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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
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Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

Nov 01, 2014

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Page 1: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 2: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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)

Page 3: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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)

Page 4: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

T = 8 mm

SIMPLE MODEL = 1 tumor < 1cm, early diagnosis, did not have time to spread,

Therapeutic deflation

Page 5: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

T = 18 mm

1 N+

SIMPLE MODEL = 1 tumor < 1cm, early diagnosis, did not have time to spread,

Therapeutic deflation

Page 6: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 7: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

T = 8 mm

REALITY = 1 tumor < 1cm, early diagnosis, may have already metastased…

x N+ / M+

Page 8: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 9: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?
Page 10: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

Can we decrease aggressivness of small tumors locoregional treatments ?

Can we identify sub-groups candidates to Therapeutic deflation ?

Page 11: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 12: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 13: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

RRadiotherapy + 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

Page 14: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 15: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

. 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

Page 16: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 17: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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 %

Page 18: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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 …

Page 19: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 20: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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+

Page 21: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

Breast 3D Radiotherapy

Page 22: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?
Page 23: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

Tumorectomy + Radiotherapy

Good Cosmetic Results for majority of patients

Toledano et al. IJROBP 2007

Page 24: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

Niméus-Malström E et al. Br Cancer Res 2008

All Reccurences are not the same …

Page 25: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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)  

Page 26: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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

Page 27: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

Schroen et al. JCO05

Ballast et al. IJROBP06 Relation between distance to RT Type of breast surgery for T1

16 40 80 >80

Page 28: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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.

Page 29: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

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 »

Page 30: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

The American « engouement » for mammosite

Abbott et al.(SEER) Cancer 2011

Clinical Application before scientific proof

Page 31: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

CONSENSUS STATEMENT

ACCELERATED PARTIAL BREAST IRRADIATION CONSENSUS STATEMENT FROMTHE 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; yDepartment of Radiation Oncology, The University ofTexas M. D. Anderson Cancer Center, Houston, TX; zDepartment of Radiation Oncology, Medical College of Virginia, Virginia

Commonwealth University, Richmond, VA; xDepartment of Radiation Oncology, University of Medicine and Dentistry of New Jersey –Robert Wood Johnson Medical School, New Brunswick, NJ; kDepartment 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; yyDepartment of RadiationOncology, William Beaumont Hospital, Royal Oak, MI; zzDepartment of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON,

Canada; xxDepartment of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; kkHarvard Radiation OncologyResidency 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 645candidate 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 evidenceand, 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 clinicaltrial is acceptable, (2) a ‘‘cautionary’’ group, for whom caution and concern should be applied when consideringAPBI 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-breastirradiation (WBI) is an established treatment with a much longer track record that has documented long-termeffectiveness and safety.

Reprint requests to: Benjamin D. Smith, M.D., 2200 BergquistDrive, Suite 1, Lackland AFB, TX 78236. Tel: (210) 292-5589;Fax: (210) 292-3773; E-mail: [email protected]

Supplementary material for this article can be found at www.redjournal.org.

This document was prepared by the Accelerated Partial BreastIrradiation Consensus Statement Task Force of the Health ServicesResearch Committee of the American Society for Radiation Oncol-ogy (ASTRO).

Before initiation of this Consensus Statement, all members of theTask Group writing the Statement were required to complete conflictof interest statements. These statements are maintained at ASTROHeadquarters in Fairfax, VA, and pertinent conflict information ispublished with the report. Individuals with disqualifying conflictshave been recused from participation in this Consensus Statement.

ASTRO Consensus Statements present scientific, health, andsafety information and may to some extent reflect scientific or med-ical opinion. They are made available to ASTRO members and tothe public for educational and informational purposes only. Anycommercial use of any content in this Statement without the priorwritten consent of ASTRO is strictly prohibited.

Adherence to the guidelines set forth in this Consensus Statementwill not ensure successful treatment in every situation. Furthermore,

these guidelines should not be deemed inclusive of all propermethods 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 thephysician and the patient in light of all the circumstances presentedby 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 tothe 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 andtreatment 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 researchand discussions on the topic. There may be new developments thatare not reflected in this Statement, and that may, over time, be a basisfor ASTRO to consider revisiting and updating the Statement.

