Systemic treatment in advanced hepatocellular carcinoma (HCC) refers to the use of medications or therapies that are administered throughout the body to target cancer cells beyond the liver. HCC is the most common type of liver cancer and often presents at an advanced stage, making systemic therapies crucial in managing the disease.
One of the main categories of systemic treatment for advanced HCC is targeted therapies. Targeted therapies are designed to selectively inhibit specific molecules or pathways involved in tumor growth, thereby blocking the signals that support cancer cell survival and proliferation. Sorafenib and lenvatinib are examples of targeted therapies that have been approved for the first-line treatment of advanced HCC. They target vascular endothelial growth factor (VEGF) receptors, which play a key role in promoting the growth of new blood vessels necessary for tumor growth. By inhibiting these receptors, these drugs can help slow down tumor growth and improve patient outcomes.
In addition to sorafenib and lenvatinib, other targeted therapies have shown promising results in the treatment of advanced HCC. Regorafenib, for instance, is a multi-kinase inhibitor that targets several pathways involved in tumor angiogenesis, cell proliferation, and survival. Cabozantinib is another multi-kinase inhibitor that has been approved as a second-line treatment option for patients who have progressed on or are intolerant to prior systemic therapy. These targeted therapies have demonstrated efficacy in improving overall survival and delaying disease progression in patients with advanced HCC.
Another significant advancement in systemic treatment for advanced HCC is the use of immune checkpoint inhibitors. Immunotherapy has revolutionized cancer treatment in recent years, including for HCC. Immune checkpoint inhibitors, such as nivolumab and pembrolizumab, work by blocking proteins that act as checkpoints on immune cells, such as programmed cell death protein 1 (PD-1) or its ligand (PD-L1). By doing so, these drugs help restore and enhance the immune system's ability to recognize and eliminate cancer cells. Checkpoint inhibitors have shown promising results, with some patients experiencing durable responses and improved overall survival.
2. HCC is primarily caused by chronic hepatitis B and C infections, alcohol abuse,
aflatoxin exposure, and NAFLD.
HCC has a global incidence of over 800,000 cases annually, with the highest rates in
regions with a high prevalence of hepatitis infections, resulting in a 5-year survival
rate of approximately 18%.
Early-stage HCC can achieve 5-year survival rates exceeding 70% with surgical
resection or transplantation, while systemic therapies extend survival in advanced
cases.
5 year Survival rates vary, with early diagnosis and treatment offering the best
outcomes - 30-70% in localized cases, dropping to <10% in advanced cases.
Rigorous post-treatment surveillance, including imaging and AFP tests, is crucial for
early recurrence detection.
4. Assess tumor site, location, and
extrahepatic metastases
Assess underlying liver function
Optimize medical therapy, consider PVE + TACE if
major resection needed, especially right hepatectomy
Intraoperative evaluation to assess resectablility
Child-Pugh class A or non
cirrhosis, and potentially
resectable
Child-Pugh class B/C or significant
portal hypertension, or otherwise
unresectable
Liver transplant candidate?
Unresectable
Complete resection
Consider intraoperative
ablation if positive margin:
evaluate for transplant;
consider bridging therapy
while awaiting transplant
Monitor for relapse
Extrahepatic mets
No
Systemic therapy for patients with adequate performance status and
underlying liver function ( child- Pugh class A or no cirrhosis)
Individualize care for Child- Pugh class B cirrhosis, depending on
severity of underlying liver function, and performance status
Best supportive care for Child –Pugh class C cirrhosis
Liver only
Evaluate for transplant, consider
bridging therapy while awaiting
transplant
Assess disease extent
Yes
Assess underlying liver function
5. Copyrights apply
Assess
underlying liver
function
Child Pugh C
Child Pugh class A/B
or no cirrhosis
Best supportive
care
Assess intrahepatic tumor burden,
presence of macrovascular invasion
Portal vein
invasion/occlusion/thrombus
Large intrahepatic tumor burden (eg.
Multiple tumors<5 cm or any >5
cm),no macrovascular
invasion/obstruction
1 to 2 tumors, none >5
cm, no macrovascular
invasion
Choice of therapy depends on extent of PVTT, availability of
locoregional treatment and local expertise
Options include:
Systemic therapy (preffered for lobar or main portal vein
involvement: Vp3, Vp4) if performance status and underlying
liver function are adequate
HAIC with or without sorafenib(where available
TARE
SBRT
Proton beam irradiation
TACE plus RT
Lenvatinib plus TACE
Resection
Options include:
Systemic chemotherapy(preffered)
TARE
TACE
TACE plus Lenvatinib
HAIC (where available)
SBRT (SELECT CASE)
Options includes:
RFA or microwave ablation
TACE plus RFA or microwave ablation
TARE
External beam radiation therapy,
including SBRT
10. Hepatic resection is a potentially curative treatment for HCC and is preferred for eligible
patients.
