MELD score component, calculation and mortality prediction
1. Introduction
Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide, accounting for more than 500,000 deaths annually. Major risk factors include chronic liver disease and liver cirrhosis due to hepatitis B and C viral infections, alcoholic liver disease and non-alcoholic steatohepatitis (NASH). Surgical resection and liver transplantation are the only potentially curable options for patients with HCC. While surgical resection is the treatment of choice in patients with good hepatic function, it is contraindicated in those with moderate to severe cirrhosis (Child class B or C), leaving these patients with liver transplantation as the only option. Moreover, transplantation is the optimal treatment even for small, otherwise resectable disease. This is a reflection of a number of factors. Liver transplantation will most likely result in a microscopically negative resection, which is the most effective oncologic treatment. Most HCCs are multifocal especially in the background of cirrhosis, though pre-neoplastic lesions may not be visible on perioperative evaluation; they are likely to continue to evolve into new primary HCCs. Furthermore, transplantation eliminates cirrhosis and restores normal hepatic function. However, limited organ availability mandates the restriction of liver transplantation to patients with early stage tumors who are not candidates for resection.
2. Organ allocation
In an effort to prioritize liver transplant candidates according to the highest short-term risk of mortality from end stage cirrhosis, the model for end-stage liver disease (MELD) scoring system was implemented in 2002 (table 1). To impart more urgent access to liver transplantation for patients with small HCCs, additional points within the scoring system were allotted to these patients. This is done to equilibrate their risk of death in comparison with the mortality of end-stage cirrhosis. The original scoring exception included lesions smaller than 2 cm, which resulted in an over distribution of donor livers to patients with HCC (with many expected small tumors turning out not to be HCC on explanted pathology). Therefore, the scoring exception was modified later by reducing the upgrade for Stage II tumors and eliminating it for Stage I tumors. Using the American Liver Tumor Study Group Modified TNM staging system, current UNOS guidelines do not allow upgrading of candidates with Stage I disease, irrespective of biopsy confirmation; only candidates with Stage II HCC disease are upgraded on the waiting list to a MELD score of 22 (equivalent to a 15% probability of candidate death within 3 months) with the intent to shorten their waiting time. From 2002-2007 in UNOS database, patients with an “HCC MELD-exception” had similar survival to patients without HCC.
MELD score component, calculation and mortality prediction Serum bilirubin (mg/dL) Serum creatinine (mg/dL) INR MELD = 3.8[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.6[Ln serum creatinine (mg/dL)] + 6.4 * If a patient has had 2 or more hemodialysis treatments or 24 hours of CVVHD in the week prior to the time of the scoring, Creatinine will be set to 4 mg/dL |
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MELD score - <9 - 10–19 - 20–29 - 30–39 - >40 |
Mortality in 3 months 1.9 % 6.0 % 19.6 % 52.6 % 71.3% |
3. Criteria for transplantation
Retrospective study by
CHILD – PUGH SCORE | |||
Clinical and laboratory parameter |
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||
1 | 2 | 3 | |
Encephalopathy (grade) | None | 1-2 | 3-4 |
Ascites | None | Slight | Moderate |
Albumin (g/dL) | > 3.5 | 2.8-3.5 | < 2.8 |
Prothrombin time prolonged (sec) | 1-4 | 4-6 | 6 |
Bilirubin (mg/dL) · For primary biliary cirrhosis |
< 2 < 4 |
2-3 4-10 |
> 3 > 10 |
Class A = 5–6 points; Class B = 7–9 points; Class C = 10–15 points. Class A: Good operative risk Class B: Moderate operative risk Class C: Poor operative risk |
The strict application of the Milan criteria by UNOS for MELD upgrades allocation disadvantages patients with HCC with tumor profiles exceeding the criteria’s maximal size or multifocal parameters but in whom favorable outcomes after liver transplantation have been demonstrated. There is an ongoing debate within the liver transplantation community regarding whether to expand indications for liver transplantation as primary therapy for HCC. For patients with HCC disease beyond Milan criteria in whom there is no macroscopic evidence of vascular invasion or extrahepatic spread, the survival rates after liver transplantation are generally comparable with patients transplanted for disease within the criteria. Most groups report a 5-year survival of more than 50% in patients transplanted for HCC beyond Milan, which many investigators have argued is the minimum acceptable survival rate. In 2001
Group from Edmonton have study Total Tumor Volume (TTV) in patients with HCC who had liver transplant based on Milan or UCSF criteria in 3 centers and they found TTV < 115 cm3 has lower recurrence rate than TTV > 115 cm3. In same study they also found that patients beyond Milan but within TTV < 115 cm3 had survivals similar to those of patients within Milan. On the contrary, patients with TTV >115 cm3 demonstrated lower survival than those within TTV <115 cm3 when pathology (5-year: 47% versus 79%, P < 0.001) and radiology staging (5-year: 53% versus 76%, P < 0.1) was used.