Conflict of interest: D. W. Arthur, T. B. Julian, D. A. Todor, andF. A. Vicini have served as consultants to SenoRx, Irvine, CA.Acknowledgments—The authors thank Drs. Beryl McCormick, LoriPierce, Leonard Prosnitz, Abram Recht, Alphonse Taghian, andDavid Wazer for their critical review of the manuscript.

Received Feb 4, 2009. Accepted for publication Feb 25, 2009.

987

Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 4, pp. 987–1001, 2009Copyright ! 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

CONSENSUS STATEMENT

ACCELERATED PARTIAL BREAST IRRADIATION CONSENSUS STATEMENT FROMTHE 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; yDepartment of Radiation Oncology, The University ofTexas M. D. Anderson Cancer Center, Houston, TX; zDepartment of Radiation Oncology, Medical College of Virginia, Virginia

Commonwealth University, Richmond, VA; xDepartment of Radiation Oncology, University of Medicine and Dentistry of New Jersey –Robert Wood Johnson Medical School, New Brunswick, NJ; kDepartment 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; yyDepartment of RadiationOncology, William Beaumont Hospital, Royal Oak, MI; zzDepartment of Radiation Oncology, Juravinski Cancer Center, Hamilton, ON,

Canada; xxDepartment of Radiation Oncology, Medical College of Wisconsin, Milwaukee, WI; kkHarvard Radiation OncologyResidency 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 645candidate 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 evidenceand, 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 clinicaltrial is acceptable, (2) a ‘‘cautionary’’ group, for whom caution and concern should be applied when consideringAPBI 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-breastirradiation (WBI) is an established treatment with a much longer track record that has documented long-termeffectiveness and safety.

Reprint requests to: Benjamin D. Smith, M.D., 2200 BergquistDrive, Suite 1, Lackland AFB, TX 78236. Tel: (210) 292-5589;Fax: (210) 292-3773; E-mail: [email protected]

Supplementary material for this article can be found at www.redjournal.org.

This document was prepared by the Accelerated Partial BreastIrradiation Consensus Statement Task Force of the Health ServicesResearch Committee of the American Society for Radiation Oncol-ogy (ASTRO).

Before initiation of this Consensus Statement, all members of theTask Group writing the Statement were required to complete conflictof interest statements. These statements are maintained at ASTROHeadquarters in Fairfax, VA, and pertinent conflict information ispublished with the report. Individuals with disqualifying conflictshave been recused from participation in this Consensus Statement.

ASTRO Consensus Statements present scientific, health, andsafety information and may to some extent reflect scientific or med-ical opinion. They are made available to ASTRO members and tothe public for educational and informational purposes only. Anycommercial use of any content in this Statement without the priorwritten consent of ASTRO is strictly prohibited.

Adherence to the guidelines set forth in this Consensus Statementwill not ensure successful treatment in every situation. Furthermore,

these guidelines should not be deemed inclusive of all propermethods 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 thephysician and the patient in light of all the circumstances presentedby 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 tothe 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 andtreatment 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 researchand discussions on the topic. There may be new developments thatare not reflected in this Statement, and that may, over time, be a basisfor ASTRO to consider revisiting and updating the Statement.

Conflict of interest: D. W. Arthur, T. B. Julian, D. A. Todor, andF. A. Vicini have served as consultants to SenoRx, Irvine, CA.Acknowledgments—The authors thank Drs. Beryl McCormick, LoriPierce, Leonard Prosnitz, Abram Recht, Alphonse Taghian, andDavid Wazer for their critical review of the manuscript.

Received Feb 4, 2009. Accepted for publication Feb 25, 2009.

