original rePort

Protocolul Comisiei Multidisciplinare pentru Decizie

Terapeutic (CDT) n Cancerul de Sn
Institutul Oncologic Prof. Dr. Ion Chiricu
Alexandru Eniu1, Gabriela Morar-Bolba1, Carmen Lisencu1, Daniela Martin1, Mihaela
Galatr1, Bogdan Fetica1, Alin Rancea1,2
1) Institutul Oncologic Prof. Dr. I. Chiricu Cluj Napoca; 2) Universitatea de Medicin i Farmacie Iuliu
Haieganu Cluj Napoca
Comitetul de lucru
Dr. Alexandru Eniu oncologie medical, coordonator
Dr. Radu Tnsescu radioterapie, oncologie medical, coordonator
Dr. Gabriela Morar-Bolba oncologie medical
Dr. Carmen Lisencu imagistic, radioterapie
Dr. Daniela Martin radioterapie
Dr. Mihaela Galatr anatomie patologic
Dr. Bogdan Fetica anatomie patologic
Dr. Alin Rancea chirurgie
Dr. Daniela Grecea radioterapie, oncologie medical
Dr. Carmen Popa radioterapie
Scopul acestui articol este de a prezenta Protocolul pe care Comitetul Multidisciplinar pentru Decizie terapeutic al Institutului Oncologic Prof. Dr. Ion
Chiricu l-a elaborat pentru a standardiza conduita diagnostic i terapeutic propus pacientelor cu cancer de sn ce se adreseaz Institutului. Membrii
comitetului au alctuit i discutat aceste indicaii, selectnd dintre opiunile terapeutice multiple oferite de ghidurile internaionale actuale propuse de
European Society for Medical Oncology (ESMO), St. Gallen Consensus Conference, Advanced Breast Cancer Consensus Conference (ABC), Societatea
German (AGO), National Comprehensive Cancer Network (NCCN), cele considerate adecvate nivelului de resurse i interveniilor terapeutice disponibile
n Institut. Acest protocol a fost prezentat i discutat n plen, n decursul ultimilor 3 ani, la conferinele naionale de oncologie din Romnia, i a fost supus
procesului de peer-review extern de ctre 5 experi internaionali n domeniul cancerului mamar. Datorit evoluiei continue, rapide, a cunotinelor n
acest domeniu, dup publicare, recomandrile protocolului vor fi actualizate semestrial n varianta on-line publicat pe site.
Cuvinte cheie: protocol terapeutic, cancer mamar
Abrevieri: AGO Arbeitsgemeinschaft Gynaekologische Onkologie; AHC antecedente heredo-colaterale; APP antecedente personale patologice;
CDIS carcinom ductal in situ; CDT comitet decizie terapeutic; CLI carcinom lobular invaziv; CLIS carcinom lobular in situ; CMI carcinom
mamar invaziv; CMO cancer mamar operabil; DT doz total; GMI ganglioni mamari interni; GSC ganglioni supraclaviculari; IA Inhibitor
de Aromataz; ICV ganglioni infraclaviculari; LA limfadenectomie axilar; LVI invazia spaiului limfovascular; MRM mastectomie radical
modificat; MS mastectomie simpl; NCI National Cancer Institute; PCT polichimioterapie; PT perete toracic; QA asigurarea calitii; R margini
pies de excizie;R1 margini microscopic pozitive; RE receptori estrogenici; RPg receptori progesteronici; RT radioterapie; RTE radioterapie
extern; S+A sectorectomie cu limfadectomie axilar.
Coninut:
I. PROTOCOL IMAGISTIC
1. Screeningul oportunistic
2. Imagistica de diagnostic
3. Situaii particulare
4. Diagnostic histopatologic
5. Reperaj pre-operator
6. Evaluarea rspunsului imagistic la chimioterapie neoadjuvant
7. Evaluarea rspunsului imagistic la hormonoterapie neoadjuvant
8. Inserie clip marcaj pat tumoral
9. Urmrirea pacientei cu cancer de sn tratat
II. TRATAMENT CHIRURGICAL
1. Chirurgie cu intenie curativ n prim timp
2. Chirurgia dup tratament sistemic neoadjuvant
3. Chirurgia n boala metastatic

III. ANATOMIA PATOLOGIC

1. Examinarea pieselor de biopsie tru-cut, mammotome, biopsia incizional
2. Examinarea pieselor de sectorectomie sau mastectomie
3. Examinarea limfoganglionilor axilari
4. Examinare Imunohistochimic Standard
5. Examinare Carcinom ductal in situ
6. Examinare Carcinom microinvaziv
7. Examinare Neoplazia lobular
IV. TRATAMENT ADJUVANT SISTEMIC
1. Bilan iniial
2. Indicaii PET-CT
3. Cerine examen histopatologic post chirurgie cu intenie curativ
4. Indicaie tratament in funcie de subtip
5. Definiie menopauza
6. Hormonoterapie adjuvant

Eniu et al

7. Indicaie tratament adjuvant Luminal A

8. Indicaie tratament adjuvant Luminal B HER2 negativ
9. Indicaie tratament adjuvant Luminal B HER2 pozitiv
10.Indicatie tratament adjuvant non luminal HER2 pozitiv
11. Indicaie tratament adjuvant Triplu negativ
12. Aprecierea riscului de transmitere genetic
13. Urmrire post terapeutic
V. TRATAMENT NEOADJUVANT
1. Indicaie
2. Motivaie
3. Bilan iniial
4. Selecie tip tratament
5. Hormonoterapie neoadjuvant

6. Chimioterapie neoadjuvant
7. Carcinomul inflamator
VI. RADIOTERAPIA
1. Carcinom ductal in situ
2. CMO: categorii terapeutice
3. Interval chirurgie-radioterapie
4. Radioterapia i tratamentul sistemic
5. Radioterapia paliativ
VII. BOALA METASTATIC
1. Bilan la progresie
2. Selecia terapiei n boala metastatic
3. Selecia hormonoterapiei n boala metastatic
4. Selecia chimioterapiei n boala metastatic

I. PROTOCOL IMAGISTIC

Sn dens heterogen fr mamografie anterioar

Mamografie pozitiv
1.2. Excepii
< 40 ani Investigaii imagistice dup regulile de la >
40 ani n situaiile:
Risc genetic crescut (BRCA+)
AHC (antecedente heredo-colaterale) pozitive se
ncepe cu 10 ani nainte de vrsta de apariie la ruda de
gradul I (>25 ani) sau dup 40 de ani
APP (antecedente personale patologice) ce includ:
Cancer mamar
CLIS (carcinom lobular in situ)
Radioterapie pe peretele toracic n antecedente (la
10 ani post radioterapie)

Imagistica snului n IOCN (Institutul Oncologic

Cluj-Napoca)
Urmeaz ntotdeauna consultului clinic i const n
mamografie i/sau ecografie.
Rezonana magnetic nuclear (RMN) pentru sn se face
doar la indicaia CDT.
Raportul imagistic este ntocmit conform Lexiconul
BIRADS (Tabelul I), unic pentru toat imagistica (evalueaz
ambii sni). Rezultatele eliberate n IOCN precizeaz doar
scorul care clasific leziunea (formaiunea).
Tabelul I.
Imagine (formaiune)

Densitate parenchimal

0 aspect indeterminat, investigaii

imagistice suplimentare n momentul
diagnosticului

1 adipos omogen

1 aspect normal (fr formaiuni)

2 adipos heterogen

2 aspect benign

3 dens heterogen

3 aspect probabil benign

4 dens omogen

4 aspect suspect de malignitate

5 aspect probabil malign
6 malignitate confirmat

Atitudine decizie imagistic:

BIRADS 0 de elucidat i convertit n alt categorie
n acelai timp diagnostic;
BIRADS 3 urmrire la 6 luni;
BIRADS 4 i 5 diagnostic histo-patologic
Excepie fibroadenomul palpabil care va beneficia
de urmrire la 6 luni

1. Screeningul oportunistic
1.1. Pacienta fr semne obiective sugestive
include i mastodinia ca unic simptom la prezentare
< 40 de ani
Nu se investigheaz imagistic n IOCN
40 ani
mamografie
+ ecografie dac Sn dens omogen

2. Imagistica de diagnostic
Semne obiective:
Tumor palpabil;
Modificri tegumentare sugestive pentru cancer
mamar;
Secreia mamelonar spontan, unilateral, unicanalar;
Adenopatie axilar suspect clinic;
Metastaze viscerale cu punct de plecare neprecizat;
Modificri de volum i form, unilaterale, ale glandei
mamare recent aprute.
30 ani Ecografie
+ Mamografie la BIRADS 4 sau 5 la ecografie
30 ani Mamografie
+ ecografie dac BIRADS 0;4;5 (sn i axil)
Densitate parenchimal
crescut (sn dens omogen,
dens heterogen)

3. Situaii particulare
3.1. Brbat simptomatic se aplic regulile de la femei
3.2. Pacient simptomatic excepii
30 ani, <40 ani ecografia ca prim intenie dac:
Sn cu implant(augumentare)
< nodul cunoscut i documentat imagistic anterior
ca probabil benign staionar de cel puin 6 luni/EHP
(examen histopatologic) benign
sarcin
lactaie

Protocolul CDT n cancerul de sn

4. Diagnostic histopatologic
4.1. BIRADS 4 sau 5 clinic manifest sau infraclinic:
Confirmarea prin puncie este prima indicaie pentru
pacientele candidate la tratamentul neoadjuvant i
recomandabil ca fiind premergtoare oricrei terapii
(inclusiv chirurgie)
4.1.1. Puncie biopsie (PB)
Pistolet automat;
Ac de maxim 14 G;
2-5 fragmente;
Ghidaj imagistic recomandabil (ecografic de preferin)
Concordan histopatologie
BIRADS

Neconcordan histopatologie
BIRADS

Atitudine n funcie de histopatologie

Repetare PB

Neconcordan

Biopsie chirurgical

4.1.2.Biopsie asistat de vacuum (ghidat ecografic sau

mamografic) recomandat pentru:
Focare de microcalcificri
+/ Distorsiuni arhitecturale fr centru opac
+/ Proliferate intrachistice
+/ Proliferate intraductale
Este recomandat inserarea clipului de marcaj n
patul tumoral n momentul biopsiei i este obligatorie
la excizie imagistica complet
4.2. Leziuni cu potenial malign B3
Hiperplazia ductal atipic HEDA
Neoplazia intraepitelial lobular LIN
Adenoza sclerozant complex
Tumora phyllodes
Adenomioepiteliomul.
Decizie CDT
4.3. Biopsia chirurgical indicaii:
2 puncii biopsii neconcordante (ex-aspect sugestiv de
malignitate, histologie benigna)
Puncia-Biopsie nu poate fi efectuat din motive tehnice
Dac biopsia asistat de vacuum nu este posibil din
motive ce in de localizarea leziunii sau din motive
tehnice, n cazul leziunilor infraclinice reprezentate de:
Focar de microcalcificri fr mas asociat vizibil
ecografic
Distorsiune arhitectural fr centru opac
Proliferat intraductal
Proliferat intrachistic
Dac pacienta refuza puncia biopsie.

