Curing cancer by replacing livers!
BACKGROUND: The bile duct is a thin tube, about four to five inches long, that reaches from the liver to the small intestine. The major function of the bile duct is to move a fluid called bile from the liver and gallbladder to the small intestine, where it helps digest the fats in foods. Bile Duct Cancer or Cholangiocarcinoma is a cancerous (malignant) growth in one of the ducts. (SOURCE: www.ncbi.nlm.nih.gov, www.cancer.org)
Bile duct cancer is extremely rare, only two out of every 100,000 people are diagnosed with this disease, and most patients are over the age of 65. Both men and women can contract bile duct cancer. Based on its location, bile duct cancer is divided into three groups: Intrahepatic, Perihilar (also called hilar), and Distal. Intrahepatic bile duct cancers develop in the smaller bile duct branches inside the liver, Perihilar in the hilum, where the hepatic ducts have joined and are just leaving the liver, and Distal bile duct cancers are found further down the bile duct, closer to the small intestine. (SOURCE: http://www.cancer.org)
SYMPTOMS: Symptoms for bile duct cancer may differ depending on the location, but people with bile duct cancer may experience some of these symptoms: clay-colored stools, fever, itching, loss of appetite, weight loss, pain in the upper right abdomen that may radiate to the back, and yellowing of the skin (jaundice).
TREATMENT: The goal is to treat the cancer and the blockage it causes. Endoscopic therapy with stent placement can temporarily relieve blockages in the biliary ducts and relieve jaundice in patients. Laser therapy combined with light-activated chemotherapy medications is another treatment option for those with blockages of the bile duct. When possible, surgery to remove the tumor is the treatment of choice, and may result in a cure. Traditionally, the disease is treated with resection, surgically removing the tumor, but in many cases the cancer tends to continue to spread around the bile duct. In the past, patients with non-resectable bile duct cancer had little chance of survival.
A TRANSPLANT FOR CANCER CURE: A liver transplant may be an option when bile duct tumors have not spread outside the liver but they cannot be completely removed by surgery. Radiation therapy and chemotherapy are usual treatments before a liver transplant. Although tumors can recur after transplantation, in some cases, liver transplantation is considered a cure. Because these patients don't have chronic liver disease like a typical transplant candidate, the United Network for Organ Sharing automatically gives them extra points on the liver allocation system so that they have a fair spot on the list, relative to the urgency of their disease. Typically, a liver is available within three to six months. During surgery, doctors remove all of the liver and bile duct and perform the liver transplant. Bile duct cancer patients who undergo traditional surgery have a 30% to 40% five-year survival rate. For patients who cannot have surgery, survival is only 5% to 10%. Early data for treatment with liver transplant suggests five-year survival of 75% to 85%, which is similar to overall liver transplant survival rates. (SOURCE: www.mayoclinic.org, University of Michigan Medical School)
Dr. Christopher Sonnenday discusses liver transplantation for bile duct cancer patients who meet the criteria.
Talk about bile duct death to cancer.
Dr. Sonnenday: Bile duct cancer or Cholangiocarcinoma is a rare cancer that affects the plumbing system of the liver if you will. The liver has a system that drains bile from the liver into the intestine. Bile is what helps you absorb fats and other nutrients out of your diet and that system can be a site for tumors to form. It’s a relatively rare form of cancer, there are approximately three thousand cases a year in the United States. But it is a particularly dramatic cancer in that most patients who have the disease present relatively late in their course with disease that has already spread to other organs. So unfortunately the death rate associated with bile duct cancer is quite high, with only 15% of all patients with the disease alive five years after diagnosis. Therefore it is a particularly scary cancer both for patients and physicians.
Is it that it doesn’t present with many symptoms?
Dr. Sonnenday: Bile duct cancer is tricky for a number of reasons. I think a lot of the bad outcomes that we see with this cancer have to do with the fact that it often presents very late in its course. It doesn’t typically cause symptoms until the cancer gets large enough or grows in such a way that it actually blocks the entire bile duct itself which then produces jaundice and causes people to seek medical attention. But often by the time that happens the tumor might be quite advanced. Sometimes these tumors spread relatively early in their course so even though the cancer in the bile duct or the liver might be small they already have tumor elsewhere. The outcomes from this cancer I think have been poor primarily because we just have difficulty diagnosing people at a time when they’re the most treatable.