987

Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 4, pp. 987–1001, 2009Copyright ! 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

such patients, relatively few patients of this age have actuallyenrolled in such trials. Therefore, the Task Force thought thatthe data were too limited to determine this age cohort’s suit-ability. Few women aged <50 years have been treated withAPBI in prospective single-arm studies, and thus, the TaskForce strongly recommended against APBI outside of a clin-ical trial for this patient group at this time. It was noted thatdata 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 <50years (76); however, there were only 70 patients aged <50years in this study, and the median follow-up time wasonly 48.5 months. Therefore, the panel thought that confir-matory data were required before endorsing off-protocolAPBI for this younger patient group. Finally, the Task Forcerecommended that carriers of deleterious BRCA1 or BRCA2mutations, or individuals with a personal or family history

consistent with the presence of a mutation, should not receiveAPBI 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

Table 2. Patients ‘‘suitable’’ for APBI if all criteria arepresent

Factor Criterion

Patient factorsAge $60 yBRCA1/2 mutation Not present

Pathologic factorsTumor size #2 cm*T stage T1Margins Negative by at least 2 mmGrade AnyLVSI Noy

ER status PositiveMulticentricity Unicentric onlyMultifocality Clinically unifocal with total size

#2.0 cmz

Histology Invasive ductal or other favorablesubtypesx

Pure DCIS Not allowedEIC Not allowedAssociated LCIS Allowed

Nodal factorsN stage pN0 (i-, i+)Nodal surgery SN Bx or ALNDjj

Treatment factorsNeoadjuvant 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 lymphnode biopsy; ALND = axillary lymph node dissection.

Criteria are derived from data (when available) and conservativepanel judgment.

* The size of the invasive tumor component as defined by theAmerican 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 andultrasonography/mammography) and the total lesion size (includingfoci 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.

Table 3. ‘‘Cautionary’’ group: Any of these criteria shouldinvoke caution and concern when considering APBI

Factor Criterion

Patient factorsAge 50–59 y

Pathologic factorsTumor size 2.1–3.0 cm*T stage T0 or T2Margins Close (<2 mm)LVSI Limited/focalER status Negativey

Multifocality Clinically unifocal with total size2.1–3.0 cmz

Histology Invasive lobularPure DCIS #3 cmEIC #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 ProjectB-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 andultrasonography/mammography) and the total lesion size (includingfoci of multifocality and intervening normal breast parenchyma)falls between 2.1 and 3.0 cm.

Table 4. Patients ‘‘unsuitable’’ for APBI outside of a clinicaltrial if any of these criteria are present

Factor Criterion

Patient factorsAge <50 yBRCA1/2 mutation Present

Pathologic factorsTumor size* >3 cmT stage T3-4Margins PositiveLVSI ExtensiveMulticentricity PresentMultifocality If microscopically multifocal >3 cm in

total size or if clinically multifocalPure DCIS If >3 cm in sizeEIC If >3 cm in size

Nodal factorsN stage pN1, pN2, pN3Nodal surgery None performed

Treatment factorsNeoadjuvant 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).

APBI consensus statement d B. D. SMITH et al. 991

such patients, relatively few patients of this age have actuallyenrolled in such trials. Therefore, the Task Force thought thatthe data were too limited to determine this age cohort’s suit-ability. Few women aged <50 years have been treated withAPBI in prospective single-arm studies, and thus, the TaskForce strongly recommended against APBI outside of a clin-ical trial for this patient group at this time. It was noted thatdata 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 <50years (76); however, there were only 70 patients aged <50years in this study, and the median follow-up time wasonly 48.5 months. Therefore, the panel thought that confir-matory data were required before endorsing off-protocolAPBI for this younger patient group. Finally, the Task Forcerecommended that carriers of deleterious BRCA1 or BRCA2mutations, or individuals with a personal or family history

consistent with the presence of a mutation, should not receiveAPBI 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

Table 2. Patients ‘‘suitable’’ for APBI if all criteria arepresent

Factor Criterion

Patient factorsAge $60 yBRCA1/2 mutation Not present

Pathologic factorsTumor size #2 cm*T stage T1Margins Negative by at least 2 mmGrade AnyLVSI Noy

ER status PositiveMulticentricity Unicentric onlyMultifocality Clinically unifocal with total size

#2.0 cmz

Histology Invasive ductal or other favorablesubtypesx

Pure DCIS Not allowedEIC Not allowedAssociated LCIS Allowed

Nodal factorsN stage pN0 (i-, i+)Nodal surgery SN Bx or ALNDjj

Treatment factorsNeoadjuvant 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 lymphnode biopsy; ALND = axillary lymph node dissection.

