diagnostically and therapeutically. Therapeutically, lipiodol is used as a vehicle to deliver a chemotherapeutic agent. Although most chemoembolization therapies apply to HCC, patients with other tumors may also benefit from such treatment. The role of embolization and chemoembolization in colorectal metastases is not clear.
Treatment of neuroendocrine liver metastases
There is no consensus as to the type of embolotherapy that is most useful in the treatment of neuroendocrine liver metastasis. The use of both embolization and chemoembolization has been advocated. The primary objective of embolotherapy in treating neuroendocrine liver metastasis is to reduce tumor bulk, reduce hormone levels, and palliate symptoms. These objectives may be achieved with either embolization or chemoembolization.
King et al have prospectively studied 34 patients with unresectable neuroendocrine liver metastases to assess the safety and efficacy of treatment with yttrium-90 radioactive microspheres. The results demonstrated that relatively long-term responses may be achieved with radioembolization with yttrium-90 resin microspheres in some patients with nonresectable neuroendocrine liver metastases.68
Treatment of progressive liver metastases
A combination of long-term subcutaneous administration of octreotide acetate, intra-arterial administration of 5-fluorouracil, and tumor chemoembolization has been shown to effectively control progressive liver metastasis and to provide excellent symptomatic palliation in patients with hepatic metastasis from functional carcinoid tumors. Interferon therapy for midgut carcinoid liver metastasis appears to be more effective when used in combination with hepatic arterial embolization.
Treatment protocol for the embolization of carcinoid and islet cell metastases
The following are contraindications for embolization: hepatic encephalopathy; biliary obstruction; hepatopetal portal flow; tumor load of more than 50% of the liver (although this criterion is not strictly adhered to; in 1 case, part of the liver was embolized); bilirubin level >2 mg/dL; lactic dehydrogenase level >425 U/L; and aspartate aminotransferase level >100 U/L.
All patients receive 10 mg of phytonadione intravenously before the procedure. Premedication involves oral lorazepam, 0.25 mg/kg 1 hour before the procedure. Otherwise, the patient receives nothing by mouth beginning at midnight before the procedure.
Somatostatin analogues are routinely used in active tumors before and after embolization to prevent carcinoid crises. Femoral catheterization and positioning of the catheter are performed in a selective or superselective method. Portal vein patency must be confirmed by obtaining a roadmapping angiogram. An intra-arterial injection is administered under direct visualization to prevent reflux into gastroduodenal or splenic vessels. Embolization is performed with Ultra Ivalon, 250-400 µm, mixed with 3-4 mL of Omnipaque (iohexol) 300. At the authors' institution, 1 lobe or segment of the liver is embolized at a time, depending on the tumor load.
Intravenous cefuroxime (750 mg) and metronidazole (500 mg) are administered 3 times a day for 5 days. Patients are admitted to a high-dependency ward; they should be mobilized after 6 hours of bed rest. Postoperative analgesics are administered if and when required by the patient. All patients receive intravenous ranitidine (an H2 antagonist) 3 times a day until they resume eating. Patients are discharged home after 3 days or when systemic symptoms are seen to be resolving.
CT scanning is performed 10-14 days after embolization. 5-hydroxyindoleacetic acid (5-HIA) levels are evaluated at the 6-week outpatient follow-up appointment. Embolization is repeated in 3-6 months, depending on the response.
Complications of chemoembolization
Vast discrepancies in complication rates have been reported. In one large series of 351 patients, the reported complications included the following69 :
- Severe postembolization syndrome (15.1%)
- Hepatic injury (30.8%), as indicated by abnormal liver function test results, acute hepatic failure, and hepatic infarction
- Gallbladder infarction (14%)
- Nontarget embolization (4.6%)
- GI bleeding (2.8%)
- Septicemia (2.6%)
- Pulmonary embolism (1.7%)
- Splenic infarction (1.1%)
- Tumor rupture (0.8%)
- Intrahepatic biloma (0.8%)
- Liver abscess (0.3%)
- Spinal cord injury (0.3%)
- Mortality at 30 days (2.6%)
In a study by Sakamoto et al of a large series involving 2300 chemoembolizations, reported a lower complication rate of 4.4% was reported. Complications were related to the use of chemoembolic agents and to the manipulation of the catheter or guidewire. In this study, complications included the following70 :
- Acute hepatic failure (0.26%)
- Liver abscess (0.22%)
- Intrahepatic biloma (0.87%)
- Hepatic infarction (0.17%)
- Multiple intrahepatic aneurysms (0.26%)
- Cholecystitis/gallbladder infarction (0.30%)
- Splenic infarction (0.08%)
- GI mucosal lesion (0.22%)
- Pulmonary embolism/infarction (0.17%)
- Tumor rupture (0.04%)
- Variceal bleeding (0.13%)
- Complications related to catheter manipulation (1.52%)
- Perforation of the celiac axis or its branches (0.17%)
The complication rates reported in a series by Chung et al appear excessive.69 In their series, patients with Child group C disease and cirrhosis were included, and some patients also had portal vein thrombosis. Moreover, whether the procedure was performed superselectively or globally was not clearly described in the article. Other series report a lower complication rate.