What are the treatments now?
Dr. Sonnenday: The only potentially curative treatments for bile duct cancer all involve some sort of surgical treatment. The basic principle is to remove the affected portion of the bile duct and the liver. The other treatments that are applied to this disease in patients who don’t have a surgical option include chemotherapy and radiation. Those treatments are clearly not definitive -- or more specifically not curative. They can extend the lives of people with fairly advanced disease on the order of several months but they’re not definitive treatments. The patients who are fortunate enough to be cured of this disease are diagnosed early enough in their course that they have surgical options and the disease can be removed completely, and then they have the good fortune of it not recurring. It can be complicated to get those people through that entire course to a cure.
Talk about transplanting the entire organ to cure this cancer.
Dr. Sonnenday: In part because of some of the things I just mentioned this is a difficult disease to diagnose and can be relatively advanced by the time we pick it up. Surgical treatments, although they can be curative in select patients, are complicated and may involve removing entire segments of the liver and the bile duct and complex reconstruction of the bile duct. The thought came about that well perhaps obviously liver transplantation which removes the liver and the bile ducts in their totality would be the most definitive treatment.
In the past actually transplant has not been applied to cancers, not just in the liver but in other organs as well. In organ transplantation, you take an organ from a deceased person and put it in to the intended recipient. In order to prevent the recipient’s immune system from rejecting that organ they are placed on antirejection drugs. If someone has microscopic cancer left over anywhere the antirejection drugs are kind of like gasoline to that fire. And historically patients who were transplanted for cancers often did really terribly in the long term because the cancers would come back they would come back very aggressively. We have learned from a few select examples that if you pick patients who are relatively early in their course with no evidence of disease outside the liver, then bring them through appropriate selection protocols, and then transplant them that their outcomes can be excellent. Again with the idea that you’re of course not leaving any cancer cells behind at all and you’ve done this very definitive operation removing the entire liver and giving them a new one.
Liver transplantation for cancer was first done successfully for the more common form of liver cancer called hepatocellular cancer. As an extrapolation of that experience, certain centers became interested in trying this for bile duct cancer. Because there are some patients with bile duct cancer in which the cancer is relatively small and confined and has not spread to other organs, but because of its involvement of either the bile ducts themselves or of the blood vessels that run kind of along with the bile ducts there’s not a way to surgically remove the affected portion and leave the patients with enough liver to sustain life. Liver transplant is a way to get around that problem. Small tumors that are confined to the liver and bile ducts have not spread elsewhere but don’t have a surgical resection option -- those are really the patients for whom we think transplant has a role.
What are the criteria for a patient who would be able to have the transplant?
Dr. Sonnenday: Patients for whom we think liver transplantation can be a treatment for their bile duct cancer are subjected to two different levels of selection criteria. The first is about their cancer: is the cancer confined to the liver and the bile ducts itself? We do a series of tests to make sure that there’s no evidence of cancer elsewhere including the surrounding lymph nodes. The patient can’t have an appropriate surgical resection option. The reason that we exclude patients who have a resection option even though the outcomes could at least theoretically be as good or better with transplant is that we just don’t have enough transplanted organs available for all the people already who need one. To offer liver transplantation to people who have other treatment options at this point we don’t think it’s appropriate. So, appropriate patients have to have bile duct cancer confined to the liver and bile ducts and not have a surgical resection option.
Then they have to be a transplant candidate by all the traditional criteria. They can’t have other medical conditions that would prevent them from getting the most appropriate outcomes after transplant. Patients with other cancers, or patients with advanced heart disease or lung disease -- things that would make the recovery from transplant more difficult – are not candidates for liver transplantation. Those are the same criteria that we use for any of our patients who are being considered for liver transplant.
What are the risks for patients?
Dr. Sonnenday: As I tell patients, liver transplantation is an enormous undertaking. It’s not something that you would ever sign up for if you didn’t absolutely need it. The process of getting the transplant can be prolonged including the evaluation process, waiting for an organ, and the emotional rollercoaster of when you’re going to get called in. Then there’s the risk of the actual surgical procedure itself, which has become safer as we’ve gotten better at the operation and the anesthesia and ICU care has improved as well. Nevertheless, there are still potential fatal complications of the actual operation itself. Beyond that, it’s an enormous change in the patient’s lifestyle and just their overall health that generally requires months to recover from completely. I tell people after liver transplant it’s three to six months at least until you’re back full speed, after you’ve regained your strength, your functional status, and your endurance. It really is a prolonged process and there are things that are unique to transplant, again many of them related to the antirejection drugs. Examples include infections -- due to being more susceptible to certain disease processes that might be minor in otherwise healthy people but are more severe in patients who are immunosuppressed.
