Guide Progress in Hepatocellular Carcinoma Treatment

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Cirrhosis caused by hemochromatosis or alcoholism has also been associated with high incidence of HCC. Amongst patients with HBV infection, incidence is increased in those with active hepatitis or persistent antigenemia. This association has been well documented in a number of studies 3,4. Using appropriate restriction endonuclease diagestion and southern blot analysis, this genomic integration has been demonstrated in almost three- fourths of patients with HCC 5. Several mechanisms have beenpostulated to explain the putative role played by the hepatitis B virus in the causation of HCC.

These include the possibilities that HBV may contain transforming genes that produce oncogemc products, or virus-induced rearrangement of cellular DNA may alter genes controlling cell growth, or integrated viral DNA may contain promoter and enhancer segments whichmight inappropriately activate cellular oncogenes. In a prospective study of patients with chronic liver disease from Osaka, Japan, it was observed that risk of liver cancer increased almost four-folds in patients with anti-HCV antibodies Monoclonal antibody 6A10 against Aflatoxin B 1 adducts was used for detection.

Alcoholism is also implicated in the etiology of HCC. Alcohol gives rise to alcoholic cirrhosis, a chronic liver disease, which may predispose the patient to develop HCC. It has been observed that some hepatic tumor cells express surface estrogen and androgen receptors. With a mean follow-up of 4. Elevated serum testosterone levels correlated with an increased risk of HCC. This association remained significant even after the adjustment for otherHCC risk factors Drugs that block the testosterone recepiors are being evaluated as therapeutic modalities in the treatment of HCC Clinical Features HCC occurs most commonly in middle aged to elderly men.

Patients often present with constitutional symptoms like anorexia and weight loss. On examination, there may be a palpable irregular mass arising from the liver. Since HCC is a very vascular tumor, a hepatic bruit may be heard. Diagnosis Patients at the time of presentation, having clinical signs and symptoms referable to HCC carry a dire prognosis.

Screening is possible in high risk populations, such as patients with cirrhosis and chronic hepatitis C virus, or hepatitis B virus carriers. Sensitive immunoassays can detect increase in serum alpha fetoprotein AFP or des-garnma-carboxyprothrombin in some patients with small and asyniptornatic HCC 17, This in combination with liver ultrasound, increases the diagnostic yield in screening studies.

It is also useful for monitoring recurrence. Serum AFP levels correlate closely with tumor size A new assay of AFP using monoclonal antibody may enable the clinicians to distinguish benign from malignant liver disease Des-gamma-Carboxyprothrombin: An abnormal prothrombin which is found in the serum of patients with HCC. Levels are undetectable in the normal subjects. A number of othermethods have also been used to diagnose and screen forHCC. None has yet proven better than AFP as a screening test. Imaging modalities Any hepatic mass in a patient with chronic hepatitis or cirrhosis must be considered malignant and differentiated from a benign lesion.

A numberof imaging modalities are used to detect HCC. Ultrasonography is frequently used to screen high-risk populations and should be the first study done when HCC is suspected. Ultrasonography can detect tumors 1 cm in size or more It is inexpensive and an effective diagnostic and screening tool. For most tumors, it is probably as sensitive as any other imaging modality It has equal or increased sensitivity compared to radionucleide scans. It can also be used to guide the aspiration needle and to better define the anatomy.

Recently, a new method for the contrast enhancement of hepatic tumors using ultrasonography has been found to be useful. This is currently one of the most sensitive methods for detecting small HCC Radionucleide-labelled colloid scan is also used for detection of HCC. It may be required if ultrasound is not helpful, if surgery is planned, or if uncertainty exists as to the extent of the tumor. Technetium 99m sulphur colloid is used for hepatic scintigraphy.

This study is based on uptake of colloid by the hepatic reticuloendothelial system. It results in photopenic areas in the liver. Gallium scan is better in cases with lot of background activity due to cirrhosis. Computerized axial tomography CAT scan can detect and delineate the extent of hepatic tumors. It is relatively sensitive, non- invasive and can detect most tumors greater than 3 mm in size Coeliac axis angiography is sensitive and indispensable before surgery It gives information about the extent of the tumor and arteriovenous supply before surgical resection of the tumor.

