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SAUDI GASTROENTEROLOGY ASSOCIATION GUIDELINES Table of Contents   
Year : 2007  |  Volume : 13  |  Issue : 5  |  Page : 1-24
Diagnosis and management of hepatocellular carcinoma


College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia

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How to cite this article:
Abdo AA, Al Abdul Karim H, Al Fuhaid T, Sanai FM, Kabbani M, Al Jumah AR, Burak K. Diagnosis and management of hepatocellular carcinoma. Saudi J Gastroenterol 2007;13, Suppl S1:1-24

How to cite this URL:
Abdo AA, Al Abdul Karim H, Al Fuhaid T, Sanai FM, Kabbani M, Al Jumah AR, Burak K. Diagnosis and management of hepatocellular carcinoma. Saudi J Gastroenterol [serial online] 2007 [cited 2020 Oct 30];13, Suppl S1:1-24. Available from: https://www.saudijgastro.com/text.asp?2007/13/5/1/30865



   Goals of the Guidelines Top


  1. To provide a concise evidence-based review of the diagnosis and management of hepatocellular carcinoma (HCC)
  2. To help initiate plans to prevent HCC
  3. To enhance early and accurate diagnosis of patients with HCC.
  4. To suggest an evidence-based approach for the management of HCC patients
  5. To facilitate a more effective referral system between primary/ secondary care physicians and tertiary care centers where advanced treatments are available.
  6. To help adopt a more effective triaging system of patients within tertiary care centers.
  7. To create a complementary system between the major tertiary care centers whereby specific centers may specialize in certain aspects of management or care.
  8. To identify research questions that are applicable to our local circumstances and resources, and to facilitate recruiting patients in these studies.



   Methods Top


After due recognition of the high prevalence of HCC in Saudi Arabia, the difficulties often encountered in accurate diagnosis, the need for evidence-based management and appropriate referral of HCC patients; a committee was formed from the editors at King Khalid University Hospital (KKUH) in Riyadh (first three editors, AAA, HAK, TF) who subsequently compiled the first draft of these guidelines.

These editors first performed a comprehensive literature search on all aspects of the epidemiology, natural history, risk factors, diagnosis, and management of HCC. All literature was examined critically and the available evidence was then classified according to its strength.

After approval and implementation of the initial guidelines at KKUH, it was decided to utilize these guidelines as a backbone for a national project for Saudi Arabia. Three other editors (FMS, MK, AJ) from three of the major hospitals in Saudi Arabia joined at this stage and put in a considerable effort in updating the document. After that, representative expert contributors were invited to review the document. All contributors (who are experts in different specialties related to HCC management from different institutions in Saudi Arabia) then further refined and updated the sections related to their expertise. Multiple meetings were then called to approve the final document. After that, The Saudi Gastroenterology Association formed a committee, which reviewed these guidelines and approved them as the " Saudi Guidelines for the Diagnosis and Management of Hepatocellular Carcinoma".

The recommendations were based on the best available evidence but were tailored to the needs of the patients in Saudi Arabia.

We have benefited from the two published European guidelines. The first is the conclusion of the Barcelona - 2000 European Association for the Study of the Liver conference,[1] and the second is the guidelines published by the British Society of Gastroenterology.[2] In addition, we have benefited from a special dedicated supplement issue of Gastroenterology (November 2004) containing extensive reviews of the topic, and from the American Association for the Study of the Liver (AASLD) guidelines that were recently published.[3]

We hope that these guidelines will improve the care of patients suffering from HCC and facilitate the performance of research in this important medical problem.

Grading of recommendations

Grade A : Recommendation based on at least one high quality randomized controlled trial or at least one high quality meta-analysis of well-done randomized controlled trials.

Grade B : Recommendation based on high quality casecontrol

or cohort studies or a high quality systematic review.

Grade C : Recommendation based on non-analytic studies (case reports or case series).

Grade D : Recommendation based on expert's opinion only.


   Epidemiology Top


Prevalence

HCC is the most common primary malignancy of the liver. It represents the fifth most common cancer and the third most common cause of cancer death worldwide.[4] It has a variable geographical distribution around the world. The incidence in developing countries is two to three times higher than in Western countries. For example, in Eastern Asia and Middle Africa the age-adjusted incidence rate (AAIR) ranges from 20-28 cases per 105 in men while it is about 1-3 per 105 in Northern Europe, Australia and North America.[4] In the United States the incidence of HCC has increased from 1.4 per 105 population at the period from 1976-1980 to 2.4 per 105 population for the period from 1991-1995.[5]

In Saudi Arabia, liver cancer accounts for 6.1% of all newly diagnosed cancers according to the most recent cancer registry covering the years 1999-2000.[6] HCC was the second most common cancer affecting Saudi males and the eighth most common cancer affecting females with an overall age standardized rate of 4.5/100,000 population. Male to female ratio is 279:100. In Saudi Arabia, HCC accounts for 87.6% of all liver cancers. The median age at diagnosis is 65 years for males and 60 years for females. This incidence of HCC in Saudi Arabia is not surprising given the high prevalence of the two major risk factors, namely hepatitis B and hepatitis C infections. In a large epidemiologic study by Al Faleh et al, 7% of Saudi children were found to be positive for HBsAg.[7] Not until universal vaccination was applied in Saudi Arabia did this prevalence rate decrease to less than 0.3%.[8] Since the initial epidemiologic studies showing high prevalence of hepatitis B were done in children who are now adults, it is estimated that about 20% of these patients will probably develop cirrhosis along with an annual risk of 1-4% for HCC. Based on these figures the incidence of HCC is expected to increase dramatically in the Kingdome in the next 30 years. Hepatitis C is also common in Saudi Arabia with a prevalence rate of 1-3% of the population,[9] which further increases the risk of HCC. More recently, the incidence of hepatitis C seems to have decreased to about 1.1%.[10]

The incidence of HCC increases with age. The mean age of acquisition is clearly lower in areas of high endemicity such as in China and Africa, where in Mozambique for example, more than 50% of affected men are younger than 30 years of age.[11] In general, HCC is more common in men than in women especially in areas with high prevalence.[4]

Three relatively small studies done in the 1980's described some aspects of the epidemiology of HCC in Saudi Arabia. In the first study by Kingston et al , all cases of liver tumors were studied over a period of 2 years in King Faisal Specialist Hospital in Riyadh.[12] A total of 104 cases of HCC were found. These patients were predominantly male (6:1 ratio). In the second study by Ashraf et al, 75 patients with HCC were described from the Gizan area in Southern Saudi Arabia.[13] Eighty percent of these patients were males. In the third study by Atiyah and Ali, the clinico-pathological features of 54 patients with HCC were described.[14] The male to female ratio was found to be 10:1 with a peak incidence age between 40-60 years.

Risk factors

The most significant risk factor for the development of HCC is the presence of cirrhosis, regardless of its etiology. Some of the important risk factors will be discussed briefly.

Cirrhosis

The development of cirrhosis is the major risk factor for the development of HCC regardless of the cause. The annual incidence of HCC in patients with compensated cirrhosis is about 3%.[15] European cohort studies have reported that, among persons who died of a liver related cause, HCC was responsible in 54% to 70% of patients with compensated cirrhosis of different etiologies and in 50% of patients with HCV related cirrhosis.[16],[17] This is thought to be secondary to a potent tumor promoter effect.[18] Male sex, age, and duration of cirrhosis are associated with an increased risk of HCC in patients with cirrhosis.[19]

Hepatitis B virus (HBV)

This is considered the strongest epidemiologic factor associated with HCC in the majority of countries but more importantly in Asia and Africa. The carrier state of hepatitis B early in life carries a lifetime relative risk of developing HCC of over 100,[20] while the annual incidence of HCC in hepatitis B patients with cirrhosis exceeds 2%.[21],[22],[23] Many factors are important in determining the risk of HCC in HBV infected patients. The most important factor is the stage of the liver disease. In a summary of all the follow-up studies of patients with hepatitis B, it was found that in HBV carriers with persistently normal ALT the annual incidence of HCC was 0%. This incidence increased to 1.2% in patients with histological active hepatitis, and between 2-6% in patients with established cirrhosis.[24] On the other hand, studies from Asia suggest that the annual incidence of HCC in HBV carriers is around 0.5%.[23],[25] Another two related important factors are the race and the age of infection. In Caucasian HBV carriers, HCC occurs most often in the setting of cirrhosis[21] but in Africa and South East Asia, HCC may develop more frequently in non-cirrhotic livers.[22] This is thought to be related to the duration of infection or to dietary aflatoxin.

HBV is thought to be carcinogenic both directly and indirectly[18] because HBV DNA is integrated into cellular DNA of the host and can be demonstrated in HCC cells in 95% of the cases.[26]

Hepatitis C virus (HCV)

This is considered the most important risk factor for HCC in Western countries and Japan. In a meta-analyses of 32 case control studies, the estimated risk for the development of HCC was 17.5-fold greater in HCV carriers than in non carriers.[27] Almost all HCC in hepatitis C patients occurs in those who have developed cirrhosis, where the yearly incidence varies between 3 to 8 %.[15],[28],[29] In Japan, the summary of HCC incidence rate was 1.8 per 100 person years in subjects with chronic hepatitis C without cirrhosis and 7.1 in those with compensated cirrhosis.[30] This suggests that hepatic parenchymal disease plays a major role in the development of cancer in this disease.[19] To further clarify the importance of the stage of liver disease in the risk of HCC in HCV infected patients, Colombo summarized the follow-up studies of patients with hepatitis C.

