In the univariate analysis, variables associated with survival since diagnosis included the Milan-out criteria at diagnosis, the number of LRT received before transplantation, and the Child-Pugh score and AFP levels at diagnosis. In the multivariate analysis, both Milan-out criteria at diagnosis and AFP levels at diagnosis were independently associated with worse survival (hazard ratio [HR] of 1.7 [IC 95%, 1.34-4.55; P = 0.01 and 1.53; 95% confidence interval [CI], 3.8-6.1; P = 0.02]).
Treatment failure occurred in 36 cases (20%), 16 (44%) due to tumor progression in the WL, 7 (20%) due to death on the WL secondary to decompensated liver disease, and 13 cases due to HCC recurrence (9% of the 146 LT patients). Treatment failure according to Milan criteria occurred significantly more in the group of Milan-out patients. Of those within Milan (n = 148), treatment failure occurred in 23 (15%) cases, due to HCC recurrence (n = 9, 7% of 126 LT patients), death secondary to liver disease (n = 4, 17%), and dropout secondary to tumor progression (n = 10, 43%). In turn, among Milan-out patients (n = 29), treatment failure occurred in 13 (45%) (4 due to HCC recurrence [20% of 20 LT cases], 3 deaths (10%) on the WL due to liver disease, and 6 [21%] dropout for tumor progression in the WL) (Figure 3).
Tumor Progression or Death in WL
Besides the Milan criteria, other factors significantly associated with treatment failure in the univariate analysis were the number of LRT received before WL and AFP levels at diagnosis. In the multivariate analysis, only the variable Milan-in/Milan-out at time of HCC diagnosis remained in the model (HR, 1.7; 95% CI, 1.34-4.55; P = 0.010) (Table 4).
Thirteen patients were diagnosed with HCC recurrence at a median of 18 months (range, 6-24 mo) since LT.
In the univariate analysis, factors associated with recurrence were Milan-out criteria and AFP levels at diagnosis, female gender (P = 0.04), and high MELD score (P = 0.045) and AFP levels (P = 0.034) at time of LT. In the multivariate analysis, out-of-Milan criteria (HR, 1.43; 95% CI, 1.23-6.5; P = 0.048), MELD score at LT (HR, 1.23; 95% CI, 1.03-4.5; P = 0.046), and female gender (HR, 1.32; 95% CI, 1.4-3.7; P = 0.03) remained significant in the model (Table 5).
Although Milan criteria have been used for years as the criteria to include patients in the WL for LT, many authors consider these criteria to be too restrictive. Indeed, patients with intermediate stages, after the application of LRT, can achieve substantial tumor volume reduction and be successfully transplanted.17,18 In fact, in recent years, several centers have endorsed these new expanded criteria and equate the survival of these patients with that of patients with tumors in the initial stages.19,20 Data on downstaging results though are controversial, due to a variety of reasons, particularly the differences in LRT, the wide variability in WL duration and particularly, the lack of intention-to-treat analyses since HCC diagnosis but rather survival analyses from transplantation.
We aimed to analyze our results in a large transplant center where WL times are typically shorter than those reported by other United States or European centers, a factor that could result in different outcomes, as well as focusing on an intention-to-treat analysis from time of HCC diagnosis. Major findings from this study can be summarized as follows: (1) treatment failure, including death in the WL from liver disease, dropout due to tumor progression or post-LT HCC recurrence in those transplanted, occurred at a significantly higher rate in those who exceeded Milan criteria and who underwent a downstaging protocol. In fact, the Milan in/out variable was the only variable that remained significant in the multivariate analysis and (2) despite lower rates of treatment efficacy on intention-to-treat analysis, survival in the short term was good and similar to that achieved by patients fulfilling the Milan criteria. In the longer term, however, after a 5 years follow-up, survival rates dropped to be significantly worse than those achieved by patients with HCC Milan-in criteria but can still be considered extremely favorable when compared with other local therapies.