Long-term relapse-free survival rates average 40% or better, with five-year survival rates
as high as 90% in carefully selected patients.
The median PFS following hepatic resection for HCC can vary but is often in the range of
15 to 20 months.
the median OS after hepatic resection for HCC typically ranges from 30 to 60 months.
The recurrence-free survival after HCC resection is also variable and can range from 20
to 60 %at 5 years.
The 5-year survival rate after hepatic resection for HCC can vary widely, with reported
rates ranging from 40% to 70% or more in carefully selected patients.
These rate is influenced by factors such as tumor stage, liver function, and the presence of any
complications
11. Ideal Candidates for Resection:
Solitary HCC lesion in the liver
No radiographic evidence of invasion of hepatic
vasculature.
Well-preserved hepatic function (Child-Pugh class A).
No evidence of portal hypertension
Performance status suitable for surgery.
Tumor located in a resectable position (not near major
vessels or vital structures).
Possible candidates for Resection:
Mild portal hypertension
Tumor in a location amenable to
resection (with consideration of
surgical techniques).
Relative Contraindications to
Resection:
Child-Pugh class B cirrhosis.
Moderate to severe portal
hypertension.
Multiple HCC lesions
Tumors near major vessels, which
would require extensive resection.
Advanced disease stages with
vascular invasion (e.g., AJCC stage
IIIB, IVA, IVB).
Absolute Contraindications to Resection:
Child-Pugh class C cirrhosis.
Extensive vascular invasion
Distant metastases.
Poor performance status.
Inoperable comorbidities that significantly increase surgical
risk.
Lack of adequate hepatic function for regeneration after
resection.
12. •Tumors located in the peripheral regions of the liver (e.g., segments
2, 3, 4, 5, and 6) are often more suitable for resection because they
are easier to access and do not involve critical structures.
•Tumors located in central or deep regions of the liver, near major
blood vessels, or adjacent to vital structures, may pose challenges
for resection due to the increased risk of bleeding or damage to
vital structures during surgery.
•The ability to achieve negative surgical margins (complete tumor
removal) is a key consideration in resection.
Tumor
Location:
•The extent of PVTT is categorized into stages, typically as VP1, VP2,
VP3, and VP4, with VP1 indicating the least extent of thrombus and
VP4 indicating the most extensive thrombus involving the main
portal vein and its branches.
•In general, patients with VP1 or limited VP2 thrombus may be
considered for resection
•For patients with more extensive PVTT (VP3 or VP4), resection is
often considered high-risk.
Portal
Vein
Tumor
Thrombus
(PVTT):
13. Parameter Ablation Resection
Method
Minimally invasive, local destruction of tumor tissue
using techniques like RFA, microwave ablation,
cryoablation, etc.
Surgical removal of the tumor along with a margin of healthy liver tissue.
Invasiveness
Minimally invasive; performed percutaneously (through
the skin) or laparoscopically in some cases.
Invasive; requires general anesthesia and abdominal incisions.
Tumor Size
Typically suitable for smaller tumors,(3 cm) especially
those located in less critical areas of the liver.
Suitable for larger tumors, including those in critical locations.(may be 5 cm)
Liver Function
Appropriate for patients with relatively well-preserved
liver function.
Challenging for patients with compromised liver function or advanced liver
disease.
Recovery Time
Shorter recovery time; patients often discharged the
same day or the day after the procedure.
Longer recovery time; hospital stay and postoperative care required for
several days to weeks.
Complications
Fewer complications, less postoperative pain, and lower
risk of bleeding.
Potential for complications such as bleeding, infection, and impaired liver
function.
Curative Potential
Effective in achieving complete tumor eradication,
especially for small tumors.
Also offers curative potential, often considered the gold standard for tumor
removal when feasible.
Follow-up
May require repeat ablation sessions for recurrent or
residual tumors during follow-up.
Requires regular follow-up for recurrence monitoring, but with a lower
likelihood of recurrence compared to ablation.
Overall Survival
Survival outcomes may be slightly lower compared to
resection for larger tumors or more advanced disease.
Can offer higher survival rates for appropriate candidates, especially in
early-stage disease.
Patient Selection
Typically for patients with smaller tumors, well-
preserved liver function, and suitable tumor locations.
Suitable for patients with larger tumors, well-preserved liver function, and
tumors in various locations.
14. Parameter Resection
Radiofrequency
Ablation (RFA)
All-Cause
Mortality
Not significantly superior
HR: 0.80 (95% CI 0.6-1.08)
Cancer-Related
Mortality
Odds Ratio:
17.4%
Odds Ratio:
37.4%
Risk of Serious
Adverse Events
23.3% 1.7%
Quality of
Evidence
Low
Parameter Resection
Local Ablation
(RFA/MWA with or
without TACE)
5-Year Overall
Survival
not significantly better
HR: 0.85 (95% CI 0.55-1.29)
5-Year Relapse-Free
Survival
Favored surgery
HR: 0.75 (95% CI 0.62-0.92)
Local Recurrence
Rates
Favored surgery
HR: 0.45 (95% CI 0.26-0.79)
Risk of Bias
Risk of bias due to lack of information on
randomization method, baseline
imbalances, or missing data.
table comparing trial data from a 2017 Cochrane
analysis of four trials
2021 meta-analysis of seven randomized
trials
16. Liver transplantation offers a potential cure for patients with HCC who are not surgical candidates
due to underlying liver dysfunction.
