Liver Cancer

"We fight liver cancer with a quiver full of arrows."

-- Dr. Mark Roh

WHAT IS THE LIVER?

The liver is the largest gland in the body (approximately 1500 grams) and is located in the right upper quadrant of the abdomen. It is glossy in appearance and dark red in color from the rich supply of blood flowing through it. Approximately 25% of the cardiac output flows to the liver.






Anatomy of the Liver

Theanterior surface of the liver is triangular in shape, made of two lobes. The right lobe is the larger of the two, measuring 6 to 7 inches in length. The left lobe is 3 inches in length.




Ligaments connect the upper surface of the liver to the diaphragm and the abdominal wall and the under surface to the stomach and duodenum. The gall bladder is located on the under surface of the right lobe of the liver. Neighboring organs include the colon, the intestines, and the right kidney.




The Liver Up Close

When viewed under a microscope, the liver is seen as large network of units called hepatic lobules. The hepatic lobule is very small and looks like a six-sided cylinder.






The lobule itself is surrounded by connective tissue and has 5 to 7 clusters of vessels around its edges. These vessels include a branch of the portal vein, a branch of the hepatic artery, and a bile duct.

A central vein runs through the middle of the lobe and is surrounded by cords of liver cells that radiate out in all directions. Between these cords are wide thin-walled blood vessels called sinusoids. All of the blood drains into a hepatic vein which then circulates throughout the body.

Below is a biopsy from a normal liver. The white arrows demonstrate the hepatic sinusoids and the dark arrow represents the portal pedicle. Blood flows into the liver through the portal pedicle, past the hepatic sinusoids (which contain normal liver cells called hepatocytes) into the central vein and then out of the liver.



Function of the Liver

Sometimes referred to as the great chemical factory of the body, the liver creates, regulates, and stores a variety of substances used by thegastrointestinal system, and it serves a number of important digestive functions.






HOW LIVER CANCER DEVELOPS?
Primary liver (hepatocellular) cancer is often related with hepatitis B and hepatitis C virus infection. Infection leads sequentially through chronic hepatitis, cirrhosis, to hepatocellular carcinoma (HCC).
Cirrhosis itself is a risk factor for HCC, irrespective of etiology. Almost 80% of HCCs occur in cirrhotic livers. This association has led many to look at the influence of alcohol on HCC etiology, and alcohol consumption, particularly when combined with smoking, shows a strong influence on HCC incidence.
Other etiologic factors include aflatoxins, which are derived from the fungus Aspergillus flavus in poorly stored grain crops.
Metastatic liver cancer is resulted from cancer of other organs. Colon-rectal cancer is the most common source of metastatic liver cancer.

HOW TO DETECT LIVER CANCER?
Symptoms

Early stages of cancer can be asymptomatic and may go undetected for months or even years. When symptoms do develop, they are most pronounced as pain.

Pain associated with cancer is a result of several possibilities: invasion or destruction of normal tissue with cancer cells; stretching of internal tissue by tumor growth; pressure of tumor on an organ; blockage of a vital passageway by the tumor; and infection caused by cancer.



Other symptoms may include loss of appetite, loss of weight, fever of unknown origin, limb weakness, sensory loss, or an absence of tendon reflexes in the limb.

Liver cancer, both primary and metastatic, often exhibits symptoms of general malaise as well as pain and tenderness. The discomfort is usually of a moderate degree and most often in the upper or upper right part of the abdomen. In more advanced cases, symptoms of jaundice, a yellowing of the skin and eyes, may also appear.

Frequently, patients with liver tumors are asymptomatic (have no symptoms). The diagnosis is made during an examination as part of a routine follow-up after cancer treatment. If a patient with colon cancer is going to develop metastatic disease in the liver, this will occur most likely within two years. Occasionally patients with liver tumors will develop symptoms such as pain, abdominal fullness, fever, or jaundice.

When your primary care physician finds a reason to suspect cancer in the liver, you will be advised to undergo a series of diagnostic tests. Some of these tests are noninvasive and require a brief visit to a clinic or lab. Others are more involved and may require an overnight stay in a hospital.

Blood Tests
A series of blood test are ordered to determine your general state of health and the health of your liver.

Additional blood tests, usually referred to as Liver Function Tests, may be used to determine the overall functional condition of your liver. Your liver must be in satisfactory functional condition to be able to tolerate treatment.

