1. Small Breast Cancers Radiotherapy:
Locoregional Treatments particularities ?
(Infiltrative Cancers)
Dr Alain Haim TOLEDANO – Radiation Oncologist
Centre de Radiothérapie HARTMANN - Levallois-Perret
Head of Medical & Oncology Department– American Hospital of Paris

2. William HALSTEAD
First mastectomy in 1882
. Spread of tumor cells in a contiguous manner
. lymph. spreading / extensionà « En bloc » dissection
. Ly. diffusion : precursor, instigator of metastases
. Node : barrier for tumor cells dissemination
. Importance of Nodes Anatomy
. Little importance of « bloodstream » in diffusion
. Tumor is autonomous, independant of its host
. Breast Cancer = Locoregional Desease
. Locoregional Treatment : determinant for prognosis
. No consideration to tumor multicentricity
Hypothesis William HALSTEAD (1894)

3. Bernard FISHER
NSABP Leader
. No orderly pattern of tumor cell dissemination
. lymph. spreading/ embolisat°: no « en bloc » dissect°
. Ly. diffusion : indicator rather than instigator of mets
. Node : Ineffective barrier to tumor cell spread
. Regional Lymph Nodes are of Biologic Importance
. Importance of « bloodstream » in dissemination
. Complexe Host-Tumor: interrelationships, affect disease
. Operable Breast Cancer = Systemic Disease
. Locoregional Treatment : No impact on Overall Survival
. Multicentricity : not necessaryprecursor of cancer dev.
Hypothèses Bernard FISHER (1968)

4. T = 8 mm
SIMPLE MODEL =
1 tumor < 1cm, early diagnosis, did not have time to spread,
Therapeutic deflation

5. T = 18 mm
1 N+
SIMPLE MODEL =
1 tumor < 1cm, early diagnosis, did not have time to spread,
Therapeutic deflation

6. T = 38 mm
x N+ / M+
Good Theory the more often: so, screening, curative TT
without sequellae…
SIMPLE MODEL =
1 tumor < 1cm, early diagnosis, did not have time to spread,
Therapeutic deflation

7. T = 8 mm
REALITY =
1 tumor < 1cm, early diagnosis, may have already metastased…
x N+ / M+

8. T T
×
. Why 20-30% of Node Negative breast Cancers = Mestastases at 10 ans ?
HALSTEAD vs FISHER
Which reality small of T ?
A third hypothesis « the spectrum thesis » (1994) considers breast cancer
to be a heterogeneous disease that can be thought of as a spectrum of
proclivities (tendencies) extending from a disease that remains local
throughout its course to one that is systemic when first detectable

10. Can we decrease aggressivness of small
tumors locoregional treatments ?
Can we identify sub-groups candidates to
Therapeutic deflation ?

11. R
Radiotherapy + Tamoxifen (n=386)
Tamoxifen (n=383)
. Phase III trial, randomised, inclusions 1992 – 2000
. 769 patients, 5.6 years median follow-up
. Age > 50 years. T < 5 cm (T1, T2). Free Exerese Margins. N-
. Stratification : Size (<,>2 cm) . ER . Node Statut . Center
. 1572 eligibles patients , 899 refused the study = 57,2%
. 159 patients (/769) did not received the 5 years TAM (75/383p arm TAM)
NEJM 2004

12. RT + Tam Tam Valeur p
5 years Local recurrence
Rate - 611 pts T1
0,4% 5,9% < 0,001
5 y Recurrence Number 27 54
8 y Loval Recurrence Rate
(n = 86 pts)
3,5% 17,6% < 0,05
5 y axillary recurrence rate
0,5% 2,5% 0,048

13. R
Radiotherapy + Tamoxifen (n=317)
Tamoxifen (n=319)
. Phase III trial, randomised, inclusions 1994 – 1999
. 636 patients, 5 years median follow-up
. Age > 70 year<s . T1 . Free Exerese Margins . N- . HR+
. Stratification : . Axillary dissection . Age <> 75 ans

14. RT +
Tam
Tam Valeur p
5 y Local Recurrence Rate 1% 4% < 0,001
At 10 years DFS Hugues JCO 2013 98% 90% <0,05
5 y Recurrence Number 2 16
Metastatic Recurrences
(n = 86 pts)
7 7 ns
Secondary Mastectomy 2 6 ns

15. . Phase III trial, randomised, inclusions 1996 – 2004
. 869 patients, 53,8 months median follow-up
. Middle Age 66 years . T < 3 cm . Free Margins . HR+ . Gr I,II . N-
. Stratification : . Age . Hormo.tt . Node Statut . Grade . Center
Radiotherapy + Tam or AI (n=414)
Tam or AI (n=417)
R

16. RT + Ho Ho Valeur p
5y Local recuurence Rate
À 6 ans
0,4%
0,4%
5,1%
9%
0,001
5 y Reccurence Number 2 19

17. n Phase III trial, randomised
n 264 patients, 12,1 years median follow-up
n Middle Age > 40 years . T < 2 cm . Free Margins > 1 cm
n HR+ . N- . « low agressivity » (Ki 67<10%, phase S < 7%)
n Stratification : . Age . Hormon.tt . Node Statut . Grade . Center
Radiotherapy
Observation
R
Local Recurrence
- 11, 6 %
p= 0,0013
- 27,2 %

18. Rechute locale
RT + Ho
Rechute locale
Ho
Fischer et al.
at 8 ans
2,8 % 16,5 %
Fyles et al.
at 8 ans
3,5 % 17,6 %
Hughes et al.
at 7 ans
1 % 7 %
Potter et al.
at 6 ans
0,4 % 9 %
Holli et al.
at 12 ans
11,6 % 27,2 %
Historically : Local recurrence Rate – arm without Radiotherapy :
- 35 % RL at 8 years ; Clark , JNCI 1996
- 24 % RL at 10 years ; Liljegren , JCO 1999
Less selected Tumors …

