Treatment Options for Liver Cancer

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Treatment Options for Liver Cancer: What You Need to Know

Presented by: Robert G. Gish, MD

A dedicated program of the Hepatitis B Foundation

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Treatment Options for Liver Cancer

What You Need to Know

[April 27, 2015]

Presented by: Robert G. Gish, MD

Professor Consultant, Stanford University, California

Medical Director, Hepatitis B Foundation


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How Liver Cancer Develops

Healthy Liver

Cirrhotic Liver

Liver Cancer

In a healthy liver, chemical signals tell liver cells when to grow/multiply, and when to stop

In a liver damaged by hepatitis infection, cirrhosis (scarring), or other diseases, abnormal cells may grow out of control and become cancerous

you do not have to have cirrhosis to be at risk for, or to have, liver cancer


In a healthy liver, chemical signals tell liver cells when to grow and multiply to form more cells, and when to stop growing and multiplying

In a liver damaged by the hepatitis virus (HBV or HCV), cirrhosis, or other diseases, abnormal cells may grow and multiply out of control, and become cancerous

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How Liver Cancer Develops

1540 years

Chronichepatitis

Cirrhosis

3%5% per year

Liver cancer

(HCC)

Hepatitis B or C

Diabetes

Alcohol

Aflatoxins

Inflammation

Cell damage

Uncontrolled cell growth

Fatty Liver

Iron

Risk factors


0.5% per year

Pathogenesis of human hepatocellular carcinoma (HCC). Chronic hepatitis B and C and associated liver cirrhosis represent

major risk factors for HCC development, being implicated in more than 70% of HCC cases worldwide. Additional etiological factors,

which often represent co-factors of an underlying HBV- or HCV-related chronic liver disease, include toxins and drugs (e.g., alcohol,

aflatoxins, microcystin, anabolic steroids), metabolic liver diseases (e.g., hereditary hemochromatosis, a1-antitrypsin deficiency),

steatosis, non-alcoholic fatty liver diseases and diabetes. Hepatocarcinogenesis is a multistep process that may last for decades and

involves the progressive accumulation of different genetic alterations ultimately leading to malignant transformation. Regardless of the

etiological agent, malignant transformation of hepatocytes is believed to occur through a pathway of increased liver cell turnover,

induced by chronic liver injury and regeneration, in a context of inflammation and oxidative DNA damage. Dysplastic nodules and

macroregenerative nodules are considered as pre-neoplastic lesions. The detailed analysis of HCC development in experimental

animals and the comparison of the results with HCC in humans has identified a variety of genomic and molecular alterations in fully

developed HCC and to a lesser extent in morphologically defined pre-neoplastic precursor lesions. At least four pathways that regulate

either cell proliferation or cell death (i.e., the phospho-retinoblastoma (pRb), p53, transforming growth factor-b (TGF-b) a nd

b-catenin pathways) are affected in HCCs.

Viral hepatitis and liver cancer: the case of hepatitis C

M Levrero

Oncogene (2006) 25, 38343847

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Spotlight on Prevention

Liver cancer can be prevented by eliminating the major risk factors

Prevention of hepatitis B and C infections

The hepatitis B vaccine is the worlds first anti-cancer vaccine because it prevents hepatitis B, a leading cause of liver cancer

No hepatitis C vaccine, but treatments can eliminate (cure) the virus and prevent cancer

Prevention of cirrhosis

~ 80% of people with liver cancer also have cirrhosis

Prevent cirrhosis by preventing hepatitis B and C infections, treating HBV, curing HCV, eliminating alcohol intake, maintaining a healthy weight / diet

Liver Cancer Prevention


Prevention is the most effective treatment.

Liver cancer is largely preventable through elimination of the major risk factors.:

Chronic hepatitis B or C

Cirrhosis (eg, associated with excessive alcohol intake, fatty liver disease, aflatoxins)

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Why Are Screening and Surveillance So Important for Early Detection of HCC?

In people with chronic HBV infection, liver cancer can develop with or without cirrhosis, so screening/surveillance is essential

In people with chronic HCV infection, cirrhosis occurs before liver cancer develops

Screening/surveillance increases likelihood of finding liver cancer early and offering the chance of better survival

More treatment options for early-stage liver cancer

Early detection may increase treatment success

Offer cure to some patients with HCC

Proceed to liver transplant before the cancer is too large


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Who Needs Liver Cancer Screening?

