Liver transplantation · Liver cancer
Told your liver cancer is too advanced for a transplant?
For some patients with liver cancer, a transplant is the treatment most likely to cure it. The rules on who qualifies are stricter than for other patients — but they are not a single yes-or-no line. Here is what the criteria and the trials actually say.
The short answer
- A transplant can cure some patients with hepatocellular carcinoma (HCC), because it removes the tumour and the diseased liver together.
- The Milan criteria are the standard: one tumour up to 5 cm, or up to three tumours each up to 3 cm.
- Beyond Milan is not automatically no. Expanded criteria exist, and tumours can sometimes be shrunk back within limits — known as downstaging.
- Tumour size is not the whole story. The blood marker AFP predicts whether the cancer will come back almost as strongly.
- What usually rules transplant out: spread into major blood vessels or outside the liver.
Why a transplant, and why the rules are strict
Most liver cancer grows in a liver already damaged by cirrhosis. Removing only the tumour leaves the diseased liver behind, where new tumours can form. A transplant removes both.
The difficulty is that cancer cells may already have escaped the liver before the operation. After a transplant, the medicines that prevent rejection weaken the immune system — and any cancer left in the body can grow faster. So teams select patients whose cancer is likely to be confined to the liver.
The Milan criteria
In 1996, a team in Milan showed that carefully selected patients did well after transplantation. In their original study of 48 patients, 75% were alive four years later. Their selection rules became the international standard:
| Milan criteria | |
|---|---|
| One tumour | Up to 5 cm |
| Or up to three tumours | Each up to 3 cm |
| And | No invasion of blood vessels, no spread outside the liver |
The current European guideline still uses Milan as the reference standard.
Beyond Milan: the expanded criteria
Milan was designed to be safe, not to be the limit of what is possible. Several teams have since shown that some patients with larger or more numerous tumours also do well:
| Criteria | Limits | What it adds |
|---|---|---|
| UCSF (2001) | One tumour under 6.5 cm, or up to three tumours with the largest under 4.5 cm and a total under 8 cm | Larger tumour size |
| Up-to-seven (2009) | Size of the largest tumour in cm + number of tumours = 7 or less | Among patients beyond Milan but within up-to-seven, without microscopic vessel invasion: 71.2% alive at 5 years |
| AFP model (2012) | Combines tumour size, number and AFP level into a score | Tumour biology, not just size |
| Malatya (Turkey, 2020) | Largest tumour 6 cm or less, AFP 200 ng/ml or less, GGT 104 IU/L or less, and a well or moderately differentiated tumour | Blood markers and tumour grade |
Different centres use different expanded criteria. Being outside the criteria used at one centre does not always mean being outside the criteria used at another.
AFP: why a blood test matters as much as a scan
Alpha-fetoprotein (AFP) is a protein many liver cancers release into the blood. A high AFP often signals a more aggressive tumour.
In the study that developed the AFP model, patients with a score above 2 had a 50.6% risk of the cancer returning within five years. Patients with a score of 2 or less had an 8.8% risk.
Patients with an AFP above 1,000 ng/ml should not be considered for a transplant — unless treatment brings the level down and keeps it down.
Downstaging: shrinking the cancer first
If a tumour is beyond the criteria, treatments applied directly to the liver — such as chemoembolisation or ablation — can sometimes shrink it back within limits. This is called downstaging.
- The European Society of Organ Transplantation recommends that all patients beyond transplant criteria, without spread outside the liver or invasion of major blood vessels, should be considered for downstaging.
- Success is judged using established criteria that combine tumour size and AFP.
- The response must last over time before transplantation — a tumour that shrinks briefly and grows back is a warning sign.
Does downstaging actually work?
The XXL trial is the only randomised trial to test it. Patients whose cancer was beyond Milan but was successfully and durably downstaged were assigned either to a transplant or to continued non-transplant treatment.
| At 5 years | Transplant | No transplant |
|---|---|---|
| Alive | 77.5% | 31.2% |
| Alive and tumour-free | 76.8% | 18.3% |
The trial was small — 45 patients — and closed early, so the results must be read with caution. But the difference is large.
While waiting for a transplant, patients may also receive bridging therapy — the same liver-directed treatments, used to keep the cancer under control. The European consensus recommends considering it wherever feasible. Patients who have received immunotherapy need a washout period of at least four weeks before transplantation.
The living donor question
With a living donor, the transplant can be scheduled — the patient does not wait on a list while the cancer may grow. The international living donor guideline states that patients with cancer beyond the Milan criteria may benefit from a living donor transplant, but there is no agreement on how far the limits can be extended.
There is a second side to this decision. A living donor accepts a real risk (about 1 in 500). The team has to weigh that risk against the recipient's realistic chance of staying cancer-free. When the chance of the cancer returning is very high, an honest team may advise against asking a family member to take that risk.
What usually rules a transplant out
- Spread of the cancer outside the liver.
- Invasion of major blood vessels by the tumour.
- AFP above 1,000 ng/ml that does not come down with treatment.
- A cancer that keeps growing despite treatment.
"Beyond Milan means no transplant."
For many patients, it does. But expanded criteria, downstaging and living donation mean that some patients beyond Milan can still be considered. Ask whether your case has been assessed against more than one set of criteria.
For the general conditions a transplant candidate must meet, see who can have a liver transplant.
Medically reviewed by Prof. Dr. Murat Tuncer
Nephrologist and transplant physician. This guide was prepared by the BookingHospital medical team from international guidelines, consensus reports and clinical trials.
Told your cancer is beyond the limits? Send us your scans
Send your most recent CT or MRI report, your AFP results over time, and details of any treatment you have had. We will tell you honestly whether an evaluation is worthwhile — including when the answer is no.
Medical disclaimer. This article is general information based on published guidelines and studies. It is not personal medical advice, it does not establish a doctor–patient relationship, and it cannot replace assessment by a multidisciplinary liver cancer and transplant team. Criteria differ between centres and are applied to each patient individually.
References
- Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334(11):693–699.
- Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival. Hepatology 2001;33(6):1394–1403.
- Mazzaferro V, Llovet JM, Miceli R, et al. Predicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis. Lancet Oncol 2009;10(1):35–43.
- Duvoux C, Roudot-Thoraval F, Decaens T, et al. Liver transplantation for hepatocellular carcinoma: a model including α-fetoprotein improves the performance of Milan criteria. Gastroenterology 2012;143(4):986–994.
- Ince V, Carr BI, Bag HG, et al. Liver transplant for large hepatocellular carcinoma in Malatya: the role of gamma glutamyl transferase and alpha-fetoprotein, a retrospective cohort study. World J Gastrointest Surg 2020;12(12):520–533.
- Mazzaferro V, Citterio D, Bhoori S, et al. Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial. Lancet Oncol 2020;21(7):947–956.
- Claasen MPAW, Sneiders D, Rakké YS, et al. European Society of Organ Transplantation (ESOT) consensus report on downstaging, bridging and immunotherapy in liver transplantation for hepatocellular carcinoma. Transpl Int 2023;36:11648.
- European Association for the Study of the Liver. EASL Clinical Practice Guidelines on liver transplantation. J Hepatol 2024;81(6):1040–1086.
- Miller CM, Quintini C, Dhawan A, et al. The International Liver Transplantation Society Living Donor Liver Transplant Recipient Guideline. Transplantation 2017;101(5):938–944.