19. New breast cancers molecular classifications
What is the impact on recurrence ?
Genetic Substratum for the different biological profiles
Luminal A : RO+ ou RP+ Her2-
Luminal B : RO+ou RP+ Her2+
Her2+ : RO- RP-Her2+
Basal : RO-RP-Her2-
. 797 patients (Dana-Farber, Massachusetts), fu 70 months
. Sub-types : Luminal A, Luminal B, Her2+, Basal
Local Recurrences : Her2+ & Basal > Luminal A & B (p=s)
Metastases : Her2+ & Basal > Luminal A & B (p=s)
N’Guyen et al. JCO 2008
Local Recurrence rate is associated to :
Factors HR ajusted IC-95% p-valeur
HER-2 9.2 1.6-51 0.012
Triple NEG 7.1 1.6-31 0.009
Nguyen PL et al. JCO 2008;26:2373-8

20. Joensuu et al. Clin Cancer Res 2003
pT1a
HER2+
/
N-­‐
T<
1
cm
Press et al. J Clin Oncol 15:2894-2904
5-10 mm
HER2-
HER2+
HER2-
HER2-
HER2+
HER2+

21. Breast 3D Radiotherapy

23. Tumorectomy + Radiotherapy
Good Cosmetic Results for majority of patients
Toledano et al. IJROBP 2007

24. Niméus-Malström E et al. Br Cancer Res 2008
All Reccurences are not the same …

25. T1 , N0 without systemic treatment :
- 90% 10 years - Recurrence Free Survival (RFS)
- 75% 10y RFS if Grade III and/or emboles vasc.
1259
ptes
T1N0
of
NSABP
/
RFS
at
8
ans
Surgery
alone
Surgery
+
systemic
<
RE
-­‐
81%
90%
(chemo)
RE
+
86%
93%
(Tam)

26. For 4 locoregional recurrences avoided at 5 years = 1 saved life at 15 years

27. Schroen et al. JCO05
Ballast et al. IJROBP06Relation between distance to RT
Type of breast surgery for T1
16 40 80 >80

28. Irradiation Partial Accelerated
2 concepts :
- Irradiation of a partial breast volume
- Irradiation hypofractionnated accelerated
Up to 30% of women in North America
who undergo breast-conserving surgery
do not undergo breast irradiation, in
part because of the inconvenience of
the therapy and its cost.

29. French physiologist Claude Bernard,
who focused attention on deductive scientific
research, and who stated that :
Bernard C: Introduction àl’Etude de la Médecine Experimentale. Paris, France, J.B. Bailliere, 1865
“A hypothesis, is the obligatory starting point of all
experimental reasoning, and is only of value if it can be
tested »

30. The American « engouement » for mammosite
Abbott et al.(SEER) Cancer 2011
Clinical Application before scientific proof

