Liver Cancer

Epidemiology

Hepatocellular carcinoma is the most common malignancy in Southeast Asia and in Africa with 1 million new cases each year. In Western Europe and the US the incidence is 3 per 100,000 inhabitants. In China hepatic carcinoma has become the second cause of death by cancer. Liver cancer is unusual in Europe. In Europe standardized incidence by age group is 7 per 100,000 men and 2 women per 100,000 justifying almost 2% of all cancers.).

In Romania in 1996 the incidence was 7.2 in 100.0000 inhabitants and the mortality rate of 9 per 100,000.

In Romania the estimated incidence for 2000 was 8.74 per 100,000 population and mortality of 9.21 per 100,000 inhabitants.

Risk Factors

1) viral hepatitis infections B, C and cirrhosis. Liver cancer is associated with cirrhosis in 50-80% of patients. 5% of cirrhotic patients eventually develop hepatocellular cancer. Infection with hepatitis B and C appears to be the most significant cause of liver cancer, especially in patients with permanent antigenemia and in those with chronic hepatitis aggressive. B virus infection results from infection at birth or in childhood affects individuals 40 years or younger. B virus chronic carriers at risk 100 times more likely to develop liver cancer compared with non-carriers, which decreases if the infection was acquired in adult life. At an increased risk of liver cancer patients are older than 50 years with both viruses present. There is evidence that patients with both infections who consume more than 80 grams of alcohol per day have an increased risk of developing liver cancer compared with patients who did not consume alcohol. People carrying the virus B with first degree relatives with type B hepatitis and hepatocellular cancer is associated with an increased risk of developing liver cancer. B virus infection can be prevented by vaccination. Preventing C virus infection is based on the prevention of transmission of infection by blood transfusion or blood products. Vaccination is not for the virus C.

2) chemical carcinogens (aflatoxin B) fungus Aspergillus flavus Aflatoxin produced under certain conditions of heat and humidity has been implicated as etiologic factor in primary liver cancer in some countries where this mycotoxin occurs in food ingested in large quantities (stored grain) . Exposure to aflatoxin may be synergistic with hepatitis B virus infection

Workers who were exposed to vinyl chlorides developed liver sarcomas.

3. Obesity in the US appears to be an important risk factor for liver cancer and is the main contributor nonalcoholic liver fybrosis which may be linked to a rise in hepatocellular cancer.

4. Iron overload (hemochromatosis) due to hemochromatosis in some patients untreated was associated with an increased risk of death from liver cancer by up to 45%.

5. Insulin resistance syndrome that is manifested by obesity and diabetes appears as a risk factor. Diet rich in vegetables may decrease the risk of liver cancer.

6. Oral contraceptives and anabolic androgenic steroid use are risk factors minors.

Histology types

I. malignant epithelial tumors

1) Hepatocellular carcinoma 90%

2) Hepatocellular fibrolamellar carcinoma 1%

3) Hepatoblastoma

4) Peripheral cholangiocarcinoma and carcinoma colangiocelular 10%

5) Liver cystadenocarcinoma, squamous cell carcinoma

II. Malignant mesenchymal tumors (rare)

– angiosarcoma, hemangioendoteliosarcom

– leiomyosarcoma, fibrosarcoma

– mesenchymal sarcoma

III. Metastatic Tumors

The tumors that metastasize to the liver most often during their natural evolution are: melanoma, bladder, colon tumors, pancreas and breast carcinoma. As absolute numbers, metastases occur most frequently in decreasing order: lung, colon, pancreatic, breast, gastric.

Signs and symptoms:

– Pain in the right upper quadrant or right shoulder,

– Weight loss, loss of appetite,

– Fever, liver tumor,

– Signs decompensated cirrhosis (ascites, edema, jaundice, hepatomegaly, splenomegaly).

Paraneoplastic syndromes

1. Hypoglycemia

2. Hypercalcaemia

3. Erythrocytosis in 3-12%

4. Hypercholesterolemia in 10-40%

5. Disfibrinogenemia

6. Carcinoid syndrome

7. Late cutaneous porphyria

8. Sexual change:  gynecomastia, testicular atrophy and early puberty

9. Increase globulin- binding- tyroxine.

Tumor markers:

Alpha Feto protein (AFP) is the best tumor marker for HCC (HCC).

