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REVIEW OF SELECTED LIVER CANCER ABSTRACTS FROM THE AASLD MEETING IN SF 2008 FOR NATAP
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AASLD Nov 2008
Authors: Robert Gish MD and Catherine Frenette MD
CPMC
PROTEOMICS, GENOMICS AND BIOMARKERS:
"Initial proteomic analysis in hepatocellular carcinoma, identification of protein differences between normal and neoplastic tissues in cirrhotic and noncirrhotic patients."
Abstract 434-AASLD, Pleguezuelo.
For the management of HCC, investigators continue to explore the ability to determine risk of developing cancer, risk of progression once cancer is diagnosed and determine the overall prognosis in patients with HCC by looking at proteomic, genomic and biomarker analyses. In this abstract, a comparison was made between liver cancer tissue and non cancer surrounding tissue in cirrhotic and non cirrhotic patients. The investigators described a profile differential between cancer and noncancer tissue. The authors described that 12 proteins were up-regulated in tumor tissue in patients with cirrhosis and 4 proteins were up-regulated in patients with cancer without cirrhosis. A number of proteins were down regulated in HCC tissue, including a number of mitochondrial proteins. These newly described proteomic profiles may improve screening for HCC and subsequently improve the management of HCC by determining who is at risk of HCC and also determining who is at risk of more rapidly progressive disease. In addition, these tests may enhance the overall prognosis of patients with HCC and potentially permit clinicians to choose which therapeutic options for the treatment of hepatocellular carcinoma should be initiated.
"Biomarkers predicting outcome in patients with hepatocellular carcinoma, results from random biopsies from the SHARP trial."
Abstract 149-AASLD, Llovet.
In this study, six plasma biomarkers, included VEGF, soluble VEGFR-2, VEGRF-3, C-KIT, hepatocyte growth factor (HGF) and RAF-21, and one tumor biomarker p-ERK were evaluated to assess survival or clinical correlation of sorafenib response with data extracted from the SHARP trial. Results of this study demonstrated that VEGF plasma levels were independently associated with overall survival in HCC patients treated with sorafenib. Low HGF levels and the high C-KIT levels were associated with longer survival in patients treated with sorafenib. Positive p-ERK staining in liver tissue and decreased levels of HGF in plasma after sorafenib therapy were associated with longer times to (slower) disease progression. This data gives further support to the use of serum biomarkers and liver tissue assessment to help assess patients for risk of disease progression and predict better response profiles.
"Use of alpha fetoprotein and platelet count prediction of hepatocarcinogenesis in patients with hepatitis C."
Abstract 506-AASLD, Tateyama.
Biomarkers have an emerging role in the management of hepatocellular carcinoma. Alpha fetoprotein does not appear to be useful for screening, but alpha fetoprotein, alone or in combination with other biomarkers such as AFP-L3% and DCP, may predict an increased future risk of hepatocellular carcinoma or risk of recurrent disease after a specific intervention. In this study, the authors identified that an AFP greater than 20 ng/mL or an AFP above the "healthy levels" in the 6 to 20 range, indicates a future risk for hepatocellular carcinoma in patients with HCV. They further concluded that the combination of AFP and platelet count may result in useful information about when to initiate screening and when to intensify surveillance in patients who are at risk of HCC.
"Novel fucosylated biomarkers for the early detection of hepatocellular carcinoma."
Abstract 127-AASLD.
Clinicians and researchers continue to look for better biomarkers to identify patients with an increased risk of hepatocellular carcinoma, when to perform surveillance for HCC, and biomarkers that may indicate an increased risk of recurrent disease after ablative therapies, resection, or transplantation. In this study of 277 patients, a new fucosylated AFP biomarker showed an improved performance, especially when the fucosylated hemopexin was combined with glycoprotein 73 (GP73) This panel had had a sensitivity of 100%, specificity of 85%, and an AUROC of 95% for the diagnosis of HCC. This data would lend support if we can further expand our biomarker panel to assist in the recognition of hepatocellular carcinoma in patient with a known liver mass.
HEPATITIS C AND HEPATOCELLULAR CARCINOMA:
"HCV and liver cancer patients have characteristic mutations in the core gene."
Abstract 79, Fishman.