31. CONSENSUS STATEMENT
ACCELERATED PARTIAL BREAST IRRADIATION CONSENSUS STATEMENT FROM
THE AMERICAN SOCIETY FOR RADIATION ONCOLOGY (ASTRO)
BENJAMIN D. SMITH, M.D.,*y
DOUGLAS W. ARTHUR, M.D.,z
THOMAS A. BUCHHOLZ, M.D.,y
BRUCE G. HAFFTY, M.D.,x
CAROL A. HAHN, M.D.,k
PATRICIA H. HARDENBERGH, M.D.,{
THOMAS B. JULIAN, M.D.,#
LAWRENCE B. MARKS, M.D.,** DORIN A. TODOR, PH.D.,z
FRANK A. VICINI, M.D.,yy
TIMOTHY J. WHELAN, M.D.,zz
JULIA WHITE, M.D.,xx
JENNIFER Y. WO, M.D.,kk
AND JAY R. HARRIS, M.D.{{
*Radiation Oncology Flight, Wilford Hall Medical Center, Lackland AFB, TX; y
Department of Radiation Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, TX; z
Department of Radiation Oncology, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA; x
Department of Radiation Oncology, University of Medicine and Dentistry of New Jersey –
Robert Wood Johnson Medical School, New Brunswick, NJ; k
Department of Radiation Oncology, Duke University Medical School,
Durham, NC; {
Shaw Regional Cancer Center, Veil, CO; #
Department of Human Oncology, Allegheny General Hospital, Pittsburgh,
PA; **Department of Radiation Oncology, University of North Carolina Medical School, Chapel Hill, NC; yy
Department of Radiation
Oncology, William Beaumont Hospital, Royal Oak, MI; zz
Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON,
Canada; xx
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; kk
Harvard Radiation Oncology
Residency Program, Boston, MA; and {{
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s
Hospital, Boston, MA
Purpose: To present guidance for patients and physicians regarding the use of accelerated partial-breast irradia-
tion (APBI), based on current published evidence complemented by expert opinion.
Methods and Materials: A systematic search of the National Library of Medicine’s PubMed database yielded 645
candidate original research articles potentially applicable to APBI. Of these, 4 randomized trials and 38 prospec-
tive single-arm studies were identified. A Task Force composed of all authors synthesized the published evidence
and, through a series of meetings, reached consensus regarding the recommendations contained herein.
Results: The Task Force proposed three patient groups: (1) a ‘‘suitable’’ group, for whom APBI outside of a clinical
trial is acceptable, (2) a ‘‘cautionary’’ group, for whom caution and concern should be applied when considering
APBI outside of a clinical trial, and (3) an ‘‘unsuitable’’ group, for whom APBI outside of a clinical trial is not gen-
erally considered warranted. Patients who choose treatment with APBI should be informed that whole-breast
irradiation (WBI) is an established treatment with a much longer track record that has documented long-term
effectiveness and safety.
Reprint requests to: Benjamin D. Smith, M.D., 2200 Bergquist
Drive, Suite 1, Lackland AFB, TX 78236. Tel: (210) 292-5589;
Fax: (210) 292-3773; E-mail: benjamin.smith@lackland.af.mil
Supplementary material for this article can be found at www.
redjournal.org.
This document was prepared by the Accelerated Partial Breast
Irradiation Consensus Statement Task Force of the Health Services
Research Committee of the American Society for Radiation Oncol-
ogy (ASTRO).
Before initiation of this Consensus Statement, all members of the
Task Group writing the Statement were required to complete conflict
of interest statements. These statements are maintained at ASTRO
Headquarters in Fairfax, VA, and pertinent conflict information is
published with the report. Individuals with disqualifying conflicts
have been recused from participation in this Consensus Statement.
these guidelines should not be deemed inclusive of all proper
methods of care or exclusive of other methods of care reasonably di-
rected to obtaining the same results. The ultimate judgment regard-
ing the propriety of any specific therapy must be made by the
physician and the patient in light of all the circumstances presented
by the individual patient. ASTRO assumes no liability for the infor-
mation, conclusions, and findings contained in its consensus state-
ments. In addition, these guidelines cannot be assumed to apply to
the use of these interventions performed in the context of clinical tri-
als, given that clinical studies are designed to evaluate or validate in-
novative approaches in a disease for which improved staging and
treatment are needed or are being explored.
This Consensus Statement was prepared on the basis of informa-
tion available at the time the Task Group was conducting its research
and discussions on the topic. There may be new developments that
CONSENSUS STATEMENT
ACCELERATED PARTIAL BREAST IRRADIATION CONSENSUS STATEMENT FROM
THE AMERICAN SOCIETY FOR RADIATION ONCOLOGY (ASTRO)
BENJAMIN D. SMITH, M.D.,*y
DOUGLAS W. ARTHUR, M.D.,z
THOMAS A. BUCHHOLZ, M.D.,y
BRUCE G. HAFFTY, M.D.,x
CAROL A. HAHN, M.D.,k
PATRICIA H. HARDENBERGH, M.D.,{
THOMAS B. JULIAN, M.D.,#
LAWRENCE B. MARKS, M.D.,** DORIN A. TODOR, PH.D.,z
FRANK A. VICINI, M.D.,yy
TIMOTHY J. WHELAN, M.D.,zz
JULIA WHITE, M.D.,xx
JENNIFER Y. WO, M.D.,kk
AND JAY R. HARRIS, M.D.{{
*Radiation Oncology Flight, Wilford Hall Medical Center, Lackland AFB, TX; y
Department of Radiation Oncology, The University of
Texas M. D. Anderson Cancer Center, Houston, TX; z
Department of Radiation Oncology, Medical College of Virginia, Virginia
Commonwealth University, Richmond, VA; x
Department of Radiation Oncology, University of Medicine and Dentistry of New Jersey –
Robert Wood Johnson Medical School, New Brunswick, NJ; k
Department of Radiation Oncology, Duke University Medical School,
Durham, NC; {
Shaw Regional Cancer Center, Veil, CO; #
Department of Human Oncology, Allegheny General Hospital, Pittsburgh,
PA; **Department of Radiation Oncology, University of North Carolina Medical School, Chapel Hill, NC; yy
Department of Radiation
Oncology, William Beaumont Hospital, Royal Oak, MI; zz
Department of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON,
Canada; xx
Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; kk
Harvard Radiation Oncology
Residency Program, Boston, MA; and {{
Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s
Hospital, Boston, MA
Purpose: To present guidance for patients and physicians regarding the use of accelerated partial-breast irradia-
tion (APBI), based on current published evidence complemented by expert opinion.
Methods and Materials: A systematic search of the National Library of Medicine’s PubMed database yielded 645
candidate original research articles potentially applicable to APBI. Of these, 4 randomized trials and 38 prospec-
tive single-arm studies were identified. A Task Force composed of all authors synthesized the published evidence
and, through a series of meetings, reached consensus regarding the recommendations contained herein.
Results: The Task Force proposed three patient groups: (1) a ‘‘suitable’’ group, for whom APBI outside of a clinical
trial is acceptable, (2) a ‘‘cautionary’’ group, for whom caution and concern should be applied when considering
APBI outside of a clinical trial, and (3) an ‘‘unsuitable’’ group, for whom APBI outside of a clinical trial is not gen-
erally considered warranted. Patients who choose treatment with APBI should be informed that whole-breast
irradiation (WBI) is an established treatment with a much longer track record that has documented long-term
effectiveness and safety.
Reprint requests to: Benjamin D. Smith, M.D., 2200 Bergquist
Drive, Suite 1, Lackland AFB, TX 78236. Tel: (210) 292-5589;
Fax: (210) 292-3773; E-mail: benjamin.smith@lackland.af.mil
Supplementary material for this article can be found at www.
redjournal.org.
This document was prepared by the Accelerated Partial Breast
Irradiation Consensus Statement Task Force of the Health Services
these guidelines should not be deemed inclusive of all proper
methods of care or exclusive of other methods of care reasonably di-
rected to obtaining the same results. The ultimate judgment regard-
ing the propriety of any specific therapy must be made by the
physician and the patient in light of all the circumstances presented
