METAANALISIS MAMA

Transcripción

1 METAANALISIS MAMA La radioterapia un tratamiento sistemico???!!!! La radioterapia post- Cirugia Conservadora. La radioterapia post-mastectomia. La radioterapia loco regional CMI. Hugo Marsiglia Institut Gustave Roussy, Villejuif, France.

2 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama 1.- Pacientes ancianas: CALG-B; PRIME2 2.- Hipofraccionamiento: START trials. 3.- Hipofraccionamiento: f-imrt trial. 4.- Irradiación parcial: EBRT: RAPID / IORT: TARGIT & ELLIOT. 5.- Ganglio centinela(+) Cirugia vs RT: EORTC AMAROS 6.- RT post-mastectomia y linfadenectomía axilar.: META-ANÁLISIS 7.- Irradiación ganglionar CMI: Hennequin/ EORTC Márgenes: Guía de consenso ASSO ASRO. 9.- BSGC: Guía de Práctica Clínica ASCO.

3 Proyectos / programas 1.- Determinación lecho tumoral por clips 2.-ganglio centinela bajo anestesia local staging prequimioterapia neoayuvante 3.- Ca-15-3 predictor de respuesta terapeutica en tratamiento sistemico recidiva/metastasis. 4.- Ca-15-3 prescripción en enfermedad localmente avanzada para orientar estadificación. 5.- oligometastasis : sinergias nuevos fármacos + Cyberknife /Tomoterapia 6.- Reirradiaciones pared toracica con Tomoterapia en recidivas post Cx-RT 7.- Reirradiaciones cyberknife /Tomoterapia metastasis oseas 8.- Estudio multicentrico reposicionamiento en cancer de Mama IOERT EN PRESERVACION AREOLA

4 DESARROLLOS TECNOLOGICOS/INVESTIGACION IOERT PROYECTO IOERT : Bases bibliograficas IOERT : MODELO IDEAL PARA DEFINIR PERFILES DE RADIOSENSIBILIDAD. ESCALADA DE DOSIS EN PACIENTES JOVENES :BOOST IOERT IOERT BOOST :INVERSION DE LA SECUENCIA TERAPEUTICA CIRUGIA QUIMIO RT

5 Adjuvant RT in breast cancer Alternative hypotheses Koscielny S, Tubiana M et al. Breast cancer, relationship between the size of the primary tumour and the probability of metastatic dissemination. Brit J Cancer 49: , 1984 Arriagada R, Lê MG et al. Long-term effect of internal mammary chain treatment. Results of a multivariate analysis of 1204 patients with operable breast cancer and positive axillary nodes. Radiother Oncol 11, , 1988 Auquier A, Rutqvist LE, Høst H et al. Post-mastectomy megavoltage radiotherapy: the Oslo and Stockholm trials. Eur J Cancer 28: 433-7, 1992 Arriagada R, Rutqvist LE et al. Adequate locoregional treatment in early breast cancer may prevent secondary dissemination. J Clin Oncol 13: , 1995

6 2007;356:

7 Are these effects surprising or no predicted? NO Several publications predicted such effects in patients with a higher risk of local recurrence, mostly based on Scandinavian studies However, the subject did not interest most oncologists Possibility of secondary dissemination disregarded Paradigm (para-dogma) of systemic disease Arriagada R et al. Radiother Oncol 11: , 1988 Auquier A et al. Eur J Cancer 28: 433-7, 1992 Arriagada R et al. J Clin Oncol 13: , 1995 Overgaard M et al. NEJM & Lancet, 1997, 1999.

8 Not to miss any MODERATE differences in long-term survival EBCTCG cooperation The world s breast cancer trialists have shared their data every 5 years since 1985 (EBCTCG) By many MODERATE gains (including that from breast screening), treatment has almost halved UK breast cancer mortality at ages 35-69

9 TAMOXIFEN NEW DRUGS MODERN RT NEW RT

10 Evolution: 1950 to present Improved targeting. Improved conformality of dose distribution Increased number of beams. Increased number of beam angles. Increased volume of normal tissues exposed to entry dose. Increased volume of normal tissues exposed to exit dose.

