Surgical Treatment of Hepatocellular Carcinoma (HCC)
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.
Liver Cancer Clinical Program