It was found that the annual risk for development of HCC was 0.4% for unselected HCV carriers with persistently high values of ALT, but it rose to 1.7% in patients with the histological diagnosis of chronic active hepatitis and to 2.5% in those with compensated cirrhosis.[24] Although HCV does not integrate into the host genome, there is some evidence that the virus is directly oncogenic.[31]

Alcohol

The risk of HCC is increased up to 40% with heavy alcohol consumption.[32] In a study from Italy, the risk of HCC was found to be 13 times greater in drinkers than in non-drinkers.[33] In a recent met-analyses of 3 cohort and 17 case-control studies there was a clear trend toward increased risk of HCC in heavy drinkers.[34] Infection with HCV or HBV in alcoholic drinkers clearly increases this risk suggesting a synergistic effect.[35],[36]

Aflatoxin B1

Aflatoxin B1 derived from Aspergillus flavus and Aspergillous parasiticus is an important risk factor for HCC in parts of Africa and Asia.[19] Most authorities believe that the effect of Aflatoxin is only important in patients who have pre-existing chronic hepatitis B.[1]

Other risk factors

In patients with hereditary hemochromatosis, the estimated risk of development of HCC is increased 200 times more than the general population once cirrhosis is established[37] with an annual risk of 5%,[38] mostly with advanced cirrhosis but also rarely in patients without cirrhosis.[39] HCC develops occasionally in Wilson's disease but usually in association with cirrhosis.[40] Other inherited metabolic diseases of the liver such as type 1 glycogen storage diseases and alfa 1 antitrypsin deficiency may all be associated with HCC.

The studies on the effect of smoking on the risk of HCC are conflicting but this is probably a minor risk factor.[19] Early small studies on chronic oral contraceptive pills showed an increased risk of HCC with a relative risk of 3.8 to 13.5, but larger more recent studies showed no increased risk at all.[41] HCC may also develop in 40% of patients with membranous obstruction of the inferior vena cava.[42]

Natural history

The natural history of HCC depends on the stage of the disease but generally carries a poor prognosis in the majority of cases. Tumor size at presentation is an important factor in the natural history but its use as a sole predicting factor is hindered by the fact that tumordoubling time may in fact be very variable. In some patients the tumor growth is slow, doubling in size in twenty months or more, while in others the tumor grows much faster and doubles in less that 1 month.[43],[44] In symptomatic patients in China and Africa, death usually ensures within four months,[45] while other reports have suggested a longer survival and a more indolent course in Western countries.[46] Other important factors in the natural history include the stage of the underlying liver disease and the patient's performance status as discussed in the staging systems below.


   Conclusions Top


  • HCC is a common tumor in Saudi Arabia and the incidence is likely to increase dramatically in the next 30 years.
  • There are no large epidemiologic studies to define this disease in Saudi Arabia.
  • Hepatitis B and hepatitis C appear to be the two most important risk factors for HCC in Saudi Arabia but other risk factors need to be studied further.


Recommendations

  • Much more resources should be allo-cated to this important medical problem in Saudi Arabia.
  • Large epidemiologic studies are needed to further define the epidemiologic fea-tures of HCC in Saudi Arabia.
  • Patients with cirrhosis of any etiology, but especially cirrhosis caused by hepati-tis B or C, are at an increased risk for the development of HCC and these patients should be targeted for a screening pro-gram (Grade A)
  • The incidence of HCC in those with hepati-tis B infection without underlying cirrhosis, in Saudi Arabia needs to be studied further be-fore firm screening recommendations can be given.


Clinical features

The classical features of HCC include right upper quadrant abdominal pain and weight loss. Weakness, abdominal swelling, non-specific gastrointestinal symptoms, and jaundice are other presenting features. Special clinical scenarios should raise the suspicion of HCC. These include acute deterioration of liver function in a patient with stable cirrhosis, new onset ascites, and acute intraabdominal bleeding.

Physical findings vary according to the stage of the disease. If the tumor is small, no signs may be found except those related to underlying cirrhosis where present. In more advanced cases, hepatomegaly is common, with the possibility of palpating a mass or a hard irregular liver surface which in turn may be tender. A bruit may be heard over the liver. Ascites is often found, most commonly as a result of the underlying cirrhosis leading to portal hypertension but rarely due to tumor invasion of the peritoneum. Muscle wasting is common and is usually progressive.

HCC is known to cause many paraneoplastic syndromes. These are generally rare, but important to identify. Type B hypoglycemia is seen in 5% of patients and may be seen early in the disease.[47] Polycythemia may be seen in less than 10% of patients.[48] Hypercalcemia may also be seen in the absence of bone invasion. Skin manifestations like pityriasis rotunda have been described. Other less likely paraneoplastic features include sexual dysfunction, watery diarrhea, thyrotoxicosis, neuropathy, and carcinoid syndrome.[19]

In the three epidemiological studies done on patients with HCC in Saudi Arabia, patient's presentations were not different from those described above. In the study by Ashraf et al , 91% of the patients presented with hepatic enlargement, 76% with abdominal pain, 33% with splenic enlargement, and 33% with ascites.[13] Abnormal liver function tests were found in 97% of the patients. The study by Kingston et al was very similar in its findings.[12]


   Conclusions Top


HCC usually presents with weight loss and right upper quadrant pain in addition to the symptoms and signs of underlying liver cirrhosis.

Recommendations

In patients with stable cirrhosis, rapid de-terioration of liver function, new onset ascites, weight loss, or increased jaundice should initiate investigations for HCC (Grade C).


   Diagnosis Top


Radiological features

Various imaging modalities particularly cross-sectional imaging are essential keys in the management of patients with HCC. These powerful techniques allow the detection, characterization and staging of HCC, as well as planning the appropriate therapy and follow-up of these patients post-treatment.

Ultrasonography (US)

At the present time, the main role of US towards the diagnosis of HCC lies in screening. While US has the advantage of being safe, easily available, and being cost effective, it is hindered by its low specificity and its operator dependent nature. Newly discovered focal liver masses in patients with liver cirrhosis have a high likelihood of being HCC.[2] Abdominal US is associated with a sensitivity and specificity of 20-51% and 92-96% respectively for detecting lesions consistent with HCC in patients with cirrhosis.[49],[50] The majority of small masses are homogeneously hypoechoic rendering them indistinguishable from regenerating nodules.[51] Detection rates for lesions between 2 to 3 cm and 1 to 2 cm with US are estimated to be as low as 20% and 13%, respectively.[52] Larger HCC tend to follow a mosaic pattern due to fatty degeneration or coagulation necrosis. Occasionally HCC appears hyperechoic, which is probably due to fatty changes or dilated sinusoids. HCC may present variously as a solitary mass or a dominant mass with surrounding satellite nodules, or multifocal masses, or less commonly as a diffusely infiltrating mass.

In more advanced cases of HCC, vascular invasion, particularly of the portal vein, and biliary obstruction may occur. In spite of the limitations of US in diagnosing HCC, due to its low cost, safety and availability, it is still considered the best initial test to be performed when HCC is suspected.

Computerized tomography (CT)

Using multi-detector scanners, triphasic CT scan of the liver has proven to be very useful in the diagnosis of HCC. This technique encompasses non-contrast, hepatic arterial (HA) and portal venous (PV) phases. Arterial and portal venous phases are acquired around 20 and 60 seconds from the start of injection respectively, by a power injector intravenously at a rate of 4 cc/sec.

This technique utilizes the fact that the blood supply to HCC is predominantly from the hepatic artery resulting in a hypervascular nature. Consequently, HCC appears hyperdense during the HA and relatively hypodense during the PV phases due to contrast washout. Large HCC is typically inhomogeneous. Imaging during the arterial phase of the contrast pass is of paramount importance if a small HCC is to be detected and the relatively specific diagnosis of HCC to be made. This phase has also replaced conventional angiogram in delineating the hepatic arterial anatomy prior to liver transplantation.

In recent studies, contrast-enhanced CT scan has been reported to have sensitivity and specificity rates of 71-80% and 80-96% respectively, compared with explants histology.[55]

CT has the advantage of detecting extrahepatic spread and accurately staging HCC. Its local extension and complications including vascular invasion, biliary obstruction and peritoneal hemorrhage due to tumoral rupture are exquisitely demonstrated with CT. Presence of small abdominal lymphadenopathy does not upstage the tumor as it is common in patients with cirrhotic patients without underlying HCC, especially in patients with hepatitis C.[56]

Magnetic resonance imaging

This test has become the diagnostic procedure of choice for HCC in many institutions.[57] While HCC has variable signals on T1 weighted imaging, it is usually hyperintense on T2. Because of the abundant neovascularity, HCC enhances vividly during the arterial phase of gadoliniumenhanced imaging. In the portal venous phase, HCC is usually isointense. In the delayed phase, HCC will be hypointense because of contrast medium wash out. If the tumor is well-differentiated, it exhibits a high signal on T1 weighted imaging that is likely attributed to fat deposition, copper or glycoproteins, and is therefore isointense on T2 weighted imaging.[58]

Hepatic angiography

Hepatic angiography in the present era has no significant role in the diagnosis of HCC. It is however, sometimes used to delineate the hepatic artery anatomy when planning OLT. It is also an essential component during chemoembolization of HCC.

Laboratory investigations

Serum alfa fetoprotein (AFP)

AFP is an alfa 1 globulin that is normally present in high concentrations in fetal serum but in only minute concentrations in adults. The seven major studies reporting on the sensitivity and specificity of AFP in screening for HCC are nicely summarized by Daniele and colleagues and show sensitivities of 39-65%, specificities of 76-94%, but a poor positive predictive value of 9-50%.[59] In a recent systematic review it was confirmed that AFP has a poor diagnostic ability to detect HCC at any level of pretest risk.[60] However, as a confirmatory test in patients with a mass on imaging studies, AFP determination remains clinically useful.[61]

AFP presence and level of elevation is related to many factors, most importantly the prevalence of the disease. In high endemic areas the vast majority of patients have an elevated level (above 20 ng/mL) and more than 75% of patients have levels that are higher than 500 ng/L. These figures are lower in patients from low prevalence areas for HCC. In addition, the mean serum level in high incidence areas is around 60,000 ng/mL compared to about 3000 ng/mL in regions with low incidence.