Debate: Optimal treatment of localized HCC? - Ablation

Lipoidol, an ether ester of poppy seed fatty acid oil combined with iodine, is a contrast medium which is, selectively retained intumorvessels and small tumor nodules. By emulsifying an anti-tumor agent with lipoidol, the tumor can selectively be necrosed before surgery. Apercutaneousliverbiopsy orcytologic examination of fine needle aspirate should be done to differentiate the tumor from benign lesions.

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Although histologic confirmation of HCC is necessary, possibility of dissemination of tumor along the biopsy needle track must be considered. Fine needle biopsy or aspiration of the tumor is therefore preferable. If histologic confirmation is not possible as in patients with cirrhosis and severe coagulopathy, a rising semmAFP, tumorvascularity on angiography and a focus of lipoidol retention are sufficient to establish the diagnosis of HCC.

Efforts are currently underway to evaluate precancerous and early cancerous lesions further by using oncogene analysis, chrornosomal rearrangement and staining of the extracellular matrix antigens and Mallory bodies Staging criteria for hepatocellular carcinoma A staging system based upon clinica lcharacteristics that recognizes the contribution of underlying liver disease has been developed by Okuda and colleagues This is presented in Table II.

The natural history of Hepatocellular carcinoma HCC can be unifocal, multifocal or infiltrative. A distinct clinicopathologic type is fibrolameller variety. This usually occurs in young adults, has no association with cirrhosis and carries a better prognosis. Frequent presentation of HCC at an advanced stage has lead to two common misconceptions regarding the disease.

Firstly, it is regarded as a rapidly growing tumour and secondly, that it is a universally fatal disease. In fact, HCC is slow growing and can be cured if detected and surgically resectedat an early stage 40, HCC is relatively slow growing in comparison to other adenocarcinomas such as breast or colon cancer.

Growth rate of this cancer has been documented in studies by Sheu and co-workers from Taiwan 42, Doubling time of the tumor ranged from 1 to 14 months, the median being four months. Furthermore, for early detection of an average growth rate HCC, screening need only be done once a year.

This should detect most tumors at a stage when they are still potentially resectable with subsequently favourable outcome. HCC is locally invasive and invades vascular structures such as inferior vena cava or portal vein Autopsy studies indicate that frequent sites of metastasis include lungs, adrenals, bones, diaphragm.

CNS as well as direct extension of the tumor through the portal and hepatic venous systems. Because of lack of comparative trials, the choice of treatment is a decision based upon the size and number of the tumors and underlying liver function as well as availability of local expertise and interest. Surgery Presently surgical resection offers the only chance of cure for patients with HCC. Factors that limit resectability include presence of metastases. Important factors requiring assessment prior to surgery include measurement of hepatic synthetic function as indicated by semm albumin and bilirubin levels as well as prothrombin time.

Cirrhosis alone is not a contraindication to surgery as long as hepatic function is not decompensated. In general, tumor recurrence is the main cause of poor prognosis in patients operated for HCC. Many factors including tumor size, resection margins and portal vein invasion have been analyzed to prognosticate the risk of tumor recurrence. Patients with tumor size less than or equal to 5 cms or a solitary tumor have a better disease free survival than those with tumor size greater than 5cms or with multifocal disease.

DNA ploidy also affects overall survival. Patients with aneuploid tumors have greater tendency to recur early after hepatic resection as compared to patients with diploid tumors. Those with poor prognostic factors may benefit from multimodality approach and require closer follow-up Despite improvements in resection techniques such as the ultrasonic dissector and the argon gas coagulator, most patients with HCC remain un resectable. This is usually due to the extent of intra-hepatic disease. It is in these patients that multimodality approach may offer improved chances of survival by reducing intrahepatic disease and increasing the subsequent resectability.

In a recent study. Twenty-one patients had initially resectable tumors. Fourteen patients had initially unresectable lesions. They subsequently underwent resection. This suggests that some patients with unresectable tumors may become operable with survival rates which are similar to those with initially resectable cancer Transplantation: This appears to be a rational form of therapy for patients with both decompensating cirrhosis and HCC. The role oforthotopic liver transplantation OTL in the treatment of primary hepatic diseases is now widely accepted However, rate of tumor recurrence is high.