Criteria are derived from data (when available) and conservativepanel judgment.

* The size of the invasive tumor component as defined by theAmerican 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 andultrasonography/mammography) and the total lesion size (includingfoci 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.

Table 3. ‘‘Cautionary’’ group: Any of these criteria shouldinvoke caution and concern when considering APBI

Factor Criterion

Patient factorsAge 50–59 y

Pathologic factorsTumor size 2.1–3.0 cm*T stage T0 or T2Margins Close (<2 mm)LVSI Limited/focalER status Negativey

Multifocality Clinically unifocal with total size2.1–3.0 cmz

Histology Invasive lobularPure DCIS #3 cmEIC #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 ProjectB-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 andultrasonography/mammography) and the total lesion size (includingfoci of multifocality and intervening normal breast parenchyma)falls between 2.1 and 3.0 cm.

Table 4. Patients ‘‘unsuitable’’ for APBI outside of a clinicaltrial if any of these criteria are present

Factor Criterion

Patient factorsAge <50 yBRCA1/2 mutation Present

Pathologic factorsTumor size* >3 cmT stage T3-4Margins PositiveLVSI ExtensiveMulticentricity PresentMultifocality If microscopically multifocal >3 cm in

total size or if clinically multifocalPure DCIS If >3 cm in sizeEIC If >3 cm in size

Nodal factorsN stage pN1, pN2, pN3Nodal surgery None performed

Treatment factorsNeoadjuvant 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).

APBI consensus statement d B. D. SMITH et al. 991

such patients, relatively few patients of this age have actuallyenrolled in such trials. Therefore, the Task Force thought thatthe data were too limited to determine this age cohort’s suit-ability. Few women aged <50 years have been treated withAPBI in prospective single-arm studies, and thus, the TaskForce strongly recommended against APBI outside of a clin-ical trial for this patient group at this time. It was noted thatdata 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 <50years (76); however, there were only 70 patients aged <50years in this study, and the median follow-up time wasonly 48.5 months. Therefore, the panel thought that confir-matory data were required before endorsing off-protocolAPBI for this younger patient group. Finally, the Task Forcerecommended that carriers of deleterious BRCA1 or BRCA2mutations, or individuals with a personal or family history

consistent with the presence of a mutation, should not receiveAPBI 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

Table 2. Patients ‘‘suitable’’ for APBI if all criteria arepresent

Factor Criterion

Patient factorsAge $60 yBRCA1/2 mutation Not present

Pathologic factorsTumor size #2 cm*T stage T1Margins Negative by at least 2 mmGrade AnyLVSI Noy

ER status PositiveMulticentricity Unicentric onlyMultifocality Clinically unifocal with total size

#2.0 cmz

Histology Invasive ductal or other favorablesubtypesx

Pure DCIS Not allowedEIC Not allowedAssociated LCIS Allowed

Nodal factorsN stage pN0 (i-, i+)Nodal surgery SN Bx or ALNDjj

Treatment factorsNeoadjuvant 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 lymphnode biopsy; ALND = axillary lymph node dissection.

Criteria are derived from data (when available) and conservativepanel judgment.

* The size of the invasive tumor component as defined by theAmerican 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 andultrasonography/mammography) and the total lesion size (includingfoci 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.

Table 3. ‘‘Cautionary’’ group: Any of these criteria shouldinvoke caution and concern when considering APBI

Factor Criterion

Patient factorsAge 50–59 y

Pathologic factorsTumor size 2.1–3.0 cm*T stage T0 or T2Margins Close (<2 mm)LVSI Limited/focalER status Negativey

Multifocality Clinically unifocal with total size2.1–3.0 cmz

Histology Invasive lobularPure DCIS #3 cmEIC #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 ProjectB-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 andultrasonography/mammography) and the total lesion size (includingfoci of multifocality and intervening normal breast parenchyma)falls between 2.1 and 3.0 cm.