11 FROM CURE IMRT 8% % I A 83 % 3D 7% 68% 81% 2005 Linac 2D % 63% + 9% Tamoxifene Co % on survival Années % OS improvement 58% 55% For RH+ patients

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13 BREAST MORPHOLOGY

14 Local treatments and radiotherapy comparisons Summary - BCS ± RT - Decrease of recurrences and improved BCM - Similar relative reduction on recurrence in all subgroups - Predictive factors on the importance of absolute recurrence reduction to be further analysed, mainly in N- patients - BCS + RT vs Mastectomy - BCS + RT: more LR, but mainly in younger patients (< 40) - Mastectomy ± RT - Effective in reducing recurrence, BCM and overall mortality in all N+ patients EBCTCG Next Round: Oxford, september 2014

15 Event Long-term iatrogenic effects of breast cancer Radiotherapy Time scale: minimal time of observation Loco-regional recurrence Mortality Iatrogenic Years Arriagada R, Acta Oncol, 45: 514-6, 2006

16 The EBCTCG worldwide cooperation Total number of trials ever received by EBCTCG / /6 2010

17 The EBCTCG worldwide cooperation Thousands of patients ever received by EBCTCG / /6 2012

18 Isolated loco-regional recurrences in the trials of any type of radiotherapy (RT) versus no RT Isolated local recurrence Absolute difference in risk of isolated local recurrence: 20%, mostly within the first 5 years. EBCTCG, Lancet 366: , 2005

19 15-year breast cancer mortality in the trials of any type of radiotherapy (RT) versus no RT (Total: 24,000 women randomised in 46 trials) Breast cancer mortality Absolute difference in risk of death from breast cancer: 4%, mostly after the first 5 years. Little difference in breast cancer mortality during the first 5 years. EBCTCG, Lancet 366: , 2005

20 Local treatments and radiotherapy comparisons - Increased local control survival effects - Equivalence? : BCS + RT vs Mastectomy - Predictive factors: BCS ± RT - Mastectomy ± RT - Late iatrogenic effects (Lancet 378: , 2011)

21 Local treatments and radiotherapy comparisons - Predictive factors: BCS ± RT Lancet 378: , 2011

22 ANY recurrence Any recurrence means: loco-regional recurrence and/or distant metastases Only the first recurrence was recorded in several trials Not possible to analyse competing risks In September 2010, contralateral breast cancer (CBC) was included in ANY recurrence rates. In all further analyses and publications, CBC are and will be considered separately

23 Predictive factors - BCS ± RT - Lancet 378: , November Is the absolute RT effect homogeneous among all subgroups of patients?

24 Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year mortality in women with early breast cancer 10,801 women in 17 randomised trials Early Breast Cancer Trialists Collaborative Group (EBCTCG) Lancet 378: , 2011

25 BCS ± RT All patients Any first recurrence: excludes contralateral breast cancer

26 Radioterapia post BCS

27 BCS ± RT : T1 N- T1 N- patients Lumpectomy ER+ Tam + RT benefits on recurrence according to: Age Grade Black + white bar: Black bar: White bar: Absolute recurrence rate in group without RT Absolute recurrence rate in RT group Absolute recurrence gain related to RT

28 N- patients, predictive factors of RT effect

29 BCS ± RT : 5,682 T1 N- patients RT benefits on recurrence according to: Lumpectomy vs more ER+ Tam+ ER- ER+ Tam- Age Grade

30 17 estudos, ~ 11,000 pacientes Baixo risco: pt1-2, N-, margens negativas, ou idade > 65, e/ou RH+

31 Local treatments and radiotherapy comparisons Mastectomy ± RT

32 Mast+AC+RT vs. Mast+AC Year 2000 NIH consensus conference: RT recommendations after mastectomy, axillary clearance and pathology (p) of nodes (N): pn0 : no RT pn4+ : RT pn1-3: more uncertainty

33 I Post-mastectomy RT in breast cancer From first to last meta-analyses From pessimism to optimism From selected to general facts From old fashioned to modern techniques Knowledge of late side effects (thanks to long-term follow-up)

34 Post-mastectomy RT in breast cancer First meta-analysis Overall survival after 10 years of follow-up Cuzick J et al. Cancer Treat Rep 71: 15-29, 1987

35 Adjuvant RT in breast cancer First meta-analysis: consequences Contraindication of post-mastectomy radiotherapy because of late over mortality Cardiovascular complications? Second cancers? Cuzick J et al. Cancer Treat Rep 71: 15-29, 1987

36 September 2012 NB: All results are preliminary

37 Trials of Mastectomy + AD ± RT Eligibility: Unconfounded Began before 2005 Included: 24 trials RT to CW, SCF and/or axilla, and (most trials) IMC Excluded: 5 trials with no RT to CW 2 trials with pre-operative RT 38

38 Mast+AC+RT vs. Mast+AC 2/3 availability of pathological staging (p) of nodes Nodes # randomised Node-negative: pn (All N-) (1847) Node-positive: pn pn (All N+) (9106)

39 ANY FIRST RECURRENCE (%) Trials Mast + AD ± RT: pn1-3 RECURRENCE women Mast+AD 52.4% Mast+AD+RT 38.9% year gain 13.5 % (SE 2.0) Years since randomisation EBCTCG 2012: provisional results not for publication or citation 40

