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    Practice Pearls: Hepatocellular Carcinoma

    Evidence syntheses and practical tips on HCC management.
    Welcome to Practice Pearls: quick, current, and easy-to-digest insights on HCC to help inform patient care, from diagnosis to follow-up. Let us know what you think!
    HCV and HCC: Ask the experts
    The evolving role of hepatitis C as a risk factor for HCC
    theNNT

    How is the landscape of hepatitis C virus (HCV) management changing since the advent of direct-acting antivirals? 

    Richard K. Sterling, MD, creator of the FIB-4 Index for Liver Fibrosis : “The development of DAA and non-invasive assessments of liver disease severity have dramatically changed how we approach and manage chronic HCV. The overall safety and tolerability of DAA also have expanded the patient population we can treat. Those with compensated cirrhosis or MELD <15 have similar high sustained virologic response (SVR) compared to those without cirrhosis, although they may require longer treatment or addition of ribavirin to the DAA. Data also suggests that those with mild decompensation (MELD 15-20) can be treated successfully although a percentage may worsen. In this group, we often evaluate for liver transplant first. In those with more severe decompensation (MELD >20), treatment should be done in liver transplant centers with expertise in managing these patients… with increased use of DAA, NASH is becoming the most common indication for liver transplantation.”

    Douglas T. Dieterich, MD, professor of medicine, Mount Sinai: “It’s evolved quite a bit. There was no treatment [for HCV] until 1991, and that treatment was horrible. Horrible side effects, and low success rates. Then, for the next 20 years or so, there was no treatment available until the late ‘90s. The disease was only even first named in 1992. It was very hard to isolate it... in 2001, the combination of pegylated interferon and ribavirin was approved, and there was no progress at all between 2001 and 2011, with about a 25% cure rate with 48 weeks of terrible side effects. In 2011, the 2 new protease inhibitors telaprevir and boceprevir were approved, but they were add-ons to PEG and ribavirin. And they not only added but exponentially increased side effects. The real-world results went from about 25%-40% cure rates, and the side effects were unbelievably difficult...in November 2011, we saw the presentation of just one drug, sofosbuvir and ribavirin, cure 100% of hep C patients, genotypes 2 and 3, which sort of shook the world. And 2 years later, sofosbuvir was on the market, and basically, the days of interferon were over.”

     width=Paul Y. Kwo, MD, ACG guideline author: “The advent of direct-acting antiviral agents for hepatitis C has revolutionized the treatment of this infection. There are few other chronic diseases that can be cured with a short course of therapy that is well-tolerated.  We are seeing fewer patients listed for transplant for hepatitis C, and increasing awareness among many of the patients who were hesitant to take interferon-based therapies are coming in to be treated with our new direct-acting antiviral agents.“

    MELD purgatory: Ask the experts
    Does MELD purgatory exist? How should these patients be managed?
    MDCalc Editorial Team

    Paul Y. Kwo, MD: “MELD purgatory is a condition where one cures a patient with hepatitis C with decompensation, but they fail to improve sufficiently to be removed from a transplant list, yet do not worsen enough to be transplanted. In general, if one’s MELD is below 20, and they are cured of their hepatitis C, there is about a 20% chance they can be delisted successfully with re-compensation. All transplant centers approach this slightly differently, but the general trend is that those with hepatitis C who require transplant are not treated prior to transplantation, as hepatitis C can easily be treated post-transplant . Also, there is increasing use of hepatitis C positive donor livers which can be used for hepatitis C positive recipients and hepatitis C non-exposed recipients, much as we use hepatitis B core positive donors for liver transplant.”

    Richard K. Sterling, MD: “There is a MELD Score beyond which treatment may be safe and beneficial, but that is center-specific. When deciding on HCV treatment in someone on the transplant list, the patient must be made aware that their MELD Score may improve to the point where they no longer have the same priority ... and that if they are SVR, they may not be eligible for an HCV positive organ, which might also prolong their wait.”

    Douglas T. Dieterich, MD: “I think [MELD purgatory] is an artificial construct that doesn’t exist, frankly. When people first started taking DAAs, their MELD Score would drop some, but what happens is the score continues to drop, so that was only a measurement that people looked at 6 months after starting treatment - their livers improved some, but not enough. With more time, now, it turns out their livers continue to improve. So actually, very few patients are getting transplanted for hep C-related cirrhosis.