Table 4. Patients ‘‘unsuitable’’ for APBI outside of a clinicaltrial if any of these criteria are present

Factor Criterion

Patient factorsAge <50 yBRCA1/2 mutation Present

Pathologic factorsTumor size* >3 cmT stage T3-4Margins PositiveLVSI ExtensiveMulticentricity PresentMultifocality If microscopically multifocal >3 cm in

total size or if clinically multifocalPure DCIS If >3 cm in sizeEIC If >3 cm in size

Nodal factorsN stage pN1, pN2, pN3Nodal surgery None performed

Treatment factorsNeoadjuvant 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).

APBI consensus statement d B. D. SMITH et al. 991

Page 32: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?
Page 33: Alain Toledano : Small Breast Cancers Radiotherapy : Locoregional Treatments particularities ?

Articles

www.thelancet.com Vol 383 February 15, 2014 603

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trialJayant S Vaidya, Frederik Wenz, Max Bulsara, Jeff rey S Tobias, 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, Alastair Thompson, John A Dewar, Helle M R Holtveg, Steffi Pigorsch, Mary Falzon, Eleanor Harris, April Matthews, Chris Brew-Graves, Ingrid Potyka, Tammy Corica, Norman R Williams, Michael Baum, on behalf of the TARGIT trialists’ group

SummaryBackground 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 fi rst 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 stratifi ed 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 fi nal pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute diff erence in local recurrence in the conserved breast, with a prespecifi ed non-inferiority margin of 2·5% at 5 years; prespecifi ed 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 diff erence 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 signifi cantly 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 signifi cantly 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.

IntroductionAdjuvant 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 refi ned and personalised approach to adjuvant radiotherapy, we designed the TARGIT-A (TARGeted Intraoperative radioTherapy Alone) trial.6 The

Lancet 2014; 383: 603–13

Published OnlineNovember 11, 2013http://dx.doi.org/10.1016/S0140-6736(13)61950-9

This online publication has been corrected. The corrected version fi rst appeared at thelancet.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

Clinical Trials Group, Division of Surgery and Interventional Science, University College London, London, UK (Prof J S Vaidya PhD, C Brew-Graves MSc, I Potyka PhD, M Metaxas PhD, N R Williams PhD, Prof M Baum MD); Department of Radiation Oncology (Prof F Wenz 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 S Tobias 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,

Articles

www.thelancet.com Vol 383 February 15, 2014 603

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trialJayant S Vaidya, Frederik Wenz, Max Bulsara, Jeff rey S Tobias, 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, Alastair Thompson, John A Dewar, Helle M R Holtveg, Steffi Pigorsch, Mary Falzon, Eleanor Harris, April Matthews, Chris Brew-Graves, Ingrid Potyka, Tammy Corica, Norman R Williams, Michael Baum, on behalf of the TARGIT trialists’ group

SummaryBackground 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 fi rst 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 stratifi ed 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 fi nal pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute diff erence in local recurrence in the conserved breast, with a prespecifi ed non-inferiority margin of 2·5% at 5 years; prespecifi ed 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 diff erence 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 signifi cantly 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 signifi cantly 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.

IntroductionAdjuvant 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 refi ned and personalised approach to adjuvant radiotherapy, we designed the TARGIT-A (TARGeted Intraoperative radioTherapy Alone) trial.6 The

Lancet 2014; 383: 603–13

Published OnlineNovember 11, 2013http://dx.doi.org/10.1016/S0140-6736(13)61950-9

This online publication has been corrected. The corrected version fi rst appeared at thelancet.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

Clinical Trials Group, Division of Surgery and Interventional Science, University College London, London, UK (Prof J S Vaidya PhD, C Brew-Graves MSc, I Potyka PhD, M Metaxas PhD, N R Williams PhD, Prof M Baum MD); Department of Radiation Oncology (Prof F Wenz 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 S Tobias 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,

Articles

www.thelancet.com Vol 383 February 15, 2014 607

versus 15 patients for EBRT (3·3%, 1·9–5·8 vs 2·7%, 1·5–4·6; p=0·72), non-breast-cancer mortality was 12 patients for TARGIT versus 27 patients for EBRT (1·3%, 0·7–2·8% vs 4·4%, 2·8−6·9; p=0·016). Thus, in absolute terms, there were four additional local recurrences but 13 fewer deaths in the prepathology TARGIT stratum (fi gure 3; appendix).

