This document discusses non-surgical treatment options for hepatocellular carcinoma (HCC). It describes various local ablative therapies like radiofrequency ablation (RFA), microwave ablation, irreversible electroporation, cryotherapy, and ethanol injection. It also discusses regional therapies like hepatic artery embolization and chemoembolization. Systemic therapies mentioned include chemotherapy, targeted therapy, immunotherapy, and hormonal therapy. Specific treatment options like RFA, microwave ablation, stereotactic radiation therapy, and transarterial chemoembolization are described in further detail. The document emphasizes that treatment should be guided by the patient's liver function and cancer stage.

1. NON SURGICAL MANAGEMENT OF
HEPATOCELLULAR CARCINOMA
Presenter- Dr. Abhishek raj
3rd year surgery PGT

2. • Hepatocellular carcinoma (HCC) represents a challenging malignancy of
global importance . It is the fifth most common solid tumor in terms of
incidence and the third leading cause of cancer-related death
worldwide.

3. • Its incidence mirrors that of chronic liver injury, which is
predominantly attributable to
• Viral hepatitis infection both hepatitis B and C
• Other etiologic factors that trigger chronic liver injury and cirrhosis
include alcohol; Alcoholic Liver Diseases
• Nonalcoholic steatohepatitis , commonly associated with morbid
obesity and diabetes;
• and other metabolic diseases, for instance, .hemochromatosis

4. • Fundamental challenge in HCC is the coexistence of underlying liver
injury and hepatic dysfunction as the premalignant environment in
the majority of patients.
• Both the underlying cirrhosis and the tumor itself impact the HCC
patient’s overall survival. Thus there is a need to evaluate the
cirrhosis status of patients with liver cancer to guide treatment
decisions.

5. • Add one slide here on Treatment Options

6. Non surgical treatment Options for
Hepatocellular Carcinoma
• Local ablative therapies
• Cryosurgery
• Microwave ablation
• Ethanol injection
• Acetic acid injection
• Radiofrequency ablation
• Proton or carbon ion therapy
• Conformal radiation therapy
• Stereotactic radiation therapy

7. • Regional therapies: hepatic artery transcatheter treatments
• Transarterial chemotherapy
• Transarterial embolization
• Transarterial chemoembolization
• Transarterial yttrium-90 microspheres
• Transarterial
• 131
• I-lipiodol
• Palliative low-dose radiation therapy

9. • Systemic therapies
• Chemotherapy
• Targeted therapy (sorafenib)
• Immunotherapy
• Hormonal therapy
• Oncolytic virotherapy

10. Radiofrequency Ablation(RFA)
• Radiofrequency ablation involves the application of high frequency
(375-480 kHz) alternating current to the target tissue by using a
needle like applicator, with cell death resulting from frictional heating.
• Active tissue heating occurs only within a few millimeters of the
exposed tines of the applicator, and larger-volume tissue destruction
mainly relies on conductive heating.
• RFA probes are usually placed under ultrasound or computed
tomography (CT) guidance either directly to or iteratively around the
tumor to create a confluent ablation zone.

11. • Tumors adjacent to larger (>3 mm) blood vessels may be
undertreated due to the thermal sink effect.
• In patients with Child-Pugh class A cirrhosis, data suggest thermal
ablation can rival surgery when tumors are solitary and smaller .They
are more suitable for central and deep lesions

12. Microwave Ablation
• Microwave Ablation Like RFA, microwave (MW) ablation (MWA) uses
electromagnetic waves to produce heating.
• Unlike RFA, the MW energy is not an electrical current and is in a
much higher frequency range that extends from 300 MHz to 300 GHz.
• The broader deposition of MW energy creates a much larger zone of
active heating. MW applicators available for clinical use generally
operate in the 900 to 2,450 MHz range.

13. • The rapidly alternating electric field of the MW antenna causes water
molecules to spin rapidly in an attempt to align with electromagnetic
charges of opposite polarity. MW tissue heating occurs because of the
induction of kinetic energy in surrounding water molecules.
• Microwave ablation (MWA) appears to have potential to improve the
rate of complete ablation achieved with RFA in tumors that are larger
than 2 to 3 cm or multiple. Device specific safety and efficacy data,
including predictability and reproducibility, are warranted.

14. • MWA seems to have potential to overcome the limitations of RFA in
the treatment of tumors in perivascular location as it is less
influenced by heat sink effect.

15. IRREVERSIBLE ELECTROPORATION
• Irreversible electroporation (IRE) is a novel, non–thermal injury, ablative
technology that uses multiple short pulses (pulse length, 70-90 µsec) at
high voltage (2250-3000 volts) of electrical energy to induce permanent
electroporation of the tissue.
• IRE is a dynamic phenomenon by which cell membrane integrity is
compromised by inducing permanent nanopores using transmembrane
electrical distortion.
• Using an electrical field of 2500 V/cm3 , it is postulated that IRE creates
nano-sized pores (0.08-0.5 µm) in the cell membrane that are unable to
reseal, because the electrical pulse strength and duration surpass the cell
membrane threshold, permanently damaging the plasma membrane.

