metaanalisis 2011-2014 mama la radioterapia un tratamiento ... · local treatments and radiotherapy...
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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
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-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+
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
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
Irradiación axilar y carga tumoral
© Manuel Algara
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
Últimos ensayos clínicos en el tratamiento radioterápico del
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%
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
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%
Últimos ensayos clínicos en el tratamiento radioterápico del
cáncer de mama: RT mamaria interna + FSC
Struikmans H.: EJC 2014
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
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
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
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
Budach W.: BMC-RO 2014
N = 7.170
(1): 2.5 Gy per fraction, 4 fractions per week
(1)
Últimos ensayos clínicos en el tratamiento radioterápico del
cáncer de mama: RT mamaria interna + FSC
Budach W.: BMC-RO 2014