In the postpathology stratum—ie, when TARGIT was delivered as a delayed procedure by reopening the lumpectomy cavity, 1153 patients—the diff erence 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 fi ve 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 (fi gure 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 diff erent from Kaplan-Meier estimates, showing that these risks did not bias the main results (data not shown).

Analysis limited to the mature cohort, fi rst 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 diff erences in 5-year estimates for these outcomes for the whole cohort,

the mature cohort, and the earliest cohort. It demonstrates the stability of the results with longer follow-up and the trade-off s between the two outcomes.

For the secondary outcome of complications 6 months after randomisation, we noted no signifi cant diff erence in any protocol-defi ned wound-related complication. 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-nifi cant diff erence in 5-year risk of regional recurrence

Number at riskTARGIT

EBRT

0

16791696

1

12511244

2

963956

3

679674

4

491479

5

290296

0

5

10

Recu

rrenc

e (%

)

A Local recurrence

Log-rank p=0·042

TARGIT 23 eventsEBRT 11 events

Number at riskTARGIT

EBRT

0

16791696

1

12511243

2

966957

3

683676

4

495481

5

294297

0

5

10

Recu

rrenc

e (%

)

B Regional recurrence

Log-rank p=0·609

TARGIT 8 eventsEBRT 6 events

Number at riskTARGIT

EBRT

0

17211730

1

12851272

2

997978

3

706693

4

514496

5

309302

Years

0

5

10

Mor

talit

y (%

)

C Death

Log-rank p=0·099

TARGIT 37 eventsEBRT 51 events

Figure 2: Kaplan-Meier analysis of local recurrence in the conserved breast, regional recurrence (axillary and supraclavicular), and deathsLocal recurrence was the primary outcome, death was a secondary outcome, regional recurrence was an exploratory outcome. Three of the 14 regional recurrences had breast recurrence as well (one TARGIT and two EBRT). (A) Local recurrence in the conserved breast. (B) Regional recurrence. (C) Death. TARGIT=targeted intraoperative radiotherapy. EBRT=external beam radiotherapy.

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% for TARGIT 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.

Table 2: Causes of death other than breast cancer in all patients

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The patient and tumour characteristics and trial profi le are in the appendix. The risk-adapted design is shown in the trial profi le—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 (appen dix). There was no signifi cant diff erence 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 signifi cantly 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 (fi gure 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 (fi gures 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 diff er 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

Number at riskTARGIT

EBRT

0

17211730

1

12851272

2

997978

3

706693

4

514496

5

309302

Years

0

5

10

Mor

talit

y (%

)

A Breast cancer deaths

0

17211730

1

12851272

2

997978

3

706693

4

514496

5

309302

Years

B Non-breast cancer deaths

Log-rank p=0·56 Log-rank p=0·0086

TARGIT 20 eventsEBRT 16 events

TARGIT 17 eventsEBRT 35 events

Figure 1: Kaplan-Meier analysis of breast cancer deaths and non-breast-cancer deaths(A) Breast cancer. (B) Non-breast-cancer. TARGIT=targeted intraoperative radiotherapy. EBRT=external beam radiotherapy.

Events; 5-year cumulative risk (95%CI) Absolute diff erence*

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 of TARGIT

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www.thelancet.com Vol 383 February 15, 2014 603

Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trialJayant S Vaidya, Frederik Wenz, Max Bulsara, Jeff rey S Tobias, 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, Alastair Thompson, John A Dewar, Helle M R Holtveg, Steffi Pigorsch, Mary Falzon, Eleanor Harris, April Matthews, Chris Brew-Graves, Ingrid Potyka, Tammy Corica, Norman R Williams, Michael Baum, on behalf of the TARGIT trialists’ group

SummaryBackground 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 fi rst 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 stratifi ed 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 fi nal pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute diff erence in local recurrence in the conserved breast, with a prespecifi ed non-inferiority margin of 2·5% at 5 years; prespecifi ed 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 diff erence 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 signifi cantly 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 signifi cantly 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.

