Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis

Incomplete

Mazzaferro. "Liver Transplantation for the Treatment of Small Hepatocellular Carcinomas in Patients with Cirrhosis". NEJM. 1996. 334(11):693-699.
PubMed • Full text • PDF

Clinical Question

Among cirrhotic patients with early, but unresectable hepatocellular carcinoma, is liver transplantation a viable treatment modality?

Bottom Line

Orthotopic liver transplantation is a viable treatment option for cirrhotics with unresectable hepatocellular carcinoma, and identifies criteria for patients most likely to benefit from transplantation. 4-year survival in this series was 75%, recurrence-free survival was 83%.

Milan Criteria

• single lesion ≤5 cm
• ≤ 3 separate lesions, all ≤ 3 cm
• absence of vascular invasion,
• absence fo regional nodal/distant metastasis

Major Points

Historically, orthotopic liver transplantation (OLT) was not considered a viable approach for cirrhotics with hepatocellular carcinoma (HCC), due to high rates of perioperative mortality, disease recurrence, and long term survival. However, observation that patients with incidentally discovered HCC were found to have equivalent long term survival and substantially lower recurrence rates led to speculation that transplant would benefit early, but otherwise unresectable HCC.

The Milan Criteria was the first series to define criteria for patients likely to benefit from OLT. This observational study demonstrated a 75% 5 year survival with 83% recurrence free survival at 4 years.

Guidelines

"American Society of Transplantation and American Association for the Study of Liver Diseases 2013 Practice Guidelines:" [1]

• OLT is an effective therapy for hepatocellular carcinoma within the Milan criteria (1-A)
• OLT may be an option for hepatocellular carcinoma in excess of the Milan criteria in combination with tumor downstaging to Milan criteria (2-C)

Design

• Prospective, observational single center study of 295 patients with unresectable hepatocellular carcinoma (HCC)
• Single center at the Instituto Nazionale Tumori from January 1991 to December 1994
• 60 patients eligible for inclusion as early stage tumors and eligible for transplant
• 48 patients transplanted during the study time period

Population

Inclusion Criteria

• Unresectable tumor defined by location, multifocality, or due to presumed hepatic insufficiency of the residual hepatic segment
• Single tumor
  • < 5cm OR
  • ≤ 3 tumors ≤ 3cm in size
• HCC confirmed by biopsy or alpha fetal protein measurement > 300ng/mL

Exclusion Criteria

• Clinical suspicion for hematologic or lymphatic metastasis

Baseline Characteristics

• 48 patients transplanted
  • Child Pugh
    • A 12
    • B 21
    • C 15
• Oncologic treatment determined by child’s pugh category at listing
• 38 men, 10 women
• Median Age 52 (39-60)
• Etiology of Cirrhosis

  • 11 Hepatitis B Virus (HBV)
  • 32 Hepatitis C Virus (HCV)
  • 2 HBV & HCV
  • 3 Other
• T Stage
  • T1/2 33
  • T3/4 15
• Tumor nodules
  • 1 25
  • ≥2 25
• Capsule
  • Present 16
  • Absent 30
  • Unknown 2
• Reason unresectable
  • Advanced cirrhosis 36
  • Multifocal tumor 7
  • Central tumor 5

Interventions

• Child Pugh A/B (33) received pretreatment therapy
  • hepatic artery chemoembolization (n = 26)
    • iodized oil + doxorubicin (n = 14)
    • iodized oil + mitoxatrone (n = 12)
  • percutaneous alcohol ablation (n = 1)
  • prior hepatic resection (n = 1)
  • patients not treated (n = 5)
• Child Pugh C (15) received no treatment
• No post transplant chemoradiotherapy unless tumor detected

• Surgical technique
  • Venovenous bypass 22/48 (45%) patients
  • IVC preservation 26/48 (55%) patients

• Immunosuppression regimen: cyclosporine, azathioprine, corticosteroids
  • azathioprine stopped after 1 month
  • corticosteroids stopped after 6 months
  • cyclosporine maintenance
  • rejection episodes treated with corticosteroids, tacrolimus for refractory cases

Outcomes

Primary Outcomes

• Median followup 26 months (9-54)
• Acturial survival at 4 years 75%
• Recurrence-free survival at 4 years 83%

• 2 retransplantation for recurrent HBV/HCV
• 4 recurrent HCC
  • Median time to recurrence 3 months

• 8/48 deaths at followup
  • 3 perioperative
  • 2 recurrent cancer

Secondary Outcomes

“Comparisons are Clinical Concordance with Pathologic Staging vs. Upstaged”

• 35/48 (73%) of explanted livers were concordant with preoperative inclusion criteria (single tumor < 5cm or < = 3 tumors <= 3cm)
• 13/48 (27%) did were clinically understaged compared to pathologic examination

Actuarial 4 year survival

85% vs. 50%, p = .01

Disease free survival

92% vs. 59%, p = .002

Subgroup Analysis

“Comparisons are Preoperative Chemoembolization vs. No Treatment”

4 Year Survival

79% vs. 69%, no significant difference reported

Disease free survival

87% vs. 78%, no significant difference reported

Adverse Events

• 1/60 death awaiting transplant
• 11/60 listed but did not receive transplant during study period

Criticisms

• Subsequent analysis argue the Milan Criteria is too stringent, arguing that larger tumors can be safely resected with equivalent outcomes
• This initial study did not address this criteria in the context of tumor downstaging. Prospective evidence indicates this may be an appropriate strategy .
• OPTN Guidelines as of April 11, 2022 define a downstaging protocol if candiates meet one or more of the following [2]
  • 1 lesion > 5cm, but ≤ 8cm
  • 2-3 lesions that meet all of the following
    • ≥1 lesion > 3cm AND each lesion ≤ 5cm AND total diameter of all lesions ≤ 8cm
  • 4-5 lesions each < 3cm, and a total diameter ≤ 8cm

Funding

• No specific funding

Further Reading

https://www.wikijournalclub.org/wiki/WikiJournalClub:Administrators