Family history of liver cancer (or family history unknown)

Asian and Pacific Islander immigrants and their children

African immigrants and their children

Co-infection with HIV, HBV and/or HCV

Elevated liver cancer biomarkers (AFP, AFPL3%, or DCP)

Screening: first test; Surveillance: all subsequent testing

American Association for Study of Liver Diseases recommends:

All men with hepatitis B: start screening/surveillance at age 40 years

All women with hepatitis B: start screening/surveillance at age 50 years

HBV patients with cirrhosis

And the following high-risk groups may need screening/surveillance earlier and more frequently:


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Liver Cancer Screening and Surveillance

The goal is to diagnose liver cancer as early as possible

Screening: the first test

Surveillance: all subsequent testing (regular monitoring)

Common blood tests

- Complete blood count (CBC)

- Alpha-fetoprotein blood test (AFP)

- Additional FDA-cleared blood tests (include AFPL3%, DCP)

Imaging studies

- Ultrasound (US)

with elastography- Computed tomography (CT or CAT scan)

- Magnetic resonance imaging scans (MRI)


American Association for the Study of Liver Diseases (AASLD) and Asian Pacific Association for the Study of the Liver (APASL) guidelines recommend AFP and US screening every 6-12 months.

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Diagnosing Liver Cancer


Diagnosis of liver cancer is made by imaging

Liver tumor biopsy is sometimes used to confirm diagnosis of liver cancer or stage disease

Most common biopsy type is percutaneous needle biopsy

A minimally invasive surgical removal of a small piece of liver cancer tissue to examine under the microscope

Usually performed as an outpatient hospital procedure

Procedure is relatively short with a 3- to 8-hour recovery period in the hospital to prevent bleeding at biopsy site

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Staging of Liver Cancer

Staging is a medical term to describe how far the cancer has progressed in a patient and the status of the patients liver as well as the patient functional status

Helps health care providers determine the best course of treatment

Liver cancer often is diagnosed at more advanced stages because many people dont have symptoms in early stages

There are several staging systems for liver cancer; not all health care providers use the same system


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4 Stages of Liver Cancer: TMN

Staging helps determine treatment options

Stage I

Tumor is small and found in one part of the liver

Stage II

Several small tumors or a single tumor that has spread to nearby blood vessels

Stage III

One or more tumors that might have spread to nearby parts of the body, such as the stomach, blood vessels or lymph nodes

Stage IV

One or more tumors in the liver, and cancer cells have spread to other parts of the body


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5 Stages of Liver Cancer: BCLC

Staging helps determine treatment options

Stage 0

Tumor is small and found in one part of the liver, no cirrhosis; surgery is recommended

Stage A

Several small tumors or a single tumor in the setting of cirrhosis;

transplant is recommended

Stage B

One or more tumors that might have spread to nearby parts of the body;

ablation therapy is recommended

Stage C

One or more tumors in the liver, and cancer cells have spread to other parts of the body;

systemic therapy is recommended


Stage D: extensive disease: palliative care is recommended

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Managing Liver Cancer


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Managing Liver Cancer

How well the liver is working when the person is diagnosed

Stage of cancer, including number/size of tumors and whether the cancer has spread outside the liver

Overall health of the person being treated

An individual treatment plan depends on several factors


Team Approach for Treatment

It takes a team to treat liver cancer:

Hepatologist (liver specialist)

NP/PA/RN team

Pharmacist

Surgeon/transplant surgeon

Pathologist

Radiologist (diagnostic and interventional)

Medical oncologist (cancer specialist)

Radiation oncologist (radiation cancer specialist)


Treatment OptionsLiver Transplantation

Surgical replacement of diseased liver with healthy liver

Transplantation only possible if tumors are small and have not spread to nearby blood vessels or outside the liver

Orthotopic transplantation: use healthy liver from a person who has recently died

Living donor transplantation: use part of a healthy liver from a living person

Most people needing a new liver are placed on a waiting list

and continue to receive treatment while waiting


Treatment OptionsSurgery

Resection: Surgical removal of tumor

Treatment of choice if tumor is small, in one section of the liver and patient does not have portal hypertension

Possible in persons with good liver function, despite liver disease (very early cirrhosis, chronic hepatitis B or C, fatty liver)

Many patients not eligible (tumor too large or too many; reduced liver function or portal hypertension [large spleen, varices, low platelet] caused by cirrhosis)

Fewer than 30% of tumors are resectable


Treatment OptionsLocalized

Procedures that damage or eliminate the tumor locally

for tumors that cannot be surgically removed

to prepare a patient for surgical treatment or transplant


Radiofrequency ablation (RFA)Microwave ablation (MwA)

Transarterial chemoembolization (TACE)

Transarterial bead chemoembolization (TABE)

Radiotherapy

Radioembolization (TARE)

Cryotherapy (freeze the tumor)


Radiofrequency (or microwave[MwA]) ablation (RFA):