IntroductionAdjuvant 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 refi ned and personalised approach to adjuvant radiotherapy, we designed the TARGIT-A (TARGeted Intraoperative radioTherapy Alone) trial.6 The

Lancet 2014; 383: 603–13

Published OnlineNovember 11, 2013http://dx.doi.org/10.1016/S0140-6736(13)61950-9

This online publication has been corrected. The corrected version fi rst appeared at thelancet.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

Clinical Trials Group, Division of Surgery and Interventional Science, University College London, London, UK (Prof J S Vaidya PhD, C Brew-Graves MSc, I Potyka PhD, M Metaxas PhD, N R Williams PhD, Prof M Baum MD); Department of Radiation Oncology (Prof F Wenz 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 S Tobias 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,

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Table 6. Randomized trials comparing whole-beast irradiation with APBI

Trial NMedian

follow-up (y)Lumpectomy

cavity definition Arms IBTRTumor 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 fractionsusing 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 7fractions b.i.d. (n = 88) or external-beam RTwith 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 yp = 0.50

At 5 yp = NR

At 5 yp = NR

At 5 yp = NR

YBCG 174 8 ‘‘A combination ofpreoperative informationif available, scar position,and patient recollection’’

(1) Whole-breast RT: 40 Gy in 15 fractionsfollowed by boost of 15 Gy in 5 fractions

4% (4/90) . 9% (8/90) . 73%

(2) APBI: 55 Gy in 20 fractions usingexternal-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 yp = 0.07 p = NR p = 0.05{ p = 0.75

ChristieHospital

708 5.4 Not specified (1) Whole-breast RT: 40 Gy in 15fractions without a boost

11.0% (24/355) . . . 71%

(2) APBI: 40–42.5 Gy in 8 fractions using8–14-MeVjj electrons to an average field sizeof 8 ! 6 cm. PTV constituted the entirequadrant of the index lesion

19.6% (52/353) . . . 73%At 7 yp < 0.001{

At 7 yp = NR

Abbreviations: LRF = local–regional failure; CSS = cause-specific survival; OS = overall survival; IORT = intraoperative radiotherapy; RT = radiotherapy; HDR = high-dose-rate; NR = notreported; 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.

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use of breast magnetic resonance imaging (MRI) in patientsselected for APBI.

Narrative. To date, only one published study has assessedthe potential utility of breast MRI in a cohort of patients whomet at least some of our inclusion criteria for APBI. In thisstudy involving 79 women, MRI identified occult foci ofpathologically confirmed multicentric disease in 10% of pa-tients and multifocal disease in an additional 28% of patients(90). At present there are no data to suggest that incorporationof breast MRI for patients treated with APBI will result ina lower risk of IBTR. The Task Force agreed that therewere insufficient data to justify recommendation of routinebreast MRI for patients selected for APBI. Nevertheless,the Task Force acknowledged that future studies may demon-strate a benefit derived from breast MRI and that some pa-tients and physicians may elect to pursue MRI despite thelimited data currently available.

For patients receiving APBI, how should multidisciplinarycare be integrated with surgery and medical oncology?

Consensus statement. The decision regarding conven-tional WBI vs. APBI should be made only after the patient’sconsultation with a radiation oncologist and a complete path-ologic evaluation of the lumpectomy specimen. For patientswho will receive adjuvant chemotherapy, it is recommendedthat APBI be performed first and that there should be an in-terval of at least 2 to 3 weeks between completion of APBIand initiation of chemotherapy.