4.4. Situaii particulare

4.4.1. Multifocalitatea puncie biopsie pentru una din
formaiunile tumorale
4.4.2. Multicentricitatea puncie biopsie pentru cel
puin 2 tumori, cele mai ndeprtate
4.4.3. Bilateral sincron puncie biopsie bilateral
4.4.4. Carcinomul inflamator:
cu tumor evideniat imagistic puncie biopsie din
tumor
tumor neevideniabil biopsie tegumentar punch
1 repetare dac histopatologie negativ, urmat de biopsie
chirurgical, dac HP rmne negativ
4.4.5. Adenopatie axilar cu punct de plecare neprecizat
puncie biopsie sau biopsie chirurgical din adenopatia
axilar
4.4.6. Boala Paget
fr tumor Biopsie mamelonar/areolar (punch/
biopsie chirurgical)
cu tumor puncie biopsie din tumor i/sau punch
din mamelon/areol

5. Reperaj preoperator obligatoriu pentru

tumori infraclinice
Ghidat imagistic-eco, mamografic prin stereotaxie
Harpon metalic
Marcaj tegumentar dac condiiile locale ce in de
volumul snului, localizarea tumorii permit
Verificarea imagistic intra sau postoperatorie
(imediat) a piesei de excizie este obligatorie

6. Evaluarea rspunsului la chimioterapia

neoadjuvant
Recomandat
dup 2-4-6 cicluri (decizia trebuie luat dup discuie
imagistician oncolog medical)
dac clinic boala este n evoluie
dac clinic s-a obinut rspunsul maxim
oricnd se consider de ctre oncologul medical de a
fi contributiv la decizia terapeutic imediat
Investigaii: (decizie n funcie de bilanul iniial i
metoda aleas n funcie de vizibilitatea tumorii)
Mamografie ipsilateral
Ecografie intit Tumor + Axil

7. Evaluarea rspunsului la hormonoterapia

neoadjuvant
Recomandat:
dup 4-6 luni de hormonoterapie
dac clinic boala este n evoluie
dac clinic s-a obinut rspunsul maxim
Investigaii: (decizie n funcie de bilanul iniial)
Mamografie ipsilateral
Ecografie intit Tumor + Axil

Eniu et al

8. Inserie clip marcaj pat tumoral

la pacientele n curs de terapie neoadjuvant
(chimioterapie, hormonoterapie) cnd se preconizeaz o
remisie complet (nainte de remisia clinic complet)
numai n situaia n care se recomand conservarea
snului de ctre oncolog i se dorete acest lucru de ctre
pacient.

9. Urmrirea pacientei cu cancer de sn

tratat
Anual mamografie bilateral ecografie (conform
recomandrilor din screening)
Efectuarea unei mamografii ipsilaterale de referin
la 6 luni de la ncheierea radioterapiei n caz de tratament
conservator.

II. TRATAMENT CHIRURGICAL

1. Chirurgie cu intenie curativ n prim timp
1.1. Bilan preoperator:
1. Examen clinic general;
2. Examen senologic (clinic inspecie + palpare:
sni i arii ganglionare axilare, supraclaviculare i
laterocervicale);
3. Istoric medical (factori de risc pentru cancer mamar,
comorbiditi/apreciere risc genetic);
4. Laborator: hemograma, probe hepatice (ALT, AST,
bilirubina, fosfataza alcalina, LDH i gama GT); calciu seric,
creatinin seric, uree seric, glicemie, teste coagulare, ECG;
5. Bilan imagistic sn conform protocolului de
imagistic;
6. Puncie biopsie pentru confirmare malignitii pentru
toate leziunile suspecte clinic i imagistic (tip histologic,
grad, receptori estrogenici, receptori progesteronici, scor
Her 2, Ki 67);
7. Biopsie chirurgical dac 2 puncii biopsie histologic
negative (vezi protocol imagistic);
8. Ecografie abdominal dac exist suspiciune sau
prezen de metastaze Computer tomografie
9. Radiografie toracic dac exist suspiciune sau
prezen de metastaze Computer tomografie
10. Dac este stadiul IIIA operabil opional scintigrafie
osoas
Examinri ghidate de simptome:
Computer tomografie torace n caz de simptome i/
sau semne respiratorii;
Computer tomografie abdomen-pelvis n caz de
simptome i/sau semne abdomino-pelvine, probe hepatice
modificate;
Scintigrafie osoas n caz de durere osoas, fosfataza
alcalin crescut.

PET/CT Indicaii rambursate n Romnia:

evaluarea cazurilor de suspiciune de recidiv local
sau la distan n cazul investigaiilor imagistice standard
(CT i/sau RMN) neconcludente;
evaluarea cazurilor cu leziuni metastatice considerate
operabile, pe baza testelor standard imagistice (CT i/sau RMN)
1.2. Contraindicaiile chirurgiei cu intenie curativ
n prim timp
Absolute
Tumor cT4a-d
Axil N2
Boal metastatic (M1)
Relative Tumor cT3
1.3. Contraindicaii absolute pentru sector + axil
Imposibilitatea efecturii RTE post-operator;
2 sau mai multe tu n cadrane diferite (multicentricitate);
Microcalcificrile extinse, difuze (mai mult de 1
cadran), cu aspect malign;
Margini pozitive dup excizii repetate;
Tumorile stadializate la diagnostic T4.
1.4. Contraindicaii relative sector + axil
Vrst < 35ani;
Mutaie BRCA1 sau BRCA2;
Colagenoze;
Raportul tumorii/ snului nefavorabil pentru
operaie conservatoare;
Localizarea tumorii n cadranul central;
2 sau mai multe tu n acelai cadran (multifocalitate);
Invazie vascular extensiv;
Componen intraductal extensiv.
1.5. Intervenii chirurgicale
sectorectomie + limfadenectomie axilar de nivel I i II
(S+A) sau mastectomie radical modificat (MRM), n care
limfadenectomia axilar este tot de nivel I i II. Nivelul III
se extirp numai n cazul existenei, aici, a unor adenopatii
cu aspect intraoperator suspect de invazie
pentru cazurile cT1, cT2; cN0 (clinic i imagistic)
stadializarea axilei se poate face prin tehnica ganglionului
santinel (GS).
1.6. Elemente de tehnic
sectorectomie + limfadenectomie axilar elemente
de tehnic;
inciziile pentru sectorectomie i limfadenectomie
axilar separate, arcuate, dup liniile lui Langer n
cadranele superioare sau arcuate/radiare n cele inferioare;
margine macroscopic de 1cm;
margine mai mare pentru a evita reexcizia n:
o tumor > 2cm
o tumor palpabil
o tumor cu CIE
o tumor cu histologie lobular
o cazurile N +

Protocolul CDT n cancerul de sn

1.7. Situaii particulare

1.7.1. Evitarea limfadenectomiei axilare
Limfadenectomia axilar poate fi evitat n caz de
cN0 i:
CDIS (carcinom ductal in situ)
pT1a
pT1b, leziune nonpalpabil, G1 nuclear, fr invazia
spaiului limfovascular
pT1a-b, carcinom tubular sau coloid
ganglion santinel negativ
ganglion santinel micrometastatic
1-2 GS pozitivi, sectorectomie + iradiere extern sn
carcinom mamar invaziv (femei n vrst,
sectorectomie, risc anestezic crescut i care vor primi
hormonoterapie indiferent de N)
1.7.2. Carcinom inflamator MRM dup tratament
neoadjuvant dac este operabil
1.7.3. Debut axilar fr tumor n sn: MRM sau
radioterapie exclusiv CDT
1.7.4. Boala Paget
CDIS: sectorectomie + radioterapie sau MS
(multicentric, extins)
CMI (carcinom mamar invaziv): sectorectomie +
limfadenectomie axilar i radioterapie sau MRM.

1.7.5. Carcinom bilateral sincron sau metacron

chirurgie identic bilateral (dac e posibil)
1.7.6. Recidiv local (RL)
dup S+A: MS
dup MRM: excizie larg (eventual cu plastron de
perete toracic), dac e posibil i bilanul la distan este
negativ
1.7.7. Carcinomul n timpul sarcinii i alptrii S+A
sau MRM n funcie de trimestru i de situaia local
1.7.8. Carcinomul mamar la brbat MRM

2. Chirurgia dup tratament sistemic

neoadjuvant
Dac exist clip de marcaj n patul tumoral:
reperaj imagistic al clipului nainte de operaia
conservatoare
verificarea imagistic a exciziei n timpul chirurgiei
MRM indicaie conform stadiului iniial
Marcarea intraoperatorie a patului tumoral

3. Chirurgia n boala metastatic

Mastectomia de curire hemoragii necontrolabile
Alte indicaii doar dup discuie n CDT

10

III. ANATOMIE PATOLOGIC

1. Examinarea pieselor de biopsie tru-cut,
mammotome, biopsia incizional
1.1. Examinare macroscopic pentru piesele de
biopsie tru-cut, mammotome, biopsia incizional
numrul i dimensiunea fragmentelor
detalii macroscopice ex. culoarea, consisten
(biopsia incizional)
prezena tegumentului sau altui tip de esut n piesa
biopsic
1.2. Examen microscopic Biopsie Tru-cut, Mammatome,
biopsie incizional
Numrul i dimensiunea cumulat a fragmentelor
eantionate (se va corela cu macroscopia)
Calitatea fragmentelor eantionate (fixare, morfologie):
interpretabile, greu interpretabile, neinterpretabile
Tipul histologic (conform Clasificrii OMS n
vigoare): se vor specifica dac exist mai multe tipuri
histologice, procentul pe care l ocup fiecare i se vor grada
separat dac este posibil
Gradul Nottingham (Anexa1) (i la cazurile tratate)
Procentul din suprafaa examinat ocupat de tumor
Celularitatea n patul tumoral
Leziuni epiteliale asociate
Prezena embolilor intralimfatici/intravenoi (n
coloraia uzual HE sau n coloraia IHC pentru: D2-40, CD34)
Prezena infiltratelor tumorale perineurale