Investigators have previously published that the hepatitis C core region may be involved in the development of hepatocellular carcinoma in patients with chronic hepatitis C infection. This abstract further details the development of HCC in patients with hepatitis C genotype I. Specific core gene sequence mutations, including position 2098, were associated with an increased risk of hepatocellular carcinoma in both full-length and partial sequence analysis of the HCV genome. This data provides early credence that hepatitis C gene sequencing may be useful in identifying patients who are at high-risk for hepatocellular carcinoma, The association of hepatitis gene variations has been described in hepatitis B were genotype C and the presence of core promoter mutations has been associated with an increased risk of HCC.
HEPATITIS B AND HEPATOCELLULAR CARCINOMA:
Hepatitis B and risk for hepatocellular carcinoma
"High trough hepatitis B virus DNA level was associated with increased risks for hepatocellular carcinoma in a 10-year longitudinal follow-up study." Abstract 124 AASLD, Chan.
It has now been clearly demonstrated in studies in Africa, Europe and Asia that HBV DNA levels, at baseline, and long-term, relate to the further risk of development of hepatocellular carcinoma and cirrhosis. This study by Chan was a case-controlled study on 506 prospectively followed hepatitis B patients who were seen in Hong Kong since 1997. The authors identify that individuals with a high nadir HBV DNA level of 6 log copies/mL had a higher risk of hepatocellular carcinoma compared to those individuals at 3 log copies/mL. In patients who were treatment naïve and patients who received antiviral therapy, the nadir of HBV DNA level of 3.5 log copies/mL had a statistically increased risk of HCC compared to patients with lower HBV DNA levels at 2.5 log copies/mL. Overall, the study supported the previous work by Chen from Mainland China, Chen from Taiwan and authors from other regions that supports that serum HBV DNA levels drive HCC risk, and patients with lower HBV DNA levels, long-term, have a lower risk of developing hepatocellular carcinoma.
HCC SCREENING and SURVEILLANCE--
HEPATOCELLULAR CARCINOMA SCREENING AND SURVEILLANCE:
"Detecting undiagnosed cirrhosis and monitoring quality of surveillance for hepatocellular carcinoma using stored data from the computerized patient records: a pilot study."
Abstract 120-AASLD, Crocker.
Surveillance for hepatocellular carcinoma is now standard of care in patients who are deemed at risk for HCC development, as per the AASLD guidelines from 2005. This study evaluated VA Medical Center electronic medical records to identify patients who were potentially at risk for developing hepatocellular carcinoma including identifying patients with hepatitis C or cirrhosis. They highlighted in the study that liver enzymes, liver enzyme pattern and platelet data would allow a computerized data-based analysis to indicate patients who potentially have cirrhosis or were at increased risk of hepatocellular carcinoma. They were able to identify over 1000 patients with a calculated fibrosis score of greater than 3, who had not yet been identified as having cirrhosis or at an increased risk of HCC, and who had not had liver imaging during the proceeding year. In over 500 patients who were diagnosed with cirrhosis in their medical chart, nearly half of these patients had not had liver imaging within the last year. This abstract provides support for the use of electronic health record surveillance to provide additional screening and follow-up surveillance to identify patients at risk of HCC. It needs to be determined as to whether this aggressive data base review would result in improved outcomes, increased number of patients cured of their liver cancer by liver transplant, and the ability to provide life-prolonging therapies such as ablative treatments or oral multi-kinase inhibitors.
"Implementation of AASLD hepatocellular carcinoma practice guidelines in North America, two years of experience."
Abstract 128-AASLD, Khalili.
This abstract describes two years of implementation, in Toronto, of the Hepatocellular Carcinoma Screening Protocol based on the AASLD HCC practice guidelines. This abstract demonstrated data that this screening protocol led to detection of a larger number of small tumors, including, HCCs, with the median size of 1.77-cm. 22% of the "early" lesions detected in this study were hemangiomas. This screening protocol was found to be resource intense, and the authors suggested that the modified imaging strategies may help decrease the amount of resource utilization per cancer found.
RISK FACTORS FOR HEPATOCELLULAR CARCINOMA:
"Use of exogenous insulin or sulfonylureas as a potential risk factor for hepatocellular carcinoma in hepatitis C patients with diabetes mellitus."
Abstract 51-IASL, Taniguchi.
