Background
Hepatocellular Carcinoma (HCC) is a major health concern:
1. Over 700,000 cases are diagnosed annually
2. One of the leading causes of cancer-related death
3. Main event leading ot deaeth in patients with cirrhosis
Risk Factors:
1. HBV
2. HCV
3. Alcohol-related cirrhosis
4. Non-alcoholic steatohepatitis
5. Smoking
6. Metabolic syndromes?
7. Coffee may diminish risk
Molecular Events: What Have We Learned?
Expectations from the biomedical community for genetic studies:
1. Easily risk-stratify patients
A. Risk for developing HCC
B. Risk for HCC recurrence following "curative: therapy
C. Disease prognostication for existing HCC
2. Identify common and dominant oncogenic pathways
A. Carcinogenesis
B. Invasion and metastases
3. Institute targeted and curative therapies using a personalised medicine approach
Progress has been slow and disappointing because of the following:
1. Cancers are far more complex than realized
2. Cancers are more genetically heterogeneous than appreciated
3. Genetic information are quite difficult to analyse from a systems biology perspective
4. Nature of genetic information are protean
A. Expression signatures, miRNA profiling, long non-coding RNAs, copy number aberrations, deep exome sequencing, hemizygous and homozygous deletions and promoter methylation
5. Distinction between driver mutations and passenger mutations
6. Cancer genetics between tumor and non-tumor tissues
7. Time variations of cancer programs, such as original tumor vs. metastasis genetic features
8. Genetic heterogeneity not only between tumor nodules in the same patient, but also within a single tumor nodule
A. Intraturmoral heterogeneity suggests existence of distinct pools of cancer stem-like cells that display different tumorigenicity and independent genomic evolution
9. Impact of the tumor microenvironment in tumor biology, especially on target therapy
Current Understanding of the HCC Tumor Genetics
1. Risk Stratification for Developing HCC
A. Single nucleotide polymorphisms that affect oxidative stress and detoxifying pathways, iron metabolism, inflammation-cytokine-chemokine systems and DNA synthesis and repair mechanisms
B. EGFR
C. Somatic mutations activating telomerase reverse transcriptase promoter in cirrhotic preneoplastic macronodules and early HCC
2. Risk Stratification for HCC Recurrence
A. Both the tumor and the non-tumor expression signature predict tumor recurrence
B. Recurrences after curative therapy may be de novo cancers arising in the cirrhotic liver instead of metastases
C. Surrounding liver signature may have more oncogenic risk or perhaps a feature that makes mestastatic nesting and progression less effective
a. IL-6 downstream signature compatible with inflammatory cytokine-driven carcinogenesis
D. Microvascular invasion by HCC is an established risk factor for recurrence, but the expression signature was not strongly predictive of recurrent disease
E. Proliferative molecular expression signature + adverse non-tumor molecular signature + satellite nodules = disease recurrence
3. Oncogenic Pathways
A. Three major pathways were identified to be associated with HCC:
a. WNT/beta-catenin
b. Proliferation
c. Hepatoblastoma-like
B. Molecular signatures are broad and no overlap exists between studies
C. No targetable oncogenic pathways, therefore difficult to make their way into clinical practice
4. miRNA Profiling
A. Comprehensive analysis of miRNA expression patterns in HCC showed dysregulation of numerous miRNAs
B. Studies by Llovet and coworkers showed that miR-517a may be upregulated and was found to be a true oncomir. However, targeting miRNAs therapeutically has yet to be proved
5. Genome-wide Surveys
A. Wnt/beta-catenin, p53, PI3K/Ras signalling pathways, oxidative and endoplasmic reticulum stress modulators, and chromatin remodelling are commonly altered by somatic mutations or homozygous deletions
B. mTOR inhibitors, epigenetic modulators, and the tumor microenvironment may be additional therapeutic targets
Screening and Diagnosis
1. Work-up should be done for nodules 10mm or greater, as HCC is more likely
2. Alpha-Fetoprotein (AFP) has no clinical value for screening and diagnosis, novel biomarkers for early HCC are needed
