• Aucun résultat trouvé

Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for a common language

N/A
N/A
Protected

Academic year: 2022

Partager "Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for a common language"

Copied!
4
0
0

Texte intégral

(1)

Article

Reference

Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for

a common language

MAJNO, Pietro, MAZZAFERRO, Vincenzo

MAJNO, Pietro, MAZZAFERRO, Vincenzo. Living donor liver transplantation for hepatocellular carcinoma exceeding conventional criteria: questions, answers and demands for a common language. Liver Transplantation , 2006, vol. 12, no. 6, p. 896-8

DOI : 10.1002/lt.20808 PMID : 16721768

Available at:

http://archive-ouverte.unige.ch/unige:37008

Disclaimer: layout of this document may differ from the published version.

1 / 1

(2)

EDITORIAL

Living Donor Liver Transplantation For Hepatocellular Carcinoma Exceeding Conventional Criteria

Questions, Answers and Demands For a Common Language

Pietro Majno1and Vincenzo Mazzaferro2

1The Geneva Liver Cancer Study Group, Visceral and Transplantation Surgery, University Hospitals, Geneva, Switzerland, and2Digestive Surgery and Liver Transplantation Unit, National Cancer Institute, Milan, Italy Received January 18, 2006; accepted March 18, 2006

See Article on Pages 912 and 934

In this issue of Liver Transplantation two studies bring new data to the topic of living-donor transplanta- tion (LDLT) for hepatocellular carcinoma (HCC), offer- ing the opportunity for some comments.1,2

Since LDLT became available, two concerns have puzzled hepatologists and surgeons involved with HCC.

a) The impact of the procedure on the results of trans- plantation. Would Conventional Milan Criteria (CMC), validated for patients on a waiting list for cadaveric LT,3 hold true also for living donation? In addition, the over- all impact of the LDLT on intention-to-treat results was difficult to estimate, with the confounding effects of diminishing waiting time and dropouts, a technically more demanding operation, and possibly the loss of a selection effect of waiting time on patients with more aggressive tumors.

b) The impact of the unrestricted graft resource on the access to transplantation. In a condition where the rules have been dictated by scarcity, limiting transplan- tation to patients with a good prognosis, some patients are not constrained by donor availability: a family mem- ber wanting to donate regardless of the degree of benefit for the recipient. What are the limits and the duties associated with this new resource?

The two studies from Kyoto (93 patients) and Essen (34 patients) devoted to LDLT for HCC provide interest- ing data and thoughts on both points.

In the two studies, macrovascular invasion and dis- tant metastases were firm exclusion criteria, and the two studies present patients as within and without CMC.

For patients meeting CMC. (53% in Kyoto and 56% in Essen), the incidence of recurrences was between 13%

and 15%; therefore CMC, when aimed at selecting pa- tients with the lowest chances of recurrence are valid also for LDLT, confirming previous reports.4,5 Overall survival (68% at 4 years in Kyoto and 60% at 3 years in Essen) was similar, but not quite equal, to what has been reported from the best series. Because non-cancer deaths were high (19/93 patients in Kyoto -20%, and a hospital mortality of 9/34 patients in Essen - 26%), the lower survival observed can probably be attributed to the deliberate choice of not denying LDLT, a technically more complex procedure, to patients with advanced liver disease in both programs, and to patients with ABO incompatible donors in Japan.

For patients exceeding CMC. (47% in Kyoto and 44%

in Essen), the situation is more complex. In the Kyoto study, recurrences were more frequent (35% vs. 15%

for patients within CMC), but survival was regarded as

Abbreviations: LDLT, living-donor liver transplantation; HCC, hepatocellular carcinoma; CMC, conventional Milan criteria.

Address reprints to Vincenzo Mazzaferro, MD, G.I. Surgery and Liver Transplantation, National Cancer Institute, Via Venezian 1, 20133 Milan, Italy.

Telephone: 39-02-23902760; FAX: 39-02-2664584; E-mail: vincenzo.mazzaferro@istitutotumori.mi.it DOI 10.1002/lt.20808

Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 12:896-898, 2006

©2006 American Association for the Study of Liver Diseases.

(3)

similar (59% at 4 years, vs. 68%;P⫽0.65). The absence of a significant difference in survival has to be taken with caution, since the small number of patients in- creased the chance of a type II error, and the follow-up was short. In the study from Essen, the 15 patients who did not meet the Milan criteria at pathology staging had a 3-year recurrence-free survival of less than 50%.

Both studies fail to identify, outside CMC, categories with a predictably better outcome, and show that we lack a common language to investigate and report on these patients. In both studies the area outside CMC was probably vast, including patients just beyond the borders and patients further away, receiving transplan- tation after a variety of treatments and responses to them, after a wide range of time intervals from the diagnosis of HCC, and for tumors of unequal degrees of differentiation. While this heterogeneity is unavoidable, we need to represent it consistently in order to decrease its confounding effects. A common language is not be- yond reach: for the morphologic markers of disease severity (size and number of tumor nodules) for in- stance, patients could be plotted on a graph as illus- trated in Figure 1. Standardization of such minimal requirements for reporting would show how far patients are distributed outside the limits of CMC, and how robust is the claim that alternative criteria based on number and size, such as the ones reported in the series summarized in Figure 2, can be used instead.

