Radioterapia post-chirurgia
moderne indicazioni sulla ba
della risposta alla
chemioterapia neoadiuvant
A. Fozza
Early use of CT might improve survival compared with standard postsurgical CT! not prove
Randomised clinical trials have established that NACT given before surgical removal of breast
cancer provides equivalent survival outcomes to CT after upfront surgical resection
Pathological extent of disease is modified in 80–90% of patients who receive NACT
20–40% of women with cN+ disease are converted to ypN0 disease after NACT, and this
percentage might be substantially higher in women with HER2-overexpressing tumours who
receive trastuzumab-based NACT
Primary tumor response is likely a barometer for tumor sensitivity to therapy
and may be use to help guide decisions regarding additional systemic
therapy
NACT can increase the fraction of women eligible for breast-conservation
therapy
14 studies randomizing 5500 women
  NACT is widely used in the treatment of locally advanced breast cancer and is increasingly
used for treatment of women with early stage breast cancer
  NACT is established treatment option also for early breast cancer pts
Ė possibile ridurre i trattamenti locali in pz che rispondono bene alla NACT ??!
"  Chi risponde alla NACT potrebbe avere meno bisogno di una tp locoregionale
"  Chi risponde alla NACT potrebbe avere maggior beneficio in LC e OS dall’aggiunta di tp locoregionali
È fondamentale definire dei sottogruppi di pz che dopo NACT e CH possono beneficiare o meno di
un trattamento RT locoregionale ma...
NO dati disponibili di studi randomizzati di NACT e RT adiuvante
ON-GOING RANDOMISED CLINICAL TRIAL
•  NSAPB B-51 / RTOG 1304 (open to accrual)
cT1-3 cN1 ! NACT e ypN0 ! se mastectomia PMRT+RT N vs stop
! se BCS RT breast +N vs solo RT breast
•  ALLIANCE A011202 (open to accrual)
Stage II-III (cT1-3 cN1) ! NACT e SLNB + ! ALND vs axillay RT
•  SUPREMO (selective use of postoperative radiotherapy after mastectomy) (closed accrual)
Mastectomia ! pT1-2 pN0-1 ! PMRT vs NO PMRT
NACT
Studi PROSPETTICI RANDOMZZATI
efficacia della CT (NSAPB B18-B27) ! estrapolati retrospettivamente dati LRR
udi RANDOMIZZATI/METANALISI
CH UPFRONT + CT/OT +/- RT
DBCCG 82b-82c, British Columbia Trial
MA.20
EBCTCG
dicazioni sulla base dello stadio
LINICO-PATOLOGICO (III) pre CT
RT
Studi RETROSPETTIVI
di NACT + CH +/- RT
•  MD Anderson 2002-2011
•  Fowble LB 2011
Indicazioni sulla base dello stadio
CLINICO (II-III) pre NACT e risposta
PATOLOGICA
NACT
Trial PROSPETTICI RANDOMZZATI
3088 pts stadio I-III clinico NACT+ CH:
•  mastectomia NO RT
•  BCS + RT breast
55% cT1-2 cN0
20% cT1-2 cN1
16% cT3 cN0
9% cT3 cN1
Stadio I-II
Stadio III
NACT is equivalent to ACT and ad
of taxanes improves response
NACT
ANALISI RETROSPETTIVA di trial PROSPETTICI RANDOMZZATI
NACT
ANALISI RETROSPETTIVA di trial PROSPETTICI RANDOMZZATI
MASTECTOMIA
NACT
ANALISI RETROSPETTIVA di trial PROSPETTICI RANDOMZZATI
BCS + RT breast
Poche ricadute in siti anatomici in pCR ???!!
