2005 Update. The Philippine College of Surgeons' Evidence-based Clinical Practice

Guidel ines on the Diagnosis and Management of Breast Cancer: Early Breast

Canceq Locally Advanced Breast Cancer, Locally Recurrent Breast Cancer and

Metastatic Breast Cancer\

Adr iano V. Laudico, M.D. , F.P.C.S. ; Gemma Leonora B.Uy ' M.D. ;

Arturo S. de la Pefia, M.D., F.P.C.S.; Narciso S. Navarro Jr., M.D., F.P.C.S.;

Edgardo R. Cortez, M.D., F.P.C.S.; Nelson D. Cabaluna, M.D., F.P.C.S.;

Daniel A. dela Paz, M.D., F.P.C.S. and Orl ino C. Bisquera, M.D., F.P.C.S.

Starter Statement

Tlr is information, based on the Phi l ippine Col lege of

Surgeons (PCS) Clinical Practice Guidelines, is intended

to assist doctors and patients in the management of

breast cancer. The PCS Cl ir i ical Pract ice Guidel ines

were developed by a diverse panel of 'experts. Tlrese

guidel ines are statements of the PCS regarding the

scierrt i f ic evidence and i ts view of current ly accepted

approaches to treatment,These guidel ines are not intended to replace br"r t to

assist the expert ise and cl in ical judgment of physicians

in the managementof i r rdiv idual pat ients. Each pat ient 's

si tuat ion must be evaluated individual ly. I t is importarrt

to discuss the guidel ines and al l pert inent information

regardirig treatment options with the patient because it

is the preference of a wel l - inforrned pat ient which ought

to be the major consideration in the decision-rnaking

process .

Acknowledgment

This project of the Phi l ippine Col lege of Surgeons was

partly sLrpported by the International Breast Cancer

Research Foundation (fBCRF) and the Surgical Research

Unit (SRU) of the Department of Surgery, Phi l ippine

Cenera l Hosp i ta l and Co l lege o f Med ic ine , Un ivers i ty

of the Phi l ippines Mani la. The SRU staff who provided

assistance was Ms. Madonna R. Balbacal.

,., /

PJSS Vol. 61, No. 3, July-September,2006 PIss lililliTiiiililtili

Execut ive Summary

The Phi l ippine Col lege of Surgeons (PCS) publ ished i ts

f i rst Evidence-based Cl inical Pract ice Guidel ines(EBCPG) on the diagnosis and management of breast

cancer in 2001r '2 S ince then, numerous h igh qua l i t y

cl in ical t r ia ls have been publ is lred, part icLt lar ly on the

benef ic ial role of hormonal therapy in both the adj uvant

and metastatic setting and the beneficial role of cytotoxicchemotherapy. These publ icat ions have resulted in

mod i f i ca t ions in o ther c l in ica l p rac t ice gLr ide l i r res

including that of the U.S. Nat ior ial ComprehensiveCancer Network (NCCN)3 in the 20005 arrd the St.Gal len Internat ional Expert Consensus in 2003'

The inc idence o f ,b reas t cancer among women in thePh i l ipp ines is expec ted to cont inue to r i se . The g loba l

observaf ibn that fert i l i ty decreases as a country 'seconomic development progresses and the increasing"westernizat ion" of Phi l ippine l i festyles are the major

factors tlrat are expected to contribute to tlre anticipatedrise in incidence.5

The 2001 PCS EBCPG was reviewed in its entirety, and

when no new evidence was discovered, the 200 1 gu idel i nes

were retained. Only those publications that were not

included in the 2001 guidelines are cited in tlre Lrpdate.

The l i teratr"rre search metlrod, levels of evidence,

categories of re.commendations, and cl in ical quest iorrs

were esser r t ia l l y s im i la r to those used in the 2001gu ide l ines . The Techr r ica l Work ing Group (TWG) had

b e e n r e g r : l a r l y m o n i t o r i n g t h e m a j o r s o u r c e s o f

pub l i ca t ions s ince the fo rmula t io r r o f the f i rs t se t o f

i l0

2005 Update. EBCPG on the Diagnosis and Management of Breast Cancer

gu ide l ines , namely , the Pubmed (Med l ine) o f the U.S.National Library ofMedicine and Tlie Cochrane Library.

The Technical Working Group consists ofDr. AdrianoV. Laudico as principal investigator and Drs. Orlino C.Bisquera, Nelson D. Cabaluna, Edgardo R. Cortez, DanielA. dela Paz, Arturo S. de la Pefia, Narciso S. Navarro Jr.and Gemma Leonora B.Uy as members.

Operational Defi nitions

Early Breast Cancer

The definitiorr of early breast has been retained, namelythat used by the EBCTCG: "In women with early breastcancer, all detectable cancer, is by definition, restricted tothe breast and in the case ofnode positive patients, the locallyrnph nodes can be removed surgically."

Unresectable Locally Advanced Breast Cancer

Using the EBCTCG def ini t ion of ear ly breast cancerand the 2002AJCC Cancer Staging, unresectab le locallyadvanced breast wi l l include: I ) unresectable cl in ical lystaged I I IB lesions (unresectable T4 lesions); and,2) cl in ical ly staged I I IC lesions (N3 lesions)- N3a,metastasis in ipsi lateral infraclavicular lymph node(s);N3b, metastasis in ipsilateral internal mammary node(s)and axillary lymph node(s);N3c, metastasis in ipsilateralsupraclavicular lymph nodes.

Recurrent breast cancer is the reappearance of thedisease anywhere in the body fol lowing pr imarytreatment (usually mastectomy or breast conservingsurgery, with or without adjuvant therapy).

Hermone - responsive metastasis refers to metastaticfesiorrs which decrease in size or disappear afterendocrirre therapy.

Hormone - refractory metastasis refers to metastaticlessiorrs which fai l to respond to at least 3 fypes ofendocrine treatment.

Levels of Evidence

L Evidence from at least one properly designedrandomized controlled trial or meta-analysis.

IL Evidence from at least one wel l designed cl i r r icaltrial without proper random ization, from prospectiveor cohort or case-control analytic studies (preferablyfrom one center), f rom mult iple t ime-series studies,or from dramatic results in uncontrolled experiments.

IIL Evidence from opinions of respected authorities on, the basis ofclinical experiences, descriptive studies,

or reports of expert committees.

Categories of Recommendations

Category l: Recommendations that were approved byconsensus (at least 75o/o of the multisectoral expertpanel).

Category .8. Recommendations that were somewhatcontroversial and did not meet consensus.

Category C. Recommendations that caused realdisagreements among members of tlre panel.

The TWG prepared the first draft of the manuscriptwhich consisted of a summary of the strongest evidenceassociated with the cl in ical quest ions and the suggestedrecommendations. The first draft was discussed andrnodified by a Panel of Experts convened by the PCS onNovember 12,2005 at the PCS bui lding. A second draftwas prepared by the TWG and this was discussed in aPubl ic Forum on December 6, 2005 during the 6l ' tAnnual Cl inical 'Congress of the PCS held at the EDSASharigrila Hotel. The updated guidelines were thenapproved by the PCS Board of Regents on March 25,2006.

Panel ofExperts:

1. RayB. Malilay, M.D. (Chairman; Philippine SocietyofGeneral Surgeons)

2. Samuel D. Ang, M.D. (Philippine Society ofGeneralSurgeons)

3. Eric Arcilla, M.D. (Philippine Association of Plastic,Reconstructive and Aesthetic Surgeons)

4. Kathleen Baldivia, M.D.(Phi l ippine Radiat ion

Oncology Society)

I l t

l12

5. Alfred Allen B. Buenafe, M.D. (Philippine SocietyofGeneral Surgeons)

6. Conrado C. Cajucom, M.D. (Philippine Society ofGeneral Surgeons)

7. DominadorM. Chiong, Jr, M.D. (Philippine Society

ofGeneral Surgeons)8. Alejandro C. Dizon, M.D. (Philippine Society of

General Surgeons)9. Alex A. Erasmo, MD. (Surgical Oncology Society

of the Philippines)I 0. D iv ina Esteban, M.D . (Philippine Society of Oncologt)1l. Henry G. Falcotelo, M.D. (Philippine Academy of

Head and Neck Surgery, Inc.)12. Graciux Y. Fernando, M.D. (Philippine Society of

Medical Oncology)13. Mark R. Kho, M.D. (Philippine Society of General

Surgeons)14. Esperanza R. Lahoz, M.D. (Philippine Society of

General Surgeons)15. Fernando L. Lopez, M.D. (Philippine Society of

General Surgeons)16. Manuelito A. Madrid, M.D. (Philippine Society of

Pathologists)17. Gabriel L. Martinez, M.D. (Philippine Society of

General Surgeons)18. Ma. Crist ina L. Santos, M.D. (Phi l ippine Society of

General Surgeons)19. Rey Melchor F, Santos, M.D. (Philippine Society of

General Surgeons)20. Edgardo T. Tan, MD. (Academy of Fi l ip ino

Neurosurgeons)2 l. Enrico Tangco, M.D. (Philippine Society ofOncologt)22. Roe I S. To lentin o, MD . (P hil ipp in e S o c i ety of Onc o lo g)

2 3 . Denn is Tudtud, MD. (P hil ipp ine S o c i ety of Me dic al

Oncology)

Summary of Recommendations

l . Early Breast Cancer

A. Diagnosis

l . In pat ients with a palpable breast mass in which

cancer is suspected, BIOPSY is mandatory. (Level,

Category A)

PJSS Vol. 61, No, 3, July-September, 2006

2. Fine needle aspiration cytology (FNAC) is the initialdiagnostic procedure in patients with a palpable

breast mass in which cancer is suspected. In areaswhere there is no cytopathologist, core needle biopsyis an acceptable ini t ia l diagnost ic opt ion. (Level I ,Category A)

3. I f the FNAC result is mal ignant, the pat ient isoffered the different treatment options. (Level I,Category A)

4 . I f the FNAC resu l t i s ben ign bu t c l in ica l f ind ings

are real ly highly suspicious for breast cancer, ei ther

a core needle or an open biopsy is done. (Level I l ,

Categoly A)

5. The PCS should set up standards regarding FNAC.(Category A)

6. If the FNAC is unsatisfactory or interpreted as

suspicious, core needle biopsy or open biopsy is

advised. (Category A)

7. Fordeepseatedtumorsd" I cm in size, sonographicallyguided FNAC or core needle biopsy is recommended.

In places where sonography is unavailable, open biopsyis done, (Level II, Category A)

8. Frozen sect ion histology is done only when thepatient requests it. (Level II, Category A)

9. In premenbpausalwomen who are suspected to haveearly breast cancer and who prefer to undergoadjuvant oophorectomy, a core needle biopsy (CNB)

;. will provide sufficient tumor tissue to determinehormone receptor status preoperatively. (Level I,

Category A)

10. Mammography, sonography and o ther b reas t

imaging studies do not improve the accuracy of

arriving at a preoperative diagnosis and should not

be used routinely to alter the clinical diagnosis in

patients with a palpable breast mass suspicious for

cancer. (Level II, Category A)

11. In women'with early breast cancer, preoperat ive

mammography is recommended to detect sLrbclinicaldisease in the contralateral breast, and also in the

ipsilateral breast for those patients who will undergo

breast conservation treatment. (Level II, Category A)

2005 Update. EBCPG on the Diagnosis and Management of Breast Cancer

12. In asymptornat ic women with early breast cancer,there is no evidence that the use of an intensivepreoperat ive metastat ic work up increases survival .Furthermore, these exams (chest X-ray, bone scan,

bone X-rays, l iver ul t rasound, l iver scan, and l iverenzymes) have low diagnostic yield and are nobetter than clinicopathologic factors like tumor size,histologic differentiation (grade), axillary nodal

status, and hormone receptor status, in predicting

distant metastases. Therefore, they should not berout inely done. (Level I I , Category A).

