UPDATE ARTICLE

Management Of Primary Breast Cancer

K L Cheung,* MBBS(HK), FRCSEd, FCSHK,Department of Surgery

The University of Hong Kong

Summary

The current management of primary breast cancer is based on a selective combination approach using surgery of lesser

extent, radiotherapy and systemic therapy. It aims at achieving excellent locoregional control and improved survival with

minimal morbidity. This article describes a rational approach to the management of primary operable breast cancer < 5 cm

in size. Its success is measured by the rates of locoregional recurrence and long-term survival, which would be separately

addressed. A brief discussion would also be made on the management of ductal carcinoma in situ and the follow-up policy

for women after treatment of the primary cancer. (HK Pract 1997; 19: 256-263)

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Introduction

The management of primarybreast cancer has evolved fromradical surgery introduced by WilliamStewart Halsted more than a centuryago1 to a selective combinationapproach using surgery of lesserextent, radiotherapy and systemictherapy. It aims at achievingexcellent locoregional control andimproved survival with minimalmorbidity. This article describes a

rational approach to the managementof pr imary operable breast cancer< 5 cm in size.

Local control - manage-ment of the breast

Surgery

Halsted's operation of radicalmastectomy is no longer popularsince modified radical mastectomy of

Patey where the pectoralis major ispreserved offers s i m i l a r localcontrol.2 The local recurrence rateof modified radical mastectomy issimilar to that of breast conservationwith wide local excision followed byintact breast irradiation.3 ,4 Recentlarge-scale randomised s tudies alsoconfirm no difference in survival.5

From the oncological point ofview, a cancer of s m a l l size e.g.< 3 cm (larger cancer may be suitableif the breast is of large size), and

* Address for correspondence: Dr K L Cheung, Department of Surgery, Tung Wah Hospital, 12 Po Yan Street, Hong Kong.

(Continued on page 258)

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the absence of multifocal disease ona mammogram are the two mostimportant preoperative criteria torecommend breast conservation as anoption of treatment. The location ofthe cancer and the size of the breastare certainly factors that could affectthe cosmetic outcome. Proximity ofthe cancer to the nipple-areolacomplex does not preclude breastconservation. Only 10% ofsubareolar cancers require excision ofthe nipple-areola complex to obtainadequate margin.6 After wide localexcision, the specimen is carefullyexamined. In case of involved orinadequate margin e.g. < 0.5 cm atone place, a re-excision should beconsidered though some would givean boost dose of irradiation to thearea concerned. On the other hand,if the margin is involved orinadequate in multiple areas, or ifthere is lymphovascular permeation,especially in younger women,conversion to mastectomy (necessaryin approximately 10% of cases)should be carried out owing to anunacceptably high chance of localrecurrence after breast conservationwhen these histological factors arepresent. Using such strict selectioncriteria, a 2.2% local recurrence ratein 3 years could be achieved.7

Women with cancer failing thesecriteria undergo mastectomy. Plasticreconstruction should be offered.Methods include simple implantinsertion, pedicled latissimus dorsiflap with an implant, pedicled orfree transverse rectus abdominismyocutaneous (TRAM) flap,depending on the condition of theskin, previous irradiation, presenceof scars in the donor area and veryimportantly the woman's choice.

Subcutaneous mastectomy, preservingthe nipple, with implant insertion isalso a simple and safe option sinceno significant difference in localrecurrence rates could bedemonstrated, provided that thenipple ducts are carefully examinedhistologically to ensure absence oftumour.8 Immediate reconstructionis favoured since it is associatedwith better psychological outcomebut no adverse effect on additionaltherapy.

Radiotherapy

The use of intact breastirradiation after conservative surgeryhas been addressed. On the otherhand, in the mastectomy group, therate of local recurrence, as definedby a histologically proven lesion inor deep to the mastectomy skinflaps, remained as high as 23% andmult iple risk factors of flaprecurrence have been identified viz.poor histological grade, positivenodal status and lymphovascularpermeation.9 Selective addition offlap irradiation when these factorsare present has dramatically reducedthe local recurrence rate to around5%.

Assessment of local control

The success of the managementof the breast is reflected by thelocal recurrence rate which should beless than 10% in 5 years.10 In factover 70% of flap recurrence developwithin the first 2 years." Most ofthem are manageable by simpleexcision with or withoutradiotherapy and systemic therapy.

Using strict selection criteria forbreast conservation and jud ic iousaddition of flap i r radiat ion aftermastectomy have virtually eliminateduncontrollable local recurrencecommonly seen in the old days.