Outside CMC, however, tumor size and number are insufficient to stratify patients in categories with rea- sonably predictable outcomes. Understandably so, be- cause CMC, as similar size-number criteria from previ- ous publications,6 were aimed at predicting a good outcome in patients who fulfilled them, rather than a

poor outcome in patients who exceeded them. Addi- tional parameters that enter the HCC equation (i.e. tu- mor, treatment and time factors, alpha-fetoprotein, mo- lecular signatures of vascular invasion etc.) need to be tested.7,8Some of them are easy to define. Criteria of response to treatment are available– possibly a surro- gate marker of favorable tumor behavior or a selection tool by increasing observation time– with a category of patients who have been downstaged to within CMC and are stable for 6 months, or an other category of patients who are downstaged to predefined extended criteria, but whose disease does not progress after a variable waiting time.9-11Patients outside CMC could be strat- ified by a biopsy and transplanted if the tumor is well or moderately well differentiated.12Patients with tumors that rapidly increase in size, with rising alpha-fetopro- tein, and that do not respond to treatment are associ- ated to high chances of dropout from the waiting list for cadaveric organs;13they should probably be excluded or studied separately within controlled trials, to know whether LDLT, by decreasing the waiting time, may merely transform dropouts into recurrences.

Beside a structured and reproducible approach, are there any additional duties when using the new supply of organs that LDLT represents? In our opinion, we need to restrict the procedure to an area were it can not be considered futile. This because health resources de- voted to transplantation (if not donors –arguably) be- long to the community, and because the psycho-social outcome of donors in cases where the recipient trans- plant has failed is insufficiently known.14The limit of 50% survival at 5 years has been taken as a reasonable Figure 1. Proposed minimal requirements for presenting new

predictive criteria outside Conventional Milan Criteria (ficti- tious cases). Patients for whom recurrences or a recurrence- free follow-up of 3 years are available are plotted on the graph showing tumor number and size. An additional variable of the investigation (e.g. tumor differentiation grade or downstag- ing) can be represented as a number or a letter in each point.

The distribution shows at a glance how far the patients are outside traditional criteria, and how robust is the claim that new criteria can replace Conventional Milan Criteria in pre- dicting a good outcome.

Figure 2. Paradigm of the “metro ticket” (modified from8).

The graph shows how different number-size criteria predict the outcome of liver transplantation for hepatocellular carci- noma in various Centers. The model is based on number and size of the nodules identified by radiological preoperative staging (Milano,3 Pamplona,16 New York Mt Sinai17) or by postoperative pathological staging (Paris Paul-Brousse,6San Francisco,18Pittsburgh19, Dallas Tumor Registry,20Japan Multicentric Study21), or as estimated outcome in prospective studies on extended criteria (Barcelona9). The fact that some Centers appear more than once reflects the different size and number combinations by which criteria can be met (e.g. for conventional Milan criteria, 1 nodule up to 5 cm or 3 nodules up to 3 cm).

EDITORIAL 897

LIVER TRANSPLANTATION.DOI 10.1002/lt.Published on behalf of the American Association for the Study of Liver Diseases

(4)

point to start discussions in our programs,9bearing in mind that the benefit of LDLT is better appreciated in terms of gain in life expectancy (linked to recipient age and alternative treatments) than in terms of survival.15 The call for caution concerning LDLT in HCC patients over 60 in the study by Malago` et al. is particularly relevant in this respect.

Within the limits suggested above, LDLT appears as a unique opportunity to probe in a systematic way the largely unexplored territory of the extended indication to transplantation for HCC in which cadaveric graft shortage prevents more liberal selection criteria. Land- marking the area outside CMC into reproducible cate- gories with an intermediate risk of recurrence (whose validity can be tested prospectively) seems to us the most urgent task, is well within reach, and is almost a moral obligation considering the formidable investment of all parties involved in the procedure.

ACKNOWLEDGMENTS

The authors thank the members of the teams in Ge- neva, in particular Professor Gilles Mentha and Profes- sor Philippe Morel; and in Milan, Doctor Enrico Regalia and Doctor Marcello Schiavo, for the valuable input in discussing the issues of the editorial.

REFERENCES

1. Takada Y, Ueda M, Ito T, Sakamoto S, Haga H, Maetani Y, et al. Living-donor liver transplantation as a second line therapeutic strategy for patients with hepatocellular car- cinoma. Liver Transpl 2006;12:912-919.

2. Malago M, Sotiropoulos G, Nadalin S, Valentin-Gamazo C, Paul A, Lang H et al. Living donor liver transplantation for hepatocellular carcinoma: A single center preliminary re- port. Liver Transpl 2006;12:934-940.

3. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti, A, Bozzetti, F et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrho- sis. N Engl J Med 1996;334:693-699.

4. Todo S, Furukawa H; Japanese Study Group on Organ Transplantation. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experience in Japan. Ann Surg 2004;240:451-459; discussion 459- 461.

