EORTCAMAROStrial临床试验课件.doc

EORTC_AMAROS_trial临床试验课件Radiotherapy or surgery of the axi 1 I a after a positive sentinel node in breast cancer patients: final analysis of the EORTC AMAROS trialBy the EORTC Breast Cancer Group and Radiation Oncology GroupIn collaboration with the Dutch BOOG Group Name of presenter and ALMANAC Trialists' Group Function of presenter Emiel J. T.RutgersThe Netherlands Cancer Institute, AmsterdamCl ini cal tri al information: NCT00014612BackgroundSentinel node SN biopsy has replaced the axillary lymph node dissection ALND if cNOIf axillary SN+ AxSN+ and indication for axillarytreatment, ALND is standard of careALND is associated withhi gh rates of si de effectsAxillary radi otherapy AxRT providesgoodregional control with Iimi ted si de effects in cNO Deutsch etal, IJROBP 2008Hoebers et al, Cancer 2000Fisher et al, NEJM 2002Louis-Sylvestre et al, JCO 2004IIypothesisAxillary radiotherapy provides local control and survival comparable to ALND with fewer si de effects in women with a positive axillary SNEligibility Criteria InclusionExc1usionInvasive breast cancer Multicentric disease0.5-5 cmNeoadjuvant Clinically NOsystemic treatmentBCT or mastectomy Previous axillary Any age treatmentInformed consentPrior malignancyTrial designAxSN+AxSN+ALNDALNDcTl-2SNBRRNONOAxRTAxRTAxSN-AxSN-Stratification: institutionAdjuvant systemic therapy by choiceObjectivesPrimary: To demonstrate non-inferiority in axi1lary recurrence rate Secondary:1.To compare overall survival OS and disease- free survival DFS2.To compare Iymphedema, shouIder function andQuality of Life QoLEndpoints and statistical designPrimary: 5-years axillary recurrence free rateNon inferiority hypothesis design: assumption: ALND 98%; AxRT 96%one-sided log-rank; alpha 0.05; power 80%52 events neededSecondary: Efficacy: OS and DFSSafety: shoulder function, 1ymphedema, QoLAxRTTiming:Start 12 weeks after SNBExtent:level I + II + III + medial SCDose & schedule: 25 x 2 Gy or equivalentQuality control:dummy runHurkmans et al, Radiother Oncol 2003ALNDTiming: 12 weeks after SNBExtent:Level I + II mandatoryLeveI III optionalAdditional AxRT:N 4 positive nodesRESULTSAccrual of study 10981Theoretical4, 500Study4, 000Expected today: 4766Observed today: 48133,500Expected ly: 2983,000Observed ly: 205Expected 2y: 8942, 500Observed 2y: 5602,000Expected Q4+Q5: 262Observed Q4+Q5: 1591, 500Expected Q8+Q9: 298Observed Q8+Q9: 2051,00050023/09/02 22/09/04 22/09/06 21/09/08 21/09/10 20/09/12 Timeyears from start2001- 2010: 4806 patients enrolled 4766 required Number of patientsAll included patientsn 4806SNB not identified SNB otherSNB negative AxSNB positiveN 132 2.7% N 120 2. 5%N 3131 65.1% N 1425 29. 7%Intent-to-treat i I IALND AxRTsamp 1eN 744 N 681lOnot eligible 8ExcludedExcluded85 ITC only before amendment 67N 146N 14651 Non-compliance 71ALND Per Protocol PPAxRTN 598 sampleN 535Efficacy analyses OS and DFS:1.per protocol PP2.by intent-to-treat ITT Both PP and ITT analyses gave similar resultsIntent~to~treat analysis reportedTreatment complianceALND AxRT744 pts 681 ptsRandomized treatment 631 84.8 %590 86. 6 %Both treatments415.5 %1 0. 1 %Cross-over466. 2 %68 10. 0 %No axillary treatment243. 2 %223.2 %Baseline clinical ALND AxRT744 pts 681 ptsMedian age Q1-Q356 48 - 64 55 48 - 63 Menopausal stage38. 1 % 42. 5 %pre-menopausalpost-menopausal57. 7 % 54. 5 %Median tumor size Q1-Q317 mm 13 - 22 18 mm 13 - 23 Grade 24. 1 % 22. 6 %147. 8 % 45. 7 %225. 8 % 29. 4 %359.2 %Pre-operative ultrasound axilla 61. 5 %Baseline treatment ALND AxRT744 pts 681 ptsBreast surgery81.9 %BCS 81.8 %17. 1 %Mastectomy 17. 8 %Systemic treatment61. 3 %chemotherapy 60. 9 %hormonal therapy 77. 1 %78.6 %immunotherapy 6. 4 %6.0 % no systemi c treatment 9. 4 %9.0 %RT breast/chest wa 1 1 84. 8 % 87. 7 %SN results ALND AxRT744 pts 681 ptsMedian number of SN2 1-3 2 1-3removed Q1-Q3Size of metastases in SNinacroinetastases 59. 4 % 61. 5 %mi crometastases 28. 9 % 28. 6 %ITC 11.7 % 9. 8 %Straver et al, Ann Surg Oncol 2010ALND results ALND744 ptsMedian number of all nodes removed Q1-Q3 15 12-20 Number of additional positive nodes besides SN0 67. 1 %25.0 %1-37. 8 %N 4Axillary recurrence rate 5-years axiI I ary recurrence rate: ALND 0.43% 4 / 744 events 0.54%AxRT 1. 