AFP elevation of less than 500 ng/mL may be seen in patients with active necroinflammatory changes in the liver secondary to active hepatitis. In fact, in one study, of 44 HBV carriers with elevated AFP levels detected during surveillance for HCC, only 6 were found to have HCC on further investigations and in 18 patients the elevated AFP was associated with an exacerbation of underlying liver disease.[62] A progressively rising AFP level even at low concentrations is highly suggestive of HCC.[63],[64] Elevations above 1000 ng/mL have a high specificity rate.

AFP level may also be affected by the patient's age. The younger the patient, the more likely is the level to be raised and a higher level attained. Provided that the patients are age-matched, no gender differences are seen in the level of AFP. No obvious correlation exists between the serum concentration of AFP and any of the clinical or biochemical features of the tumor or the survival time after diagnosis. However, some studies have shown that symptomatic patients have a higher level of AFP than asymptomatic patients. Studies are now under way to try and refine the assay of AFP in order to try to improve its specificity including the detection of fucosylated AFP which is more specific for malignant hepatocytes.[19]

Other tumor markers are under investigation but are not primed for clinical use yet. These include Des-y-carboxy prothrombin and alfa-l-fucosidase.

Histological sampling

Obtaining a tissue diagnosis for HCC is not considered a mandatory step in the majority of cases of HCC. In liver nodules less than 2 cm in size, confirmatory histology or fine needle aspiration FNA is important to diagnose HCC as current radiological methods are not accurate enough to establish a definitive diagnosis. However, it should be borne in mind that the false negative rate of biopsy in these small lesions is about 40%.[65]

On the other hand, in the case of nodules above 2 cm in diameter the diagnosis of HCC may be established confidently without requiring histological evidence.[66],[67] In these patients the likelihood of this lesion being HCC is more than 95%.[68],[69] Combining this high likelihood of HCC to the advantage of new imaging studies detecting arterial perfusion, the diagnosis of HCC can be made positively in the majority of cases without biopsy. These tests offer the advantage that they can differentiate HCC from benign liver lesions and secondary tumors with a high degree of accuracy.[70],[71],[72] Among 160 patients with 225 focal liver lesions evaluated by means of sequential radiological imaging studies, in preparation for planned surgical therapy, the preoperative diagnostic accuracy rate without histological confirmation was reported to be 98.2%, with a sensitivity of 100%, and a specificity of 98.9%.[66] In addition, it has been reported that the overall false negative rate for FNA or even trucut biopsy in detecting HCC is as high as 20%.[71],[73],[74] An important, although seemingly rare, complication of tumor biopsy is needle tract tumor seeding. This complication has been estimated to occur in about 1-5% of biopsies and is especially important if the patient is awaiting liver transplantation or resection.[65],[70],[74]

In liver lesions without cirrhosis or in situations when imaging is unclear, tissue diagnosis is important.[75] If histology is required, the highest rate of diagnostic accuracy (97%) is achieved by combined use of FNA cytology plus intranodular and extranodular fine needle microhistology.[76] Liver biopsy may be useful not just in the diagnosis of HCC but also to evaluate the rest of the liver to guide further therapy. If the clinical presentation is doubtful and the stage of cirrhosis needs further clarification then a biopsy of the non-tumorous liver may be helpful.

The European Association for the Study of the Liver recommended non-invasive HCC diagnostic criteria that can be used in cirrhotic patients. These include two coincident imaging techniques showing focal lesion(s) more than 2 cm in size with arterial hypervasularization or one imaging technique showing the above in addition to an AFP >400 ng/mL.[1] If a diagnosis cannot be reached by these non-invasive criteria then a histological confirmation is warranted. The British Society of Gastroenterology has also recommended a similar approach.[2]

The recent guidelines by the American Association for the Study of the Liver went a step further in this non-invasive approach to the diagnosis of HCC and recommended that only one imaging modality showing the typical early arterial enhancement and venous washout would be enough to diagnose HCC if the lesion is larger than 2 cm and the liver is cirrhotic.[3]

In an interesting, recent study examining the non-invasive criteria recommended by these guidelines, Bolondi et al prospectively compared the presence of arterial hypervasularity on contrast perfusional US and CT to results of biopsy in 72 liver nodules.[77] They found that in nodules larger than 2 cm all lesions demonstrating arterial hypervascularity turned out to be HCC. In lesions less than or equal to 2 cm only 71% of these lesions were diagnosed as HCC. On the other hand, 8.3% of proven HCC on biopsy did not show typical hypervascular enhancement on radiological examinations (all less than 3 cm). This study strongly supports the non-invasive criteria of relying on radiological tests only, without biopsy in lesions larger than 2 cm, and performing biopsy in lesions less than or equal to 2 cm.

Diagnosis recommendations

  • US should be the initial radiological investigation performed when HCC is suspected (Grade C).
  • Further imaging should be performed if an abnormality is found or if the suspicion of HCC is high even if the US is normal (Grade C).
  • Triphasic CT scan and MRI are the radiological procedures of choice to confirm the diagnosis of HCC (Grade B).
  • It is extremely important that the CT scan is done in a standard triphasic technique and is read by a trained abdominal radiologist (Grade A).
  • The diagnosis of HCC may be positively made if the following conditions are achieved (Grade B):

    1. The liver is cirrhotic

    2. The lesion is larger than 2 cm in diameter

    3. One of the two following criteria is met:

    a. AFP is higher than 400 ng/L and one imaging modality confirms early arterial enhancement and venous washout.

    OR

    b. AFP is normal and two imaging modalities confirm early arterial enhancement and venous washout.
  • A histological diagnosis is recommended in the following circumstances (Grade B):

    1. If a lesion is found in a non-cirrhotic liver and radiological investigations are not conclusive for hemangioma, focal nodular hyperplasia, or adenoma.

    2. If the suspicion of HCC is high but the non-invasive criteria mentioned above are not satisfied.
  • Although AFP is a poor screening tool for HCC, it should be measured in all suspected cases. Levels below 400 ng/L are suggestive of HCC, but may be seen in patients with active hepatitis without HCC. Levels above 1000 ng/L are more specific for HCC. A persistently increasing AFP is highly suggestive of HCC (grade B).


Staging

After establishing the diagnosis of HCC, the next step in the management of such patients should entail staging of the disease. This should only be done if treatment is to be offered. An ideal staging system should be able to separate patients into distinct clinical groups based on survival so that appropriate treatment modalities can be applied. This system should be able to incorporate the tumor characteristics as well as the liver function.

There are now more than 10 staging systems for HCC. They each have their specific advantages and disadvantages. We will briefly review here the most clinically relevant systems.

TNM classification system

This system is similar to other cancers classification systems.[78] It has the advantage of accurately describing the tumor characteristics and stage, but it does not take into consideration the underlying liver function. Liver function is extremely important in the long-term prognosis of the patient as well as in deciding on some therapeutic modalities like resection or transplantation. In addition, the TNM classification system does not seem to be able to predict the rates of tumor recurrence after OLT, a feature that has a very important prognostic value and is not related to the liver function. In an analysis of 58 patients who underwent OLT for HCC there was no difference in the rates of tumor recurrence comparing TNM stages 1 and 4.[79]

Okuda classification system

This system takes into account both the tumor characteristics and the liver function.[80] It is basically based on gross tumor factors and is not very useful clinically. It has enjoyed wide acceptance at a time when there were limited options for patients with HCC and the main goal of a classification system was to separate patients with advanced disease who should only be offered palliative care, from patients who should be included in clinical trials. This system serves this purpose well as it is excellent in identifying the very advanced patient who will likely not tolerate any mode of therapy (Okuda 3). On the other hand this system performs less well when it tries to separate other less advanced patients.[81] This is mainly related to the simple fact that before stage 3 there are only two other stages, one and two. These will include a heterogeneous group of patients some of whom may have good prognosis while others do not.

Cancer of the liver Italian program (CLIP) classification system

This system has been developed based on a large retrospective analysis of 435 Italian patients with HCC using a Cox proportion hazard model.[82] This system has the advantage over the Okuda score in that it is evidence-based and in that it gives more leeway to assess patients who are not so terminal.[81] It has been further prospectively validated in two Italian studies of 196 and 154 patients[83] with HCC, and retrospectively in 662 Japanese patients.[84] In the Japanese and an Italian study, this scoring system was found to be superior to the Okuda system. Some groups have criticized the CLIP score for not being adequately assessed in patients undergoing radical resection.[81]

Barcelona clinic liver cancer classification system (BCLC)

This scoring system is very clinically oriented. It takes into account the three major factors that are important in deciding the treatment options i.e. the tumor stage, the liver function, and the patient's performance status.[85] It clearly separates patients with early disease who should undergo aggressive therapy, from end-stage patients. This system is difficult to interpret when factors are not aligned with the designed table. For instance, a patient who has Child-Pugh category C cirrhosis, a small lesion, and excellent performance status, would be inaccurately classified by this system. In addition, this system has not been externally validated.