3. Biopsy has false-negative results, 40% in HCC ≤2cm
4. Imaging characteristic of HCC is intense arterial contrast uptake followed by contrast "washout" in delayed venous phase in either MR or CT for nodule >
A. Still has a limited sensitivity
5. Novel imaging technologies or liver-specific contrasts need to be developed to permit diagnosis for the nodules without these specific findings
Outcome Prediction
1. Barcelona Clinic Liver Cancer (BCLC) has been used for diagnosis and staging of HCC. End-staged liver disease should be evaluated by Child-Pugh classification, not BCLC
2. Child-Pugh or MELD should not be used solely for evaluating liver function and life expectancy
A. SBP, refractory ascites, hyponatremia, encephalopathy and other parameters indicate end-staged liver disease
3. Biomarkers, such as AFP, VEGF, angiopoietin-2, c-Kit may be used for stratification prior to randomization
4. Timing and pattern of progression, as it influences survival after treatment
Treatments
Endpoint of treatment is to improve survival with quality-of-life preservation. Technical feasibility is not a surrogate for improved survival, and therapeutic recommendation has to be driven by evidence-based, risk-benefit analysis.
Open Issues in Surgical Management of HCC in the Era of Liver Transplantation
Resection and transplantation achieve the best outcomes in well-selected candidates (5 yr survival of 60~80%) and compete as the first option in patients with early tumors and well-preserved liver function on an intention-to-treat (ITT) analysis.
Current Decision Making in LT
1. In American and Europe, less than one patient out of three of those enlisted receives LT. Even living-related LR, use of marginal cadaveric donors, and the non-heart beating donors have not significantly modified this trend.
2. Implementation of the Milan Criteria (MC) resulted in the increase of the HCC patients. MELD score accurately predicts poor short-term outcome in cirrhosis.
3. But the heterogeneity of tumor presentation and the variability of response to treatments impede an accurate prediction of progression, effective transplantation and survival after transplantation in HCC patients.
Transplant Selection Criteria for HCC
1. Milan Criteria:
A. HCC≤5 cm or
B. Multiple HCC≤3 nodules ≤3cm
C. No macrovascular invasion on radiographic staging
2. Many consider MC as restrictive and have proposed other criteria, but have only expand candidates by a small margin
3. Patient drop-out on the waiting list due to HCC progression is problematic, and robust evidence of the efficacies of resection, ablation TACE or TARE is lacking
A. The reasons for drop-out in non-tumor patients differ from those linked to HCC. A equitable approach for all enlisted patients is not yet available.
4. Excessive priority for HCC with respect to non-tumor indications would result in increased post-transplant tumor recurrences.
5. A standardized criteria for enlisting or delisting HCC patients and identification of those patients at a high risk of drop-out are a priority.
A. AFP has shown prognostic potential, AFP≤400 ng/ml + total tumor volume (TTV) ≤
a. HCC patients on the waiting list with AFP>15 ng/ml/month and baseline serum level of AFP >200 ng/ml display significantly worse outcomes .
6. Future expansion of criteria should maintain an overall survival of ≥50% at 5 years.
Pretransplant HCC Downstaging
1. Downstaging is defined as the reduction of the HCC burden to meet acceptable criteria for LT.
2. The goal is to select a more favorable tumor biology assessed by response to treatment
3. Treatment of choice: 1. TACE, 2. RFA
4. Most programs use the Milan Criteria as the endpoint of downstaging to be maintained for at least 3-6 months.
5. Lack of a reproducible and validated approach for baseline staging, assessment of down-staging, delisting criteria and absence of robust ITT analysis prevented this approach in guidelines.
Treatment of the Very Early HCC
1. The application of LT at very early stages of HCC development is futile. Very early tumors can remain dormant for a long period of time, and doubling time may exceed 10 ~20 months. Resection and ablation have achieved excellent survival outcomes, range of 60~70% at 5 years.