Eniu et al

Carcinom in situ asociat: se va specifica, tipul

acestuia i ct reprezint acesta din patul tumoral
Necroz tumoral
Microcalcificri
Infiltrare inflamatorie peritumoral
Se va specifica dac au fost fcute coloraii IHC pentru
celulele mioepiteliale (CD10, p63, CK5/6, actin, S100)
sau pentru tipuri speciale de carcinoma (Ex: e-caderina,
cromogranina)
Se va clasifica biopsia conform Sistemului de Raportare
UK National Health Service Screening Programme (B1B5) Anexa 2

2. Examinarea pieselor de sectorectomie sau

mastectomie
2.1. Descrierea piesei de excizie
Fixat/nefixat
Tipuri de esuturi prezente n pies
Secionat/nesecionat intraoperator
Mrimea piesei (3 dimensiuni, dac este excizat n bloc)
Descrierea tegumentului (ex. cicatrici) i a dimensiunii
acesteia dac este prezent
Dac exist elemente de orientare intraoperatorie (fire
textile, harpon metalic, clip metalic, clip carbon)
Dac nu exist repere piesa va fi declarat ca neorientabil
2.2. Date despre Tumor
Descrierea (unic/multipl, form, consisten, culoare etc)
Mrimea (cel puin 2 dimensiuni)
Corelarea cu aspectul imagistic dac acesta este disponibil

Protocolul CDT n cancerul de sn

Relaia cu marginile chirurgicale i cu reperele

intraoperatorii (dac exist)
2.3. Modificri macroscopice suplimentare
Ex: biopsii anterioare, chiste, implante
2.4. Descrierea eantioanelor prelevate pentru
prelucrarea la parafin, banc de esuturi, esut
proaspt pentru diagnostic molecular
tipul histologic (conform Clasificrii OMS n vigoare):
se vor specifica dac exist mai multe tipuri histologice,
procentul pe care l ocup fiecare i se vor grada separat dac
este posibil;
gradul Nottingham (i la cazurile tratate);
procentul din suprafaa examinat ocupat de tumor;
leziuni epiteliale asociate;
prezena embolilor intralimfatici/intravenoi (n
coloraia uzual HE sau n coloraia IHC pentru: D2-40,
CD34);
prezena infiltratelor tumorale perineurale;
carcinom in situ asociat: se va specifica, tipul
acestuia i ct reprezint din patul tumoral;
necroz tumoral;
microcalcificri;
infiltrate inflamatorii peritumorale;
distana fa de margini (separat pentru componenta
invaziv i pentru cea in situ);
se va specifica dac au fost fcute coloraii IHC pentru
celulele mioepiteliale (CD10, p63, CK5/6, actina, S100)
sau pentru tipuri speciale de carcinoma (Ex: e-caderina,
cromogranina);
cazul va fi clasificat pTNM (Anexa 3).
Pentru cazurile cu terapie neoadjuvant chemo-endocrin
(care nu au fost diagnosticate prin biopsie incizional):
se va calcula Scorul RCB i clasa RCB (Residual
Cancer Burden) (Anexa 5)
opional se va aprecia rspunsul la terapie folosind
sistemul Miller-Payne
cazul va fi clasificat ypTNM (Anexa 3)

3. Examinarea limfoganglionilor axilari

Numr
Localizare, dac a fost specificat de chirurg
Dimensiunea maxim a metastazelor macroscopic
vizibile
Numrul total de limfoggl. izolai
Numrul limfoggl. metastazai
Prezena efraciei capsular
Diametrul celei mai mari metastaze limfoggl.
Repartiia limfoggl. metastazai pe etajele piesei (dac
exist marcaj intraoperator)
Limfoganglionul santinel: protocol standard

11

4. Examinare Imunohistochimic Standard

(IHC)
4.1.Aprecierea IHC a pozitivitii tumorii pentru
receptorii hormonali (estrogen RE, progesteron RPg)
Se apreciaz procentual numrul celulelor tumorale
(componenta invaziv) pozitive
Se apreciaz intensitatea (slab, moderat, intens)
Se va specifica dac exist martori (celule netumorale)
pozitive
Se calculeaz Scorul Allred (Anexa 4) i se specific
semnificaia acestuia
Se va meniona dac exist vicii de procesare tisular ce
pot afecta calitatea examinrii
4.2.Aprecierea IHC indicelui de proliferare cu
ajutorul lui Ki67
Se apreciaz procentual numrul celulelor tumorale
(componenta invaziv) pozitive (se numr 500 nuclei cu
obiectiv de 40x)
Se va specifica dac exist martori (celule netumorale)
pozitive (ex. limfocite)
Se va meniona dac exist vicii de procesare tisular ce
pot afecta calitatea examinrii
4.3. Testare IHC a supraexpresiei HER 2:
scor 0 : absena marcajului sau marcaj n <10% din
celule = absena supraexpresiei;
scor 1+ : marcaj membranar incomplet n >10% din
celule = absena supraexpresiei;
scor 2+ : marcaj membranar circumferenial de
intensitate mic/medie n >10% din celulele tumorale =
supraexpresie slab, necesit confirmarea amplificrii genice
prin ISH;
scor 3+ : marcaj membranar circumferenial intens n
10% din celulele tumorale = supraexpresie puternic.
4.4.Indicaiile determinrii RE i RPg :
la cazurile netratate de carcinom mamar invaziv;
la recidive/metastaze de carcinom mamar invaziv;
la cazurile tratate la indicaia clinicienilor;
la cazurile de carcinom ductal in situ.
4.5.Indicaiile determinrii Ki 67
la cazurile netratate de carcinom mamar invaziv.
Indicaiile determinrii HER 2
la cazurile netratate de carcinom mamar invaziv;
la recidive/metastaze de carcinom mamar invaziv;
la cazurile tratate la indicaia clinicienilor.

5. Examinare Carcinom ductal in situ

dimensiuni (n cazul asocierii cu carcinomul invaziv
se va aprecia % din volumul tumoral)
tipul histologic (Clasificarea OMS in vigoare)

12

Eniu et al

gradul nuclear
necroz
microcalcificri
leziuni asociate
distana fa de marginile de rezecie la piesele
de excizie chirurgical (lumpectomie/sectorectomie,
mastectomie)
se va specifica dac au fost fcute coloraii IHC pentru
celulele mioepiteliale (CD10, p63, CK5/6, actina, S100) sau
pentru diagnosticul diferenial (Ex: E-caderina)
vse va clasifica pTNM: pTis
evaluarea RE, RPg.

6. Examinare Carcinom microinvaziv

Max. 1 mm diametru
Numrul focarelor
Distana fa de marginile de rezecie la piesele
de excizie chirurgicale (lumpectomie/sectorectomie,
mastectomie)
Se va specifica dac au fost fcute coloraii IHC pentru
celulele mioepiteliale (CD10, p63, CK5/6, actina, S100) sau
pentru tipuri speciale de carcinom(Ex: E-caderina)
vPosibil ca dimensiunile reduse s nu permit aprecierea
gradului Nottingham i a RE, RPg, KI 67 i HER 2!
vClasificarea pTNM: pTmic

1.4. Laborator: hemograma, probe hepatice (ALT, AST,

bilirubina, fosfataza alcalin); Calciu seric, creatinin seric
1.5. Bilan imagistic sn conform protocolului de
imagistic
1.6. Examen histologic complet (vezi cerine)
1.7. Discuie prezervare fertilitate adaptat la caz
1.8.Elucidarea statusului menopauzal (dac exist
dubii, testare estradiol i FSH)
1.9.Ecografie abdominal dac suspiciune sau
prezena metastaze computer tomograf (CT)
1.10.Radiografie torace dac suspiciune sau prezena
metastaze computer tomograf
Dac stadiu III opional scintigrafie osoas
1.2.Examinri ghidate de simptome:
computer tomograf (CT) torace simptome respiratorii
sau suspiciune radiografie torace
computer tomograf (CT) abdomen pelvis simptome,
probe hepatice modificate, examen clinic modificat
scintigrafie os durere osoas, fosfataza alcalin
crescut
1.3. PET/CT (vezi indicaii)

7. Examinare Neoplazia lobular

2. PET CT Indicaii rambursate n Romnia:

Tipul histologic:
hiperplazie lobular atipic
carcinom lobular in situ
carcinom lobular pleomorf in situ
% lobulilor afectai
Se va preciza dac au fost fcute coloraii
imunohistochimice pentru celule mioepiteliale (CD10,
p63, CK5/6, actina, S100) sau pentru diagnosticul diferenial
(E-cadherina).

evaluarea cazurilor de suspiciune de recidiv local

sau la distan n cazul investigaiilor imagistice standard
(CT i/sau RMN) neconcludente;
evaluarea cazurilor cu leziuni metastatice considerate
operabile, pe baza testelor standard imagistice (CT i/sau
RMN)

IV. TRATAMENT ADJUVANT SISTEMIC

1.Bilan iniial
1.1. Examen clinic general
1.2. Examen senologic (clinic inspecie + palpare sn
i arii ggl)
1.3. Istoric medical (comorbiditi/apreciere risc genetic)

3.Cerinte pentru histopatologia post

chirurgie definitiv:

Numr (tumori multiple histologie separat)

Status margini rezecie (cu specificarea distanei minime)
Numr de ganglioni excizai
Numr de ganglioni invadai
Grad SBR modificat Nottingham
Receptori Estrogenici (RE)
Receptori progesteronici (RPg)
Scor HER2
Ki 67
Invazia vascular, invazia limfatic, perineural.

Protocolul CDT n cancerul de sn

13

4. Indicaie pentru tratamentul adjuvant n funcie de subtip

5. Statusul Postmenopauzal
Femei peste 60 de ani;
Ovariectomie bilateral;
Femei peste 50 ani cu stoparea spontan a menstrelor
n urm cu mai mult de 12 luni;
Femei peste 50 ani cu stoparea menstrelor de peste

12 luni secundar chimioterapiei sau histerectomiei i nivele

FSH (LH) i estradiol n valorile corespunztoare celor de
postmenopauz.