Insulin and insulin-like growth factors are known mediators of carcinogenesis. Patients with diabetes, metabolic syndrome and fatty liver are at increased risk for hepatocellular carcinoma especially in the setting of cirrhosis. In this abstract, the authors describe a cross-sectional and hospital-based registry in 2004 and 2007 in which 351 patients with hepatitis and 194 patients with HCC were enrolled in this study. They identified that exogenous insulin administration in combination with sulfonylureas resulted in an increased risk of hepatocellular carcinoma. Whether any of these medications actually increased the risk directly or whether hepatitis C combined with metabolic syndrome in patients who were undergoing treatment and surveillance in the fatty liver are at increased risk was not able to be gleaned from the study data. Whether insulin treatment will be considered as a primary risk factors for hepatocellular carcinoma remains to be elucidated and large prospective studies would be needed to truly answer this important question.. If indeed insulin and sulfonylureas result in an increased risk of HCC, this would provide strong support for physician advocacy of patients who have hepatitis C undergo early and aggressive weight loss and modification of their metabolic syndrome, without use of diabetes-specific treatment modalities. Further research is clearly needed in this important area.
"Pattern of serial HBV DNA levels and HCC development in patients with cirrhosis."
Abstract 841, Kwan.
In this study, 325 patients who were diagnosed with HCC between 2005 and 2007 were evaluated. Approximately 50 patients had HBV DNA levels for greater than one year before the development of HCC. This was a double-case control study. It identified that patients with cirrhosis with consistently high HBV DNA of greater than 104 copies/mL had more than a three-fold increased risk of HCC that individuals with less than 104 copies/mL. This abstract provides further support that increased HBV DNA levels, over time, increase the risk of development of hepatocellular carcinoma.
"Hepatocellular carcinoma is the main indication for a liver transplantation among HBV patients in the era of nucleoside and nucleotide analog therapies."
Abstract 1437-AASLD, Hahn.
With the advent of markedly improved anti-HBV therapies, fewer and fewer patients are presenting with end-stage liver disease to liver and liver transplant center. This was recently demonstrated by Dr. Kim at AASLD Boston, 2007. In this study there was further support to Dr. Kim's analysis that states that fewer and fewer patients are presenting with liver failure due to hepatitis B attributed to improved HBV control and HBV suppression, and these patients are now living long enough, as well as due to intensified and a more compliant screening and surveillance, to develop hepatocellular carcinoma. This provides support that community based screening for hepatitis B may lead to identification of patients with earlier stages of disease, and potentially earlier intervention that may improve outcomes, but this needs to be applied in combination with compliant HCC surveillance to allow intervention in those patients with HCC, which may further improve their overall survival or opportunities to undergo a liver transplantation.
"Interferon therapy for hepatitis C patients curatively treated for hepatocellular carcinoma with percutaneous therapies."
Abstract 1241-AASLD, Goto.
Interferon has the ability to cure hepatitis C disease. In patients who have hepatitis C, advanced liver disease in hepatocellular carcinoma, one needs to consider treating hepatitis C after treatment for hepatocellular carcinoma, to potentially inhibit disease progression. In this study an important addition to this contention was demonstrated stating that patients who had hepatitis C, who were treated with interferon and had an SVR, had markedly reduced risk of recurrent HCC after that interferon treatment. With improvements in survival at three, five and seven years that were substantially better than individuals who did not have an SVR after interferon treatment, this survival benefit may relate to decreased risk of disease progression and/or recurrent HCC.
"HCC in patients with hepatitis C cirrhosis and sustained virologic response with interferon and ribavirin therapy in a META-analysis."
Abstract 1440, Jaganmohan.
This is a study that evaluated publications from PubMed, Ovid, Cochrane, Embase and the ISI Web of Science and reviewed the treatment of patients who had chronic HCV infections and cirrhosis who underwent treatment with interferon and ribavirin. The authors performed a Meta-analysis of these studies and demonstrated the odds of HCC development in non-SVR groups was 5.1-fold higher when compared to patients who had a sustained virologic response. The author's concluded that combination therapy of interferon and ribavirin resulted in a significant reduction in the development of HCC in patients who had hepatitis C cirrhosis and who achieved SVR on treatment. This publication would provide further support for focusing on patients in ones clinical practice who have hepatitis C and advanced disease or cirrhosis and to counsel patients about the benefits of antiviral therapy that could potentially lead to decreased rates of liver cancer and thus improved patient outcome.
