Hepatitis C Information Central

Adult primary liver cancer

General Information

Hepatocellular carcinoma is a tumor that is relatively uncommon in the United States; however, it is the most common cancer in some other parts of the world. Hepatocellular carcinoma is potentially curable by surgical resection, but surgery is the treatment of choice for only the small fraction of patients with localized disease.[1] Prognosis depends on the degree of local tumor replacement and the extent of liver function impairment. Therapy other than surgical resection is best administered as part of a clinical trial. Such trials evaluate the efficacy of systemic or infusional chemotherapy, hepatic artery ligation or embolization, and radiolabeled antibodies, often in conjunction with surgical resection and/or radiation therapy. In some studies of these approaches, long remissions have been reported.[1] Hepatocellular carcinoma should be distinguished from bile duct cancer (cholangiocarcinoma) as well as from metastatic cancer that originates in another organ.

Hepatocellular carcinoma is associated with cirrhosis in 50%-80% of patients; 5% of cirrhotic patients eventually develop hepatocellular cancer, which is often multifocal.

Hepatitis B infection [1,2] and Hepatitis C infection [3 appear to be the most significant causes of hepatocellular carcinoma worldwide, particularly in patients with continuing antigenemia and in those who have chronic active hepatitis.

Aflatoxin has also been implicated as a factor in the etiology of primary liver cancer in parts of the world where this mycotoxin occurs in high levels in ingested food.[2,4] Workers who were exposed to vinyl chloride before controls on vinyl chloride dust were instituted developed sarcomas in the liver, most commonly angiosarcomas. Other sarcomas of smooth muscular and vascular origin are also found.

The primary symptoms of hepatocellular carcinoma are those of an hepatic mass. Among patients with underlying cirrhotic disease, a progressive increase in alpha-fetoprotein (AFP) and/or in alkaline phosphatase or a rapid deterioration of hepatic function may be the only clue to the presence of the neoplasm. Infrequently, patients with this disease have polycythemia, hypoglycemia, hypercalcemia, or dysfibrinogenemia.

The biologic marker AFP is useful for the diagnosis of this neoplasm. By a radioimmunoassay technique, 50%-70% of patients in the United States who have hepatocellular carcinoma have elevated levels of AFP. However, patients with other malignancies (germ cell carcinoma and, rarely, pancreatic and gastric carcinoma) also demonstrate elevated serum levels of this protein. AFP levels have been shown to be prognostically important, with the median survival of AFP-negative patients significantly longer than that of AFP-positive patients.[5,6] Other prognostic variables include performance status and liver functions.[7]

Patients scheduled for possible resection require preoperative assessment with angiography in conjunction with helical computed tomographic (CT) scan or magnetic resonance imaging (MRI) with magnetic resonance angiography; these scans have obviated the need for most angiography. Information on the arterial anatomy is helpful for the operating surgeon and may eliminate some patients from consideration for resection. Dynamic CT and MRI scans can document the relationship of the tumor to the hepatic and portal veins (and, on occasion, involvement of these structures), delineating tumors for which the chances for surgical cure are remote.

References:

1. DiBisceglie AM, Rustgi VK, Hoofnagle JH, et al: NIH conference: hepatocellular carcinoma. Annals of Internal Medicine 108(3): 390-401, 1988.
2. Blumberg BS, Larouze B, London WE., et al: The relation of infection with Hepatitis B agent to primary hepatic carcinoma. American Journal of Pathology 81(3): 669-682, 1975.
3. Tsukuma H, Hiyama T, Tanaka S, et al: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. New England Journal of Medicine 328(25): 1797-1801, 1993.
4. Alpert ME, Hutt MS, Wogan GN, et al: Association between aflatoxin content of food and hepatoma frequency in Uganda. Cancer 28(1): 253-260, 1971.
5. Stillwagon GB, Order SE, Guse C, et al: Prognostic factors in unresectable hepatocellular cancer: Radiation Therapy Oncology Group study 83-01. International Journal of Radiation Oncology, Biology, Physics 20(1):65-71, 1991.
6. Izumi R, Shimizu K, Kiriyama M, et al: Alpha-fetoprotein production by hepatocellular carcinoma is prognostic of poor patient survival. Journal of Surgical Oncology 49(3): 151-155, 1992.
7. Yamashita Y, Takahashi M, Koga Y, et al: Prognostic factors in the treatment of hepatocellular carcinoma with transcatheter arterial embolization and arterial infusion. Cancer 67(2): 385-391, 1991.
8. Karl RC, Morse SS, Halpert RD, et al: Preoperative evaluation of patients for liver resection: appropriate CT imaging. Annals of Surgery 217(3): 226-232, 1993.

