management of hcc, an update

Management of Hepatocellular Carcinoma

“An Update”

Mohammed A. Suwaid, SHO, Internal Medicine

Ahmed Heshmat Gado, MD, Internal Medicine

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver, accounting for more than 90% of primary liver cancers. Worldwide, HCC is the fifth most common cancer and the third most common cause of cancer related deaths.

INTRODUCTION

In the past decade HCC has gone from being an almost universal death sentence to a cancer that can be prevented, detected at an early stage, and effectively treated.

Physicians caring for patients at risk need to provide a high-quality screening, proper management of screen-detected lesions, and provision of therapy that is most appropriate for the stage of disease.

INTRODUCTION

Care of the patient with HCC involves multidisciplinary teams (Tumor Boards), including hepatologists, pathologists, medical oncologists, surgeons, liver transplant specialists, interventional radiologists, and to some extent radiation oncologists. In this setting, the hepatologist plays a central role in directing the treatment plan because he is responsible for assessing the degree of liver function impairment and suitability of various therapies. He must ensure that only treatments of proven value are administered. This specific expertise is important since HCC usually appears on a background of liver disease.

► Jordi Bruix, and Morris Sherman; Management of Hepatocellular Carcinoma: An Update; AASLD Practice Guidelines 2011.

RISK FACTORS

Patients at risk of developing HCC can be divided into two categories:1- With cirrhosis: hapatitis B & C, alcohol, genetic hemochromatosis, autoimmune hepatitis, non-alcoholic steatohepatitis, primary biliary cirrhosis, and α1-antitrypsin deficiency.2- Without cirrhosis: hepatitis B carriers, family history of HCC, Asian males ≥ 40 y, Asian females ≥ 50 y, and Africans ≥ 20 y.

► NCCN Clinical Practice Guidelines in Oncology; Hepatobiliary Cancers, Version 1, 2010.

SURVEILLANCE OF HCC IN HIGH RISK GROUPS

The guiding principle of surveillance should be that the best available screening test should be chosen, and it should be applied regularly. Combined use of α-fetoprotein (AFP) and ultrasonography (U/S) increases detection rates, but also increases costs and false-positive rates. ● AFP-only surveillance had a 69% detection rate & 5% false positive rate.● U/S alone had an 84% detection rate & 2.9% false positive rate. ● The combination has a 92% detection rate & 7.5% false positive rate. In the Unites States, U/S alone costs about $2000 per tumor found, whereas the combination costs about $3000 per tumor found.► Jordi Bruix, and Morris Sherman; Management of Hepatocellular Carcinoma: An Update; AASLD Practice Guidelines 2011.


So, the AASLD (American Association for the Study of Liver Diseases) guidelines 2010 recommends that:1. Surveillance for HCC should be performed using U/S.2. Patients should be screened at 6 month intervals.3. The surveillance interval does not need to be shortened for patients at a higher risk of HCC.

While the NCCN (National Comprehensive Cancer Network) Practice Guidelines 2010 recommends the addition of AFP to increase the likelihood of detecting HCC in the screening setting as U/S is highly operator dependent.


In Egypt (75 million), 20% (15 million) of people are HCV positive, 50% of them (7.5 million) will develop cirrhosis, and of those cirrhotic patients, 14% (1.05 million) will develop HCC late in the course of the disease.Surveillance increases the chance of early detection of HCC and doubles the chances for curative options, including locoregional ablation therapy and liver transplantation. Furthermore, to improve the chances of curative options. So, implementation of HCC surveillance program should be recommended in Egypt.

► A. R. El-Zayadi, H. M. Badran, S. Shawky, S. Emara, and M. Sobhi. Effect of surveillance for hepatocellular carcinoma on tumor staging and treatment decisions in Egyptian patients; Asian Pacific Association for the Study of the Liver 2010.

DIAGNOSIS OF HCC

It depends on:● Classic radiological appearance. ● Biopsy which is interpreted by an expert pathologist.● Diagnostic AFP level (in the not-at-risk patients).

CLASSIC RADIOLOGICAL APPEARANCE

HCC can be diagnosed radiologically, without the need for biopsy if the typical imaging features are present. This requires a contrast-enhanced study (MDCT-scan or Dynamic MRI). In the arterial phase, HCC enhances more intensely than the surrounding liver. In the venous phase, the HCC enhances less than the surrounding liver. This is known as ‘‘washout’’. In the delayed phase, the presence of ‘‘washout’’ persists, and sometimes ‘‘washout’’ is only present in the delayed phase. The presence of arterial uptake followed by washout is highly specific for HCC. Contrast enhanced U/S has been dropped off from the diagnostic work up as it does not differentiate intrahepatic cholangiocarcinoma (ICC) from HCC.► Jordi Bruix, and Morris Sherman; Management of Hepatocellular Carcinoma: An Update; AASLD Practice Guidelines 2011.