Severe hepatic dysfunction, multifocal tumors, bilobar tumors or centrally located tumors are the strongest factors favouring total hepatectonw and OTL over partial hepatectomy. Patients with extra hepatic disease should not be treated by either surgical method and a thorough search for extrahepatic disease must be under-taken before surgical intervention. Chemotherapy Treatment of HCC patients with chemotherapy has thus far yielded a low response rate and poor survival.

Prognostic factors like performance status, sex, age, presence of jaundice. Okada et al retrospectively analyzed the significance of different prognostic factors in patients who received systemic chemotherapy inaphase II trial These can be used to classify patients into different prognostic groups with an impact on survival. Design and analysis of future clinical trials should incorporate these prognostic factors.

In most controlled trials, alkylating agents have been of little use except for intravenous Ifosfomide. This drug merits further trials to fully evaluate its potential.


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Combination chemotherapy: In general, nothing is gained by adding cytostatics in the management ofHCC. It only leads to increased toxicity. So far none of the combined treatments have given results superior to single agents This selects out patients with favourable prognostic factors. Although local tumor shrinkage occurs, considerable toxicity, morbidity, and at time mortality is associated with this therapy.

Itis also associated with severe toxicity limiting the dose to be administered and decreasing the duration of treatment. It only responds to termination of therapy. Biliaiy sclerosis may also occur and is related to drug-induced cholestatis. It is an irreversible complication Onset of toxicity may be decreased or delayed by utilizing a lower dose of the drug. These include: a Time modified drug delivery involves infusing greatest amount of drug during the periods of maximally expected resistance to toxicity i.

This work is preliminary and results are yet to be reported. Pharmacologic modulation of FUDR toxicity has also been tried with co-administration of dexamethasone. Dipyridamole, an anti-platelet agent, may play a role in limiting the biliary damage from FUDR; a chemical arteritis and microvascular thrombosis resulting in fibrosis. Trials are presently in progress. External radiation: This has a limited role as doses greater than rads within three weeks lead to radiation hepatitis.

Surgical ligation of the hepatic artery leads to preferential ischemia and necrosis of the tumor. However, surgical ligation later leads to the development of collateral vessels thus defeating the aim. Embolization of hepatic artery can be achieved by using vaso occlusive agents such as starch microspheres, gelfoam, angiostat or polyvinyl alcohol. This therapy, if delivered preoperatively, may allow for simplerand after hepatic resections. Chemo-embolization is another modality where anti tumour effect of the drug is enhanced by interruption of blood flow resulting in increased local concentration of the drug.

It also induces tumor ischemia. Systemic side effects such as nausea and vomiting are also decreased in frequency and severity. A common finding after chemo-embolization is radiological evidence of tumor necrosis. Though not a standard response criteria, this often correlates with pathologic evidence of tumor destruction 70, Enhancement of intra-arterial chemotherapy: This is done by using contrast dye Lipoidol. Lipoidol concentrates in the liver tumor tissue due to its abnormal vascular structure.

Percutaneous intra-tumor alcohol injection: This causes immediate coagulation necrosis due to small vessel damage It is done under ultrasound guidance. Liver lesions less than 3 cms in diameter have been rendered necrotic. It is specially useful for patients with solitary tumors. Long term utility of this approach and impact on survival remain to be proven in prospective randomized trials. Cryosurgery: In this technique, cryo-probes are used to circulate liquid nitrogen through the tip which freezes tissue within a 3 ems radius from the trocar.

At less than 20 degrees centigrade, most cells tumor and non-tumor undergo instant freezing and are killed. It is useful for treating small lesions There is, however, significant toxicity due to gamma emmision from iodine isotope. Another radiolabelled isotope yttrium 90 interferes with the Fab end of the antibody and concentrates in hyperplastic liver rather than the primary tumor Hormonal agents: It has been observed that hepatic tumors express estrogen and androgen receptors This has prompted the use of agents like tamoxifen anti-estrogen and androcur anti- androgen as?

A recent study suggests an effect of Interferons Provocative gene therapy: Huber and colleagues reported an innovative approach involving retroviral-mediated, gene-therapy for the treatment of neoplastic diseases This approach exploits the transcriptional differences between normal and neoplastic cells to achieve selective killing of cancer cells.