High-frequency electrical currents destroy tumor

RFA probe

Tumor

Radiofrequency heat

Images: Society of Interventional Radiology (SirWeb.org), Johns Hopkins (hopkins-gi.org)

This can cure small tumors

Some patients have combination therapy with TABE or TARE

Best option if patient cannot have surgery / transplant but disease is localized with bilirubin less than 3 and no ascites

Side effects include pain or bleeding: rare

Very rare events of tumor spreading (seeding or tracking)

Target heat to the tumor with less exposure to other parts of the liver


Normal liver gets 75% of blood supply from portal vein; 25% from hepatic artery

Tumor gets most of its blood supply from the hepatic artery

Injection into the hepatic artery and into the tumor spares most of the normal liver

Prevents most of chemotherapy drugs being absorbed into circulation; kills the tumor by cutting off its blood supply

Treatment Options

Chemoembolization (TACE) or Bead (TABE)

Tumor

Catheter placement forchemoembolization

Liver

Portal vein


Hepaticartery

Multiple studies with anti tumor effect, no survival benefit

Chemoembolization of Unresectable Hepatocellular Carcinoma: A Review

Douglas E. Ramsey, AB, Jean-Francois H. Geschwind, MD

Appl Radiol.2004;33(3).

http://www.medscape.com/viewarticle/474054_3.

Image adapted from/can be found at: http://www.uphs.upenn.edu/radiology/patient/services/ir/info/chemo.html

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Images: Society of Interventional Radiology (SirWeb.org), Johns Hopkins (hopkins-gi.org)

Delivers embolic material to tumor to decrease/cut blood flow

Slowly delivers chemotherapy so systemic effect of drugs is small

Can kill most of localized tumors that are up to 7-9 cm

Transarterial bead chemoembolization (TABE):

Anticancer drugs delivered on plastic beads directly into tumor to block blood supply to the tumor and have slow release of the cancer drugs


Improving Survival in Liver Cancer

Precision TACE using beads (TABE)can improve survival

% probability of survival at 12 months

~98% with TABE; ~82% with TACE

% probability of survival at 24 months

~91% with TABE; ~63% with TACE

TABE, Transarterial bead chemoembolization


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Images: Society of Interventional Radiology (SirWeb.org), CancerHelp UK (cancerhelp.org.uk)

Radiotherapy:

High-energy radiation kills cancer cells and shrinks tumor

Radioactive beads or external beam radiation


Transarterial radioembolization (TARE):

Reduces tumor size, but is not a cure

May make patients eligible for other therapies (radiofrequency ablation, surgery, transplantation)

One FDA-cleared method uses implanted glass beads or resin to deliver high-dose radiation directly to tumor; spares healthy liver cells

Usually an outpatient procedure

Treatment OptionsTargeted Therapies

Therapies that enter the bloodstream and reach the whole body (systemic)

Newer biologic therapies that specifically target the tumor

Unlike chemotherapy, which kills both tumor cells and healthy cells, targeted therapies block specific pathways in the tumor

may have different or less severe side effects than chemotherapy

Targeted therapies may be oral (pills, tablets)


Treatment OptionsTargeted Oral Drug

Nexavar (sorafenib) is the first FDA-approved oral drug to treat liver tumors that cannot be surgically removed

A targeted oral therapy approved for primary liver cancer in more than 70 countries

Blocks tumor cell signals so tumor cells cant grow or multiply

Reduces formation of new blood vessels that provide oxygen and nutrients to the tumor cells


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What to Ask Your Health Care Team

What are my treatment options and how will they help?

If I have hepatitis B or C, do I need antiviral treatment?

Oral therapies can cure HCV or suppress HBV

Can you explain my blood test or imaging results to me?

Do I need more tests or need to see any other doctors before we decide on my treatment?


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What to Ask Your Health Care Team

What will the treatment involve?

What are the possible side effects of treatment?

What are the chances that the cancer will come back?

Can I get a copy of all of the results?


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Life After Treatment

Take time to recover, heal and discover your new normal

May still feel the effects of treatment

May experience changes in food, activities, support

Stay active, eat a healthy diet, coffee and tea are safe and good for liver health

Make sure you keep all medical follow-up visits

Talk to your health care team about a wellness plan

Talk to your health care provider about your familys cancer risk

For more information

Read Facing Forward from the National Cancer Institute

Visit www.LiverCancerConnect.org


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Follow-Up Care: What Is Involved?