Allocation and MELD Exception Score:
Allocation of donor organs in the US is managed by the Organ Procurement Transplantation
Network (OPTN), operated by the United Network for Organ Sharing (UNOS).
Deceased donor allocation is based on the Model for End-Stage Liver Disease (MELD) score,
predicting survival in cirrhotic patients.
Patients with HCC receive MELD exception scores based on tumor size and number (T2 stage
and AFP <1000 ng/mL).
Exception points are granted after six months on the waitlist, limited to MMAT-3 (median MELD
at the region of the donor hospital minus 3 points).
• Immediate points are given to recurrent cases.
• These criteria apply in the setting of cirrhosis.
Bridging Therapy:
• Waitlist times can be lengthy, making bridging therapy crucial to maintain eligibility.
• Options include embolization, RFA, EBRT, or partial hepatectomy.
• Selection depends on the patient's specific needs.
Living Donor Liver Transplantation (LDLT):
• LDLT provides a way to avoid the prolonged wait for a deceased donor organ, crucial for HCC
17. • Approach Variability: No single best approach for these patients; clinical practice varies.
• Factors Influencing Treatment Selection: Severity of underlying liver disease, tumor size
and distribution, vascular supply, patient's performance status, and local expertise.
• Historical Management: Traditionally, liver-directed approaches such as ablation (if feasible),
arterially-directed therapy, or radiotherapy were common for these patients.
• Changing Landscape: Emergence of effective systemic therapies in HCC has led to
consideration of systemic therapy even for those eligible for liver-directed therapy.
• Variability in Expert Care: Different centers offer varying approaches due to uncertainty in
the relative benefits of these strategies.
• Disparate Guidelines: 2022 BCLC guidelines recommend initial systemic therapy for diffuse
infiltrative, extensive bilobar liver involvement, portal invasion, or performance status 1-2.
• Arterial embolization is preferred for well-defined nodules, preserved portal flow, and
performance status 0. Few trials compare these strategies, including combined locoregional
and systemic therapy.
• Alternative Recommendations: Some guidelines suggest locoregional therapies for liver-
limited HCC without macrovascular involvement.
• Preference for Locoregional Therapy: Many centers favor locoregional liver-directed
therapy for fit patients with limited tumor burden and adequate liver reserve.
18. • Patient Profile: Liver-isolated, unresectable HCC patients ineligible for transplantation with limited intrahepatic tumor
burden and no PVTT.
• Preferred Initial Approach: Locoregional liver-directed therapy (e.g., ablation, arterially-directed therapies, external
beam RT) recommended.
• High local response rates (up to 70%).
• Favorable local tumor control rates (66-90%).
• Favorable safety profiles.
• Systemic Therapy Consideration: No evidence that initial systemic therapy is safer, better tolerated, or more effective
in this setting compared to more advanced disease.
• Choice of Locoregional Approach: Individualized based on principles:
• Local thermal ablation (RFA, MWA) preferred for one or a few relatively small tumors.
• Ablation suitable for Child-Pugh class A or B cirrhosis.
• May serve as "bridging" therapy for transplant candidates.
• Other liver-directed therapies (e.g., TACE, TARE, HAIC, EBRT) for tumors not amenable to local ablation.
• Combined Locoregional Approaches: TACE plus RFA preferred for intermediate-sized HCC (3-5 cm).
• SBRT
• Role of Multiagent HAIC: particularly for patients with large intrahepatic tumor burden or PVTT.
• Locoregional + Systemic Therapy: Increasingly tested in combination with molecularly-targeted agents and
immunotherapy.
• No demonstrated benefit from adding systemic therapy to arterial embolization for limited intrahepatic tumor
burden.
• Larger phase III trials with newer agents required for conclusive evidence.
19. • Patient Profile: Patients with liver-isolated HCC ineligible for surgical resection or liver
transplantation, presenting a large intrahepatic tumor burden.
• Recommended Initial Approach: Systemic chemotherapy is suggested rather than
locoregional treatment alone or a combination of systemic and locoregional treatment.
• Preferred Systemic Therapies: For most patients:
• Atezolizumab plus bevacizumab.
• If bevacizumab is contraindicated, durvalumab plus tremelimumab.
• Molecularly targeted therapy is a secondary option.
• Alternative Approach: Hepatic arterial infusion chemotherapy (HAIC) is an option where
technical expertise is available.
• However, HAIC is not preferred due to a lack of direct comparative data with systemic therapy.
