What is Hepatocellular Carcinoma (HCC)?
Primary liver cancer—that is, cancer that starts in the liver—is called hepatocellular carcinoma, or HCC for short. HCC almost always happens to people who have had liver disease for many years. In the United States the most common causes are infection with the hepatitis C virus or from excessive alcohol intake; around the world, hepatitis B is the leading cause of liver cancer. Around 800,000 people get HCC every year, making it the fifth most common cancer worldwide. Compared to most other cancers treatment is more difficult, though, so nearly 750,000 people die of HCC each year, making it number two, behind only lung cancer as the leading cancer killer.
Whatever the underlying disease, it takes many years of continual liver damage before HCC develops; in most cases cirrhosis, a hardening of the liver due to built-up scar tissue, is already present. HCC usually grows slowly in its early stages; as a result HCC can usually be cured if discovered early enough.
Screening for HCC
People with any type of cirrhosis are at risk to develop HCC; when cirrhosis is due to hepatitis B or C, the risk is especially high—up to five percent every year. Since we know who is at risk, HCC is a perfect target for screening and surveillance, and doing scans every six months has been proven to save lives. While guidelines recommend ultrasound for this purpose because it is cheap and widely available, up to 30 percent of early cancers can be missed by ultrasound. For this reason, at Mount Sinai, as at many centers where effective treatments like liver resection and transplantation are available to treat early HCC, we use more sensitive methods for screening like CT scan or MRI.
Diagnosis of HCC
For most types of cancer, a biopsy (a sample of the tumor tissue) is necessary to establish the diagnosis. This is not the case, though, for HCC. In a person who has cirrhosis, finding a mass in the liver with a rich blood supply that it lights up in a characteristic way on CT or MRI scan after dye injection is accepted around the world to be as good as a biopsy. Not every HCC has the typical appearance, and occasionally HCC develops in someone who has no known liver disease; in such cases biopsy may still be necessary. Now that we have entered the era of personalized medicine where treatments are being developed that can target the specific genetic abnormalities in a particular person’s cancer, the role of biopsy to provide tissue for genetic analysis is likely to increase.
Staging of HCC
Cancer staging is a way of classifying people with cancer based on the extent of the cancer and other relevant factors into groups with roughly similar prognosis; in some instances staging is directly linked to treatment. For most cancers staging is according to guidelines produced by the American Joint Commission on Cancer (AJCC). The AJCC system includes three things: the extent of the tumor in the liver (T), whether it has spread to nearby lymph nodes (N), and whether it has spread, or metastasized, to more distant places (M). For most people with cancer surgery is the primary treatment, and AJCC staging is primarily focused on them; in fact, HCC staging according to AJCC can only be done on people who have had surgery since it depends on things the pathologist finds on examining the part of the liver that was removed. This is a problem for HCC, since as a result of the underlying liver disease many people cannot undergo surgery even though they have early HCC, and as a result most doctors who treat HCC don’t rely on the AJCC system.
The Barcelona Clinic Liver Cancer staging system (BCLC) was developed to enable staging of all people with HCC. A key feature of BCLC is that it links the stage of HCC to the recommended treatment based on critical analysis of medical evidence. BCLC staging has been adopted in guidelines both in the U.S. and in Europe as the best staging system, and it is how we stage HCC at Mount Sinai. People with a single small (less than 2cm) HCC are at the earliest stage that can be detected; they are called BCLC class 0. BCLC class A comprises people with HCC that is potentially curable and includes people with a single HCC up to 5cm in diameter or 2-3 nodules of HCC up to 3cm in diameter and without invasion of blood vessels or spread outside of the liver based on scans. It also includes people with single HCC larger than 5cm, if their liver function is normal and they can undergo surgical resection.
Treatments for BCLC classes 0 and A HCC include resection, transplantation, and thermal ablation. People with HCC beyond the limits that define BCLC class A but that is still confined to the liver without invasion of blood vessels or distant spread are in BCLC class B. The treatment for BCLC class B HCC is chemoembolization. HCC that has invaded large blood vessels that can be identified on scans or has spread outside of the liver is considered BCLC class C as long as the liver function and general condition of the person affected remains good enough that treatment is possible. According to BCLC the treatment for class C is the drug called sorafenib, though many centers including Mount Sinai also add direct treatment of the tumors in the liver when the extent of blood vessel invasion or spread outside the liver is limited. When HCC is advanced to the point where the liver (and the person) can no longer function well enough to tolerate treatment it is considered BCBC class D, and the recommended treatment is supportive care.