6. Hormonoterapie adjuvant
Pentru pacientele sub 45 ani, amenoreea postchimioterapie contraindic IA de prim intenie! *

Pre-menopauza

Menopauza

1. Tamoxifen 5 ani

1. Tamoxifen 2 ani + IA 3 ani (anastrozol, exemestane)

menopauza IA 5 ani CDT

2. IA 5 ani (anastrozol, letrozol, exemestan)

pre-menopauza TAM pn la 10 ani

3. IA 2-3 ani + Tamoxifen pana la 5 ani

Opiune:
+ agonist LH-RH 2-5 ani

4. Tamoxifen 4.5-6 ani + IA 5 ani ( letrozol, anastrozol)

DISCUIE CDT
Contraindicaii Tamoxifen (tromboza venoas profund)
Agonist LH-RH + IA
Agonist LH-RH
Continuarea HT peste 5 ani

5. Tamoxifen 5 ani daca contraindicaii IA

14

Eniu et al

7. Indicaie tratament adjuvant Luminal A hormonoterapie pentru toate pacientele, chimioterapie

conform schemei

8. Indicaie tratament adjuvant Luminal B, HER2 negativ hormonoterapie pentru toate pacientele,
chimioterapie conform schemei

Protocolul CDT n cancerul de sn

9. Indicaie tratament adjuvant Luminal B HER2 pozitiv hormonoterapie, chimioterapie, tratament

anti HER2 conform schemei

10. Indicaie tratament adjuvant Luminal A chimioterapie, tratament anti HER2 conform schemei

15

16

Eniu et al

11. Indicaie tratament adjuvant triplu negativ recomandat nrolarea pacientelor n trialuri clinice,
chimioterapie conform schemei

12. Apreciere risc transmitere genetic

Calcul:
Mutaie genetic cunoscut n familie
Cancer de sn la o femeie nainte de 30 ani
Cancer de sn la o femeie ntre 30-39 ani
Cancer de sn la o femeie ntre 40-49 ani
Cancer de sn la o femeie ntre 50-70 ani
Cancer de sn la un brbat
Cancer de ovar

Punctaj
5
4
3
2
1
4
3

Se adun scorul fiecrei linii parentale separat (maternal/

paternal)
Indicaie pentru testare genetic:
Scor 5
excelent indicaie
Scor 4 sau 3 indicaie posibil
Scor 2 sau 1 utilitate medical redus

13. Urmrire post terapeutic

controale periodice la 3-4 luni n primii 2 ani, la 6 luni
n urmtorii 3-5 ani, ulterior controale anuale;
anamnez i examen obiectiv;
mamografie ipsilateral (chirurgie conservatoare) i
contralateral la 1-2 ani;
RMN mamar poate fi indicat n cazul pacientelor tinere
cu sni deni i predispoziie genetic/familial- discuie
n CDT;
pentru pacientele care urmeaz hormonoterapie cu
Tamoxifen se recomand consult ginecologic anual;
pentru pacientele care urmeaz hormonoterapie cu

inhibitori de aromataz evaluarea periodic a densitii

osoase este recomandat;
n cazul pacientelor simptomatice sau n cazul
evidenierii unor modificri patologice la examenul obiectiv
sunt indicate examinri suplimentare intite.
Recomandri
stil de via: exerciii fizice regulate; creterea n
greutate i obezitatea influeneaz negativ prognosticul
pacientelor cu cancer mamar;
terapia de substituie hormonal trebuie descurajat
(crete riscul de recuren);
fizioterapia este recomandat cu scopul prevenirii
i tratamentului limfedemului i cu scopul prevenirii i
corectrii defectelor de postur ca urmare a mastectomiei;
este recomandat iniierea prompt a antibioticoterapiei
n cazul unor leziuni infectate la nivelul membrului superior
la pacientele care au urmat limfadenectomie axilar
evaluarea calitii vieii pacientelor dup ncheierea
tratamentului.

V. TRATAMENT NEOADJUVANT
1. Indicaie:
1. Conversie la operabilitate a tumorilor iniial
inoperabile (LABC)
2. Carcinomul Inflamator
3. Conservarea snului (carcinom mamar operabil)
4. Testarea sensibilitii la chimioterapie a tumorii
primare

Protocolul CDT n cancerul de sn

17

2. Motivaie:

3.6. Examen histologic complet (vezi cerine)

1. Obinerea pCR (rspuns complet patologic)

mbuntire supravieuire
(Selecie histologii cu rat mai mare de RC )
2. Individualizarea tratamentului: beneficiu de
supravieuire

3.7. Discuie prezervare fertilitate adaptat la caz

3. Bilan iniial
3.1. Examen clinic general
3.2. Examen senologic (clinic inspecie + palpare sn
i arii ggl)
3.3. Istoric medical (comorbiditi/apreciere risc
genetic)
3.4. Laborator: hemograma, probe hepatice (ALT, AST,
bilirubina, fosfataza alcalina); Calciu seric, creatinin seric
3.5. Bilan imagistic sn conform protocolului de
imagistic

3.8. Elucidarea statusului menopauzal (dac exist dubii,

testare estradiol i FSH)
3.9.Ecografie abdominal dac suspiciune sau
prezena metastaze computer tomograf (CT)
3.10. Radiografie torace dac suspiciune sau prezena
metastaze computer tomograf
Dac stadiu III opional scintigrafie osoas
3.2.Examinri ghidate de simptome:
computer tomograf (CT) torace simptome respiratorii
sau suspiciune radiografie torace
computer tomograf (CT) abdomen pelvis simptome,
probe hepatice modificate, examen clinic modificat
scintigrafie os durere osoas, fosfataza alcalin
crescut

4. Selecie tip tratament (chimioterapie/hormonoterapie)

18

5. Hormonoterapie neoadjuvant

6. Chimioterapia neoadjuvant

Eniu et al

Protocolul CDT n cancerul de sn

19

7. Carcinom inflamator

Tratament adjuvant : HT dac HR+, Her2 dac Her2 +

VI. RADIOTERAPIA
1. CDIS tratament
1.1. Chirurgia
1.1.1. Tratament conservator:
excizie larg (margini 2 mm) fr evidare axilar + RT
1.1.2. Mastectomie simpl SNB reconstrucie
imediat
leziuni multicentrice
leziuni multifocale, margini pozitive dup recup
tumora > 3-5 cm + G3 + comedo + vrsta tnr? CDT
1.2. Radioterapia adjuvant
1.2.1. Volume int: sn pat tumoral
fracionare standard
DT = 50Gy/25 fr/5 sptmni 10 Gy/5 fr/supraimpresiune
pat tumoral
1.2.2. Hipofracionare
paciente n vrst, comorbiditi, handicap motor
1.2.3. CDIS: radioterapie i grupe de risc discuie n
comisia pentru decizie terapeutic
risc sczut fr RT? (>65 ani, T<10 mm, G1, subtip

clinging & micropapilar, RE+, RP+, R10 mm, biologie

favorabil
risc crescut boost? (vrsta tnr, tumor mare,
palpabil, peste 3 cm, G3, receptori hormonali abseni,
margine profund < 2mm)
1.3. Tratament sistemic
dac receptorii hormonali sunt pozitivi se poate
administra tamoxifen profilactic

2. Cancer mamar operabil: categorii

terapeutice
2.1. Chirurgia
2.1.1. Tip chirurgie
sector + SNB/limfadenectomie axilar + RT
MRM RT
2.1.2. Margini de rezecie neinvadate ( no tumor on ink)
preferabil margini (R) 1mm pentru componenta
invaziv
R 2 mm pentru componenta CDIS
margini pozitive (CDI/ CDIS) reexcizie
excp. CLIS, R focal microscopic pozitive
2.1.3. LA: nr. ganglioni evidai nivel axilar I+II: 8-10

20

Eniu et al

2.2. Individualizarea tratamentului local vs. risc

Prognostic nefavorabil

Prognostic favorabil

RH-, Her2+
Triplu negativ

RE+, RP+, Her2 = 0

postmenopauz

risc crescut fr RT

Hipofracionare

risc f-cie de vrst, stadium

APBI

risc f-cie de rspuns la PCT

RT: boost

2.3. Radioterapia i tratamentul conservator

2.3.1. Volume int
Tip chirurgie

RT: vol. int

Tip fracionare

pN0

sn pat tumoral*

standard/ HF

pN+

sn pat tumoral* + GSC/ICV,

nivel III/GMI

standard

sector+LA

* marcarea patului tumoral cu clipuri titan conform protocolului tehnic

de radioterapie

2.3.2. Doz total (DT), fracionare

Fracionare standard
DT= 50 Gy/ 25fr +/- boost 10-16 Gy/5-8 fr/5-7 spt
Hipofracionare
DT= 42.5 Gy/16fr/ 3.2 spt, D/fr= 2.66Gy (protocol
Whelan)
DT= 40 Gy/15 fr/ 3 spt, D/fr= 2.67Gy (START B,
Yarnold)
2.3.3. Supraimpresiunea patului tumoral: 10-16 Gy
Cine beneficiaz?
vrst < 51 ani
invazia spaiului limfovascular (LVI)
R< 1mm/ focal pozitive
CDT: paciente > 50 ani, fr LVI
G3, T>2-3 cm
RE, RP neg., axil +
tratament sistemic
Beneficiu mai modest la pacientele n vrst, fr factori
de risc; administrarea supraimpresiunii se va considera
individual.
2.3.4. QA i supraimpresiunea patului tumoral
Informaii preoperatorii:
mamografie
ecografie
CT /RMN n poziia de tratament fuziune cu CT
planning
Informaii postoperatorii:
marcarea intraoperatorie a patului tumoral cu clipuri
de titan pentru a crete acurateea localizrii (se plasarea 3-5
clipuri de titan n cavitatea de sector, nainte de reconstrucia
snului: pe planul profund al rezeciei/ m. pectoral, lateral pe
pereii cavitii, la mijlocul patului tumoral, cardial i caudal)
protocol operator, orientarea i marcarea marginilor
specimenului chirurgical
buletin HP, extinderea microscopic a marginilor libere

2.3.5. Regimuri fracionare alternative: hipofracionarea

Cine beneficiaz?
paciente > 50 ani
pT1N0, pT2N0
G1,2
chirurgie conservatoare, margini negative (R0)
Standard minim acceptabil: planning 2D cu optimizarea
omogenitii D n ax central
Simulare CT, planning 3D, ameliorarea distribuiei dozei,
risc mai mic de toxicitate cutanat/ fibroz
2.3.6. Hipofracionare + boost
factori de risc supraimpresiunea patului tumoral
regim optim de fracionare cnd se preconizeaz
administrare boost?
Yarnold: 40 Gy/15 fr/ 22 zile
boost: 10-16 Gy, 2Gy/ fr
2.4. Radioterapia dup MRM
2.4.1. Indicaiile RT post MRM
Tip chirurgie

