METAANALISIS 2011-2014 MAMA La radioterapia un tratamIento sistemico ???!!!! La radioterapia post- Cirugia Conservadora. La radioterapia post-Mastectomia. La radioterapia loco regional CMI.

Hugo Marsiglia [email protected] Institut Gustave Roussy, Villejuif, France.

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 22922-10925 8.- Márgenes: Guía de consenso ASSO – ASRO. 9.- BSGC: Guía de Práctica Clínica ASCO.

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 .

10.-.IOERT EN PRESERVACION AREOLA

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

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: 709-15, 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, 213-22, 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: 2869-78, 1995

2007;356:2399-2405.

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: 213-22, 1988 Auquier A et al. Eur J Cancer 28: 433-7, 1992 Arriagada R et al. J Clin Oncol 13: 2869-78, 1995 Overgaard M et al. NEJM & Lancet, 1997, 1999.

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

TAMOXIFEN

NEW DRUGS

MODERN RT

NEW RT

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.

FROM CURE … 72%

IMRT 8%

IA

83 %

2010

3D

68%

7%

81%

2005 63%

Linac 2D

63%

1980 4.6% on survival

Co-60

Années 1970

3% OS improvement

58% 55%

+ 9%

Tamoxifene

For RH+ patients

BREAST MORPHOLOGY

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

Long-term iatrogenic effects of breast cancer Radiotherapy Time scale: minimal time of observation Event Loco-regional recurrence Mortality Iatrogenic

5

10

15

20

Years Arriagada R, Acta Oncol, 45: 514-6, 2006

25

The EBCTCG worldwide cooperation Total number of trials ever received by EBCTCG

1000 900

823

800

713

700

567

600 500

431

400 300

200

171  2013

100 0

1984/5

1990

1995

2000

2005/6

2010

The EBCTCG worldwide cooperation Thousands of patients ever received by EBCTCG 800

661

700

577

600 500

422

463

400 300 200 100

60

 2013

0

1984/5

1990

1995

2000

2005/6

2012

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: 2087-2106, 2005

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: 2087-2106, 2005

Local treatments and radiotherapy comparisons - Increased local control  survival effects - Equivalence? : BCS + RT vs Mastectomy

- Predictive factors: BCS ± RT (Lancet 378: 1707-16, 2011) - Mastectomy ± RT - Late iatrogenic effects

Local treatments and radiotherapy comparisons

- Predictive factors: BCS ± RT Lancet 378: 1707-16, 2011

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

Predictive factors

- BCS ± RT

- Lancet 378: 1707-16, November 2011 - Is the absolute RT effect homogeneous among all subgroups of patients ?

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: 1707-16, 2011

BCS ± RT

All patients

Any first recurrence: excludes contralateral breast cancer

Radioterapia post BCS

BCS ± RT : T1 N- patients Lumpectomy ER+ Tam +

T1 N-

RT benefits on recurrence according to:

Age Grade

Black + white bar:

Absolute recurrence rate in group without RT

Black bar:

Absolute recurrence rate in RT group

White bar:

Absolute recurrence gain related to RT

N- patients, predictive factors of RT effect

BCS ± RT : 5,682 T1 N- patients

RT benefits on recurrence according to: Lumpectomy vs more ER+ Tam+ ERER+ TamAge Grade

17 estudos, ~ 11,000 pacientes

Baixo risco: pT1-2, N-, margens negativas, ou idade > 65, e/ou RH+

Local treatments and radiotherapy comparisons

Mastectomy ± RT

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

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)

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

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

September 2012 NB: All results are preliminary

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

Mast+AC+RT vs. Mast+AC 2/3 availability of pathological staging (p) of nodes

Nodes

# randomised

Node-negative: pN0

1354

(All N-)

(1847)

Node-positive: pN1-3

3344

pN4+

2876

(All N+)

(9106)

Trials Mast + AD ± RT: pN1- 3 RECURRENCE 60

2801 women

Mast+AD 52.4%

ANY FIRST RECURRENCE (%)

50 40.3

40

Mast+AD+RT 38.9% 30 29.3

20

10

10-year gain 13.5 % (SE 2.0) 0 0

5 10 Years since randomisation

40 EBCTCG 2012: provisional results not for publication or citation

Mast+AC+RT vs. Mast+AC Any death by pathological nodal status (pN) pN0

903 events in 1354 women

pN1-3

pN4+

1934 events in 3344 women 2134 events in 2876 women

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

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%

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%

EBCTCG meta-analysis. Recidiva Loco-regional 1º. RT vs NoRT.

N+(1) vs N+(2-3)

Beneficio RT

Tratamiento sistémico

Beneficio RT

Irradiación axilar y carga tumoral

© Manuel Algara

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

Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC

13 centers in France

N = 1.407 01/1991 – 12/1997 m-FU 11.3 y Estadio I-II Central-Medial ó N+ Mastect < 75y

R

WBI + FSC

Adj CT +/- HT

A

N

WBI + CMI + FSC

H0 – H1: OS-10 de 40% a 50% Objetivo principal: OS-10 Hennequin C.: IJROBP 2013

Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC

Hennequin C.: IJROBP 2013

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 22922/10925 46 centers in 13 countries

N = 4.004 1.996 – 2.004 m-FU 10.9 y Estadio I-III Central-Medial ó N+ BCS o mastect

R

WBI

Adj CT +/- HT

A

N

WBI + CMI + mFSC

H0 – H1: OS-10 de 75% a 79% Objetivo principal: OS-10 Secundarios: DFS. MFS. Cause of death Struikmans H.: EJC 2014

Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC CARACTERÍSTICAS DE LAS PACIENTES Mediana de edad: 54 y. Postmenopaúsicas: 59% Estadio I: Estadio II: Estadio III:

33.8% 52% 14.2%

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

Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC Mediana de seguimiento: 10.9 años, Muertes observadas: Grupo IM-MS RT: Grupo no IM-MS RT: hazard ratio [HR],

19.1% 21.4% (0.87)

OS-10 82.3% 80.7% p=NS (0.0556)

Supervivencia Libre de Enfermedad Grupo IM-MS RT: Grupo no IM-MS RT: hazard ratio [HR], (0.89)

DFS-10 72.1% 69.1% p=0.044

Incidencia de Metástasis Grupo IM-MS RT: Grupo no IM-MS RT: hazard ratio [HR],

MFS-10 75% 78% p=0.020

15.9% 19.6% (0.86)

pN 0 1-3 4-9 >9

HR 0.79 0.89 0.85 1.00

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

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

Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC

N = 7.170

(1)

(1): 2.5 Gy per fraction, 4 fractions per week

Budach W.: BMC-RO 2014

Últimos ensayos clínicos en el tratamiento radioterápico del cáncer de mama: RT mamaria interna + FSC

Budach W.: BMC-RO 2014