Cellular Classification

Malignant tumors of the liver are primarily adenocarcinomas, with two major cell types: hepatocellular and cholangiocarcinoma.

Histologic classification is as follows:

hepatocellular carcinoma

(liver cell carcinoma)

hepatocellular carcinoma

(fibrolamellar variant)

cholangiocarcinoma

(intrahepatic bile duct carcinoma)

mixed hepatocellular cholangiocarcinoma
undifferentiated

Hepatoblastoma rarely occurs in adults.

Note: The fibrolamellar variant is important because an increased proportion of these patients may be cured if the tumor can be resected. It is more frequent in young women.

Stage Information

The American Joint Committee on Cancer (AJCC) has designated TNM stages for liver cancer as follows: [1]

TNM Definitions

Primary tumor (T)

TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Solitary tumor 2.0 cm or less in greatest dimension without vascular invasion
T2: Solitary tumor 2.0 cm or less in greatest dimension with vascular invasion; or multiple tumors limited to one lobe, none more than 2.0 cm in greatest dimension without vascular invasion; or a solitary tumor more than 2.0 cm in greatest dimension without vascular invasion
T3: Solitary tumor more than 2.0 cm in greatest dimension with vascular invasion; or multiple tumors limited to one lobe, none more than 2.0 cm in greatest dimension, with vascular invasion; or multiple tumors limited to one lobe, any more than 2.0 cm in greatest dimension, with or without vascular invasion

T4: Multiple tumors in more than one lobe or tumor(s) involving a major branch of portal or hepatic vein(s)

Note: For classification, the plane projecting between the bed of the gallbladder to the inferior vena cava divides the liver into two lobes.

Regional lymph nodes (N)

NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis

Note: The regional lymph nodes are the hilar (i.e., those in the hepatoduodenal ligament, hepatic and periportal nodes). Regional lymph nodes also include those along the inferior vena cava, hepatic artery, and portal vein.Any lymph node involvement beyond these nodes is considered distant metastasis and should be coded as M1.

Distant metastasis (M)

MX: Presence of distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

Note: Metastases occur most frequently in bones and lungs.

AJCC Stage Groupings Stage 1

T1, N0, M0

Stage 2

T2, N0, M0

Stage 3

T1, N1, M0
T2, N1, M0
T3, N0, M0
T3, N1, M0

T4, any N, M0

any T, any N, M1

For purposes of treatment, patients with liver cancer are grouped as localized resectable , localized unresectable , or advanced disease. These groups are described with the following TNM correlations:

Localized Resectable

(T1, T2, T3, and selected T4; N0; M0)

This type of liver cancer is confined to a solitary mass in a portion of the liver that allows the possibility of complete surgical removal of the tumor with a margin of normal liver. Liver function tests are usually normal or minimally abnormal, and there should be no evidence of cirrhosis or chronic hepatitis. Only a small percentage of liver cancer patients will prove to have such localized resectable disease. Preoperative assessment that includes computed tomography and/or MR scanning should be directed toward determining the presence of extension of tumor across interlobar planes, involvement of the hepatic hilus, or encroachment on the vena cava. A resected specimen should contain a 1- to 2-centimeter margin of normal liver. Patients with chronic hepatitis and cirrhosis are at high risk when surgical resection is performed.