60-70% of patients with HCC had AFP values> 20 mg / l, although diagnostic values ​​must be greater than 500μgl. It is recommended that the diagnosis of HCC to be considered and ultrasonography performed at alfaFP values> 20μg / l but

Des-gamma-carboxy prothrombin is increased to 91% of patients with HCC. It can help in the diagnosis of HCC alfaFP not secret.

Increased gamma-glutamyl transpeptidase is associated with poor prognosis.

Screening

Patients at high risk include: HBs Ag positive patients for HCV, patients with chronic active hepatitis, cirrhotic patients (HCV, HBsAg, alcohol, hemochromatosis antitrypsin deficiency, biliary cirrhosis stage IV) infection with HBV or HCV childhood

In high-risk patients are recommended: alpha fetoprotein determination (AFP) and ultrasonography every 6 months to 6-12 months. If the node is highlighted liver forth, depending on its size follow the diagnosis algorithm. If you find an increase in AFP is recommended evaluating the liver by imaging (abdominal ultrasound, CT / MRI liver). If it finds hepatic node follow the diagnostic algorithm. Unless nodules in the liver are highlighted follow by AFP and liver imaging at 3 months.

The screening is valuable in detecting HCC in an early stage resection rate increases and prolongs survival with a cost / efficiency acceptable.

The diagnosis of hepatic nodules

The node is discovered incidentally or hepatic screening. If the nodule is <1 cm is performed CT / MRI at 3-6 months. If the nodule is stable tracking imaging continues 3-6 months. If the nodule grows and is between 1-2cm or ≥ 2 cm is recommended liver biopsy or FNA. If confirmed positive HCC is subject to further treatment. If negative seeks further by repeating imaging and biopsy.

In patients with intrahepatic lesions in ultrasound or CT and normal levels of AFP and not suitable for curative treatment, but are candidates for palliative treatment is needed fine needle biopsy tumor.

In patients who do not consider palliative treatment is not recommended because of the risk of bleeding puncture tumor, tumor rupture and tumor seeding

Diagnosis and staging are based on:

– History, clinical examination,

– Blood count, liver tests

– Tumor markers (alphafetoprotein> 500μg / dl)

– Abdominal ultrasound, Doppler ultrasonography,

– Abdominal CT, magnetic resonance imaging (MRI)

– Chest radiography, bone scintigraphy if indicated

Staging T.N.M

Primary Tumor (T)

Tx – primary tumor cannot be evaluated

T0- no evidence of primary tumor

≤ 2cm tumor T1 Solitary without vascular invasion

≤ T2 solitary 2cm tumor with vascular invasion

– multiple tumors in one lobe, ≤ 2 cm without vascular invasion

– solitary tumor> 2 cm without vascular invasion

-T3- solitary tumor> 2 m, with vascular invasion

– multiple tumors in one lobe, ≤ 2cm with vascular invasion

– multiple tumors in a single lobe,> 2cm, with or without invasion of the vascular

-T4- multiple tumors in more than one lobe

– invasion of a major branch of the portal vein or liver

– visceral peritoneum perforation

Regional lymph nodes (N)

Nx- regional lymph nodes cannot be assessed

N0- no regional lymph node metastases

Regional lymph node metastases N1-

Distant metastasis (M)

MX distant metastasis cannot be assessed

M0- no distant metastases

Distant metastasis M1 shows

Stages:

St. T1 N0 M0 I

St.II T2 N0 M0

St.III T3 N0 M0 A

St.III T1 N1 M0 B

                          T2 N1 M0

                          T3 N1 M0

St.IV A T4 any N M0

St.IV Any T Any N B M1

TREATMENT

After evaluation the following circumstances exist:

I. operable disease or transplant

II. Inoperable disease

III. Local disease but inoperable due to comorbidities or bad performance status

IV. Metastatic disease

I. operable disease or transplantation (through performance status or comorbidities)

Tumor resection is recommended:

– Child-Pugh class A, B

– Without portal hypertension

– Adequate tumor location

– Adequate hepatic reserve

– Suitable outstanding liver

It is recommended transplatul if UNOS is eligible and meets the criteria:

– A tumor ≤ 5 cm or 2-3 tumors ≤ 3 cm each

– No macrovascular invasion

– No extrahepatic disease

If it is not eligible for transplant tumor resection is recommended.

