Article Text

Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation
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1. J M Llovet1,
2. X Mas2,
3. J J Aponte2,
4. J Fuster1,
5. M Navasa1,
6. E Christensen3,
7. J Rodés1,
8. J Bruix1
1. 1Barcelona-Clínic Liver Cancer (BCLC) Group, Liver Unit, Institut d'Investigacions Biomédiques August Pi I Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia, Spain
2. 2Epidemiology-Biostatistics Unit, Institut d'Investigacions Biomédiques August Pi I Sunyer, Hospital Clínic, University of Barcelona, Catalonia, Spain
3. 3Clinic of Internal Medicine, Bispebjerg University Hospital, Copenhagen, Denmark
1. Correspondence to:
Dr J M Llovet, BCLC Group, Liver Unit, IDIBAPS, Hospital Clínic, c/Villarroel 170, 08036-Barcelona, Catalonia, Spain;
jmllovet{at}clinic.ub.es

## Abstract

Background: Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor.

Aims: To assess the cost effectiveness of adjuvant therapy while waiting for liver transplantation in HCC patients.

Method: Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment—resection was limited to Child-Pugh's A patients with single tumours, and percutaneous treatment was considered for Child-Pugh's A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months.

## RESULTS

### Probability of being transplanted and overall survival

The probability of being transplanted and the overall survival are depicted in figs 2 and 3. Surgical resection increased the transplantation rate from 3.7% to 10.7% for waiting lists of six and 24 months, respectively. The seven year probability of survival increased for patients undergoing resection compared with standard management, and was higher than 10% for waiting lists exceeding one year. Percutaneous treatments increased the probability of being transplanted and the seven year survival in all waiting times. These benefits became clinically relevant when the waiting time exceeded one year.

Figure 2

Probability of being transplanted (A) and seven year intention to treat survival (B) comparing patients with hepatocellular carcinoma undergoing resection versus conservative management while on the waiting list for liver transplantation.

Figure 3

Probability of being transplanted (A) and seven year intention to treat survival (B) comparing patients with hepatocellular carcinoma undergoing percutaneous treatment versus conservative management while on the waiting list for liver transplantation.

### Cost effectiveness

The results of the CEA are shown in figs 4 and 5, and table 3. Resection provided a clinically relevant net gain in LE ranging from 4.8 to 6.1 months if waiting times exceeded six months. The CEA shows that the MCYLS was less than $40 000 for lists of 12–24 months. Ethanol injection achieved a clear gain in LE, ranging from 5.2 to 6.7 months, increasing according to the length of the waiting list. Its cost effectiveness ratio was less than$23 000/year of life saved (fig 5). Undiscounted results did not statistically differ from those discounted at 3%.

Table 3

Cost effectiveness analysis of performing adjuvant therapy according to risk group and length of waiting list

Figure 4

Cost effectiveness analysis of surgical resection for hepatocellular carcinoma versus conservative management while on the waiting list for liver transplantation. Cost effectiveness ratio and marginal effectiveness in terms of gains in life expectancy are shown according to length of waiting time.

Figure 5

Cost effectiveness analysis of percutaneous treatments for non-surgical hepatocellular carcinoma versus conservative management while on the waiting list for liver transplantation. Cost effectiveness ratio and marginal effectiveness in terms of gains in life expectancy are shown according to length of waiting time.

### Sensitivity analysis

The results of the sensitivity analysis are shown in table 4. Our model was most sensitive to variations in the dropout rate and survival after OLT. When assuming the highest benefit as a result of treatment (best scenario: relative decrease of 20% in dropout rate), gains in LE were relevant (resection 3.3–8.3 months; PEI 6.8–9.1 months), with a cost effectiveness ratio always below $60 000/year of life saved. When considering scenarios of poor outcome after resection (worst scenario: relative increase of 20% in dropout rate), this treatment provided a minimal benefit in LE, with a marginal cost ranging from$135 600/year of life saved (six month waiting list) to $43 650/year of life saved (24 month waiting list). Conversely, even in this worst scenario, PEI offered gains in LE always exceeding three months, with a marginal cost per year of life of less than$32 000.

Table 4

Sensitivity analysis for the best and worst scenarios of dropout rate and survival after orthotopic liver transplantation (OLT) according to risk group and length of waiting time (range 6–24 months)*

