This post marks the first in a series reviewing different cholangiocarcinoma treatment modalities. Moving forward, one post each month will look at the present state of a common treatment including an interview with a leading expert on the subject. Please use the comments to share your feedback on information you would like to see in future posts and any treatments or doctors you would like to see us highlight.
If you want to start a spirited debate in the cholangiocarcinoma community, one of your best bets would be to bring up liver transplantation as a treatment for our disease. Typically, responses come back in one of three buckets. 1. Individuals who aren’t close to cancer treatment tend to voice excitement at the possibility of swapping out the diseased organ for a new one. 2. Those closer to cholangiocarcinoma treatment cite the litany of challenges patients face when pursuing transplant, often coming to the conclusion that there isn’t a case for transplant with cholangiocarcinoma. 3. A select few, typically surgeons who have seen transplants executed with success will tell you transplant is an option, with some caveats.
Dr. John Fung falls into that latter category. A transplant surgeon by trade, Dr. Fung started his career as a Fellow under Dr. Thomas Starzl, the forefather of liver transplantation and the surgeon who performed the first successful liver transplant in 1967. After his time with Dr. Starzl Dr. Fung held several appointments including Director of the Cleveland Clinic Health System Center for Transplantation and most recently Director of the University of Chicago’s Transplantation Institute. Dr. Fung has kept his late mentor’s spirit for innovation and progress alive in his own work, and he has published over 1,000 medical articles and book chapters.
We met with Dr. Fung when the C.A.R.E. team visited University of Chicago in early October, and he was kind enough to sit with us and answer some questions around liver transplantation. His responses both give insight into the best candidates for this approach and help dispel some of the myths around liver transplant as a treatment for cholangiocarcinoma.
A history of cholangiocarcinoma and transplant
According to Dr. Fung, transplant for liver cancers dates back to the beginning of liver transplantation in the 1960’s. Those initial transplants were performed specifically on patients whose tumors were too large to remove. Unfortunately most of these patients experienced recurrences and ultimately died. Several decades passed before surgeons began to tenuously reevaluate transplantation as a treatment path in liver cancer.
“For many years, liver cancer was felt not to be a good indication for transplant because of the high recurrence rate.” - Dr. Fung
While Dr. Fung was training at the University of Pittsburg in the 1990’s, they transplanted a mix of roughly 25 intrahepatic and Klatskin tumor (hilar) cholangiocarcinoma patients with poor results. He believes the size of the tumors and the high likelihood of metastases led to the poor survival rates following these surgeries. Following the disheartening results, they again suspended transplants in cholangiocarcinoma patients.
Over the last 20 years, the tide began to change in hepatocellular carcinoma, and Dr. Fung attributes much of this to earlier disease detection and highly selective patient evaluations. He believes that transplant for cholangiocarcinoma patients can yield similarly successful results, and the protocols that have been developed to evaluate patients for cholangiocarcinoma are indeed showing early success. The present challenge with cholangiocarcinoma is the lateness of diagnosis for many patients.
The present state of transplant for cholangiocarcinoma
Per Dr. Fung, there is a very specific set of criteria he employs in selecting cholangiocarcinoma patients for liver transplant. The patient must have active, localized disease; signs of possible distant metastases such as lymph involvement exclude patients from transplant. He clarified that lymph nodes can be removed, but in most cases the cancer has already spread beyond the lymph node, so removing the lymph node does not eliminate the problem.
If a patient has localized disease, the next step would be to observe the behavior of the tumor over a period spanning from months to even years. Other interventions may be applied during this time, but the surgeon would want to be involved to help guide which treatments to use so as to not cause a conflict with the potential transplant. For example, a hypothetical patient could be on the standard course of chemo through this observation period, but if radiation were proposed, the transplant surgeon would need to evaluate where and how to ensure anatomy needed during or after the transplant would not be damaged.
Dr. Fung himself has transplanted a small number of cholangiocarcinoma patients who have been eligible based on this criteria, and thus far the results have been very positive. The most important factor in long-term survival is knowing whether or not microscopic cells are present elsewhere in the body, which is why the waiting period, while counter-intuitive, is critical to evaluation and long-term success.