2. Large case-control series and modelling studies support RFA as a potential alternative for very early HCCs.
3. Decision making for small tumors when all three modalities (ablation, resection and LT) could be applied is difficult, and few data robustly guide physicians including pattern of recurrence, patient conditions, liver status and treatment applicability.
Post-transplantation Follow-up and Treatment Upon Recurrence
1. No evidence-based recommendation exists that can be applied after transplantation in order to promptly detect and treat HCC recurrence.
2. Early dissemination is likely to have poorer prognosis than late recurrence
3. The extent any treatment approach results in improved survival is unknown
Locoregional Treatment
1. Locoregional treatments aim to induce tumor necrosis. The RECIST criteria are not informative as necrosis may not be paralleled by tumor burden reduction.
2. The goal in ablation is to achieve complete response recognized by the absence of tumor contrast uptake by contrast enhanced US, CT or MRI.
3. However, TACE seldom achieves complete response and the magnitude of response takes into account the presence of residual viable tumor tissue. Lipoidol accumulation in the tumor is not accurate to reflect necrosis.
4. Extent of tumor necrosis has been correlated with outcome after ablation or TACE. Partial necrosis in patients with multifocal disease is the issue at hand.
Ablation
1. RFA is currently the 1st line technique for ablation. Ethanol injection has less local control efficacy but has a role when the residual viable tissue is minimal or when the location of the tumor implies risk of adverse events.
A. RFA and ethanol injection have the same efficacy for tumors ≤2 cm
2. Ablation and surgery in patients with HCC <3 cm have similar survival rates. Thus, both can be 1st line can the patients' conditions should be considered.
3. For HCC>3 cm or multifocal HCC, resection or TACE+ RFA is suggested to improve survival. Evidence is needed.
4. Currently, there is no effective approach to reduce risk of recurrence.
TACE
1. TACE is the 1st-line option for BCLC B patients. Median survival exceeds 4 years due to restrictive selection of patients.
2. Tolerance to the procedure has improved by the use of drug-eluting beads that obstruct arterial vessels and slowly release chemotherapy.
3. Sorafenib + TACE: the efficacy and sequence have not been proven.
4. TARE uses the local action of beta radiation through the lodging of yttrium-loaded glass or resin spheres in vessels feeding the tumor. Cohort studies suggests that it provides similar survival rates to TACE and sorafenib in the setting of portal vein thrombosis (PVT).
Systemic Therapy and Endpoints Reconsideration in HCC
1. Sorafenib is an oral multikinase inhibitor with antiangiogenic and antiproliferative action.
2. Two RCTs showed that a significant 30% improvement in survival with an adequate safety profile.
3. There is an urgent need to identify biomarkers and develop functional imaging techniques that would predict who responds best or when efficacy is lost.
A. Tumor progressions at imaging does not equal to impaired survival
4. Most of the data used today sets date of intervention as time zero. The timing and nature of the previous evolutionary events in HCC patients prior to using any therapeutic intervention has not been studied. Similarly, the impact of progression pattern in survival should be further studied.
5. So far, none of the agents or combinations have exceeded the benefits of sorafenib, although there are drugs in development.
Clinical Outcome
2. Time and events between diagnosis and first treatment, and the timing and
pattern of recurrence/progression is usually dismissed.
3. This may result in a poorer prognostic evaluation of the patients and prevent a proper design and assessment of treatment options.
Conclusion:
1. Major changes have occurred in the diagnosis and management of HCC
2. Hopefully prevention plans to reduce the impact of risk factors, and earlier diagnosis and more effective therapies will induce a major reduction of liver cancer-related death and eliminate HCC from the top position of cancer killers
(Reference: Gut. 2014 May;63(5):844-55. doi: 10.1136/gutjnl-2013-306627. Epub 2014 Feb 14.)
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