B. Staging and Follow Up of Early Breast Cancer

I 3. The rout ine use of an intensive metastat ic work upfol lowing treatment for women with early breastcancer does not improve survival rates compared to

symptom directed fol low up, and should not berout inely Lrsed. (Level I , Category A)

14. Follow-up consists of careful li istory and physical

examinat ion and annual mammography of the

contralateral and preserved breast. (Level I, CategoryA)

C. Surgical Treatment of Early Breast Cancer

15. The pr irnary treatment of ear ly breast cancer is

e i ther rnod i f ied rad ica l mastec tomy or b reas tconserv ing surgery p l r , rs rad io therapy . Breas tconserving surgery sl iould include complete excisionof t l re pr imary tutnor in the breast and an axi l lary

d issec t ion to de termine noda l s ta tus . (Leve l I ,Category A)

I t is the pat ient who wi l l make the informed choice. Hormone (estrogen/progesterone) Receptor-Posit ive

16. More extensive sLlrgery is done in order to remove Cases

all gross tumor' (Level I' category A) 24. patie'ts witlr irivasive earry breast cancers that are

D. Adjuvant Treatment estrogen or progesterone receptor-posit ive shor-r ld

be cons idered fo r ad juvant endocr ine therapy

Adjtrvant Radiotherapy regardless of patient age, menopausal status, lymph

node status, HER2/neu stat l ls and whether or not

17. AdjLrvant radiotherapy fol lowing modif ied radical adjr-rvar, t chemotherapy is to be given. (Level I ,

nrastectomy does not improve survival in al l cases Category A)

r 1 3

of ear ly breast cancer and should not be rout inelygiven. (Level I, Category A)

18. Adjuvant radiotherapy fol lowing modif ied radical

mastectomy may decrease the probability of Iocal

recurrence in certain pat ients with a high r isk of

local recurrence ( tumor greaterthan 5 cm; less than

I mm pathologic margin; 4 or more posit ive axi l lary

nodes), or when the surgeon is not certain about the

adequacy of the locoregional resect ion. (Level I ,

Category A)

19. Radiotherapy to the preserved breast tissue is an

integral part ofbreast conserving surgery for early

breast cancer (Level I, Category A)

Adj uv ant Sys temic Therapy

20. Hormone receptor status (estrogen/progesterone) shou ld

be the main consideration used in selecting the type

of adjuvant treatment. (Level I, Category A)

21. There should be a determined effort to make

immunohistochemistry l rormone receptor assays

avai lable in strategic locat ions in the country, as

well as efforts at standard izing the method standard.(Category A)

22. Interpr etati on of imm unoh i stochem i stry h o rmon e

receptor assays should be done using the Al l red

;"fcorin* system, (Level II, Category A).

23. Estrogen receptor assay may be deterrnirred f i rst ,

and i f the result is negat ive, progesterone receptor

assay is done. (Category A)

tl4

25. In premenopausal women who are considered foradjuvant endocrine therapy, the combination ofovarian suppression (surgical or radiation ovarianablation, or by LHRH analogs) plus tamoxifen resultsin a greater survival benefit compared to eithertreatment alone. (Level I, Category A)

26. ln premenopausal women with hormone receptor-posit ive tumors who are considered for adjuvantoophorectomy, luteal phase oophorectomy offersgreater survival benefit compared to follicular phaseoophorectomy. (Level I I , Category A)

27.There should be a determined and continuing effortto establish a standardized national breast cancerpathology report ing system that rout inely andrel iably includes prognost ic features, such as thepresence or absence of angiolymphatic invasion,'and nuc lear and h is to log ic g rades s tandard .(Category A)

28. Women with hormone receptor-positive tumors,negative axillary nodes and favorable prognosticfeatures do not derive a clinically favorable risk/benef i t olr tcome with the addit ion of adjuvantcytotoxic chemotherapy to adjLrvant endocrinetherapy. (Level I I , Category A)

29. Women with hormone receptor-posit ive tumors,posit ive axi l lary, nodes and unfavorable prognost icfeatures may derive a clin ically favorable risk/benefitor l tcome with the addit ion of adjuvant cytotoxicchemotherapy to adj uvant endocrine therapy. (LevelII, Category A)

30. In wornen with hormone receptor-posit ive tumorswho will receive both tamoxifen and cytotoxicchemotherapy, tamoxifen should be started afterthecomplet ion of chemotherapy. (Level I , Category A)

31. In postmenopausal women with hormone receptor-positive tumors, tamoxifen or aromatase inhibitors maybe used as adjuvant therapy. (Level I, Category A)

Hormone (estrogen/progesterone) Receptor-NegativeCases

32. ht women with hormone receptor-negat ive tumors,adj uvant endocrine therapy is generally not indicated

,tt. l

PJSS Vol. 61, No. 3, July-September, 2006

and adjuvant chemotherapy may be benef ic ial .(Level I, Category A)

3 3 . T h e u s e o f a c o m b i n a t i o n o f c y t o t o x i cchemotherapeutic drugs for adjuvanttherapy resultsin a greater survival benefit compared to the use ofa single drug. The use of anthracycl ine containingcombinations may result in a greater survival benefitcompared to the CMF regimen. (Level I , CategoryA)

34. The use o f four cyc les o f AC (adr iamyc i r r +cyc lophosphamide) combina t ion fo r ad juvantchemotherapy may result in a survival benefit that issimilar to that obtained with six cycles of CMF.(Level I, Category A)

3 5 . T h e u s e o f n e w e r c o m b i n a t i o n s o f a d j u v a n tchemotherapy, which are in general more toxic andmore expensive should not be rout inely used, andshould be reserved for women with unfavorablep r o g n o s t i c f a c t o r s f o r w h o m a p a r t i c u l a rchemotherapeutic combination may offer a clin icallyfavorable risk/benefit outcome. (Level I, CategoryA)

36. Premenopausal women with hormone receptor-negat ive tumors who wi l l not be able to receiveadjuvant chemotherapy, should be offered adjuvantlu tea l phaqe oophorec tomy may prov ide somesurvival benef i t . (Level I I , Category A)

2. IJnresectable Local ly Advanced Breast Cancer

37. Hormone receptor status (estrogen/progesterone)should be the main consideration used in selecting thetype of neoadjuvant therapy. (Level, Category A)

Hor mone (e s tr o gen/pr o ge s t er one) Re c e p t o r - P o s i t iv eCases

38. Wornen with local ly advanced breast cancers t l ratare hormone receptor-posit ive should be consideredfor neoadjuvant endocrine therapy regardless ofpat ient age, menopausal status, HER2/neLr status, orwhether or not neoadjuvant chemotherapy is to begiven. (Level I I , Category A)

2005 Update . EBCPG on the D iagnos is and Management o f Breas t Cancer

39. In pfemenopausal women wit l i horrnone receptor-positive tumors who are considered for adjuvantooph orectomy, I uteal p h ase ooph orectomy rn ay offergreater survival benefits cornpared to follicular phaseoophorectorny. (Level II, Category A )

40. Women with horrnone receptor-positive tumors whohave bad local primary tumor characteristics andother unfavorable prognostic features may have abetter clin ical risk/benefit outcome with the additionof neoadjuvant cytotoxic chernotherapy comparedto r reoad juvant endocr ine therapy . (Leve l I I ,Category A)

41. Women with hormone receptor-posit ivetumors whoare going to receive both tamoxifen and cytotoxicclremotherapy should be started on tamoxifen onlyafter tlre cornpletiorr of chemotherapy. (Level II,Category A)

42. Postrnenopausal wotnen with hormone receptor-posit ive tumors may be given ei ther tamoxifen oraronlatase i nli ibitors for n eoadj uvant therapy. (LevelI I , Category A)

Hormon e (estrogen/progesterone) Receptor-NegativeCase,s

43. h"r womeu with hormone receptor-negat ive tumors,neoadjuvant endocrine therapy is general ly notindicated, and rreoadjuvant chemotherapy may bebenef ic ial . (Level I l , Category A)

44. The use of anthracycl ine containing chernotherapycornbinat ior ls may be more benef ic ial than thosethat do not corrtain anthracycl i l re. (Level I I , CategoryA )

45. The newer chemotherapeut ic cornbinat ions wlr ichare in general more toxic arid more expensive sl-rouldnot be rout inely used, but instead be reserved forwomen in whom a part icular chemotherapeut icconrbinat ion may offer a cl in ical ly favorable r isk/berrefit oLltcome. (Level II, Category A)

46. Premenopausal women with hormone receptor-negative tumors but may not be able to receiveneoadjuvant chemotlierapy. (Level II, Category A)

47. When neoadjuvant treatrnent results in a resectablepr imary tumor , mod i f ied rad ica l mastec tomyfollowed by radiotherapy to tlie chest wall maydelay local recurrence. (Level I I , Category A)

3. Recurrent or Metastatic Breast Cancer (Stage IV)

48. The primary goal of therapy for patients with stageIV breast cancer is pal l iat ion. Pal l iat ive care is theact ive total care of pat ients whose disease is nolonger responsive to curative treatment. The goal ofpal l iat ive care is the achievement of the best qual i tyof l i fe for pat ients and their famil ies. Control of paina n d o t h e r s y m p t o m s , a n d a l l e v i a t i o n o fpsychological , social and spir i tual problems areparamount. (Level I, Category A)

49. The WHO Method of cancer pain rel ief s lroLr ld beimmediately started for al l pat ients with Stage IVbreast cancer who complain of pain. (Level I ,Category A)

50. Ac t ive an t icancer t rea tment does no t rep lacepa l l ia t i ve care , and pa l l ia t i ve care s l rou ld bemaintained in patients who are receiving activearrticancer treatment. (Level I, Category A)

Hormone Respons ive Metastas is

5 1 . Patients with hormone responsive metastatic lesionsand whose general condit ion indicates that t l reycould benefit from systemic anticancer treatrnent,benef i t f rorn sequent ial endocrine t l ierapy. (Level l ,Category A)

52. Sequential endocrine treatment should be continueduntilthe patient is considered to be hormone refractory.A minimum of three types of endocrine treatmentshould have been given before beiug considered ashonnone refractory. (Level I, Category A)

53. Premenopausal women with l rormone responsivemetastat ic lesions and whose general condit ior iindicates that they cor,rld benefit from endocrinetherapy, may derive more benefit from ovariansuppression plus tamoxifen compared to ovariansuppression alone. (Level I, Category A)

i l6

54 .