Staging recommendations

  • Liver tumor weekly rounds should be started at every tertiary care center dealing with HCC patients. In this meeting, all cases of liver tumors should be discussed. The group should be composed of a hepatologist, an oncologist, a hepatobiliary surgeon, and an intervention radiologist. The goal of this meeting is to discuss new cases of liver tumors and to reach a joint decision on the most appropriate management route for these patients. It will also improve recruitment in clinical trials and will facilitate the teaching of residents and fellows (Grade D).
  • Patients with a liver mass should be evaluated in the weekly liver tumor rounds. This evaluation will help determine the next step in obtaining a final diagnosis, determine the extent of hepatic involvement, rule out extrahepatic disease, evaluate the general medical status and performance of the patient, and evaluate functional hepatic reserve (Grade D).
  • Initial evaluation of patients with HCC should include the following (Grade D):

    1. A complete history

    2. A full physical examination

    3. Initial laboratory tests including: A complete blood count, random serum glucose, serum electrolytes, renal function, alfa-feto protein, serum calcium, prothrombin time, and liver function tests.

    4. Chest X-ray (or a CT chest if there are suspi-cious lesions for metastases on the chest X-ray)

    5. Bone scan (only on initial visit and every 9 months thereafter)
  • Follow up visits should also include all the above tests at least every 3 to 6 months as long as the patient is in an active treatment arm of the management plan (Grade D).
  • It is clear that no single classification system is superior to the others with there being advantages and disadvantages for each one.
  • Although each staging system has its own advantages and disadvantages, the CLIP score enjoys epidemiologic support and prospective validation while the BCLC is probably preferred in planning future treatment (Grade B).



   Management Top


Liver transplantation

Orthotopic liver transplantation (OLT) is theoretically the best treatment for HCC because it results in the widest possible resection margins from the cancer, removes the remaining liver tissue that is at risk for the development of de novo cancer, and restores hepatic function.[81] The major practical obstacle is the extreme shortage of organs which makes this an impractical option in the present circumstances.

In 1996, Mazzaferro and colleagues reported their experience in transplanting patients with HCC.[86] They reported a 75% 4 year survival rate when using the criteria of only transplanting single HCC's that are less than 5 cm, or multiple HCC's that are less than 3 in number and less than 3 cm each. The excellent survival rates seen in the Mazzaferro series was confirmed by many other series using the same inclusion criteria.[87] These criteria (named the Milan criteria) have been accepted as 'standard of care' and are applicable to date. The survival data presented in the Mazzaferro series demonstrated comparable survival of patients receiving OLT with and without HCC. In addition, the recurrence rates post-transplantation, when these criteria are used, is extremely low. Practically speaking, these criteria were developed at a time when the waiting list for OLT was around 6 months, while the present era waiting lists are much longer, allowing patients to drop out of the transplant list because of contraindications. These contraindications include: extrahepatic spread, increase in size of the tumor beyond transplantation criteria, or vascular invasion. This clinical observation has been shown elegantly by the Llovet et al group who compared, in an intent-to-treat analysis, the 2 year survival of patients transplanted in two periods, and found a drop in survival from 84% to 54% as the mean waiting time increased from 62 days to 162 days.[88]

Many strategies have been suggested to overcome these major limitations in transplantation for HCC. One is living-related transplantation. There are limited data on this modality in HCC but preliminary data of living-related transplantation in non- HCC patients shows that it is probably as effective as cadaveric transplantation.[89] Multiple statistical and mathematical models have also shown that living-related transplantation for HCC may be cost-effective and life-saving, compared to cadaveric transplantation[90],[91]

The other method used to increase the accessibility to transplantation is to expand the tumor size criteria described by Mazzaferro. Yao et al , reported on the survival of 70 consecutive patients undergoing OLT for HCC including 25% with either solitary tumors 5-6.5 cm in diameter, or less than or equal to 3 nodules each being less than or equal to 4.5 cm with total tumor diameter less than 8 cm.[54] These patients' survival was not different from patients transplanted according to the Milan criteria. This series (and many recent abstracts from other centers) suggest that the Milan criteria can indeed be expanded which may give patients the opportunity to stay on current waiting lists. A different approach to the expansion of the Milan criteria was presented by investigators from the University of Pittsburgh.[92] These investigators suggest that size should not be a selection criterion for transplantation but rather other histologic and radiologic factors including: vascular invasion, lymph node spread, and obvious metastatic spread. Results using this approach are encouraging, with only 9% recurrence rates being reported, but is disadvantaged by not being studied prospectively or requiring a pre-transplantation histology.

In patients with small HCC's and advanced liver disease, liver transplantation is clearly a better option compared to resection but, owing to the organ shortage, another strategy has been suggested. This strategy starts with radical resection and is followed with salvage transplantation if the patient develops liver failure. Markov modeling by Majno et al showed that this may not be a cost-effective strategy given the high recurrence rate and that primary OLT may be better.[93]

In many centers, adjuvant therapy is given to delay the progression of HCC while patients are awaiting OLT or shrink the size of the tumor in order to fit OLT criteria (down staging). For instance, RFA has been tried in a number of small case series. In a recent study, 50 patients meeting the Milan criteria were treated with RFA and with a mean waiting time of 9.5 months before transplantation there were no dropouts from the waiting list. This study showed a 3-year survival of 83% and a 4% post-transplantation recurrence.[94]

Similarly, chemoembolization has been used in this setting. In a study by Graziadei et al , 48 patients satisfying the Milan criteria were treated with chemoembolization while waiting for transplantation. They reported no waiting list drop-outs and 5-year survival rates of 94% despite a mean waiting time of 178 days.[95] In another study, 45 patients were treated in a similar protocol with a 6 month 15% drop-out rate due to tumor progression and 25% at 12 months.[96] One study compared patients who received chemoembolization with those who did not and found that responders to treatment fared better than non-responders with a trend towards improved survival compared with the untreated group.[97] Most importantly, complications arising from chemoembolization in these pre-transplantation patients were rare and did not frequently cause drop-outs from the list in the majority of the studies.[87]

It is important to note here that the survival of patients discovered to have incidental tumors in explanted livers is similar to patients transplanted without evidence of tumor.

In Saudi Arabia, although liver transplantation is available and successful and while a long and rich experience has accumulated over the last 10 years, all programs are crippled by the lack of organ donation. With current long waiting lists, OLT does not seem to be a practical option for the majority of HCC patients in Saudi Arabia. Living-related transplantation is being increasingly performed in the Kingdom and its role in HCC is yet to be defined. With the encouraging post-OLT survival rates for HCC obtained with the Mazzaferro criteria and the extreme lack of donors in Saudi Arabia, we recommend using these criteria as the current transplantation criteria and only expanding them in limited circumstances. We also recommend that living-related transplantation be expanded and studied further in the management of HCC.

Hepatic resection

Rapid advances in the field of hepatobiliary surgery have occurred in the past 20 years making major hepatic resection a less morbid procedure. In most large centers in the world, operative mortality in cirrhotic patients is less than 5%.[98] In fact, some leading centers report no mortality after over 100 consecutive cases.[99],[100]

Although tumor resection removes the visible portion of the cancer, it is clearly inferior to transplantation in that it cannot guarantee the removal of invisible tumor seeding. Resection also entails leaving the non-tumorous portions of the liver, which by itself is at high risk of developing malignancy. Furthermore, this surgery does not address the underlying disease and fails to improve hepatic function.

Unfortunately, there are no randomized studies that prove the effectiveness of resection in managing patients with HCC. Large series of liver resection for HCC report a 38-65% 3-year survival and 33-44% 5-year survival[84]. The population in these studies was heterogeneous with different stages of cirrhosis. In patients with small HCCs and relatively preserved liver function, Bismuth et al have shown excellent long term survival results of 40% and 26% at 5 and 10 years respectively.[101]

When more stringent criteria are applied, survival rates have been reported to be as high as 50% in 5 years.[102] These criteria include solitary tumors less than 5 cm in diameter, with no evidence of vascular invasion or extra-hepatic spread, and with either no evidence of cirrhosis or well-compensated Child-Pugh class A cirrhosis. When all the patients in Japan treated with hepatic resection were considered, the most powerful predictor of survival was the combination of three factors: AFP, tumor size, and the number of tumors.[103]

One of the major factors determining the candidacy of patients for radical resection is the stage of the underlying liver disease. Although many surgeons still use the Child-Pugh classification to assess the liver function and would perform a liver resection on non-cirrhotic Child-Pugh class A, or good Child-Pugh class B patients,[98] we feel that the best evidence suggests that other parameters may be more accurate in determining surgical hepatectomy risk in terms of hepatic decompensation. Two such parameters have been shown to be most predictive of decompensation post liver resection. These are: signs of clinically relevant portal hypertension (defined as presence of varices, splenomegaly, platelet count <100,000 or a hepatic veinous pressure gradient > 10 mm Hg) and elevated bilirubin (more than 1 mg/dl).[104] When these criteria are used to select patients, the 5 year survival after resection may be as high as 70%.[88]

Two issues make this modality difficult. First, the majority of patients with HCC will either have too advanced a liver disease that makes liver resection impossible, or have extensive disease at the time of presentation. For this reason, most series show that less than 10% of patients with HCC will be candidates for resection.[104] This problem is expected to be even worse in Saudi Arabia since effective HCC screening programs are not widely implemented. The other problem is that even in patients who undergo resection, the intra-hepatic recurrence rate is high (around 50-60% in 5 years).[105],[106] This recurrence rate is directly proportional to the tumor size. In addition, patients are at an increased risk for new tumors since the cirrhotic liver has not been removed.