Assuming a 50% five year survival rate after OLT (worst scenario), the estimates of LE decreased in all cases. For this scenario, PEI retained a cost effectiveness ratio for all waiting times but resection was cost effective only for waiting times exceeding two years ($43 074/MCLYS). ## DISCUSSION The excellent results of liver transplantation for early HCC are curtailed by the increasing dropout rate while waiting for a donor, thus worsening outcome when analysed on an intention to treat basis.1,4 Several strategies have been postulated to decrease the impact of exclusions. Living donor liver transplantation, domino and split liver transplantation, as well as use of marginal livers are policies currently applied in some transplant units. A decision analysis has recently shown that living donor liver transplantation compared with OLT is cost effective for early HCC for waiting times exceeding seven months.35 However, implementation of these strategies is complex, and will probably be restricted to leading transplant units. This has led most centres to administer antitumoral treatments on entering HCC patients onto waiting lists.13–18 The benefits of this policy are unknown as prospective RCTs in the field are lacking and they are seen as almost unfeasible due to the cost, heterogeneity, and complexity of the medical interventions. This uncertainty prompted us to conduct a decision analysis to address the clinical benefits and cost effectiveness of adjuvant treatment. The model applies the best curative therapies available for the selected strata of HCC candidates for OLT and considers a waiting time between six and 24 months. This strategy predicts moderate gains in LE in almost all cases, and the gain remains below the accepted cost effectiveness ratio ($50 000/per year of life saved).30–34 In fact, it compares favourably with accepted medical interventions, such as implantable cardioverter-defibrillator for coronary heart disease ($26 000–40 000 per year of life) or haemodialysis ($42 000/quality adjusted life year saved).32–34 Surgical resection was cost effective while waiting for at least one year. After this time, surgery increased the transplantation rate, with moderate gains in LE and an acceptable cost effectiveness ratio. In contrast, LE gains and cost effectiveness ratio were less favourable (\$74 000 per year life gained) with shorter waiting times. There may be some concerns on the applicability of this invasive therapy while on the waiting list. As an alternative, primary liver resection and “salvage OLT” (performed when recurrence or decompensation after resection occurs) have been postulated to save organs.36 We have applied this policy over the last decade, where resection was considered as the firstline option, but unfortunately less than 10% of candidates benefited.1

Surgery is feasible for patients with preserved liver function and single tumours but it is too risky in subjects with impaired hepatic function and/or multiple HCC sites.2–5 Their high morbidity and mortality impede any benefit of surgery. Accordingly, these patients were modelled to receive percutaneous treatment, which was identified as cost effective in all scenarios. It could be argued that PEI is not the sole effective therapy for non-surgical HCC and that other widely used alternatives such as RF thermal ablation,26,37 chemoembolisation,13–18 or even chemotherapy38 could be modelled. Ethanol injection is a safe, cheap, and effective treatment that achieves a 40–80% response for patients with small HCC21–24 and the available studies provide robust information for decision analysis. RF thermal ablation as a primary treatment for HCC may have similar efficacy.37 Compared with PEI, its increased cost and the impact of complications may balance the benefits of reduced hospital stay. However, we have recently reported a 10% rate of tumour seeding after RF thermal ablation associated with subcapsular location or an aggressive tumoral pattern. Therefore, although there are no studies on its benefit when applied during the waiting list, we discourage this procedure prior to OLT.26 Finally, chemoembolisation is the standard antitumoral treatment for HCC prior to OLT in most transplant programs. Its antitumoral effect, even when using high dose chemotherapy, is less than that of PEI, and despite the fact that some authors have suggested benefits in patients with a favourable response to therapy (downstaging),13 there are no RCTs showing the benefit of this strategy. In addition, studies assessing this point have not identified a difference in tumour recurrence and survival attributable to therapy.

The sensitivity analysis disclosed that ethanol injection was beneficial and cost effective in all ranges used but the benefits of resection decreased when varying the assumptions of the model. In the worst scenarios for dropout rate and survival after OLT (five year survival 50%), resection provided poor gains in LE regardless of the length of the waiting list, with an expensive cost effectiveness ratio. These controversial benefits may be representative of transplantation centres achieving poor results after surgery as a consequence of both limited technical skills and expertise of the group. In support of this, it has recently been reported that OLT centres in the USA that perform less than 20 transplantations per year have mortality rates higher than those at larger centres.39 Thus decision makers should consider these data to warrant implementation of economic resources for the most efficient groups. As done for most decision analyses, we used local costs for cost effectiveness estimations. However, it is clear that health costs in Southern Europe are lower than in Northern countries or even in the USA. Accordingly, in areas where local economics are largely higher, the cost effectiveness of some scenarios may be lost.

The current analysis was limited by the scarcity of data on exclusions during the waiting list. For untreated patients we have assumed a dropout rate ranging from 15% to 36% at one year of waiting time, for the two reference cases. In the sensitivity analysis, these values varied by 20% up/down in the best/worst scenarios. These assumptions were derived from our reported data on exclusions, and are in accordance with recent 1999 data from the UNOS, where patients removed from the list due to death or other reasons in the USA ranged from 26% to 41%.9

In summary, our study indicates that adjuvant treatment on entering HCC patients onto a waiting list for OLT is cost effective and recommended in almost all scenarios. Patients with well preserved liver function and a single HCC, waiting for at least one year, may benefit from surgical resection but for shorter waiting times the economic investment is controversial. In non-surgical patients, percutaneous treatments are cost effective in all waiting times and thus their application is warranted.

## Acknowledgments

Supported by grant SAF 004-98 from the Comisión Interdepartamental de Ciencia y Tecnología, and a grant from the Fundació La Marató TV3, 1999.