55 .

Hor mon e Refr ac t ory Me t as t as is

Women with Stage IV breast cancer whose disease

is hormone refractory, or with symptomatic visceral

metastasis, or with tumors that are hormone receptor-

negat ive, and whose general condit ion indicates

that they could benefit from systemic anticancer

treatment, may benefit from cytotoxic chemotherapy'

(Level I, Category A)

When cytotoxic chemotherapy is being considered

for women with Stage IV breast cancer and their

general condition indicates that they may benefit

from it. The potential benefits and toxicities should

be carefully explained to the patient. (Level I,

Category A)

Radiotherapy For Paiffil Bone Metaslasis

56. Radiotherapy may be benef ic iaI in rel ievingpainful

bone metastasis. (Level I, Category A)

Radiotherapy/surgery For Skin or Soft Tissue

Metastasis

57. Radiotherapy or l imited surgery may be benef ic ial

in some cases of skin or soft t issue metastasis.

(Level II, Category A)

Bisphosphonates For Bone Metastasis

58. Breast cancer pat ients with evidence of 'bone

destruct ion on plain radiographs, or Computed

Tomography (CT), or Magnetic Resonance Imaging

(MRI) may benefit from bisphosphonates. (Level I,

Category A)

59. The use o f b isphosphonates in the absence o f

radiographic evidence of destructive bone metastases

is not recommended. (Level I , Category A)

60. The use of bisphospl ionates in women with Stage IV

breast cancer without evidence of bone metastases

is not recommended. (Level l , Category A)

., l:'\t

PJSS Vol. 61, N0.3, July-September' 2006

61. The use of bisphosphonates as adjuvant therapy is

not recommended. (Level II, Category A)

Bone Health In Women With Breast Cancer

62. Health care professionals who take care of women

with breast cancer should take an active role in the

monitor ing ofbone lreal th, part icular ly i r i the regular

assessment of osteoporosis r isk. (Category A)

Introduct ion

The Phi l ippine Col lege of Surgeons (PCS) had pub l ished

i t s E v i d e n c e - b a s e d C l i n i c a l P r a c t i c e G L r i d e l i n e s

(EBCPG) on the diagnosis and management of breast

cancer in 2001. r '2 S ince then, numerous h ig l i qua l i t y

cl in ical t r ia ls have been publ ished, part icular ly on the

beneficial role of hormonaltherapy in both the adj uvant

and metastatic setting, and the consequent effects on the

benef ic ial role of cytotoxic chemotherapy. These

publ icat ions have resulted in modif icat ions in other

cl in ica\ pract ice guidel ines includ ing that of the Nat ional

Comprehensive CancerNetwork (NCCN) in the United

States3 and the Internat ional Expert Consensus (St.

Ga l len) .4Tl ie incidence of breast cancer among women in the

Phi l ippines is,expected to cont inue to r ise' The global

observat ion that fert i l i ty decreases as a cortntry 's

economic development progresses, and the i t rcreasing "

westernizat ion " of Phi l ippine l i festyles are t l re major

factors that are expected to contribute to tlre anticipated

rise in incidence.5The 2001 PCS EBCPG was reviewed in i ts ent i rety,

and when no new evidence was discovered, the 2001

guidel ines were retained. Only those publ icat ions that

were not included in the 2001 guidel ines are ci ted in the

update.

Methods

T l ie l i te ra tu re search method, leve ls o f ev idence,

categories of recommendations, and cl i r r ical quest ions

were essent ial ly s imi lar to those used in the 2001

guidel ines.

2005 Update. EBCPG on the Diagnosis and Management of Breast Cancer

Results

A. Diagnosis

Recommendations

L [n patients with a palpable breast mass in which

cancer is suspected, BIOPSY is mandatory. (Level

I, Category A)

2. Fine needle aspiration cytology (FNAC) is the initial

diagnostic procedure in patients with a palpable

breast mass in which cancer is suspected. In areaswhere there is no cytopathologist, core needle biopsy

is an acceptable ini t ia l diagnost ic opt ion. (Level I ,

Category A)

3. I f the FNAC result is mal ignant, the pat ient is

offered tlre different treatment options. (Level I,

CategorY A)

4. I f the FNAC result is ben ign but cl in ical f ind ings are

real ly highly suspicious for breast cancer, ei ther a

core needle or an open biopsy is done. (Level I I ,

Category A)

5, The PCS shoLrld set up standards regarding FNAC.(Category A)

6. If the FNAC is unsatisfactory or interpreted as

sr-rspicious, core needle biopsy or open biopsy is

advised. (Category A)

7 . F o r . d e e p s e a t e d t u m o r s d " 1 c m i n s i z e ,

sorrographical ly gLr ided FNAC or core needle biopsy

is recommended. In p laces where sonography

facilities are unavailable, open biopsy is done. (Level

I I , Category A)

8. Frozen sect ion histology is done*only when thepat ient requests i t . (Level I I , Category A)

There wi l l be instances when a premenopausal

pat ient with early breast cancer prefers adjuvant

oophorectotny. S ince it is more efficient and practical to

perform the oophorectomy and mastectomy under a

single anesthesia, i t would be important to know the

lrornrone receptor status of the tumor beforehand'

9. In premenopausal women who are suspected to

have early breast cancer and who prefer to undergoadjuvantoophorectomy, a core needle biopsy (CNB)

wi l l provide suff ic ient tumor t issue to determinehormone receptor status preoperatively. (Level I,

Category A)

The recommendations on the role of preoperative

breast imaging examinations in women with a suspiciottspalpable breast mass are retained.

10 . Mamrnography , sonography and o ther b reas t

imaging studies do not improve accuracy in arr iv ingat a preoperat ive diagnosis and should not be used

rout inely to al ter the cl in ical diagnosis in pat ierr ts

with a palpable breast mass suspicious for cancer.(Level lI, Category A)

I 1. In wonlen with early breast cancer, preoperat ive

mammography is recommended to detect subcl inicaldisease in the contralateral breast, and also i rr the

ipsi lateral breast for those pat ients who wi l l undergo

breast conservat ion treatment. (Level I I , Category

A)

12.In asymptomatic women with early breast cancer,

there is no evidence that the use of an intensive

preoperat ive metastat ic work up increases survival '

Furthermore, these exalns (chest X-ray, bone scan,

bone X-rays, l iver ul t rasound, l iver scan, and l iver

,enzymes) have low diagnost ic yield and are no

better than cl in icopatho logic factors l ike tu mor size.

histologic di f ferent iat ion (grade), axi l lary nodal

status, and hormone receptor status, in predict ing

distant metastases. Therefore, tlrey should not be

ror.r t inely done. (Level I I , Category A)

B. Staging and Fol low Up of Early Breast Cancer

The recommendations on postoperat ive survei l lance

are simi lar. The 2005 NCCN Guidel ines and the 1999

Guide l ines o f the Amer ican Soc ie ty o f C l in ica l

Oncologists (ASCO) both recommend careful history,

phys ica l examinat ion and mammograp l ry o f the

contralateral and preserved breast. "Data are not

ltl

l t 8

sufficient to recommend routine bone scans, chestradiograplrs, hematologic blood counts, tumor markers,liver u ltrasonograms, or computed tomography scans."7

13. The rout ine use of an intensive metastat ic work upfollowing treatment for women with early breastcancer does not increase survival compared tosymptom directed fol low up, and should not berout inely used. (Level I , Category A)

14. Fol low up consists of a careful history and physicalexaminat ion and annua l mammography o f thecontralateral and preserved breast. (Level I, CategoryA)

C. Surgical Treatment of Early Breast Cancer

The 2001 recommendations are retained. The Z\-yearand 25-year follow up of two trials comparing radicalmastectomy, total mastectomy and breast-conservingsurgery followed by irradiation had reported survivalbenef i ts that were simi lar to earl ier results.s 'e

15. The pr imary treatment of ear ly breast cancer ise i ther mod i f ied rad ica l mastec tomy or b reas tconserv ing surgery p lus rad io therapy . Breas tconserving surgery slrould include complete excisionof the pr irnary tumor in the breast, and an axi l larydissect ion to determine nodal status. (Level I .Category A)

I t is the pat ient wlro wi l l make the informed choice.

16. More extensive surgery is done in order to removeal l gross tumor. (Level I , Category A)

D. Adjuvant Treatment

I t is in t l re adj uvant treatment of ear ly breast cancer thatnra jo r changes are recommended because o f t l resubsequent pLrb l i ca t ion o f h igh leve l ev idence, and, insome instarrces the consensLls of some expert panelguidel ines that may be appl icable to the Phi l ippinepract ice sett ing.

' t/1.'

PJSS Vol. 61, No. 3, July-September, 2006

Adjuvant Radiotherapy

The role of adjuvant radiotherapy following totalmastectomy is essentially unclranged except for somegeneral agreement on what constitutes a patient who isat "high r isk" of local recurrence and for whom adj uvantradiotherapy may decrease the risk of local recurrence.

While there had been qual i ty reports on survivalbenefits following adjuvant radiotherapy, the precisecharacteristics of the subsets of patients that couldderive a cl in ical ly s igni f icant survival benef i t , the longterm side effects and the cost-effectiveness are sti I I to bedetermined.r0'r2 The St. Gal len Internat ional ExpertConsensus report states that "Tailoring postmastectomyrad ia t ion therapy recommendat ions fo r ind iv idLra lpat ients remains a pr ior i ty for addit ional research."a The2005 NCCN Guidel ines also stated that t l rere wassubstantial controversy among panel members whenthey were deliberating on postmastectomy radiatiorr tothe chestwal l , supraclavicr.r lar lyrnph nodes, and internalmammary nodes.