Tumor markers are of significant value for diagnosis of liver cancer, and can offer specific information about liver cancer. AFP test which will measure the level of alpha fetoprotein (AFP), CEA test will detect the level of carcinoembryonic antigen (CEA).

AFP is produced in the fetus but decreases steadily and becomes normal by 6 - 12 months of age. This substance is produced by patients with hepatocellular carcinoma or germ cell tumors. Approximately 70 - 90% of patients with hepatocellular carcinoma will have levels that range from above normal (greater than 20 ng/ml) to 10,000,000 ng/ml. A small elevation in AFP may occur in patients with non-malignant disease such as cirrhosis or viral hepatitis. Like CEA, AFP is used to monitor the effectiveness of cancer treatment in patients with hepatocellular carcinoma and germ cell tumors. Increasing levels of these markers is associated with tumor growth, but the absence of an elevation can not be interpreted as an absence of tumor.

CEA is a protein that is normally produced in the fetus during the first two trimesters of pregnancy. It is also produced by adenocarcinomas of the digestive system (such as the colon and rectum, pancreas, stomach), lung, and breast. The highest levels of CEA are seen in patients with liver metastases from colon cancer. Serial measurements of CEA during treatment provide important information on the efficiency of treatment. After undergoing treatment for colon cancer the CEA level should return to normal. If the treatment is incomplete, the CEA will not become normal.

The most common use for CEA is to monitor patients for the early detection of recurrent or metastatic cancer. By detecting metastatic cancer early, the treatment options are greater and more successful. Unfortunately, not all patients with cancer will have elevated CEA levels. Discuss your CEA results with your physician and determine if CEA monitoring can be helpful in your care. A normal level for a non-smoker is <~3 ng/ml and 3 - 5 ng/ml for a smoker.

Ultrasound
Most ultrasound tests take only a few minutes and results are obtained immediately. In patients with liver tumors, ultrasound is used to locate and measure the size of a tumor and to determine if it is solid or cystic.

In addition, ultrasound is an important modality that is used at the time of surgery and is called intraoperative ultrasound. This examination should be performed on all patients who undergo a surgical procedure on the liver. It will identify all of the tumors within the liver and clarify the relationship to blood vessels in the liver. The probe is placed directly on the liver at the time of surgery. This test provides critical information that will influence the treatment strategy.




T-Scan or MRI

Results from CT or MRI scans may reveal tumors and aid in determining the number and location. They can also detect organ disorders or abnormal structures, blocked ducts, and abnormal tissues.




Liver Biopsy
Often times a liver biopsy will be ordered because it provides reliable information for a cancer diagnosis. A biopsy involves the collection of a small tissue sample that is then examined under a microscope. Biopsies may be assisted by ultrasound or CT scans or may be performed using a laparoscope.


Colonoscopy and Laparoscopy
Colonoscopy may be ordered if there is reason to suspect primary colorectal cancer or if patients have had colon cancer in the past. A colonoscope is a highly flexible instrument used to examine the entire length of the colon. The instrument is a tiny viewing camera that gives off light and allows the physician to see inside the patient's colon. During colonoscopy, a small tissue sample will be obtained for laboratory analysis (called a biopsy).

Laparoscopy is similar to colonoscopy except that it uses an instrument called a laparoscope. The laparoscope is a small tube-like device used primarily for examining the liver and pancreas. For this test, a small cut is made in the abdomen to insert the instrument. The surgeon may use this opportunity to perform a biopsy.

Staging of Liver Cancer

Each type of cancer has specific staging criteria. In general the different stages can be summarized as follows:

Stage I: Localized and Resectable
Tumor is found in one location of the liver and could be treated surgically.

Stage II: Localized and Possibly Resectable
Primary tumor is found in one or more locations in the liver and may be treated surgically. The decision to surgically treat the disease will depend upon the experience of the physician.

Stage III: Advanced



HOW TO TREAT LIVER CANCER?