Treatments for HCC
Hope for a cure for HCC depends on removing or in some other way destroying the tumor before it spreads. The fact that most people with HCC have cirrhosis greatly complicates matters; what is good from the standpoint of treating the cancer may be bad from the standpoint of the liver. Only with an interdisciplinary team made up of transplant and cancer surgeons, hepatologists (medical liver specialists), radiologists, and oncologists working together can the best decisions be made and treatments—both surgical and nonsurgical—can be carried out.
The Liver Cancer Program team is skilled in performing surgical procedures—including liver resection and liver transplantation—to treat hepatocellular carcinoma (HCC).
Liver Resection for HCC
Liver resection means removing the part of the liver that contains the tumor, including a rim of normal liver tissue around the tumor. A normal liver has an amazing ability to regenerate, meaning to grow back. Within a month after surgery to remove part of the liver, the remaining liver will grow until it is the same size as the liver originally was (minus the tumor, of course). For those few people with HCC who don’t have cirrhosis, resection is clearly the treatment of choice. The majority of people with HCC have cirrhosis, though, and a cirrhotic liver doesn’t regenerate as quickly or as completely as a normal one. Another concern with resection to treat HCC in people with cirrhosis is that the cirrhosis is the cause of the HCC, new HCC’s can form in the future, even if the current one is cured. Even with these shortcomings, there are many people with HCC and cirrhosis for whom resection is the best treatment.
Cirrhosis can result in two separate problems for the liver: liver failure and portal hypertension. The liver produces many important proteins and removes several toxins and waste products from the blood; with liver failure the liver can’t keep up these vital functions. We classify the degree of liver failure by a scale developed many years ago called the Child-Pugh classification, which rates liver failure as class A, B, or C. Only people in class A are able to safely undergo resection. The scar tissue in a cirrhotic liver also can choke off the blood flow through the liver, leading to high pressure in the veins bringing blood from the stomach, spleen, and intestines to the liver—this is called portal hypertension and can lead to complications including internal bleeding and the build-up of fluid in the abdomen. This pressure causes the spleen to enlarge and trap the small clotting cells called platelets. Therefore, a low platelet count is a reliable sign of portal hypertension. When the platelet count is less than 100,000 we avoid doing a liver resection. It is much more common for people with hepatitis B to develop HCC when the liver function is still normal and resection is possible than it is for people with hepatitis C.
The size of the tumor is not so important; as long as there is a single well-defined HCC that is confined to one region of the liver, resection may be possible. When there is more than one tumor, resection is not the ideal treatment since most cases with more than one HCC are the result of spread of the cancer within the liver, and the possibility of other small, unrecognized tumors is high. When scans show that HCC has begun to invade blood vessels in the liver it is considered an advanced stage and the chance of spread outside the liver is high. When vein invasion is present only on one side of the liver we believe that resection still offers a small chance for cure and probably longer survival than other available treatments.
The chances of survival after resection of HCC are in the range 80-92 percent at one year, 61-86 percent at three years, and 41-74 percent at five years, and the likelihood of HCC recurrence is around 20 percent, 50 percent, and 75 percent at one, three, and five years. With close follow-up we can usually find recurrent HCC at an early stage when it can still be successfully treated. The main things that affect the likelihood of HCC recurrence are the size and number of tumors, the level of the alpha-fetoprotein tumor marker, invasion of HCC into the blood vessels, and the tumor grade (how abnormal the cancer cells are).
The most common place for HCC to recur is in the remaining liver. HCC recurrence in the liver can be either the result of growth of tumor cells that were left behind when the resection was done, or an entirely new HCC. During the first two years after resection most recurrences are of the first type, which we call true recurrence, whereas after two years most recurrences are new tumors, which we call de novo HCC. We don’t yet have a proven way to lower the chances of true HCC recurrence. The best hope is for the drug sorafenib—we at Mount Sinai are leading a large international study called the SHARP trial where 550 people are receiving sorafenib after resection and another 550 are receiving a placebo. It hasn’t been long enough yet for us to know if the addition of sorafenib provides better results.