by the individual patient. ASTRO assumes no liability for the infor-
mation, conclusions, and findings contained in its consensus state-
Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 4, pp. 987–1001, 2009
Copyright Ó 2009 American Society for Radiation Oncology. Published by Elsevier Inc.
Printed in the USA.
0360-3016/09/$–see front matter
doi:10.1016/j.ijrobp.2009.02.031
consistent with the presence of a mutation, should not receive
APBI outside of a clinical trial because of the absence of lit-
erature supporting the use of APBI in this setting.
Table 2. Patients ‘‘suitable’’ for APBI if all criteria are
present
Factor Criterion
Patient factors
Age $60 y
BRCA1/2 mutation Not present
Pathologic factors
Tumor size #2 cm*
T stage T1
Margins Negative by at least 2 mm
Grade Any
LVSI Noy
ER status Positive
Multicentricity Unicentric only
Multifocality Clinically unifocal with total size
#2.0 cmz
Histology Invasive ductal or other favorable
subtypesx
Pure DCIS Not allowed
EIC Not allowed
Associated LCIS Allowed
Nodal factors
N stage pN0 (i-
, i+
)
Nodal surgery SN Bx or ALNDjj
Treatment factors
Neoadjuvant therapy Not allowed
Abbreviations: APBI = accelerated partial-breast irradiation;
LVSI = lymph–vascular space invasion; ER = estrogen receptor;
DCIS = ductal carcinoma in situ; EIC = extensive intraductal com-
ponent; LCIS = lobular carcinoma in situ; SN Bx = sentinel lymph
node biopsy; ALND = axillary lymph node dissection.
Criteria are derived from data (when available) and conservative
panel judgment.
Table 3. ‘‘Cautionary’’ group: Any of these criteria should
invoke caution and concern when considering APBI
Factor Criterion
Patient factors
Age 50–59 y
Pathologic factors
Tumor size 2.1–3.0 cm*
T stage T0 or T2
Margins Close (<2 mm)
LVSI Limited/focal
ER status Negativey
Multifocality Clinically unifocal with total size
2.1–3.0 cmz
Histology Invasive lobular
Pure DCIS #3 cm
EIC #3 cm
Abbreviations as in Table 2.
* The size of the invasive tumor component as defined by the
American Joint Committee on Cancer (81).
y
Patients with ER-negative tumors are strongly encouraged to
enroll in the National Surgical Adjuvant Breast and Bowel Project
B-39/Radiation Therapy and Oncology Group 04-13 clinical trial
(78).
z
Microscopic multifocality allowed, provided the lesion is clini-
cally unifocal (a single discrete lesion by physical examination and
ultrasonography/mammography) and the total lesion size (including
foci of multifocality and intervening normal breast parenchyma)
falls between 2.1 and 3.0 cm.
APBI consensus statement d B. D. SMITH et al. 991
Table 2. Patients ‘‘suitable’’ for APBI if all criteria are
present
Factor Criterion
t factors
e $60 y
CA1/2 mutation Not present
logic factors
mor size #2 cm*
tage T1
rgins Negative by at least 2 mm
de Any
SI Noy
status Positive
lticentricity Unicentric only
ltifocality Clinically unifocal with total size
#2.0 cmz
tology Invasive ductal or other favorable
subtypesx
e DCIS Not allowed
C Not allowed
ociated LCIS Allowed
factors
tage pN0 (i-
, i+
)
dal surgery SN Bx or ALNDjj
ment factors
oadjuvant therapy Not allowed
breviations: APBI = accelerated partial-breast irradiation;
= lymph–vascular space invasion; ER = estrogen receptor;
Table 3. ‘‘Cautionary’’ group: Any of these criteria should
invoke caution and concern when considering APBI
Factor Criterion
Patient factors
Age 50–59 y
Pathologic factors
Tumor size 2.1–3.0 cm*
T stage T0 or T2
Margins Close (<2 mm)
LVSI Limited/focal
ER status Negativey
Multifocality Clinically unifocal with total size
2.1–3.0 cmz
Histology Invasive lobular
Pure DCIS #3 cm
EIC #3 cm
Abbreviations as in Table 2.
* The size of the invasive tumor component as defined by the
American Joint Committee on Cancer (81).
y
Patients with ER-negative tumors are strongly encouraged to
enroll in the National Surgical Adjuvant Breast and Bowel Project
B-39/Radiation Therapy and Oncology Group 04-13 clinical trial
(78).
z
Microscopic multifocality allowed, provided the lesion is clini-
cally unifocal (a single discrete lesion by physical examination and
ultrasonography/mammography) and the total lesion size (including
foci of multifocality and intervening normal breast parenchyma)
falls between 2.1 and 3.0 cm.
APBI consensus statement d B. D. SMITH et al. 991
such patients, relatively few patients of this age have actually
enrolled in such trials. Therefore, the Task Force thought that
the data were too limited to determine this age cohort’s suit-
ability. Few women aged <50 years have been treated with
APBI in prospective single-arm studies, and thus, the Task
Force strongly recommended against APBI outside of a clin-
ical trial for this patient group at this time. It was noted that
data from the University of Wisconsin prospective single-
arm study indicated that the risk of IBTR may not be exces-
sively high among appropriately selected women aged <50
years (76); however, there were only 70 patients aged <50
years in this study, and the median follow-up time was
only 48.5 months. Therefore, the panel thought that confir-
matory data were required before endorsing off-protocol
APBI for this younger patient group. Finally, the Task Force
recommended that carriers of deleterious BRCA1 or BRCA2
mutations, or individuals with a personal or family history
consistent with the presence of a mutation, should not receive
APBI outside of a clinical trial because of the absence of lit-
erature supporting the use of APBI in this setting.
Regarding pathologic characteristics, the Task Force rec-
ommended measuring the maximum size of the invasive
Pure DCIS Not allowed
EIC Not allowed
Associated LCIS Allowed
Nodal factors
N stage pN0 (i-
, i+
)
Nodal surgery SN Bx or ALNDjj
Treatment factors
Neoadjuvant therapy Not allowed
Abbreviations: APBI = accelerated partial-breast irradiation;
LVSI = lymph–vascular space invasion; ER = estrogen receptor;
DCIS = ductal carcinoma in situ; EIC = extensive intraductal com-
ponent; LCIS = lobular carcinoma in situ; SN Bx = sentinel lymph
node biopsy; ALND = axillary lymph node dissection.
Criteria are derived from data (when available) and conservative
panel judgment.
* The size of the invasive tumor component as defined by the
American Joint Committee on Cancer (81).
y
The finding of possible or equivocal LVSI should be disre-
garded.
z
Microscopic multifocality allowed, provided the lesion is clini-
cally unifocal (a single discrete lesion by physical examination and
ultrasonography/mammography) and the total lesion size (including
foci of multifocality and intervening normal breast parenchyma)
does not exceed 2 cm.
x
Favorable subtypes include mucinous, tubular, and colloid.
jj
Pathologic staging is not required for DCIS.
* The size of the invasive tumor component as defined by the
American Joint Committee on Cancer (81).
y
Patients with ER-negative tumors are strongly encouraged to
enroll in the National Surgical Adjuvant Breast and Bowel Projec
B-39/Radiation Therapy and Oncology Group 04-13 clinical tria
(78).
z
Microscopic multifocality allowed, provided the lesion is clini
cally unifocal (a single discrete lesion by physical examination and
ultrasonography/mammography) and the total lesion size (including
foci of multifocality and intervening normal breast parenchyma
falls between 2.1 and 3.0 cm.
Table 4. Patients ‘‘unsuitable’’ for APBI outside of a clinical
trial if any of these criteria are present
Factor Criterion
Patient factors
Age <50 y
BRCA1/2 mutation Present
Pathologic factors
Tumor size* >3 cm
T stage T3-4
Margins Positive
LVSI Extensive
Multicentricity Present
Multifocality If microscopically multifocal >3 cm in
total size or if clinically multifocal
Pure DCIS If >3 cm in size
EIC If >3 cm in size
Nodal factors
N stage pN1, pN2, pN3
Nodal surgery None performed
Treatment factors
Neoadjuvant therapy If used
Abbreviations as in Table 2.
If any of these factors are present, the Task Force recommends
against the use of APBI outside of a prospective clinical trial.
* The size of the invasive tumor component as defined by the
American Joint Committee on Cancer (81).

