metaanalisis 2011-2014 mama la radioterapia un tratamiento ... · local treatments and radiotherapy...

METAANALISIS 2011-2014 MAMA

La radioterapia un tratamIento sistemico ???!!!!

La radioterapia post- Cirugia Conservadora.

La radioterapia post-Mastectomia.

La radioterapia loco regional CMI.

Hugo [email protected]

Institut Gustave Roussy, Villejuif, France.

Últimos ensayos clínicos en el tratamiento radioterápico del

cáncer de mama

6.- RT post-mastectomia y linfadenectomía axilar.: META-ANÁLISIS

4.- Irradiación parcial: EBRT: RAPID / IORT: TARGIT & ELLIOT.

2.- Hipofraccionamiento: START trials.

7.- Irradiación ganglionar CMI: Hennequin/ EORTC 22922-10925

5.- Ganglio centinela(+) Cirugia vs RT: EORTC AMAROS

1.- Pacientes ancianas: CALG-B; PRIME2

8.- Márgenes: Guía de consenso ASSO – ASRO.

9.- BSGC: Guía de Práctica Clínica ASCO.

3.- Hipofraccionamiento: f-IMRT trial.

Proyectos / programas

6.- Reirradiaciones pared toracica con Tomoterapia en recidivas post Cx-RT

4.- Ca-15-3 prescripción en enfermedad localmente avanzada para orientar estadificación .

2.-ganglio centinela bajo anestesia local staging prequimioterapia neoayuvante

7.- Reirradiaciones cyberknife /Tomoterapia metastasis oseas

5.- oligometastasis : sinergias nuevos fármacos + Cyberknife /Tomoterapia

1.- Determinación lecho tumoral por clips

8.- Estudio multicentrico reposicionamiento en cancer de Mama .

10.-.IOERT EN PRESERVACION AREOLA

3.- Ca-15-3 predictor de respuesta terapeutica en tratamiento sistemico recidiva/metastasis .

DESARROLLOS TECNOLOGICOS/INVESTIGACION

IOERT

ESCALADA DE DOSIS EN PACIENTES JOVENES :BOOST IOERT

IOERT : MODELO IDEAL PARA DEFINIR PERFILES DE RADIOSENSIBILIDAD.

IOERT BOOST :INVERSION DE LA SECUENCIA TERAPEUTICA CIRUGIA QUIMIO RT

PROYECTO IOERT : Bases bibliograficas

Adjuvant RT in breast cancerAlternative 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 ?

• 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.

NO

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

MODERN RT

NEW RT

NEW DRUGS

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.

63%

FROM CURE …

Co-60Années 19703% OS improvement

55%

58%

Linac 2D 1980

4.6% on survival

63%

3D 7%

2005

81%

+ 9%Tamoxifene

For RH+

patients

IMRT 8%

68%

I A 83 %2010

72%

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

5 10 15 20 25Years

Event

Loco-regional recurrence

Iatrogenic

Mortality

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

171

431

567

713

823

0

100

200

300

400

500

600

700

800

900

1000

1984/5 1990 1995 2000 2005/6 2010

Total number of trials ever received by EBCTCG

The EBCTCG worldwide cooperation

2013

Thousands of patients ever received by

EBCTCG

60

422463

577

661

0

100

200

300

400

500

600

700

800

1984/5 1990 1995 2000 2005/6 2012

The EBCTCG worldwide cooperation

2013

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

Breast cancer mortality

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)

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


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-T1 N- patients

Lumpectomy

ER+ Tam +

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+

ER-

ER+ Tam-

Age

Grade

17 estudos, ~ 11,000 pacientes

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


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

Cuzick J et al. Cancer Treat Rep 71: 15-29, 1987

Overall

survival after

10 years of

follow-up

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

Nodes # randomised

Node-negative:

pN0 1354

(All N-) (1847)

Node-positive:

pN1-3 3344

pN4+ 2876

(All N+) (9106)

2/3 availability of pathological staging (p) of nodes

10-year gain 13.5 % (SE 2.0)

Mast+AD+RT 38.9%

40.3

29.3

Mast+AD 52.4%

2801 women

0

10

20

30

40

50

60

AN

Y F

IRS

T R

EC

UR

RE

NC

E (

%)

0 5 10Years since randomisation

RECURRENCE

40

Trials Mast + AD ± RT: pN1- 3

EBCTCG 2012: provisional results not for publication or citation

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

pN0 pN1-3 pN4+

903 events in 1354 women 1934 events in 3344 women 2134 events in 2876 women

Lancet 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

METAANALISIS 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)

Tratamiento sistémico

Beneficio RT

Beneficio RT

EBCTCG: 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

CONCLUSIÓN META-ANÁLISIS

Poortmans P.: 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


cáncer de mama: RT mamaria interna + FSC

R

A

N

WBI + FSC

WBI + CMI + FSC

Estadio I-II

Central-Medial

ó N+

Mastect

< 75y

N = 1.407

01/1991 – 12/1997

m-FU 11.3 y

Objetivo principal: OS-10

Hennequin C.: IJROBP 2013

Adj CT +/- HT

13 centers in France

H0 – H1: OS-10 de 40% a 50%



Hennequin C.: IJROBP 2013



R

A

N

WBI

WBI + CMI + mFSC

Estadio I-III

Central-Medial

ó N+

BCS o mastect

N = 4.004

1.996 – 2.004

m-FU 10.9 y

Objetivo principal: OS-10

Secundarios: DFS. MFS. Cause of death

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

Struikmans H.: EJC 2014

Adj CT +/- HT

46 centers in 13 countries

H0 – H1: OS-10 de 75% a 79%




Mediana de edad: 54 y.

Postmenopaúsicas: 59%

Estadio I: 33.8%

Estadio II: 52%

Estadio III: 14.2%

Linfadenectomia axilar total 54%. Parcial: 38%. BSGC: 7%.

pN+: 55.6%

Cirugía conservadora: 76.1% (85% reciben “boost”)

Mastectomía: 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%.

CARACTERÍSTICAS DE LAS PACIENTES



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

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).

pN HR

0 0.79

1-3 0.89

4-9 0.85

>9 1.00




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.




Budach W.: BMC-RO 2014

N = 7.170

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

(1)



Budach W.: BMC-RO 2014

metaanalisis 2011-2014 mama la radioterapia un tratamiento ... · local treatments and radiotherapy...

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