The best way to prevent new, de novo HCC is to treat the liver disease that caused the problem. Treatment of hepatitis B is easy and effective with once-a-day medicines such as adefovir, entecavir, or tenofovir that have virtually no side-effects. While it doesn’t cure the infection, the treatment stops the virus from reproducing, slowing the development of cirrhosis and lowering the chance of developing HCC. Treatment of hepatitis C has also been shown to lower the chance of developing new HCC, but until recently hepatitis C treatment has been a long and difficult process requiring a year-long series of injections. Recently, however, a new medicine called sofosbuvir has been approved that enables cure of most people with hepatitis C, without injections.
Liver Transplantation for HCC
In the early days of liver transplantation many people were transplanted to treat advanced liver cancer. Before long, poor results led us to realize this was a bad idea, and for many years having HCC was considered a reason not to have a transplant. In 1996, doctors from Milan, Italy published a paper where they showed that liver transplants for people with early HCC did just as well as people transplanted because of cirrhosis without cancer. They included people with either one tumor with a diameter ≤5 cm, or 2-3 tumors all ≤3 cm. These limits have come to be known as the “Milan Criteria” and are used around the world by transplant centers to decide who gets priority on the transplant waiting list.
The results of liver transplantation for HCC have long depended not just on whether the cancer was cured, but also on whether the underlying liver disease came back. If hepatitis C is active before transplant, it always comes back afterwards and in many cases damages the new liver; by five years 25 percent will have cirrhosis again, and the five-year survival has been 10 percent worse for people with hepatitis C compared to other liver diseases. We are all hoping that the recent approval of sofosbuvir, the new medicine that has been highly-effective in trials, will change this.
The other factor that affects the results of transplants for HCC is the shortage of donor organs. People with HCC that meets the Milan criteria get priority on the waiting list. Here’s how the system works: For people who need transplants because their liver is failing from cirrhosis, priority is based on how sick they are as measured by the MELD score, a number between 6-40 that is calculated based on three blood tests (bilirubin, creatinine, and prothrombin time/INR). When a donor liver becomes available, it is offered to the transplant candidate in the region who has the highest MELD score. If there is more than one person with that score, the liver goes to the one that has been at or above that score for the longest time. People with HCC within the Milan criteria usually don’t have such bad liver failure, but they still need transplants urgently or the cancer will grow and spread, so they are automatically given a MELD score of 22. Every three months, as long as the HCC doesn’t grow beyond the Milan criteria, their score goes up by 2-3 points. The score you need to get a transplant depends on a number of things including your blood type, what region of the country you are in, and how many sick people there are waiting at the moment, but on average it takes a score in the low- to mid-30’s to get a liver in New York State so most people have to wait a year or more. During that time we do our best to keep the HCC from growing using nonsurgical treatments because if it grows beyond the Milan criteria priority will be lost, and without priority there’s no way to get a donor liver. About 20 percent of people who go on the waiting list because of HCC drop out before they get a liver. People with two or three tumors, with a single tumor bigger than 3.5 cm, or with an alpha-fetoprotein tumor marker higher than 200, have an especially high chance of dropping out.
For people with HCC that meets the Milan criteria the chances for success of a transplant are high: 70-80 percent will live more than five years, and the chance of cancer coming back is only around 10 percent. The Milan criteria are very good at picking out a group of people who will do well, but they’re not nearly as good at telling who will do poorly: We at Mount Sinai showed that in a group of 43 people who got transplants even though their HCC was bigger than 5 cm, 44 percent lived more than five years. For many cancer operations that would be a great result; the trouble with transplants is that donor livers are scarce, and it would be a poor use of that scarce resource to use a liver for someone with a 44 percent chance of success when using it in another patient can give 75 percent.
Why should the size and number of tumors matter? After all, the entire liver is removed when we do a transplant. The reason is because as tumors grow in size and number they develop the ability to invade blood vessels and spread outside of the liver. There is nothing magic about the Milan criteria; it’s just that you have to draw the line somewhere. Everyone knows that there are many people with HCC beyond the Milan criteria who could be cured with a transplant; the question is, how to identify them? Not every HCC behaves the same way; some grow to a large size without invading blood vessels and spreading, while others invade and spread when they are small. We at Mount Sinai are leading the worldwide research effort to find molecular tests that can tell which HCC’s are bound to come back after transplant and which, despite being beyond the Milan criteria, will not, but these tests aren’t yet ready for use in people. The way we have now to try to sort out the “good” vs. the “bad” HCC’s is by what we call down-staging.