Outcomes of chemoembolization
In a meta-analysis of randomized controlled trials, Llovet et al found that chemoembolization improves survival in a subset of patients with unresectable HCC; chemoembolization may be considered the standard treatment for these patients.71 Tamoxifen does not affect the survival of patients with advanced disease.
Carcinoids and islet tumors produce potent hormones, such as serotonin, gastrin, somatostatin, glucagon, adrenocorticotropic hormone, insulin, and other polypeptides. The control of symptoms is the primary objective of the therapy because the lifespan of patients is long regardless of treatment. However, once medical treatment fails, patients may benefit from hepatic embolization with polyvinyl alcohol, Gelfoam, and/or coils, either alone or in combination with chemotherapy.
Ocular melanoma frequently metastasizes to the liver. In this situation, the response rate to chemotherapy is poor. A 46% response rate has been reported after chemoembolization with a combination of cisplatin and polyvinyl alcohol.
Cryoablation
Cryoablation is the oldest thermal ablation technique. It was first suggested by Cooper.72 The technique involves the ablation of tumor by delivering subfreezing temperatures via penetrating or surface cryoprobes. The thermally conductive material of the tip of the cryoprobes allows them to be cooled –20º C to –30º C; the shaft of the probe and hoses are insulated. The subfreezing temperatures cause cell death by denaturing cellular protein, rupturing the cell membrane, dehydrating the cell, and causing ischemic hypoxia (see Images 4-6).73,74
Liver, metastases. Photograph of the various types of cryosurgery probes available.
Liver, metastases. Photograph of a cryosurgery probe and ultrasonography in use.
Liver, metastases. Ultrasonographic monitoring of the freezing created by cryosurgery probe.
Both primary and metastatic unresectable liver tumors can be treated with ablation. Generally, 4 or fewer tumors are selected for treatment, although a higher number of tumors of neuroendocrine origin may be treated. Contraindications include extrahepatic disease and situations in which general anesthesia cannot be used.
At present, cryoablation necessitates an open operation, although some tumors may be treated laparoscopically. US is used for guiding the procedure. Depending on the size of the tumor, 1 or 2 probes are placed in the center of the tumor, with the edge of the tumor incorporated within the range of the probe. Cryogenic material, such as liquid nitrogen, is circulated through the probe. An ice ball is formed at the end of the probe, incorporating the tumor. The ice ball appears as an echogenic, expanding ball with shadows.
Freezing is continued until a 5- to 10-mm margin of normal liver tissue surrounding the tumor is also ablated. The tumor is generally frozen twice with a 5- to 10-minute interval between the 2 ablations. After the second ablation, the system is rewarmed to remove the probes and allow packing. There is a small risk of bleeding from the tumor site and of tumor dissemination along the probe tract. A single cryoablation technique is generally sufficient to completely eradicate the tumor.
A CT scan is obtained immediately after ablation, with follow-up scanning at 6 and 12 months and then yearly. The treated tumors appear as low-attenuating avascular areas that decrease over time. Initially, a faint area of ring enhancement may be present as a result of an inflammatory response in the surrounding normal liver.
The major limitation of cryoablation is that it requires laparotomy or at least laparoscopy under general anesthesia and a 3- to 5-day hospital stay. To the authors' knowledge, no prospective comparative studies have been performed with cryoablation and percutaneous ablation techniques.