40 Mast+AC+RT vs. Mast+AC Any death by pathological nodal status (pn) pn0 pn1-3 pn events in 1354 women 1934 events in 3344 women 2134 events in 2876 women

41 METAANALISIS 2014 In all 22 trials for which data were available, radiotherapy was given to the chest wall and the supraclavicular or the axillary fossa (or both). In 20 of these 22 trials it was also given to the internal mammary chain Lancet 2014

42 EBCTCG meta-analysis. Recidiva Loco-regional 1º. RT vs NoRT. N0 vs N+ Mastect+RT N0 No beneficio Mastect+RT N+ RL: -18% Rec: -11% SG: - 8%

43 EBCTCG meta-analysis. Recidiva Loco-regional 1º. RT vs NoRT. N(1-3) vs N(4+) Mastect+RT N+(1-3) RL: -16.5% Rec: -11.5% SG: - 8% Mastect+RT N+ (>3) RL: -19% Rec: -9% SG: - 9.3%

44 EBCTCG meta-analysis. Recidiva Loco-regional 1º. RT vs NoRT. N+(1) vs N+(2-3) Beneficio RT Tratamiento sistémico Beneficio RT

45 Irradiación axilar y carga tumoral Manuel Algara

46 CONCLUSIÓN META-ANÁLISIS EBCTCG: Lancet 2014 in the present analysis, about one breast cancer death at 20 years was avoided for every 1 5 recurrences avoided at 10 years Poortmans P.: Lancet 2014 In 20 of 22 trials RT was given to the chest wall and FSC or the axilla fossa (or both) and it was also given to the internal mammary chain

47 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC 13 centers in France N = / /1997 m-fu 11.3 y Estadio I-II Central-Medial ó N+ Mastect < 75y R A N WBI + FSC WBI + CMI + FSC Adj CT +/- HT H0 H1: OS-10 de 40% a 50% Objetivo principal: OS-10 Hennequin C.: IJROBP 2013

48 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC Hennequin C.: IJROBP 2013

49 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC The benefit of regional irradiation in stage I III breast cancer: 10 years results of the EORTC ROG and BCG phase III trial 22922/ centers in 13 countries N = m-fu 10.9 y Estadio I-III Central-Medial ó N+ BCS o mastect R A N WBI WBI + CMI + mfsc Adj CT +/- HT H0 H1: OS-10 de 75% a 79% Objetivo principal: OS-10 Secundarios: DFS. MFS. Cause of death Struikmans H.: EJC 2014

50 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC Mediana de edad: 54 y. Postmenopaúsicas: 59% Estadio I: 33.8% Estadio II: 52% Estadio III: 14.2% CARACTERÍSTICAS DE LAS PACIENTES Linfadenectomia axilar total 54%. Parcial: 38%. BSGC: 7%. pn+: 55.6% Cirugía conservadora: Mastectomía: 76.1% (85% reciben boost ) 23.9% (73% reciben RT pared y 7% RT axila) Tratamiento sistémico adyuvante: pn+: 99% / pn0: 66.3% QT+HT: 33%; QT solo: 33%; HT solo: 33%. Struikmans H.: EJC 2014

51 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC Mediana de seguimiento: 10.9 años, Muertes observadas: OS-10 Grupo IM-MS RT: 19.1% 82.3% Grupo no IM-MS RT: 21.4% 80.7% hazard ratio [HR], (0.87) p=ns (0.0556) Supervivencia Libre de Enfermedad DFS-10 Grupo IM-MS RT: 72.1% Grupo no IM-MS RT: 69.1% hazard ratio [HR], (0.89) p=0.044 Incidencia de Metástasis MFS-10 Grupo IM-MS RT: 15.9% 75% Grupo no IM-MS RT: 19.6% 78% hazard ratio [HR], (0.86) p=0.020 pn HR > Fibrosis cardiaca: (1.3% vs 0.7%, P =.07) Cardiopatia: (8% vs 6.9%; P =.20), ( left-sided breast cancer, the outcome was not significantly worse ). Toxicidad pulmonar (6.8% vs 3.0%; P <.0001). Struikmans H.: EJC 2014

52 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC CONCLUSIÓN: With a median follow-up of more than 10 years, postoperative RT to the IM-MS LN improves overall, disease free and distant metastases free survival in patients with stage I III breast cancer without an increase in non-breast cancer related mortality. Therefore, we suggest to strongly consider radiation therapy to the internal mammary and medial supraclavicular lymph nodes for patients with involved axillary LN and/or a medially located primary tumour. Struikmans H.: EJC 2014

53 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC N = (1) (1): 2.5 Gy per fraction, 4 fractions per week Budach W.: BMC-RO 2014

54 Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC Budach W.: BMC-RO 2014