TRADITIONAL TREATMENT
Surgical resection:This therapy offers the potential for cure in patients with clinical stage ⅠandⅡdisease in whom solitary tumor is less than or equal 2 cm without vascular invasion, or solitary tumor is ￡2cm,with vascular invasion; multiple tumors(only one lobe),none >2cm,no vascular invasion; solitary tumor is>2cm,no vascular invasion. Long-term survival is achieved in 40% to 60% of patients who undergo a potentially curative resection, varing from various centers.
Systemic chemotherapy: More recent trials have generally failed to confirm single agent or combination chemotherapy response rates higher than over 10% in untreated patients.
Ratiation therapy has not showed a survival benefit.
NOVAL THERAPIES

Transarterial chemoembolization(TACE):


This technique has become one of the most popular and effective treatments for patients with unresectable HCC. The rationale for this treatment is the fact that the HCC derives its blood supply exclusively from hepatic artery in contrast with the rest of the liver, which is also served by the portal vein. The branch of the hepatic artery supplying the tumor is occluded at the time of arteriography by injection of lipiodol or/and gelatin-sponge particles, which results in necrosis of the tumor. Chemotherapeutic agents, which are often mixed with lipiodol, is simultaneously given. Institutional chemotherapy protocols very but may include dororubicin hydrochloride,epirubicin hydrochloride, mitimycin C, cisplatin, or floxuridine used in either single or combination therapy.

The initial response is a greater than 50% tumor reduction in at least 30% of patients. The median survival is about 20 months after TACE alone. Overall cumulative survival rates are 69% at 1 year, 42% at 2 years, 22% at 3years,13% at 4 years, and 10 %at 10 years. In non-randomized trial of intra-arterial chemotherapy or a combination of embolization and intra-arterial chemotherapy, a survival advantage was seen in the chemoembolization arm (22% versus 4%).Thus the effect of vascular occlusion may potentiate the effects of chemotherapy.

Some randomized clinical trials have found that, despite retrospective studies demonstrating a benefit of TACE, TACE offers no improvement in survival compared with supportive therapy alone. Nevertheless, TACE may result in good objective responses in the tumor, may be considered a useful adjunct to other therapies, such as surgical resection, cryoablation, and liver transplantation.

Chemical ablation: Percutaneous injection of absolute ethanol or 50% acetic acid under ultrasound guidance may result in necrosis of tumor and around the injection site to a diameter of 3 to 4 cm. Multiple injection sessions are often needed to completely ablate the tumor. Percutaneous ethanol injection (PEI) has been shown to result in survival comparable to that resection for small and solitary HCC, and is more suitable for patients with decompensated liver disease who would not tolerate surgery.
It was reported that this therapy produced 5-year survivals of 43% for small HCC.A group of 43 patients with HCC less than 3 cm received one of following three therapies (1)chemolipiodolization (C-LIP), (2)C-LIP followed by gelatin sponge TAE (transarterial embolization), or (3)PEI, and demonstrated a decrease in local recurrence with PEI. Local recurrences at 1 year were 61%, 29% and 20% for patients with C-LIP, C-LIP/TAE and PEI. Another data showed a 10-year survival of 66% for singleHCC less than 2cm.In pooled data on 11 000 patients with HCC from Japan,3-year survival for surgical resection, PEI, or embolization was 58%, 53%, and 20%,respectively. But the method is not suitable for larger liver cancer.




Radiofrequency ablation(RFA):

Of all the tumors of the liver HCC with cirrhosis responds best to treatment with RFA. The reason for a good response in this form of tumors is probably due to the characteristic features of HCC, which offers better heat conduction. It is clear that RFA is one of useful primary therapies in patients with unresectable HCC, especially in cases with a poor liver reserve from cirrhosis and with multiple and/or deep-sited lesions.

Compared with PEI, pecutaneous RFA requires fewer treatment sessions and may achieve superior tumor necrosis of small (less than 3 cm) HCC. In a large series of 110 cirrhotic patients undergoing RFA, there was no motality. Complications occurred in 12.5% of patients. Seventy percent of patients were percutaneously, and more than 50% were Child class B or C. Local recurrence at the RFA site occurred in only 3.5% of patients treated.

Both the site and the size of the lesions determine the success of RFA. Those lesions close to vessels offer the poorest response as a result of conduction and dissipation of heat by the blood flow. Hence, some additional modalities should be used available when treating these perivascular lesions.







Interstitial laser coagulation: This is a procedure for the treatment of unresectable hepatic tumors using local light delivery to thermally coagulate solid tumor. According to some studies, the effective tumor size for this procedure is 5cm or less, although this figure is currently under debate. Some limitations of this procedureare (1)the absence of a means for real-time monitoring of heat buildup and charring effects;(2)the ineffectiveness of this procedure on high fibrous tumors; and (3)the lack of any evidence of actual patient survival benefit.
Cryoablation:It was reported that forty patients with hepatic malignancy underwent cryoablation and the estimated18-month survival was 60% and 30% for patients with HCC and with colorectal metastasis, respectively. Another authors treated 4 patients with recurrent HCC after previous curative hepatectomywith cryoablation. All their patients were still alive with a survival after cryoablation ranging from 12 to 23 months. One study has demonstrated that the median survival for HCC patients after cryoablation was 36 months. A larger 235 patients with HCC trial suggested that 1-, 3- and 5-year survival rates of 78%, 54% and 40%,respectively,after cryoablation.


