IS Case 620: Hepatocellular carcinoma (HCC)
2014, UR Imaging Sciences
Publication Date: 20140915
BACKGROUND: HCC Hepatocellular carcinoma (HCC) is a primary cancer of the liver. It occurs predominantly in patients with chronic liver disease, particularly hepatitis B, hepatitis C and cirrhosis. In addition, alcohol abuse serves as a significant risk factor. HCC is the fifth most common cancer in men and eighth most common cancer in women, resulting in about 500,000 deaths a year. The incidence of HCC in underdeveloped and developing countries is over twice the incidence of that in developed countries. For example, in 2000 the United States had an incidence rate of only 8.7 per 100,000, compared to an incidence of 17.43 per 100,000 in developing countries . However, with its link to the hepatitis C epidemic and the increasing prevalence of nonalcoholic fatty liver disease, HCC represents the fastest growing cause of cancer mortality in the United States .
Recent work suggests that the cancer develops from the hepatic stem cells. These cells proliferate as a response to chronic regeneration caused by certain viral injuries. As a result, patients may develop acute ascites, jaundice, encephalopathy or variceal bleeding. Thus, early diagnosis is imperative in order to provide effective treatment . Detection requires the combination of a high index of clinical suspicion, imaging modalities, tests for tumor markers and tissue diagnosis. HCC has a specific diagnostic criteria on imaging, early enhancement during arterial phase on contrast imaging followed by washout of contrast during portovenous phase (Figure 1). Thus, the method of treatment of HCC should be based on the presence of cirrhosis, extent of disease, tumor growth patterns, metastatic properties and the status of the patient (1). HCC are hypervascular on angiography (Figure 2). Treatment options include surgical resection, liver transplantation and locoregional therapies including ablative therapies (radiofrequency ablation, cryoablation, microwave ablation and irreversible electroporation), transcather arterial chemoembolizaton (TACE) and yttrium-90 microsphere radioembolization.
In general, radioembolization is well tolerated. However, rare complications may result from the irradiation of non-tumor tissues. This includes pneumonitis, cholecystitis, gastrointestinal ulcerations and liver damage. In HCC patients, liver toxicity is the most challenging adverse event since the majority of tumors arise in cirrhotic livers with reduced functional reserve. In addition, a variable incidence of liver decompensation including ascites (0-18%) and encephalopathy (0-45%) have been reported. In the largest series reported thus far, the incidence of radioembolization-induced liver disease in cirrhotic patients was 9.3% . Reported mild side effects to 90Y include fatigue, some abdominal pain, nausea and fever. However, these effects should subside after 10 days .
In conclusion, 90Y radioembolization is a prominent method of treatment for those candidates who meet the clinical criteria. The strong selectivity with the radioactive microspheres allows for very precise treatment of patients with various liver cancers such as HCC, metastatic colorectal and breast cancers, along with an array of other metastatic cancers. The clinical preparation and procedural actions taken allow for a radiation friendly and minimally invasive therapy with advantageous outcomes.
Hepatocellular carcinoma (HCC)
Treatment Methods: TACE
One method of treatment is transcatheter arterial chemoembolization (TACE), which is an image-guided and non-surgical procedure that can be performed to treat malignant lesions within the liver (1). TACE is commonly performed by interventional radiologists who gain access to the tumor through the hepatic artery in order to deliver specific chemotherapeutic drugs such as doxorubicin, cisplatin, mitomycin or some combination of these drugs (Figure 3). TACE is often performed as a palliative method of treatment or as a pre-transplant method in order to reduce the stage of the tumor(s) in the liver so that the patient meets the specific guidelines for liver transplantation [4-6].
This non-surgical procedure involves gaining access to the hepatic artery using a catheter, which has been inserted in the groin through the femoral artery. Once the catheter is located in the liver, the tumor can be targeted through hepatic arteries using small catheters in order to deliver the chemotherapeutic drugs while also decreasing damage to the other healthy liver parenchymal tissue. The advantages to this procedure include a minimally invasive therapy, fewer complications and also a very minimal recovery time compared to surgery.
Like other treatments, there are certain criteria that a patient must meet for tumor resection or hepatic transplantation. Therefore, certain ablative techniques such as microwave coagulation therapy (MCT) and radiofrequency ablation (RFA) have been developed to treat patients with liver cancers such as HCC. RFA, unlike other ablative techniques used to be favored among other types due to its relative simplicity, low cost, and minimally invasive procedural techniques (Figure 4) .
Radiofrequency ablation is commonly used to treat HCC. It works by heating the liver tumors to over 60oC which then causes a variety of affects to affect the tumors. Upon these changes in cellular temperature, water is removed from the cells which results in necrosis. Also this temperature change causes the cellular proteins to denature and cellular membranes to dissolve . RFA allows an effective minimally invasive technique for liver tumor ablation, and when couples with TACE, it can make larger tumors become possible for these treatments. Ultimately, with complications such as hemorrhage, liver failure, hemothorax and pleural effusion, at a very low rate of incidence, RFA is a successful method of treatment with promising outcomes (Figure 5) .
