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Adult primary liver cancer


Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
TNM definitions
AJCC stage groupings
Stage I
Stage II
Stage IIIA
Stage IIIB
Stage IVA
Stage IVB
Localized resectable
Localized unresectable
Advanced
TREATMENT OPTION OVERVIEW
LOCALIZED RESECTABLE ADULT PRIMARY LIVER CANCER
T1, T2, T3, and selected T4; N0; M0
LOCALIZED UNRESECTABLE ADULT PRIMARY LIVER CANCER
Selected T2, T3, and T4; N0; M0
ADVANCED ADULT PRIMARY LIVER CANCER
Any T, N1 or M1
RECURRENT ADULT PRIMARY LIVER CANCER

GENERAL INFORMATION

Hepatocellular carcinoma is a tumor that is relatively uncommon in the United States, although its incidence is rising.[1] 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.[2] 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.[2] 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% to 80% of patients; 5% of cirrhotic patients eventually develop hepatocellular cancer, which is often multifocal.

Hepatitis B infection [2,3] and hepatitis C infection [4] 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. A series found that male patients older than 50 years of age who have both hepatitis B and hepatitis C infection may be at particularly high risk for hepatocellular cancers.[5][Level of evidence:3iii]

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.[3,6] 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 a 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% to 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.[7,8] Other prognostic variables include performance status and liver functions.[9]

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.[10] Laparoscopic evaluation may detect metastatic disease, bilobar disease, or inadequate liver remnant, and therefore obviate the need for open surgical exploration.[11]

References:

  1. El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma in the United States. New England Journal of Medicine 340(10): 745-750, 1999.

  2. Mor E, Kaspa RT, Sheiner P, et al.: Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Annals of Internal Medicine 129(8): 643-653, 1998.

  3. Blumberg BS, Larouze B, London WT., et al.: The relation of infection with hepatitis B agent to primary hepatic carcinoma. American Journal of Pathology 81(3): 669-682, 1975.

  4. 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.

  5. Chiaramonte M, Stroffolini T, Vian A, et al.: Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85(10): 2132-2137, 1999.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Lo CM, Lai EC, Liu CL, et al.: Laparoscopy and laparoscopic ultrasonography avoid exploratory laparotomy in patients with hepatocellular carcinoma. Annals of Surgery 227(4): 527-532, 1998.


CELLULAR CLASSIFICATION

Malignant tumors of the liver are primarily adenocarcinomas, with 2 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 cm or less in greatest dimension without vascular
invasion
T2: Solitary tumor 2 cm or less in greatest dimension with vascular
invasion; or multiple tumors limited to one lobe, none more than 2 cm
in greatest dimension without vascular invasion; or a solitary tumor
more than 2 cm in greatest dimension without vascular invasion
T3: Solitary tumor more than 2 cm in greatest dimension with vascular
invasion; or multiple tumors limited to one lobe, none more than 2 cm
in greatest dimension, with vascular invasion; or multiple tumors
limited to one lobe, any more than 2 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) or invasion of adjacent organs other
than the gallbladder or perforation of the visceral peritoneum

Note: For classification, the plane projecting between the bed of the gallbladder and the inferior vena cava divides the liver into 2 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. Involvement of the inferior phrenic lymph nodes should also be considered M1.

Distant metastasis (M)

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

Note: Metastases occur most frequently in bones and lungs. Tumors may extend through the capsule to the diaphragm.


AJCC stage groupings


Stage I

T1, N0, M0


Stage II

T2, N0, M0


Stage IIIA

T3, N0, M0


Stage IIIB

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


Stage IVA

T4, Any N, M0


Stage IVB

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 unresectable

(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 to 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: AJCC Cancer Staging Manual. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 97-101.

  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% to
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] Hepatic transplantation for
hemangioendothelioma, fibrolamellar hepatocellular carcinoma, and small
(<5 cm) hepatocellular carcinoma in patients with or without cirrhosis has
been associated with 5-year survivals of 20% to 30%.[8][Level of evidence:
3iiiA]

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.[9]

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. Nagorney 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. Pichlmayr R, Weimann A, Oldhafer KJ, et al.: Appraisal of transplantation for malignant tumours of the liver with special reference to early stage hepatocellular carcinoma. European Journal of Surgical Oncology 24(1): 60-67, 1998.