NACT
ANALISI RETROSPETTIVA di trial PROSPETTICI RANDOMZZATI
•  NO hystologic pre-treatment N+ confirmation and small number of pts
•  Assessing LRR:
- Simultaneus systemic and LRR
- If systemic relapse NOT necessarly routine assessments for LRR
Dati sul LRR potrebbero essere SOTTOSTIMATI
NACT
Studi PROSPETTICI RANDOMZZATI
efficacia della CT (NSAPB B18-B27) ! estrapolati retrospettivamente dati LRR
udi RANDOMIZZATI/METANALISI
CH UPFRONT + tp sistemica +/- RT
BCCG 82b-82c, British Columbia Trial
A.20
BCTCG 2005-2011
dicazioni sulla base dello stadio
LINICO-PATOLOGICO (III) pre CT
RT
Studi RETROSPETTIVI
di NACT + CH +/- RT
• MD Anderson 2002-2011
• Fowble LB 2011
Indicazioni sulla base dello stadio
CLINICO (II-III) pre NACT e risposta
PATOLOGICA
Trial RANDOMIZZATI di CH UPFRONT (MASTECTOMIA +DLA) + CT/OT +/- RT
(N+ pts)
OS
Sequencing of surgery and CT should not alter this
Stadi II-III: mastectomia+ tp sistemica (OT o
+/- RT su parete e N:
•  In LABC (T3-T4, pN+) RT diminuisc
LRR e aumenta OS
Trial RANDOMIZZATI di CH UPFRONT (MASTECTOMIA +DLA) + CT +/- RT
Stadio clinico II-III
LR
Rianalisi di 1000 pts
DSS
OS
Aumento in LC potrebbe determinare
un aumento della OS in pz con bass
rischio di ripresa sistemica
(pN1, pT1, ER+, HER-2 neg)
METANALISI di CH UPFRONT (MASTECTOMIA +DLA) + CT +/- RT
L
pN-
pN0 pts the 5-year LRR after mastectomy and
LND was only 6% even in the absence of RT ! RT
duces it to 2%, the absolute 5-year gain is only
% and there is no significant reduction in 15-year
C mortality
pN+ pts the 5-year LRR rate after mastectomy
nd ALND is 23% without RT and RT reduces it to
%. The proportional reduction in the LRR rate by
T is similar in pN+ and in pN-, the absolute 5-year
ain is much larger (17%).
pN+ pts the 15-year BC mortality + or - PMRT is
% vs 60% ! absolute reduction of 5%
BC
pN+
METANALISI di CH UPFRONT (MASTECTOMIA +DLA) + CT +/- RT
EBCTCG Lancet 2005
EBCTCG Lancet 2005
Improved LC at 5 years resulted in a highly statistically
gnificant improvement in both BCS and OS at 15 years
The absolute reduction in the 5-year rate of LRR between
eatment groups was proportional to the absolute reduction
15-year breast-cancer mortality
Treatments that had ≥ 10% reduction in the 5-year
sk of LR, BC mortality was reduced by 1.6% at 5 years, 3.7%
t 10 years, and 4.9% at 15 years.
The addition of RT significantly improved 15-year absolute
S after BCS by 5.3% (P = 0.005) and after mastectomy in Treatments with little effect on the risk of LR have no
effect on mortality.
ode-positive patients by 4.4% (P = 0.001)
Those with a greater effect on such recurrence have a
corresponding reduction in mortality
RANDOMIZZATO di CH UPFRONT (BCS + DLA) + CT /OT+ RT linfonodale
ASCO 2011
1832 pNo high risk pts or pN
BCS + WBRT vs
BCS + WBRT + RNI
provements in LC and DFS and a trend in OS with the addition of nodal RT to
east RT
NACT
Studi PROSPETTICI RANDOMZZATI
efficacia della CT (NSAPB B18-B27) ! estrapolati retrospettivamente dati LRR
udi RANDOMIZZATI/METANALISI
CH UPFRONT + tp sistemica +/- RT
BCCG 82b-82c, British Columbia Trial
A.20
BCTCG 2005-2011
dicazioni sulla base dello stadio
LINICO-PATOLOGICO (III) pre CT
RT
Studi RETROSPETTIVI
di NACT + CH +/- RT
• MD Anderson 2002-2011
• Fowble LB 2011
Indicazioni sulla base dello stadio
CLINICO (II-III) pre NACT e risposta
PATOLOGICA
Trial RETROSPETTIVI di CH + ACT vs NACT + CH (senza RT)
Stadio clinico I-III
150 pts stadio clinico I-III: NACT + mastectomia e NO RT vs 1031 CH upfront
Trial RETROSPETTIVI di NACT + CH (mastectomia) senza RT
Stadio clinico II-III
150 clinical stage I-IV:
• 1% stage I
• 43% stage II (cT1-2 N1, cT3 N0)
• 23% stage IIIA (cT1-3 N2)
• 25% stage IIIB (cT4 cN0-2)
• 7% stage IV (cM1)
•  Pre-treatment factors that positively correlated with
LRR were increasing T stage (P < .0001) and
increasing combined clinical stage (P <.0001).