Another method of treatment of HCC uses radioembolization to deliver certain radioactive materials to the desired tumor(s). Specifically, this is a type of brachytherapy involving the delivery of microspheres (glass or resin) which contain the beta-emitting isotope yttrium-90 (90Y). This isotope is effective because it has a target treatment range of approximately 2-3 mm, which is effective because it can treat the desired tumor, while also saving healthy liver parenchyma [8-9]. The size of the microspheres is an important factor in the procedure, because the beta-emitting spheres should be small enough to gain access to the target tumor, however they must be large enough to clog the capillary beds and to prevent the microspheres from passing directly through the liver. Similarly, patients eligible for the procedure must have solid tumors and a life expectancy of at least 3 months [1, 8-9]. Before the procedure, a consultation with the physician should be done in order to discuss the procedure and determine potential candidacy.
90Y Radioembolization: Patient Criteria
90Y radioembolization can be a palliative treatment in that it does not provide a cure but helps slow down the growth of the disease and alleviate symptoms. The procedure serves as an option for patients who are not good candidates for other treatments such as surgery or liver transplantation. In general, 90Y is used to shrink tumors and inhibit proliferation. For a small number of patients, treatment with 90Y can cause marked shrinkage of the liver tumor, so that it allows for surgical removal at a later date .
Due to the risk of treatment complications and toxicity, it is essential that only properly selected patients undergo radioembolization. Components of the selection process include a thorough clinical evaluation of the patient’s history and performance status . Clinical laboratory tests such as blood count, serum creatinine, albumin, lactate dehydrogenase and prothrombin time should also be completed. In addition, chest X-rays, tumor marker assays, CT/magnetic resonance imaging scans of the abdomen and pelvis, portal vein assessment and arteriography studies are important in determining the patient’s eligibility for repeat radioembolization . Some relative contraindications are abdominal ascites, severe portal hypertension and liver shunting estimated at over 20% (Figure 6). Absolute contraindications are decompensated liver function, hepatic encephalopathy, pregnancy and uncorrectable liver shunt to the GI tract or lungs. Similarly, it has been found that total bilirubin remains the most important pretreatment indicator of post-radiation success in radioembolization .
When taking into account the overlap of indications of most local ablative therapies, it has been suggested that, due to the presence of numerous bilobar tumors, intra-arterial therapies are optimal in most patients. For those with HCC in particular, radioembolization should be the standard therapy choice . However, individuals with clearly compromised functional status are at a high risk for liver failure and morbidity associated with treatment. Therefore, a number of nonradioactive ablative therapies should be considered for small, limited-number hepatic tumors .
Cancer should be limited to the liver, along with metastatic colorectal and neuroendocrine tumors. But, there is new pertinent data showing the positive results of radioembolization to other metastatic cancers such as breast and intrahepatic cholangiocarcinomas [3,8]. As a result of a lack in controlled phase III combinatorial studies of systemic chemotherapy with 90Y radioembolization, a conservative approach is generally favored and systemic therapies should be discontinued two weeks prior to radioembolization. However, chemotherapy may be restarted two weeks following the radioembolization .
Ideal candidates for 90Y do not have an infiltrative type HCC or bulk disease, tumor replacement of liver at least 50% with an albumin level less than 3.0g/dL, previous intra-arterial liver treatment, total bilirubin levels less than or equal to 2 mg/dL, or previous external-beam liver radiation therapy .
90Y Radioembolization: Clinical Preparation and Radiation Tools
There are predominantly two main radioembolization products used throughout the world for these specific procedures, both containing 90Y. Generally, resin microspheres are used in Asia and the European Union. They are also used in the United States for treatment of metastatic colorectal cancer (mCRC) in combination with other therapeutic agents . The other product used involves glass microspheres, which is used in the United States to treat HCC and in other countries to treat various liver cancers (8). Although they both contain 90Y, the two materials may differ in size, density, dose calculations and embolic capability .
Radioembolization treatment with yttrium-90 involves a very detailed planning for the actual procedure. Using both computer tomography (CT) and magnetic resonance imaging (MRI), the tumor(s) are mapped in order to determine their location, size and multiplicity. Also, the vasculature feeding the tumor should be mapped using hepatic angiography in order to locate the proper vessels to inject the microspheres to allow effective treatment. Similarly, the vessels that may potentially carry the microspheres away from the tumor are mapped to prevent radiation damage to other abdominal organs [1,8-9]. It is common to use technetium-99m-labeled macroaggregated albumin (99mTc-MAA) to estimate the size of the microspheres, and the uptake of 99mTc-MAA can be found in organs. If there is uptake in the stomach or small bowel, the appropriate vessels can be embolized to prevent distribution of the radioactive microspheres .
When beginning the procedure, a sedative will be used along with local anesthesia to numb the puncture site. Once numb, access will be gained into the hepatic artery using a catheter from a puncture in the femoral artery. Once the catheter is tracked through the arteries to the site of the tumor under image guidance, the 90Y microspheres are deposited and lodged in the capillaries at the tumor site. Since all of the blood that feeds the tumor comes from hepatic artery, this method will selectively block off the blood and nutrients feeding the tumor [1,9].