Cryoablation is suited for the treatment of large tumors. Long-term follow-up data show some survival benefit. Sheen reported that hepatic cryotherapy is effective and safe, as demonstrated by a significant reduction in postoperative CEA concentrations and the low risk complications.75 However, this initial short-term success was not reflected in the 5-year survival rates. Cryotherapy for noncolorectal metastases had a greater long-term survival benefit and is a useful means of controlling symptoms. Goering et al showed that survival rates after hepatic cryotherapy tumor ablation of metastatic noncolorectal primary tumors and recurrence rates of local hepatic tumors are similar to those of resection alone.76
Microwave ablation
Microwave ablation uses a microwave generator and reusable needle electrodes to ablate tumors. Microwaves cause vibration and rotation of molecular dipoles, resulting in the thermal coagulation of tissues. The mechanism of action in living tissues is the rotation of water molecules. The microwaves are emitted from the distal segment of a percutaneously placed probe. These microwaves cause thermal coagulation of adjacent tissues. Generally, microwave ablation is limited to patients with 4 or fewer tumors each less than 5 cm. A single ablation procedure results in a coagulated area less than 2 cm. The procedure is US guided. During the procedure, which normally lasts 60 seconds, a hyperechoic area near the tip of the electrode is observed.77,78,79
Treatments may be repeated every 2 days until the whole tumor is ablated. Beppu et al evaluated the effectiveness of local ablation therapy in patients with liver metastases from colorectal cancer.80 They used radiofrequency ablation (RFA), microwave ablation, or both. Their regional recurrence rate at therapeutic sites was 15% (median follow-up, 2.5 y). The cumulative 5-year survival rates were 37% with local ablation, 41% with hepatic resection, and 5% with regional chemotherapy. They concluded that RFA and microwave ablation are radical and safe local-regional therapies that provide adequate local control and that contribute to long-term survival.
Ethanol ablation
When injected into neoplastic cells, ethanol causes dehydration of the cytoplasm, coagulation necrosis, and subsequent fibrosis. In tumor vessels, ethanol causes necrosis of endothelial cells, platelet aggregation, and thrombosis leading to tissue ischemia. Ethanol has been extensively used as local treatment of primary and metastatic liver neoplasms worldwide.81
Generally, a 21-gauge multihole conical-tip needle connected to tubing is used to inject 95% alcohol in an image-guided procedure (usually, US is used to guide the procedure). The area of infarction produced by ethanol ablation cannot be reproduced because it depends on the histologic characteristics, degree of vascularity, presence or absence of a tumor capsule and septa, and tissue consistency of the tumor. Ethanol ablation is generally performed for HCC in cirrhotic patients. Patients with tumors less than 30% of the total liver volume are usually chosen for ethanol ablation. Tumors smaller than 5 cm may be ablated on an outpatient basis with multiple sessions under local anesthetic. General anesthesia is generally reserved for procedures in larger tumors.
Contraindications include extrahepatic disease, portal vein thrombosis, Child class C cirrhosis, a prolonged prothrombin time (<40%), and a platelet count less than 40,000/mm3. Ethanol appears to be safe and inexpensive, and the procedure is repeatable. In small and medium-sized HCC lesions, the results of ethanol ablation are comparable to those of surgery. Tumors as large as 8 cm can be ablated. Ethanol appears to be less effective for treatment of liver metastases than thermal ablation techniques.
Major complications, such as peritoneal hemorrhage, hemobilia, and liver abscess, have been reported in 1.7% of cases. These have been reported with a multisession technique under local anesthesia with no mortality. However, a higher complication rate of 4.6% and a mortality rate of 0.7% have been reported with a single-shot technique performed in patients with larger tumors and under general anesthesia.
Radiofrequency ablation
RFA works on the principle that alternating current operated within the radiofrequency range can produce focal thermal injury in tissues. Shielded probes are used to deliver energy to target tissues. The tip of the probe conducts the current, which causes local ionic agitation, frictional heat, and coagulation necrosis. With temperatures in excess of 500°C, coagulation necrosis within a 2- to 5-cm diameter area of tissue is produced.82,83,84,85,86,87,68
The equipment required is a radiofrequency generator and electrodes. Various options of commercially produced electrodes are available in various sizes. The RadioTherapeutics Corporation (Sunnyvale, CA) provides a 14-gauge needle with retractable prongs; Radionics Inc. (Burlington, MA) supplies a 17-gauge internally cooled straight needle or a 3-needle cluster.