SCREENING AND SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA:
"Liver cancer screening practices in all providers with a high prevalence of hepatitis B infected Asian patient population."
Abstract 1457-AASLD, Khalili.
Screening and surveillance for hepatocellular carcinoma is now the standard of care in high-risk individuals. This is the analysis in the San Francisco Safety Net System of primary and specialty providers who underwent a survey as to their screening and surveillance practices in their medical practices. Most common HCC surveillance tool was an AFP every 6 to 12 months, in combination with an ultrasound in 60% of individuals (with the ultrasound being performed every 12 months). Interestingly, transaminases in 72% of responders and an HBV viral load in 38% responders were being utilized as surveillance tools for HCC. One-quarter of practitioners were not familiar with the AASLD surveillance guidelines. This practitioners surveyed reported that lack of access to radiology services was the most common barrier to screening. The practitioners who had a better and more compliant surveillance practice had more than 25% of their patients being Asian. These practitioners also had a history of being active in vaccinating for hepatitis B or hepatitis A as well as a knowledge base that identified those individuals at high-risk for HCC. These practitioners were also aware of national screening and surveillance guidelines that had been published by national organizations. The authors concluded that HCC surveillance by providers was dependent on the prevalence of at-risk patients within a given practice and provider knowledge. This abstract highlights the need for community education to improve screening practices for HCC.
"Early detection and predictors of hepatocellular carcinoma in a prospective cohort study of patients with cirrhosis in the U.S."
Abstract 1462, Singal.
This group identified at a single center that the incidence of HCC in their screening population, patients with cirrhosis, was 2.4 per 100 person/years. Elevated baseline AFP, Child's B or C cirrhosis and male gender were associated with increased risk. The use of statins for hyperlipidemia was associated with a decreased risk of HCC. They also demonstrated that ultrasound and alpha fetoprotein were complimentary in triggering further evaluations that led to the diagnosis of HCC in an early stage of 75% of patients.
TREATMENT OF HEPATOCELLULAR CARCINOMA:
TREATMENT ACCESS
"Are there racial and ethnic differences for survival of hepatocellular carcinoma in an equal-access system?"
Abstract 1432, Gui.
This was a Kaiser Permanente Northern California data base analysis during 1998 and 2004. Kaiser Permanente is a well-established large HMO that has an extensive data base for health care analysis in the Northern California region. 1000 patients with a diagnosis of HCC were identified in this data analysis. The authors were able to look across Hispanics, Caucasians, Blacks and Asians, and identified either equivalent or improved survival in the Asian patients, and did not find any difference between the stage of disease in Caucasian, Asians, Hispanics or Blacks at the time of that diagnosis. In an equal-access system, there was no significant difference in the stage of disease across different ethnic groups with the diagnosis of HCC.
TACE, RADIOFREQUENCY ABLATION AND OTHER ABLATIVE THERAPIES:
"Transcatheter arterial chemoembolization plus radiofrequency ablation for hepatocellular carcinoma, in comparison with surgical resection".
Abstract 426-IASL, Kagawa.
The investigators discussed the use of radiofrequency ablation in combination with TACE compared to surgical resection. There has been a new evolution since the recent JAMA article utilizing TACE followed by RFA in a randomized control study compared to TACE alone that identified combination ablation therapy resulted in a marked improvement in survival with combination therapy resulting in more centers utilizing combination (ablation) therapy for HCC. In this AASLD abstract, TACE-RFA was evaluated in comparison to surgical resection. Overall survival was comparable between TACE with RFA compared to surgery. This abstract would support the trend towards minimally invasive ablative procedures as opposed to more complex surgical resection for the management of HCC risking liver failure, especially in those patients with more advanced disease (presence of portal hypertension). It also supports the overall trend toward using combination modalities to treat HCC rather than any single treatment alone.
"Radioembolization with yttrium 90 glass microspheres for advanced hepatocellular carcinoma, results from a European pilot-based study."
Abstract 1444, Hilgard.
