[MOL] Hepatocellular carcinoma..... [00298]

Caring for the Patient With Hepatocellular Carcinoma

Rowen K. Zetterman, MD, FACG

Introduction
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and has a worldwide distribution. HCC is associated with many underlying conditions and events, including hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (with or without cirrhosis); endstage liver diseases due to ethanol ingestion, hemochromatosis and alpha-1-antitrypsin deficiency; exposure to environmental toxins, such as aflatoxin; and administered medications, such as anabolic steroids.
A symposium on HCC held at the 64th Annual Scientific Meeting of the American College of Gastroenterology in Phoenix, Ariz, October 18, 1999, discussed the screening, diagnostic, and therapeutic options available to the gastroenterologist evaluating at-risk patients or managing patients with confirmed disease.

Screening and Diagnosis
Establishing a proper screening strategy first requires determination of who should be screened. Although not expanded in this discussion, all patients with at-risk disorders should be considered for screening. In most cases, this means screening those with cirrhosis, especially when HBV, HCV, ethanol, or alpha-1-antitrypsin deficiency are causative diseases. Those individuals with Wilson's disease and primary biliary cirrhosis appear to be at less risk for HCC.
In data presented by Dr. K. Rajender Reddy of the University of Miami School of Medicine, serum alpha-fetoprotein (AFP) was noted to be a readily available screening test, with a sensitivity of 30%-79% and a specificity of 76%-89%.^[1] In patients with HCC, 68% will have an AFP > 15 ng/mL and 36% will have an AFP > 200 ng/mL. If a cutoff of 100 ng/mL was used in testing, a sensitivity of 21% and specificity of 93% was reported. Ultrasonography can also be employed for screening, with a sensitivity of 70% and a specificity of 93%. Findings of a hepatic mass on ultrasound suggestive of HCC include a peripheral halo about the mass, hypoechoic character of the mass (occasionally hyperechoic), and a mosaic pattern. Color Doppler at ultrasound may assist with both the diagnosis and vessel assessment in anticipation of potential resection.
Other screening modalities discussed at this session included dynamic and spiral CT scan, CT arteriography and portography, and use of contrast agents at CT (such as Lipiodol). The T2 weighted image on magnetic resonance imaging (MRI), especially when contrast agents such as gadolinium or magnetic iron oxides are used, can also be helpful. In general, the lack of availability, as well as the associated cost, limit the effectiveness of these modalities. By contrast, angiography and scintigraphy have a low yield in screening.

Cost-Effectiveness of Screening
The related cost of finding HCC while screening HCV- or HBV-infected patients has been determined to be approximately $25,000-$72,000/tumor detected.^[2] When assessed by quality life year gained, screening those with Child-Pugh Class A cirrhosis is associated with a cost of $25,000-$55,000/life year gained.^[3] By comparison, screening at-risk populations for colon cancer has a cost of approximately $25,000/life year gained.^[4]
A US survey of practicing clinicians regarding their screening practices for patients with endstage liver disease, showed that only 36% screened nontransplantation candidates for HCC while 80% screened their liver transplantation candidates. Is this level of surveillance sufficient for the pretransplant patient? While it is critical to know if a patient being considered for transplantation has HCC, the improved ability to provide adequate therapeutic options to those with small HCC lesions suggests that screening should be offered to all at-risk patients.

Screening Recommendations
An aggressive screening program was recommended during the program; the guidelines are as follows:

For patients at "extremely high risk," such as those with cirrhosis associated with active ethanol ingestion and HCV infection, ultrasonography and serum alpha-fetoprotein measurements should be done every 3 months.
For patients considered "high risk," such as those with cirrhosis due to HBV, HCV, or hemochromatosis, serum alpha-fetoprotein measurements should be taken every 3 months and a hepatic ultrasound every 6 months.
For patients considered to be at "moderate risk" from cirrhosis due to autoimmune hepatitis or alcoholism, annual alpha-fetoprotein measurement and hepatic sonogram were suggested.

Primary Therapy - Orthotopic Liver Transplantation or Resection?
Surgical therapy offers the opportunity for cure in patients with HCC. However, the surgical options are limited by the size of the tumor, location of the tumor, the presence or absence of vascular invasion, associated vascular thromboses, and the character and severity of underlying liver disease.
The next presenter in this forum, Dr. J. Michael Henderson, discussed surgical options for patients found to have HCC.^[5] He noted that more surgical strategies are now available because of an improved understanding of the natural history of cirrhosis and HCC; better imaging techniques (including intraoperative ultrasound), which can identify tumors early, assess evidence of local and distant spread, and define tumor margins; and the development of treatment options that permit reduction of tumor volume and/or reduce growth and metastases while the patient awaits more definitive therapy (such as orthotopic liver transplantation).

Hepatic Resection
Liver resection for HCC can be effective in selected patients. Factors associated with the overall efficacy of resection include coexisting cirrhosis, adequacy of tumor resection margins, presence or absence of vascular invasion, and the size of tumor at presentation. The ability to identify and resect only a single vascular lobule of the liver has also increased the number of patients with cirrhosis who can be resected. Dr. Henderson reported that in one study, only 30% of patients (n = 286) with cirrhosis were deemed resectable compared with 54% of patients (n = 126) with HCC who lacked cirrhosis.^[6] In this study, lobectomy was performed in 59% of patients with cirrhosis versus in 81% of those lacking cirrhosis; the associated operative mortality was 5% and 3.7%, respectively.