    “A Fool with a Tool Remains a Fool”
    Insights from Milan Criteria creator
    Vincenzo Mazzaferro, MD

    How did you develop a clinical interest in HCC? Was there a particular clinical experience or patient encounter you had?

    My interest in oncology started in medical school. When I decided to be a surgeon, the liver was the most challenging area to develop, and therefore any cancer affecting the liver, primary or secondary, was a natural consequence of my scientific and clinical research.

    What pearls, pitfalls and/or tips do you have for physicians using your clinical decision tools (Milan Criteria, Metroticket Calculator, etc) at the bedside? Do you know of cases when recommendations have been applied, interpreted, or used inappropriately?

    I think that a fool with a tool remains a fool. Tools such as calculators are instruments to ease decisions but are not able to replace personal judgment and multidisciplinary discussions. The tools we have developed in prognostication of liver cancer treated with transplantation may help in deciding on patient listing and priority but remain instruments to be balanced with many other parameters of disease and with the response to different therapies. 

    How do you use the tools in your own practice?

    We use tools in daily practice and during multidisciplinary meeting with specialists of other areas. Tools and calculators are also very important when discussing and informing the patients and their families on the possible consequences of various therapies.

    Do you have any thoughts on criticisms of the Milan Criteria as too restrictive and potentially excluding patients who might benefit from liver transplant?

    The Milan Criteria were designed in a period of high disregard of cancer as a transplant indication. In fact, the Milan Criteria resuscitated the interest in liver transplantation as a cancer operation. As with any restrictive criteria, the drawback was the possible exclusion of tumor conditions that were potentially curable, although beyond the described limits. However, over the years, we have expanded the criteria with the Up-to-7 limits and in a more dynamic approach with the “Metroticket concept” of individualized prognosis, including alpha-fetoprotein (AFP) as a surrogate of tumor biology in the calculator available on MDCalc and published in Gastroenterology 2018.

    Where are there deficits in HCC research?

    HCC is a tumor in the interest of multiple fields - oncology, hepatology, surgery, interventional radiology, etc. This may generate some competition that does not always help. A more pragmatic and broad cooperation among different fields of research should be implemented in the case of liver cancer. Trial designs are not always optimal and this is a consequence of unbridged differences of different contesting groups (i.e., east-west, pharmacologic-non pharmacologic, hepatologic-oncologic etc.)

    Is there any research you're working on now that you are particularly excited about? 

    Augmented reality in surgical oncology, immunotherapy and innovative loco-regional approaches to liver cancer, and expansion of the area of interest in transplant oncology.

    Choosing a specialty
    How 4 liver disease experts first got interested in hepatology
    MDCalc Editorial Team

     width= Richard K. Sterling, MD: 'I first became interested in liver disease while getting my master’s in biochemistry at the University of Texas, Austin while focusing on intermediary metabolism. My decision to become a hepatologist was also influenced in large part due to my interactions with my chairman of medicine, Dr. Willis Maddrey, while a student at Jefferson Medical College.'

     width=Ashwani K. Singal, MD: 'I always had interest in alcohol-related liver diseases since my time in India. After coming to the US in 2005, I was involved in an invited review article on hepatitis C and alcohol , which was published in the Journal of Clinical Gastroenterology in 2007. The literature review during this endeavor furthered my interest. This led to writing and proposing an intramural grant application at the University of Texas Medical Branch in Galveston, Texas. Since then, my interest continued growing and remains until today.'

     width=Vincenzo Mazzaferro, MD:  'My interest in oncology started in medical school. When I decided to be a surgeon, the liver was the most challenging area to develop, and therefore any cancer affecting the liver, primary or secondary, was a natural consequence of my scientific and clinical research.'

     width= Paul Y. Kwo, MD: 'One of my first patients that I cared for when I was an intern was a patient who underwent liver transplantation. I was fascinated by the pictures he showed me of what he looked like prior to transplant and how he recovered. In addition, the hepatitis C virus was identified while I was a resident. Our service was filled with individuals with non-A non-B hepatitis, and this discovery gave hope to these individuals that there may be treatments identified.'

    LFTs, liver chemistries, liver panel, liver profile: which is it?
    ACG guideline author on correct terminology
    MDCalc Editorial Team

    Routine labs related to the liver are often erroneously referred to as “LFTs”. We asked Dr. Paul Kwo, first author of the ACG clinical guideline on liver chemistries, to give his insights: 

    “Liver chemistries are indirect markers of hepatobiliary disease. LFTs, or liver function tests as they have been called for years, connote that these blood tests are reflective of the true function of the liver. That is true for some tests, such as bilirubin and protime, but not for the majority of liver chemistries we measure.”