Newer ablative therapies for the treatment of HCC including embolization with radioactive microspheres, laser photo activation, cryosurgery and other methods continue to be explored in practice and clinical trials. In this study, outcomes after radioembolization with microspheres for advanced HCC was analyzed in this European phase II study. Fifty-seven patients were analyzed, and the authors demonstrated that in this small case study that radioembolization with yttrium 90 glass microspheres were safe and effective in terms of tumor response. Tumor response was defined by radiographic criteria and reduction in AFP levels. Survival rates were 98% at one month, 96% at three months, and 53% at one year, with a mean overall survival at 657 days. This data from this phase II study suggests that a phase III study with radioembolization with yttrium 90 glass microspheres would be important and a comparison to standard TACE therapy should be considered as part of this trial.
"Radiofrequency ablation for hepatocellular carcinoma, progression beyond Milan criteria and implications as neoadjuvant treatment prior to transplantation."
Abstract 83, Fernandes.
Radiofrequency ablation has emerged as the best percutaneous ablative therapy for managing HCC. Previous data has shown that RFA is comparable to surgical resections. In this study, the authors evaluated the use of RFA for down-staging patients. RFA was effective in reducing tumor progression, especially within the first six months after initial treatment. This data will be useful to liver transplant centers who have longer waiting times, and will lend credence to further support for combination therapy, RFA therapy, RFA-TACE or RFA and multi-kinase inhibitors to further extend waiting times to allow patients to both be down-staged to fall within Milan criteria, or individuals who are within Milan criteria to extend their ability to remain on the wait list and undergo potentially curative liver transplant surgery.
MULTI-KINASE INHIBITOR:
ORAL KINASE INHIBITORS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA:
"Sorafenib therapy for advanced hepatocellular carcinoma, single center experience on 43 patients." Abstract 436-AISL, Zimmerman.
Sorafenib therapy has now been approved in the United States and in many countries world-wide as an oral therapy for hepatocellular carcinoma that improves survival. It is approved for HCC in the United States for patients with "unresectable hepatocellular carcinoma" although there are more restricted indications in other countries such as Canada. In this study, a single-center experience with 43 patients was described utilizing a lower initial sorafenib starting dose of 400 mg a day compared to 400 mg b.i.d., which is the currently approved dose, in patients with advanced HCC. Dose escalation took place at four weeks of treatment to 800 mg a day, and the medication appeared to be well-tolerated in many patients at both doses. We would like to highlight that this was a heterogeneous study population, with some patients having sorafenib as the first treatment option, whereas other patients were treated with sorafenib after liver resection or ablation. Clinical response to sorafenib was seen in 19 patients, with stable disease in 14 and partial remission in 3. Treatment related side effects due to sorafenib were seen in approximately one-half of patients. This abstract further extends on our data base in terms of sorafenib therapy in clinical practice, allowing us to further refine our care and management of patients' hepatocellular carcinoma.
"Tolerability and efficacy of sorafenib in recurrent hepatocellular carcinoma after liver transplantation in a case-controlled study."
Abstract 3, Dharancy.
The data for sorafenib as a multi-kinase inhibitor was published recently in the New England Journal of Medicine, under the title of the "SHARP Study", which highlighted the information that led to the approval in the United States, and a number of other countries, the use of sorafenib for patients with unresectable hepatocellular carcinoma. An area in question is whether we can use sorafenib after liver transplantation. In this study, using a case-controlled study analysis, the authors looked at 14 patients who underwent liver transplant compared to 14 patients in a nontransplant group who were administered sorafenib for the treatment of hepatocellular carcinoma. Patients received sorafenib 400 mg twice daily. This study highlighted that sorafenib resulted in a substantial number of adverse events in post-liver transplant patients. It was challenging in the data analysis to determine the effects on recurrent disease due to the small study size, and the important fact that there was a great heterogeneity in terms of the post-liver transplant suppression, including mTOR inhibitors in eight patients. The mTOR pathway may be involved in hepatocellular carcinogenesis and inhibitors in the mTOR pathway may inhibit HCC development or progression. Importantly there is a marked increased risk using mTOR inhibitors in combination with sorafenib, so there is a potential of marked increased risk of side-effects by inhibiting multiple pathways, including more extensive skin reactions and diarrhea. Interestingly, the liver transplant group was at a higher risk of disease progression, which also may have been influenced by the presence of immunosuppression and loss of control over hepatocellular carcinoma progression. We will need to be cautious about the use of sorafenib after liver transplantation until a larger prospective study takes place in a controlled and monitored setting.