33. Risk-adapted targeted intraoperative radiotherapy versus
whole-breast radiotherapy for breast cancer:5-year results
for local control and overall survival from theTARGIT-A
randomised trial
Jayant SVaidya, FrederikWenz, Max Bulsara, Jeffrey STobias, David J Joseph, Mohammed Keshtgar, Henrik L Flyger, Samuele Massarut,
Michael Alvarado, Christobel Saunders,Wolfgang Eiermann, Marinos Metaxas, Elena Sperk, Marc Sütterlin, Douglas Brown, Laura Esserman,
Mario Roncadin, AlastairThompson, John A Dewar, Helle M R Holtveg, Steffi Pigorsch, Mary Falzon, Eleanor Harris, April Matthews,
Chris Brew-Graves, Ingrid Potyka,Tammy Corica, Norman RWilliams, Michael Baum, on behalf of theTARGIT trialists’ group
Summary
Background The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative
radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year
results for local recurrence and the first analysis of overall survival.
Methods TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal
carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with
blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation
occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after
lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the
TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on
final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local
recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified
analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes
included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684.
Findings Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients
were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of
1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median
follow-up of 2 years and 5 months (IQR 12–52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local
recurrence in the conserved breast was 3·3% (95% CI 2·1–5·1) for TARGIT versus 1·3% (0·7–2·5) for EBRT
(p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT:
2·1% (1·1–4·2) versus 1·1% (0·5–2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group
difference was larger than 2·5% (TARGIT 5·4% [3·0–9·7] vs EBRT 1·7% [0·6–4·9]; p=0·069). Overall, breast cancer
mortality was much the same between groups (2·6% [1·5–4·3] for TARGIT vs 1·9% [1·1–3·2] for EBRT; p=0·56) but
there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5% [2·3–5·2]; p=0·0086),
attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7–5·8) for
TARGIT versus 5·3% (3·9–7·3) for EBRT (p=0·099). Wound-related complications were much the same between
groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731,
p=0·029).
Interpretation TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an
option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative
Lancet 2014; 383: 603–13
Published Online
November 11, 2013
http://dx.doi.org/10.1016/
S0140-6736(13)61950-9
This online publication has been
corrected.The corrected version
first appeared atthelancet.com
on February 14, 2014
See Comment page 578
Copyright ©Vaidya et al. Open
Access article distributed under
the terms of CC BY-NC-ND
ClinicalTrialsGroup, Division of
Surgery and Interventional
Science, University College
London, London, UK
(Prof J SVaidya PhD,
C Brew-Graves MSc, I Potyka PhD,
M Metaxas PhD,
N RWilliams PhD,
Prof M Baum MD); Department
of RadiationOncology
(Prof FWenz MD, E Sperk MD),
and Department ofGynecology
andObstetrics
(Prof M Sütterlin MD),
University MedicalCentre
Mannheim, University of
Heidelberg, Heidelberg,
Germany; Department of
Biostatistics, University of
Notre Dame, Fremantle,WA,
Australia (Prof M Bulsara PhD);
Department of Radiation
Oncology (Prof D J Joseph FRACR,
T Corica BSc), and
Department of Surgery
(Prof C Saunders FRACS),
www.thelancet.com Vol 383 February 15, 2014 603
Summary
Background The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative
radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year
results for local recurrence and the first analysis of overall survival.
Methods TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal
carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with
blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation
occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after
lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the
TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on
final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local
recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified
analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes
included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684.
Findings Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients
were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of
1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median
follow-up of 2 years and 5 months (IQR 12–52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local
recurrence in the conserved breast was 3·3% (95% CI 2·1–5·1) for TARGIT versus 1·3% (0·7–2·5) for EBRT
(p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT:
2·1% (1·1–4·2) versus 1·1% (0·5–2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group
difference was larger than 2·5% (TARGIT 5·4% [3·0–9·7] vs EBRT 1·7% [0·6–4·9]; p=0·069). Overall, breast cancer
mortality was much the same between groups (2·6% [1·5–4·3] for TARGIT vs 1·9% [1·1–3·2] for EBRT; p=0·56) but
there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5% [2·3–5·2]; p=0·0086),
attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7–5·8) for
TARGIT versus 5·3% (3·9–7·3) for EBRT (p=0·099). Wound-related complications were much the same between
groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731,
p=0·029).
Interpretation TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an
option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative
to postoperative EBRT.
Funding University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH
Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer
Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.
Introduction
Adjuvant whole-breast external beam radiotherapy
(EBRT) is deemed mandatory after lumpectomy for
breast cancer on the basis of the reduction of local
recurrence in the conserved breast and of breast cancer
mortality.1
Even in highly selected patients, omission of
radiotherapy increases the risk of local recurrence.2–5
To develop a more refined and personalised approach to
adjuvant radiotherapy, we designed the TARGIT-A