Milan criteria: - Single lesion ≤ 5 cm or - ≤3 nodules each ≤ 3 cm Without vascular invasion. |
"UCSF’’ expanded criteria: - Single lesion ≤ 6.5 cm or - ≤ 3 nodules with the largest tumor ≤ 4.5 cm and total tumor diameter ≤ 8 cm Without vascular invasion. |
4. Pre-transplant treatment for HCC
The major limitation for liver transplantation as therapy for early-stage HCC is the insufficient number of donor livers. There is always a waiting period between candidate listing and transplantation. If the waiting period extends over a sufficient length of time, the tumor will grow and eventually hinders transplantation. In a study by
5. Percutaneous ablation therapy
5.1. Bridging therapy
Bridge therapy is used to decrease tumor progression and the dropout rate from the liver transplantation waiting list. It is considered for patients who meet the transplant criteria. A number of studies have investigated the role of locoregional treatment as a bridge to liver transplantation in patients on a waiting list. These studies included radiofrequency ablation (RFA), transarterial chemoembolization (TACE), surgical resection, conformal radiation therapy, and sorafenib as “bridge” therapies.
5.1.1. TACE
The rationale for using TACE as a bridge therapy prior to OLT is to control tumor growth while the patient awaits an organ. In addition, TACE could cause significant tumor necrosis, which may reduce tumor dissemination, making it a potential neoadjuvant therapy. TACE can also be used to learn more about the natural history and behavior of a particular tumor prior to liver transplantation.
Although pre-liver transplantation TACE does not influence post-LT overall survival and disease-free survival, it remains indicated in context of clinical trial when the period on the waiting list is more than 6 months.
5.1.2. Percutaneous ablation therapy
Patients with small tumors can have ablation either by percutaneous ethanol injection, radiofrequency or any other technique. Pre-transplant RFA ablation for HCC as a strategy to reduce dropout has been addressed in view studies. More than 80% of patients were in the Milan criteria with approximately 1 year on the waiting list. The dropout rate ranged from 0 to 14%. In a nonrandomized series from Toronto of 74 patients bridged using ablation compared with 79 non-bridged patients, the analysis of dropout for tumor progression identified a difference (p < 0.005) that became apparent only with prolonged waiting time superior to 300 days.
The main concern with this approach is seeding due to tumor puncture as has been reported for diagnostic biopsy. However, puncture-related seeding is usually a case of poorly differentiated tumors and to peripheral tumors that cannot be approached through a rim of non-tumoral liver.
In conclusion, due to small size of these studies and the heterogeneous nature of the study populations, as well as the absence of randomized clinical trials evaluating the utility of bridge therapy for reducing the liver transplantation waiting list dropout rate, limit the conclusions that can be drawn. Therefore, if liver transplantation can be done without significant delay (i.e. within 6 month) would the optimum. However, in patients whose waiting time is predicted to be prolonged, an RCT of TACE and/or ablation as bridging therapy to decrease dropout of transplantation could be justified.