It should be noted that the cryoablation reported by above authors was mainly performed through intraoperative approach with a large invasion, while in an our prospective trial (from Fuda Cancer Hospital Guangzhou), total of 105 masses in 65 patients with HCC underwent percutaneous hepatic cryoablation. The cryoablation was performed with the Cryocare System (Endocare, Irvine, CA, USA) using Argon gas as a cryogen. Two freeze-thaw cycles were performed, each reaching a temperature of –180°C at the tip of the probe. PEI was given in 36 patients with tumor mass larger than 6 cm in diameter 1-2 weeks after cryoablation and then once per week for 4 to 6 sessions. 65 patients with HCC receiving this combined therapy were followed up for a median duration of 14 months, 50.8 % of patients are currently free of tumor and 33.8 % are alive with tumor recurrences. Among the 41 patients who were followed up for more than one year, 78% are alive despite of tumor recurrence. Only 10.8 % died from tumor recurrence with an overall survival of the 13.2 months. Of the patients who had CT scan available for review, 88.4% had a shrinkage of tumor masses. Of the 22 patients who received biopsies of their cryoablated tumor masses, all but one showed only dead tumor cells or scar. Of the patients who had an increased AFP preablatively, 91.3% had a decrease of AFP to normal or nearly normal levels during postablative 3-6 months.

Combination of percutaneous cryoablation with PEIis a good strategy. This is based on following facts. During cryoablation, freezing would occur in three main areas:(1) The center of iceball near the cryoprobe, where freezing would be rapid and the temperature would be lowest.(2) The middle of the iceball, where the tissue experienced intermediate cooling rate. (3) The periphery of the iceball, where slow rates of cooling would occur. The cytotoxic effect from rapid cooling was the greatest in the center of the iceball, while cells at the periphery of the iceball might survive, particularly if the tumor abutted a large intrahepatic blood vessel that abrogated the effects of tissue cooling. The surviving tumor cells would result in recurrence of the disease. Ethanol could diffuse into the tumor cells and cause nonselective protein denaturation and cellular dehydration, leading to coagulated necrosis. Therefore, after cryoablation which could destroy the majority of tumors, PEI used at periphery of tumor could destroy residue tumor tissues. It is obvious that cryoablation in combination with PEI had a complementary effects on preventing recurrence.In 36 patients with tumor masses larger than 6 cm in diameter was given combination of cryoablation with PEI,1 recurrent tumors were seen in 7 patients, but, in whom, only 3 had recurrence at the original cryosite, suggesting the effectiveness of this combined therapy.

Sequential therapy of TAC-percutaneous cryoablation can result in better outcome for unresectable liver cancer. Here list our paper [Abstract], which has been published:

Sequential treatment of transarterial chemoembolization (TACE)-percutaneous cryoablation for unresectable primary liver cancer

Objective：To evaluate the effectiveness of sequential treatment ofchemoembolization(TACE)-percutaneous cryoablation for unresectable primary liver cancer (PLC).

Method:Three hundred and sixty patients with PLC were received the therapy.Intrahepatic tumor masses were larger than 5 cm in size. 220 patients had single mass in liver and others had multiple masses but which numbered less than 5.The patients with thrombosis of portal vein,hepatic failure(serum bilirubin of more than 34 mmol/L,prothrombin time of more than 3s over the control) and obvious ascites were excluded from the treatment schedule. The tumors of all patients were considered to be unresectable through comprehensive comment. Transarterial chemoembolization was completed according to routine method. The branch of the hepatic artery supplying the tumor is occluded at the arteriography by injection lipiodol mixed with chemotherapeutic agents(adrimycin,cisplatin and mitomycin) and gelfoam.Two weeks later, if CT scanning showed good response,percutaneous cryoablation should be given,otherwise,the chemoembolization should be completed again (generally no more than 3 times). The cryoablation was performed with the Cryocare system(Endocare,USA) by using argon gas as a cryogen. Temperature in targeting tissue reached to under –160°C for 10 to 15 min,and then,helium was sended to increase the temperature to 20°C. Two freeze-thaw cycles were performed.One month after cryoablation,the chemoembolization of one or two times may be further performed if necessary.

