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RESEARCH PRODUCT

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial

Christian KleinChristophe DuvouxJames J. PowellAndreas A. SchnitzbauerAndreas A. SchnitzbauerBart Van HoekRoberto TroisiCarl ZülkeJohann HaussLionel RostaingItxarone BilbaoRené AdamJ. GugenheimTom M. GantenHeiner WoltersVictor Sanchez TurrionFred FändrichKoert P. De JongSimone I. StrasserPeter NeuhausSilvio NadalinOlivier ChazouillèresChristian GraebGiorgio RossiMichael HeiseMichael HeiseJan LerutP. LambyAndré RoyKarl-walter JauchGerd OttoAngela SchlittJens BrockmannThomas BeckerDarius F. MirzaHans J. SchlittJan SchmidtPatrizia BurraStefan SchreiberJürgen KlempnauerJacques PirenneErnest HidalgoAndrea PronethUmberto CilloNorman M. KnetemanIngrid MutzbauerPhilippe WolfNeville V. JamiesonUmberto ValentePhilippe BachellierEdward K. GeisslerGunnar SöderdahlThomas SolimanAntonio Daniele PinnaSherrie BhooriJohann PratschkeSusanne BeckebaumWolf O. BechsteinMagnus RizellT. ScholzVincenzo MazzaferroRaimund MargreiterHeikki MäkisaloMichele ColledanUtz SettmacherRudolf SteiningerAlfred KönigsrainerGeorges-philippe PageauxMarkus Rentsch

subject

MaleTime FactorsIntention to Treat Analysimedicine.medical_treatmentMedizinPROGRESSIONKaplan-Meier EstimateLiver transplantationGastroenterologyImmunosuppressive Agent0302 clinical medicineEVEROLIMUSRENAL-CELL CARCINOMARisk FactorsMedicine and Health SciencesClinical endpointAge FactorSirolimuProspective StudiesIMMUNOSUPPRESSIONTOR Serine-Threonine KinaseTOR Serine-Threonine KinasesHazard ratioLiver NeoplasmsAge FactorsImmunosuppressionMiddle AgedCANCER3. Good healthIntention to Treat AnalysisEuropeRAPAMYCIN INHIBITORSTreatment OutcomeTARGETLocalLiver Neoplasm030220 oncology & carcinogenesisCombinationDisease ProgressionSURVIVAL[SDV.IMM]Life Sciences [q-bio]/Immunology030211 gastroenterology & hepatologyDrug Therapy CombinationFemaleImmunosuppressive Agentsmedicine.drugHumanAdultmedicine.medical_specialtyCanadaCarcinoma HepatocellularTime Factor[SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/SurgeryRisk AssessmentDisease-Free Survival03 medical and health sciencesYoung AdultDrug TherapyInternal medicinemedicineHumansAdult; Age Factors; Aged; Australia; Canada; Carcinoma Hepatocellular; Disease Progression; Disease-Free Survival; Drug Therapy Combination; Europe; Female; Humans; Immunosuppressive Agents; Intention to Treat Analysis; Kaplan-Meier Estimate; Liver Neoplasms; Male; Middle Aged; Neoplasm Recurrence Local; Prospective Studies; Risk Assessment; Risk Factors; Sirolimus; TOR Serine-Threonine Kinases; Time Factors; Treatment Outcome; Young Adult; Liver Transplantation; TransplantationRECURRENCEMETAANALYSISAgedSirolimusTransplantationEverolimusIntention-to-treat analysisbusiness.industryRisk FactorCarcinomaAustraliaHepatocellular3126 Surgery anesthesiology intensive care radiologySurgeryLiver TransplantationTransplantationProspective StudieNeoplasm RecurrenceSirolimusNeoplasm Recurrence Localbusiness

description

International audience; BACKGROUND:We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC).METHODS:In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint.RESULTS:Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874).CONCLUSIONS:Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.TRIAL REGISTRATION:ClinicalTrials.gov NCT00355862.

yearjournalcountryeditionlanguage
2016-01-31
https://hdl.handle.net/1887/117549