Narrative. To promote appropriate multidisciplinary can-cer care, the Task Force strongly recommended that the de-cision to treat a patient with APBI should be made only afterthe patient’s consultation with a radiation oncologist and re-view of the final pathology specimen. Committing a patientto APBI by, for example, placing a brachytherapy catheterin the breast at the time of breast-conserving surgery, pre-cludes the fully informed consent that is needed when usingAPBI. Furthermore, multiple prior studies have demon-strated that placement of the brachytherapy catheter in thelumpectomy cavity at the time of breast-conserving surgery

approximately doubles the risk of seroma formation (22,47–50, 52).

For patients who will be receiving adjuvant chemotherapy,a retrospective analysis from the MammoSite registry single-arm trial reported an association between initiation of adju-vant chemotherapy within 3 weeks of the last MammoSitetreatment and an increased risk of both radiation recall skinreaction and suboptimal cosmesis (91). Although this findingrequires validation, the Task Force believed these data weresufficient to recommend a 2- to 3-week interval betweencompletion of APBI and the initiation of systemic chemo-therapy. There were no data regarding timing of adjuvant en-docrine therapy with APBI and, as with conventional WBI,sequential or concurrent irradiation and endocrine therapyseem to be reasonable options.

According to published clinical and dosimetric data, howdo the various techniques for APBI compare?

Consensus statement. Interstitial brachytherapy is thetechnique with the longest follow-up reported, whereas fol-low-up data for other APBI techniques remain limited. Atpresent there are insufficient clinical and dosimetric data todetermine the optimal technique for APBI delivery.

Narrative. As shown in Table 7, interstitial brachytherapywas identified as the APBI technique having the longest pe-riod of follow-up data (an average of 5.4 years). In contrast,average follow-up was 2.3 years for MammoSite, 2.1 yearsfor intraoperative radiotherapy, and 1.0 years for three-di-mensional conformal radiotherapy/intensity-modulated ra-diotherapy (3D-CRT/IMRT). Reported risks of IBTR bytreatment technique are presented in Fig. E1. At present theTask Force believes that there are insufficient data to comparethe different treatment techniques with respect to their effec-tiveness or toxicity.

Regarding technical and dosimetric issues, there are cleardifferences between the available modalities. Because oftheir noninvasive nature, external-beam–based approachesseem to minimize the risk of seroma formation and infectioncompared with brachytherapy approaches (12, 39, 57, 58,64). Three-dimensional conformal radiotherapy offers excel-lent target coverage and dose homogeneity, but at the poten-tial expense of inferior conformality and increased doses tothe uninvolved ipsilateral breast, heart, and lung (92–96). In-tensity-modulated radiotherapy and TomoTherapy (Tomo-Therapy Incorporated, Madison, WI) (TomoTherapy maybe considered computed axial tomography [CT]-guidedIMRT) improve upon 3D-CRT approaches by enhancingconformality, with a possible reduction in high doses of radi-ation delivered to the uninvolved ipsilateral breast, heart, andlung. However, IMRT and TomoTherapy may result ina modest decrease in planning target volume (PTV) coverage(92–95), and the panel expressed concern that certain appli-cations of these treatment approaches might also increasethe volume of adjacent organs exposed to low doses of radi-ation, depending on the beam arrangement selected. Com-pared with photon therapy, proton therapy may decreasethe dose to the uninvolved ipsilateral breast, heart, and lung

Table 7. Comparison of clinical studies by APBI treatmenttechnique

Treatmenttechnique

Totalpatients

Total follow-up(patient-years)

Averagefollow-up (y)

Interstitial 1,321 7,133 5.4MammoSite 1,787 4,110 2.3Intraoperative 681 1,430 2.1External beam

3D-CRT/IMRT 319 335 1.0Protons 40 20 0.5

Abbreviations: 3D-CRT = three-dimensional conformal radio-therapy; IMRT = intensity-modulated radiotherapy. Other abbrevi-ation as in Table 2.

Data are derived from prospective single-arm studies as listed inTable E1, with the average follow-up reflecting the average of thereported median follow-up times weighted by sample size.

996 I. J. Radiation Oncology d Biology d Physics Volume 74, Number 4, 2009NSABP 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

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Which Real target volume for breast Radiotherapy ?

Underevaluation of phenomenoms at distance of tumorectomy bed : microenvironment..

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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.

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« 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

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