I t shou ld a lso be no ted tha t ax i l la ry rad ia t ionfo l low ing a to ta l ax i l la ry d issec t ion subs tan t ia l l yincreases the risk of perrnanent and severe lymphedema.rsFurthermore, i t had been reported t l iat an increased r iskof lung f ibrosis may occur fol lowing the combined useof radiat ion and tamoxifen.r4'rs

17. Adjuvant radiotherapy fol lowing modif ied radicalmastectomy does not improve survival in al l cases

iof ear ly breast cancer and should not be rout inelygiven. (Level I , Category A)

18. Adjuvant radiot l ierapy fol lowing modif ied radicalmastectomy may decrease the probabi l i ty of localrecurrence in certain patients with a high risk ofIocal recurrence (tumor greater than 5 cm; less than1 mrn pathologic margin; 4 or more posit ive axi l larynodes), or when the surgeon is not certain about theadequacy of the locoregional resect ion. (Level I ,Category A) '

19. Radiotherapy to the preserved breast t issue is anintegral part of breast conserving sLrrgery for earlybreast cancer (Level I, Category A)

2005 Update ' EBCPG on the D iagnos is and Management o f Breas t cancer

Adjuvant Systemic Therapy

It is in the adjuvant systemic therapy for early breastcancer that the major changes in the recommendationsoccur. Pract ical ly al l updated treatment guidel ines nowstress the paramount importance of hormone receptorstatus in tlre choice of adjuvant systemic therapy. ,,The

NCCN Guidel ines cal l forthe determinat ion of estrogenand progesterone receptor conterrt in allprimary invasivecancers."3 The St. Gallen International Expert Consensusreport states that "Recomrnendations for patient careare so cr i t ical ly dependent on assessment of endocrineresponsiveness that the inrportance of high-qual i tysteroid hormone receptor determination and standardizedqLrarrt i tat ive report i rrg cannot be overemphasized."a

The determinat ion and quant i f icat ion of estrogena n d p r o g e s t e r o n e r e c e p t o r s b y m e a n s o fi mm u noh istochem istry ( l HC) metlrods have faci l i tatedlrormone receptor determinat ion and has now replacedthe very expensive and relat ively less rel iable l igand-banding assay.16 Although IHC may be an even betterpredictor of response to adjLrvant endocrine t l rerapy,r?problems in standardization and interpretation stil l occurand account for the large number of false-negativeresults in many countr ies. An unpubl ished observat ionirr India credits the use of buffered formalin as fixativefor specimens and the use of the Al l red scoring systemrsfor a substantial decrease in false-negative readings anda hormone receptorpositive proportion that approximatesthose in deve loped count r ies .

The Al l red scoringsystem is perhaps the only rnethodthat has been prospect ively val idated with disease freesurv iva lp robab i I i t y in a la rge numbero fpa t ien ts (1 ,982women wi th ear ly b reas t cancer ) . I t invo lves theproport iorr of posi t ive-staining tumor cel ls ( 0 = none; I< l / 1 0 0 ; 2 = I / 1 0 0 t o 1 / 1 0 ; J : l / 1 0 t o l / 3 ; 4 : l l 3 t o213; and 5 > 213 ), and an intensity score which representsthe average intensity of posi t ive tumor cel ls ( 0 = none;I = weak, 2 = intermediate; and 3 = strong ). The best cutpoint is a score of greater than 2. Thus, only those slideswhich ei ther had no tumor cel l staining at al l (score : 0)or weak staining was observed in less than 1/100 cel ls(score = 2) were read as negative. Currently, however,rnany pathologists stil l use the arbitrarily determined

cut po in t o f less than l /10 s ta in ing ce l l s and read suc l rsl ides as a negat ive assay.

20. Hormone receptor status (estrogen/progesterone)should be the main considerat ion used in select ingtype of adjuvant treatment. (Level I, Category A)

2 l .There shou ld be a de termined e f fo r t to makeimmunohistochernistry hormone receptor assayavai lable in strategic locat ions in the country, aswell as efforts at standardizingthe method. (CategoryA)

22. Interpretation of immunohistochemistry hormonereceptor assays should be done usirrg t l re Al l redscoring system. (Level I I , Category A).

Most of the pr imary tumors that are considered to behormone receptor-positive are estrogen receptor(ER)-posit ive, In the report by Harvey, et al . , 71 percent of al ltumors were de ter rn ined to be ER-pos i t i ve . rT AVietnamesereport included sending some paraffin blocksfrorn Vietnam (105 of 1,622) to a reference laboratoryin Austral ia for staining and interpretat ion. Table Ishows the comparison in two age-groups between s l idesstained in Vietnam and Austral ia. ( Van To T, et al ;Unpubl ished data)

The proportiop of tumors that are ER-negative bLrtare PR-posit ive is mLrch smal ler, and i t may not be cost-effective to routinely order assays of both hormonessim ultaneous ly. Seq uential assays may be more practical.

23. Estrogen receptor assay may be deterrnirred first.and i f the result is negat ive, progesterone receptorassay is done. ( Category A)

Hormone (estrogen/progesterone) Receptor-PositiveCases

In 1993, the Scot t i sh t r ia l (no t inc luded in theEBCTCG meta-analyses) reported comparable surv ivalrates between adjuvant ovarian ablation (surgical orr a d i a t i o n ) v e r s u s C M F c h e m o t h e r a p y a m o n gpremenopausal women with positive axillary nodes.When analyzed by estrogen receptor status, "it seemsthat ovarian ablation is the rnore effective treatrhent for

n9

t20 PJSS Vol: 61, No. 3, July-September' 2006

Table 1. Comparison befween esffogen receptor immunohistochemisUy in Nvo age-groups between Vietnamese paraffin

blocks stained in Vietnam and those stained in a reference laboratory in Australia.

Hospital-K blocksstained in Ausftalia(n = 105)N ER+ (%)

Australian Cases(n= 32)

N ER+ (%)

Hospital-K blocksstained in Vietnam(t= 1622)N ER+ (%)

p-value

0.720 .83

596 58.3334 55.8

13 69.9t9 84.2

68.985. r

58A 1

< 50 years2 50 years

patients with ER-posit ivetumors, wl 'rereas CMF may be

more effective for patients with low ER content orl " lone" , l9

ln 2002, Jonat, et al. reported that adjuvant medical

oophorectomy using goserel in, a luteiniz ing hormone-

releasing hormone (LHRH) analog, resulted in a disease-

f r e e s u r v i v a l ( D F S ) s i m i l a r t o a d j u v a n t C M F

chemotherapy among ER-positive patients with positive

axi l lary nodes.20 In the same journal issue, Jackesz, et al .

reported that goserel in plus tamoxifen resulted in

significantly better relapse-free survival (RFS) and local

r e c u r r e n c e - f r e e s u r v i v a l c o m p a r e d t o c M F

clremotherapy.2lAlso in 2002, Love, et al . publ ished an RCT that

cornpared adj uvant oophorectomy plus tamoxifen versus

observat ion fol lowed by the same hormonal therapy

upon recurrence in 709 premenopausal Vietnamese and

Chinese women. For al l study pat ients (ER-posit ive,

ER-negative, ER-unknown) The S-year disease-free

survival increased frorn 58 percent to 72 percent and

overal l survival (OS) from 68 percentto 77 percentwith

adjuvant treatment. Among 288 cases wit l r ER-posit ive

tLrmors, the 5-year disease-free survival increased from

58 percent to 80 percent and over-al l survival f rom 78

percent to 83 percent.22The Asian populat ion involved in the Love report

demonstrated that tlre frequency and intensity of hot

f luslres, vaginal discharge, and genital prur i tus were the

on ly symptoms to occur more f req t ren t ly in the

oophorectomy plus tamoxifen-treated pat ients. In the

first I 2 months, 77 percentreported hot flushes ofgrade

I or more and 44 percent reported grade 2 or more (3-5

lrot fluslres per day or more). Over 3 years, these

episodes had dropped to 23 percent with nrajority beinggrade 1.23

Beith, et al. reported that among women who received

d o x o r u b i c i n p l u s c y c l o p h o s p h a m i d e a s a d j u v a n t

chemotherapy, the occurrence of grade 4 neutropenia

was observed to be higher at 54 percent as among Asians

compared to 19 percent in Caucasians'24 The higher

l ikel ihood ofnotreceivingthe planned dose is important

for c l in ical decision making. Bonadonna, et al . , l rad

reported that with CMF clremotherapy, the 2l'year

probabi l i ty of survival s igni f icant ly decreased in those

who received less than 85 percent of the planrred dose'

Those who received less tharr 65 percent of the plar ined

dose had the same survival rate as those who did not

receive adj uvant chemotherapy.25I t has a lso long been suspec ted tha t a rna jo r

mechanism ofiaction of adjuvant cytotoxic chemotherapy

is endocrine related. Survival benef i ts (DFS and OS)

are proportionally h igher among premenopausal womell

who developbd permanent amenorrhea compared to

th'ose women whose menses persisted.26-27 In the Scottish

tr ial , among pat ients who had regular menses' 30 percent

of pat ients under 40 years and 85 percent of t l rose 40

years or older became amenorrheic after CMF adjrrvarrt

chemotherapy.'e In the CMF arm of the ZEBRA study,

26 percent of patier,ts yotlnger than 40 years arrd 90

percent of those older than 40 years were amenorrheic

after 3 years.2oThe observat ion that the probabi l i ty of indLrcirrg

amenorrhea, and the possible greater survival berref i t

that comes with i t , is much lower among yot l l lger women

fo l low ing ad juvant chemotherapy can a lso have

important c l in ical i rnpl icat ions. In the Vietnamese

populat ion, rnul t ivar iate analysis showed that age less

2005 Update. EBCPG on the Diagnosis and Management of Breast Cancer

than 40 years was an independent significant predictor

of shorter survival.2s This observation has been repeated

in many other reports.2e'33The 15-year follow up of patients included in the

meta-analysis by the EBCTCG on the effects of

chemotherapy and hormonal therapy shows that the

benefits observed after l0 years have been retained.3a

Although HER-2 overexpression was a negative

prognostic factor for overall survival, Love et al. found

that premenopausal women with HER-2 positivetumors

are more likely to respond to adjuvant treatment with

ovarian ablat ion and tamoxifen than those whose tumors

are l lon-overexpressing. 35'36

24, Pat ients with invasive early breast cancers that are

estrogen or progesterone receptor- posi t ive should

to be considered for adjuvant endocrine tlierapy

regardless of pat ient age, menopausalstatus, lymph

node status, HER2/neu status, or whether or not

adjuvant chemotherapy is to be given. (Level I ,

Category A)

25, In premenopausal women who are considered for

adjuvant endocrine therapy, the combination of

ovarian suppression (surgical or radiat ion ovarian

ablation, or by LHRH analogs) plus tamoxifen results

in a longer survival benefit compared to either

treatment alone. (Level I, Category A )

Endocrine adjuvant treatment has tradi t ional ly been

mostly the use of tamoxifen at20 mg dai ly for 5 years in

both prernenopausa l and pos tmenopausa l women '

Among premenopausa l wonten , the use o f combined

endocrine therapy consist ing of tamoxifen plus ovarian

suppression (surgical or radiat ion ovarian ablat ion, or

by tlre use of an LHRH analog) has been found to confer

larger srrrvival benef i ts cornpared to using eaclr type of

endocrine therapy alone.