Trial RETROSPETTIVI di NACT + CH (mastectomia) senza RT
•  Pathologic and treatment factors tha
positively correlated with LRR were siz
the residual primary tumor (P .0048)
increasing number of involved lymph
nodes (P < .0001), and no OT (P.0013
•  The 5year-LRR rate for the 18 pts with
pCR was 19% (95% CI, 6% -48%)
Achievement of pCR does not preclude the need for postmastectomy radiation if
warranted by the pretreatment stage of the disease.
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
68% stadio III
cT1-2 cN2
cT3 cN1-2
cT4
cN2
Stadio clinico II-III
676 pts: 542 PMRT e 134 no PMRT
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
LRR rate
PMRT: LC and OS benefit for cT3 or stage III disease and ypN2
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
Stadio clinico I-II
Stadio clinico
132 stage I-II pts
Stadio patologico
N = 83
N = 56
N = 42
N = 46
N = 19
N=6
5 year LRRFS
19% CR
73% PR
6% SD
2% PD
Overall 5 yr LRR
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
• 
• 
• 
• 
• 
• 
• 
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
stage I-III in pCR
Stadio clinico II-III
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
Stadio clinico II
162 cT3 N0
Trial RETROSPETTIVI di NACT + CH (mastectomia) +/- RT
Stadio clinico II
(57 ps)
(32 pts)
cT3N0 with NAC without
PMRT had a significant
risk of LRR, even in ypN0.
PMRT was effective in
reducing the LRR rate
PMRT should be considered for patients with clinical cT3N0 disease also in ypN0
(62 pts)
(11 pts)
Breast cancer physicians (University of California)
4 Hypothetical clinical case scenarios
MEDLINE and Cochrane databases)
vidence tables with endpoints of LRF, DFS and OS
cal stage II (T1-2 N0-1)
d >40 years
PgR +
1 and no LVI and no ECE
≤10% risk of LRF
without PMRT
ed data support stage IIIA (cT3 N1, cT1-3 N2)
pCR as low risk
RT has risks (pulmonary risks, cardiac risks, lymphedema, secondary malignancies). The potential
benefits of RT need to be considered in the context of these risks. Care must be taken to minimize the
isks and optimize the therapeutic ratio
Studies that consider reductions in local therapies on the basis of good response to systemic
herapies should be undertaken with caution and within the confines of a retrospective trial
The weight of the evidence suggests PMRT and nodal RT in conjunction with breast RT provide the mos
survival benefits also in those patients who are good responders to systemic therapy ! absent
participation in a clinical trial, responders to preoperative chemotherapy should generally receive locoregion
RT
Continually trying to identify subgroups of patients and individualizing therapy accordingly.
Personalized medicine is certainly the current rage, and the attraction of such an approach is self-evident.
CONCLUSIONI
Non dati di studi randomizzati di NACT e RT ma trial ONGOING
Stadio III (LABC: cT3 N1, cT4, cN2) ! sempre RT mammella/parete e N (vantaggi in LC e OS)
Stadio II (cT1-2 cN1, cT2-3 cN0):
se ypT3 e/o ypN1-2 ! RT mammella/parete e N
se ypT1-2 ypN0 ! RT mammella; su parete e N in base a stadio clinico (cT3 vs cT1-2, cN1 vs
cN0, ypT2 vs ypT1) e FdR ??!
se ypT0 ypN0 (pCR) ! RT mammella; su parete e N in base stadio clinico (cT3 vs cT1-2, cN1 vs c
e FdR ??!