RT: vol. int

Tip fracionare

1-3

PTGSC/ICV

Standard

>4

PT+GSC/ICV

MRM
pN+

pN0
T3

PT

Standard

R1

PT boost*

Standard

R< 1mm

PT

Standard

* margine profund marcat

2.4.2. CMO: RT post MRM, risc intermediar

Tip chirurgie

Factori de risc

CDT

LVI+

RT, dac > 2 FR

MRM
pT2, pN0

RE, RP neg.
R< 1mm
< 50 ani
G3
CLI
CDT comitet decizie terapeutic

2.4.3. Putem exclude RT post MRM?

Tip chirurgie

Risc sczut

CDT

> 50 ani

fr RT

MRM
pT1, pT2
pN1, 1 ggl.+, baza axilei

R0
L0, V0
G1
RE+, RP +

CDT comitet decizie terapeutic

Protocolul CDT n cancerul de sn

2.5. Managementul ariilor ganglionare

CT-Sim recomandat la pacienii la care este planificat
radioterapia regiunilor ganglionare pentru a ncadra volumul
int ganglionar i a reduce doza la nivelul organelor
sntoase.
2.5.1. RT axilei: indicaii
disecie standard nivel axilar I+II fr RT axilei
disecie axilar incomplet, N+
disecie axilar incomplet, N0, tumori G2/ G3
2.5.2. RT GSC/ICV: indicaii
>pN2a pN3b: > 4N+/ nivel III axilar+/cGMI+ i > 1N+
pN+, EEC> 2mm
disecie axilar incomplet, N+
N3
pN1a CDT (SUPREMO)
2.5.3. RT i GMI
(p)N2b: cGMI+
(p)N3b: cGMI+ i N+
pN+, tumori mari centrale/ cadrane interne

3. Interval chirurgie-radioterapie
3.1. Nu exist un prag de siguran, debut RT ct
mai devreme posibil n prezena factorilor de risc
3.2. Factori predictivi pentru recidiv local:
vrsta
margini, LVI+
DT, tratament sistemic administrat
3.3. Interval optim: 6-8 sptmni, fr chimioterapie
adjuvant
3.4. Studii retrospective: RT timing vs. recidiva local,
supravieuire (> 12-20 spt. crete rata recidivei
locale)

21

5.3. Metastaze cerebrale pentru pacienii cu IP/IK

bun: DT= 30 Gy/ 10 fr/ 2 sptmni
5.4. Tumori inoperabile, avansate loco-regional:
diferite scheme de hipofracionare
5.5. Tumori inoperabile, avansate loco-regional, la
pacieni vrstnici, cu comorbiditi: DT= 30 Gy/10
fr/2 sptmni sau DT= 36 Gy/ 6 fr/6 sptmni

VII. BOALA METASTATIC

1. Bilan la progresie:
1. Ecografie abdominal CT (nu se efectueaz CT
craniu de rutin)
2. Rgr torace CT
3. Scintigrafie os
4. Mamografie
5. PET/CT
a. evaluarea cazurilor de suspiciune de recidiv local
sau la distan n cazul investigaiilor imagistice
standard (CT i/sau RMN) neconcludente;
b. evaluarea cazurilor cu leziuni metastatice
considerate operabile, pe baza testelor standard
imagistice (CT i/sau RMN)
6. Laborator (+CA 15-3)
7. Biopsie recidiv/metastaz: RE, RP, Her2
8. Discutarea prognosticului (incurabil, dar tratabil)

2. Selecia terapiei n boala metastatic

Terapie

Factori

HT

status RH (tu. primar, metastaz)

rspuns anterior la terapie
ILB

4. RT i tratamentul sistemic
4.1. Tamoxifen
secvenial
dac tratamentul a fost iniiat postoperator, se continu
concomitent cu RT
4.2. Inhibitori de aromataz (Anastrozol, Letrozol)
concomitent cu RT
4.3. Transtuzumab
concomitent
sn, PT stg.: achiziie de date + planning 3D, limitarea
includerii cordului n cmpuri, fr a compromite acoperirea
volumului int

5. Radioterapia paliativ

Chimio

necesitatea control rapid simptome

rspuns anterior la terapie
ILB
ncrctur tumoral
vrsta (nu contraindic absolut tratamentul)
comorbiditi

Trastuzumab

HER2 (tu primar/meta),

tratament anterior anti-Her2

Bifosfonai

meta os (osteolitice sau simptomatice)

scop: reducere evenimente scheletale (fract, RTE, chir)
reducere durere

HT- preferat
Asocierea HT + CT este contraindicat
HER2

B. endocrin responsiv
(HR+, IL lung, esuturi
moi/os, meta viscerale
asimptomatice)

B. endocrin nonresponsiv

5.1. Metastaze osoase: DT= 8 Gy/ 1fr sau 20 Gy/5 fr/5 zile

ER

5.2. Metastaze vertebrale, meningeale, ganglionare:

DT= 20 Gy/ 5fr/ 5 zile

HER2-negativ

Hormonoterapie (HT)

Chimioterapie (CT)

HER-pozitiv

Anti-HER2 direct + HT

Anti-HER2 + CT

22

Eniu et al

3. Selecia hormonoterapiei n boala metastatic

POSTMENOPAUZ

* Steroidal dup non-steroidal IA; Non-steroidal dup steroidal AI;

Protocolul CDT n cancerul de sn

4. Selecia chimioterapiei n boala metastatic

4.1. Principii
Monoterapia secvenial preferat fa de polichimioterapie
Polichimioterapie:
boal rapid progresiv
criz visceral
necesitatea unui control rapid al simptomelor/bolii
Linia I: antracicline sau taxani, monoterapie
Doxorubicin 60mg/mp, Farmorubicin 100mg/mp
q3w
Docetaxel 75-100 mg/mp q3w
Paclitaxel 80-90 mg/mp q3w
Reluare antracicline: dac DFI>1 an, fr atingerea
dozei cumulative toxice
Reluare taxani: dac DFI > 1 an
Opiune: taxani + bevacizumab
Dup antra/taxani:
Capecitabina
Vinorelbina
Doxorubicina liposomala
Gemcitabina
Platina (TNBC?)
Etoposid (po)
Ciclofosfamida (po) (TNBC?)
Evaluarea terapiei: 2-3 cicluri (aprox.2 luni)
Clinic
Imagistic
Biologic
Terapia: pn la PD sau toxicitate inacceptabil
Integrarea ngrijirilor suportive i paleative
Regimuri de polichimioterapie:
A60C, E100C, FE75C
A-T (Doxorubicin 50mg/mp, docetaxel 75mg/mp)
Paclitaxel 80mg/mp + carboplatin AUC 2 q1w
CMF
Docetaxel 75 mg/mp+ capecitabina 1250mg/mp
Gemcitabina 1250 mg/mp d1,8Paclitaxel 175 mg/mp

Bibliografie
1. Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart
M, Thrlimann B, Senn HJ; Panel members. Personalizing the
treatment of women with early breast cancer: highlights of the St
Gallen International Expert Consensus on the Primary Therapy of
Early Breast Cancer 2013. Ann Oncol. 2013 Sep;24(9):2206-23.
doi: 10.1093/annonc/mdt303. Epub 2013 Aug 4.
2. Senkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson
A, Zackrisson S, Cardoso F; ESMO Guidelines Working Group.
Primary breast cancer: ESMO Clinical Practice Guidelines for
diagnosis, treatment and follow-up.Ann Oncol. 2013 Oct;24 Suppl
6:vi7-23. doi: 10.1093/annonc/mdt284. Epub 2013 Aug 22
3. Cardoso F, Harbeck N, Fallowfield L, Kyriakides S, Senkus E; ESMO
Guidelines Working Group. Locally recurrent or metastatic breast
cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment
and follow-up. Ann Oncol. 2012 Oct;23 Suppl 7:vii11-9

23
4. Cardoso F, Costa A, Norton L, Cameron D, Cufer T, Fallowfield
L, Francis P, Gligorov J, Kyriakides S, Lin N, Pagani O, Senkus
E, Thomssen C, Aapro M, Bergh J, Di Leo A, El Saghir N, Ganz
PA, Gelmon K, Goldhirsch A, Harbeck N, Houssami N, Hudis C,
Kaufman B, Leadbeater M, Mayer M, Rodger A, Rugo H, Sacchini
V, Sledge G, vant Veer L, Viale G, Krop I, Winer E. 1st International
consensus guidelines for advanced breast cancer (ABC 1). Breast.
2012 Jun;21(3):242-52. doi: 10.1016/j.breast.2012.03.003. Epub
2012 Mar 16.
5. Guidelines of the AGO Breast Committee, Breast Cancer Guidelines
, update 8 Nov 2012, Accesed 20 Dec 2013, http://www.ago-online.
de/en/guidelines-mamma/
6. NCCN Clinical Practice Guidelines in Oncology, Breast Cancer,
V.1.2014, Accessed 20 Dec 2013, http://www.nccn.org/professionals/
physician_gls/f_guidelines.asp#breast
7. Daniel B.Kopans. Breast Imaging, 3rd edition,Lippincot
-Williams;2007
8. Gh.Peltecu.Tratamentul Conservator al Cancerului Incipient,Editura
Universitara Bucuresti;2003
9. Dupont WD, Parl FF, Hartmann WH, Brinton LA, Winfield
AC, Worrell JA, Schuyler PA, Plummer WD, Breast cancer risk
associated with proliferative breast disease and atypical hyperplasia
, Cancer. 1993 Feb 15;71(4):1258-65
10. American Cancer Society Breast Cancer Advisory Group.
American Cancer Society guidelines for breast screening with
MRI as an adjunct to mammography, CA Cancer J Clin. 2007 MarApr;57(2):75-89.
11. Mann RM, Kuhl CK, Kinkel K, Boetes C.Breast MRI: guidelines
from the European Society of Breast Imaging. Eur Radiol. 2008
Jul;18(7):1307-18. Epub 2008 Apr 4.
12. Levine P, Simsir A, Cangiarella J.Management issues in breast
lesions diagnosed by fine-needle aspiration and percutaneous core
breast biopsy. Am J Clin Pathol. 2006 Jun;125 Suppl:S124-34
13. Pijnappel RM, van den Donk M, Holland R, Mali WP, Peterse JL,
Hendriks JH, Peeters PH.Diagnostic accuracy for different strategies
of image-guided breast intervention in cases of nonpalpable breast
lesions. Br J Cancer. 2004 Feb 9;90(3):595-600.
14. Fishman JE, Milikowski C, Ramsinghani R, Velasquez MV, Aviram
G.US-guided core-needle biopsy of the breast: how many specimens
are necessary?; Radiology. 2003 Mar;226(3):779-82. Epub 2003 Jan
15.
15. Yeow KM, Lo YF, Wang CS, Chang HK, Tsai CS, Hsueh
C.Ultrasound-guided core needle biopsy as an initial diagnostic
test for palpable breast masses. J Vasc Interv Radiol. 2001
Nov;12(11):1313-7.
16. Burbank F, Forcier N.Tissue marking clip for stereotactic
breast biopsy: initial placement accuracy, long-term stability,
and usefulness as a guide for wire localization. Radiology. 1997
Nov;205(2):407-15.
17. Egyed Z, Pntek Z, Jray B, Kulka J, Svastics E, Kas J, Lszl
Z.Radial scar-significant diagnostic challenge. Pathol Oncol Res.
2008 Jun;14(2):123-9. Epub 2008 Apr 12.
18. Parker SHBurbank FJackman RJAucreman CJCardenosa GCink
TMCoscia JL Jr, et al.Percutaneous large-core breast biopsy: a
multi-institutional study. Radiology. 1994 Nov;193(2):359-64.
19. Eniu A, Carlson RW, El Saghir NS, Bines J, Bese NS, Vorobiof D,
Masetti R, Anderson BO, Breast Health Global Initiative Treatment
Panel. Guideline Implementation For Breast Healthcare In Low- And
Middle-Income Countries: Treatment Resource Allocation. Cancer.
2008 Oct 15;113(8 Suppl):2269-81