(TARGeted Intraoperative radioTherapy Alone) trial.6
The
Lancet 2014; 383: 603–13
Published Online
November 11, 2013
http://dx.doi.org/10.1016/
S0140-6736(13)61950-9
This online publication has been
corrected.The corrected version
first appeared atthelancet.com
on February 14, 2014
See Comment page 578
Copyright © Vaidya et al. Open
Access article distributed under
the terms of CC BY-NC-ND
ClinicalTrials Group, Division of
Surgery and Interventional
Science, University College
London, London, UK
(Prof J SVaidya PhD,
C Brew-Graves MSc, I Potyka PhD,
M Metaxas PhD,
N RWilliams PhD,
Prof M Baum MD); Department
of Radiation Oncology
(Prof FWenz MD, E Sperk MD),
and Department of Gynecology
and Obstetrics
(Prof M Sütterlin MD),
University Medical Centre
Mannheim, University of
Heidelberg, Heidelberg,
Germany; Department of
Biostatistics, University of
Notre Dame, Fremantle,WA,
Australia (Prof M Bulsara PhD);
Department of Radiation
Oncology (Prof D J Joseph FRACR,
T Corica BSc), and
Department of Surgery
(Prof C Saunders FRACS),
Sir Charles Gairdner Hospital,
Perth,WA, Australia;
Department of Clinical
Oncology (Prof J STobias FRCR),
and Department of Pathology
(M Falzon FRCPath), University
College London Hospitals,
London, UK; Department of
Surgery, Royal Free Hospital,
London, UK
(Prof M Keshtgar PhD,
Prof J S Vaidya); Department of
Surgery,Whittington Hopsital,
TARGIT stratum (figure 3; appendix).
In the postpathology stratum—ie, when TARGIT was
delivered as a delayed procedure by reopening the
lumpectomy cavity, 1153 patients—the difference in local
recurrence in the conserved breast between the two groups
was larger than 2·5%: TARGIT 5·4% (95% CI 3·0–9·7) vs
EBRT 1·7% (0·6–4·9; p=0·069). Breast-cancer mortality
was three patients for TARGIT versus one patient for
EBRT (1·2%, 0·4–4·2 vs 0·5%, 0·1–3·5; p=0·35), and non-
breast-cancer mortality was five patients for TARGIT
versus eight patients for EBRT (1·58%, 0·62–3·97 vs
1·76%, 0·7–4·4; p=0·32). Thus, in absolute terms, there
were eight additional local recurrences and one less death
in the postpathology TARGIT stratum (figure 3).
The results of a comparison26
of cumulative incidence
for local recurrence in the presence of competing risks
(death and withdrawal from trial) were no different from
Kaplan-Meier estimates, showing that these risks did not
bias the main results (data not shown).
Analysis limited to the mature cohort, first reported in
2010 (n=2232, median follow-up now 3 years 7 months),
in which most events had occurred (32 of 34 local
recurrences and 85 of 88 deaths), yielded much the same
results (data not shown).
Table 3 shows the Z score and pnon-inferiority for the primary
outcome of local recurrence in the conserved breast, for
the whole cohort, the mature cohort, and the earliest
cohort. Non-inferiority is established for the whole
cohort and for prepathology patients but not for post-
pathology patients.
Figure 4 shows the primary (local recurrence in the
conserved breast) and secondary outcomes (deaths) for
the prepathology stratum. It shows the differences in
5-year estimates for these outcomes for the whole cohort,
There were fewer grade 3 or 4 radiotherapy-related skin
complications with TARGIT than with EBRT (four of
1721 vs 13 of 1730, p=0·029).
In post-hoc exploratory analyses, we noted no sig-
nificant difference in 5-year risk of regional recurrence
Number at risk
TARGIT
EBRT
0
1679
1696
1
1251
1244
2
963
956
3
679
674
4
491
479
5
290
296
0
5
10
Recurrence(%)
A Local recurrence
Log-rank p=0·042
TARGIT 23 events
EBRT 11 events
Number at risk
TARGIT
EBRT
0
1679
1696
1
1251
1243
2
966
957
3
683
676
4
495
481
5
294
297
0
5
10
Recurrence(%)
B Regional recurrence
Log-rank p=0·609
TARGIT 8 events
EBRT 6 events
Number at risk
TARGIT
EBRT
0
1721
1730
1
1285
1272
2
997
978
3
706
693
4
514
496
5
309
302
Years
0
5
10
Mortality(%)
C Death
Log-rank p=0·099
TARGIT 37 events
EBRT 51 events
Figure 2: Kaplan-Meier analysis of local recurrence in the conserved breast,
regional recurrence (axillary and supraclavicular), and deaths
Local recurrence wasthe primary outcome, death was a secondary outcome,
regional recurrence was an exploratory outcome.Three ofthe 14 regional
recurrences had breast recurrence as well (oneTARGIT andtwo EBRT). (A) Local
TARGIT EBRT
Other cancers 8 16
Cardiovascular causes
Cardiac* 2 8
Stroke 0 2
Ischaemic bowel 0 1
Other† 7 8
Total 17 35
5-year risk 1·4% forTARGIT versus 3·5% for EBRT; log-rank p=0·0086.
TARGIT=targeted intraoperative radiotherapy. EBRT=external beam radiotherapy.
*Included one “sudden death at home” in EBRT group. †TARGIT: two diabetes,
one renal failure, one liver failure, one sepsis, one Alzheimer’s disease, one
unknown; EBRT: one myelopathy, one perforated bowel, one pneumonia, one old
age, four unknown.
The patient and tumour characteristics and trial profile
are in the appendix. The risk-adapted design is shown in
the trial profile—eg, of the 1140 patients allocated TARGIT
in the prepathology stratum, 219 received TARGIT and
EBRT as per protocol, because they were shown to
have characteristics of high-risk disease postoperatively
(appendix). There was no significant difference between
prepathology and postpathology in the timing of delivery
of EBRT (p=0·58). Most cancers were small and of good
prognosis (87% [2685 of 3082] were up to 2 cm, 85%
[2573 of 3032] grades 1 or 2, 84% [2610 of 3112] node
negative, 93% [2874 of 3093] oestrogen-receptor positive
and 82% [2462 of 3016] progesterone-receptor positive)
and detected by screening 69% [2102 of 3063]. The appen-
dix shows tumour characteristics and main results as per
treatment received.
93·7% [3234 of 3451] of patients were seen within the
year before datalock or had at least 5 years of follow-
up (appendix). The whole cohort of 3451 patients
had a median follow-up of 2 years and 5 months
(IRQ 12–52 months), 2020 patients had a median follow-
up of 4 years, and 1222 patients had a median follow-up
of 5 years. The mature cohort of 2232 patients, which was
originally reported in 2010, had a median follow up of
3 years and 7 months (IRQ 30–61 months).
Table 1 shows detailed results for the local recurrence
in the conserved breast (primary outcome), any other
recurrence (exploratory outcome), and death (secon-
dary outcome).
The 5-year risks for local recurrence in the conserved
breast for TARGIT versus EBRT were 3·3% (95% CI
2·1–5·1) versus 1·3% (0·7–2·5; p=0·042). Breast cancer
mortality was much the same in the two groups: 2·6%