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They described this approach for the treatment of HCC. Replication-defective retroviruses were constructed containing a varicella-zoster virus thymidine kinase VZV TK gene that is transcriptionally regulated by either the hepatoma-associated aipha-fetoprotein or liver associated albumin transcriptional regulatory sequences. After retroviral infection, expression of VZV TK was linked to either aipha-fetoprotein or albumin-positive cells.

HCC is a preventable disease. Additionally, poor prognosis associated with HCC may be improved ifitcanbe detected and treated at an early stage. This can be achieved by utilizing AFP and ultrasonography in high risk patients. Forthose with more advanced disease, several modes of treatment are available with the potential to improve survival and ability to provide significant palliation. Multimodality therapies are generally more effective.


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Proper selection of patients and therapy require understanding of biology of the tumor, intm-tumoml blood flow, tumor extent and hepatic function Novel therapeutic approaches for patients with unresectable HCC have promising initial results. Further trials are indicated. Muir, C. Cancer incidence in five continents.

International Agency for Research in Cancer, 2. Tribell, C. Prevalence of hepatocellular carcinoma and relation to cirrhosis. Hepatology, ; Beasley, R. P Hepatitis B virus as the etiologic agent in hepatocellular carcinoma: Epidemiologic considerations. Hepatology, ; Hepatitis B virus.

The major etiology ofhepatocellular carcinoma. Charles, S. Mott Prize. Cancer, Shafritz, D. Intigration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma: Studies in percutaneous biopsies and postmortem tissue specimens.

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Kew, M. Hepatitis C virus antibodies in Southern African blacks with hepatocellular carcinoma. Discontinued publication For more information click here. Previous article Next article. Issue 5. Pages September - October Download PDF. Related content.

FDA Approves Hepatocellular Carcinoma Therapy, Cabozantinib

GE Portuguese Journal of Gastroenterology. This item has received. Under a Creative Commons license. Article information. The authors concluded that continued surveillance is recommended for CHB patients on antiviral therapy. However, comparative data among these therapies is lacking. It is an oral multikinase inhibitor that increases apoptosis and reduces cell proliferation and angiogenesis, approved in for the treatment of HCC in patients who are not candidates for surgery or local ablation and do not have severe cirrhosis.

So, according to some authors, AEs may represent a surrogate of response and be associated with a favorable outcome, encouraging sorafenib continuation rather than its interruption. In a very recent prospective study 13 seeking to measure the efficacy of a sorafenib dose reduction regimen, adjusted on patient's tolerability, and aimed at increasing the exposure to the drug, the authors concluded that in patients with advanced hepatocellular carcinoma, sorafenib dose adjustments based on inducing tolerability of relevant AEs prolong drug exposure and maximize survival.

The two studies published in this issue of GE underline, as key messages, the importance of HCC surveillance, even in chronic hepatitis B patients on successful antiviral therapy, and the benefits of sorafenib in the treatment of advanced HCC, with the best results being probably obtained in cases with AEs that do not preclude maintenance of therapy. Altekruse, K. McGlynn, M. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from to J Clin Oncol, 27 , pp. Mittal, H. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol, 47 , pp.

Marinho, J. Giria, M. Rising costs and hospital admissions for hepatocellular carcinoma in Portugal — World J Gastroenterol, 13 , pp. CDC recommendations for the identification of chronic hepatitis C virus infection among persons born during — Lu, W. Seto, R. Zhu, C. Lai, M. Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection. World J Gastroenterol, 19 , pp. Shomura, T. Kagawa, K. Shiraishi, S.

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Hirose, Y. Arase, J. Koizumi, et al. Skin toxicity predicts efficacy to sorafenib in patients with advanced hepatocellular carcinoma. World J Hepatol, 6 , pp. Reig, F. Torres, C. Rodriguez-Lope, A. Forner, N. LLarch, J. Rimola, et al. Early dermatologic adverse events predict better outcome in HCC patients treated with sorafenib. J Hepatol, 61 , pp. Bettinger, M. Schultheiss, E. Knuppel, R. Thimme, H. Blum, H. Diarrhea predicts a positive response to sorafenib in patients with advanced hepatocellular carcinoma. Hepatology, 56 , pp.

Estefan, M.