The debate about giving donor organs to patients of advanced age has always been present in liver transplantation. Many minds have wrestled with this topic. A review by Keswani et al.1 concluded that although advanced age is a negative risk factor, advanced age alone should not exclude a patient from liver transplantation. The Alberta hepatocellular carcinoma (HCC) algorithm for liver transplantation,2 a modification of the Barcelona criteria3 for age, states that a liver transplant candidate should be younger than 70 years of age and that a patient between the ages of 65 and 69 years should have no comorbidities. Aloia et al.4 showed that older recipient age is associated with lower posttransplant survival rates. These investigators developed an older recipient prognostic score using 5 factors: ventilator status, diabetes mellitus, hepatitis C virus, creatinine levels ≥ 1.6 mg/dL, and combined recipient and donor age ≥ 120 years. When the older recipient prognostic score was >2 points, the 5-year survival rate was less than 50% (typically a barrier indicating a futile liver transplant). Lipshutz et al.5 agreed that when other risk factors for mortality are controlled in older recipients, age itself should not be used to limit liver transplantation.
In this issue of Liver Transplantation, Schwartz et al.6 join the debate and point out the difficult justice-versus-utility decision that all liver transplant selection committees face on a regular basis in granting a donor liver to an elderly patient. A justice argument favors giving a liver transplant to a healthy elderly person because that person will have better survival with the liver than without it; a utility argument favors giving a donor liver to a younger patient so that the organ will be used longer.
Because of the possibility of HCC recurrence, transplantation for HCC engenders a similar justice-versus-utility decision to perform or not perform transplantation for a patient with HCC. By addressing HCC in the setting of advanced age, Schwartz et al.6 have brought into focus 2 controversial topics—liver transplantation for the elderly and liver transplantation for HCC—within a single study.
Debate has raged around HCC since February 2002 when Model for End-Stage Liver Disease (MELD) exception points started to be granted to patients with HCC in the United States.7 Even though the worldwide incidence of HCC has tremendously increased,8 the number of patients involved is only a small percentage of the total. Tiong and Maddern9 reported that only 20% of cases of HCC are amenable to curative resection or liver transplantation. However, the adoption of the MELD allocation system has led to a 6-fold increase in the number of patients undergoing transplantation for HCC together with a much higher survival rate for patients with HCC versus patients undergoing transplantation for other etiologies.7, 10 Modifications were made to the MELD score after its institution with the goal of making the allocation system fair to patients without HCC.11 Still, the argument persists that liver transplantation for patients with stage II HCC and Child A cirrhosis results in a very low survival benefit and may not be the optimal use of scarce donor livers.12
Now, maybe by combining these 2 controversial topics, advanced age and HCC, we can develop recommendations that balance both justice and utility for the elderly patient with HCC who is healthy enough to receive a liver transplant.
Schwartz et al.6 used data from the United Network for Organ Sharing to examine overall transplant survival for recipients ≥ 70 years of age who received MELD exception points for HCC. The overall posttransplant survival of elderly patients with HCC was compared to the survival of younger cohorts. The study revealed a decreased overall post–liver transplant survival rate in the older recipients versus the younger cohorts, regardless of the HCC diagnosis. The difference in survival emerged after 18 months and became accentuated 5 years after transplantation when the relative difference between the older and younger recipients approximated 15%. However, a decrease in survival was noted in the younger cohort with an HCC diagnosis versus the younger recipients with a non-HCC diagnosis. Schwartz et al. found that the older patients with HCC fared no worse than the older patients with other indications for transplantation, and they concluded that as long as chronological age does not eliminate an individual's transplant candidacy, a tumor diagnosis should not prejudice the granting of MELD exception points for recipients otherwise falling within the accepted criteria for transplantation.
Knowing that this issue concerns only 0.91% of the population in Schwartz et al.'s study6 and 0.94% of the population during the year following Schwartz et al.'s study, we might lose enthusiasm for this discussion. However, our enthusiasm returns when as care providers we must counsel our ≥70-year-old patients and frame the question from their point of view. These patients could not care less that their survival is lower than the survival of a younger group or that their survival is the same as the survival of other members of their age group who have different etiologies of liver disease. Their question is what is their survival after liver transplantation in comparison with other options available to them. Depending on the patient's Child-Pugh classification and tumor characteristics, the options to consider for a person ≥70 years old with HCC who meets the transplant criteria for adequate cardiac, pulmonary, renal, and health status are as follows: (1) do nothing, (2) undergo ablation therapy, (3) undergo liver resection, or (4) undergo liver transplantation. How should this person be advised?
Few recent studies have reported on the option of doing nothing in the elderly patient with HCC. Massarweh et al.13 reported that elderly patients with HCC (76.2 ± 6.2 years of age) who underwent no treatment had survival rates no different from those of patients treated with only radiofrequency ablation (RFA). These authors reported that the lack of difference in the results might have been due to poor patient selection; that is, the patients who underwent RFA might have had excessive tumor burdens or higher medical risks than the patients who received no treatment. Despite the lack of evidence, most clinicians would advise ablation therapy, surgical resection, or liver transplantation for a 70-year-old or older patient with end-stage liver disease and HCC who otherwise meets the transplant criteria.