• Lenvatinib plus TACE: An option based on the LAUNCH trial, primarily conducted in Asian
patients, predominantly with HBV-related HCC (87%).
• Applicability to other populations is uncertain.
• Definition of "Large Intrahepatic Tumor Burden: No consensus definition exists.
• Consider the "Up-To-Seven" criteria from the Asia-Pacific group: HCC with a sum of the size of the
largest tumor (in cm) plus the total number of tumors exceeding seven.
20. Outcome Measure TARE (90Y Microspheres) Sorafenib
Tumor Response Rate (%) 16.5 1.7
Adverse Events Fewer More
Disease Control Rate (%) 41.8 42.7(NS)
Time to Tumor Progression
(months)
5.88 5.36 (NS)
Median Overall Survival (months) 8.8 10(NS)
One-Year All-Cause Mortality (%) 63 53
•SIRveNIB Trial: Participants: 360 Asia-Pacific patients with newly diagnosed unresectable
HCC (without extrahepatic spread).
•Treatment Arms: Random assignment to sorafenib (400 mg twice daily) or a single injection of
90Y microspheres.
21. French Trial:
Participants 467 patients in France,Child-Pugh Class A Cirrhosis 83%
Tumor Characteristics :
Over one-half with multiple tumors, 20% with bilobar disease,34% with tumor burden >25% of the liver
Treatment Arms:-Sorafenib or TARE
Outcome Measure TARE (90Y Microspheres) Sorafenib
Objective Tumor Response
(%)
19 12
Adverse Events Fewer Fewer
Liver Dysfunction Rates Similar Similar
Median Survival (months) 8 9.9
Treatment-Related Deaths 19 (8%) 12 (5%
22. Study Phase III STAH Trial SORAMIC Trial Cochrane Analysis (2020)
Patient Population Advanced HCC Inoperable Liver Cancer HCC Patients
Number of Patients 339 424 N/A
AJCC Stage Stage III, IVA or IVB Not eligible for TACE N/A
Extrahepatic Spread 36% of enrolled Not specified N/A
PVTT 28% Vp3-4 Not specified N/A
Treatment Groups
Sorafenib vs. Sorafenib +
TACE
Sorafenib vs. Sorafenib +
Radioembolization
Sorafenib vs. Sorafenib +
Radioembolization
Overall Survival (OS) No improvement in OS
No significant
improvement in OS (12.1
vs. 11.4 months)
Similar survival
Liver Function Worsened with TACE Not specified
Fewer serious adverse
effects
Hyperbilirubinemia
14.5% with TACE +
Sorafenib
Not specified Not specified
Adverse Events N/A
Higher rates of grade 3 or
4 adverse events
N/A
Cochrane Analysis
Conclusion
N/A N/A
Evidence highly
insufficient
Quality of Evidence N/A N/A Very low quality
23. LAUNCH Trial Findings
Patient Population 338 patients
87%
The enrolled patient population had relatively locally advanced
disease (70 % PVTT, 80 % multifocal, 68 % large tumors) or
extrahepatic disease spread (55 %)
HBV-Related HCC
Treatment Lenvatinib (8 or 12 mg daily) Lenvatinib + "on-demand" TACE
Median Overall Survival (OS) 11.5 months 17.8 months
HR (OS) 0.45 (95% CI 0.34-0.55)
Median Progression-Free Survival
(PFS)
6.4 months 10.6 months
HR (PFS) 0.43 (p < 0.001)
Objective Response Rate 25% 54%
Grade 3/4 Adverse Events ALT Elevation: 1.2% ALT Elevation: 17.6%
AST Elevation: 1.8% AST Elevation: 22.9%
Hyperbilirubinemia: 3.0% Hyperbilirubinemia: 9.4%
Median Duration of Treatment 5.1 months 8.2 months
Discussion
Need for more Western
population data
Need for more Western
population data
24. • HAIC Procedure
• Content:
• Hepatic Arterial Infusion Chemotherapy (HAIC) is
a precise treatment for liver cancer.
• Procedure: A catheter is used to deliver potent
chemotherapy drugs directly into the hepatic
artery, targeting liver tumors.
• Image Placeholder: Insert an image that
illustrates the procedure, such as a catheter or a
medical illustration.
•Indications: HAIC is suitable for select patients with
unresectable liver tumors.
•Benefits: Offers localized treatment, reduces systemic
side effects, enhances effectiveness when combined
with other therapies, and requires close monitoring.
•Side Effects: May include localized discomfort, liver
enzyme elevations, and other manageable effects.