5.2. Liver resection
Advances in liver surgery have significantly improved the safety of resection. Resection can be used as a treatment for HCC prior to liver transplantation in three different settings. First, resection can be used as a primary therapy, and liver transplantation reserved as a ‘‘salvage’’ therapy for patients who develop recurrence or liver failure. A second justification for resection prior to transplantation is that it helps refine the selection process. Resection, indeed, gives access to detailed pathological examination of the tumor and the surrounding liver parenchyma. Important prognostic information can be obtained from the entire resected tumor, including differentiation (which proved to be heterogeneous within the tumor), satellite nodules, microvascular invasion, and capsular effraction. As a result, resection may help deny transplantation in patients with tumors apparently within the Milano criteria but with histological features of especially poor prognosis (undetected macrovascular invasion in particular). On the other hand, resection may help decide transplantation in patients with tumors slightly outside the Milano criteria but with histological features of good prognosis. Third, resection can be used as a ‘‘bridge’’ therapy for patients who have already been enlisted for liver transplantation. Resection as the first line treatment for patients with small HCC with preserved liver function, followed by salvage transplantation only for recurrence or liver failure is an attractive option. Initial resection with negative margins, gives rapid access to an effective therapy, without the need for a donor, and offers 5-year survival rates exceeding 50% with a good quality of life. The main obstacle to this strategy is the risk of ‘‘loss of chance’’ in case of rapid and extensive recurrence not amendable to salvage liver transplantation. At the time of recurrence, salvage liver transplantation is only applicable in patients with a tumor within the Milan criteria. Initial data showed that patients with HCV infection who developed recurrence after partial resection had multifocal tumors and/or vascular invasion at the time of recurrence.
Although limited resection appears to be sufficient in this setting, it is associated with increased risk of post resection liver failure and is only appropriate for patients with peripheral tumors and Child A cirrhosis and no portal hypertension. As disadvantage for this approach the subsequent liver transplantation would be more difficult due to increase operative time and blood loss. The use of laparoscopic approaches for peripheral tumors may further contribute to expand this strategy by minimizing technical difficulties during the transplant procedure.
5.3. Tumor dowenstaging
The role of downstaging of tumors before liver transplantation has been explored. Downstaging is done using HCC directed therapy that aims at reducing the size and/or number of HCC lesions.
6. Living donor transplantation
Efforts to address the large waiting list of liver transplantation candidates and to decrease the dropout rate have included several strategies such as living donor LT, domino LT, split LT, the use of extended criteria donors, and donors after cardiac death. Living donor LT appears to be an effective option for patients with HCC within the Milan criteria, essentially equivalent in terms of survival to OLT, and it is cost effective if waiting times exceed 7 months. There are few data to support the use of living donor LT for patients with HCC who exceed the Milan criteria, although its use for this purpose is becoming increasingly common.
7. Immunsupression
Immunsupresion is used post liver transplantation to reduce graft rejection but, especially in transplantation for HCC, is associated with a risk of tumor growth. While results of liver transplantation including survival and rates of rejection were dramatically improved in cyclosporine treated patients compared with "historical controls", a high incidence of neoplasm and its aggressive phenotype were found to be due to cyclosporine and its activation of transforming growth factor-beta (TGFβ).
On the other hand, the calcineurin-independent immunosuppressive agent sirolimus, a binder of mTOR, inhibits tumor growth in cell lines, and it inhibits primary and metastatic tumor growth
Several retrospective reports suggest a lower risk of post-transplant tumor recurrence in patients with HCC with the use of sirolimus as compared to other types of immunosuppressive agents (such as the calcineurin inhibitors tacrolimus and cyclosporine). However, these reports are limited by small size and uncertainty as to whether the observed benefits were due to a specific antitumor effect or an impact on liver transplant in general.