26. \ t premenopausal women with hormone receptor-

posit ive tutnors who are considered for adjuvant

oophorectorny, luteal phase oophorectomy may offer

greater survival benefit compared to fo ll icr"rlar phase

oophorectotny. (Level II, Category A)

From the Vietnamese study, Love, et al . in a subset(pos t - l roc) ana lys is d iscovered tha t t l re h ig l ies tprobability of DFS was observed among women who

underwent luteal phase oophorectomy (DFS 83%) as

c o m p a r e d t o t h o s e w h o h a d f o l l i c u l a r p h a s e

oophorectomy (DFS 54%). The subset consist ing ofwomen 44 years of age or younger and witli a menstrualcycle duration of at most 35 days were interpreted to bea population more likely to have ovulatory menstrualcycles and were therefore more likely to be producing

progesterone during the luteal phase of their menstrualcycle. Another intr iguing subset analysis showed that

even women with ER-negat ive tumors could have

benef i t ted f rom lu tea l phase oophorec torny p lus

tamox i fen .3? These observa t ions add ev idence to

l ingering theories that an abrurpt lowering of elevated

estrogen and progesterone can influence micrometastaticgrowth.38-ar

There are two important c l i r r ical quest ions regardingadjuvant endocrine t l rerapy for hormone receptor-posit ive cases: I ) Is adjuvant endocrine therapy cl in ical ly

beneficial for axillary node-negative cases?, and,

2) When is the addition of combination chemotherapy to

endocrine therapy cl in ical ly benef ic ial?While there are no robust f indings from randomized

tr ials to answer t l re specif ic and numerous cl in ical

si tuat ions that could be involved to answer these two

quest ions, there is now wide agreement based on

retrospect ive and post-hoc analysis of numerous tr ia ls

as to,what const i tutes "favorable prognost ic featLlres"

and conversely, what "unfavorable prognost ic features"

Tl ie absence of spread to t l re axi l lary nodes and a

hormone receptor posi t ive turnor are t l re most establ ished

and strongest good prognost ic factors. On top ofthese,

1) absence o f ang io lymphat ic invas ion ;2) low nuc leargrade (Grade l ) ; 3 ) lowh is to log ic g rade (Grade l ) ;

4) srnal l pr i rnary tumor (<2 cm); 5) not of yoLrng age(> 40 years): and, 6) no HER-2 overexpression, may be

considered asfavorable prognosticfeatures. Tlrus, a 52year old woman with a 0.7 crn tumor which slrows no

angiolymphatic invasion, and low nuclear and histologicgrade, and no HER-2 overexpression, would have to

ponder long and hard in order to decide i f the potent ial

l2l

122

risk ofthe harmful effects ofadj uvant endocrine therapywil l be worth the very modest expected survivalbenef i t .a2

On the other hand, the presence of spread to theaxillary nodes and a hormone receptor negative tumorare tlre most established and strongest unfavorableprognostic factors. On top of these, 1) presence ofangiolymphatic invasion;2) high nuclear grade (Grade

3); 3) high histologic grade (Grade 3); 4) big pr imaryt u m o r ( > 5 c m ) ; 5 ) b a d c l i n i c a l p r i m a r y t u m o rcharacteristics (T4 tumors); 6) young age (<35 years);

andT) presence ofHER-2 overexpression, may decreasesurvival and can be considered unfavorable prognostic

factors. Thus, a 32year old woman with a 7.0 cm tumorwhich shows angiolymphatic invasion and Grade 3nuclear and histologic grades may benefit substantiallyf r o m t h e a d d i t i o n o f c o m b i n a t i o n c y t o t o x i cchemotlrerapy to combined endocrine therapy.

In between these two extremes wherein the riskibenefit expectations appear to be clear cut there arel tumerous si tuat ior is comprising a "middle ground"

wherein the r isk/benef i t expectat ions are less clear andless prec ise ly p red ic tab le . The pre ference o f theindividual patient should therefore be respected afterthoroughly and trr-rtlrfr.rlly informing her of the risks andbenef i ts of the var ious treatment opt ions that areappl icable to her cl in ical s i tuat ion.

There have been many reports on the use of HER-2

overexpression as a prognostic and predictive factor inbreast cancer. Current ly, there is should be a determir iedeffort to staridardize the assay method and there remainssome controversy as to the cost-effectiveness of itsrout ine use. I t has been reported that HER-2lneuoverexpression was highly associated with negativelrormone receptor status, Grade 3 lesions and young age.The I ikel ihood of HER2/neu posit iv i ty in a hormonereceptor posi t ive, Grade 1 or 2 tumor was 6.1 percent.a3

2l . Tl ' rere sl ioLr ld be a determined and cont inuing effortto establ ish a standardized nat ional breast cancerpathology reporting system that routinely andrel iably i rrc ludes prognost ic features, such as thepresence or absence of angiolymphatic invasion,and nuclear and histologic grades. ( Category A)

.'),i.1

PJSS Vol. 61, No. 3, July-September, 2006

28. Women with hormone receptor-posit ive tumors andnegative axillary nodes and who have favorableprognost ic features may not der ive a cl in ical lyfavorable risk/benefit outcome with the addition ofadjuvant cytotoxic chemotherapy to adjuvantendocrine therapy. (Level II, Category A)

29. Women with hormone receptor-positive tumors andpositive axillary nodes and who have unfavorableprognost ic features may derive a cl in ical ly favorablerisk/benefit outcome with the addition of adjuvantcytotoxic chemotherapy to adjuvant endocrinetherapy. (Level II, Category A)

The simultaneous use of adjuvant tamoxifen andadjuvant combination chemotherapy had been shown to

result in poorer survival benef i t compared to the

s e q u e n t i a l u s e o f c h e m o t l r e r a p y f o l l o w e d b ytamoxifen.aa'45

30. In women with hormone receptor-posit ive tumorswho wi l l receive both tamoxifen and cytotoxic

chemotherapy, tamoxifen shou ld be started after thecomplet ion of chemotherapy, (Level I , Category A)

Several t r ia ls have provided prel iminary evidencethat the use of a new class of endocrine therapy drugs,the aromatase iphibi tors result in signi f icant but modestsurvival benefit compared to tamoxifen in the adjuvanttherapy o f pos tmenopausa l women w i th hormonereqeptor -pos i t i ve b reas t cancer . The ATAC t r ia lderntinstrated that the use of anastrozole alone as firstline adjuvant treatment conferred a significant 2.9percent absolute survival benefit over tamoxifen aloneat year 4.a6 After 5 years on tamoxifen, letrozole use

resulted in a signi f icant 6.0 percent absolute disease-free survival benefit at year 4 compared to placebo.a?

Switching to exemestane after two to three years oftamoxifen therapy resulted in a signi f icant 4.7 percent

absolute disease-free survival benef i t at year 4 compared

to women who cont inued tamoxifen therapy.a8

Whi le there are s t i l l no pub l i shed repor ts tha t d i rec t l ycompare the t l r ree aromatase inhibi tors in the cl in icalsett ings involved in these three tr ia ls, i t may be current lyassumed that their efficacy and toxicity profiles are

2005 Update. EBCPG on the Diagnosis and Management of Breast Cancer

comparable. Aromatase inhibi tors, when compared to

tamoxifen, lrad consistently demonstrated lower risks

for endometrial cancer and thromboembolic events and

c e r e b r o v a s c u l a r a c c i d e n t s b u t l r i g h e r r i s k s f o r

osteoporosis, arthralgia, myalgia and elevation of serum

cholesterol .Aromatase inh ib i to rs shou ld no t be used in

premenopausa l women. The NCCN def in i t ion o f

menopaLrse is: "Menopause is generally the permanent

cessation of menses, and as the term is util ized in breast

cancer management includes a profound and permanent

decrease in ov4rian estrogen synthesis. Reasonable

cr i ter ia for determining menopause include any of the

fo l low ing

. Pr ior bi lateral ooPhorectornY

. Age > 60 years

. Ag" < 60 years and amennorheic for 12 or more

months in the absence of chemotherapy, tamoxifen,

toremifene, or ovarian suppression and FSH and

estradiol level in the postmenopausal range

. If taking tamoxifen or toremifene, and age < 60

years, then FSH and plasma estradiol level in

postmenopausal ranges

It is not possible to assign menopausal status to

won len w l ro a re rece iv ing an LH-RH agon is t o r

antagonist . In women premenopausal at the t ime of

adjuvarrt chemotlrerapy, amenorrhea is not a rel iable

indicator of menopausal status."3

31 . In postmenopausal wometr with hormone receptor-

positive tumors, tamoxifen or aromatase inliibitors

rnay be used as adjuvant therapy. (Level I, Category

n t

H or m one (e s tr o gen/pr o g e s t er one) Re c e p t or -N e gat iv e

Cases

32.ln wolnen with hormone receptor-negative tumors,

adjuvant endocrine therapy is generally not indicated

and adjuvant chemothercpy may be beneficial'(Level I, Category A)

3 3 . T h e u s e o f a c o m b i n a t i o n o f c y t o t o x i cchemotherapeutic dru gs for adj uvant therapy resu lts

in greater survival benefit compared to the use of a

single drug. The use of anthracycl ine containing

combinations may result in a greater survival benefit

compared to the CMF regimen. (Level I , CategoryA)

34. The use of four cycles of AC (adriarnycin +

cyc lophosphamide) combina t ion fo r ad juvant

chemotherapy may result in a survival benefitthat is

simi lar to that obtained with six cycles of CMF.(Lavel I, Category A)

35. The newer chemotherapeut ic regimens should not

be routinely used because tliey are more toxic and

expensive. They should be reserved for women with

unfavorable prognostic factors for whom a particular

chemotherapeutic comb ination may offer a c I i n i cal ly

favorable risk/benefit otttcome. (Level l, CategoryA)

36. Premenopausal women with hormone receptor-

negat ive tumors who wi l l not be able to receive

adjuvant chemotherapy should be offered adjuvant

luteal phase oophorectomy may provide some

survival benefit. (Level Il, Category A)

t

Unfortunately, many of the published randomized

tr ials on neoadjuvant therapy for " local ly advanced"

breast cancer included T3 pr imary tumors (> 5 cm) and

manytWestern treatment guidel ines include Stage I I IA

cases in their def ini t ion of local ly advanced breast

car lcer. This has resulted in an overlap of c l i t i ical

categories as many cases labeled as local ly advanced

would also fal lwi thin the EBCTCG def ini t ion of ear ly

breast cancer. This has also resulted in tlre par-rcity of

Level I evidence on the management of breast cancer

cases that fal l under our def ini t ion of local ly advanced

breast cancer. An explanation for this n'ray be the fact

that such cases are getting to be quite rare in Western

populat ions so that t r ia ls may neither be feasible nor

worthwhile.Despite the global shift in preference for tlre use of

endocrine treatment for hormone receptor-positive breast

cancer in both the adiuvant and metastatic''setting,

124

neoadjLrvant chemotherapy is stil l widely considered as

the standard forrn of treatment for "locally advanced"

breast cancer. Notwithstanding the fact that no survival

benefit over postoperative adjuvant treatment has been

demonstrated, there has been an increasing interest in

the role of hormonaltherapy for local ly advanced breast

cancer .an-53 The main cons idera t ions fo r the new

recommendations are therefore indirect evidence and

the necessity for consistency in the recommendations

on the use of sYstemic treattnent.