25. Treatment Comparison HAIC (FOLFOX) Superselective TACE
Patient Population 315 Asian patients Unresectable large HCCs
Underlying HCC Risk Factor 89% HBV
Cirrhosis (Child-Pugh Class A) 81%
Treatment Regimens HAIC (FOLFOX) Superselective TACE
Median Overall Survival 23.1 months 16.1 months
HR (OS) 0.58 (95% CI 0.45-0.75)
Objective Response Rate 46% 18%
Median Progression-Free Survival
(PFS)
9.6 months 5.4 months
Tolerability Better
Serious Adverse Effects (%) 19% 30%
Adverse Effects with HAIC
(FOLFOX)
Abdominal pain, catheter
thrombosis/dislocation, gastric ulcers
(with GI bleeding)
HAIC showed significantly better Median Overall Survival, a higher Objective Response Rate,
longer Median Progression-free Survival, and Better Tolerability.
26. • Most Common Macrovascular Invasion: PVTT is the predominant form of
macrovascular invasion observed in Hepatocellular Carcinoma (HCC).
• Clinical Implications:
• PVTT development often signifies worsening liver function.
• Patients with PVTT are more vulnerable to metastatic disease spread.
• Higher risk of complications linked to portal hypertension.
• Reduced tolerance for treatment compared to those without PVTT.
• Prognosis and Survival:
• PVTT, especially Vp3 or Vp4 involvement, is associated with a grim prognosis.
• Patients receiving supportive care alone typically survive for only two to four months.
27. •Extent and Classification:
• The extent of PVTT significantly impacts HCC
prognosis.
• Classification system used: Liver Cancer Study
Group of Japan's five-tier system.
• Classification Levels:
• Vp0: No tumor thrombus in the portal vein.
• Vp1: Segmental thrombus distal to the second-
order branches without direct involvement.
• Vp2: Invasion of a second-order branch.
• Vp3: Tumor thrombus in a first-order branch
(right or left lobar).
• Vp4: Tumor thrombus in the main portal vein
trunk or contralateral to the primarily involved
lobe (or both)
28. Extensive PVTT (Vp3 or
Vp4):
Lesser PVTT (Vp1 or
Vp2):
Systemic Therapy immunotherapy,
such as atezolizumab plus bevacizumab
Hepatic Arterial Infusion Chemotherapy
(HAIC) with or without sorafenib
Lenvatinib Plus TACE
Transarterial chemoembolization
(TACE
Stereotactic body radiation therapy
(SBRT)
Transarterial radioembolization (TARE)
Hepatic resection
29. Combining 3D-CRT and TACE for Unresectable HCC with PVTT
• Patient Series: A registry database series included 412 patients with unresectable HCC
complicated by portal vein tumor thrombosis (PVTT). Nearly half had bilateral or main portal
vein involvement.
• Treatment Approach: Patients received focal three-dimensional conformal radiation
therapy (3D-CRT) combined with TACE. TACE was administered either before or after
radiation therapy and included agents like lipiodol and cisplatin gelatin sponge.
• Outcomes:
• Objective Response: 40% of patients demonstrated an objective response in the PVTT,
indicating tumor shrinkage or control.
• One-Year Survival: 43% of patients were still alive at one year.
• Hepatotoxicity: Notably, 10% of patients experienced grade 3 or 4 hepatotoxicity, typically
occurring during or within three months of completing radiation therapy.
• Potential for Improved Outcomes: Newer planning methods for radiation therapy, such as
3D-CRT or hypofractionated stereotactic body radiation therapy (SBRT), show promise:
• Objective Response Rates: With RT alone targeted to the portal vein thrombus, objective
response rates have ranged from 39% to 62%
30. In a clinical trial, TACE (Transarterial Chemoembolization) combined with RT was
compared to sorafenib in treatment-naïve patients with liver-confined HCC invading the
first or second branch of the portal vein, with preserved unilateral portal blood flow. All
patients had Child-Pugh class A liver function.
Treatment Details:
• TACE plus RT group: RT started within three weeks of the first TACE session. RT
involved delivering 45 Gy using 3D-CRT planning with a fraction size of 2.5 to 3 Gy.
• TACE procedure repeated every 6 wks for the first 6 months and every 6 to 8
weeks thereafter.
Results:
TACE plus RT group showed significantly better outcomes compared to the sorafenib
group:
• Higher Progression-Free Survival (PFS) rate at 12 weeks (87% versus 34%).
• Higher radiographic response rate at 24 weeks (33% versus 2%).
• Longer median time to progression (31 versus 12 weeks).
• Greater median overall survival (55 versus 43 weeks).
31. Transarterial Radioembolization (TARE), also known as radioembolization, is an emerging
treatment option for HCC with PVTT. This therapy involves the targeted delivery of radioactive
microspheres directly to liver tumors.
Indications:
• TARE is often considered for patients with unresectable HCC complicated by PVTT.
• It is generally suitable for individuals with preserved liver function (usually Child-Pugh class
A) and a degree of vascular invasion that can be targeted with this approach.
• TARE offers several advantages:
• Precise targeting: It delivers radiation directly to the tumor, minimizing damage to healthy
liver tissue.