    —Paul Y. Kwo, MD, FACG, FAASLD

    HCV and HCC: Ask the experts
    The evolving role of hepatitis C as a risk factor for HCC

    How is the landscape of hepatitis C virus (HCV) management changing since the advent of direct-acting antivirals? 

    Richard K. Sterling, MD, creator of the FIB-4 Index for Liver Fibrosis : “The development of DAA and non-invasive assessments of liver disease severity have dramatically changed how we approach and manage chronic HCV. The overall safety and tolerability of DAA also have expanded the patient population we can treat. Those with compensated cirrhosis or MELD <15 have similar high sustained virologic response (SVR) compared to those without cirrhosis, although they may require longer treatment or addition of ribavirin to the DAA. Data also suggests that those with mild decompensation (MELD 15-20) can be treated successfully although a percentage may worsen. In this group, we often evaluate for liver transplant first. In those with more severe decompensation (MELD >20), treatment should be done in liver transplant centers with expertise in managing these patients… with increased use of DAA, NASH is becoming the most common indication for liver transplantation.”

    Douglas T. Dieterich, MD, professor of medicine, Mount Sinai: “It’s evolved quite a bit. There was no treatment [for HCV] until 1991, and that treatment was horrible. Horrible side effects, and low success rates. Then, for the next 20 years or so, there was no treatment available until the late ‘90s. The disease was only even first named in 1992. It was very hard to isolate it... in 2001, the combination of pegylated interferon and ribavirin was approved, and there was no progress at all between 2001 and 2011, with about a 25% cure rate with 48 weeks of terrible side effects. In 2011, the 2 new protease inhibitors telaprevir and boceprevir were approved, but they were add-ons to PEG and ribavirin. And they not only added but exponentially increased side effects. The real-world results went from about 25%-40% cure rates, and the side effects were unbelievably difficult...in November 2011, we saw the presentation of just one drug, sofosbuvir and ribavirin, cure 100% of hep C patients, genotypes 2 and 3, which sort of shook the world. And 2 years later, sofosbuvir was on the market, and basically, the days of interferon were over.”

     width=Paul Y. Kwo, MD, ACG guideline author: “The advent of direct-acting antiviral agents for hepatitis C has revolutionized the treatment of this infection. There are few other chronic diseases that can be cured with a short course of therapy that is well-tolerated.  We are seeing fewer patients listed for transplant for hepatitis C, and increasing awareness among many of the patients who were hesitant to take interferon-based therapies are coming in to be treated with our new direct-acting antiviral agents.“

    MELD purgatory: Ask the experts
    Does MELD purgatory exist? How should these patients be managed?

    Paul Y. Kwo, MD: “MELD purgatory is a condition where one cures a patient with hepatitis C with decompensation, but they fail to improve sufficiently to be removed from a transplant list, yet do not worsen enough to be transplanted. In general, if one’s MELD is below 20, and they are cured of their hepatitis C, there is about a 20% chance they can be delisted successfully with re-compensation. All transplant centers approach this slightly differently, but the general trend is that those with hepatitis C who require transplant are not treated prior to transplantation, as hepatitis C can easily be treated post-transplant . Also, there is increasing use of hepatitis C positive donor livers which can be used for hepatitis C positive recipients and hepatitis C non-exposed recipients, much as we use hepatitis B core positive donors for liver transplant.”

    Richard K. Sterling, MD: “There is a MELD Score beyond which treatment may be safe and beneficial, but that is center-specific. When deciding on HCV treatment in someone on the transplant list, the patient must be made aware that their MELD Score may improve to the point where they no longer have the same priority ... and that if they are SVR, they may not be eligible for an HCV positive organ, which might also prolong their wait.”

    Douglas T. Dieterich, MD: “I think [MELD purgatory] is an artificial construct that doesn’t exist, frankly. When people first started taking DAAs, their MELD Score would drop some, but what happens is the score continues to drop, so that was only a measurement that people looked at 6 months after starting treatment - their livers improved some, but not enough. With more time, now, it turns out their livers continue to improve. So actually, very few patients are getting transplanted for hep C-related cirrhosis.

    ...
    “A Fool with a Tool Remains a Fool”
    Insights from Milan Criteria creator

    How did you develop a clinical interest in HCC? Was there a particular clinical experience or patient encounter you had?