24
20. Perry N, Broeders M, de Wolf C, et al., editors. 4th edition.
Luxembourg: Office for Official Publications of the European
Communities; 2006. European Commission. European Guidelines
for Quality Assurance in Breast Cancer Screening and Diagnosis.
21. Lakhani S, R.; Ellis, I. O.; Schnitt, S. J.; Tan, P. H.; Van De Vijver,
M. J. (Eds.). WHO Classification of Tumours of the breast. Lyon:
IARC, 2012.
22. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM,
Allison KH, Allred DC, Bartlett JM, Bilous M, Fitzgibbons P, Hanna
W, Jenkins RB, Mangu PB, Paik S, Perez EA, Press MF, Spears
PA, Vance GH, Viale G, Hayes DF; American Society of Clinical
Oncology; College of American Pathologists. Recommendations
for human epidermal growth factor receptor 2 testing in breast
cancer: American Society of Clinical Oncology/College of American
Pathologists clinical practice guideline update. J Clin Oncol. 2013 Nov
1;31(31):3997-4013. doi: 10.1200/JCO.2013.50.9984. Epub 2013 Oct
23. Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL,
Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks
DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne
CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep
FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D,
Wheeler T, Williams RB, Wittliff JL, Wolff AC. American Society
of Clinical Oncology/College Of American Pathologists guideline
recommendations for immunohistochemical testing of estrogen
and progesterone receptors in breast cancer.J Clin Oncol. 2010 Jun
1;28(16):2784-95. doi: 10.1200/JCO.2009.25.6529. Epub 2010 Apr
19. Review.
24. Sahoo S, Lester SC. Pathology of breast carcinomas after
neoadjuvant chemotherapy: an overview with recommendations
on specimen processing and reporting. Arch Pathol Lab Med.
2009;133(4):633642.
25. Loprinzi CL, Thome SD. Understanding the utility of adjuvant
systemic therapy for primary breast cancer. J Clin Oncol 2001;
19:972-979.
26. Perou CM, Sorlie T, Eisen MB et al. Molecular portraits of human
breast tumours. Nature 2000; 406: 747752.
27. Nielsen TO, Hsu FD, Jensen K et al. Immunohistochemical and
clinical characterization of the basal-like subtype of invasive breast
carcinoma. Clin Cancer Res 2004; 10: 53675374.
28. Jeffrey SS, Lonning PE, Hillner BE. Genomics-based prognosis and
therapeutic prediction in breast cancer. J Natl Compr Canc Netw
2005; 3:291-300
29. Desmedt C, Haibe-Kains B, Wirapati P et al. Biological processes
associated with breast cancer clinical outcome depend on the
molecular subtypes. Clin Cancer Res 2008; 14: 51585165.
30. Cheang MCU, Chia SK, Voduc D et al. Ki67 index, HER2 status,
and prognosis of patients with luminal B breast cancer. J Natl Cancer
Inst 2009; 101: 736750.
31. Goldirsch A, Wood WC, Coates AS, Gelber RD, Thurlimann B, Senn
HJ, and Panel members Strategies for subtypes Dealing with the
diversity of breast cancer: highlights of the St Gallen International
Expert Consensus on the Primary Therapy of Early Breast Cancer
2011, Annal of Oncology 22:1736-1747, 2011
32. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of
dose-dense versus conventionally scheduled and sequential versus
concurrent combination chemotherapy as postoperative adjuvant
treatment of node-positive primary breast cancer: first report of
Intergroup Trial C9741/Cancer and Leukemia Group
33. Dowsett M, Nielsen TO, AHern R et al. Ki67 in breast cancer:
recommendations from the International Ki67 in Breast Cancer
Working Group. J Natl Cancer Inst.

Eniu et al
34. Early Breast Cancer Trialists Collaborative Group (EBCTCG).
Effects of chemotherapy and hormonal therapy for early breast
cancer on recurrence and 15 year survival: an overview of the
randomized trials. Lancet 2005; 365:1687-1717
35. Fisher B, Dignam J, Bryant J, et al. Five versus more than five
years of tamoxifen therapy for breast cancer patients with negative
lymph nodes and estrogen receptor-positive tumors. Journal National
Cancer Inst; 1996; 88:1529-1542
36. Baum M, Budzar AU, Cuzick J, et al. Anastrozole alone or
in combination with tamoxifen for adjuvant treatment of
postmenopausal women with early breast cancer: first results of the
ATAC randomized trial. Lancet; 359:2131-9, 2002
37. Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole
in postmenopausal women after five years of tamoxifen therapy for
early-stage breast cancer. New England Journal Medicine; 349:1793802, 2003
38. Fisher B, Anderson S, Tai-Chiu E, et al. Tamoxifen and chemotherapy
for axillary node-negative, estrogen receptor-negative breast cancer:
findings from National Surgical Adjuvant Breast and Bowel Project
B-23. J Clin Oncol 2001;19:931-942.
39. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL,
Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham
DL, Bryant J, Wolmark N. A multigene assay to predict recurrence
of tamoxifen-treated, node-negative breast cancer. N Engl J Med.
2004 Dec 30;351(27):2817-26.
40. International Breast Cancer Study Group. Colleoni M, Gelber S et al.
Tamoxifen after adjuvant chemotherapy for premenopausal women
with lymph nodepositive breast cancer: international Breast Cancer
Study Group Trial 13-93. J Clin Oncol 2006; 24: 13321341.
41. Mamounas EP, Bryant J, Lembersky B, et al. Paclitaxel after
doxorubicin plus cyclophosphamide as adjuvant chemotherapy for
node-positive breast cancer: results from NSABP B-28. J Clin Oncol
2005; 23:3686-3696.
42. Millikan RC, Newman B, Tse CK et al. Epidemiology of basal-like
breast cancer. Breast Cancer Res Treat 2008; 109: 123139.
43. Dignam JJ, Dukic V, Anderson SJ et al. Hazard of recurrence and
adjuvant treatment effects over time in lymph node-negative breast
cancer. Breast Cancer Res Treat 2009; 116: 595602.
44. Aebi S, Sun Z, Braun D et al. Differential efficacy of three cycles
of CMF followed by tamoxifen in patients with ER-positive and
ER-negative tumors: long-term follow up on IBCSG Trial IX. Ann
Oncol 2011 [epub ahead of print 31 January 2011] doi:10.1093/
annonc/mdq754.
45. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes
from adding sequential paclitaxel but not from escalating doxorubicin
dose in an adjuvant chemotherapy regimen for patients with nodepositive primary breast cancer. J Clin Oncol 2003; 21:976-983.
46. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for
node-positive breast cancer. N Engl J Med 2005; 352:2302-2313.
47. Davidson ND, ONeill AM, Vukov AM, et al. Chemoendocrine
Therapy for Premenopausal Women With Axillary Lymph Node
Positive, Steroid Hormone ReceptorPositive Breast Cancer: Results
From INT 0101 (E5188). Journal of Clinical Oncology, Vol 23, No
25 (September 1), 2005: pp. 5973-5982
48. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant
chemotherapy for operable HER2-positive breast cancer. N Engl J
Med 2005; 353:1673-1684.
49. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab
after adjuvant chemotherapy in HER2-positive breast cancer. N Engl
J Med 2005; 353:1659-1672.
50. Dennis Slamon, Wolfgang Eiermann, Nicholas Robert, Tadeusz

Protocolul CDT n cancerul de sn

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.
62.

Pienkowski, Miguel Martin, Michael Press, John Mackey, John

Glaspy, Arlene Chan, Marek Pawlicki, Tamas Pinter,Vicente Valero,
Mei-Ching Liu, Guido Sauter, Gunter von Minckwitz, Frances Visco,
Valerie Bee, Marc Buyse, Belguendouz Bendahmane, Isabelle
Tabah-Fisch, Mary-Ann Lindsay, Alessandro Riva, and John Crown,
for the Breast Cancer International Research Group; Adjuvant
Trastuzumab in HER2-Positive Breast Cancer; New England Jurnal
of Medicine. october 6, 2011, vol. 365 no. 14
Luca Gianni, Wolfgang Eiermann, Vladimir Semiglazov, Alexey
Manikhas, Ana Lluch, Sergey Tjulandin, Milvia Zambetti,
Federico Vazquez,Mikhail Byakhow, Mikhail Lichinitser, Miguel
Angel Climent, Eva Ciruelos, Beln Ojeda, Mauro Mansutti, Alla
Bozhok, Roberta Baronio,Andrea Feyereislova, Claire Barton,
Pinuccia Valagussa, Jose Baselga; Neoadjuvant chemotherapy with
trastuzumab followed byadjuvant trastuzumab versus neoadjuvant
chemotherapy alone, in patients with HER2-positive locally advanced
breast cancer (the NOAH trial): a randomised controlled superiority
trial with a parallel HER2-negative cohort. Lancet 2010; 375: 37784
Joensuu H, Bono P, Kataja V et al. Fluorouracil, epirubicin, and
cyclophosphamide with either docetaxel or vinorelbine, with or
without trastuzumab, as adjuvant treatments of breast cancer: final
results of the FinHer Trial. J Clin Oncol 2009; 27: 56855692.
Early Breast Cancer Trialists Collaborative Group. Adjuvant
chemotherapy in oestrogen-receptor-poor breast cancer: patient-level
meta-analysis of randomised trials. Lancet 2008; 371: 2940
Kaufmann M, Hortobagyi GN, Goldhirsch A et al. Recommendations
from an international expert panel on the use of neoadjuvant
(primary) systemic treatment of operable breast cancer: an update.
J Clin Oncol 2006; 24: 19401949.
Fisher B, Brown A, Mamounas E, et al. Effect of preoperative
chemotherapy on local-regional disease in women with operable
breast cancer: Findings from National Surgical Adjuvant Breast and
Bowel Project B-18. Journal Clinical Oncology; 1997; 15:2483-2493
Eiermann W, Paepke S, Appfelstaedt J, et al. Preoperative treatment of
postmenopausal breast cancer patients with letrozole: a randomized
double-blind multicenter study. Ann Oncol. 2001;12:1527-1532.
Ellis MJ, Coop A, Singh B, et al. Letrozole is more effective
neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/
or ErbB-2-positive, estrogen receptor-positive primary breast
cancer: evidence from a phase III randomized trial. J Clin Oncol.
2001;19:3808-3816.
Smith IE, Dowsett M, Ebbs SR, et al. Neoadjuvant treatment of
postmenopausal breast cancer with anastrozole, tamoxifen, or both
in combination: the Immediate Preoperative Anastrozole, Tamoxifen,
or Combined With Tamoxifen (IMPACT) multicenter double-blind
randomized trial. J Clin Oncol. 2005 Jul 5; [Epub ahead of print].
Early Breast Cancer Trialists Collaborative Group (EBCTCG).
Effects of radiotherapy and of differences in the extent of surgery
for early breast cancer on local recurrence and 15-year survival: an
overview of the randomized trials. Lancet 2005; 366:2087106.
Early Breast Cancer Trialists Collaborative Group (EBCTCG).
Effect of radiotherapy after breast-conserving surgery on 10year recurrence and 15-year breast cancer death: meta-analysis of
individual patient data for 10 801 women in 17 randomised trials.
Lancet. 2011; 378: 170716
BIG 3-07/TROG 07.01 A randomized phase III study of radiation
doses and fractionation schedules for DCIS of the breast
Omlin A, Amichetti M, Azria d, et al. Boost radiotherapy in young
women with ductal carcinoma in situ: a multicentre, retrospective
study of the Rare Cancer Network. The Lancet Oncology, Volume
7, Issue 8, Pages 652 656, August 2006