Medical follow-up visits are very important

To check that the cancer has not spread or returned

To manage any side effects that might occur

Regular imaging and blood tests will be required for several years after surgery and/or a liver transplant

Maintain your health insurance since you will have follow-up visits for many years

Keep records of all blood test results, imaging studies, surgery and discharge reports, and list of medications


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Therapies in DevelopmentWhats in the Pipeline?

Treatments being developed; in clinical trials

New targeted therapies

Combinations of targeted therapies

Immunotherapy (use patients immune system to kill tumor)

New ways to deliver chemotherapy/radiation directly into tumor


Many of these therapies in development are being studied in clinical trials. Ask your health care team if there are any trials that might be suitable for you.

Strategies in Development

Attack proteins that help tumor grow

Tivantinib, cabozantinib, foretinib, lenvatinib, axitinib

Target cancer stem cells

Combinations of targeted therapies

Sorafenib with chemotherapy

Sorafenib with RFA, TACE, TABE, TARE, radiotherapy

Combinations of TACE, RFA, proton therapy


Many of these therapies in development are being studied in clinical trials. Ask your health care team if there are any trials that might be suitable for you.

Immunotherapy

Drugs that help immune system recognize and kill cancer cells

Spontaneous immune responses frequently observed

Strategy does not depend on liver function

Can be combined with ablation

Currently this is only for research (clinical trials)


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Types of Immunotherapy

Checkpoint inhibitors

Target molecules that regulate immune response to cancer cells

Cancer vaccines

Encourage immune system to attack cancer cells

Adoptive T-cell therapy

Genetically/chemically modify patients immune cells (T cells) to specifically attack cancer cells


All of the strategies mentioned here are in clinical trials. For more information, visit the website of the National Cancer Institute or clinicaltrials.gov

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Types of Immunotherapy

Monoclonal antibodies

Attack specific targets on cancer cells

Cytokines

Messenger cells help control immune system

Cancer-killing virus therapy

Modified virus causes tumor to self-destruct; stimulates immune response to cancer


All of the strategies mentioned here are in clinical trials. For more information, visit the website of the National Cancer Institute or clinicaltrials.gov

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Promising Immunotherapies

Ramucirumab

Phase III REACH study- improved overall survival

Nivolumab

Tremelimumab

Phase II trial in patients with hepatitis C (HCV)

Reduced time to progression of cancer

Reduced HCV viral load by stimulating immune system to attack HCV


The National Cancer Institute is studying several therapies for liver cancer. For example, they are studying tremelimumab, a cancer treatment drug that helps the immune system recognize and destroy cancer cells. Researchers want to see if it can be used to treat advanced liver cancer. The drug will be given with one of two types of treatment for liver cancer. The first type, transarterial catheter chemoembolization (TACE), injects chemotherapy drugs into the tumor through the main blood vessel that is feeding it. That blood vessel is then closed off to help keep the drugs in the tumor longer. The second type, radiofrequency ablation (RFA), uses a heated probe to destroy the tumor tissue. Researchers want to study how safe and effective these treatments are with the study drug.

All of the therapies listed here are in clinical trials.

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Clinical Trials

Study whether a drug is safe and effective in people

May not get study treatment, but will get standard treatment

Learn more about liver cancer clinical trials

Join our webinar on Wed May 27, 1:30 pm EDT

Register at www.livercancerconnect.org


The Hepatitis B Foundations Liver Cancer Connect program is organizing a webinar on clinical trials. Please join us on May 27 at 1:30 pm Eastern time to learn about what clinical trials are and how you can participate in a trial.

You can register for the webinar on the liver cancer connect website, www.livercancerconnect.org.

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www.LiverCancerConnect.org

A Dedicated Program of the Hepatitis B Foundation


Treatment options

Clinical trials

Liver cancer centers

Information for newly diagnosed

Talking to your health care team

Drug watch

The Hepatitis B Foundations website, Liver Cancer Connect, is a patient-focused resource on liver cancer. It provides a directory of liver cancer centers, a drug watch, a list of clinical trials, and information in easy-to-understand language about diagnosis, screening, and treatment options.

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Liver Cancer Connect Drug Watch


The Liver Cancer Connect website has a drug watch- a list of therapies in development for liver cancer. The list is updated regularly.

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Key Messages

Know your risk - Family history, hepatitis, cirrhosis...

Get screened and regular monitoring (surveillance) Early diagnosis saves lives

Know the symptoms - Get checked immediately if you have any signs or symptoms of liver cancer

Get informed - Talk to your health care provider about treatment options and clinical trials for liver cancer


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Question and Answer Time

Use the chat box on your screen to type and send your questions to the presenter

Your questions will be seen only by the presenter

Please note, the presenter cannot give treatment recommendations or advice on a persons personal medical condition


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Documents

Treatment Options for Liver Cancer