8. Surveillance
There is no consensus as to the optimal approach for post-transplant surveillance. Guidelines from the National Comprehensive Cancer Network (NCCN) suggest the follow up after liver transplant with triphasic CT every 3-6 months for 2 years, then every 6-12 months. AFP levels every 3 months for 2 years, if initially elevated, then every 6-12 months.
9. Survival
There is a clear survival benefit and low recurrence rate after transplantation for hepatocellular carcinoma. When surgeons adhere to Milan criteria, 5-year survival rates after transplantation range from 70% to 80%, and tumor recurrence rates are approximately 10%. Since the initial report by Yao and colleagues that demonstrated acceptable survival rates using the UCSF criteria (90% 1-year survival rates and 75% 5-year survival rates) and showed no survival deference from Milan criteria in 1,3 and 5 years, long-term survival need to be further identified.
10. Recurrence
Tumor recurrence remains a main limitation to the long-term survival of patients following liver transplantation for HCC. While the majority of patients recur in the first two years after transplantation, late recurrence is not infrequent. Most common sites of recurrence are liver graft, lung, bone, abdominal lymph nodes, adrenal glands and peritoneum. The incidence of recurrent HCC following transplantation has been reported to vary, ranging from 6-56%. However, in cases in which the Milan selection criteria were adopted, risk of recurrence decreased to 10–15% at 5 years. While several recipient and tumor specific factors are prognostically important, primary tumor size, number of lesions, grade of tumor and presence of vascular invasion have been noted to be the most significan clinical risk factors for both recurrence and survival. De-novo tumor development from recurrent hepatitis and cirrhosis in the liver graft can occur, however presence of microscopic foci of disease in lymph nodes or distant organs at the time of transplantation, as well as hematogenous or peritoneal tumor dissemination during transplantation, are mechanisms attributed to disease recurrence. Recurrent disease following liver transplantation for HCC may involve an extrahepatic site in 10-43% of patients.
Successful surgical salvage has been reported for intrahepatic and/or confined extrahepatic HCC metastases. In a study by
Reports of repeat liver transplantation as a treatment of recurrent intrahepatic HCC are limited to a few very select case series and is not the standard of care.
Another potential approach to intrahepatic HCC recurrence is the utilization with TACE and RFA.
Systemic therapeutic options for recurrent HCC are limited. While cytotoxic agents have traditionally had marginal effect in the treatment of HCC, systemic therapy with molecular targeted therapy has been shown to prolong survival in recent trials. Sorafenib, a multi-targeted kinase inhibitor, demonstrated a significant overall survival benefit in patients with advanced or metastatic HCC when compared with placebo in two separate Phase 3 trials. These studies were carried out in patients who presented initially with advanced disease (mostly liver confined disease), and did not include patients who had previously undergone curative-intent therapy, such as surgical resection or liver transplantation. A number of retrospective studies have reported acceptable safety data for sorafenib in liver transplant patients, with very few unexpected toxicities or interaction with immunosuppressive medications. The numbers in these studies are small, and there is clearly a need for a prospective trial to fully assess the potential survival benefit of sorafenib in this setting.
Radiation therapy is another option for patients with recurrent unresectable HCC. Three dimensional conformal radiation, as well as stereotactic body radiation therapy and radioembolization, have been utilized in the treatment of primary unresectable HCC. In addition, radiation therapy is a treatment option for symptomatic palliation of extrahepatic disease.
Abbreviation
HCC Hepatocellular carcinoma
HIF-1α Hypoxia-inducible factor 1, alpha
MELD Model for end-stage liver disease
RFA Radiofrequency ablation
PEI Percutaneous ethanol injection
TACE Transarterial chemoembolization
TGFβ Transforming growth factor-beta
TNM Classification of Malignant Tumors (Tumor, lymph Node, Metastasis)
VEGF Vascular endothelial growth factor
UNOS United Network for Organ Sharing
UCSF University of California, San Francisco
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