5. Hwang S, Lee SG, Joh JW, Suh KS, Kim DG. Liver trans- plantation for adult patients with hepatocellular carci- noma in Korea: comparison between cadaveric donor and living donor liver transplantations. Liver Transpl 2005;11:

1265-1272.

6. Bismuth H, Chiche L, Adam R, Castaing D, Diamond T, Dennison A. Liver resection versus transplantation for hepatocellular carcinoma in cirrhotic patients. Ann Surg 1993;218:145-151.

7. Bruix J, Sherman M; Practice Guidelines Committee, American Association for the Study of Liver Diseases.

Management of hepatocellular carcinoma. Hepatology.

2005;42:1208-36.

8. Llovet JM, Schwartz M, Mazzaferro V. Resection and liver transplantation for hepatocellular carcinoma. Semin Liver Dis. 2005;25:181-200.

9. Bruix J, Llovet JM. Prognostic prediction and treatment strategies in hepatocellular carcinoma. Hepatology 2002;

35:519-524.

10. Graziadei IW, Sandmueller H, Waldenberger P, Koenig- srainer A, Nachbaur K, Jaschke W, et al. Chemoemboli- zation followed by liver transplantation for hepatocellular carcinoma impedes tumor progression while on the wait- ing list and leads to excellent outcome. Liver Transpl 2003;9:557-563.

11. Yao FY, Hirose R, LaBerge JM, Davern TJ 3rd, Bass NM, Kerlan RK Jr, et al. A prospective study on downstaging of hepatocellular carcinoma prior to liver transplantation.

Liver Transpl 2005;11:1505-1514.

12. Cillo U, Vitale A, Bassanello M, Boccagni P, Brolese A, Zanus G, et al. Liver transplantation for the treatment of moderately or well-differentiated hepatocellular carci- noma. Ann Surg 2004;239:150-159.

13. Llovet JM, Sala M, Fuster J, Navasa M, Pons F, Sole´ M, et al. Predictors of drop-out and survival of patients with hepatocellular carcinoma candidates for liver transplan- tation. Hepatology 2003;38:763A.

14. Morris PJ, Monaco AA. The living donor. Transplantation.

2003;76:1242-1269.

15. Sarasin FP, Majno PE, Llovet JM, Bruix J, Mentha G, and Hadengue A. Living donor liver transplantation for early hepatocellular carcinoma: A life-expectancy and cost-ef- fectiveness perspective. Hepatology 2001;33:1073-1079.

16. Herrero JI, Sangro B, Quiroga J, Pardo F, Herraiz M, Cienfuegos JA, Prieto J. Influence of tumor characteristics on the outcome of liver transplantation among patients with liver cirrhosis and hepatocellular carcinoma. Liver Transpl 2001;7:631-636.

17. Roayaie S, Frischer J, Emre H, Fishbein TM, Sheiner PA, Sung M, et al. Long-term results with multimodal adju- vant therapy and liver transplantation fort he treatment of hepatocellular carcinomas larger than 5 cm. Ann Surg 2002;235:533-539.

18. Yao FY, Ferrel L, Bass N, Watson JJ, Bacchetti P, Venook A, et al. Liver transplantation for hepatocellular carci- noma: expansion of tumor size limits does not adversely impact survival. Hepatology 2001;33:1394-1403.

19. Marsh JW, Dvorchik I. Liver organ allocation for hepato- cellular carcinoma: are we sure? Liver Transpl 2003;9:693- 696.

20. Molmenti E, Klintmalm G. Liver transplantation in asso- ciation with hepatocellular carcinoma: an update of the International Tumor Registry. Liver Transpl 2002;8:736- 748.

21. Todo S, Furukawa H. Living donor liver transplantation for adult patients with hepatocellular carcinoma: experi- ence in Japan. Ann Surg 2004;240:451-461.

898 EDITORIAL

LIVER TRANSPLANTATION.DOI 10.1002/lt.Published on behalf of the American Association for the Study of Liver Diseases

Références

Documents relatifs

After preparation, the cells are injected in the microfluidic network and exposed to trains of different number of pulses (171 or 271 pulses) varying their amplitude (35 or 45

Earlier studies from the European Liver Transplant Registry (ELTR) reported a 5-year overall survival of 49% in patients undergoing liver transplantation for non-cirrhotic HCC

The psoas muscle transversal diameter predicts mortality in patients with cirrhosis on a waiting list for liver transplantation A retrospective cohort study.7. The psoas

[r]

In an earlier paper [6 ], B. Simon and the author introduced a notion of ultracontractivity which makes sense for a variety of second order.. elliptic operators. In

Finally, this literature review informs us that besides ensuring excellent clini- cal practice, rapidly developing countries need to think about continuing medical

In another study, 129 patients inside Milan criteria were compared with 48 patients outside the criteria receiving downstaging treatment; the results showed comparable

Scaling characteristics of the time series were calculated by using three methods of data processing: spectral analysis (FFT), the Burlaga-Klein (BK) method and the Higuchi (H)