37. Hormone receptor status (estrogeniprogesterone)

should be the main considerat ion used in select ing

the type ofneoadjuvant therapy' (Level II, Category

A)

Hormone (estrogen/progesterone) Receptor'Positive

Cases

38. Women with locally advanced breast cancers that

are hormone receptor-posit ive should be considered

for neoadjuvant endocrirre therapy regardless of

patient age, menopausal status, HER2/neu status, or

whether or not neoadjuvant chemotherapy is to be

given. (Level I l , CategorY A)

39. ln premenopausal women with hormone receptor-

positive tumors who are considered for adjuvant

oophorectomy, luteal phase oophorectomy may offer

greater survival benefit compared to follicular pliase

oophorectomy. (Level I I , Category A )

40. Women with hormone receptor-positive tumors

who have bad local primary tumor characteristics

and other unfavorable prognostic features may have

a better clinical risk/benefit outcome with the

addition of neoadjuvant cytotoxic chemotherapy

compared to neoadj uvant endocrine therapy. (Level

l l , Category A)

41. Women wi th hormone receptor -pos i t i ve tumors

who are going to receive both tarnoxifen and

cy to tox ic chemotherapy shou ld be s ta r ted on

tamoxifen after the completion of chernotherapy.(Level II, Category A)

.,:ii,l

PJSS Vol. 61, No' 3, July-September, 2006

42. Postmenopausal women with hormone receptor-

positive tumors may be given either tamoxifen or an

aromatase inhibitor for neoadj uvant therapy. (Level

II, Category A)

Hormone (est4ogen/progesterone) Receptor-Negative

Cases

43. ln women with hormone receptor-negat ive tumors,

neoadjuvant endocrine therapy is general ly t tot

indicated, and neoadjuvant chemotherapy may be

beneficial.(Level II, CategorY A)

44. The use of anthracycl ine containing chernotherapy

combinat ions may be more benef ic ial than t l rose

that do not contain anthracycline. (Level II, Category

A)

45. The newer chemotherapeut ic combinat ions wl i ich

are in general more toxic and more expensive should

not be routinely used but instead be reserved for

women in whom a particular chemotheraper-rtic

combinat ion may offer a cl in ical ly favorable r isk/

benef i t outcome. (Level I I , Category A)

46 In premenopausal women with l rormone receptor-

negat ive tumors but may not be able to receive

neoadj uvant chemotherapy, neoadj uvant lutbal pliase

oophorec{omy may provide some benefit. (Level II,

Category A)

47. When neoadjuvant treatment results in a resectable

,. primary tumor, a modified radical mastectomy

followed by radiotherapy to the chest wall may

delay local recurrence. (Level II, Category A)

3. Recurrent or Metastatic Breast Cancer (Stage IV)

Metastatic breast cancer can either be recurrent cancer

or i t can be the ini t ia l c l in ical presentat ion. Both are

Stage IV (M1) breast cancer. The management of both

are essent ial ly s ' imi lar so that the 2005 Lrpdate groups the

two together , un l i ke the 2001 Gu ide l ines .

Although act ive ant icancer treat lnent may prolorrg

the life of some patients with Stage IV breast cancer'

they are not curative. Furthermore, many patients with

2005 Update . EBCPG on the D iagnos is and Management o f Breas t Cancer

Stage IV breast cancer suffer from distressing syrnptoms

that severely impair the quality of life of the patient and

the patient's family. The primary goal of therapy for

Stage IV breast cancer is to del iver the best pal l iat ive

care.5a'56

48. The primary goal of therapy for patients with Stage

IV breast cancer is palliation. Palliative care is the

active total care of patients whose disease is no

longer responsive to curative treatment. The goal of

pal l iat ive care is the achievement of the best qual i ty

of life for patients and their families. Control of pain

a n d o t h e r s y m p t o m s , a n d a l l e v i a t i o n o f

psychological , social and spir i tual problems are

paramount. (Level I, CategorY A)

49. The WHO Method o f cancer pa in re l ie f shou ld be

imnrediately started for al l pat ients with Stage IV

breast cancer who complain of pain. (Level I ,

Category A)

50. Ac t ive an t icancer t rea tment does no t rep lace

pa l l ia t i ve care , and pa l l ia t i ve care shou ld be

maintained in pat ients wlro are receiving act ive

ant icancer treatrnent. (Level I . Category A)

The active anticancer treatment of patients with

Stage IV breast cancer may prolong l i fe and improve the

q u a l i t y o f l i f e o f s o m e p a t i e n t s w i t h s p e c i f i c

characteristics of metastatic disease, but is not curative.

T h e N C C N G u i d e l i n e s s u m m a r i z e s t h e c u r r e n t

phi losophy on the act ive ant icancer treatment of Stage

IV breast cancer: "Therefore, t reatments associated

with ni inimaltoxici ty are preferred. Tl ius, t l re use of the

min i rna l l y tox ic endocr ine therap ies is p re fe r red to the

use of cytotoxic therapy whenever reasonable."3

The character ist ics of metastat ic disease among

wofnen with Stage IV breast cancer that have a high

probability of not responding to endocrine therapy are:

I ) metastat ic Iesions are not l imited to soft t issue and/

or bone; and/or,2) metastat ic lesions are not l imited to

asymptomatic visceral metastasis; and/or, 3) a short

disease-free interval (< 2 years following prirnary

treatment). Tlrese are consider ed hormone nonresponsive

metastat ic lesiotts.

t25

Hormone Respons ive Metas tas is

51 . Pat ients with hormone responsive metastat ic lesions

and whose general condit ion indicates that they

could benefit from systemic anticancer treatment,

may benefit from sequential endocrine therapy.(Level 1, Category A)

The initial endocrine treatment is continued until the

deve lopment o f new metas ta t i c les ions , and/or ,

p r o g r e s s i o n o f c u r r e n t l e s i o n s w h i c h i n d i c a t e

refractor iness to the current endocrine treatment. A

second type of endocrine treatment is started until a

refractory status is reached, and a third endocririe

treatment is given, and so on. A minimum of three types

of endocrine treatment should have been giverr urr t i l the

patient is cousidered to be hormone refractory.

Tarnoxifen (20 mg dai ly) has been t l re tradi t iorral

ini t ia l endocrine treatment for hormolre responsive

metastat ic lesions, and megestrol acetate (80-160 mg

dai ly) the second l ine drug. Aromatase inhibi tors

(anas t rozo le I mg da i l y ; le t rozo le 2 .5 mg da i l y ;

exemestane 25 mg daily) have been reported to have

cl inical ly s igni f icant advantages over tamoxifen and

megestrol acetate when used ei ther as f i rst l ine or as

second l ine endocrine therapy.5T-6r Other endocrine

drugs that are Qenefic ial are diethylst i lbestrol (DES)

and fulvestrsvl6263 but both are not currently available

in the Phi l ippines. There is st i l l no good evidence to

r e c o - m m e n d t h e o p t i m a l s e q u e n c e o f e n d o c r i n e

treatinents.

52 . Sequent ia l endocr ine t rea tment shou ld be cont inued

unt i l t l i e pa t ien t i s cons idered to be l ro rnrone

refractory. A minimum of three types of endocrine

treatment shor"rld have been given before beirrg

considered as hormonerefractory. (Level l, Category

A)

A m e t a - a n a l y s i s o f f o u r c l i n i c a l t r i a l s t h a t

randomized 506 premenopausal women with advanced

breast cancer to LHRH agonist alone versus LHRH

agonist plus tamoxifen reported that the combined

t rea tment had a s ign i f i can t surv iva l be ,ne f i t and

126

progressiorl-free survival benefi t6awith a median survivalof6.8 ysars.

53. Premenopausal women witl, hormone responsivemetastatic lesions and whose general conditionindicates that they could benefit from endocrinetherapy , der ive more benef i t f rom ovar iansuppression plus tamoxifen compared to ovariansuppression alone. (Level I , Category A)

Hormone Refractorv Metastasis

54. Women with Stage IV breast cancer whose diseaseis hormone refractory, or with symptomatic visceralmetastasis, or with tumors that are hormone receptor-negative, and whose general condition indicatesthat they could benefit from systemic anticancertreatment, rnay benefit from cytotoxic chemotherapy.(Level I, Category A)

The Coclrrane Database of Systematic Reviewsi n c l u d e d t h e o b s e r v a t i o n t h a t : 1 ) c o r n b i n a t i o nchemotherapy showed rnodest si gni f icant improvementi n o v e r a l l s u r v i v a l a n d t i m e t o p r o g r e s s i o n b u tsigni f icant ly worse toxici t ies65 , and, 2) taxane-containing combinat ions appear to improve overal lsurvival , t ime to progression and overal l response.66

55. When cytotoxic chemotherapy is being consideredfor women with Stage IV breast cancer and tlreirgeneral corrdi t ion indicates that t l iey may benef i tf rom i t , the potent ial benef i ts and toxici t ies shouldbe caref i r l ly explained to the pat ient. (Level I ,Category A)

PainfLrl bone metastases may benefit from a slrortcourse of radiotherapy, often given in addit ion toendocri ne tlr erapy.67-68 The fraction ation sched u le shouldbe ta i lo red to ind iv idua l pa t ien ts by tak ing in toconsiderat ion the general condit ion of the pat ient,accessibi l i ty and t l re l i fe expectancy of the pat ient.

Radiotherapy for Painful Bone Metastasis

56. Rad io therapy may be benef ic ia l in re l iev ing pa in fu lbone metastasis. (Level I , Category A)

PJSS Vol . 61, No.3, July-September, 2006

Radiotherapy, and occasionally limited surgery, maybe benef ic ial in some instances of skin or soft t issuemetastasis, also often done in addition to endocrinetherapy.