– Tracking is done by imaging and AFP to 3 months in the first 2 years, then every 6 months and annually thereafter next 3 years

II. Unresectable

Treatment options:

– Sorafenib (Child-Pugh class A and class B-category)

– Chemotherapy plus radiotherapy in the context of a clinical trial

– Locoregional therapy

– Supportive therapy

– Systemic and intra-arterial chemotherapy in a clinical trial

– Stereotactic conformal radiotherapy in clinical trial

III. Local disease but inoperable due to comorbidities or bad performance status

Treatment options:

– Sorafenib (Child-Pugh class A and class B-category)

– Clinical trial

– Locoregional therapy

– Supportive therapy

– Stereotactic conformal radiotherapy in clinical trial

IV metastatic disease

Treatment options:

– Sorafenib (Child-Pugh class A and class B-category)

– Supportive therapy

– Clinical trial

Therapeutic indication

a) Patients with normal or increased liver size, absence or controlled ascites, encephalopathy and without laboratory tests indicate that PP> 60% albumin> 3 g / dl, TGP <150ui / l and the retention rate green indocyanine (ICG) is greater than 0.8 mg / kg / minute, liver resection is recommended.

b) In patients with small liver, untreatable ascites, encephalopathy, laboratory tests indicate that PP <60% albumin <3 g / dl, GPT> 150 IU / l do not recommend surgery.

Stage I, II and III A

a) For small tumors (≤5cm) and compensated liver function liver resection is recommended.

In patients with a contraindication to surgical treatment is recommended cryosurgery or ethanol injection.

Class 5-6 points: Risk good operator

Class B 7-9 points: Risk Moderate operator

Class C 10-15 points: Risk badly operator

b) For tumors> 5 cm localized with compensated liver function, liver resection is recommended.

c) For localized tumors unresectable hepatic artery chemoembolisation is recommended. It can be associated radiotherapy.

d) For multiple tumors, recommend chemoembolization of the hepatic artery.

e) For patients with hepatic carcinoma and decompensated cirrhosis are recommended symptomatic treatment.

Stage III B and IV A

Regional chemotherapy is recommended catheter inserted into the hepatic artery or systemic chemotherapy depending on the patient’s condition.

Stage IV B. Systemic chemotherapy is recommended or symptomatic depending on the patient’s condition

Therapeutic Methods

Surgery

Surgical resection provides the best results. Only 10% are resectable solitary HCC.

For large liver tumors practice lobectomy. Survival at 5 years is 20-30%.

For small liver tumors (<5cm) 5-year survival rate is 50-60%. In patients with unresectable HCC cytoreductive recommended by hepatic artery catheterization and its ligature followed by administration of chemotherapy: cisplatin, adriamycin, 5 or Floxuridine FUR. If there is a marked decrease in tumor sequential tumor resection is recommended.

Liver transplantation has been shown effective for small tumors (<4 cm) with a 5-year survival of 57%. It is indicated only for tumors T1 and T2 some limited to a lobe without vascular invasion. After curative resection 5-year recurrence rate is 60-70%. Therefore it is necessary to follow patients through determination and ultrasound alfafetoproteinei 2-3 months for 5 years.

Chemoembolisation transcatheter arterial using the Seldinger technique is indicated for the treatment of unresectable HCC (st.II, IIIA, IIIB) with acceptable liver function. Useful agents for embolization are LIPIODOL and gelatin absorbable. As cytostatic agents are used 2 or 3 of these chemotherapy: cisplatin, Adriamycin, 5 FUR, Mitomycin C is repeated 1-3 months. 3-6 courses are normally required to control the tumor. The survival to 5 years with this method is 7-20%.

Guided percutaneous ethanol injection intralesional ultrasound is used in patients with 1-3 nodules <3 cm in greatest diameter, with surgical contraindication. Inject 10-20 ml sterile ethanol 3x / week 12 administration. In hepatocarcinoma high (> 5cm) is not recommended. Instead ethanol can be given 15-50% acetic acid. Survival at 5 years is similar to that obtained by surgical resection.

Palliative radiotherapy has limited value. The doses used are 25-30 Gy whole liver with pain relief in 80% of patients. It is used in unresectable hepatocellular carcinoma.

Joined external radiotherapy 21Gy 5 FUR 500 mg / m2 and doxorubicin 15mg / m2 / day on days 1, 3, 5, 7 with a partial response rate of 25%. It is used in patients with unresectable disease.