• Lower risk of arterial ischemia: The smaller particle size of microspheres used in TARE
(around 32 microns) suggests reduced risk of blocking blood flow, making it potentially
safer in the setting of portal vein thrombosis.
Efficacy:
• Some retrospective studies have suggested that TARE may lead to better survival outcomes
compared to initial treatment with sorafenib, especially in certain patient subgroups.
• These studies indicate that TARE can achieve tumor control and improve patient survival in
select cases.
• TARE is generally well-tolerated, and rates of severe adverse effects appear to be lower
compared to other locoregional therapies, such as TACE.
32. • Limited Trial Data: Experience with SBRT for primary liver tumors complicated by PVTT
is limited but growing, with no direct trials comparing SBRT to systemic therapy.
• Efficacy Example: A prospective evaluation of 102 patients with HCC, not eligible for
surgical resection, TACE, or RFA, underwent SBRT. The median prescription dose was
36 Gy in six fractions. Patients had advanced disease with multiple lesions, large tumor
size, and PVTT. Despite these challenges, one-year local control was 87%, with a
median time to local progression not reached at a median follow-up of 31.4 months. The
one-year survival rate was 55%.
• Comparison with TARE: A meta-analysis of 37 studies (observational or single-arm
prospective) found differences in overall response and local control rates, favouring
SBRT over TARE. However, the response rate in PVTT was similar with both modalities
(39% with SBRT, 35% with TARE), as was overall survival at one and two years.
33. Four trials have suggested a significant survival benefit for HAIC over sorafenib alone, with
some patients even downstaged to potentially resectable disease after HAIC treatment.
Phase III Trial: In a randomized phase III trial, sorafenib was compared to sorafenib plus HAIC
in Chinese patients with HCC and PVTT. The combined therapy group showed a significantly
higher median overall survival (13.4 versus 7.1 months), indicating a survival benefit. However,
it was associated with higher rates of treatment-related grade 3 or 4 neutropenia,
thrombocytopenia, and vomiting.
Patients in these trials had various characteristics, including HBV-related HCC, and a
proportion had tumor invasion of the main portal vein (Vp4)
Trial Comparison Patient Characteristics Tumor Downstaging Survival Benefit
Oxaliplatin-Based HAIC vs.
Sorafenib
- 66% had macrovascular
invasion - Approximately
50% had extensive liver
involvement or Vp-4 PVTT
- 16 out of 130 patients
experienced tumor
downstaging (12%)
- Significant survival
advantage with HAIC:
Median OS 10.8 months vs.
5.7 months with sorafenib -
Hazard ratio for death:
0.343 (95% CI 0.219-0.538)
Second Trial :-
34. Chinese Trial - TACE Plus Sorafenib or Lenvatinib in First-Line
Treatment
Parameter TACE Plus Sorafenib TACE Plus Lenvatinib
Patient Group 64 patients with HCC and PVTT
Safety and Tolerability BETTER
Efficacy FAVOURABLE
Median Time to Progression
- Short median time to tumor
progression (4.7 months)
- Short median time to tumor
progression (3.1 months)
Median Overall Survival
- (10.8 months)
not statistically significant
- (14.5 months)
Limitations
- Lack of control group with systemic therapy alone - No data on
combining TACE with modern immunotherapy-based systemic
therapy
35. The IMBrave150 trial demonstrated a survival benefit for Atezo/Bev
compared to sorafenib alone.
• About 43% of trial participants had PVTT, including some with Vp4 disease.
• Randomization was stratified based on the presence or absence of
macrovascular invasion.
• Subgroup analysis revealed treatment benefits across all subgroups, including
those with PVTT.
• Median overall survival was 14.2 months with Atezo/Bev vs. 9.7 months with
sorafenib (HR for death 0.68, 95% CI 0.47-0.98).
• Patients without PVTT also experienced a survival benefit (HR for death 0.66,
95% CI 0.47-0.92).
The IMBrave150 trial demonstrated the effectiveness of Atezolizumab Plus
Bevacizumab in improving survival outcomes for HCC patients with PVTT, highlighting its
potential as a treatment option.
36. In the HIMALAYA trial, which established the survival benefit of tremelimumab plus
durvalumab compared to sorafenib as initial therapy for advanced hepatocellular
carcinoma (HCC), a subgroup analysis examined the impact of macrovascular invasion.
Here are the key findings:
• HIMALAYA Trial:
• 103 out of the 393 patients assigned to durvalumab plus tremelimumab had macrovascular
invasion (26 percent).
• Preplanned subgroup analysis showed that treatment effects were generally consistent
across all treatment groups, including patients both with and without macrovascular invasion
37. • SHARP Trial:
• A prespecified subgroup analysis within the phase III SHARP trial showed that sorafenib's
survival benefit extended to patients with macrovascular invasion.
• In this subgroup, the median survival was 8.1 months with sorafenib versus 4.9 months with
placebo. However, the extent of vascular invasion was not described.