Down-staging means treating HCC that is beyond the Milan criteria using the various nonsurgical treatments in order to reduce the size and/or number of tumors down to within the Milan criteria. If you think about it, down-staging alone doesn’t make sense—if cancer has grown to where it has begun to spread outside the liver, what good does it do to shrink the tumor in the liver? The answer is the other key part of down-staging: the pssage of time. The idea is that we treat the HCC in the liver, hopefully to stop it from progressing and spreading, and then wait and watch for a while to give any tumor cells that had escaped before the treatment time to grow into tumors that we can see. We believe based on what we know about how HCC grows that six months is a reasonable length of time to wait after down-staging. Not everyone who goes through down-staging with hopes for a transplant makes it, bur for the ones who do the results are as good as for people who start out with HCC within the Milan criteria.
Living Donor Liver Transplantation
Because of the great ability of the liver to regenerate, we are able to take part of the liver from a healthy person and use it to perform a transplant; both the part that we transplant and the part that remains in the donor grow to full size within a month or so. A living donor has to be healthy, under age 55 or so, be close to the same size as or larger than the recipient (but not very over-weight), have a compatible blood type, and have a strong relationship with the recipient. For people with HCC within Milan criteria a living donor transplant can eliminate the transplant waiting list, and for people with HCC beyond the Milan criteria a living donor is usually the only way that a transplant can be done.
The Liver Cancer Program team is skilled in providing the full range of nonsurgical treatments for hepatocellular carcinoma (HCC), including the following.
Nonsurgical Locoregional Therapy
Most people with HCC, either because of the size, number, and location of the tumors or because of poor liver function, cannot have a resection. We have a number of ways that we can treat HCC in the liver without surgery. These treatments fall into two main categories: direct destruction (ablation) either by injection of chemicals or by placing a device into the tumor to burn it or by way of the blood supply (embolization), injecting particles and/or medicines to be carried into the tumor and cut off its blood supply. Locoregional therapy may be the main treatment for people with early stage HCC (BCLC A) who are for some reason not able to have resection or a liver transplant, and for people with intermediate stage HCC (BCLC B). We at Mount Sinai are now studying whether locoregional treatment can help people with more advanced HCC (BCLC C), as well. One of the main uses of locoregional treatment is in people who are waiting for a liver transplant to keep their HCC from growing during the time it takes to get a liver.
- Ethanol injection: The injection of 95 percent ethyl alcohol (ethanol) into HCC tumors has been practiced for many years and is a very effective way to destroy small tumors (less than 2 centimeters; one inch is about 2 1/2 cm). A thin needle is placed into the tumor and the injection is guided by either ultrasound or CT scan. Ethanol injection has mostly been replaced by thermal ablation, but it still has a role to treat small tumors near structures like the gallbladder or intestine that it would be dangerous to burn.
- Thermal ablation: Over the past fifteen years thermal ablation using radiofrequency energy or, more recently, microwaves, has for the most part replaced ethanol injection. A special needle is placed into the tumor under ultrasound or CT scan guidance and is connected to a generator that causes the tumor and the surrounding liver to heat to a temperature where it is burned, and the cancer cells are killed. The chances that thermal ablation can destroy an HCC completely depend on the size of the tumor: below 2 cm it is over 90 percent successful, around 80 percent between 2-3 cm, and around 65 percent between 3-4 cm; we don’t use thermal ablation for tumors more than 4 cm in size since the chance of success is too low. All of the techniques that require putting a needle into a tumor depend on the skill of the radiologist in being able to place the needle safely and accurately; there are some locations in the liver where that can be extremely difficult or impossible. In particular tumors that sit at the top of the liver near the lungs can be difficult targets and trying to hit them risks puncturing the lung. Tumors that sit right next to large blood vessels are difficult to treat with thermal ablation because the blood flowing in the vessel keeps the tumor cool and prevents it from being killed.
- Irreversible electroporation: This is a new technology where two or more needles are placed parallel to each other around the tumor and connected to a generator that creates a very high voltage electrical field between the needles, causing irreversible injury to the cells within the field. This technology has the advantage that it does not damage normal structures the way that thermal ablation can, but the need to place multiple needles makes it technically difficult. We are developing experience now with electroporation, and its ultimate role remains to be determined.