Localized Unresctable

(selected T2, T3, and T4; N0; M0)

This type of cancer appears to be confined to the liver, but surgical resection of the entire tumor is not possible despite a localized mass because of location within the liver or concomitant medical conditions (such as cirrhosis). Patients with locally unresectable fibrolamellar variant hepatomas may be considered for liver transplantation.[2-5]

Advanced

(any T, N1 or M1)

Advanced liver cancer is cancer that is present in both lobes of the liver or has metastasized to distant sites. Median survival is usually 2-4 months. The most common metastatic sites of hepatocellular cancer are the lungs and bone. Multifocal disease in the liver is common, particularly when cirrhosis or chronic hepatitis is present.

References:

1. Liver, (including intrahepatic bile ducts). In: American Joint Committee on Cancer: Manual for Staging of Cancer. Philadelphia: JB Lippincott Company, 4th ed., 1992, pp 89-91.
2. Farmer DG, Rosove MH, Shaked A, et al.: Current treatment modalities for hepatocellular carcinoma. Annals of Surgery 219(3): 236-247, 1994.
3. Ringe B, Wittekind C, Weimann A, et al.: Results of hepatic resection and transplantation for fibrolamellar carcinoma. Surgery, Gynecology and Obstetrics 175(4): 299-305, 1992.
4. Venook AP: Treatment of hepatocellular carcinoma: too many options? Journal of Clinical Oncology 12(6): 1323-1334, 1994.
5. Iwatsuki S, Starzl TE, Sheahan DG, et al.: Hepatic resection versus transplantation for hepatocellular carcinoma. Annals of Surgery 214(3):221-229, 1991.

Treatment Option Overview

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

Localized Resectable Adult Primary Liver Cancer T1, T2, T3, and selected T4; N0; M0

Treatment options:

Standard:

Surgery: Resection of the localized liver cancer varies from segmental resection to trisegmental (80%) resection. In series of carefully selected patients, partial hepatectomy has resulted in a 5-year survival of 10%-30%. Hepatic carcinoma is frequently multifocal and may involve multiple sites throughout the liver at the time of exploration, even when a dominant mass is found on preoperative assessment. Preoperative assessment should also include a search for extrahepatic metastases, since this condition will also preclude the planned hepatic resection. Resection that involves more than a wedge of liver is poorly tolerated (high mortality rate) in patients with cirrhosis or chronic active hepatitis. These are generally contraindications to major hepatic resection but may not contraindicate hepatic transplantation.[1-7]

Under clinical evaluation:

Because of the high proportion of patients who experience relapse following surgery for localized hepatic cancer, adjuvant approaches have been employed using regional arterial infusion of the liver or systemic therapy with chemotherapeutic agents. There are no data, thus far, that support improved survival with adjuvant approaches. Localized recurrences in the liver may occasionally be successfully treated by re-resection.[8]

References:

1. Starzl TE, Koep LJ, Weil R, et al: Right trisegmentectomy for hepatic neoplasms. Surgery, Gynecology and Obstetrics 150(2): 208-214, 1980.
2. Nagomey DM, van Heerden JA, Ilstrup DM, et al: Primary hepatic malignancy: surgical management and determinants of survival. Surgery 106(4): 740-749, 1989.
3. Iwatsuki S, Starzl TE, Sheahan DG, et al:: Hepatic resection versus transplantation for hepatocellular carcinoma. Annals of Surgery 214(3):221-229, 1991.
4. MacIntosh EL, Minuk GY: Hepatic resection in patients with cirrhosis and hepatocellular carcinoma. Surgery, Gynecology and Obstetrics 174(3): 245-254, 1992.
5. Farmer DG, Rosove MH, Shaked A, et al: Current treatment modalities for hepatocellular carcinoma. Annals of Surgery 219(3): 236-247, 1994.
6. Ringe B, Wittekind C, Weimann A, et al: Results of hepatic resection and transplantation for fibrolamellar carcinoma. Surgery, Gynecology and Obstetrics 175(4): 299-305, 1992.
7. Venook AP: Treatment of hepatocellular carcinoma: too many options? Journal of Clinical Oncology 12(6): 1323-1334, 1994.
8. Lai EC, Lo CM, Fan ST, et al: Postoperative adjuvant chemotherapy after curative resection of hepatocellular carcinoma: a randomized controlled trial. Archives of Surgery 133(2): 183-188, 1998.

