Liver Cancer Or Hepatocellular Carcinoma (HCC) - Standard Treatment Guidelines

Liver cancer or primary liver cancer or hepatocellular carcinoma (HCC) is, as the name suggests, a primary malignant tumor arising from the liver cells or hepatocytes. It usually arises on a background of cirrhosis, but it may even arise in non-cirrhotic livers. The etiology of cirrhosis may be hepatitis B, hepatitis C, alcohol or even non-alcoholic steatohepatitis. Liver cancer has been reported as the 5th most common cancer and the third most common cause of cancer related mortality in the world literature.

Ministry of Health and Family Welfare has come out with the Standard Treatment Guidelines for Liver Cancer Or Hepatocellular Carcinoma (HCC). Following are its major recommendations.

Case definition:

For both situations of care (mentioned below*)

Secondary care centers: Any space occupying lesion (SOL) or a nodule in the liver detected either on ultrasonography, CT scan or MRI, in a patient who has underlying cirrhosis, should be considered as an HCC unless proved otherwise. The presence of high AFP >400ng/ml confirms the diagnosis of the SOL/nodule being HCC. However, normal AFP levels do not exclude the presence of HCC. Appearance of a new SOL in liver even in patients, who do not have underlying cirrhosis, should be investigated with HCC being the first differential diagnosis.

Tertiary care centers:

1. In a patient who has cirrhosis any SOL, more than 2 cm, if it shows enhancement in the arterial phase and washout in the delayed phase, on at least one dynamic imaging (either a triple phase contrast CT scan of abdomen or dynamic contrast enhanced MRI of the abdomen), should be labeled as HCC unless proved otherwise, irrespective of alpha feto protein (AFP) levels.

2. In a patient who has cirrhosis, and the SOL is between 1-2 cm, then the typical contrast enhancement and washout pattern needs to be demonstrated on at least two imaging modalities to make a diagnosis of HCC

3. Patients who have SOL in the liver but do not have cirrhosis, or those who have atypical enhancement characteristics on dynamic imaging, the diagnosis of HCC can be confirmed by characteristic microscopic features on a biopsy of the lesion or fine needle aspiration cytology of the lesion.

Where ever possible efforts should be made to make a non-invasive diagnosis of HCC, that is, without putting any needle in to the tumor.

Incidence of The Condition In Our Country

In our country, the reported incidence of HCC is 1.2 /100,000 females per year and 2.7/100,000 males per year and a prevalence of 1.9% of all cancers, based on population cancer registry data.

In a prospective study in patient with cirrhosis, the reported incidence is 1.6 per 100 person years of follow up.

Differential Diagnosis

Differential diagnosis include all other causes of mass /SOL in the liver. These can be either benign or malignant

Benign liver masses	Malignant liver masses
Hemangioma	Metastases from other malignant tumors (secondaries)
Focal nodular hyperplasia	Cholangiocarcinoma
Hepatocellular adenoma
Complex liver cysts

These lesions can be differentiated from HCC by means of characteristic imaging findings of these lesions as well as the clinical setting of presentation.

Prevention And Counseling

The most important risk factors for the development of liver cancer are hepatitis B infection, hepatitis C infection, alcoholic cirrhosis, non-alcoholic steatohepatitis related cirrhosis, and other causes of cirrhosis. Therefore the most important preventive measures would be to prevent development of these diseases. The following measures can me considered to be preventive strategies for HCC:

1. Vaccination against hepatitis B

2. Universal screening of donated blood for hepatitis B and C and discarding of infected units

3. Preventive strategies for diabetes and obesity

4. Strategies to prevent alcoholism

At present there is no recommended chemopreventive strategy, once a patient becomes cirrhotic.

