PR2155 IC10 Hepatocarcinoma

risk factors, pathogenesis, surveillance, signs n symptoms, treatments and factors determining treatments

What are some risk factors for HCC?

Hepatitis B/C infection

Advanced fibrosis cirrhosis (main factor)

NASH or NAFLD

Male more likely

alcohol + other environmental exposure (tobacco smoke, aflotoxin)

Diabetes

Obesity

genetic predisposition

Risk factor HBV infection vs HCV?

HBV: chronic HBV infection can increase the risk of HCC

10-20% without fibrosis

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HCV: HCC rarely occurs in HCV infected. More common in baby boomer generation.

NASH and NAFLD as risk factors for HCC?

HCC in AFLD/NASH often diagnosed in patient without cirrhosis associated with alte onset diagnosis and higher tumour burden

How does alcohol contribute to HCC as a risk factor?

Drives hepatocarcinogenesis

* increase mutagenic acetyldehyde, oxidative stress, DNA damage
* generating carcinogenic tissue microenvironment

Describe the stages of liver damage and progression to HCC.

Healthy→ chronic liver disease, viral hepatitis, alcohol, NAFLD→ steatosis (inflammation)→ scaring of the liver → fibrosis→ liver cell destruction →cirrhosis→ malignant transformation → HCC

How does genetic predisposition risk factor play a part in HCC?

Alpha 1 - antitrypsin (AAT) deficiency → protein produced by liver to protect lungs

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Hemochromatosis→ body builds up too much iron

What is the pathogenesis of HCC?

Pathogenesis of HCC is complex and multifactorial, involving both genetic (hereditary hemochromatosis and alpha-1 antitrypsin deficiency.) and environmental factors as well as ill conditions of the patient (NAFLD, cirrhosis), metabolic toxicity (diabetes, obesity etc)

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Development of HCC is a multistep process that involves the activation of oncogenes and the inactivation of tumor suppressor genes.

What are the primary preventions for HCC?

Vaccination

* Hep B

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Lifestyle modification

* alcohol
* tobacco smoking
* diet

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Environment interventions

* blood screening for blood donors (dont unintentionally transfer HCV)

Who are the patients who need secondary prevention?

Patients who already have hepatitis/Advanced cirrhosis

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also the patients who are obese, diabetic, etc

What is the main focus of secondary prevention for HCC?

Early detection with screening

* improved early tumor detection, curative treatment rates, and survival
* cost effective

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Chemoprevention

* treatment of underlying disease such as HBV HCV metabolic syndrome

Who should receive screening in secondary prevention?

High risk population

* patient with cirrhosis, child-pugh stage A B C
* different guidelines have different classifcations of high risk, but they all recommend cirrhosis patient to receive routine screening

How often should the patient of high risk receive screenings in secondary prevention of HCC?

Every 6 months (some 4-8mo)

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What imagine does the screening use for screening for HCC in secondary prevention?

Ultra-sonography with or without AFP biomarker testing

What is involved in the chemoprevention in secondary prevention of HCC?

Treatment of underlying disease

* HBV HCV metabolic syndromes

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Avoid potentially hepatotoxic medications

Which group of paitents are suitable for chemoprevention in secondary prevention of HCC?

Patient who are already exposed tp aetiological agents

What are some examples of hepatotoxic medication?

NSAIDs

Lipid lowering agents: statins, niacin

Antibiotics : Isoniazid (TB), tetracycling, augmentin

Antifungal: itraconazole, azoles

Methotrexate

What is involved in the tertiary prevention of HCC?

Chemoprevention of HCC recurrence in patients already exposed to aetiological agents

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post treatment monitoring

* reduce recurrence
* reduce de novo carcinogenesis in cirrhotic liver

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already diagnosed with HCC

What are some signs and symptoms of HCC?

The symptoms are not directly related to the tumour growth but are more related to the underlying cirrhosis etc

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signs and symptoms

* hepatomegaly, splenomegaly
* early satiety
* nausea and vomiting
* loss of appetite
* weight loss
* abdominal or right shoulder blade pain
* ascites
* Jaundice
* Pruritus

How do we diagnose HCC?

Blood test (liver function test)

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Imaging test (CT MRI)

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Liver biopsy

When do we need to send a patient to diagnostic imaging for further evaluation?

When Ultrasound and AFP are positive

>10mm lesion

>20microg/ml AFP

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Go for biopsy if suspecting HCC

What stage renders localised treatment of HCC?

very early

early

Intermediate

What stage renders systemic treatment of HCC?