16. • The clinical indication for IRE of liver tumors must be made based on
• (1) tumor biology,
• (2) tumor size less than 4 cm,
• (3) tumor location within 5 mm or less of a vital structure that needs
to be spared.

17. Cryotherapy
• Cryotherapy causes cell death by a variety of physical and chemical
mechanisms, depending on the rate of cooling, absolute depth of
hypothermia, rate of thawing, number of freeze-thaw cycles used,
and delayed effects of post thaw ischemia. When a cryoprobe is
inserted into the liver, three overlapping zones of injury develop
within the ice ball.
• The dynamics of the freezing process cause different mechanisms of
injury in these three idealized zones

18. • The rate at which tissue cools affects the proportion of cells killed by
a single freeze cycle.
• Maximal cell death is achieved at slow and rapid cooling rates
(although through different mechanisms), whereas greatest cell
survival is seen with intermediate cooling rates.
• Cellular dehydration causes lethal injury at slow cooling rates,
whereas rapidly cooled cells are destroyed by the mechanical action
of ice crystallization and expansion

19. • There is approximately a 60% (range, 40%-82%) reduction in AFP
levels after cryotherapy in patients with elevated preoperative AFP.
• Reduction of AFP serum levels after cryotherapy does not clearly
translate into a survival benefit.
• For primary liver cancer patients treated with cryotherapy alone, the
5-year actuarial survival is approximately 30%.
• RFA has replaced cryoablation as preferred ablation therapy.

20. ETHANOL INJECTION(PEI)
• This technique consists of injecting 95% ethanol in liver tumors
through a needle to induce coagulative necrosis and a fibrous
reaction. In general, multiple sessions of the procedure are needed to
achieve adequate responses.
• Among ablative techniques, PEI was the first percutaneous treatment
introduced in clinical practice

21. • RFA appears to be superior to PEI in regard to local recurrence rates,
overall survival, and event-free survival.
• Despite higher long-term recurrence rates and inferior overall survival, PEI
has specific indications. Lesions in the liver hilum and close to major
vessels are adequate sites for this procedure, where chemical injection can
be performed more safely than thermal ablation.
• Another modest benefit is that the cost of ethanol injection is
approximately 100 times less than for RFA

22. Conformal radiation therapy(RT)
• RT for liver tumors has been limited by the tolerance of the liver and
the surrounding normal organs to even relatively low doses of
radiation.
• Techniques typically consist of innovations designed to minimize
normal hepatic irradiation and enhance target conformality, such as
intensity-modulated radiotherapy (IMRT), image-guided radiotherapy
(IGRT), and the use of motion management.

23. • Intensity-modulated RT is a more sophisticated approach to the
planning and delivery of RT that uses computer software to define
high-dose regions for the tumor and subclinical disease and to
constrain the dose to normal organs.
• The introduction of IMRT more than a decade ago was made possible
by the use of computed tomography (CT) or magnetic resonance
imaging (MRI)
• Core beam CT (CBCT), has been developed to allow real-time
assessment of tumor positioning on the linear accelerator while the
patient is on the table before treatment delivery

24. • Early on, researchers determined that low doses of whole-liver
irradiation were ineffective in controlling gross hepatocellular
carcinoma (HCC) disease, and that higher doses resulted in high rates
of radiation hepatitis or radiation-induced liver disease (RILD)
• . The underlying mechanism of RILD has not been fully elucidated, but
it may be a combination of radiation-induced damage to both
hepatocytes and endothelial cells. The resulting clinical syndrome is
characterized by anicteric hepatomegaly, ascites, and elevated liver
enzymes, occurring up to 3 months after liver RT

25. • Stereotactic body RT (SBRT), which allows for the precise delivery of
high-dose radiation to a conformal target within the body
(extracranial), using either a single dose or a small number of
fractions .
• The ability to deliver high doses of RT is based on the more focal
treatment fields afforded by the use of IMRT and the more accurate
localization of tumors based on diagnostic-quality imaging techniques
on the linear accelerators, such as CBCT.
• Unlike the conventional RT fractionation schedule of 1.8 to 2 Gy/day,
delivered 5 days a week over 5 to 6 weeks, SBRT can deliver a very
high ablative dose of 18 to 30 Gy in 1 day or 30 to 60 Gy in 1 to 5
fractions over 1 to 2 weeks.