McQuay, et al. reviewed the literature on the utilityof radiatior-r therapy for painful bone metastasis aspubl ished in the Cochrane Database. Sze, et al . on t l reother hand reviewed the use of single versus mu ltifractionradiotherapy in the 2002 edit iorr of the CochraneDatabase.

Rad io therapy /Surgery fo r Sk in o r Sof t T issueMetastasis

57. Radiotherapy or l imited surgery may be benef ic ialin some cases of skin or soft t issue metastasis.(Level II, Category A)

In 2003, H i l lner , e t a l . pub l i shed an update o f therecornrnendat ions on the role of bisphosphonates andbone health issues in women with breast cancer by theAmerican Society of Cl inical Oncology (ASCO). Theexfensive evidence cited in the publication is the rnainbasis for the fol lowing recommendatiot ts t l rat may beu s e f u l i n t h e P l r i l i p p i n e s . T l r e b i s p h o s p l r o n a t e srecommended were parenteral s ince suff ic ient evidenceon oral preparpt ions in Arnerican pat ients were not yet

ava i lab le . They recomrnended e i ther in t raver rouspamidronate 90 mg del ivered over2 hours orzoledronicacid 4 mg given over 15 minutes every 3 to 4 weeks.Onte ini t iated, they are to be cont inued Lrnt i l there wasevidence ofsubstant ial decl ine in the pat ient 's generalperformance status. Tlre current standards of care forcancer pain management shou ld be cont inued throughoLrtbisphosphonate therapy. There was i n su ffic i errt ev idenceto recommend a role for intraverrous bisphosphonate ina d d i t i o n t o r a d i a t i o n t h e r a p y f o r p a i n f u I b o n ymetastases.6e

Bisphosphonates for Bone Metastasis

5 8 . B r e a s t c a n c e r p a t i e n t s w i t h e v i d e n c e o f b o n ed e s t r u c t i o n o r r p l a i n r a d i o g r a p h s , C o m p L r t e dTomography (CT), or Magnet ic Resotrance lmaging

2005 Update . EBCPG on the D iagnos is and Management o f Breas t Cancer

(MRI) may benef i t f rorn bisphosphonates, (Level I ,Category A)

59. The use o f b isphosphonates in the absence o f l l .radiographic evidence ofdestructive bone metastasesis not recommended. (Level I , Category A)

60. The use of bisphosphonates in women with Stage IVbreast cancer without evidence of bone metastasesis not recommended. (Level I , Category A)

61. The use ofbisphosphonates for adjuvant therapy isnot recommended. (Level I I , Category A)

Bone Health in Women with Breast Cancer

62. Healtlt care professionals who take care of womenwith breast cancer should take an act ive role in themonitor ingof bone health, part icular ly inthe regularassessment of osteoporosis r isk standard. ( CategoryA)

References

l . Matsuda MDL, Laud ico AV, Yosu ico VD, Roxas MF, Caba luna ND,Blanco FJ. Evidence-based cl i rr ical practi ce guidel ines on the di agnosisand nranagement ofbreast cancer Part I . Early Breast Cancer. Phi l ippJ Surg Spec 2000; 56( l ) :7 -30 .

2. Matsuda lv ' tDL, Laudico AV, Yosuico VD, et al. Evidence basedcl inical practice guidel ines on the diagnosis and management ofbreast cancer. Part I l . Local ly advanced breast cancer, local ly recurrentbreast cancer and metastat ic breast cancer. Phi l ipp J Surg Spec 200 I ;5 6 ( 4 ) : 1 3 5 - 1 6 4 .

3. National Conrprehensive Cancer Network. Cl inical Practice Cuidel inesin Onco logy . Breas t Cancer . Vers ion 2 .2005 05-3 l -05 .

4. Coldhirsch A, Wood WC, Celber RD, Coates AS, Thurl irnann B, SennH.l. Meeting highl ights: Updated lnternational Expert Consensus onthe prinrary therapy of early breast cancer. . l Cl in Oncol 2003;2 l ( 1 7 ) : 3 3 5 7 - 3 3 6 5 .

5. Laudico AV, Esteban DB, Redaniel MTM, Mapua CA, Reyes LM.2005 Phil ippine Cancer Facts and Estimates. Phi l ippine CancerSoc ie ty Inc . 2004; Man i la , 2004.

6. Oreene FL, Page Dl, Fleming ID, et al. A.ICC Cancer Staging Manual6rh ed i t ion. New York: Springer-Verl a g 2002, 223 -240.

7. Smith TJ, Davidson NE, Schapira, et al. American Society of Cl inicalOncology 1998 update of recommended breast cancer survei l lancegu ide l ines . J C l in Onco l 1999; l7 (3 ) :1080-1082.

8. Fisher B, Jeong JH, Anderson S, Bryant .1, Fisher ER, Wolmark N.Twenty-f ive year tbl low-up of a randomized tr ial comparing radicalmastectomy, total mastectomy and total mastectomy followed byirradiat ion. N Engl J Med 2002; 347(8):567-575.

9. Veronesi U, Cascinel l iN, Mariani L, et al. Twenty-f ive year fol low upof a randomized study comparing breast-conserving surgery withradical nrastectomy for early breast cancer. N Engl J Med 2002;347 (t6):1227 -1232.

t27

Ragaz j , Ol ivotto IA, Spinel l i J. l , et al. Locoregional radiat ion therapyi n p a t i e n t s w i t h h i g h - r i s k b r e a s t c a n c e r r e c e i v i n g a d . j u v a n tclremotherapy: 2}-year results of the Brit ish Colunrbia randomizedtr ial. J Natl Cancer Inst 2005;97\2): l l6:126.Whelan TJ, Jul ian J, Wright J,. ladad AR, Levine ML. Does locoregionalradiat ion therapy improve survival in breast cancer? A meta-analysis:J Clin Oncol 2000; l8(6): 1220-1229.Overgaard M, Jensen MB, Overgaard J, et al. Postoperativeradiotherapy in high-risk postmenopausal breast-cancer patients givenadjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG82c randomized trial; Lancet 1999; 353:1641-1648.Coen JJ, Taghian AG, Kachnie LA, Assaad Sl, Powell SN. Risk ofIymphedema after regional nodal irradiat ion with breast conservatiot lsurgery . ln t J Rad ia t Onco l B io l Phys 2003; 55(5) : 1209- l2 l 5 .Bentzen SM, Skoezylas . lZ,Overgaard M,6t al. Radiotherapy-relatedlung f ibrosis enhanced by tamoxif 'en.. l Natl Cancer Inst 1996: 88:918-922.Koe M, Polat P, Suma S. Effects of tamoxifen on pulmonary f ibrosisafter cobalt-60 radiotherapy in breast cancer patierrts. RadiotherOncof 2002; 64:17 1-17 5.Eufemio GG, Liquete MJ, Laudico AV. Quanti tat ive estrogen rece ptorassay (dextran-coated) in breast carcinoma. Phil ipp J Surg SpecI 987; 42(3) :80-85 .Harvey JM, Clark GM. Osborne CK, Al lred DC. Estrogen recsptorstatus by immunohistocytochemistry is superior to thc l igand-bindingassay for predict ing resporrse to adjuvant endocrine therapy in breastcancer . J C l in Onco l 1999; 17(5) :1474-1481.Allred DC, Harvey JM, Berardo MD. et al. Prognostic and predict ivefactors in breast cancer by immunohistocytochemical analysis. Mod.P a t h o l 1 9 9 8 : I l : 1 5 5 - 1 6 8 .Scott ish Cancer Trials Breast Group and ICRF Breast Unit, Guy'sH o s p i t a l . L o n d o n . A d j u v a n t o v a r i a n a b l a t i o n v e r s u s C M Fchemotherapy in premenopausal women with pathological stage l lb reas t carc inoma: The Scot t i sh t r ia l . Lancet 1993;341(8856) :1293-1298.Jonat W, Kaufmann W, Sauerbre i R . e t .a l . Gosere l in versuscyclophosphamlde, methotrexate and fl uorouraci I as ad.iuvant therapyin premenopausal patients with node-posit ive breast cancer: TheZoladex Early.Breast Cancer Research Associat ion Study. . t Cl inOncol 2002; 20 "(24):a628-4635.-Jskesz R, Hausmaninger H, Kubista E, et.al. Randomized adjuvantt r ia l o f tamox i fen and gosere l in versus cyc lophosphamide,methotrexate and fluorouraci l: Ev idence for the s uperiori ty oftreatnrentwith endocrine blockade in premenopausal patients with lrorntoneresponsive breast cancer - Austr ian Breast and Colorectal CancerStudy Croup Trial 5. J Cl in Oncol 2002;20(24):4621-4627.Love RR, Ba Duc N, Al lred DC, et al. Oophorectomy and tamoxifenadjuvant therapy in premenopausal Vietnanrese and Chinese rvomenwit lr operable breast cancer. J Cl in Oncol 2002t 20( | 0): 2559-2566.Lo.ve RR, Ba Duc N, Cong Binh N, et al. Symptoms associated withoophorec tomy and tamox i f 'en t rea tment tb r b reas t cancer inpremenopausal Vietrramese women. Breast Cancer Research andTreatnrent I 999; 58: 281-286.Beith JM, et al. Myelotox icity from doxorubicin and cyclophospharn ideadjuvant chemotherapy in 138 Asian and Caucasian women. ASCOProceedi ngs 2002; 21 (Pt I ) ; 64a (abstract 252).B o n a d o n n a G , V a l a g u s s a P , M o l i t e r n i A . e t a l . A d . j u v a n tcyclophosphamide, methotrexate and f luorouraci l in node- posit ivebreast cancer: The results of20 years offol low-up. N EngJ Med I 99513 3 2 Q a ) : 9 0 1 - 9 0 6 .

l 0

t2.

13.

1 4

t 6

1 5 .

t 7 .

l 8

t 9

20.

2 1 .

1 A

25

t28 PJSS Vol.-61-. No. 3, July-September, 2006

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29.

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J l .

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34

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3 6

J t .

3 8 .

3 9

40

4 1 .

42

Coldhirsch A, Gelber R, Castigl ione-Certsch M. The magnitude ofendocrine effects ofadjuvant chemotherapy for premenopausal breastcancer patients: The lnternational Breast Cancer Study Group. AnnO n c o l 1 9 9 0 ; l : 1 8 3 - 1 8 8 .Bianco AR, Del Mastro L, Gallo C, et al. Prognostic role of amenorrhearnduced by adjuvant chemotherapy in prenrenopausal patients wit l tear ly b reas t cancer . Br J Cancer l99 l ; 63 : 799-803.Love RR. Ba Duc N, Van Dinh, et al. Young age as on adverseprognostic t 'actor in premenopausal women wit lr operable breastcancer. Cl inical Breast Cancer 2002; 2(4): 294-298.Adami HO, Malker B, Holmberg L, et al. The relat ion betweensurvival and age at diagnosis in breast cancer. N Engl J Med 1986;3 | 5 : 5 5 9 - 5 6 3 .Chung M. Chang HR, Bland KL, et al. Younger women with breastcarcinonta have a poorer prognosis than older wonlen' Cancer 1996;77 :97 - 103 .Kroman N, Jensen MB, Wohlfarht J, et al. Factors inf luencing the

effect of age on prognosis in breast cancer: Populat ion'based study'Br Med .l 2000: 320:47 4-47 LColleoni M. Rotmensz N, Robertson C, et al. Very young women (<3 5years) wrth operable breast cancer: Features ofdisease at presentation.

