This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials
1. Patients with cirrhosis and unresectable hepatocellular carcinomas (HCC), either 1 tumor less than 5 cm or no more than 3 tumors less than 3 cm (Milan Criteria), who received orthotopic liver transplants (OLTs) had a 75% 4 year actuarial survival rate and an 83% rate of recurrence-free survival.
2. Patients who’s excised livers showed their HCCs were accurately staged and met Milan Criteria had statistically better survival rates than patients whose tumors where mistakenly staged too low and included in the study.
Original Date of Publication: March 1996
Study Rundown: HCC is a primary liver malignancy that often occurs in patients with chronic liver disease and cirrhosis. The development of cirrhosis and subsequent HCC is closely associated with liver damage by causes such as chronic hepatitis infections, alcohol abuse, or genetic causes. Symptoms of advanced HCC include upper right quadrant abdominal pain, an enlarged abdomen, and weight loss. Screening of known cirrhotic patients using imaging or the alpha-fetoprotein (AFP) blood biomarker now allows many HCCs to be diagnosed early. Prognosis for patients with HCC has been poor, with 5 year survival rates ranging from approx. 20-40%. Retrospective studies have suggested OLT may be a beneficial treatment compared to liver resection, especially for early stage HCC. In this small study of 48 patients with unrespectable, early stage HCC as defined by the size and number of tumors present were given orthotopic liver transplants and followed up to assess survival and recurrence. Results showed patients meeting the criteria of the study as verified by pathological examination of the liver had significantly better 4 year survival and recurrence outcomes than patients with more advanced cancers. The Milan criteria established in this study indicating OLT for early-stage HCC has good prognosis has been used in policy by insurers and organ networks to help select patients most likely to benefit from the procedure. A larger prospective cohort by Duffy and colleagues indicated that HCC at a later stage, defined by UCSF criteria as 1 tumor less than 6.5 cm in diameter, a maximum of 3 total tumors with none greater than 4.5 cm in diameter, and cumulative tumor size less than 8 cm, did not have statistically different 5 year post transplant survival rates.
In-Depth [prospective cohort]: This prospective trial was conducted at The National Cancer Institute in Milan, Italy. Patients with unresectable HCC due to multifocality, inoperable location, or causing hepatic insufficiency were evaluated for inclusion in this study (n = 295). Histologic confirmation of cirrhosis and histologic or serum confirmation of early stage HCC deemed 60 patients eligible for the study. Eligible patients were assessed via hepatic angiography and liver CT scans to confirm there was 1 tumor less than 5 cm in diameter or no more than 3 tumors each less than 3 cm in diameter. Suspicion or evidence of tumor invasion into blood vessels or lymph nodes excluded patients from the study. The study followed 48 patients (38 male, median age 52, age range 39-60) who met these criteria. Cirrhosis was caused by hepatitis infection in 45 patients. Liver function was assessed using Child-Pugh classification. Most patients classified as having intermediate or poor hepatic function (Child-Pugh class A or B) received anticancer treatment prior to transplantation (n = 26). All patients with normal liver function (n = 15) and some with intermediate or poor function (n = 5) were not pretreated with anticancer regimens. Liver transplantations were performed when a compatible liver became available. Tumor stage follow-up using ultrasound, chest radiography, and serum AFP was performed every 3 months after transplantation, abdominal and chest CT scans were performed every 6 months, and radionuclide bone scans were performed every 8 months. Follow-up time for patients in this study was a median of 26 months (range 9-54). Death following transplantation occurred in 8 patients, and 2 patients required retransplantation due to recurrent viral hepatitis. Cancer recurrence occurred in 4 patients at a median of 4 months following transplantation. For all patients who underwent liver transplantation, the survival rate at 4 years was 75% and recurrence-free survival was 83%. Survival was statistically not affected by patient age, sex, preoperative anticancer treatment, or common markers of chronic liver disease (T stage, number of tumors, serum AFP levels, and presence of a capsule). Pathological examination of excised livers indicated 13 patients (27%) had tumors that did not meet the study criteria regarding size/number of tumors. For patients who were preoperatively staged accurately, the 4 year overall survival rate was 85% and recurrence freed survival rate was 92%. Those mistakenly understaged had 4 year overall and recurrence free survival rates of 50 and 59%, respectively.
Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis. New England Journal of Medicine. 1996 Mar 14;334(11):693–700.
Duffy JP, Vardanian A, Benjamin E, Watson M, Farmer DG, Ghobrial RM, et al. Liver Transplantation Criteria For Hepatocellular Carcinoma Should Be Expanded. Ann Surg. 2007 Sep;246(3):502–11.
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