We feel that in patients without cirrhosis or with early cirrhosis (indicated by a normal bilirubin and no signs of clinically significant portal hypertension), liver resection should be considered if there is no evidence of extra-hepatic or vascular spread. As a general guideline, non-cirrhotic patients can recover well from resections that preserve at least 2 segments of functioning liver, while patients with well-compensated cirrhosis will tolerate a maximum of 2 resected functional segments of the liver. In some centers pre-operative portal vein thrombosis is performed when a resection of more than 2 functional segments of the liver is performed, with the intention of inducing hypertrophy of the remaining liver.[107]

Many experts do not consider tumor size as an important factor in deciding on resection since size may not represent a technical problem for the skilled hepato-biliary surgeons. However, we feel that the data is clear in that the larger the tumor the more likely the recurrence after resection thereby compromising the patient's survival. In addition, most studies have shown that local ablative therapies may produce similar survival compared to resection. Similarly, the most recent evidence (described shortly) shows that chemoembolization probably has a significant survival benefit, a feature not shown clearly in the case of resection. For these reasons we feel that the best treatment option in a Child-Pugh category A or B cirrhotic patient with a large tumor is probably chemoembolization rather than surgical resection, even if it is technically feasible. Surgical resection should be reserved for patients who are not cirrhotic or patients with well-compensated cirrhosis with small tumors.

In some centers, palliative surgical resection with near total tumor mass resection is practiced after which local ablative therapy is performed to deal with the remaining tumor.[98] This approach is awaiting support by prospective studies.

Ablative therapy

Most patients with HCC are unsuitable for surgical therapies due to extension of the disease, poor hepatic reserve, or coexistent morbidity. Therefore, non-surgical therapies play a central role in the management of this disease.[108] Ablation of HCC has been carried out for many years now. This could be done by either chemical means (absolute alcohol or trichloracetic acid) or physical means (cryoablation, radiofrequency ablation, microwave coagulation, or injection of hot saline). We will only discus the percutaneous ethanol injection (PEI) and radio-frequency ablation (RFA) in this review.

Percutaneous ethanol injection (PEI)

PEI is a widely accepted, minimally invasive method of treating HCC. Its acceptance is based on the ease of treatment, minimal and inexpensive therapeutic equipment required, and good clinical results. It is achieved by injection of 95% absolute ethanol into the tumor under US and/ or CT guidance. Ethanol causes cellular dehydration and subsequent necrosis of the tumor. The goal of this therapy is to achieve complete necrosis of the tumor with extension into the perineoplastic tissue. The amount needed to ablate a given HCC varies with its size. The typical amount given per session is 1-8cc, which can be done two times per week and is usually performed as an outpatient procedure under local anesthesia by an interventional radiologist. Small lesions may be ablated during a single session while larger lesions require multiple sessions to avoid excessive toxicity. Alternatively, large-volume PEI can be performed under general anesthesia.[109] Typically, no more than three lesions, each smaller than 3-5 cm, should be treated. Post procedure imaging and AFP should be obtained at one month and then every 4-6 months to assess tumor response and potential recurrence. Absence of enhancement on CT scan after the procedure is considered evidence of successful tumor necrosis.

Common side effects are pain, fever, and a feeling of intoxication. In the largest series to report complications from PEI[110] the mean number of sessions needed to destroy an HCC nodule was 6.7. One death (0.09%) and 34 complications (3.2%) were reported, and eight episodes of bleeding and seven cases of tumor seeding occurred.

PEI has a high anti-tumor efficacy in small (<3 cm) solitary HCC.[111],[112],[113] This technique is less effective in larger tumors (about 50% effect in tumors between 3-5 cm).[114],[115] In a large series of 746 patients, the 5-year survival of patients with well-compensated cirrhosis and a tumor size smaller than 5 cm who were treated with PEI was 47%, compared with 29% for patients with more advanced impairment of liver function.[112] There are no randomized controlled trials comparing resection versus alcohol injection. In the study by Livraghi et al , including 260 (<5 cm) tumors in Child-Pugh class A cirrhosis, the three year survival was 71% for surgery and 79% for PEI compared with 26% for no treatment.[110] Similarly, Castells et al reported 30 patients with HCC treated with alcohol injection who were compared to 33 patients undergoing surgical resection and found similar survival rates in the two groups.[116] Cohort studies suggest that PEI improves survival of Child-Pugh class A patients with small HCC.[113],[116] Recurrence after effective percutaneous treatment is as frequent as after surgical resection (about 50% at 3 years and above 70% in 5 years).[115],[117] The major disadvantage of PEI is the frequent need for multiple treatment sessions to achieve complete ablation of a lesion.

Although many authors caution that portal vein thrombosis and advanced Child-Pugh class C cirrhosis are contraindications for PEI, we feel that there is no clear evidence to support this claim. Most of the earlier studies have included only Child-Pugh class A or B cirrhotics as the technique was in evolution. The complication rate of patients with Child-Pugh class C cirrhosis will probably be higher but it must be understood that these patients hardly have any other option. Most physicians will not offer these modalities for a Child-Pugh class C patient because of the high underlying mortality of the liver disease precluding the patient from any meaningful clinical benefit that could be derived from percutaneous treatment.

Radiofrequency ablation (RFA)

In RFA, thermal destruction is achieved with an electric current that passes to the tumorous tissue via an electrode tip, placed percutaneously under imaging guidance, resulting in heat generation and coagulation necrosis.[118] This technique seems to be very effective with low recurrence rates. In a study by Curley et al where 149 tumors were ablated, all tumors showed initial complete ablation with the local recurrence rate at 19 months of 3.6%.[119] In another series of 126 HCCs greater than 3 cm, complete necrosis was produced in about 50% of patients.[120]

In comparison to PEI, RFA is believed to be more effective, requires less number of ablative sessions, but at an increased cost. In a comparative study between ethanol injection and RFA, complete tumor necrosis was seen in 90% of patients with RFA and 80% with ethanol injection.[120] In addition, the number of sessions required to complete the tumor necrosis was less in the RFA group. However, the complication rate was higher in RFA than in ethanol ablation group in this study. In another randomized study comparing the two modalities in small HCCs, RFA was found to be superior to PEI in treating HCCs smaller than 3 cm.[121] More recently, another large randomized study was published showing again the superiority of RFA over PEI.[122] In this study from Taiwan 157 patients with HCCs less than 4 cm were randomly assigned to conventional PEI, a higher dose PEI injection, and RFA. The rate of complete tumor necrosis was 88%, 92%, and 96% respectively. Significantly fewer sessions were needed in the RFA arm, and the tumor progression rate was lowest in the RFA arm. Most importantly, the overall survival as well as the cancer-free survival rates was significantly higher in the RFA arm. In a recent Cochrane database systematic review of all the evidence comparing RFA and PEI it was concluded that RFA achieved higher recurrence-free survival rates.[123] To date, there are no long-term survival data on RFA.

Assessing the effect of the ablation procedure in RFA is not as easy as in the case of ethanol injection. CT scan may show a cystic-density lesion that gets progressively smaller in size over time. In general, regardless of the ablative tool employed, a contrast CT at least 4 weeks after the procedure is considered to be the standard imaging modality to assess the effectiveness of the ablation.[1] There are two other technical points worth mentioning regarding RFA. This modality is less effective in central HCCs given their proximity to the large vessels resulting in heat dissipation, "the heat sink effect", due to the high blood flow in these vessels. Ablating such lesions also carries the risk of insulting major vessels and central bile ducts. RFA is technically difficult and risky when dealing with exophytic lesions, those near the gallbladder or kidney, and lesions high in the dome of the liver.

Possible side effects include bleeding from the needle site, fever, abdominal pain, and transient elevation of serum transaminases. A single report has raised the possibility of a high rate of needle tract tumor seeding (up to 12%).[124] But larger series have reported a rate of about 3%.[119] Keeping in mind the results of the studies above, it is reasonable to conclude that RFA is more effective than PEI and requires fewer sessions. It may be associated with improved survival when compared with PEI but probably at the expense of more complications.

Transarterial chemoembolization (TACE)

In this technique, catheterization is performed into the segmental hepatic artery supplying the tumor. Chemotherapeutic agents (commonly doxorubicin, cisplatinum, or mitomycin) are mixed with a water-soluble contrast agent as well as lipiodol (an oily contrast agent that is selectively concentrated in the tumor for many weeks) to form an emulsion. The emulsion is then injected into the artery followed by occlusion of the artery using a material to obstruct the flow (e.g., Gelfoam). This allows high concentration of the drug into the tumor cells, low systemic side effects, and necrosis of the tumor. Uncontrolled studies have shown that vascular occlusion with particles between 150 and 700 mol either with gelatin sponge or with polyvinyl alcohol provide good response rates. Studies are conflicting in regards to the best chemotherapeutic agent to be used.

TACE is effective in around 80% of the time to cause significant necrosis of the tumor. The so-called "post-embolization syndrome" consisting of abdominal pain, ileus, and fever may be seen in as many as 60-80% of patients. Fever usually resolves with symptomatic therapy within a few days and doesn't require prophylactic antibiotics.[125] Potential serious side effects include liver failure, severe localized pain, and formation of liver abscess. Death may be seen in as many as 4% of Child-Pugh category A patients and in as many as 10-20% of Child-Pugh B and C patients.[123]

TACE should not be done when tumor is diffuse throughout the liver; in the presence of liver failure; and with portal vein thrombosis since, the significant liver necrosis caused by the embolization in such scenarios will not be tolerated by the patient. TACE is also contraindicated in cases of porto-systemic shunts, either surgical or transjugular-intrahepatic (TIPS).

At least six randomized controlled trials have been done to evaluate embolization or TACE compared to conservative management.[126] These have all shown a significant effect on tumor size but failed to demonstrate a survival benefit. More recently, two well done, large randomized controlled trials comparing TACE to no treatment as well as a well done meta-analysis has shown clearly the effectiveness of this therapy and its survival benefits.[126]

In a large Spanish study, a clear survival advantage was shown with TACE.[127] In this trial, 112 patients with HCC were included and randomized to arterial embolization only, TACE, or control treatment. Survival at two years was 62% in the chemoembolization arm, versus 50% in the bland embolization arm, and 27% in the untreated arm. In a similar randomized study from Asia, 80 patients were randomized to receive TACE vs. medical management only.[128] TACE resulted in a marked tumor response, and the actuarial survival was significantly better in the TACE group (1-year 57%; 2-year 31%; 3-year 26%) than in the control group (1-year 32%; 2-year 11%; 3-year 3%). The likely explanation for the significant effect of TACE in those two trials is the highly selective approach the investigators took in enrollment as compared to the larger tumors and more advanced liver disease seen in the previous trials. In addition, in both these trials each patient received multiple sessions of TACE in a scheduled manner regardless of the response to the first session.