90Y Radioembolization: Dosimetry and Therapy Selection
Yttrium-90 is a beta emitter and has a half-life of 64.2 hours. This means that 94% of the energy is emitted in the first 11 days. The radioactive microspheres’ small size (25-45 microns) does not produce significant ischemic effect as compared to the larger than 100-micron particles used in TACE . Beta radiation causes the same kind of tumor cell injury as other radioactive isotopes and external beam radiation. This includes DNA damage, changes in cell functioning and reproductive cell damage .
After the microspheres are lodged in the tumors, they remain active in the body, delivering treatment for approximately ten days . Treatment activity of 90Y resin microspheres is currently determined by two methods: the body surface area (BSA) method and the partition model method . The BSA method serves as the recommended formula for the majority of patients. The formula varies the prescribed activity of 90Y with the proportion of tumor involvement within the liver and the size of the patient. Activity is reduced if there is evidence of increased lung shunt. In addition, some clinicians reduce radiation dose in highly pretreated patients or in low-volume disease. Thus, the following equation is used to determine activity :
Where: A= activity (GBq)
The recommended approach for the use with high-activity glass microspheres is consistent with the conventions of the Medical Internal Radiation Dose (MIRD) committee techniques and adjusted accordingly to the calculated shunt of particles to the lung .
Activity (GBq) = [Desired Dose (Gy)] [Mass (kg) Selected Liver Target] / 50 x [1 - F]
Where: F=fraction of injected activity deposited into the lungs as measured by the 99mTc-MAA study.
90Y Radioembolization: Post Procedural Care
Within two weeks after radioembolization, patients should plan a follow-up visit with their treating physician including interval and physical laboratory tests with imaging. Imaging studies play an important role in the assessment to radioembolization . Positron emission tomography (PET) or Computerized Tomography (CT) scanning may be used in order to assess tumor activity. However, with CT scanning, there is usually only a modest response in the liver tumor at 6 weeks. OctreoScan may also be recommended for patients with neuroendocrine tumors at 12 weeks or later. If there is no sign of recurrence after one year, the scans should be continued every six months for the next five years .
All clinical studies conducted have used CT scans (using RECIST criteria) together with tumor markers as the main measures of tumor response to radioembolization. For FDG-avid lesions, post-treatment PET imaging is the most informative measure of response, in that it detects significantly more responses to treatment than CT scanning . Despite such benefits, PET scanning is limited in its sensitivity of small lesions and is reliant on tumors that are avid to radiolabeled substrates. Therefore, CT scanning remains the only available accepted objective measure of response which can be used in clinical trials .
90Y Radioembolization: Prognosis and Outcomes
Studies have shown that treating liver tumors with 90Y radioembolization preserves the patient’s quality of life. It also produces fewer side effects than standard radiation therapy  (Figure 7). Radioembolization has been used mainly for patients with unresectable tumors and for those who are not candidates for TACE or liver transplantation .
- Jelic S, Sotiropoulous G. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010; 21(5): 59-64. PMID: 20555104
- Cormier JN, Thomas KT, Chari RS, Pinson CW. Management of hepatocellular carcinoma. J Gastrointest Surg. 2006;10(5):761-80. PMID: 16713550
- Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol. 2005; 40(3):225-35. PMID: 15830281
- Seeff LB. Introduction: The burden of hepatocellular carcinoma. J Gastroenterol. 2004;127(5):1-4. PMID: 15508071
- Cicalese L. Hepatocellular Carcinoma. Medscape. 30 May 2014. <http://emedicine.medscape.com/article/197319-overview#a0103>
- Robert H. Lurie Cancer Center. Yttrium-90 Treatment. Chicago: Northwestern Memorial Hospital, 2006. <https://www.clinicalkey.com/topics/surgery/hepatocellular-carcinoma.html>
- Lewandowski RJ, Salem R. Yttrium-90 radioembolization of hepatocellular carcinoma and metastatic disease to the liver. Semin Intervent Radiol. 2006;23(1):64-72. PMID: 21326721
- Lam MG, Seinstra BA, van den Bosch M, Louie JD, Sze DY. Abstract No. 345. Comparison between resin and glass microspheres for Yttrium-90 radioembolization treatment of hepatocellular carcinoma. J Vasc Intervent Radiol. 2013;24(4):S149.
- Kennedy A. Radioembolization of hepatic tumors. J Gastrointest Oncol. 2014;5(3):178-189. PMID: 24982766
- Kennedy A, Coldwell D, Sangro B, Wasan H, Salem R. Radioembolization for the treatment of liver tumors general principles. Am J Clin Oncol. 2012;35(1):91-99. PMID: 22363944
- Minami Y, Kudo M. Radiofrequency ablation of hepatocellular carcinoma: a literature review. Int J Hepatol. 2011; Article ID:104685. PMID: 21994847