Results: Among the follow-up period of median 21 months(6-36 months),ultrasound and /or CT showed thata complete response(CR) was seen in 30 cases (8.3%),partial response (PR) in 228 cases(63.3%),no change (NC) in 66 cases (18.3%),and progressive disease(PD) in 36 cases (10.0%). Alpha-fetoprotein(AFP) was significantly decreased and decreased into normal range,in 86.9% and 62.0%, respectively,of 229 patients with pre-therapy elevation of serum levels of this protein.Out of 258 patients with CR and PR,26.7 % had intrahepatic recurrence,but only 15.9% developed a cryosite recurrence. There were 113 cases whodied during the follow-up period,and the death reasons included widespread metastasis in 45 cases,rupture of esophageal varices in 24 cases,spontaneous peritonitis in 23 cases,hepatic encephalopathy in 14 cases and other non-liver cancer-related causes in 7 cases.Conclusion: sequential treatment of TACE-percutaneous cryoablation offers a safe and effective treatment options and may result in a shrinkage or eradication of tumor mass and increase of survival for patients with unresectable PLC.

CONCLUTION:Percutaneous cryoablation offers a safe and possibly curative treatment options for patients with HCC that cannot be surgically removed, and its integration with PEI, may serve as an alternative to partial liver resection in selective patients. Percutaneous approach is minimally invasive and allowing for a rapid recovery.

Percutaneous microwave coagulation: A histopathologic assessment of the efficacy of percutaneous microwave coagulation (PMCT) was performed in six patients with HCC who underwent PMCT 18 to 48 days prior to surgery. The main tumor measured no more than 2 cm. The area of coagulation was discretely demarcated at both macroscopic and microscopic evaluation, with a fibrous capsule at the periphery at histology. In one third of the cases, however, residual viable tumor remained outside the area of necrosis, indicating the need for an adequate safety margin. A group of 18 patients with solitary HCC less than or equal to 2 cm in maximum dimension was treated with PMCT. Imaging and clinical follow-up at 11-13 months showed imaging evidence of necrosis. All but one patient was alive with no evident local recurrence, and AFP levels had decreased in those with initially elevated levels.
A trial from China showed that 234 patients with 339 nodules of HCC undergone PMCT and were followed-up for mean period of 27.9 months. After PMCT, color Doppler flow signals disappeared in 92.0% (263/286) of the lesions. No enhancement was apparent in 89.2% (190/213) and 89.1% (41/46) of the lesions on contrast-enhanced CT and MR imaging, respectively. Posttreatment biopsies of 194 nodules showed no evidence of surviving tumor tissue in 180 nodules (92.8%). Resections of six lesions revealed complete tumor necrosis in five. The 1-, 2-, 3-, 4-, and 5-year cumulative survival rates were 92.70%, 81.60%, 72.85%, 66.37%, and 56.70%, respectively. No severe complications were seen. The result suggests that PMCT can result in a high percentage of cases without evidence of residual tumor and satisfactory long-term results.

Hormone therapy: Factors suggesting potential androgen dependence of HCC have led to application of hormone therapy. These factors are male predominance of HCC, HCC can be induced by androgen therapy, androgen receptors are expressed at high concentration in HCC, and some HCC cell lines have receptors for gonadotropin-releasing hormone. But double-blind randomized trials failed to show any benefit for antiandrogen therapy. Similarly, it has been showed that estrogen may produce liver adenoma, and that estrogen may be elevated in patients with cirrhosis, that has led to the evaluation of tamoxifen (an antagonist of estrogen receptor) in the treatment of HCC. Several small randomized trials suggested an improvement in survival in HCC patients who received tamoxifen, but a large multicenter trial is necessary.
Liver transplantation: Because many patients with moderate cirrhosis are not good surgical candidates even if they have early-stage HCC, liver transplantation has become a potential therapeutic option, may offer the potential advantages of curing the HCC as well as the underlying cirrhosis. But the method is only indicated to patients with small primary tumor, not to patients with tumor larger than 5 cm, multiple tumors, involvement of more the one lobe, vascular invasion, and diffuse tumor infiltration. In selected cases,5-year survival for stage Ⅰ,Ⅱ,and Ⅲ disease are 75%,60%,and 40%,respectively,whereas fewer than 10% of stage Ⅳ patients(multiple tumors in more than one lobe or tumors involving a major branch or portal or hepatic vein) who have received a transplant are alive at 5 years.