CLASSIC RADIOLOGICAL APPEARANCE

Since radiological diagnosis is so crucial, it is essential that imaging be properly carried out in expert centers. There are established protocols for the diagnosis of HCC that vary by the type of equipment used, define the amount of contrast to be given, the method of administering the agent, the timing of the studies after administration of contrast, and the thickness of the slices to be gathered. The physician ordering the tests should know whether the studies have been conducted under these defined conditions.

BIOPSY

A biopsy is recommended in some cases when the diagnosis of HCC is uncertain, e.g. when classic arterial enhancement is not observed by any imaging method. Nevertheless, use of needle biopsy is limited by a number of factors including risk of hemorrhage, tumor rupture or seeding in the needle track and sampling error, particularly when the lesions are between 1-2 cm. Biopsies of small lesions should be evaluated by expert pathologists to differentiate them from high grade dysplastic nodules.

► Vincent T. Devita, Samuel Hellman, and Steven A. Rosenberg; Cancer: Principles and Practice of Oncology 6th edition (July 2001).► Jordi Bruix, and Morris Sherman; Management of Hepatocellular Carcinoma: An Update; AASLD Practice Guidelines 2011.

BIOPSY

Tissue that is not clearly HCC should be stained with all the available markers including CD34, CK7, glypican 3, HSP-70, and glutamine synthetase to improve diagnostic accuracy. If the biopsy is negative for HCC, the lesion should be followed by imaging at 3-6 monthly intervals until the nodule either disappears, enlarges, or displays diagnostic characteristics of HCC. If the lesion enlarges but remains atypical for HCC a repeat biopsy is recommended.

α-Fetoprotein (AFP) Normal value: 0-20 ηg/mL

AFP has long been used for the diagnosis of HCC. It has also been a part of surveillance algorithms. However, recent studies revealed that AFP alone is insufficiently sensitive or specific for use as a surveillance assay. They also suggest that its use as a diagnostic test is less specific than was once thought because:● AFP can be elevated in ICC and in some metastases from colon cancer.● In fibrolamellar carcinoma (a variant of HCC), AFP is not elevated in 95% of cases.● It is rare for the AFP to be elevated in lesions that aresmaller than 2 cm in diameter.

►Trevisani F, D’Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, Domenicali M, et al. Serum alpha-fetoprotein for diagnosis of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 2001;34:570-75.► Vincent T. Devita, Samuel Hellman, and Steven A. Rosenberg; Cancer: Principles and Practice of Oncology 6th edition (July 2001).► Jordi Bruix, and Morris Sherman; Management of Hepatocellular Carcinoma: An Update; AASLD Practice Guidelines 2011.

α-Fetoprotein (AFP) Normal value: 0-20 ηg/mL

Therefore, the finding of a mass in the liver with a normal AFP does not exclude HCC; furthermore, when elevated, it does not automatically indicate HCC unless it exceeds a specific number (the cutoff value). The cutoff value of AFP is variable among institutions but it almost lies between 200-500 ηg/mL. Now use of AFP is restricted to:● Surveillance of HCC in conjunction with U/S.● Follow up of treated patients in whom the AFP was greatly elevated (above the cutoff value) prior to treatment.● Help diagnosis of HCC in the not-at-risk patients.

Algorithm for investigating liver nodule found incidentally or during screening of patients at high risk for HCC

< 1 cm

HEPATIC NODULE

> 1 cm

Repeat US at 3-month interval

MDCT or Dynamic Contrast Enhanced MRI

StableGrowing orChanging

Investigate according to size

Classic radiological appearance

Yes No

HCC

Other contrast enhanced study (MDCT or MRI)

Classic radiological appearance

Yes No

BiopsyPositive Negative

Follo

w u

p ev

ery

3-6

mon

ths

STAGING AND TREATMENT ALLOCATION

The prognosis of solid tumors is generally related to tumor stage at presentation. Tumor stage also guides treatment decisions. However, in HCC patients the prediction of prognosis is more complex because the underlying liver function also affects prognosis. The BCLC (Barcelona Clinic for Liver Cancer) staging system has been widely and efficiently used in several major trials to define the patient population to be recruited and to stratify them into separate prognostic categories.