Moreover, in a meta-analysis of 7 randomized trials by Llovet, TACE was again found to significantly reduce the two-year mortality from 41% in the control group vs. 27% in the TACE group.[129] This effect was only seen with chemoembolization and not with bland embolization. Interestingly, an overall objective response at 1-6 months was seen in only 35% of treated patients. This meta-analysis along with the above well-designed randomized study has shown that TACE is the only therapy in HCC that has reduced mortality in selected patients.

Since TACE can be considered as a "medical resection", it should only be performed in patients with early cirrhosis. Most of the published studies include only Child-Pugh class A patients (70-90%), Okuda stage 1 (47-90%), with multi-nodular HCC without vascular invasion (overall >95%).[129] However, a single trial showing survival benefit of TACE did include patients with Child-Pugh score B.[129] If TACE is performed, a protocol similar to the one published by the Llovet et al should be adopted until future evidence proves or disproves the utility of this protocol. In their published protocol in the randomized study mentioned above, they performed TACE at baseline, 2 months, 6 months, and every 6 months thereafter. We feel that the evidence for a survival benefit with TACE is sound and that this useful procedure should be used more often in the appropriate clinical setting.

Chemotherapy

In general, systemic chemotherapeutic agents have not shown any promising results in HCC.[104] The best single agent is doxorubicin with response rates of 10-15%.[130] More aggressive combination therapy shows no improved response.[131] In a meta-analysis of the published randomized studies on HCC, neither doxorubicin nor any chemotherapeutic agent has been shown to have any survival benefit for HCC patients.[132]

Hormonal therapy

The data on antiestrogen medications like tamoxifen has been mixed. While early studies[133],[134] and one meta-analysis showed some survival benefit, more recent, larger randomized studies showed no benefit.[135],[136] In a recent meta-analysis of all published literature, Llovet found a trend toward improved survival but without statistical significance.[129] Many studies have been performed with antiandrogens but none have shown any survival benefit.[137],[138]

Octreotide

Few prospective studies have been published to date examining the effect of octreotide on advanced HCC. In the first study, 58 patients were randomized to receive 250 g of octreotide two times a day versus no treatment.[139] The median survival was 13 months in the octreotide arm versus only 4 months in the control arm ( P =0.002). This dramatic and impressive result was not confirmed by the second study which randomized 70 patients to octreotide 250 g two times a day for 2 weeks and then the long acting octreotide, sandostatin LAR 30 mg, once monthly versus placebo.[140] The median survival was 1.93 months in the octreotide group versus 1.97 months in the placebo group. In addition, there was no significant improvement in the quality of life in this study. The negative results seen using octreotide is also supported by a multi-center retrospective study conducted in Germany which did not show any survival benefit.[141] These very poor outcomes are surprising. The control arm of the two randomized trials was quite similar according to the Okuda score but the outcome was vastly different. A possible explanation for the wide difference between the two studies could be related to the difference in the natural history between patients from the East and those from Europe. Another aspect to be considered is the tumor characteristics of the population groups studied.

The antiproliferative effect of octreotide is probably regulated by the expression of somatostatin receptors. In one study, only 40% of HCC expressed receptors by autoradiography,[142] while an immunohistochemical study showed expression of receptors in cirrhotic nodules and HCC but not in chronic hepatitis.[143]

Other agents

A randomized study using high doses of interferon alfa for treatment of HCC was performed and showed an improved survival.[144] A subsequent study showed no effect.[145]

Management recommendations

General management: (Algorithms 1-4)

  • Patients with HCC should be managed in tertiary care centers where the desired expertise is available (Grade D).
  • The management plan for patients with HCC should be constructed in a multi-disciplinary forum consisting of a hepatologist, oncologist, interventional radiologist, and a hepatobiliary surgeon (Grade D).
  • Liver tumor weekly rounds should be started at every tertiary care center dealing with HCC patients. In this meeting, all cases of liver tumors should be discussed. The goal of this meeting is to discuss new cases of liver tumors and to reach a joint decision on the most appropriate management route for these patients. It will also improve recruitment in clinical trials and will facilitate the teaching of residents and fellows (Grade D).
  • The decision on the best treatment modality should be based on the following factors (Grade B):

    1. The number of lesions.

    2. The size of the lesions.

    3. The status of the underlying liver.

    4. The status of the portal vein.

    5. The patient's performance status.

    6. The local expertise.

    7. The patients' preferences.


Liver transplantation:

  • Indications for liver transplantation are (Grade B):

    1. Liver cirrhosis.

    2. A single lesion less than 5 cm or less than 3 lesions smaller than 3 cm each.

    3. No evidence of portal vein invasion or extra-hepatic spread.

    4. No contraindications for liver transplantation.To prevent the patient from outgrowing the above transplantation criteria while waiting on the transplant list, local ablative therapy or chemoembolization may be considered to control tumor growth (Grade C).
  • The utility of cadaveric liver transplantation in the management of HCC patients in Saudi Arabia is limited due to the relative lack of donors leading to a long waiting list time. Organ donation should be enhanced.
  • Living-related transplantation should be explored in future studies in Saudi Arabia as an alternative for the long waiting lists of cadaveric transplantation (Grade B).


Liver resection

  • Indications for partial liver resection are (Grade B):

    1. Absence of cirrhosis or early cirrhosis with normal bilirubin and no signs of clinically relevant portal hypertension (defined as presence of varices, splenomegaly, platelet count <100,000 or a hepatic vein pressure gradient > 10 mm Hg).

    2. No evidence of portal vein invasion or of its main branches, or extra-hepatic spread.

    3. Tumor is technically resectable.


Local ablative therapy

  • Indications for local ablative therapy are (Grade A):

    1. Three lesions or less, that are each smaller than 4 cm in diameter.

    2. No evidence of extra-hepatic spread.

    3. Patient is not a candidate for liver resection.
  • The local ablative procedure of choice is RFA. RFA is more effective than alcohol injection especially in lesions larger than 3 cm but with a slightly higher risk (Grade A). It may be associated with improved survival. Technical considerations as regards to the site of the lesion may favor one method over the other.


Chemoembolization

  • Indications of chemoembolization are (Grade A):

    1. Single or multiple lesions more than 4 cm in diameter and less than 10 cm.

    2. No evidence of advanced cirrhosis (Child-Pugh category A or B).

    3. Patent portal vein with normal flow.

    4. Chemoembolization should be performed at baseline, 2 months, 6 months, and every 6 months thereafter for a total of 6 cycles as long as the patient is responding to therapy (Grade A).


Other therapies

  • Patients with vascular invasion, extrahepatic spread, or diffuse multifocal disease may be enrolled in a clinical trial of systemic chemotherapy therapy (Grade D).
  • Octreotide cannot be recommended based on the available evidence (Grade A).
  • Patients with Child-Pugh class C should be offered medical therapy only (Grade D).
  • A specialized palliative care team should be involved in the management of end-stage HCC (Grade D).



   Prevention Top


Prevention of infection

Vaccination program

Vaccination is a very powerful measure to reduce the infection rate of hepatitis B and hence, reduce the incidence of HCC. The nationwide hepatitis B vaccination program launched in Taiwan in 1984 led to a reduction of the hepatitis carrier rate in children from 10% to less than 1% and to a reduction in the incidence of HCC from 0.7 to 0.36 per 100,000 between 1986 and 1994.[146] In Saudi Arabia, routine hepatitis B vaccination of children was added as a part of the extended program of immunization in 1989. A dramatic reduction was noted in the prevalence of hepatitis B from 6.7% in 1989 to 0.3% in 1997.[8] No evidence is available yet on the effect of this reduction on the incidence of HCC.

No effective vaccine is available for hepatitis C so far. The prevalence of hepatitis C in the Kingdom has also dropped recently, likely secondary to improved living conditions, hygiene, and adequate blood screening measures. This will probably also reflect in a reduced incidence of HCC.

Universal precautions and management post exposure

Universal precautions of health care workers are effective in reducing the exposure to viral hepatitis. Post-exposure prophylaxis with HBIG and vaccination is important in reducing the risk of chronic hepatitis B. In the case of HCV, HCV-RNA should be measured and the patient referred for consideration for early antiviral therapy as most recent evidence suggests a very high response rate when patients are treated early.[147]

Treatment of viral hepatitis

If cirrhosis is the most important risk factor for the development of HCC, could the incidence of HCC be reduced by preventing cirrhosis or treating cirrhosis due to viral hepatitis with antiviral therapy? Many studies in hepatitis B and hepatitis C show that treatment of active hepatitis, especially when successful, may lead to a reduction in the incidence of HCC.