(1·5–4·3) for TARGIT versus 1·9% (1·1–3·2) for EBRT
(p=0·56), but there were significantly fewer non-breast-
cancer deaths in the TARGIT group than the EBRT
group (1·4%, 0·8–2·5 vs 3·5%, 2·3–5·2; p=0·0086),
attributable to fewer deaths from cardiovascular causes
and other cancers (figure 1, table 2). Overall mortality for
TARGIT was 3·9% (2·7–5·8) versus 5·3% (3·9–7·3) for
EBRT (p=0·099). Overall, in absolute terms, there were
12 additional local recurrences but 14 fewer deaths in the
TARGIT group (figures 1, 2).
Despite the poor prognostic factors for survival in the
group selected to receive TARGIT plus EBRT, as shown
by the increased breast cancer mortality (8·0%, 95% CI
3·5–17·5), local recurrence was low in that group (0·9%,
0·1–6·1), and did not differ from those who received
TARGIT alone (appendix).
In the prepathology stratum—ie, when TARGIT was
delivered during the initial lumpectomy, 2298 patients—
the risk of local recurrence in the conserved breast was
much the same for TARGIT as for EBRT: TARGIT 2·1%
(95% CI 1·1–4·2) versus EBRT 1·1% (0·5–2·5; p=0·31).
Breast-cancer mortality was 17 patients for TARGIT
5
10
rtality(%)
A Breast cancer deaths B Non-breast cancer deaths
Log-rank p=0·56 Log-rank p=0·0086
TARGIT 20 events
EBRT 16 events
TARGIT 17 events
EBRT 35 events
Events; 5-year cumulative risk (95%CI) Absolute difference*
TARGIT EBRT
All patients
Local recurrence (n=3375) 23; 3·3% (2·1–5·1) 11; 1·3% (0·7–2·5) 12 (2·0%)
Any other recurrence (n=3375) 46; 4·9% (3·5–6·9) 37; 4·4% (3·0–6·4) 9 (0·5%)
Death (n=3451) 37; 3·9% (2·7–5·8) 51; 5·3%(3·9–7·3) –14 (–1·4%)
Prepathology†
Local recurrence (n=2234) 10; 2·1% (1·1–4·2) 6; 1·1% (0·5–2·5) 4 (1·0%)
Any other recurrence (n=2234) 29; 4·8% (3·1–7·3) 25; 4·7% (3·0–7·4) 4 (0·1%)
Death (n=2298) 29; 4·6% (1·8–6·0) 42; 6·9% (4·3–9·6) –13 (–2·3%)
Postpathology‡
Local recurrence (n=1141) 13; 5·4% (3·0–9·7) 5; 1·7%(0·6–4·9) 8 (3·7%)
Any other recurrence (n=1141) 17; 5·2% (3·0–8·8) 12; 3·7% (1·9–7·0) 5 (1·5%)
Death (n=1153) 8; 2·8% (1·3–5·9) 9; 2·3% (1·0–5·2) –1 (0·5%)
TARGIT=targeted intraoperative radiotherapy. EBRT=external beam radiotherapy. *In Kaplan-Meier point estimate at
5 years (TARGIT minus EBRT). †TARGIT given at same time as lumpectomy. ‡TARGIT given after lumpectomy, as
separate procedure.
Table 1: Results of primary (local recurrence in the conserved breast), secondary (death), and exploratory
(any other recurrence) outcomes for all patients and the two strata as per timing of randomisation and
delivery ofTARGIT
www.thelancet.com Vol 383 February 15, 2014 603
results for local recurrence and the first analysis of overall survival.
Methods TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal
carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with
blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation
occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after
lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the
TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on
final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local
recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified
analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes
included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684.
Findings Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients
were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of
1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median
follow-up of 2 years and 5 months (IQR 12–52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local
recurrence in the conserved breast was 3·3% (95% CI 2·1–5·1) for TARGIT versus 1·3% (0·7–2·5) for EBRT
(p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT:
2·1% (1·1–4·2) versus 1·1% (0·5–2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group
difference was larger than 2·5% (TARGIT 5·4% [3·0–9·7] vs EBRT 1·7% [0·6–4·9]; p=0·069). Overall, breast cancer
mortality was much the same between groups (2·6% [1·5–4·3] for TARGIT vs 1·9% [1·1–3·2] for EBRT; p=0·56) but
there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5% [2·3–5·2]; p=0·0086),
attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7–5·8) for
TARGIT versus 5·3% (3·9–7·3) for EBRT (p=0·099). Wound-related complications were much the same between
groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731,
p=0·029).
Interpretation TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an
option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative
to postoperative EBRT.
Funding University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH
Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer
Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research.
Introduction
Adjuvant whole-breast external beam radiotherapy
(EBRT) is deemed mandatory after lumpectomy for
breast cancer on the basis of the reduction of local
recurrence in the conserved breast and of breast cancer
mortality.1
Even in highly selected patients, omission of
radiotherapy increases the risk of local recurrence.2–5
To develop a more refined and personalised approach to
adjuvant radiotherapy, we designed the TARGIT-A
(TARGeted Intraoperative radioTherapy Alone) trial.6
The
November 11, 2013
http://dx.doi.org/10.1016/
S0140-6736(13)61950-9
This online publication has been
corrected.The corrected version
first appeared atthelancet.com
on February 14, 2014
See Comment page 578
Copyright ©Vaidya et al. Open
Access article distributed under
the terms of CC BY-NC-ND
ClinicalTrialsGroup, Division of
Surgery and Interventional
Science, University College
London, London, UK
(Prof J SVaidya PhD,
C Brew-Graves MSc, I Potyka PhD,
M Metaxas PhD,
N RWilliams PhD,
Prof M Baum MD); Department
of RadiationOncology
(Prof FWenz MD, E Sperk MD),
and Department ofGynecology
andObstetrics
(Prof M Sütterlin MD),
University MedicalCentre
Mannheim, University of
Heidelberg, Heidelberg,
Germany; Department of
Biostatistics, University of
Notre Dame, Fremantle,WA,
Australia (Prof M Bulsara PhD);
Department of Radiation
Oncology (Prof D J Joseph FRACR,
T Corica BSc), and
Department of Surgery
(Prof C Saunders FRACS),
SirCharlesGairdner Hospital,
Perth,WA, Australia;
Department ofClinical
Oncology (Prof J STobias FRCR),
and Department of Pathology
(M Falzon FRCPath), University
College London Hospitals,
London, UK; Department of
Surgery, Royal Free Hospital,
London, UK
(Prof M Keshtgar PhD,
Prof J SVaidya); Department of
Surgery,Whittington Hopsital,