25
63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.
76.

77.

78.

Rudloff U, Jacks LM, Goldberg JI, et al. (2010) Nomogram for

predicting the risk of local recurrence after breast-conserving surgery
for ductal carcinoma in situ. J Clin Oncol 28:37623769
Gauthier ML, Berman HK, Miller C, Kozakeiwicz K, Chew K,
Moore D, Rabban J, Chen YY, Kerlikowske K, Tlsty TD. Abrogated
response to cellular stress identifies DCIS associated with subsequent
tumor events and defines basal-like breast tumors. Cancer Cell.
2007;12:479491
Van den Broek N, Van der Sangen MJ, Van de Poll-Franse LV, van
Beek MW,Nieuwenhuijzen GA, Voogd AC. Margin status and the
risk of local recurrence after breast-conserving treatment of lobular
breast cancer. Breast Cancer Res Treat 2007, Sep;105(1):63-8
Arvold ND, Taghian G, Niemierko A l, Harris JR et al. Age, Breast
Cancer Subtype Approximation, and Local Recurrence After BreastConserving Therapy. /JCO.2011.36.1105
Abdulkarim BS, Cuartero J, Hanson J et al. Increased risk of
locoregional recurrence for women with T1-2N0 triple-negative
breast cancer treated with modified radical mastectomy without
adjuvant radiation therapy compared with breast-conserving therapy.
J Clin Oncol 2011 Jul 20;29(21):2852-8.
Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after
treatment of breast cancer with standard radiotherapy with or without
additional radiation. N Engl J Med 2001; 345:137887.
Bartelink H, Horiot JC, Poortmans P, et al. Impact of a higher
radiation dose on local control and survival in breast-conserving
therapy of early breast cancer: 10-year results of a randomized boost
vs. no boost EORTC 22881-10882 trial. J Clin Oncol 2007; 25(22):
3259-65.
Ninja Antonini, Heather Jones, Jean Claude Horiot, Philip
Poortmans, Henk Struikmans, et al. Effect of age and radiation dose
on local control after breast conserving treatment: EORTC trial
22881-10882. Radiotherapy and Oncology 82 (2007) 265271
Mannino M, Yarnold JR. Local relapse rates are falling after
breast conserving surgery and systemic therapy for early breast
cancer: can radiotherapy ever be safely withheld? Radiother
Oncol.2009;90:1422. doi: 10.1016/j.radonc.2008.05.002
Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost
in the conservative treatment of early breast cancer: results of
a randomized clinical trial in Lyon, France. J Clin Oncol 1997;
15:9638.
Poortmans P, Collette L, Horiot J-C, et al. Impact of the boost dose
on local control and survival in patients with early stage breast cancer
after a microscopically incomplete lumpectomy: 10 years results of
the randomised EORTC boost trial 22881/10882. Radiother Oncol
2006;81
Poortmans P, Collette L, Horiot J-C, et al. On behalf of the EORTC
Radiation Oncology and Breast Cancer Groups. Impact of the boost
dose of 10 Gy versus 26 Gy in patients with early stage breast cancer
after a microscopically incomplete lumpectomy: 10-year results of
the randomized EORTC boost trial
Poortmans P. Evidence based radiation oncology: Breast cancer.
Radiotherapy and Oncology, 84 (2007) 84101
(Van Werkhoven E et al. Nomogram to predict ipsilateral breast
relapse based on pathology review from the EORTC 22881-10882
boost versus no boost trial. Radiother Oncol. 2011 Jul;100(1):101-7
Sanghani M et al. Validation of a web-based predictive nomogram
for ipsilateral breast tumor recurrence after breast conserving therapy.
J Clin Oncol. 2010 Feb 10;28(5):718-22
Jones HA et al. Impact of pathological characteristics on local relapse
after breast-conserving therapy: a subgroup analysis of the EORTC
boost versus no boost trial. J Clin Oncol. 2009 Oct 20;27(30):4939-47.

26
79.

80.

81.

82.

83.

84.

85.

86.

87.
88.

89.

90.

91.

92.

93.

94.

Eniu et al
Whelan T, MacKenzie R, Julian J. Randomized trial of breast
irradiation schedules after lumpectomy for women with lymph nodenegative breast cancer. J Natl Cancer Inst 2002; 94:11431150. et
al. J Natl Cancer Instl 2002, 94:1143-50
The START Trialists Group. The UK Standardisation of Breast
Radiotherapy (START) Trial A of radiotherapy hypofractionation for
treatment of early breast cancer: a randomised trial. Lancet Oncol
2008 9(4) 331-341.
The START Trialists Group. The UK Standardisation of Breast
Radiotherapy (START) Trial B of radiotherapy hypofractionation for
treatment of early breast cancer: a randomised trial. Lancet. 2008,
29; 371(9618): 10981107
. Whelan TJ, Pignol JP, Levine MN et al. Long-Term Results of
Hypofractionated Radiation Therapy for Breast Cancer. N Engl J
Med 2010;362:513-20
Smith BD, Bentzen SM, Correa CR et al. Fractionation for whole
breast irradiation: an American Society for Radiation Oncology
(ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys.
2011 Sep 1;81(1):59-68
Hopwood P, Haviland JS, Yarnold JR et al. Comparison of patientreported breast, arm, and shoulder symptoms and body image
after radiotherapy for early breast cancer: 5-year follow-up in the
randomised Standardisation of Breast Radiotherapy (START) trials.
Lancet Oncol 2010 Mar;11(3):231-40
Smith BD et al.Accelerated partial breast irradiation consensus
statement from the American Society for Radiation Oncology
(ASTRO) Int J Radiat Oncol Biol Phys 2009;74(4):987-1001
Polgar C et al. Patient selection for accelerated partialbreast irradiation (APBI) after breast-conserving surgery:
Recommendations of the Groupe Europen de CuriethrapieEuropean Society for Therapeutic Radiology and Oncology (GECESTRO) breast cancer working group based on clinical evidence.
Radiother Oncol 2010; 94(3):264-273
Rutgers E. Breast conservation in the very young. The breast (18)
2009; S11
Overgaard M, Nielsen HM, Overgaard J. Is the benefit of
postmastectomy irradiation limited to patients with four or more
positive nodes, as recommended in international consensus reports?
A subgroup analysis of the DBCG 82 b&c randomized trials.
Radiother Oncol 2007 March;82(3):247-53.
Kunkler I et al. MRC SUPREMO (BIG 2-04) Selective Use of
Postoperative Radiotherapy aftEr MastectOmy. Phase III randomised
trial of chest wall RT in intermediate- risk breast cancer
Abi-Raad et al. Patterns and Risk Factors of Locoregional
Recurrence in T1-T2 Node Negative Breast Cancer Patients Treated
With Mastectomy: Implications for Postmastectomy Radiotherapy
. Int J Radiat Oncol Biol Phys. 2011, Nov 1;81(3):151-157
Wang J et al, Adjuvant chemotherapy and radiotherapy in triplenegative breast carcinoma: A prospective randomized controlled
multi-center trial. Radiother Oncol 2011, Aug; 2: 200-204
Giuliano A, Morrow M. Should ACOSOG Z0011 change practice
with respect to axillary lymph node dissection for a positive sentinel
lymph node biopsy in breast cancer?Clin Exp Metastasis 2012
Oct;29(7):687-92
Giuliano A, Morrow M et al.Axillary Dissection vs No Axillary
Dissection in Women With Invasive Breast Cancer and Sentinel Node
MetastasisA Randomized Clinical Trial .JAMA. 2011;305(6):569-575
Strom EA, Woodward WA, Katz A, et al. Clinical investigation:
Regional nodal failure patterns in breast cancer patients treated
with mastectomy without radiotherapy. Int J Radiat Oncol Biol Phys
2005;63:15081513