Tumor size is an important consideration because 5-year survival is 57% in those with tumors < 5 cm in diameter versus 32% for those with tumors > 10 cm. In a study from Hong Kong in which HCC was principally associated with HBV infection, 244 "curative" resections were undertaken, with eventual intrahepatic recurrence developing in 43%; overall survival rate at 5 years was 20%.^[7]

Orthotopic Liver Transplantation
If resection is not feasible, is orthotopic liver transplantation with removal of the entire liver effective in managing HCC? When initially studied, it was quickly noted that liver transplantation for large tumors, even when no evidence of spread was identified, was a poor option (the associated survival was approximately 20%-40%). When recurrence of tumor is identified following transplantation, it occurs in the liver in 42% of cases and the lung in 29%. Adverse factors which increase the likelihood of HCC recurrence after liver transplantation include tumor size > 5 cm in diameter at transplantation, presence of vascular invasion, presence of positive lymph nodes, and tumors of higher grade. In an evaluation of tumor burden and liver transplantation, those patients who had a single tumor < 5 cm in diameter or no more than three tumors (none of which were > 3 cm) resulted in a 4-year survival of 75%, an operative mortality of 17%, and a tumor recurrence rate of 8%.^[8]

Summary of Surgical Recommendations

Surgery does have a role in either resection or orthotopic liver transplantation for HCC.
The key to effective resection is early identification of HCC.
Patients with HCC should be referred early for consideration of surgical therapy.
For patients requiring orthotopic liver transplantation, the tumor should be < 5 cm in diameter (if multiple tumors are present, there should be no more than three tumors and none should be > 3 cm in diameter).
In general, the best outcome will occur in the patient who is deemed resectable, whether resection or transplantation is offered.

Adjuvant and Palliative Therapies for HCC
Adjuvant or palliative therapies may be used when curative treatment is not feasible or when supplemental therapy for a patient awaiting more definitive treatment, such as orthotopic liver transplantation, is needed.
The final speaker at this symposium, Dr. Adrian DiBesceglie, discussed other treatment options for selected patients.^[9]

Local Therapy
Local ethanol injection therapy can be used to treat small lesions, typically those tumor nodules < 3 cm in diameter. With ultrasound or CT guidance, a needle is placed into the tumor and 1-8 cc injected. Multiple injections (or sessions) may be required. Contraindications to injection include diffuse tumor spread, portal vein thrombosis, and coagulopathy related to liver disease, such as thrombocytopenia or hypoprothrombinemia. In addition to 100% ethanol, hot saline and 20% acetic acid can also be used. Larger lesions are not amenable to local injection therapy.
Radiofrequency thermal ablation can be administrated by introduction of a special probe into the tumor that heats and destroys the tissue. Local recurrence is reported to be < 1% if adequate tumor destruction is achieved. Cryotherapy may be used intraoperatively. Local proton beam therapy to tumors is promising and expected to be available in the future.

Chemotherapy
Chemotherapy can be delivered directly into the tumor by direct injection (ie, cis-platinum mixed with a collagen matrix), systemically (ie, alpha-interferon or combinations of 5-fluorouracil [5-FU], mitomycin C, and doxorubicin), intra-arterially via the hepatic artery (ie, 5-FU), or by embolization of the tumor when chemotherapy agents are emulsified with gelfoam particles or agents such as Lipiodol. Chemoembolization via the hepatic artery can be selectively administered to that portion of the liver with disease in order to induce tumor necrosis.^[10] Contraindications to chemoembolization include poor performance status, portal vein thrombosis, marked ascites, or a serum bilirubin > 2 mg/dL. This technique may also be used as adjunctive therapy to control tumor growth as a patient awaits liver transplantation. Periodic CT examinations can be employed to determine if tumor nodules are adequately treated and/or growing in size and require retreatment.

Summary of Adjunctive Therapy Recommendations

Chemotherapeutic agents may be useful as adjunctive or palliative therapies.
Local injection of agents such as 100% ethanol should be reserved for small tumors (ie, < 3 cm in diameter).
Other ablative therapies such as radiofrequency or cryoablation may be used for larger, solitary lesions.
Chemoembolization can reduce tumor volume or assist in control of tumor growth while the patient awaits more definitive therapies, such as liver transplantation.

Summary - Implications for Clinical Practice

Patients at risk for HCC should be periodically screened via serum alpha-fetoprotein measurements and hepatic sonography.
Local resection should be considered, if possible, even in selected patients with associated liver cirrhosis.
Liver transplantation should be reserved for those with a tumor < 5 cm in diameter or those with </= 3 tumors, none of which is > 3 cm.
Local injections of ethanol can be used to destroy small HCC nodules.
Adjunctive therapies may be needed to control tumor growth while patients await more definitive therapies.

References

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Sarasin FP, Giostra E, Hadengue A. Cost-effectiveness of screening for detection of small hepatocellular carcinoma in western patients with Child-Pugh class A cirrhosis. Am J Med 1996;101:422-434.
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Henderson MJ. Primary therapy for HCC: resection vs transplantation [Symposium -- Hepatocellular Cancer]. Program and abstracts of the American College of Gastroenterology 64th Annual Scientific Meeting; October 16-20, 1999; Phoenix, Ariz.
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Adam R, Castaing D, Asoulay D, et al. Indications and results of liver transplantation in the treatment of hepatocellular carcinoma in cirrhosis. Ann Chir 1998;52:547-557.
DiBisceglie A. Adjuvant and palliative therapies for HCC [Symposium -- Hepatocellular Cancer]. Program and abstracts of the American College of Gastroenterology 64th Annual Scientific Meeting; October 16-20, 1999; Phoenix, Ariz.
Berger DH, Carrasco CH, Hohn DC, Curley SA. Hepatic artery chemoembolization or embolization for primary and metastatic tumors: post-treatment management and complications. J Surg Oncol 1995;60:116-121.