Advanced

What stage renders BSC (best supportive care)

Terminal

3 months prognosis

What are some of the localised treatments available?

Ablation

Resection

TACE (transarterial chemo embolisation) → arterially directed therapy

Transplant

What is the first option for early tumours?

Liver resection and transplantation

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select patient who may have a major survival benefit after grafting due to organ shortage

What is the mainstay of HCC treatment?

Surgical resection

What are the types of ablation available and how does it work?

Radiofrequency

Microwave

Cryoablation

Irreversible electroporation

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modify tumour cell temperature

How does TACE work?

localised therapy

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use of conventional chemotherapy or drug eluting beads. → isolate tumors to kill the tumor cells

What happens if localised treatments are not feasible or failed? (no reduction in lesion size)

Move on to systemic treatments

What are the systemic anti-cancer therapies available?

Chemotherapy

Targeted therapy

Immunotherapy

How does chemotherapy work?

Inhibit cancer growth by killing rapidly proliferating cells

* cell cycle specific (halt cell division in a specific phase)
* non-specific

How does targeted therapy work in anti-cancer therapy?

Monoclonal antibodies:

* recognise an antigen preferably expressed on cancer cells or immune cells
* OR target growth factors responsible for cancer growth

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Small molecules:

* inhibit kinase or enzymes responsible for activating proteins involved in intracellular signalling cascade for cell growth

How does immunotherapy work in anti-cancer therapy?

stimulate or restore the immune system to recognise and eliminate cancer cells

What is the concept in using immunotherapy?

They are the check-point inhibitors

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binding of checkpoint → T cells approve, NOT killing cancer cell

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Not binding to checkpoint → T-cells unblinded, KILLs cancer cells

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In a way it is mimicking autoimmunity

What is the first line treatment for HCC?

Immunotherapy

PD-L1 inhibitors (atezolizumab) + VEGF inhibitor (bevacizumab)

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PD-L1 inhibitor (Durvalumab) + CTLA-4 inhibitor (tremelimumab, not approved in sg)

How does PD-L1 inhibitor work?

blocking PD-L1 or PD1 allows T cell killing of cancer cell

How does CTL4-inhibitor work?

blocking CDTL-4 allows T cell killing of tumor cells

What are the side effects from checkpoint inhibitors called?

Immune-related adverse events (irAEs)

What is the mechanism of irAE (immune-related adverse events) ?

precise mechanism is unknown

* Mimicks autoimmune conditions

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compare the irAE in using PD-L1 inhibitor vs CTLA-4 inhibitors?

CTLA-4 > PD-L1

Where does irAE commonly occur?

Skin

GI

Liver

Endocrine

Pulmonary

What should you look out for in irAE or patient taking immunotherapy for HCC?

Cough

SOB

Fatigue

abdominal pain

fever

changes in weight

changes in mood/recognition

dermatitis/rash

vision changes

N/V

How to manage irAE?

generally based on organ system and the severity

* mostly reversible with steroids (corticosteroids)
* or stop therapy if its very bad
* or add on additional immunosuppression drugs (infliximab etc)

What are some of the drugs involved in targeted therapy (precision therapy) in anti-cancer therapy for HCC?

Monoclonal antibodies

* bevacizu**mab**
* Ramuciru**mab**

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Small molecule inhibitor

* sorafe**nib**
* Lenvati**nib**
* Regorafe**nib**
* Cabozanti**nib**

What are the monoclonal antibodies in targeted therapy?

Bevacizumab: VEGF (vascular endothelial growth factor) inhibitors → prevent blood vessels formation → cut off blood supply to cancer cells

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Ramucirumab : VEGF receptor blocker

What are the small molecules in targeted therapy?

target the proteins involved in signalling cascades in cell growth

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Sorafenib: multi-tyrosine kinase inhibitor (eg. inhibit production of VEGF receptors)

What are some toxicities of Bevacizumab and what should you watch out for?

Inhibition of VEGF on normal cells

Skin toxicity

Hypertension

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withhold for 28 days prior and after surgery (risk of bleeding)

What are some toxicity of sorafenib and what should you watch our for?

Risk of bleeding

Wound healing complications

Hepatotoxicity

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withhold at least 10 days before elctive surgery and for 2 weeks after until adequate wound healing

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What are the big mechanisms the anti-cancer therapies target?

Inhibit proliferation

Inhibit angiogenesis (growth of blood vessels)

Encourage killing of tumour cells (T cells)