The ongoing quest to find the appropriate patients to transplant with hepatocellular carcinoma: Milan to san Francisco to Toronto and beyond
Authors: David C. Mulligan
Journal: Hepatology (2016)

Potential conflict of interest: Nothing to report. See Article On Page 2077 Unfortunately, livers do not grow on trees (not that we would use them if they did), and the availability of suitable donor organs for the purposes of liver transplantation (LT) has desperately fallen short of the growing demand for patients with end‐stage liver disease around the world.1 Ever since we began using the Model for End‐Stage Liver Disease (MELD) for liver allocation in February 2002, we have struggled to define which patients should receive this scarce resource and at what priority (MELD exception) they should be placed when competing with patients who suffer from hepatocellular failure and manifest the wait‐list mortality calculated by their MELD score. Transplant caregivers have long struggled to identify the optimal priority to place patients who have cirrhosis and HCC and are not reasonable candidates for liver resection with a curative intent.5 Sapisochin et al.,6 in this issue, argue that the reliance of selection of patients who will have a good outcome, especially long term (out to 10 years post‐LT), should not be defined by tumor size and number as we currently utilize. These researchers recommend adding tumor histology from biopsy, cancer‐related symptoms in the patient, and alfafetoprotein (AFP) levels to further support the appropriate use of scarce livers for patients who would have poor outcomes without transplantation. Please note that a great part of the success of their long‐term patient survival has been the diligent and aggressive surveillance of their recipients posttransplant, using surgical resection, ablation, chemotherapy, sorafenib, or stereotactic body radiation therapy when any recurrences were detected.7 The importance of this topic follows many large, single‐center, as well as multicenter, reports from around the world demonstrating that tumor biology, as measured by more than just size and number without extrahepatic disease, is more predictive of successful outcome and prudent utilization of LT.5 Recently, even Vincenzo Mazzaferro himself, who originally described the Milan criteria that we so fondly use to generate MELD exception points for patients with HCC in the United States, has modified his recommendations to consider measurements reflecting tumor responsiveness to bridging or downstaging therapies and expected survivals of greater than 50% at 10 years, rather than 5 years, as the goal.10 His new paradigm focuses on HCC tumor biology, rather than the reliance of size and number, reflecting adequacy as surrogates. His recommendations were to assess patients with cirrhosis and HCC at four time points, at presentation, at least 3 months during tumor monitoring/stabilization, progression during treatment, and at the end of treatment. Patients with complete responses and single lesions have very low dropout and should not receive additional MELD exception points. Patients who have responded favorably to treatment with complete response should stay with their native MELD, and only those who show more‐aggressive tumor biology with recurrence after treatment or incomplete treatment response should have the best transplant utility. In their article, Sapisochin et al.6 stress three major themes that I think are shared by much of the recent literature, the first of which is the incomplete agreement between pretransplant imaging and posttransplant pathology. Harper et al.5 examined the Organ Procurement and Transplantation Network explant pathology form data from over 4,500 forms from April 2012 to December 2014, and found that fewer than 1% of patients received no pretransplant bridging treatments or had imaging that did not suspect HCC pretransplant. They found that of 4,550 explant forms, 3,078 (67.6%) had met all the HCC exception criteria for T2, whereas 1,339 (29.4%) did not meet criteria. Approximately 95% had undergone pretransplant ablative therapies for HCC and many had reported tumor sizes of zero (46.3%), which is out of criteria. Evidence of HCC was found in 4,242 (93.2%) at explant, and of the 2,642 within Milan T2 on imaging, 601 (22.7%) were exceeding criteria, 14.7% were T1, and 6.8% were with no evidence of HCC, whereas 55.8% were actually within Milan T2 criteria. Despite significant efforts by combined communities of radiologists, hepatologists, and surgeons, a significant inability to accurately stage HCC for patients undergoing LT continues around the world.11 The second very important theme from the Extended Toronto Criteria paper6 is the significance of monitoring AFP levels from the time a patient is evaluated, through any bridging or downstaging treatments, and to the point of transplantation. The researchers propose that patients who manifest AFP levels greater than 500 ng/mL had not only a more‐significant dropout rate on the wait list compared to those with AFP less than 500 ng/mL (49.3% vs. 10.7%), but also a significantly lower patient survival both from transplant at 1, 5, and 10 years as well as from the time of listing. (Patient survival with AFP at time of transplant was60%, 31%, and 28% in those with AFP ≥500 ng/mL vs. 90%, 76%, and 68% in those with AFP <500 ng/mL.) These effects of AFP are observed in both the patients transplanted within Milan criteria and those outside Milan criteria. Several other researchers are reporting similar findings as to the effects of AFP levels and the relationships to relaying tumor biology.5 Thus, new modeling is being developed to utilize AFP values for appropriate allocation algorithms in patients with HCC. The third important point made by Sapisochin et al. is the value of liver tumor histology. The researchers argue that despite the low complication rate of bleeding, sampling error, and tumor tract seeding, obtaining a preoperative biopsy was 90% effective in excluding patients with poorly differentiated HCC.6 There was no discussion regarding mixed HCC/cholangiocarcinoma tumor patients; however, identification of patients with poor histology was absolutely helpful to indicate patients who will have poor outcomes with or without LT. More important, having lesions that were determined preoperatively to be beyond Milan criteria only showed that 8% had poorly differentiated lesions and further underscores the importance of attempting to obtain tumor biopsies to exclude patients who would have poor outcomes. Their tumor biopsy seeding risk was 1.9%, consistent with other studies.9 Although risk is not insignificant for patients with advanced liver disease and portal hypertension, most patients with HCC tend to have relatively low calculated MELD scores at the time of diagnosis and risks are lower for many of them. The risk of bleeding is actually reported to be between 0.1% and 0.01%, but can be serious. Tumor seeding can usually be treated locally and rarely reduces survival.10 The only difficulty I can see with the Extended Toronto Criteria is the subjective aspects relating to patients with symptoms of their tumors. They concurred with the Barcelona group and others that patients with constitutional symptoms attributed to their tumors had a significantly shorter median survival of 4.9 months compared to 23.7 months in those without symptoms.6 Patients with cirrhosis and advanced liver disease also tend to have many constitutional symptoms that make it quite difficult to differentiate from symptoms that may occur related to malignancy. Although I recognize the validity of poor prognosis for those tumor patients exhibiting symptoms, I find it difficult to accurately attribute symptoms in a specific enough manner that would confidently exclude someone from transplant in patients who have advanced cirrhosis and high calculated MELD scores. Granted, many of the HCC exception patients we are currently seeing tend to have much lower calculated MELD scores and would therefore be much easier to discriminate based upon constitutional symptoms, especially in United Network for Organ Sharing regions where transplantation occurs at much lower MELD scores than I experience. In the future, as allocation improves for patients with HCC, I would surmise that differentiation by symptom manifestation may prove more difficult given that many may have more symptoms of liver disease confounding potential symptoms of their HCC. In conclusion, I believe the important themes from the article by Sapisochin et al.6 are resonating in the world literature. It is certainly time for us collectively to modify and improve allocation algorithms for patients with HCC according to many of these principles in order to select the best candidates for LT, the best timing, and the most appropriate priority to assign them as they compete with those who typically have much higher calculated MELD scores with much higher risk of death on the wait list. The Extended Toronto Criteria, like the Milan Adaptive Approach,10 are growing experiences that show us we can successfully transplant patients with excellent long‐term outcomes who have tumors beyond Milan stage II as long as we carefully select and watch the tumor behavior and follow additional parameters that are easy to measure.