Hepatitis C

Multiple prospective and retrospective studies were performed to assess the effect of treating cirrhotic hepatitis C patients on HCC incidence. In a small Japanese randomized study which was published in 1995 (and updated in 2001) it was shown that there was a reduction in the number of HCC cases in patients with cirrhosis caused by Hepatitis C treated with interferon (IFN) versus untreated patients.[148] In this study, after an average of 8.2 years of follow up, HCC developed in 73% of untreated patients but in only 27% of IFN treated patients. However, the high rate of HCC found in this study has shed doubt on its findings. Nevertheless, another study from Japan reached similar conclusions.[149] Studies from Europe though, were less clear. Two short-term studies showed no benefit of IFN on rate of HCC,[150],[151] while one showed a beneficial effect.[152] Two reasons may account for the above discrepancy. First, the response rate of IFN is much higher in Japanese patients than in European patients (due to the difference in hepatitis C genotypes). In addition, the incidence of HCC in Japanese patients is significantly higher than that in Europe. Both of these factors can account for the discrepancy between the Japanese trials and the European ones.[153]

Since this issue was not resolved by the available data, 3 separate meta-analysis[154],[155],[156] and one systematic review[157] was performed on all retrospective and prospective studies on this issue. Most of these reviews indicated that there was a significant but small effect of IFN therapy on the incidence of HCC especially in patients who achieve a sustained virological response to therapy.

There is even evidence that treatment of hepatitis C patients who are not cirrhotic may reduce the incidence of HCC. In a large retrospective study from Japan a reduction in HCC was seen in all patients receiving IFN (1.1%) compared to untreated patients (3.1%) after a median of 4.3 years of follow up.[158] This effect was seen more in patients who achieved a sustained virological response. These results are supported by two other large Japanese studies.[159],[160] From the above data, it seems reasonable to conclude that effective and early treatment of chronic hepatitis C patients with the intent to eradicate the virus and prevent the development of cirrhosis will reduce the incidence of HCC.

There are two randomized studies investigating the effect of interferon therapy in secondary prevention of recurrent HCC after surgical resection or local ablative therapies. In the first study which was done after surgical resection, the recurrence of HCC rate was similar in the IFN treated arm compared with the untreated arm in the first two years after resection but then dropped significantly afterwards.[161] In the second study, IFN was used after successful local ablative therapy and although the first recurrence rates were similar, second and third recurrence rates were significantly lowered by IFN therapy leading to a survival benefit after 7 years of follow up.[162]

Hepatitis B

The data is less clear in the case of HBV treatment probably related to the lack of effective therapy rather than the absence of effect. There is reasonable evidence to suggest that the risk of HCC in patients with chronic hepatitis B is related to the level of viral replication.[163] One randomized study reported a reduction in the rate of HCC among IFN treated patients with chronic hepatitis B from 12% to 1.5% after 1-10 years of follow up.[164] In addition, there are a number of non-randomized studies suggesting the same effect but were all unable to provide conclusive evidence because of the small number of patients [163]. At least 7 non-randomized studies investigated the effect of IFN therapy on the rate of HCC development in patients with HBV related cirrhosis and these were summarized in a recent meta-analysis [155]. This analysis suggests that indeed there is significant reduction in the incidence of HCC with IFN treatment.

Much more impressive results are seen with lamivudine. In a recent trial involving 651 patients with advanced liver cirrhosis secondary to HBV who were randomized to receive lamivudine or placebo for five years, the study had to be terminated early because of a marked reduction in mortality and achievement of end points in the lamivudine arm compared with the placebo arm.[165] The Child-Pugh score increased in 3.9% in the lamivudine arm versus 7.4% in the placebo arm. The incidence of HCC was 7.4% in the placebo arm versus 3.9% in the lamivudine arm, and these results were statistically significant. We feel that this data is clear in the importance of starting patients with end-stage HBV cirrhosis on lamivudine or newer more potent antiviral therapies like adefovir or entecavir in that this will probably reduce the chances of developing HCC.

Screening

Although many modeling data exist suggesting that screening can reduce HCC related disease-specific mortality in a cost-effective manner,[166],[167] there is only one randomized trial showing benefit,[168] while most other studies do not. In the study showing benefit from China, 18,816 patients where screened with 6-monthly AFP and ultrasound showing a reduced mortality rate by 37% in the screened arm even though the adherence to the surveillance was only around 60%.[168] The screened population in this study comprised of patients with current infection or previous exposure to HBV.

Screening for HCC meets a few but not most of the standard criteria for assessing the feasibility of screening programs.[1] This disease is the third common cause of cancer-related death worldwide. It is the second commonest cancer in Saudi men and is associated with a substantial morbidity and mortality. Although it is quite clear that the target population for HCC screening should be cirrhotic patients, especially secondary to hepatitis B or C, the majority of these patients may remain asymptomatic for a long time.[169] In addition, 20% to 56% of patients presenting with HCC may have previously undiagnosed cirrhosis. Expert opinion suggests that the best candidates for screening are Child-Pugh class A cirrhotics (as they may be candidates for resection or local ablative therapies), and Child-Pugh B and C cirrhotics who are candidates for liver transplantation.[1],[3] Because potentially curative treatment options cannot be used in all patients with HCC, some suggest that only patients who are candidates for these therapies should undergo screening.

Recommendations are not clear regarding the need to screen chronic HBV carriers. Studies from Asia suggest that the annual incidence of HCC in HBV carriers is around 0.5%.[23],[25] On the other hand, studies from North America are conflicting. Although the incidence of HCC in HBV carriers is low, it is estimated to be at least 100 times more common that the general population.[25] In many studies, this incidence was found to increase significantly after the age of 40, regardless of the presence of cirrhosis or inflammation.[170] For these reasons, if a patient is above 40 years of age or has family history of HCC then screening may be offered, otherwise the risk of development of HCC in non-cirrhotic, inactive HBV carriers is low and there is no available evidence that they need to be screened. Similarly, non-cirrhotic HCV patients do not need to be screened.[171]

After identifying the target population we need to have a safe and effective screening tool. The two screening tools available are AFP and US. AFP has a low sensitivity (about 40-60%), a reasonable specificity (80-90%), but a poor positive predictive value of 9-32%, which makes it a poor screening tool.[166] In spite of its low sensitivity, screening using AFP has been shown in one study to lead to earlier detection of HCC at treatable stage.[172] As a screening tool for HCC, US has a sensitivity of about 70% (depending on the size of the lesion and the operator), a specificity of about 90%, but similar to AFP, a poor positive predictive value of 14%.[166] Better results were reported in a more recent study on patients who were on a waiting list for liver transplantation, were the sensitivity was 58%, specificity 94%, and positive predictive value of 69%.[173]

Most authorities suggest a screening interval of 6 months based on data suggesting that the time from undetectable lesion to a 2 cm lesion is about 4-12 months.[1]

Another problem with screening for HCC is the absence of a clear recall policy. There are no evidence-based suggestions as to what are the confirmatory tests required once a patient has a positive screening test. As discussed above in the diagnosis section, most authorities recommend two imaging studies that demonstrate early perfusion, or a tissue diagnosis.

The last but not the least requirement of an effective screening program is the ability to demonstrate a reduction in mortality from the disease at hand by early detection of the disease through this screening tool. In the case of HCC, there are no randomized studies supporting this. Some small studies have shown that tumors detected by screening are usually smaller and more amenable to potentially curative therapies. These studies were summarized and tabulated by Collier and Sherman.[166] For example, in a study from Japan, 81% of 391 HCC detected by surveillance were considered suitable for curative resection compared with 46% of 1,251 symptomatic HCC.[174] When all the available studies of tumors detected by surveillance were considered, 50-75% were unifocal and 3 cm or less in size and thus potentially curable, but in the majority of studies, only 29-54% were actually resected due to the presence of other contraindications.[166] All the studies in this area are subject to lead time bias resulting in a false impression of an extended survival which in fact is secondary only to longer detection and not due to a real prolongation of life compared to unscreened patients. In their own screening program, Sherman et al screened 1,069 HBV carriers for periods of 6 months to 5 years.[175] Over this period, 14 tumors were detected, of which six were resected. Two tumors recurred after resection and one patient died while only 3 patients survived more than 2 years from diagnosis. Five other screening programs results are summarized by Collier and Sherman, all showing that you need a large number of patients to be able to detect early tumors.[166]

In a recent study from Spain, Velazquez et al screened 463 cirrhotic patients every 3-6 months using AFP and US.[176] They restricted the study to patients between ages of 40 and 65. They excluded screening patients with advanced liver disease (Child-Pugh class C) as they were not candidates for any therapy and so should not be screened. The investigators diagnosed 38 patients with HCC during a mean of 33 months follow-up. This study identified men older than 55 years of age with HCV infection and some degree of liver impairment as the highest risk for HCC. Young alcoholics or young HBV carriers were at low risk.

At least three studies have been performed to assess the cost-effectiveness of screening for HCC. Allowing for limitations, all studies showed that the cost of these screening programs compared to the number of lives saved is within what would be considered a cost-effective screening tool.[177],[178],[179]

Given the above data, although evidence of a significant impact of screening for HCC on patients' survival or long term outcome is lacking, it seems reasonable to recommend non-invasive measures such as US and AFP to screen high risk patients i.e. patients with cirrhosis especially secondary to viral hepatitis. The screening of HBV carriers without cirrhosis, although recommended by some authors, cannot be supported by evidence at this time.

Prevention recommendations

  • Vaccination of people at risk for hepatitis B infection should be encouraged (Grade B).
  • Post-exposure prophylaxis for hepatitis B should be implemented in all hospitals (Grade B).
  • Post-exposure testing for hepatitis C using PCR-based assays, and early treatment of hepatitis C should be implemented (Grade B).
  • Consideration for treatment of all patients with hepatitis C who have elevated liver enzymes, active hepatitis on liver biopsy, and a positive HCV-RNA test, by using pegylated interferon plus ribavirin (Grade A).
  • All patients with chronic hepatitis B, elevated liver enzymes, a liver biopsy showing active inflammation or significant fibrosis, and an HBV DNA more than 105 copies/ml should be considered for antiviral therapy using pegylated interferon monotherapy, lamivudine, adefovir or entecavir (Grade A).
  • All patients with hepatitis B related end-stage liver cirrhosis should be considered for long-term lamivudine / adefovi/ entecavir therapy since this is expected to reduce the mortality and incidence of HCC (Grade A).
  • Screening using AFP and US should be implemented in all cirrhotic patients every 6 months (Grade A).
  • Screening of patients with chronic hepatitis B without evidence of cirrhosis cannot be recommended at this time but may be offered in certain high risk groups like patients above 40 years of age and in those with a family history of HCC (Grade C).
  • There is no evidence to recommend screening of patients with chronic hepatitis C without cirrhosis (Grade C).
  • Any patient with an US suggesting HCC should undergo further imaging with a triphasic CT scan or an MRI (Grade B).