Localized Unresectable Adult Primary Liver Cancer

Selected T2, T3, and T4; N0; M0

Patients whose tumors are localized but unresectable due to location in the liver, concomitant medical considerations (such as cirrhosis), or even limited bilateral tumors, may be candidates for cryosurgery. Survivals equivalent to resection have been reported.[1]

Clinical trials that use systemic chemotherapy, regional chemotherapy, and/or labeled or radiolabeled antibodies have demonstrated remission of unresectable hepatoma. Other approaches include hepatic artery ligation and embolization of the hepatic artery with gelfoam powder or muscle fragments and chemotherapy, usually adriamycin. These approaches often produce central tumor necrosis, reduction in tumor size, and relief of pain, but the benefits are usually transient. Hepatic artery ligation may offer the same benefit. However, any interference with arterial blood supply (including infusion chemotherapy) may be associated with significant morbidity and is contraindicated in the presence of portal hypertension or clinical jaundice. Liver function should be relatively unimpaired, and there should be no evidence of portal vein thrombosis in patients in whom these approaches are undertaken.

Treatment options:

1. Cryosurgery for localized, unresectable tumors.[1]

2. For selected patients with localized unresectable hepatoma, particularly patients with fibrolamellar hepatomas, liver transplantation may offer a potentially curative treatment option.[2,6]

3. Chemotherapy (regional infusion of the liver): Chemotherapeutic agents may be infused with a subcutaneous portal or implantable pump via a catheter placed in the hepatic artery. Older studies that use standard agents have demonstrated responses in 15%-30% of such cases, but newer agents and techniques (that is, biodegradable microspheres) have been evaluated in pilot trials,[7,9] as has regional chemotherapy with external-beam radiation therapy.[10] Many patients are not candidates for these approaches, which often require surgical intervention.

4. Systemic chemotherapy: Several centers are evaluating combination chemotherapy programs. Long remissions have rarely been reported, and no significant survival benefits have been conclusively demonstrated.[11,13]

5. Surgery, chemotherapy, and radiation therapy: These modalities may be combined in clinical trials for patients with a dominant hepatic mass and multifocal involvement with small amounts of tumor; surgical resection or cryosurgery of the mass may be followed by hepatic infusion of the remaining liver with chemotherapeutic agents alone or in combination with hyperthermia, radiation, or radiation with radiosensitizers.[1,11,13] Chemotherapy plus radiation has also been used to shrink tumors prior to resection.[14]

6. Intratumoral injection of alcohol for small (< 2 centimeters) tumors.[15]

7. Other approaches include the use of radiosensitizers and external-beam radiation therapy without chemotherapy. The relative radiosensitivity of normal liver tissue compared with tumor tissue must always be considered when radiation therapy is contemplated[16]

1. Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Seminars in Surgical Oncology 14(2): 171-174, 1998.
2. Iwatsuki S, Starzl TE, Sheahan DG, et al.: Hepatic resection versus transplantation for hepatocellular carcinoma. Annals of Surgery 214(3):221-229, 1991.
3. Haug Ce, Jenkins RL, Rohrer RJ, et al: Liver transplantation for primary hepatic cancer. Transplantation 53(2): 376-382, 1992.
4. Farmer DG, Rosove MH, Shaked A, et al.: Current treatment modalities for hepatocellular carcinoma. Annals of Surgery 219(3): 236-247, 1994.
5. Ringe B, Wittekind C, Weimann A, et al.: Results of hepatic resection and transplantation for fibrolamellar carcinoma. Surgery, Gynecology and Obstetrics 175(4): 299-305, 1992.
6. Vennok AP: Treatment of hepatocellular carcinoma: too many options? Journal of Clinical Oncology 12(6): 1323-1334, 1994.
7. Ensminger WD, Niederhuber JE, Dakhil J, et al.: Totally implanted drug delivery system for hepatic arterial chemotherapy. Cancer Treatment Reports 65(516): 393-400, 1981.
8. Dakhil S, Ensminger WD, Cho K, et al.: Improved regional selectivity of hepatic arterial BCNU with degradable microspheres. Cancer 50(4): 631-635, 1982.
9. Choi BI, Kim HC, Han JK, et al.: Therapeutic effect of transcatheter oily chemoembolization therapy for encapsulated nodular hepatocellular carcinoma: CT and pathologic findings. Radiology 182(3): 709-713, 1992.
10. Epstein B, Ettinger D, Leichner PK, et al.: Multimodality cisplatin treatment in nonresectable alpha-fetoprotein-positive hepatoma. Cancer 67(4): 896-900, 1991.
11. Falkson G, Moertel CG, Levin P, et al: Chemotherapy studies in primary liver cancer. Cancer 42(5): 2149-2156, 1978.
12. Olweny CLM, Katongole-Mbiddle E, Bahendeka S, et al: Further experience in treating patients with hepatic cellular carcinoma in Uganda. Cancer 46(12): 2717-2722, 1980.
13. Choi TK, Lee NW, Wong J: Chemotherapy for advanced hepatocellular carcinoma. Cancer 53(3): 401-405, 1984.
14. Sitzmann JV, Abrams R: Improved survival for hepatocellular cancer with combination surgery and multimodality treatment. Annals of Surgery 217(2): 149-154, 1993.
15. Livraghi T, Bolondi L, Lazzaroni S, et al.: Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis: a study on 207 patients. Cancer 69(4): 925-929, 1992.
16. DiBisceglie AM, Rustgi VK, Hoofnagle JH, et al: NIH conference: hepatocellular carcinoma. Annals of Internal Medicine 108(3): 390-401,1988.

Advanced Adult Primary Liver Cancer

Any T, N1 or M1 There is no standard therapy for advanced metastatic liver cancer. Such patients should be considered candidates for clinical trials exploring the usefulness of new biologicals or antitumor drugs (phase I and II studies) or combinations of existing drugs, radiosensitizers, and radiation therapy. Palliation may sometimes be achieved in such studies.

External-beam radiotherapy and chemotherapy followed by radiolabeled polyclonal antiferritin antibody produces objective response in up to 50% of patients,1 but it is a localized treatment and does not address the question of systemic disease.

References

1. Order SE, Stillwagon GB, Klein JL, et al: Iodine 131 antiferritin, a new treatment modality in hepatoma: a Radiation Therapy Oncology Group study. Journal of Clinical Oncology 3(12): 1573-1582, 1985.

Recurrent Adult Primary Liver Cancer

The prognosis for any treated primary liver cancer patient with progressing, recurring, or relapsing disease is poor. The question and selection of further treatment depends on many factors, including prior treatment, site of recurrence, presence of cirrhosis, and hepatic function as well as individual patient considerations. Resection may be possible; when feasible, prolonged survival can be attained, but most patients experience recurrence in the liver.[1] Clinical trials are appropriate and should be considered whenever possible.

References:

1. Tuttle TM, Curley SA, Roh MS: Repeat hepatic resection as effective treatment of recurrent colorectal liver metastases. Annals of Surgical Oncology 4(2): 125-130, 1997.