FdR: età<40aa, G3, LVI, ER/PgR neg, biologia sfavorev
…GRAZIE!
SLNB in cN0 pts
STUDI RANDOMIZZATI
LNB ! FNR 7-10% ma ricadute in ascella in pz con SLNB neg < 1%
NACT
STUDI RANDOMIZZATI
NSAPB B-18 ! NACT riduce la positività alla DLA dal 57% al 41%
SLNB dopo NACT in cN0 pts
STUDI RETROSPETTIVI
SLNB dopo NACT in cN0 pts ! studi retrospettivi confermano FNR uguale a FNR in pz che lo fanno
prima di NACT
! accuratezza del SLNB decresce in base a diverse variabili, tra cui cN+
SLNB dopo NACT in cN+ pts
STUDI RETROSPETTIVI
SLNB dopo NACT in cN+ pts ! studi retrospettivi riportano FNR tra il 20-27% ! DLA è lo standard
SLNB dopo NACT in cN+ pts
STUDIO DI FATTIBILITÀ
SLNB dopo NACT in cN+ pts
STUDIO DI FATTIBILITÀ
SLNB IR 84.8% (363/428)
SLNB FNR 10.7%(15/140)
SLNB IR non influenzato da T size, N
status and age
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
ACOSOG Z1071: cT0-4 cN1-2 pts
I end point: FNR in SLNB dopo NACT
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
63 cN1(bx) pts (SLNB IR 92.7%)
40% convertiti pN0 e 60% (382 pts) pN+
25 pts ≥2 SLN (criterio di elegibilità)
! 39 pts BLSN neg ma DLA +
! FNR 12.6% (39/310) (cut off FNR <10%)
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
FNR: 1 SLN ! 31.5%
2 SLN ! 21%
3 SLN ! <10%
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
tot in 4 bracci
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
I end point: FNR in SLNB dopo NACT
! 592 cN+ (no bx). SLNB IR 80.1%
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
FNR 14.2% (32/226)
NB: median SLN = 2 (come in NSABP B-32)
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
NB: pts cN0 con SLNB+ pre NACT e SLNB post NACT hanno IR 60.8%, %FN 51.6%!!! NON
NDICATO ULTERIORE SLNB DOPO NACT
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
SLNB dopo NACT in cN+ pts
STUDI PROSPETTICI
141 cN+ pts (incluse N0 i+)
SLNB IR 87.2%(123/141)
FNR 9.9% (8/81)
FNR 19%(4/21) se 1solo LSN
SLNB dopo NACT in cN+ pts
• In NSABP B-32 9.8% FNR ma solo 0.7% di recidiva ascellare
• ACOSOG Z0011 27% pts malattia in altri N oltre al SLN, ma solo 0.9% recidive ascellari.
Pts con SLN+ e non-DLA non >mts o death ! gli eventuali foci residui micro in cN0 pts
non impattano in > eventi clinici se lasciati in sede ??! NB: altro setting di pts
•  Non noti dati di long term LR e OS in pts cN+ che fanno NACT e SLNB (solo dati di
IR e FNR) ma queste pts hanno tra il 20 e 30% di rischio di malattia ascellare residua
dopo BLSN ! SLNB NO STANDARD (Morrow M, JAMA 2013)
• Studi prospettici dimostrano che FNRè <10% (sovrapponibile a quella accettata del SLNB
senza NACT SOLO se SLN ≥ 3!!! ! SAMPLING e non più SLNB
• La presenza di malattia in ascella dopo NACT puo’ impattare su ulteriori scelte tp (volumi
RT adiuvante, protocolli di ricerca)??!
SLNB dopo NACT in cN+ pts
ASCO GUIDELINES 2014