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In this issue of the Journal, Dr. Lesurtel and colleagues from Zurich apply the rating criteria for the strength of medical evidence developed by the Oxford Centre for Evidence-Based Medicine to the existing literature on transarterial chemoembolization (TACE) as neoadjuvant therapy for hepatocellular carcinoma (HCC) prior to liver transplantation (LT). The paper focuses on the effect of TACE with regard to four issues: post-LT survival, downstaging of HCC that is initially unsuitable for LT, waiting list dropout and post-LT complications.

It is evident from the outset that there is no high-level evidence available addressing any of these key issues. Although there is Level 1 evidence that TACE is effective as primary treatment for appropriately selected patients with HCC (1,2), in the LT neoadjuvant setting there are only observational studies of TACE that provide limited information due to the heterogeneity of patient and tumor characteristics, variable waiting times, use of different techniques, variable evaluation of response and lack of consensus about criteria for waiting list dropout.

A good deal of current medical practice is carried out without high-level evidence of its benefit. For example, neither hepatic resection nor LT for HCC has been studied versus no treatment in the setting of a randomized, controlled trial (RCT). Given the expense and energy expenditure involved in mounting an RCT, there must be a threshold for the significance of the information to be gained and the degree to which the answer to the question being asked is not intuitively obvious. With this in mind, let us examine the various questions asked in this paper about TACE.

  • 1
    Does TACE improve post-LT survival? The authors' assessment is that there is insufficient evidence to conclude that it does, and that studies providing higher level evidence are needed. It is not intuitively obvious whether or not TACE should improve post-LT survival, and among the existing studies there is low-level evidence pointing in both directions. The question thus seems a good one, and an RCT seems indicated; to provide the clearest answer, this trial would best be performed at centers with short waiting times where dropout is not an important issue.
  • 2
    Can downstaging with TACE convert poor candidates to good candidates? The authors' assessment is again that there is insufficient evidence and that better studies are needed. It is certainly not obvious how TACE can take a tumor that has reached a stage where dissemination has begun and, by treating the primary site, retroactively decrease the likelihood of that dissemination becoming manifest; perhaps, by improving case selection through elimination of cases that progress early after TACE, there is an indirect effect. The question is valid since we know that there is, among patients with HCC beyond Milan criteria, a substantial subset with the potential for good LT outcome, and a downstaging RCT would be very worthwhile (albeit difficult to mount in light of current organ allocation schemes).
  • 3
    Does TACE increase post-LT complications? The authors' assessment is that the current evidence is sufficient to conclude that it does not.
  • 4
    Does TACE impact on waiting list dropout? The authors' assessment is that there is insufficient evidence to conclude that it does. Among the four questions addressed, the fewest words were devoted to this one, and the discussion of dropout suggests that, based on nationwide UNOS data under the current MELD allocation system, dropout due to HCC is no longer a relevant issue in the United States.

The risk of dropout depends on a number of variables at both the transplant center and the individual patient level. In the United States, there is wide regional variation in waiting time; HCC patients at some centers face waits of a year or more despite UNOS priority. Furthermore, criteria for removing HCC patients from the waiting list vary among centers; at many European centers, for example, patients are not removed for HCC progression while waiting to beyond Milan criteria (3), whereas in the United States progression to beyond Milan results in loss of priority and thus no transplant.

It is possible to identify patients at increased risk for dropout: Yao et al. demonstrated that patients with more than one lesion or with a single lesion >3 cm have a dropout risk at 1 year of over 50% (4). While the ability of TACE to improve post-LT survival may be unclear, its ability to achieve objective tumor response is not: in the RCT documenting its efficacy (1), 35% of patients had objective responses lasting beyond 6 months, and the risk of portal invasion over 2 years was reduced from 58% to 17%. Thus, in many centers with long waiting time where progression to beyond Milan equates with dropout, HCC treatment while waiting for patients with high-risk tumors is accepted as likely enough to be beneficial that it is applied routinely.

The Barcelona group has reported a Markov simulation demonstrating that nonsurgical HCC treatment using percutaneous ethanol injection is cost-effective in increasing intention-to-treat survival through decreasing dropout (3). Investigators at centers where HCC patients face long waits, rather than comparing treatment versus no treatment, are more likely to mount a waiting-list trial comparing treatment modalities (e.g. TACE vs. ethanol injection or radiofrequency ablation); a number of such proposals are currently being considered by cooperative groups in the United States.

References

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  2. References
  • 1
    Llovet JM, Real MI, Montana X et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet 2002 May 18 ; 359: 17341739.
  • 2
    Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology 2003; 37: 429442.
  • 3
    Llovet JM, Mas X, Aponte JJ et al. Cost effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation. Gut 2002; 50:123128.
  • 4
    Yao FY, Bass NM, Nikolai B et al. A follow-up analysis of the pattern and predictors of dropout from the waiting list for liver transplantation in patients with hepatocellular carcinoma: Implications for the current organ allocation policy. Liver Transpl 2003 Jul; 9: 684692.