RFA is an effective treatment in primary and metastatic liver tumors. Patients with 4 or fewer 5-cm or smaller tumors with no extrahepatic disease are candidates for the procedures. The ideal tumor should be completely surrounded by hepatic parenchyma at least 1 cm deep to the liver capsule and 2 cm away from major hepatic vessels/bile ducts. Tumors near large blood vessels are difficult to completely ablate because of a cooling effect from flowing blood. Subcapsular tumors may be ablated, but increased procedural and postprocedural pain may be a limiting factor. Tumor ablation near the portal triad also tends to be more painful and also carries the risk of damage to major vessels and bile ducts.
As with any percutaneous liver procedure sepsis, and uncorrectable coagulopathy is a contraindication to the procedure. Another problem is with lesions located in a subdiaphragmatic position, where safe access to the tumor may not be possible because of intervening lung/pleura. In this situation, an intraoperative approach may be more suitable.
RFA may be performed with the patient under conscious sedation or general anesthesia. Electrode placement is guided with US or CT, where US is the preferred modality.
The aim of RFA is used not only to ablate the tumor but also to cause coagulation necrosis with a surrounding collar of normal liver tissue measuring 5-10 mm. A single ablation on the average requires 15 minutes to perform. Overlapping ablations may be used to treat larger tumors. Complications include bile duct injuries, abscess formation, tumor seeding along the needle tract, and diaphragmatic ablation. A 2% mortality rate has been reported. Radiofrequency has been suggested as an alternative to surgery for the treatment of liver tumor recurrence after hepatectomy. The combination of radiofrequency with other therapies and the long-term recurrence rates and effect on overall survival have yet to be assessed.
Kondo et al have shown that with intrapleural fluid infusion, radiofrequency ablation for tumors in the hepatic dome is safe and effective, resulting in satisfactory overall tumor ablation.87
Laser ablation
Reproducible tissue coagulation necrosis can be achieved by using Nd:YAG (neodymium:yttrium-aluminum-garnet) lasers. Light at an optical or near-infrared wavelength delivered via a laser fiber is converted into heat, causing thermal injury. Light energy of 2.0-2.5 W produces an area of tissue necrosis 2 cm in diameter. Portable solid-state generators can deliver laser energy. The energy is delivered via laser fiber.
Laser energy is MRI compatible. The placement of laser fibers is guided by using US, CT, or MRI.
Laser ablation is effective in both primary and metastatic liver tumors. Vogl et al achieved a local tumor control rate of 97.8% in their series of patients with liver metastases and malignant liver tumors.88,89,90 The complication rate in relation to 1441 treatments was extremely low at a rate of 2.2% with a mortality rate of 0.1%. The mean survival time was 47.7 months.
The patient selection criteria are the same as those of RFA and microwave ablation.
New Radionuclide Treatments
The European Association of Nuclear Medicine has issued guidelines on so-called "established" therapies (ie, such therapies for hyperthyroidism, thyroid carcinoma, and bone metastases; MIBG therapy; 32P therapy; lipiodol therapy; and newer therapies, including radiopeptide therapy, radioimmunotherapy of lymphoma, and microsphere therapy for liver cancer. There are several emerging clinical applications of newer radionuclide therapies for liver cancer, such as radioembolization for liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, and leucovorin chemotherapy. In patients with advanced gastroenteropancreatic liver metastases, [90 Y-DOTA0,Tyr3]octreotide can provide useful symptomatic relief and cytoreduction.
Special Concerns
- Liver metastases in multiple endocrine neoplasia (MEN) type 2A may originate from medullary thyroid carcinoma and malignant pheochromocytoma.
- Chemoembolization and/or angiography or percutaneous liver biopsy of pheochromocytoma liver metastases may provoke hypertensive crises. Therefore, before chemoembolization is performed in a patient with MEN-2, 24-hour urine samples should be collected for catecholamines, metanephrines, and vanillylmandelic acid estimations.
- Because of its unpredictable nature, arterial chemoembolization should not be considered when there is even a remote possibility of hepatic pheochromocytoma.
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Further Reading
Keywords
liver metastases, hepatic metastases, hepatic cancer, liver cancer, liver neoplasms, Kupffer cells, Kupffer's cells, space of Disse, hepatomegaly, ascites