    My interest in oncology started in medical school. When I decided to be a surgeon, the liver was the most challenging area to develop, and therefore any cancer affecting the liver, primary or secondary, was a natural consequence of my scientific and clinical research.

    What pearls, pitfalls and/or tips do you have for physicians using your clinical decision tools (Milan Criteria, Metroticket Calculator, etc) at the bedside? Do you know of cases when recommendations have been applied, interpreted, or used inappropriately?

    I think that a fool with a tool remains a fool. Tools such as calculators are instruments to ease decisions but are not able to replace personal judgment and multidisciplinary discussions. The tools we have developed in prognostication of liver cancer treated with transplantation may help in deciding on patient listing and priority but remain instruments to be balanced with many other parameters of disease and with the response to different therapies. 

    How do you use the tools in your own practice?

    We use tools in daily practice and during multidisciplinary meeting with specialists of other areas. Tools and calculators are also very important when discussing and informing the patients and their families on the possible consequences of various therapies.

    Do you have any thoughts on criticisms of the Milan Criteria as too restrictive and potentially excluding patients who might benefit from liver transplant?

    The Milan Criteria were designed in a period of high disregard of cancer as a transplant indication. In fact, the Milan Criteria resuscitated the interest in liver transplantation as a cancer operation. As with any restrictive criteria, the drawback was the possible exclusion of tumor conditions that were potentially curable, although beyond the described limits. However, over the years, we have expanded the criteria with the Up-to-7 limits and in a more dynamic approach with the “Metroticket concept” of individualized prognosis, including alpha-fetoprotein (AFP) as a surrogate of tumor biology in the calculator available on MDCalc and published in Gastroenterology 2018.

    Where are there deficits in HCC research?

    HCC is a tumor in the interest of multiple fields - oncology, hepatology, surgery, interventional radiology, etc. This may generate some competition that does not always help. A more pragmatic and broad cooperation among different fields of research should be implemented in the case of liver cancer. Trial designs are not always optimal and this is a consequence of unbridged differences of different contesting groups (i.e., east-west, pharmacologic-non pharmacologic, hepatologic-oncologic etc.)

    Is there any research you're working on now that you are particularly excited about? 

    Augmented reality in surgical oncology, immunotherapy and innovative loco-regional approaches to liver cancer, and expansion of the area of interest in transplant oncology.

    Choosing a specialty
    How 4 liver disease experts first got interested in hepatology

     width= Richard K. Sterling, MD: 'I first became interested in liver disease while getting my master’s in biochemistry at the University of Texas, Austin while focusing on intermediary metabolism. My decision to become a hepatologist was also influenced in large part due to my interactions with my chairman of medicine, Dr. Willis Maddrey, while a student at Jefferson Medical College.'

     width=Ashwani K. Singal, MD: 'I always had interest in alcohol-related liver diseases since my time in India. After coming to the US in 2005, I was involved in an invited review article on hepatitis C and alcohol , which was published in the Journal of Clinical Gastroenterology in 2007. The literature review during this endeavor furthered my interest. This led to writing and proposing an intramural grant application at the University of Texas Medical Branch in Galveston, Texas. Since then, my interest continued growing and remains until today.'

     width=Vincenzo Mazzaferro, MD:  'My interest in oncology started in medical school. When I decided to be a surgeon, the liver was the most challenging area to develop, and therefore any cancer affecting the liver, primary or secondary, was a natural consequence of my scientific and clinical research.'

     width= Paul Y. Kwo, MD: 'One of my first patients that I cared for when I was an intern was a patient who underwent liver transplantation. I was fascinated by the pictures he showed me of what he looked like prior to transplant and how he recovered. In addition, the hepatitis C virus was identified while I was a resident. Our service was filled with individuals with non-A non-B hepatitis, and this discovery gave hope to these individuals that there may be treatments identified.'

    ...
    LFTs, liver chemistries, liver panel, liver profile: which is it?
    ACG guideline author on correct terminology

    Routine labs related to the liver are often erroneously referred to as “LFTs”. We asked Dr. Paul Kwo, first author of the ACG clinical guideline on liver chemistries, to give his insights: 

    “Liver chemistries are indirect markers of hepatobiliary disease. LFTs, or liver function tests as they have been called for years, connote that these blood tests are reflective of the true function of the liver. That is true for some tests, such as bilirubin and protime, but not for the majority of liver chemistries we measure.”

    —Paul Y. Kwo, MD, FACG, FAASLD