  9. 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, percutaneous ethanol injection, or radiofrequency ablation for cancers smaller than 5 centimeters. 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 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. Any interference with arterial blood supply (including infusion chemotherapy) may be associated with significant morbidity and is contraindicated in the presence of portal hypertension, portal vein thrombosis, or clinical jaundice.

Treatment options:

1. Cryosurgery, percutaneous ethanol injection, or radiofrequency ablation for small (<5 cm), localized, unresectable tumors.[1,2]

2. For selected patients with localized unresectable hepatoma, particularly patients with fibrolamellar hepatomas, liver transplantation may offer a potentially curative treatment option.[3-7]

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% to 30% of such cases, but newer agents and techniques (that is, biodegradable microspheres) have been evaluated in pilot trials,[8-10] as has regional chemotherapy with external-beam radiation therapy.[11] Many patients are not candidates for these approaches, which often require surgical intervention.

4. Systemic chemotherapy: Durable remissions have rarely been reported, and no significant survival benefits have been conclusively demonstrated.

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] Chemotherapy plus radiation has also been used to shrink tumors prior to resection.[12]

6. Intratumoral injection of alcohol.[13,14]

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.[15]

8. Radiofrequency tissue ablation.[16]

References:

  1. Zhou XD, Tang ZY: Cryotherapy for primary liver cancer. Seminars in Surgical Oncology 14(2): 171-174, 1998.

  2. Livraghi T, Goldberg SN, Lazzaroni S, et al.: Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology 210(3): 655-661, 1999.

  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. Haug CE, Jenkins RL, Rohrer RJ, et al.: Liver transplantation for primary hepatic cancer. Transplantation 53(2): 376-382, 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. 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.

  9. Dakhil S, Ensminger WD, Cho K, et al.: Improved regional selectivity of hepatic arterial BCNU with degradable microspheres. Cancer 50(4): 631-635, 1982.

  10. 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.

  11. Epstein B, Ettinger D, Leichner PK, et al.: Multimodality cisplatin treatment in nonresectable alpha-fetoprotein-positive hepatoma. Cancer 67(4): 896-900, 1991.

  12. Sitzmann JV, Abrams R: Improved survival for hepatocellular cancer with combination surgery and multimodality treatment. Annals of Surgery 217(2): 149-154, 1993.

  13. 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.

  14. Livraghi T, Benedini V, Lazzaroni S, et al.: Long term results of single session percutaneous ethanol injection in patients with large hepatocellular carcinoma. Cancer 83(1): 48-57, 1998.

  15. Di Bisceglie AM, Rustgi VK, Hoofnagle JH, et al.: NIH conference: hepatocellular carcinoma. Annals of Internal Medicine 108(3): 390-401, 1988.

  16. Goldberg SN, Gazelle GS, Solbiati L, et al.: Ablation of liver tumors using percutaneous RF therapy. American Journal of Roentgenology 170(4): 1023-1028, 1998.


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 radiation therapy 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. Re-resection should be considered when feasible, but most patients experience recurrence, typically in the liver.[1] When re- resection is not possible, treatment options for patients with recurrent hepatocellular cancer may include the use of transarterial oily chemoembolization (TOCE), percutaneous ethanol injection therapy (PEIT), chemotherapy, or liver transplantation.[2] At a single institution in Hong Kong, 244 consecutive patients treated with curative resection were followed for intrahepatic recurrence. Of the 244 patients followed, 139 patients did not develop intrahepatic recurrence and had 1-, 3-, and 5-year survival rates of 87%, 79%, and 74%, respectively. Of the 105 patients who developed subsequent intrahepatic recurrences, 11 patients were treated with re-resection and had 1-, 3-, and 5-year survival rates of 81%, 70%, and 69%, respectively; 71 patients were treated with TOCE and had 1-, 3-, and 5-year survival rates of 72%, 38%, and 20%, respectively; 6 patients were treated with PEIT and had 1-, 3-, 5-year survival rates of 67%, 22%, 0%, respectively; the remaining 17 patients had either systemic chemotherapy or conservative treatment, and had no survivors at 3 years.[2][Level of evidence: 3iiA] Clinical trials are appropriate and should be considered whenever possible.

References:

  1. Shimada M, Takenaka K, Taguchi K, et al.: Prognostic factors after repeat hepatectomy for recurrent hepatocellular carcinoma. Annals of Surgery 227(1): 80-85, 1998.

  2. Poon RT, Fan ST, Lo CM, et al.: Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors. Annals of Surgery 229(2): 216-222, 1999.

Date Last Modified: 11/1999



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