19% 7 / 681 events 1.03%hypothesis 2%Consequence: planned comparison is underpoweredAxi1lary recurrence rate SN-5-years axillary recurrence rate:0. 72% 25/3131 events 0.80%Disease-free survivalHR:1. 17; 95%CI: 0. 93-1.51P 0.180verall survivalBreast cancerspecific deaths:ALND: 53 7. 1 %AxRT: 54 7. 9 %HR:1. 17; 95%CI: 0. 85-1.62P 0.34Results side effects50-70% form compliance at all time pointsLymphedema of the armMeasured: 1, 3 and 5 years after treatmentItems:Clinical observationTreatment for edema:-sleeve garment-lymph drainage therapy一compression therapyLymphedema: clinical observationand/or treatment40. 0%%29. 8%21.7%16. 7%13. 6%P 0. 0001 P 0. 0001 P 0. 0001Years after randomization24Lymphedema: cI ini cal observation27.8%%23. 2%22.5%15.1%13.8%10. 8%P 0.0001 P 0.0027 P 0.0001Years after randomizationLymphedema: treatment31.5% %16.8%16. 1%9. 7%6. 6%P 0.0001 P 0.0001 P 0.0001Years after randomizationShoulder functionMeasured: 1, 3 and 5 years after treatment180°Items:90°1.Ante/retroversion20° -40°2.Ab/adductionShoulder functionResults:No significant differences in all 4 excursionsTrend towards impaired movement after AxRT in first year on 1 y Relative movement:Excursion treated armExcursion untreated armMultivariateANOVA: p 0. 29Years after randomizationQuality of LifeMeasured: 1, 2, 3 and 5 years after treatmentQuestionnaire:1.EORTC-QLQ-C3O core questionnaire version 32.QLQ-BR23 breast cancer moduIeResults: No significant differencesSelected scales:arm symptoms, pain & body imageQuality of LifeResults:Trend towards more difficultiesto move the arm after ARTALNDAxRTTrend towards more swellingafter ALNDALND AxRTDiscussionThe axillary recurrence rate was far be 1 ow hypothesized, hence, the trial was underpoweredAxRT: levelI + II + III + SCImbalance in AxSN+ patients per arm- independent committee: no explanation Indication for axillary treatment?ConclusionBoth ALND and AxRT provide exceI lent and comparable locoregional control in AxSN+ patientsSignificantly less lymphedema after AxRT AxRT can be considered standardAcknowledgementWe are very gratefu1 to al 1 thepatients who participated in this trialAcknowledgementResearch fellows: Mila Donker, Marieke Straver, Philip MeijnenPrincipal investigators: Cornells van de Velde, Robert Manse I, GeertJan van TienhovenEORTC headquarters: Nicole Duez, Leen Slaets, JanBogaerts, Carlo Messina, Corneel Coens, the IDMCEORTCBreast Cancer GroupEORTC Radiation Oncology GroupDutch BOOG GroupA1AIANAC Trialists, GroupParticipating institutesArnhem, ZII Ri jnstate, the Netherlands Den Haag, Bronovo ZII, the NetherlandsHardewi jk, St Jans dal ZH, the Netherlands Groningen, UMCG, the NetherlandsHardenberg, R?pcke-Zweers ZH, the NetherlandsAmsterdam, NKI-AVL, the NetherlandsDen Haag, Haga ZH, the NetherlandsFirenze, Univ Hosp Careggi, ItalyCardiff, Univ Hosp Wales, United KingdomDrachten, ZH Nij SmelIinghe, the NetherlandsManchester, Manchester Univ Hosp, UnitedUtrecht, Diakonessenhuis, the NetherlandsKingdomLeiden, LUMC, the NetherlandsAmsterdam, AMC, the Netherlands Torino, San GiovanniBattista Hosp, ItalyDen Haag, MCH Westeinde, the Netherlands Ape! doom, Ge Ire ZH, the NetherlandsLjubljana, Univ Hosp, Slovenia Eindhoven, Catharina ZH, the NetherlandsLille, Centre Oscar Lambret, France Amstelveen, AmstellandZH, the Nether IandsDelft, R de Graaf GII, the NetherlandsGeneva, Hosp Cantonal, SwissHaarlem, Kennemer GH, the NetherlandsNijmegen, UMC St Radbout, the NetherlandsIstanbul, Marmara Univ Hosp, TurkeyGrenoble, CHUG Grenoble, FranceHaifa, Rambam Med Center, Israe1Gdansk, Medical Univ, PolandRoermond, Laurentius ZH, the Netherlands Paris, Inst Curie, France Thank youForm comp Iiance% valid forms received1 year2 years3 years 5 yearslymphedema 65. 3 - 61.9 68. 6Shoulder function 59. 6 - 56. 7 64. 0Quality of Life 64. 9 49. 6 62. 5 66. OSNBConduct:-Use of radiocolloid mandatoryDefinition of “positive axi l I ary SN” AxSN+:-At least 1 positive sentinel node in axilla-Positive: Macrometastases/micrometastases/ITC^Quality control: -Learning phase with N 30 SNB required* ITC on 1y excluded from AxSN+ group since Apri1 2008 Distant metastasis free survivalHR: 1.27; 95%CI: 0. 96-1.68P 0. 0980。