Regarding ablation therapy, 5 studies14-18 have assembled adequate documentation for tumor selection criteria, Child-Pugh status, age, and 3- and/or 5-year survival that warrants review (Table 1). All patients in these studies were more than 65 years old, with most being more than 70 years old. The percentage of males ranged from 52.9% to 77.0%. All the patients had similar tumor characteristics comparable to the Milan criteria and were amenable to ablation therapy, and they had Child-Pugh stage A/B liver disease.18 Almost all treatment involved RFA. The 3-year survival rates ranged from 77.0% to 82.0%, and the 5-year survival rates ranged from 58.0% to 65.4%. The 3- and 5-year tumor recurrence rates ranged from 49% to 78.1% and from 56% to 86%, respectively. The rate of complications from RFA ranged from 2.2% to 2.8%. However, in 2 other studies with no tumor criteria restrictions,13, 19 for patients with several tumors outside the Milan criteria,18 the 3-year survival rates with percutaneous treatments (including RFA) ranged from 39.2% to 53.4%, and the 5-year survival rates ranged from 20% to 34.2%. Thus, when a physician is counseling a patient ≥ 70 years of age whose liver status is Child-Pugh A/B, who has HCC meeting the Milan criteria, and who is amenable to ablation therapy and is healthy enough to be considered for liver transplantation, the physician could inform the patient that RFA would offer 3- and 5-year survival rates equaling or exceeding those offered by liver transplantation (Fig. 1). This is in line with the information reported by Schwartz et al.,6 who report that a patient ≥ 70 years of age with an HCC exception who undergoes liver transplantation has an expected 3-year survival rate of 66.98% and an expected 5-year survival rate of 55.49%.
|Study||Age (Years)/ Population||Male Sex (%)||HCC Criteria||Child-Pugh Class||Patients (n)||Main Treatment||3-Year Survival (%)||5-Year Survival (%)||Complications (%)|
|Takahashi et al.14||≥75/Japanese||52.9||≤5 tumors, 1 tumor of any size||A/B||107||RFA||82.0||61.0||2.8|
|Tateishi et al.15||>68/Japanese||Bilirubin < 3 mg/dL, Platelet count ≥ 5 × 104/mm3, Prothrombin time ≥ 50%||160||RFA||79.2||2.5|
|Kao et al.16||>65/Chinese||55.7||HCC < 5 cm, ≤3 tumors||A/B||158||RFA||65.4|
|Shiina et al.17||68.3 ± 8.6/ Japanese||64.1||HCC < 5 cm, ≤3 tumors||A/B||1170||RFA||80.5||60.2||2.2|
|De Giorgio et al.18||>65/Dutch||77.0||HCC < 5 cm, ≤3 tumors||A/B||102||RFA||77.0||58.0|
In some liver transplant programs, surgical resection has at times taken a back seat as a form of treatment for HCC. This is highlighted by the even more controversial topic of hepatic resection for elderly patients with HCC.20 This form of treatment should be reconsidered because over the last 20 years, there has been a continuous improvement in survival after HCC resection, even in older patients.21 A tumor that is resectable must be present together with adequate functional liver reserve for sustaining life (found mostly in patients with Child-Pugh status A but sometimes in patients with Child-Pugh status B); this makes this treatment subset of elderly patients with HCC even smaller than the other subgroups.22 There is evidence that this subgroup may be increasing in some countries.20 The survival rates of elderly patients with HCC who are able to undergo surgical resection has been reported to be 58% at 3 years and 46% at 5 years.20 Another study has reported similar survival rates after HCC resection in the elderly: 54.6% at 3 years and 43.2% at 5 years.23 These outcomes might be somewhat better if the tumors were limited to only those meeting the Milan criteria and not just resectable tumors.24 These results appear to be lower than the rates for both liver transplantation and RFA in these age groups. However, surgical resection in elderly patients with HCC does not involve the justice or utility arguments for organ allocation.
Schwartz et al.6 state that because elderly patients with HCC fare no worse than patients with other indications for transplantation, it is reasonable to conclude that as long as chronological age does not eliminate an individual's transplant candidacy, a tumor diagnosis should not prevent that patient from receiving a transplant. Liver transplantation seems reasonable for the subset of elderly patients with HCC and Child-Pugh C stage liver disease—again, for those patients who are otherwise healthy enough to undergo liver transplantation. It should be noted that others would disagree.2, 3
So, we have taken this very small subset (0.91%) of patients being reviewed by liver transplant programs and divided them into even smaller subsets of treatment categories. Some programs might elect to do nothing.2 However, most programs would administer some form of treatment.
Under Schwartz et al.'s approach,6 the subset of elderly patients whose Child-Pugh status is A/B and whose HCC is amenable to ablation therapy would undergo liver transplantation with its associated costs and possibility of early mortality, pain, and various liver transplant–associated complications (more than 40% of liver recipients25, 26); in addition, that same number of donor livers could not help other patients. In contrast, if this same elderly subgroup of patients were to undergo RFA, the cost would be much lower, the patients would suffer much less pain, the complication rate would be only approximately 2.5%,15 and the patients would live as long as, or maybe even longer than, they would have if liver transplantation had been performed; moreover, that same number of other patients would get the chance to receive a lifesaving liver transplant. When we consider this subset, it seems that both justice and utility are satisfied by the pursuit of RFA for elderly patients with HCC and a Child-Pugh score of A/B. From the perspective of justice, these patients should undergo RFA treatment instead of liver transplantation to live about the same length of time or a little longer, experience much less pain, and spend less time in the hospital. From the perspective of utility, the livers that these elderly patients would not receive could be used in patients with a probability of much longer survival.
For the subset of healthy elderly patients with adequate functional liver reserve and HCC judged to be resectable in the eyes of the surgeon, some liver programs would recommend liver resection. This course of treatment does not violate the justice or utility perspective in terms of organ allocation, but some studies have reported that survival after resection is lower than survival after both ablation therapy and liver transplantation.
As for the remaining subset of elderly patients with HCC, Child-Pugh C liver disease, and adequate health to undergo liver transplantation, it appears that Schwartz et al.'s approach6 might be the best for some patients. However, with this option, the justice and utility arguments are still with us in our selection committees.