26. Hepatic artery embolization and
chemoembolization of liver tumors
• In the absence of effective systemic therapy, much effort has been
put into developing and testing transarterial liver-directed therapies
for local tumor control. Transarterial chemoembolization (TACE) has
been the most commonly used procedure to palliate symptoms and
to prolong survival in patients with liver tumors
• TACE should be distinguished from transarterial embolization, which
uses only embolic material, and hepatic arterial infusion
chemotherapy, which uses only antitumoral chemoagents.

27. • The basic physiologic principle that makes hepatic artery
embolotherapy feasible in patients with liver tumors is the dual blood
supply to the liver. The portal vein provides more than 75% of the
blood flow to the normal hepatic parenchyma and is the primary
trophic blood supply.
• Conversely, most of the blood supply (90% to 100%) to liver tumors
comes from the hepatic artery; thus embolization of tumor-feeding
hepatic artery leads to selective ischemic damage of the tumor while
sparing the normal liver parenchyma, which is mainly supplied by the
portal vein.

28. • The pharmacokinetic advantage of locoregional drug administration
enhances the theoretical benefit. For example, hepatic drug exposure
has been estimated to be double for doxorubicin, 7 times greater for
cisplatin, 8 times greater for mitomycin C, and 10 times greater for 5-
fluorouracil (5-FU) when these were given through the hepatic artery
rather than through the systemic veins.
• The chemotherapeutic drug is dissolved in water or water-soluble
contrast agent. The drug is then mixed with Lipiodol and administered
as a water-in-oil–type emulsion

29. • In the BCLC staging system, TACE is recommended as first-line therapy
for intermediate stage HCC (multinodular, asymptomatic tumors
without vascular invasion or extrahepatic spread).
TACE can be considered as an alternative treatment with curative
intent in patients with early stage HCC who are not eligible for hepatic
resection or ablation therapy due to systemic comorbidities or
anatomic problems.
TACE induces a significant tumor necrosis without negative influence
on liver function in patients with preserved liver function. The extent of
tumor necrosis has been reported to range from 60% to 100%.

30. • Although the concept of delivering high-dose chemotherapy to the
tumor is sound, no evidence-based findings support the routine use
of conventional TACE (cTACE). Bland embolization with spherical
embolic agents or microspheres has been shown to be as effective as
cTACE in treatment of hypervascular primary and metastatic liver
tumors; it can be used instead of cTACE, thereby avoiding the added
expense and potential systemic toxicity of chemotherapy.
• Drug-eluting beads (DEBs) are specifically designed microspheres
that load a specific chemotherapeutic drug and release the drug
locally within the target tissue during an extended period. DEBs can
enhance therapeutic efficacy, and at the same time, they reduce
toxicity because of minimum systemic exposure.

31. Radioembolization
• Radioisotopes linked to either glass or resin microspheres are injected
into the HA. This outpatient treatment is typically delivered through
either the right or the left HA, although with favorable anatomy, it can
be delivered more selectively.
• Whole liver treatment is usually reserved for metastases rather than
HCC due to the risk of liver injury.
• The most common isotope is 90Y, a pure β emitter, with an effective
path length of 5 mm and a half-life of 65 hours. A total of 90% of the
energy is deposited within 5 mm of the sphere; therefore, side effects
are quite localized.

32. • The limited availability of donor organs for Orthotopic liver transplant
OLT and the dropout of patients as a result of tumor progression
limits the number of patients who are able to undergo OLT.
• Thermal ablation (radiofrequency ablation) has a limited role because
of the risk of tract seeding and the size and location of tumor.
• Radioembolization has been shown to limit progression of the
disease, which allows the patient more time to wait for donor organs
and thus increases their chance of undergoing OLT .Thus
radioembolization has a role in bridging patients to OLT.

33. • This stage includes patients presenting with vascular invasion or
extrahepatic spread who are still relatively fit, as reflected by
performance status at staging work-up, and who have preserved liver
function.
• BCLC-C patients should be evaluated for systemic therapy.
• The combination of atezolizumab with bevacizumab (Atezo-Bev) is
currently the first-choice first-line treatment, as it confers a superior
survival benefit compared to sorafenib
• The combination of cabozantinib and atezolizumab showed a
significant benefit in progression-free survival in recent

34. • Almost every class of chemotherapy has been investigated in
advanced HCC .Doxorubicin is one of the most common drug studied
for this indication.
• IFN, doxorubicin, and 5-fluorouracil (5-FU), which became commonly
known as PIAF . PIAF was subsequently modified and studied in the
outpatient setting

35. • Resection and liver transplantation represent the potentially curative
options with the longest track record. For small tumors, ablation and
radiotherapy (RT) are quite effective and may also be curative.
• Only 20% to 30% of patients are candidates for curative surgical
treatment, including hepatic resection and liver transplantation .In
addition, the disease recurs after curative resection in 50% to 70% of
patients at 5 years.