95. Whelan TJ, Olivotto I, Ackerman I, et al. NCIC-CTG MA.20: an

intergroup trial of regional nodal irradiation in early breast cancer.
J Clin Oncol. 2011
96. Sequencing of chemotherapy and radiotherapy for women following
surgery for early breast cancer. Cochrane Database of Systematic
Reviews 2013, Issue 4.
97. Hickey BE, Francis D, Lehman MH. Sequencing of chemotherapy
and radiation therapy for early breast cancer. Cochrane Database
Syst Rev. 2006;4
98. Tsoutsou PG, Koukourakis MI, Azria D, et al. Optimal timing for
adjuvant radiation therapy in breast cancer: a comprehensive review
and perspectives. Crit Rev Oncol Hematol. 2009;71:102116.
99. Punglia RS, Saito AM, Neville BA, et al. Impact of interval from
breast conserving surgery to radiotherapy on local recurrence in
older women with breast cancer: retrospective cohort analysis.
BMJ.2010;340:c845
100. Harris EE, Christensen VJ, Hwang WT, et al. Impact of concurrent
versus sequential tamoxifen with radiation therapy in early-stage
breast cancer patients undergoing breast conservation treatment. J
Clin Oncol. 2005;23:1116
101. Azria D, Belkacemi Y, Romieu G, et al. Concurrent or sequential
adjuvant letrozole and radiotherapy after conservative surgery for
early-stage breast cancer (CO-HO-RT): a phase 2 randomised trial.
Lancet Oncol. 2010;11:258265. [PubMed]
102. Recht A. Radiotherapy, antihormonal therapy, and personalised
medicine. Lancet Oncol.2010;11:215216
103. Perez EA, Suman VJ, Davidson NE, et al. Cardiac safety analysis of
doxorubicin and cyclophosphamide followed by paclitaxel with or
without trastuzumab in the North Central Cancer Treatment Group
N9831 Adjuvant Breast Cancer Trial. J Clin Oncol. 2008;26:123138
104. Hurkmans CW, Borger JH et al. Cardiac and lung complication
probabilities after breast cancer irradiation. Radiother Oncol 2000;
55: 145-51
105. Pitkanen MA, Holli KA, et al. Quality assurance in radiotherapy
for breast cancer. Acta Oncol 2001; 40:50-5
106. Hurkmans CW, Remeijer P, et al. Set-up verification using portal
imaging; review of current clinical practice. Radiother Oncol 2001;
58:105-20.
107. Bentel GC, Marks LB, et al. Variability of the location of internal
mammary vessels and glandular breast tissue in breast cancer patients
undergoing routine CT-based treatment planning. Int J Rad Oncol
Biol Phys 1999; 44:1017-25
108. Dobbs J, Greener T, Driver D. Geometric uncertainties in
radiotherapy of the breast. Geometric Uncertainties in Radiotherapy.
Defining the Planning Target Volume. The British Institute of
Radiology 2003:47-77
109. Buchalia A, Geismar D, Hinkelbein M, Schlenger L, Zinner
K, Budach V. Virtual simulation in patients with breast cancer.
Radiotherapy and Oncology 2001; 59: 267-272
110. Aird EGA, Conway J. CT simulation for radiotherapy treatment
planning. The British Journal of Radiology 2002; 75: 937949
111. White J, Tai A, Arthur D et al. Breast cancer atlas for radiation
therapy planning: consensus definitions. www.rtog.org
112. Hanbeukers B, Borger J, P. van den Ende, et al. Customized
Computed Tomography-Based Boost Volumes in Breast-Conserving
Therapy: Use of Three-Dimensional Histologic Information for
Clinical Target Volume Margins. Int J Radiat Oncol Biol Phys 2010;
75: 757-763
113. Martin D, Vitoc C, Tnsescu R, et al. Evidence Based Radiation
Oncology in Early Breast Cancer: a Brief Review. Journal of
Radiotherapy & Medical Oncology 2009; 3: 170-175

Protocolul CDT n cancerul de sn

114. Martin D, Dordai D, Tnsescu R, et al. CT Simulation for
radiotherapy in breast cancer patients. Journal of Radiotherapy &
Medical Oncology 2011, 17 (1): 13-22
115. Bentel GC, Marks LB, Hardenbergh PH, Prosnitz LR. Variability
of the deph of supraclavicular and axillary limph nodes in patients
with breast cancer: is a posterior axillary boost field necessary Int J
Radiat Oncol Biol Phys 2000; 47:755-758
116. Bentel GC, Marks LB, Hardenbergh PH, Prosnitz LR. Variability
of the location of the internal mammary vessels and glandular
breast tissue in breast cancer patients undergoing routine CT-based
treatment planning. Int J Radiat Oncol Biol Phys 1999; 44:1017-1025
117. Scrimger RA, Gonnors SG, Halls SB, Starreveld AA. CT-targeted
irradiation of the breast and internal mammary lymph nodes using
a 5-field technique. Int J Radiat Oncol Biol Phys 2000; 48:983-989
118. Baglan KL, Sharpe MB, Jaffrey D, et al.Accelerated partial breast
irradiation using 3D conformal (3D-CRT). Int J Radiat Oncol
Biol Phys 2003;55: 302-311. Dobbs HJ, Greener AG, Driver DM.
Geometric Uncertainties in Radiotherapy. Defining the Planning
Target Volume. The British Institute of Radiology 2003: 47-77.
119. Olsen NK, Pfeiffer P, Johannsen L, Schroder H, Rose C. Radiationinduced brachial plexopathy: neurological follow-up in 161
recurrence free breast cancer patients. Int J Radiat Oncol Biol Phys
1993; 26:43-49
120. Marks LB, Yorke ED, Jackson AW et al. Use of Normal Tissue
Complication Probability Models in the Clinic. Int J Radiat Oncol
Biol Phys 2010; 76, Supplement: S10S19
121. Feng M, Moran JM, Koelling T, et al. Development and validation
of a heart atlas to study cardiac exposure to radiation following
treatment for breast cancer. Int J Radiat Oncol Biol Phys 2011;
79:1018.
122. Li XA, Tai A, Arthur DW, et al. Variability of target and normal
structure delineation for breast cancer radiotherapy: An RTOG
multi-institutional and multiobserver study. Int J Radiat Oncol Biol
Phys 2009; 73: 944951.
123. The Royal College of Radiologists, Institutes of Physics and
Engineering in Medicine, Society and College of Radiographers. On
target: Insuring Geometric Accuracy in Radiotherapy 2008:48-49.
124. Holmes MD, Chen WY, Feskanich D et al. Physical activity and
survival after breast cancer diagnosis. JAMA 2005;293:2479-2486
125. Chlebowski RT, Aiello E, McTiernan A. Weight loss in breast cancer
patient management. J Clin Oncol 2002;20:1128-1143
126. Ruiterkamp J, Ernst MF. The role of surgery in metastatic breast
cancer. Eur J Cancer 2011;47(Suppl. 3):S6-22.
127. Wilcken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus
endocrine therapy alone for metastatic breast cancer. Cochrane
Database Syst Rev 2003 (2): CD002747
128. Anderson BO, Cazap E, El Saghir NS, Yip CH, Khaled HM, Otero IV,
et al. Optimisation of breast cancer management in low-resource and
middleresource countries: executive summary of the breast health
Global initiative consensus, 2010. Lancet Oncol 2011;12(4):387-98.
129. Van Poznak CH, Temin S, Yee GC, Janjan NA, Barlow WE,
Biermann JS, et al. American Society of clinical oncology executive
summary of the clinical practice guideline update on the role of
bone-modifying agents in metastatic breast cancer. J Clin Oncol
2011;20(29(9)):1221-7.
130. McQuay HJ, Collins S, Carroll D, Moore AR. Radiotherapy for the
palliation of painful bone metastases. Cochrane Library October 2008.

27
131. Aapro M, Abrahamsson PA, Body JJ, Coleman RE, Colomer R,
Costa L, et al. Guidance on the use of bisphosphonates in solid
tumours: recommendations of an international expert panel. Ann
Oncol 2008;19(3):420-32.
132. Serizawa T, Yamamoto M, Sato Y, Higuchi Y, Nagano O, Kawabe
T, et al. Gamma Knife surgery as sole treatment for multiple brain
metastases: 2-center retrospective review of 1508 cases meeting the
inclusion criteria of the JLGK0901 multi-institutional prospective
study. J Neurosurg 2010;113(Suppl.):48-52
133. Kaufman B, Mackey JR, Clemens MR et al. Trastuzumab
plus anastrozole versus anastrozole alone for the treatment of
postmenopausal women with human epidermal growth factor
receptor 2-positive, hormone receptor-positive metastatic breast
cancer: results from the randomized phase III TAnDEM study. J
Clin Oncol 2009; 27: 55295537.
134. Schwartzberg LS, Franco SX, Florance A et al. Lapatinib plus
letrozole as firstline therapy for HER-2+ hormone receptor-positive
metastatic breast cancer. Oncologist 2010; 15: 122129
135. OShaughnessy J, Dieras V, Glaspy J et al. Comparison of subgroup
analyses of PFS from three phase III studies of bevacizumab in
combination with chemotherapy in patients with HER2-negative
metastatic breast cancer (MBC). Cancer Res 2009; 69: (Abstr 207,
presented dataSABCS 2009). Brufsky A, Valero V, Tiangco B
et al. Impact of bevacizumab (BEV) on efficacy of second-line
chemotherapy (CT) for triple-negative breast cancer (TNBC):
analysis of RIBBON-2. J Clin Oncol 2011; 29: (Abstr 1010,
presented dataASCO Annual Meeting 2011).
136. Cardoso F, Di Leo A, Lohrisch C, Bernard C, Ferreira F, Piccart
MJ. Second and subsequent lines of chemotherapy for metastatic
breast cancer: what did we learn in the last two decades? Ann Oncol
2002;13:197-207.008;44(15):2218-25
137. Piccart-Gebhart Martine J, Burzykowski Tomasz, Buyse Marc,
Sledge George, Carmichael James, Luck Hans-Joachim, et al.
Taxanes alone or in combination with anthracyclines As first-line
therapy of patients with metastatic breast cancer. J Clin Oncol
2008;26:1980-6.
138. Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP,
Fitzharris B, et al. Capecitabine versus classical cyclophosphamide,
methotrexate, and fluorouracil as first-line chemotherapy for
advanced breast cancer. J Clin Oncol 2011;29:4498-504.
139. Jones D, Ghersi D, Wilcken N. Addition of drug/s to a chemotherapy
regimen for metastatic breast cancer. Cochrane Database Syst Rev
2010 (11): CD003368.
140. Coates A, Gebski V, Bishop JF, Jeal PN, Woods RL, Snyder R, et
al. Improving the quality of life during chemotherapy for advanced
breast cancer: Intermittent versus continuous chemotherapy for
breast cancer. N Engl J Med 1987;317:1490-5.
141. Gennari Alessandra, Stockler Martin, Puntoni Matteo, Sormani
Mariapia, Nanni Oriana, Amadori Dino, et al. Duration of
chemotherapy for metastatic breast cancer: a systematic review
and meta-analysis of randomized clinical trials. J Clin Oncol
2011;29:2144-9.
142. Sledge GW, Neuberg D, Bernardo P, et al. Phase Ill trial of
doxorubicin, paclitaxel, and the combination of doxorubicin and
paclitaxel as front-line chemotherapy for metastatic breast cancer:
an intergroup trial (E1193). Journal Clinical Oncology; 21:588-92,
2003.