   Areas of Suggested Research for HCC in Saudi Arabia Top


Areas of suggested research

  • Large epidemiologic studies to identify the patterns of disease and its clinico-pathological aspects in Saudi Arabia.
  • A large study to assess the feasibility, effectiveness, and cost-effectiveness of a screening program in patients with cirrhosis secondary to hepatitis B or hepatitis C, and patients with chronic hepatitis B without cirrhosis.
  • The following arms of the treatment algorithm need to be further explored by well-designed (preferably randomized) studies:

    1. Comparing resection with local ablative therapy or TACE in patients with early or no cirrhosis, and lesions less than 5 cm in size.

    2. Comparing different modalities of local ablative therapies.

    3. Comparing local ablative therapy versus TACE in lesions less than 5 cm.

    4. Role of TACE in shrinking tumors in preparation for resection or liver transplantation.

    5. Utility of newer systemic chemotherapeutic agents in non-resectable tumors versus standard medical therapy.



   Summary of Recommendations Top


Epidemiology

  • Much more resources should be allocated to this important medical problem in Saudi Arabia.
  • Large epidemiologic studies are needed to further define the epidemiologic features of HCC in Saudi Arabia.
  • Patients with cirrhosis of any etiology, but especially cirrhosis caused by hepatitis B or C, are at an increased risk for the development of HCC and these patients should be targeted for a screening program (grade A)
  • The incidence of HCC in those with hepatitis B infection without underlying cirrhosis, in Saudi Arabia needs to be studied further before firm screening recommendations can be given.


Clinical presentation

In patients with stable cirrhosis, rapid deterioration of liver function, new onset ascites, weight loss, or increased jaundice should initiate investigations for HCC (Grade C).

Diagnosis

  • US should be the initial radiological investigation performed when HCC is suspected (Grade C).
  • Further imaging should be performed if an abnormality is found or if the suspicion of HCC is high even if the US is normal (Grade C).
  • Triphasic CT scan and MRI are the radiological procedures of choice to confirm the diagnosis of HCC (Grade B).
  • It is extremely important that the CT scan is done in a standard triphasic technique and is read by a trained abdominal radiologist (Grade A).
  • The diagnosis of HCC may be positively made if the following conditions are achieved (Grade B):

    1. The liver is cirrhotic

    2. The lesion is larger than 2 cm in diameter

    3. One of the two following criteria is met:a. AFP is higher than 400 ng/L and one imaging modality confirms early arterial enhancement and venous washout. ORb. AFP is normal and two imaging modalities confirm early arterial enhancement and venous washout.
  • A histological diagnosis is recommended in the following circumstances (Grade B):

    1. If a lesion is found in a non-cirrhotic liver and radiological investigations are not conclusive for hemangioma, focal nodular hyperplasia, or adenoma.

    2. If the suspicion of HCC is high but the non-invasive criteria mentioned above are not satisfied.
  • Although AFP is a poor screening tool for HCC, it should be measured in all suspected cases. Levels below 400 ng/L are suggestive of HCC, but may be seen in patients with active hepatitis without HCC. Levels above 1000 ng/L are more specific for HCC. A persistently increasing AFP is highly suggestive of HCC (grade B).


Staging

  • Liver tumor weekly rounds should be started at every tertiary care center dealing with HCC patients. In this meeting, all cases of liver tumors should be discussed. The group should be composed of a hepatologist, an oncologist, a hepatobiliary surgeon, and an intervention radiologist. The goal of this meeting is to discuss new cases of liver tumors and to reach a joint decision on the most appropriate management route for these patients. It will also improve recruitment in clinical trials and will facilitate the teaching of residents and fellows (Grade D).
  • Patients with a liver mass should be evaluated in the weekly liver tumor rounds. This evaluation will help determine the next step in obtaining a final diagnosis, determine the extent of hepatic involvement, rule out extrahepatic disease, evaluate the general medical status and performance of the patient, and evaluate functional hepatic reserve (Grade D).
  • Initial evaluation of patients with HCC should include the following (Grade D):

    1. A complete history

    2. A full physical examination

    3. Initial laboratory tests including: A complete blood count, random serum glucose, serum electrolytes, renal function, alfa-feto protein, serum calcium, prothrombin time, and liver function tests.

    4. Chest X- ray (or a CT chest if there are suspicious lesions for metastases on the chest X-ray)

    5. Bone scan (only on initial visit and every 9 months thereafter)
  • Follow up visits should also include all the above tests at least every 3 to 6 months as long as the patient is in an active treatment arm of the management plan (Grade D).
  • It is clear that no single classification system is superior to the others with there being advantages and disadvantages for each one.
  • Although each staging system has its own advantages and disadvantages, the CLIP score enjoys epidemiologic support and prospective validation while the BCLC is probably preferred in planning future treatment (Grade B).


Management recommendations

General management: (Algorithms 1-4)

  • Patients with HCC should be managed in tertiary care centers where the desired expertise is available (Grade D).
  • The management plan for patients with HCC should be constructed in a multi-disciplinary forum consisting of a hepatologist, oncologist, interventional radiologist, and a hepatobiliary surgeon (Grade D).
  • Liver tumor weekly rounds should be started at every tertiary care center dealing with HCC patients. In this meeting, all cases of liver tumors should be discussed. The goal of this meeting is to discuss new cases of liver tumors and to reach a joint decision on the most appropriate management route for these patients. It will also improve recruitment in clinical trials and will facilitate the teaching of residents and fellows (grade D).
  • The decision on the best treatment modality should be based on the following factors (Grade B):

    1. The number of lesions.

    2. The size of the lesions.

    3. The status of the underlying liver.

    4. The status of the portal vein.

    5. The patient's performance status.

    6. The local expertise.

    7. The patients' preferences.


Liver transplantation

  • Indications for liver transplantation are (Grade B):

    1. Liver cirrhosis.

    2. A single lesion less than 5 cm or less than 3 lesions smaller than 3 cm each.

    3. No evidence of portal vein invasion or extra-hepatic spread.

    4. No contraindications for liver transplantation.
  • To prevent the patient from outgrowing the above transplantation criteria while waiting on the transplant list, local ablative therapy or chemoembolization may be considered to control tumor growth (Grade C).
  • The utility of cadaveric liver transplantation in the management of HCC patients in Saudi Arabia is limited due to the relative lack of donors leading to a long waiting list time. Organ donation should be enhanced.
  • Living-related transplantation should be explored in future studies in Saudi Arabia as an alternative for the long waiting lists of cadaveric transplantation (Grade B).


Liver resection

  • Indications for partial liver resection are (Grade B):

    1. Absence of cirrhosis or early cirrhosis with normal bilirubin and no signs of clinically relevant portal hypertension (defined as presence of varices, splenomegaly, platelet count <100,000 or a hepatic vein pressure gradient > 10 mm Hg).

    2. No evidence of portal vein invasion or of its main branches, or extra-hepatic spread.

    3. Tumor is technically resectable.


Local ablative therapy

  • Indications for local ablative therapy are (Grade A):

    1. Three lesions or less, that are each smaller than 4 cm in diameter.

    2. No evidence of extra-hepatic spread.

    3. Patient is not a candidate for liver resection.
  • The local ablative procedure of choice is RFA. RFA is more effective than alcohol injection especially in lesions larger than 3 cm but with a slightly higher risk (Grade A). It may be associated with improved survival. Technical considerations as regards to the site of the lesion may favor one method over the other.


Chemoembolization

  • Indications of chemoembolization are (Grade A):

    1. Single or multiple lesions more than 4 cm in diameter and less than 10 cm.

    2. No evidence of advanced cirrhosis (Child-Pugh category A or B).

    3. Patent portal vein with normal flow.
  • Chemoembolization should be performed at baseline, 2 months, 6 months, and every 6 months thereafter for a total of 6 cycles as long as the patient is responding to therapy (Grade A).


Other therapies

  • Patients with vascular invasion, extrahepatic spread, or diffuse multifocal disease may be enrolled in a clinical trial of systemic chemotherapy therapy (Grade D).
  • Octreotide cannot be recommended based on the available evidence (Grade A).
  • Patients with Child-Pugh class C should be offered medical therapy only (Grade D).
  • A specialized palliative care team should be involved in the management of end-stage HCC (Grade D).


Areas of suggested research

  • Large epidemiologic studies to identify the patterns of disease and its clinico-pathological aspects in Saudi Arabia.
  • A large study to assess the feasibility, effectiveness, and cost-effectiveness of a screening program in patients with cirrhosis secondary to hepatitis B or hepatitis C, and patients with chronic hepatitis B without cirrhosis.
  • The following arms of the treatment algorithm need to be further explored by well-designed (preferably randomized) studies:

    1. Comparing resection with local ablative therapy or TACE in patients with early or no cirrhosis, and lesions less than 5 cm in size.

    2. Comparing different modalities of local ablative therapies.

    3. Comparing local ablative therapy versus TACE in lesions less than 5 cm.

    4. Role of TACE in shrinking tumors in preparation for resection or liver transplantation.

    5. Utility of newer systemic chemotherapeutic agents in non-resectable tumors versus standard medical therapy.


 
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