Ann Oncol 2002: 13:273-279.Dellapascua S, Colleoni M, Gelber RD, et al, Adjuvant endocrinetherapy for premenopausal women with early breast cancer. J Cl inOnco l 2005 123:1736-17 50 ,Early Breast Cancer Trial ists' Col laborative Group. Effects ofchenrotherapy and hormonal therapy for early breast cancer onrec urrence and I 5 -year survival: an overv iew ofthe randomized tr i als.Lancet 2005: 365:1 687 -17 17.Love RR, Ba Duc N, Havighurst TC, etal. HER-2/neu overexpressionand response to oophorectonly plt ls tamoxifen adjuvant therapy inestrogen receptor-posit ive premenopausal women with operable breastcerncer . . l C l in Onco l 20031 2 l (3 ) : 453-457.Pritchard Kl. Adjuvant endocrine therapies fbr pre-/perirnenopausalwomen. Breast 2005 ; I 4 :547 -554.

Love RR, Duc NB, Dinh NV, et al. Mastectomy and oophorectomy by

menstrual cyole phase in women with operable breast cancer. J NatlCancer Inst 2002, 94(9): 662-669.Holl i K, lsola J, Hakama M, et al. Prognostic effect of t iming ofoperation in relat ion to menstrual phase of breast cancer patient-fhct

o r fh l lacy . Br J Cancer 1995:7 l ( l ) :124-127:Saad Z. Bramwell V, DutTJ, et al. Tirning of surgery in rslat ion to thernenstrual cycle in premenopausal women with operable breast cancer.Br . l Strrg 1994 8l(2):21'1 -220.

Veronesi U, Luini A, Mariani L, et al. Etfect of menstrual phase on

surgical treatment of breast cancer. Lancet 1994;343(8912): I 545-t 5 4 7 .Badwe RA; Cregory WM, Chaudary MA. et al. Timing of surgery and

menstrual cycle and survival ofpremenopausal women with operablebreast cancer. Lancet 1991; 331(81 52):1261-1264.Chia SK, Speers CH, Bryce CJ, Hayes MM, Olivotto lA. Ten-yearoutcorres in a populat ion-based cohort of rrode-negative, lymphaticand vascular invaston-negative early breast cancers without adjuvantsys tenr ic therap ies . J C l in Onco l 2004:22(9) :1630-1637 'TaLrcher S , Rudas M, Mader RM, e t a l . Do we r reed HER-2/neu tes t ingfbr al l patients with primary breast carcinoma ? Cancer 2003;

98(12):2547 -2553 .Osborne CK, Kitten L, Arteaga CL. Antagonism of chemotherapy'induced cytotoxicity for human breast cancer cel ls by antiestrogens.. l C l in Onco l 1989; 7 : 710-71 '1 .

Albain K, Green S, Ravdin P. Adjuvant chemohormonal therapy fbrprimary breast cancer should be sequential instead of concurrent:ini t ial results from intergroup tr ial 0l 00 (SWOC-88 I 4). Proc Am SocClin Oncol 2002:21 (Abstract 143)' .37a.The ATAC (Arimidex, Tamoxifen Atone or in Combination) Trial ists'Croup. Anastrozole alone or in combination with tanroxit 'en versttstamoxifen alone for adjuvant treatment of postmenopausal tvonlenwith early-stage breast cancer. Results oft lre ATAC tr ial ett icacy andsafe ty update*ana lys is , Cancer 2003; 98(9) : | 802-1810.Goss PEl lng le . lN , Mar t ino S, e t a l . A randomized t r ia l o f Ie t rozo lc inpostrnenopausal wometr after five years of talnoxiitn therapy lilrearly-stage breast cancer. New Engl J Med 2003 349(19): I 793- I 802.Coombes RC, Hall E, Gibson LJ. A randomized tr ial of exemestaneafter two to three years of tamoxifen therapy in postmenopausalwomen wi th p r imary b reas t cancer . New Eng l . l Med 2004:3 5 0 ( l l ) : 1 0 8 1 - 1 0 9 2 .Wong ZW, El l is MJ. Neoad.iuvant endocrine therapy lbr brcast carrcer:an overloolted option? Orrcology 2004: l8(4):41 l-420Semiglazov V, Senriglazov VV, lvanov VG, et al Anastrozole (A) vs

tamoxifen (T) as neoadjuvant endocrine therapy of postnrenopatrsal

breast cancer patients. Proc Am Soc Cl in Oncol 2003 I 22:880 ( abstract3 53 8) .Semiglazov V, Semiglazov VV, Ivanov VC, et al. The relat ive et ' t icacyofneoadj uvant endocrine therapy vs chemotherapy in postnrenopausal

women wi th ER-pos i t i ve b reas tcancer ' J C l in Onco l 2004;22 (Ju ly l5

S u p p l ) : 5 1 9 .Ells MJ, Coop A, Singh B. Letrozole is more eftect ive neoad.iuvantendocrine therapy than tanroxit 'err fbr Erh-l- and/or Erb-2-posit ive'estrogen receptor-posit ive primary breast cancer: Evidence fron aPhase l l l randomized t r ia l . J C l in Onco l 2001; l9 (18) :3808 '3816.Dixon JM. Role of endocrine therapy in the neoad.luvant surgtcal

se t t ing . Ann Surg Onco l 2004; I l ( l Supp l ) : I 8S-23SWorld Health Organization. Syrnptont Relief in Terminal l l lness.Wor ld Hea l th Organ iza t ion , Geneva. 1998.WHO Exper t Contmi t tee . Cancer Pa in Re l ie f ' and Pa l l ia t i vc C 'a re .WHO Technical Report Series No. 804; World l{ealth Organization,Geneva 1990.C l in ica l Prac t ice Gu ide l ine Number 9 . Managenrent o { 'Cancer Pa in .Agerrcy for FJealth Care Policy and Researoh (AHCPR) Publication

No. 94-0592; U.S. Departmrnt of Hsalth and Hunran Services. 1994.

Buzdar AU, Jonat W, Howell A, et al. Anastrozole verstts nlegestrolacetate in the treatnent of postmenopausal wonren with advancedbreast carcihoma: results of a survival update based on a conrbined,analysis of data from two mature phase l l l tr ials. Arini idex SttrdyCroup. Cancer 1998; 83(6) : I 142-1 152.Bonneterre J, Thurl imann B, Robertson JFR, et al. Anastrozole versustamoxit 'en as f irst- l ine therapy fbr advanced breast cancer in 668postmenopausal women: Results of the tamoxit 'en or arinridexiandomized group eff icacy and tolerabi l i ty study . l Cl in Oncol 2000;

18(22):31 48-31 57 .Nabholtz JM, Buzdar A, Pol lak M, et al. Anastrozole is sLrperior t tr

tamoxifen as f irst- l ine therapy fbr advanced breast cancer t lr

postmenopausal women: Results of a North American Mult icenter

Randonrized Trial. J Cl in Oncol 2000: 18(22):3758-3767.Buzc la r A , Douma J , Dav idsor r N, e t a l . Phase l l l . mu l t i cen ter . dor rb lc -

bl ind, randomized study of letrozole. an aromatase inhibitor. fbr

advanced breast cancer versus nlegestrol acetate J Clin Oncol

2 0 0 I ; I 9 ( 1 4 ) : 3 3 s 7 - 3 3 6 6 .

Mouridsen H, Cersbanovich M, Sun Y, et al SLrperior etTicacy ol '

letrozole versus tamoxit 'en as f i tst- l ine therapy tbr postmenopausal

wonren with advanced breast cancer: Results ofa Phase I l l study ofthe

lnternational Letrozole Breast Catrcer Croup.. l Cl in Oncol 200 I,

t9(t0):2596-2606.

46 .

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48

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50

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69.

2005 Update. EBCPG on the Diagnosis and Management of Breast Cancer

Osborne CK, Pippen J, Jones SE, et al. Double-bl ind, randomized tr ialcomparing the eflicacy and tolerabil ity off'ulvestallt vesus anastrozolein postnenopausal women with advanced breast cancer progressing

on prior endocrine therapy: Results of a North American tr ial . J Cl inOnco l 2002; 20( I 6 ) : 3386-3395.Howell A. Robertson.lFR, Albano J, et al. Fulvestant, formerly ICII 82.780. is as effect ive as anastrozole in posttrrenopausal wotrren wit lradvancecl breast cancer progressing after prior endocrine treatment. JC l in Onco l 2001; 20(16) : 3396-3403,Kli . in JGM, Blarney RW, Boccardo F, et al. Cornbirred tamoxifen and

lutein izrng horntone-releasing hormone (LHRH) agon ist versus LHRHalone in premenopausal advanced breast cal lcer: A nreta-analysis offbur ra r rdomized t r ia ls . J C l in Onco l 2001; l9 (2 ) :343-353.Carrick S, Parker S, Wilcken N, et al. Single agent versus cornbinationchemotherapy for metastatic breast cancer. Cocltrane Database ofSystematic Reviews, 3, 2005.

129

Ghersi D, Wilcken N, Sinres .1, Donoghue E. Taxane con(arr lrngregimens for metastatic breast cancer. Coclrrane Database ofSystenratioR e v i e w s . 3 , 2 0 0 5 .McQuay HJ, Coll ins SL, Carrol l D, Moore RA. Radiotherapy tbt thepall iat ion of painful bone metastases. The Cochrane Database of

Systematic Reviews I 999, Issue 3. Art. No.: CD00 I 793. DOI: I 0. | 002/1 4 6 5 1 8 5 8 . C D 0 0 1 7 9 3 .Sze WM, Shelley M, Held I, Mason M. Pall iat ion of nretastat ic botrepain: Single fract ion versus nrult i fract ion radiotherapy. The CochtaneDatabase of Systenratic Reviews 2002, lssue l . Art. No. CD00472 I

DOI : I 0 . 1002/ l 465 I 858.Cd00472 lHi l lner BE, Ingle JN, Chlebowski RT, et al. Atrrerican Society ol '

Cl inical Oncology 2003 Update on the role of bisphosphonates and

bone health in women with breast cancer. J Cl in Oncol 20031

2l(21):4042-4057 .

6 5