• Asia-Pacific Trial:
• An exploratory subset analysis of the phase III Asia-Pacific trial indicated that sorafenib was
beneficial for patients with macrovascular invasion and/or extrahepatic spread.
• In this subgroup, the median overall survival was 5.6 months with sorafenib versus 4.1
months with placebo. Disease control rates were 31 percent versus 12 percent. However, the
benefit was of lesser magnitude compared to patients without macrovascular invasion or
extrahepatic spread.
• Combined Analysis:
• A combined analysis of both trials revealed that 38 percent of enrolled patients had
macrovascular invasion.
• Sorafenib demonstrated benefits for patients both with and without PVTT.
• In those with PVTT, the median overall survival was 184 days with sorafenib versus 137 days
without. The extent of PVTT was not specified.
• In patients without PVTT, the median overall survival was 386 days with sorafenib versus 303
days without.
38. • REFLECT Trial:
• In the phase III REFLECT trial, approximately 20 %of enrolled patients had
macroscopic vascular invasion.
• Lenvatinib proved noninferior to sorafenib as a first-line treatment for advanced
HCC, showing similar efficacy across all predefined subgroups, including those with
macrovascular invasion and extrahepatic spread. However, patients with main trunk
PVTT (Vp4) were excluded from the trial.
• Retrospective Reports:
• In a retrospective analysis involving 41 patients with HCC complicated by Vp4
PVTT, lenvatinib achieved a significantly higher objective response rate compared to
sorafenib (54 % vs 14 %).
• Patients treated with lenvatinib had a longer median overall survival, and no patient
needed to discontinue treatment due to drug-related adverse effects.
• Another multicenter study with 61 patients, including those with advanced HCC and
Vp4 PVTT, emphasized the importance of underlying liver function. The objective
response rate among those with no worse than Child-Pugh class A cirrhosis was 27
%, while there were no responders among those with Child-Pugh class B cirrhosis.
39. • Regorafenib (RESORCE Trial):
• The phase III RESORCE trial demonstrated the efficacy of regorafenib in patients who
progressed on initial sorafenib, with 30 percent having macrovascular invasion.
• Subgroup analysis revealed that regorafenib reduced the risk of death for both patients
without and with macrovascular invasion.
• Cabozantinib (CELESTIAL Trial):
• In the phase III CELESTIAL trial, cabozantinib showed a significant survival benefit in
patients with advanced HCC who progressed after sorafenib. 27 percent of those treated with
cabozantinib had macrovascular invasion.
• A non-preplanned subgroup analysis suggested comparable benefit in patients with and
without macrovascular invasion.
• Ramucirumab (REACH-2 and REACH Trials):
• The REACH-2 trial demonstrated the benefit of ramucirumab in patients with initially high
AFP levels after sorafenib failure. Among them, 35 percent had macrovascular invasion.
• In a preplanned subgroup analysis, benefit was limited to those without macrovascular
invasion, while no benefit was seen in those with macrovascular invasion.
• However, a later combined analysis of REACH-2 and the earlier REACH trial, without AFP
level restrictions, showed a survival benefit favouring ramucirumab across all subgroups,
including those with macrovascular invasion. Multivariate analysis did not identify a single
factor predicting differential survival impact.
40. Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting
of chronic liver disease and cirrhosis.
Hepatic resection is a potentially curative therapy and the preferred treatment for eligible
patients.
Postoperative antiviral therapy improves outcomes after potentially curative treatment of
HCC that is related to hepatitis B virus or hepatitis C virus (HCV), and is indicated for
those with active viral infection.
For patients without surgically resectable disease, liver transplantation is a potentially
curative option
patients with limited intrahepatic tumor burden, we suggest liver- directed therapies
(ablation, arterially-directed therapies, external beam RT) rather than initial systemic
therapy,
For most patients with extensive involvement of a lobar branch or the main portal vein
(ie, Vp3 or Vp4 disease,suggest initial systemic therapy rather than locoregional therapy
41. The procedure begins with an angiography, during which
a catheter is inserted into an artery, typically in the groin,
and guided through the blood vessels to reach the arteries
that supply blood to the liver.
Contrast dye is injected through the catheter to visualize
the blood vessels and identify the precise location of the
liver tumor.
Once the tumor's blood supply is located, a chemotherapy
drug (most commonly doxorubicin or another
chemotherapeutic agent) is injected directly into the
arteries feeding the tumor. This allows for a high
concentration of the chemotherapy to be delivered directly
to the tumor.
After the chemotherapy injection, embolic agents, such as
small beads or particles, are injected through the catheter.
These agents block the blood vessels supplying the
tumor, causing a reduction in blood flow to the tumor.
42. Mechanism of Action: The mechanism of action of TACE involves a combination of
chemotherapy and embolization:
• Chemotherapy: The direct injection of chemotherapy into the tumor's blood supply
results in a high local concentration of the drug. This damages cancer cells and inhibits
their growth.