Transplantation and immunotherapy
Targeted therapies are arguably the most exciting modalities hitting recent cancer literature and for good reason. Early successes in drugs like Pembrolizumab and FGFR inhibitor TAS-120 are giving many patients hope, but this change in the medical landscape brings into question how an immunotherapy might impact transplant and vice versa.
When asked about these relationships, Dr. Fung said that it depends on the type of immunotherapy. In immune checkpoint inhibitors, drugs that target the interaction between T-cells and the tumor, the indiscriminate nature of the T-cell interaction with foreign tissue could initiate a rejection. This makes them a poor option in transplant scenarios.
Targeted therapies on the other hand like CAR T-cell therapy or TIL target specific antigens on tumor cells. As these therapies hone in specifically on the diseased tissue, they will not initiate rejection. The potential challenge, however, is that heavy anti-rejection immunosuppression medications can in fact ‘neutralize’ the effect of the antigen receptor cells.
When transplantation is appropriate
For the first group of people at the start of this post, transplant is appealing for cholangiocarcinoma, but Dr. Fung supports resection first when it is possible because of the potential for cure without the lifelong complications transplant can present. Liver resections and Whipple procedures are incredibly significant surgical interventions, but transplant comes with even more risk, so in Dr. Fung’s mind there isn’t a case to consider transplant where resection is possible. Additionally, liver transplants are donor dependent, and time spent waiting for a liver when resection could have been implemented greatly increases the risk of disease spread that would make both less effective towards a goal of long-term survival.
There may be a future, however, where science identifies markers on a tumor that indicate the disease is ‘more benign’. The cells will still grow, but with treatment the time to metastases might be longer in these tissues, and that might make transplant a more viable option in those patients who are also battling liver conditions such as PSC and would benefit from a liver transplant in the long run.
Live liver donation
In cases outside of cancer and specifically cholangiocarcinoma, live liver donation has provided a path to donation independent from the wait for a liver to present itself through the traditional liver donation channels. Many cholangiocarcinoma patients have caregivers, family members, even friends who would be interested in getting tested to donate part of their liver if there was a precedent for live liver donation with cholangiocarcinoma.
In the current state of transplant and cholangiocarcinoma, Dr. Fung explained that transplant surgeons are very sensitive to the risk and recovery for the donors. We are not yet to the point with survival or supporting data to recommend live liver donation in cholangiocarcinoma. In hepatocellular carcinoma, however, there have been enough studies and successes that there is a protocol for live liver transplantation. Dr. Fung’s hope is that we may get to a similar place in the future with cholangiocarcinoma.
In Klatskin tumor patients, the presiding selection process currently employed for transplant in cholangiocarcinoma is the Mayo protocol. As far as criteria, patients must have small tumors confined to the central bile duct, and, as with hepatocellular carcinoma, many of these patients have underlying liver conditions. The protocol itself instructs first local radiation, chemotherapy, a staging laparotomy to confirm local disease, and finally transplant, often using a live donor.
Final thoughts from Dr. Fung
Dr. Fung had one key recommendation for newly diagnosed cholangiocarcinoma patients, and that was to become educated before making treatment decisions. Understanding the differences between intrahepatic and extrahepatic cholangiocarcinoma helps both doctors and patients choose the appropriate treatment factoring in the possible modalities that could be employed such as transplant.
He also suggested patients make trips to major cancer centers before consenting to intervention. Second opinions are always encouraged, and there is tremendous benefit to patients when they visit the major centers. As with anything, the more experienced the practitioner with the disease, the more likely a positive outcome becomes. With regards to liver transplantation specifically, we'll give Dr. Fung the final word:
“I think the general application of liver transplant for cholangiocarcinoma is still going to be relatively rare, but having said that, there are patients that we think can be transplanted if they have a behavior of the tumor that is favorable.”
For the full interview with Dr. Fung, click on the audio link below, and be sure to tune in next time for the Cancer Patient’s Holiday Survival Guide!