34. Table 6. Randomized trials comparing whole-beast irradiation with APBI
Trial N
Median
follow-up (y)
Lumpectomy
cavity definition Arms IBTR
Tumor bed
failure LRF CSS OS
TARGIT 779 0.98 Intraoperative assessment (1) Whole-breast RT* . . . . .
(2) APBI: IORT delivering 20 Gy to cavity
surface with 50-kV photons
. . . . .
NIC,
Hungary
258 5.5 Surgical clips (1) Whole-breast RT: 50 Gy in 25 fractions
using either Cobalt-60 (n =29)
or 6–9-MV photons (n = 100)y
3.4% (4/130) 1.7% (2/130) . 96% 91.8%
(2) APBI: HDR interstitial implant to 36.4 Gy in 7
fractions b.i.d. (n = 88) or external-beam RT
with electrons to 50 Gy in 25 daily fractions
(n = 40).z
PTV defined as lumpectomy cavity +
2 cm
4.7% (6/128) 1.6% (2/128) . 98.3% 94.6%
At 5 y
p = 0.50
At 5 y
p = NR
At 5 y
p = NR
At 5 y
p = NR
YBCG 174 8 ‘‘A combination of
preoperative information
if available, scar position,
and patient recollection’’
(1) Whole-breast RT: 40 Gy in 15 fractions
followed by boost of 15 Gy in 5 fractions
4% (4/90) . 9% (8/90) . 73%
(2) APBI: 55 Gy in 20 fractions using
external-beam techniques.x
PTV not defined
12% (10/84) 8% (7/84) 24% (20/84) . 70%
At 8 y At 8 y At 8 y At 8 y
p = 0.07 p = NR p = 0.05{
p = 0.75
Christie
Hospital
708 5.4 Not specified (1) Whole-breast RT: 40 Gy in 15
fractions without a boost
11.0% (24/355) . . . 71%
(2) APBI: 40–42.5 Gy in 8 fractions using
8–14-MeVjj
electrons to an average field size
of 8 Â 6 cm. PTV constituted the entire
quadrant of the index lesion
19.6% (52/353) . . . 73%
At 7 y
p < 0.001{
At 7 y
p = NR
Abbreviations: LRF = local–regional failure; CSS = cause-specific survival; OS = overall survival; IORT = intraoperative radiotherapy; RT = radiotherapy; HDR = high-dose-rate; NR = not
reported; PTV = planning target volume. Full trial names are shown in Table 1. Other abbreviations as in Tables 2 and 5.
A period (.) indicates that data were not available.
* Details of whole-breast RT not specified.
y
One patient received a 16-Gy electron boost, and 22 received a dose <50 Gy.
z
Seven patients received a dose <50 Gy. Although patients treated with electrons received partial-breast irradiation, treatment was given using conventional fractionation and thus was not
accelerated.
x
External-beam techniques included tangents, appositional Cobalt-60 or Cesium-137 teletherapy, or en face electrons (energy not reported).
jj
Electron energy was 10 MeV for most patients and 14 MeV for patients with ‘‘large breasts.’’
{
Statistically significant comparison.
APBIconsensusstatementdB.D.SMITHetal.
Table 7. Comparison of clinical studies by APBI treatment
technique
Treatment
technique
Total
patients
Total follow-up
(patient-years)
Average
follow-up (y)
Interstitial 1,321 7,133 5.4
MammoSite 1,787 4,110 2.3
Intraoperative 681 1,430 2.1
External beam
3D-CRT/IMRT 319 335 1.0
Protons 40 20 0.5
996 I. J. Radiation Oncology d Biology d PhysicsNSABP B39 : Reexcision T bed with extemporane Negative Margins
134 reexcision : 38% of relectures = positive margins
But at > 10 mm : < 10% (n=13) Vicini ; IJROBP 2004

35. Which Real target volume for breast Radiotherapy ?
Underevaluation of phenomenoms at distance of tumorectomy bed : microenvironment..

36. pN+
pN0
Recurrence rate without adjuvant treatment
• D’après Early Breast Cancer Trialists’ Collaborative Group 1998 meta-analysis,1 adapté 2
1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.
2. Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582.
Tauxderécidive
annuel(%)
0
4
8
12
16
0 2 4 6 8 10
Années
Early Pic
Late Pic

37. « Tumor size is “Halstedian” in concept …
More than 2,000 patients entered into the National Surgical Adjuvant Breast
Project were utilized to evaluate the validity of the concept that the size of
breast neoplasms influences prognosis. It was concluded that size alone is
not as consequential to the fate of the patient as are other factors relative to
the tumor and/or host that determine the development of metastases. . . .
Since size (ie, growth) is now recognized to be dependent on such factors as
the number of proliferating cells, the length of the cycle—which is not
always uniform—the extent of cell death or cell loss and the number of
nonproliferating cells,. . . it is difficult to relate size to the age of a tumor »
« a large tumor that had not metastasized prior to its
removal may be considered early and a small one that
had already disseminated may be considered late »
Bernard FISHER
1970 monograph

38. Merci de votre attention