THE BCLC STAGING SYSTEM

It includes variables related to: ● Physical status● Liver functional status ● Tumor stage● Cancer related symptoms The main advantage of the BCLC staging system is that it links staging with treatment modalities and with an estimation of life expectancy that is based on published response rates to the various treatments.Currently, the BCLC system is the only staging system that offers such a correlation.

PHYSICAL STATUS

This can be estimated by applying ECOG* Score, as follows: 0 → Fully active, able to carry on all predisease activities with restriction. 1 → Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. 2 → Ambulatory and capable of all self-care but unable to carry

out any work activities. Out of bed >50% of waking hours. 3 → Capable of a limited self-care, >50% of daytime confined to bed or chair. 4 → Completely disabled, no self-care, totally confined to bed.

* Eastern Cooperative Oncology Group.

LIVER FUNCTION STATUS

This can be estimated by applying the Child’s-Pugh Score, as follows:

A = 5 – 6 B = 7 – 9 C = 10 - 15

3 2 1 Parameter3-4 1-2 None Encephalopathy gradeModerate Slight None Ascites<2.8 2.8-3.5 >3.5 Albumin (g/dL)>6>2.3

4-61.8-2.3

1-4<1.7

PT, prolonged (sec) or INR

>3>10

2-34-10

1-21-4

Bilirubin (mg/dL) for primary biliary cirrhosis

► Kumar & Clark’s Clinical Medicine, Seventh Edition, 2009

PORTAL PRESSURE & BILIRUBIN LEVEL

For years the selection of candidates for resection has been based on the Child’s-Pugh classification but this is known to have inconsistent predictive value. Child’s-Pugh A patients may already have significant liver functional impairment with increased bilirubin, significant portal hypertension or even minor fluid retention requiring diuretic therapy. These features indicate a more advanced liver disease and preclude resection. So, bilirubin level and portal pressure estimation are of a special value in determining the treatment plan.



Stage 0: PS 0, Child-Pugh A, single lesion < 2cm.(Very early stage → resection)● In case of normal bilirubin level & absence of clinically significant PH, more than 70% of patients will achieve 5 year survival after resection.● In clinically significant PH, patients will be more liable to postoperative decompensation (mostly ascites, especially if the right lobe is to be resected) with a 5 year survival of less than 50%.● If both PH & hyperbilirubinemia are present &/or multifocal disease, less than 30% will achieve 5 year survival regardless of their Child’s-Pugh stage.



Stage A: PS 0, Child-Pugh A-B, single lesion < 5cm or 3 lesions ≤ 3cm each.(Early stage → liver transplantation or RFA)● If there is a solitary HCC < 5cm or 3 nodules < 3cm each, liver transplantation will achieve 5 year survival in more than 70% of patients.● Patients who are not eligible for transplantation will achieve 5 year survival after RFA or PEI in more than 50% of cases.



Stage B: PS 0, Child-Pugh A-B, large/multifocal lesions, no cancer related symptoms, no macrovascular invasion or extrahepatic spread.(intermediate stage → TACE)● By TACE-alone treatment, the 2 year survival rate was 63%, while in combination with RFA the 1-, 3-, & 5 year survival rates were 97%, 77% & 56% respectively.



Stage C: PS 1-2, Child-Pugh A-B, presence of cancer related symptoms and/or vascular invasion or extrahepatic spread (LN and/or distant metastases).(Advanced stage → Sorafenib)● It increases median survival to 10.7 months & improves time to progression (TTP) to 5.5 months.

Stage D: PS > 2, Child-Pugh C.(Terminal stage→ Symptomatic treatment)● Their median survival is < 3 months.


The BCLC staging system and treatment allocation of HCC, from AASLD practice guidelines, Hepatology, Vol. 53, No. 3, 2011

Stage 0 Stage A Stage B Stage C Stage D

HEPATOCELLULAR CARCINOMA

Portal pressure/ bilirubin

Associated diseases

Increased

Normal No Yes

Resection Liver Transp. RFA

Curative Treatment

TACE Sorafenib

Palliative TreatmentSymptomatic

Treatment

RFA: Radiofrequency ablationTACE: Transarterial chemoembolization

THANKS

May 20th , 2011

management of hcc, an update

Health & Medicine

surveillance of hcc

diagnosis of hcc

risk of developing hcc

higher risk of hcc

family history of hcc

past decade hcc

risk patients

surrounding liver