Optimal Diagnostic Criteria, Investigations, Treatment & Referral Criteria

*Situation 1: At Secondary Hospital/ Non-Metro situation: Optimal Standards of Treatment in Situations where technology and resources are limited

Clinical Diagnosis:

All patients with cirrhosis of liver who develop recent worsening of their clinical status should be suspected of having developed liver cancer and should be appropriately investigated. It should be suspected when:

1. A patient who has stable cirrhosis develops new ascites

2. A cirrhotic patient develops a difficult to control ascites.

3. A stable cirrhotic develops severe constitutional symptoms, such as weight loss or anorexia.

4. Any patient, especially one who has cirrhosis, develops prolonged fever of unknown origin (FUO)

5. A patient of cirrhosis develops pain in the upper abdomen.

Investigations:

The initial investigations should include:

1. Abdominal ultrosonography which can pick up features of cirrhosis and presence of any SOL in the liver.

2. Alpha feto protein (AFP) levels: Levels of more than 10 ng /ml should raise the suspicion of HCC and should be investigated further.

Treatment:

Standard Operating procedure:

Comprehensive treatment of Liver cancer involves:

1. Treatment of the tumor

2. Treatment of cirrhosis

3. Treatment of complications of cirrhosis

4. Treatment of the virus if the cause is hepatitis B or C.

Treatment of the tumor is based on the stage of the tumor. The most commonly used staging and treatment plan followed is based on the BCLC (Barcelona clinic liver cancer) staging system. This system incorporates, not only the size and number of tumors, but also, the residual liver function, the functional status of the liver and presence or absence of extrahepatic spread.

In Patient

In the secondary care set up, the patient should be managed for complications of cirrhosis, such as GI bleeding, ascites, hepatic encephalopathy.

Out Patient

Only in cases requiring symptomatic treatment.

Referral criteria:

Patients requiring curative or palliative therapies for HCC [ such as liver transplantation, liver resection, radiofrequency ablation, percutaneous ethanol injection, trans-arterial chemoembolization, trans arterial radioembolization, and biological therapy (tyrosine kinase inhibitors or monoclonal antibodies)], should all be referred to a hepatologist or gastroenterologists with interest in managing HCC at a tertiary care center.

Even patients requiring advanced treatment for complications of cirrhosis, should be referred to tertiary care centers.

*Situation 2: At Super Specialty Facility in Metro location where higher-end technology is available

Clinical Diagnosis:

All patients with cirrhosis of liver who develop recent worsening of their clinical status should be suspected of having developed liver cancer and should be appropriately investigated. It should be suspected when:

1. A patient who has stable cirrhosis develops new ascites

2. A cirrhotic patient develops a difficult to control ascites.

3. A stable cirrhotic develops severe constitutional symptoms, such as weight loss or anorexia.

4. Any patient, especially one who has cirrhosis, develops prolonged fever of unknown origin (FUO)

5. A patient of cirrhosis develops pain in the upper abdomen.

Investigations:

The initial investigations should include:

1. Abdominal ultrosonography which can pick up features of cirrhosis and presence of any SOL in the liver.

2. Alpha feto protein (AFP) levels: Levels of more than 10 ng /ml should raise the suspicion of HCC and should be investigated further. The further investigations required are:

3. Triple phase contrast enhanced CT Scan of abdomen

4. Dynamic contrast enhanced MRI of the abdomen

5. Contrast enhanced ultrasonography

6. PET CT scan of the abdomen

7. Bone scan

8. Biopsy or FNAC of the tumor with immunohistochemical staining

9. Other tumor markers such as PIVKA-II and AFP-L3

The investigations from number 3-9 may all be required or may be required selectively for confirming the diagnosis, determining the stage of the disease, determining extrahepatic spread and suitability for treatment.

Treatment:

As has been mentioned earlier, treatment depends on the BCLC stage of the disease

Standard Operating procedure

a. In-Patient

Curative forms of therapy for liver cancer include:

1. Liver resection (surgical removal of a part of the liver involved by the tumor)

2. Percutaneous ablative therapies [burning the tumor with either radiofrequency current (radiofrequency ablation) or with injection of 100% alcohol or with injection of 50% acetic acid] or

3. Liver transplantation.

Palliative therapies include:

1. Transarterial chemoembolization,

2. Transarterial radio-embolization

3. Systemic chemotherapy.

4. Continuous intra-arterial chemotherapy through implatable port.

As mentioned earlier, BCLC staging system guides therapy as follows:

Patients with very early HCC (stage 0)and early HCC (stage A): Can be offered all forms of curative therapy:

1. Liver transplantation

2. Liver resection

3. Percutaneous ablative therapies (radio frequency ablation, percutaneous ethanol injection or percutaneous acetic acid injection therapy)

Patients with intermediate HCC (stage B):

Can be offered therapy with:

1. Transarterial chemoembolization (TACE).

2. Oral chemotherapy with biological such as sorafenib

3. Liver transplantation can be offered to patients with single large tumor or even multiple tumors, but only at experienced centres. (these would be patients outside Milan’s criteria [single tumor < 5 cm or up to 3 tumors with diameter < 3 cm])

Patients with (stage C):

Can be offered

1. Systemic chemotherapy with Sorafenib

2. Radioembolization with yttrium 99 theraspheres

Patients with end-stage disease (stage D):

Can be offered

1. Oral chemotherapy with Sorafenib

2. Symptomatic therapy

b. Out Patient

Patients being given symptomatic therapy or oral chemotherapy can be managed in the out patient setting. Follow up after curative therapies would also be done in the out patient setting.

Following percutaneous ablative therapies, patients need to undergo regular FU with a dynamic contrast imaging (either a CT or MRI scan), liver function profiles and tumor markers at regular intervals or as indicated.

d) Referral criteria:

Patients fit for undergoing liver transplantation should be referred to a hepatologist at a liver transplant center

WHO DOES WHAT? and TIMELINES

a. Doctor

1. Diagnosis and treatment(medical, radiological and surgical) of cases

b. Nurse

1. Nursing care to patients undergoing treatement at in-patients.

2. Endoscopy nurse

c. Technician

1. Endoscopy technician

2. Interventional radiology technician

3. Liver surgery technician

4. Lab technician, biochemistry/hematology lab

5. Blood bank technician

Resources Required For One Patient / Procedure

(Patient Weight 60 KGS)

(Units to be specified for human resources, investigations, drugs and consumables and equipment. Quantity to also be specified)

Situation	Human Resources	Investigations	Drugs & Consumables	Equipment
1.	Specialist MD or DM doctor, Nurse, Technician	CBC, LFT, RFT, INR, AFP, Blood cultures, urine cultures, ultrasound	IV set, IV cannulas, Syringes, Diuretics (aldactone, furosemide, torsemide), lactulose, pantoprazole oral and iv, somatostatin, terlipressin, tenofovir, entecavir, telbivudine, b complex, calcium, oral iron, UDCA, vitamin E, insulin, oral hypoglycemic drugs	Ryles tube, Sengstaken blackmore tube, Ultrasound machine, ECG machine
2.	DM gastroenterologist or hepatologist, Interventional radiologist, GI/liver transplant surgeon, biochemist, hematologist, microbiologist, Resident doctors in all specialities Nurses, technicians	Endoscopy, Multislice CT scanner, MRI, Ultrasound, PET scanner, bone scan…….in addition to what is required in CBC, LFT, RFT, INR, AFP, Blood cultures, urine cultures, ultrasound	All drugs and consumables required in liver surgeries and liver transplant surgeries, interventional radiology set up, sorafenib, ………in addition to what is required inIV set, IV cannulas, Syringes, Diuretics (aldactone, furosemide, torsemide), lactulose, pantoprazole oral and iv, somatostatin, terlipressin, tenofovir, entecavir, telbivudine, b complex, calcium, oral iron, UDCA, vitamin E, insulin, oral hypoglycemic drugs	Endoscopy equipments, Multislice CT scanner, MRI scanner, PET scanner, bone scanner, Contrast ultrasound machine and the contrast (sonovue/sonazoid) Wards, ICUs, OTs, Interventional radiology set up and all equipment required in such set ups……in addition to what is required inRyles tube, Sengstaken blackmore tube, Ultrasound machine, ECG machine

Guidelines by The Ministry of Health and Family Welfare :

Dr. Kaushal Madan Senior Gastroenterologist Medanta Medicity