• Embolization: The embolic agents block the arteries that supply the tumor, leading to
ischemia. Tumor cells deprived of oxygen and nutrients are more susceptible to
chemotherapy-induced cell death.
INDICATION
1.Unresectable HCC:.
2.Tumor Ineligibility for
Resection:
3.Curative Intent:
4.Bridge to Transplant.
5.Tumor Downstaging.
6.Local Tumor Control.
7.Palliation of Symptoms.
Contraindications for TACE in HCC
- Extensive portal vein thrombus (VP3 or VP4)
- Tumors located near critical structures (e.g.,
hepatic artery or portal vein bifurcation)
- Very large tumors (>10 cm in diameter)
- Poor liver function (Child-Pugh C)
- Advanced cirrhosis with a high MELD score
- Severe portal hypertension
- Contraindication to the procedure due to
patient's medical status
- Patients with limited life expectancy
- Presence of untreated biliary obstruction
43. The mechanism of action of TARE involves the targeted delivery of radioactive microspheres to liver
tumors. TARE primarily affects the tumor tissue while sparing healthy liver tissue
STEPS:
1. Microsphere Injection: Radioactive microspheres, which are very small beads (typically loaded with
yttrium-90, Y-90, or holmium-166, Ho-166), are injected into the hepatic artery through a catheter. The
hepatic artery is the primary blood vessel that supplies the liver.
2. Microsphere Lodgment: These microspheres are transported by the bloodstream to the smaller
arteries within the liver that feed the tumor. Since the microspheres are tiny, they can travel through the
bloodstream to reach the tumor site.
3. Selective Lodging: The microspheres are specifically designed to get trapped in the smaller blood
vessels surrounding the tumor. They become lodged in these vessels, ensuring that the radiation they
emit is concentrated in the tumor's vicinity.
4. Radiation Emission: The radioactive isotopes within the microspheres (Y-90 or Ho-166) emit high-
energy radiation. This radiation damages the DNA of the cancer cells, causing them to lose their ability
to divide and grow. It also induces cell death (apoptosis) within the tumor.
5. Minimal Impact on Healthy Tissue: Importantly, the microspheres are selectively deposited in the
tumor-feeding vessels, and their radiation is primarily delivered to the tumor itself. Healthy liver tissue,
which may be adjacent to the tumor, receives significantly less radiation, minimizing damage to the non-
cancerous parts of the liver.
6. Long-Term Effects: The radiation delivered by the microspheres continues to work over time. It not only
damages existing cancer cells but also hinders the development of new blood vessels within the tumor,
a process known as anti-angiogenesis. This can help to slow down or control the growth of the tumor.
44. The mechanism of action of TARE involves the
targeted delivery of radioactive microspheres to liver
tumors. TARE primarily affects the tumor tissue
while sparing healthy liver tissue. The mechanism
can be described in the following steps:
1.Microsphere Injection: Radioactive
microspheres, which are very small beads (typically
loaded with yttrium-90, Y-90, or holmium-166, Ho-
166), are injected into the hepatic artery through a
catheter. The hepatic artery is the primary blood
vessel that supplies the liver.
2.Microsphere Lodgment: These microspheres are
transported by the bloodstream to the smaller
arteries within the liver that feed the tumor. Since the
microspheres are tiny, they can travel through the
bloodstream to reach the tumor site.
45. 1.Selective Lodging: The microspheres are specifically
designed to get trapped in the smaller blood vessels
surrounding the tumor. They become lodged in these
vessels, ensuring that the radiation they emit is
concentrated in the tumor's vicinity.
2.Radiation Emission: The radioactive isotopes within
the microspheres (Y-90 or Ho-166) emit high-energy
radiation. This radiation damages the DNA of the
cancer cells, causing them to lose their ability to divide
and grow. It also induces cell death (apoptosis) within
the tumor.
3.Minimal Impact on Healthy Tissue: Importantly, the
microspheres are selectively deposited in the tumor-
feeding vessels, and their radiation is primarily
delivered to the tumor itself. Healthy liver tissue, which
may be adjacent to the tumor, receives significantly
less radiation, minimizing damage to the non-
cancerous parts of the liver.
4.Long-Term Effects: The radiation delivered by the
microspheres continues to work over time. It not only
damages existing cancer cells but also hinders the
development of new blood vessels within the tumor, a
process known as anti-angiogenesis. This can help to
slow down or control the growth of the tumor
Indications for SIRT in HCC:
Stage of HCC Indications
Early Stage (BCLC 0-
A)
- Unresectable HCC
Intermediate Stage
(BCLC B)
- Unresectable HCC
Advanced Stage
(BCLC C)
- Palliation of
symptoms
Contraindications
- Poor liver function (Child-Pugh C)
- Portal vein thrombosis
- Limited life expectancy
- Contraindication to the procedure
Potential Side Effects
- Fatigue
- Vomiting
- Radiation-induced liver disease