"Sorafenib inhibits STAT 3 activation in cholangiocarcinoma cells."
Abstract 151-AASLD, Blechacz.
Currently there is no proven effective therapy, oral or intravenous, that improves the survival of patients with cholangiocarcinoma. A phase-2 exploratory study with sorafenib was previously completed that did demonstrate an improvement in survival. From an exploratory analysis there appeared to be patients within that study that had a clinical benefit from sorafenib. To help define whether sorafenib should be further explored for the treatment of cholangiocarcinoma, an in vitro study was designed in a cell model of cholangiocarcinoma. In this in vitro study, sorafenib was found to interfere with STAT-3 signaling pathways and also reduced cellular expression of Mcl-1, both of which would enhance apoptosis. This pathway plus direct enhancement of TRIAL induced apoptosis indicates that that sorafenib may be useful alone, or in combination with other agents, for the treatment of human cholangiocarcinoma. A larger phase 2 or phase 3 study may need to be considered to elucidate the benefits of sorafenib in this important disease that affects over 6000 patients in the US each year, with a less than 5% 5-year survival rate.
LIVER TRANSPLANT PATIENTS and HEPATOCELLULAR CARCINOMA:
"Liver transplantation allocation to patients with hepatocellular carcinoma."
Abstract 104, Dawwas.
Liver transplantation is considered to be within the standard of care for patients with hepatocellular carcinoma who fall within the UNOS and MILAN criteria. In this abstract, a liver transplant data base was evaluated in the UK and Ireland for survival characteristics for patients with HCC who underwent liver transplantation with donor organs from high risk patients. The authors described that donor organ quality had a significant impact on the outcome (patient and graft survival) after liver transplantation for HCC. They identified that high-risk donor organs could be preferentially allocated to HCC patients, and resulted in patients having a similar long-term survival when higher risk organs were used compare to normal risk donors. This equivalency was attributed to 2 facts: 1) these patients had access to organs at an earlier time point, after HCC was diagnosed and thus were less ill with a lower medical MELD score and could thus 2) tolerate periods of liver graft dysfunction better. High-risk organs account for approximately 15% of organ donors within this UK/Ireland data base. This publication provides support that expanding organ access through the use of high risk organs and careful allocation may allow more patients to undergo liver transplant for HCC to decrease the wait list removal for disease progression.
"The effect of local regional therapy for hepatocellular carcinoma prior to liver transplantation."
Abstract 150-AASLD, Mobley.
This study was a retrospective analysis of the Organ Procurement Transplant Network (OPTN) database. This review was performed to determine if RFA or TACE, performed for the diagnosis of HCC in patients listed for liver transplant, led to improved survival on the waiting list and after liver transplantation. Importantly, when controlling for confounding factors, those patients who received local/regional therapy such as TACE or RFA, prior to listing, independently predicted improved survival during the follow-up period, with observation of 0.694. This survival benefit included both the period on the waiting list and after liver transplantation. This analysis provides strong support, due the study size and extent, that ablative interventions results in improved wait list survival and cancer free survival after liver transplantation.
"Outcome following salvage liver transplantation for recurrent hepatocellular carcinoma after resection." Abstract 585-AASLD, Hange.
Liver transplantation is the best treatment for hepatocellular carcinoma in patients with cirrhosis and portal hypertension, since it offers the only substantial long-term chance of cure. In this study, patients who had hepatocellular carcinoma fit the profile where a hepatic resection could take place, which is typical in patients with very early cirrhosis, where there is minimal evidence of portal hypertension and were Class 0 utilizing the BCLC staging system. In this study, review of the OPTN and UNOS data bases suggested that liver transplantation after liver resection, for recurrent HCC disease, showed similar short-term post-transplant survival as compared to those patients undergoing primary liver transplantation for HCC. This is an important finding that may further expand those patients who are candidates for LT. This study was limited by a small number of patients but provides support that we, as clinicians, should evaluate patients for liver transplantation after hepatic resection for those patients who have recurrent hepatocellular carcinoma.
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