Systemic chemotherapy

Currently there is no treatment protocol that can be recommended as standard treatment.

The most commonly used chemotherapy response rates were below 20%:

– Doxorubicin response rate of 20%

– Cisplatin response rate of 10%

– May FUR response rate of 9%

– Mitoxantrone with response rate of 10%.

There was no difference in survival between patients receiving chemotherapy and those untreated.

It can be used:

– Doxorubicin 50 mg / m2 i.v. day 1, repeated 3 weeks

– May FUR 500mg / m2 / day IV days 1-5, repeated 3 weeks

As a combination of chemotherapeutic agents can use the scheme proposed by Leung:

FUR 5 400 mg / m2 / day 1-4 days,

Doxorubicin 40 mg / m2 / day on day 1,

Cisplatin 20mg / m2 days 1-4

Repeat in 3 weeks with a response rate of 28%.

Regional Chemotherapy is used in patients with unresectable disease limited to the liver with adequate renal and hepatic function.

Intra-arterial chemotherapy produces response rate of 30-50%. The principle of the method is to administer chemotherapy drug in the tumor region containing artery that supplies that area. The catheter is placed through the Seldinger technique liver path femoral artery or when laparotomy. Cytostatic drugs most used are: 5 FUR, Floxuridine, Doxorubicin, Cisplatin. Side effects are: cholangitis and myelosuppression.

Intra-arterial chemotherapy after resection of liver purposes adjuvant resulted in better survival than in untreated patients postoperatively.

Sorafenib (NEXAVAR)

Sorafenib inhibits tumor growth by blocking the activity of serine / threonine and receptor tyrosine kinases in both the tumor cells located in the tumor vasculature as well.

The liver metabolizes and eliminates mainly feces, unchanged in 51%. The half-life is 24-48 hours.

Avoid use in patients with unstable coronary artery disease or recent heart attack. Gastrointestinal perforation can occur rarely as a side effect, in which case discontinue treatment. Hand-foot syndrome and rash are the most common side effects. They occur during the 6th week of treatment. Bleeding may occur and require discontinuation. Hypertension occurs early during treatment, especially in week 6 of treatment. In case of severe hypertension despite antihypertensive therapy discontinue treatment with sorafenib. It is conditioned 200mg tablet form. The daily dose is 400mg (2 tb) twice a day 1 hour before or 2 hours after meals.

Tamoxifen. About 40% of HCC patients have estrogen receptors. Studies showed no differences in survival between patients treated with doses tamoxifen 40mg / day and untreated patients.

Prognostic

1. The number and size of tumor lesions. The survival to 5 years vermiform <5 cm is 40-45%, 15-25% of multiple tumors and 10% for tumors> 5 cm.

2. Vascular invasion. Thrombosis of the portal vein or liver tumor has a poor prognosis.

3. Type of resection. Survival at 5 years for patients with curative resection was 55% and 5% for patients with non-curative resection.

4. Unfavorable prognostic factors:

–  cirrhosis

–  lymph node metastases

– Increased prothrombin time

– Males

– Age> 60 years

– bad performance status.

– Duration of symptoms <3 months

– Tumor rupture

– Aneuploidy

– High percentage of cells in S phase

Survival

Patients with liver cancer have a very poor prognosis. Relative survival for adults diagnosed during 1990-1994 was 24% at 1 year and 7% at 5 years. Survival at 5 years was slightly higher, 20% in patients under 45 years. Between 1983 1994 5-year survival increased from 4% to 9% for both sexes.

Survival at 5 years for patients treated with hepatic resection was 30-50%.

Palliative Surgery (cryosurgery or hepatic artery ligation associated with hepatic artery catheterization) has obtained a 5-year survival of 10-20%.

Chemoembolisation of the hepatic artery determined 5-year survival of 7-10%.

External or internal radiation therapy with 30Y microspheres resulted in 5-year survival of 7-10%.

Cytostatic agents cytoreductive about pressure resulted in a reduction of tumor resection followed by sequential and obtained a 5-year survival of 50-60%.

Patient tracking is done through history, clinical examination, transaminases, alkaline phosphatase, alphafetoprotein, abdominal ultrasound every 6 months to 2 then the next 3 years and then every year based on diagnosis algorithm. Recommend abdominal C. T. in patients after 6 months if they have had complete resection.