- Chemoembolization: The liver is the only organ with two sources of blood supply. Like every organ it has an artery bringing fresh, oxygen-rich blood from the heart, called the hepatic artery; the liver, however, also has the portal vein which brings all the blood that drains from the stomach, spleen, and intestines to the liver for processing before it returns to the body. The portal vein brings about 3/4 of the total blood flow to the liver. Embolization means injecting material into a blood vessel to stop the blood flow. In any other organ, embolization of its artery would lead to severe damage, but the blood flow from the portal vein protects the liver. The tumor is not so lucky; when HCC develops, it draws all of its blood from the hepatic artery, and as a result embolization can kill HCC while leaving the normal liver relatively untouched. Embolization is performed by passing a tiny plastic tube through the blood vessels under x-ray control starting in the groin or the wrist and guiding it into the branch of the hepatic artery that supplies the tumor.
Chemoembolization combines this embolization with the injection of anticancer drugs along with the particles to increase the killing of the cancer. The standard way of doing this is to inject a mixture of a drug called doxorubicin and an oily dye called ethiodol into the tumor followed by tiny beads that are about the diameter of a human hair. The beads are carried by the circulation into the small blood vessel branches in the tumor where they get caught and stop the blood flow. At Mount Sinai we are now testing a new kind of beads for chemoembolization, called drug-eluting beads, that are mixed with doxorubicin before they are injected—the doxorubicin is absorbed into the beads and released slowly once the beads have become trapped inside the tumor. Less chemo drug escapes into the circulation with drug-eluting beads, so there are fewer side-effects, and by keeping the chemotherapy in the liver they may actually work better to kill the tumor. In general, we use chemoembolization for tumors larger than 4 cm in diameter and when there is more than one tumor. People stay overnight in the hospital after chemoembolization, but are almost always well enough to go home the next day. Chemoembolization has been proven to make people with intermediate-stage HCC live longer.
- Radioembolization: Another transarterial treatment that has been gaining popularity lately is radioembolization. Rather than combining beads with chemotherapy, the beads for radioembolization contain yttrium-90, a radioactive element. They are injected into the artery just like in chemoembolization, and once they are trapped in the tumor they gradually release their radiation and kill the tumor from within. While with chemoembolization cutting off the blood flow is an important part of why the treatment works, with radioembolization far fewer particles are injected and the effect of the treatment depends almost entirely on the radiation. We are currently studying whether radioembolization can help people with HCC that has begun to invade branches of the portal vein. In people whose portal vein is blocked by tumor, chemoembolization can cause severe liver damage since the liver isn’t protected by the blood coming in through the portal vein, but radioembolization, since there are far fewer particles, doesn’t cut off enough blood supply to cause severe damage.
Immunosuppression and HCC
After a liver transplant you have to take medicine to prevent rejection. These medicines work by suppressing your immune system. We know that immune suppression can cause cancers to develop in people who have certain infections, for example, with the papilloma virus or the Epstein-Barr virus, but immune suppression doesn’t seem to have much effect on the formation of common cancers like breast cancer, colon cancer, or HCC. While not entirely proven, the medicines that we usually use to prevent rejection, tacrolimus (Prograf) and cyclosporine, may help new HCCs to grow. There is another medicine called sirolimus (Rapamune) that in addition to preventing rejection also has anticancer properties. There is an international research study going on now to see whether the results of transplants for HCC are better when sirolimus is used. Until the results of the study are available many transplant teams, including ours at Mount Sinai, use sirolimus after transplant for people with HCC, especially in cases where the HCC was more advanced.
Chemotherapy for HCC
Despite many years of research, so far there is only one medicine, sorafenib, that can make people with HCC live longer. Sorafenib works not by killing cancer but rather by stopping its growth for a while. In the study that led to the approval of sorafenib by the FDA (which was led by Mount Sinai), the 300 people with advanced HCC who received sorafenib lived an average of 7.9 months compared to 10.7 months for the 300 people who received a placebo. Currently, sorafenib is only used in patients who are not candidates for other treatments for HCC. While an important breakthrough, sorafenib is only a beginning; at Mount Sinai we continue to lead clinical trials looking for new drugs to improve results in combination with or instead of sorafenib as well as after sorafenib stops working.