Two studies published in the United States in the last 2 years report treatment failure rates of about 30% assuming the same study design as ours that is, using the same definition of treatment failure and analyzing the data on an intention-to-treat basis. In these studies, the criteria used to select the Milan-out patients was the UCSF (California) criteria; in addition, and as mentioned previously, waiting times are significantly longer, and as a result, patients undergo a significantly higher number of LRT and have more advanced liver disease (higher MELD ad Child scores) at LT.14,21 These differences might explain, in part, the higher rate of treatment failure reported in the US studies. As in our study, tumor progression and death on the WL were also greater in the Milan-out patients.
More specifically, Yao et al14 analyzed survival since diagnosis in patients with beyond UCSF criteria, UCSF and Milan criteria obtaining good results in all groups. Patients exceeding UCSF criteria but successfully downstaged to Milan also managed to obtain survival rates comparable to Milan-in patients, both from time of inclusion in the WL and from time of LT, supporting LT as a therapeutic option for these expanded criteria tumors. In the downstaging group, variables related to the worst prognosis were advanced Child (as in our sample) and AFP levels higher than 1000 mg/dL. This last parameter is not comparable with our study since we did not include patients with AFP higher than 400 ng/dL on the WL. Reasons that may explain differences in results, particularly the worse long-term results (at 5 y) in the Milan-out versus Milan-in patients both on intention-to-treat but particularly after LT may relate to differences in patient population, donor rate, and time in the WL. Indeed, longer waiting times in the United States may result in better patient selection so that tumors with more biological stability eventually undergo LT while those with a more aggressive biology are typically excluded from the WL for tumor progression.22 Interestingly, the rate of dropout for tumor progression was higher in the study by Yao et al (32%) compared with ours (20%), indirectly supporting this concept. In fact, several authors have proposed that at least 3 months of tumor stability should be required after downstaging before including a patient on the WL. This “ablate and wait” criterion is a tool to determine the biology of the tumor trying to select the least aggressive ones. The “United Network for Organ Sharing” has more recently expanded this time to 6 months,23,24 and based on the results obtained in our and the study by Yao et al, we are considering to also apply the 6 months rule in our center.
AFP levels play an important role when selecting candidates for downstaging and both static as well as dynamic levels are predictors of treatment response. Indeed, many studies have shown that patients with high AFP values have typically a lower treatment response in terms of reduction in tumor volume.25,26 In our case, although there were no statistical differences, there was a trend for greater treatment failure among patients with high AFP levels at diagnosis once included in the WL. It is important to highlight that although eventually these patients achieved adequate downstaging and were thus allowed to be included in the WL, our sample is highly selected since patients with AFP higher than 400 ng/dL were excluded.
Our study has limitations. It is a retrospective study, carried out in a single referral center for LT with few Milan-out patients recruited. We have few patients with downstaging protocol. Indeed, patients evaluated both in our center as well as elsewhere who were treated with LRT but never reached the Milan-in criteria were not referred and/or included in the WL for LT, and so the results apply to the subgroup of HCC cases with initial adequate response to LRT. In addition, the criteria for downstaging were not completely standardized in a protocol and this may have generated a selection bias. Despite these limitations, we included a relatively selected cohort of patients that adequately represents the Spanish transplant population.
In conclusion, downstaging is a valid and increasingly used tool for selecting tumors with a presumably favorable biology and greater tumor stability. Although patients successfully downstaged have worse overall intention-to-treat outcomes compared with Milan-in patients, they achieve satisfactory post-LT survival rates, greater than the “minimum” of 50% at 5 years, and thus should not be denied this therapeutic option. Whether the LT criteria following successful downstaging should be the Milan criteria as opposed to an expanded one27 requires further investigation.
We would like to thank G. Sapisochin for his helpful comments.
1. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma.Lancet20123791245–1255
2. Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology.Best Pract Res Clin Gastroenterol201428753–770
3. Clavien PA, Lesurtel M, Bossuyt PM, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report.Lancet Oncol201213e11–e22
4. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma.Hepatology200235519–524
5. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis.N Engl J Med1996334693–699
6. Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22-year experience with 467 patients at UCLA.Ann Surg2007246502–509discussion 509–511
7. Lo C. Downstaging of hepatocellular carcinoma before transplantation: an advance in therapy or just another selection criterion.Am J Transplant200882485–2486
8. Mazzaferro V, Llovet JM, Miceli R, et al; Metroticket Investigator Study GroupPredicting survival after liver transplantation in patients with hepatocellular carcinoma beyond the Milan criteria: a retrospective, exploratory analysis.Lancet Oncol20091035–43
9. Kumar Y, Sharma P, Bhatt N, et al. Transarterial therapies for hepatocellular carcinoma: a comprehensive review with current updates and future directions.Asian Pac J Cancer Prev201617473–478
10. She WH, Cheung TT. Bridging and downstaging therapy in patients suffering from hepatocellular carcinoma waiting on the list of liver transplantation.Transl Gastroenterol Hepatol2016134
11. Gunsar F. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.Exp Clin Transplant201715Suppl 259–64
12. Chapman WC, Garcia-Aroz S, Vachharajani N, et al. Liver transplantation for advanced hepatocellular carcinoma after downstaging without up-front stage restrictions.J Am Coll Surg2017224610–621
13. Xu DW, Wan P, Xia Q. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria: a review.World J Gastroenterol2016223325–3334
14. Yao FY, Mehta N, Flemming J, et al. Downstaging of hepatocellular cancer before liver transplant: long-term outcome compared to tumors within Milan criteria.Hepatology2015611968–1977
15. Bruix J, Sherman M; American Association for the Study of Liver DiseasesManagement of hepatocellular carcinoma: an update.Hepatology2011531020–1022
16. Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular carcinoma.Semin Liver Dis20103052–60
17. Xu X, Lu D, Ling Q, et al. Liver transplantation for hepatocellular carcinoma beyond the Milan criteria.Gut2016651035–1041
18. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: expansion of the tumor size limits does not adversely impact survival.Hepatology2001331394–1403
19. Yao FY, Breitenstein S, Broelsch CE, et al. Does a patient qualify for liver transplantation after the down-staging of hepatocellular carcinoma?Liver Transpl201117Suppl 2S109–S116
20. Yao FY, Kerlan RK Jr, Hirose R, et al. Excellent outcome following down-staging of hepatocellular carcinoma prior to liver transplantation: an intention-to-treat analysis.Hepatology200848819–827
21. Yao FY, Hirose R, LaBerge JM, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation.Liver Transpl2005111505–1514
22. Cillo U, Giuliani T, Polacco M, et al. Prediction of hepatocellular carcinoma biological behavior in patient selection for liver transplantation.World J Gastroenterol201622232–252
23. Agopian VG, Morshedi MM, McWilliams J, et al. Complete pathologic response to pretransplant locoregional therapy for hepatocellular carcinoma defines cancer cure after liver transplantation: analysis of 501 consecutively treated patients.Ann Surg2015262536–545discussion 543–545
24. Beal EW, Dittmar KM, Hanje AJ, et al. Pretransplant locoregional therapy for hepatocellular carcinoma: evaluation of explant pathology and overall survival.Front Oncol20166143
25. Toro A, Ardiri A, Mannino M, et al. Effect of pre- and post-treatment α-fetoprotein levels and tumor size on survival of patients with hepatocellular carcinoma treated by resection, transarterial chemoembolization or radiofrequency ablation: a retrospective study.BMC Surg20141440
26. Lai Q, Iesari S, Melandro F, et al. The growing impact of alpha-fetoprotein in the field of liver transplantation for hepatocellular cancer: time for a revolution.Transl Gastroenterol Hepatol2017272
© 2019 The Authors. Published by Wolters Kluwer Health, Inc.
27. Toso C, Meeberg G, Andres A, et al. Downstaging prior to liver transplantation for hepatocellular carcinoma: advisable but at the price of an increased risk of cancer recurrence - a retrospective study.Transpl Int201932163–172