The transplant drugs do they carry an increased risk of cancer?
Dr. Sonnenday: The antirejection drugs all work by to some degree by dialing down your immune system such that your immune system doesn’t injure the new organ. And your immune system is responsible for helping you control infection, particularly certain types of infection and also for helping you fight cancer. The immune system is one of the things in all of us that keep cancers in check. So we know at least in the long term patients who undergo transplant and stay on antirejection medication have a higher risk of certain infectious diseases and can have a higher risk of certain types of cancer as well. Certainly if they had cancer already like the patient population we’re talking about today the role of the immune suppressive drugs on their recovery and risk of recurrence is still something to be honest with you we’re learning. Different transplant centers are trying different regimens to try and minimize that risk as best we can.
What kind of success have you had with this?
Dr. Sonnenday: I think the success that we’ve seen in liver transplantation for bile duct cancer has been pleasantly surprising. This is not something that we have a lot of data on and I tell the patients who are coming to transplant for bile duct cancer that we are learning as go how this is going to play out. There’s probably only been about a hundred and fifty to two hundred patients nationally that have undergone liver transplant for bile duct cancer. The earliest of those were only done just a few years ago so we don’t have the long-term survival statistics yet completely. Having said that, the early results we’ve seen in our own patient population and at other centers that have similar protocols is that the three to five year survival for this group of patients is probably going to be somewhere in the range of seventy five percent range. That number compares really favorably to patients undergoing liver transplantation for other reasons,. And it’s far better than anything we currently do for bile duct cancer. Even the patients who are fortunate enough to have surgery, have a resectable tumor, have it removed, potentially treated after that with chemotherapy or radiation -- even those patients in the best case scenario probably have a five year survival around forty or fifty percent. So in this protocol we’re taking patients that really didn’t have a surgical option, and the results that we’re seeing so far are better than anything we’ve done in the past for bile duct cancer.
Mr. Gehle is still cancer free?
Dr. Sonnenday: He is, he’s done very well.
When you think of that is that something that five years ago you would have been able to say?
Dr. Sonnenday: No, I think that again we’re gaining experience with this. But to take someone who had an unresectable bile duct cancer -- which a few years ago was essentially a death sentence to any patient -- to take somebody like that and see them one year later, two years later, three years later is amazing. I think it is a testament both to appropriately selecting the patients who we can help with this treatment and then obviously to all the work by the patient and the team to get them through this extensive therapy.
Is there anything else that you want people to know about this?
Dr. Sonnenday: The one thing I would mention which gets to my last point is that transplant, particularly transplant for a disease as complicated as this, involves an incredible spectrum of multidisciplinary care. From the gastroenterologist and oncologists who help diagnose and get these patients on track initially, to the surgeons and their teams that bring the patients through transplant and all the postoperative care. And most of all the incredible effort the patients and their families have to expend to get them through the treatment process: to wait for transplant, to get them through the recovery process. I mean this really is a testament to what I think is one of the best things about liver transplantation in general and that this is the ultimate team sport in medicine. It requires an incredible amount of cooperation among patients and their families as well as the medical team which is inspiring. So the good results are very rewarding.
Is there anything else you would like to add:
Dr. Sonnenday: It’s just very rewarding to see patients with a very morbid complicated disease, a disease we still struggle with treating, to see them come through this complicated treatment process to the light at the end of the tunnel is amazing and very rewarding.
Mrs. Gehle said to us her husband only had two months.
Dr. Sonnenday: I think the time course can be very variable but certainly patients with unresectable bile duct cancer have a survival we think of as being measured in months. And here he is a couple of years later so I think it’s an incredible victory even in the short term. And we’re hoping that the long term results will bear that out to be true.
FOR MORE INFORMATION, PLEASE CONTACT:
Christopher J. Sonnenday, MD, MHS
University of Michigan
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