Regional control - manage-ment of the axilla

The success of the managementof the axilla is reflected by the rateof regional recurrence, defined bylymph node recurrence in theipsilateral ax i l l a , as wel l as bytreatment related long-termmorbidity. Similarly, an acceptableregional recurrence rate is less than10% in 5 years.10 A watch pol icypreviously advocated leads to aregional recurrence rate of 20% andhas now been dropped by mostcentres. Axillary surgery is requiredto obtain adequate staging of thedisease since nodal status is animportant prognostic factor and 30%of cases with no cl inical ly palpablelymph nodes have h i s to log ica l lypositive nodes in the axilla. Theregional recurrence rate wou ld behigh if involved lymph nodes are nottreated, either by surgery orradiotherapy. However one has tofind a balance between regionalcontrol and morbidity due to axillarysurgery. The more extensive thesurgery is, the more accurate thestaging would be but the chance ofnerve injury and lymphoedema isalso higher.

The most popular way ofmanaging the axilla is ax i l l a rydissection which accurately stagesthe cancer and carries low morbidityin experienced hands. The other

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option is axillary lymph nodesampling followed by treatment ofthe axilla with either formaldissection or radiotherapy. Axillarysampling is completed by performingexcisional biopsy of lymph nodesin the axilla below theintercostobrachial nerve. At least 4lymph nodes subsequently provenby histology must be obtained togive a representative sample forstaging.10 Unfortunately the regionalrecurrence rate fol lowing thisapproach seems higher. There arecentres advocating axi l la ry lymphnode sampling for small invasivecancer as well as ductal carcinomain situ (DCIS). Furthermore acombination of axillary dissectionand radiotherapy is not advisableowing to high morbidity.

Management of internal mammarylymph nodes

Most centres do not recommendroutine biopsy or empirical treatmentof the internal mammary lymphnodes since only 10% of cancerwhich have positive internalmammary lymph nodes do not haveaxil lary lymph node involvement.And most of these cancers aremed ia l ly si tuated. In centrespractising axillary lymph nodesampling, there might be a place tocarry out internal mammary lymphnode biopsy for medial cancer toimprove staging.

Adjuvant systemic therapy

Fisher's theory emphasizes theimportance of micrometastases inbreast cancer, which in most of the

time, is a systemic disease from thevery beginning.12 Adjuvant systemictherapy improves the long-termsurvival with a 5-15% absolutereduction in 10-year mortality. It isindicated whenever the chance ofmicrometastases is high. Nodalstatus was previously used as thesingle most important indicator ofmicrometastases. However, survivalanalysis showed that women withsmall, node positive cancer couldhave long life expectancy whi le asignificant proportion of women withnode negative cancer died shortlyfrom carcinomatosis. To date themost impor tant independentprognostic indicators are nodal status(cancers with 4 nodes involvedbehave worse than those wi thless), histological grade and size ofthe cancer. The NottinghamPrognostic Index (NPI) is acombination of these factors: NPI =Size (cm) x 0.2 + histological grade( 1 - 3 = I- III) + nodal status (1= no nodes, 2 = 1-3 nodes, 3 =>4 nodes). The good (NPI <3.4),moderate and poor (NPI >5.4)prognostic groups have respectively29%, 54% and 17% of all women

with primary operable invas ivecancer and 80%, 42% and 13% 15-year survival (Table 1 and Figure1)." S ince a s u r v i v a l of 80% inthe first group is comparable to thatof age-matched women (83%),adjuvant systemic therapy is notindicated. All others requiresystemic therapy to attain s u r v i v a lbenefit.

Conventionally, premenopausalwomen receive chemotherapy wi thcyclophosphamide. methotrexate and5-f luorouraci l (CMF) w h i l epostmenopausal women havetamoxifen if the cancer is oestrogenreceptor (ER) positive or CMF if itis ER negative.14 However there isevidence that the efficacy of CMF,surgical oophorectomy, r ad ia t ionmenopause or LHRH agonist such asgoserelin in reducing the circulatingoestradial level is the same.15 Theirdifferences lie in the morb id i ty ,compliance, ease of application andcost of the therapy. Therefore,some centres employ methods otherthan CMF as adjuvant systemictherapy in premenopausal womenwith ER positive cancers. Addition

Table 1: Distribution of invasive primary breast cancer accordingto the Nottingham Prognostic Index (NPI) in screened(prevalent round) and unscreened population

NPI

<3.4

3.4 - 5,4

>5.4

Screened

n %

102 76%

27 20%

5 4%

Unscreened

n

470

879

280

29%

54%

17%

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Primary Breast Cancer

Figure 1: Patient survival according to the Nottingham PrognosticIndex (NPI)

NPI<3.4

20

O 24 48 72 96 120 144 168 192

Months

of an anthracycline to the CMFregimen may be considered forwomen wi th more aggressivecancers, such as those with morethan 10 lymph nodes involved, onlyafter serious discussion with thewoman concerned since its long-term benefit in th i s already poorprognostic group may be minimaland the morbidity is certainly higher.

There are controversies on thedurat ion of adjuvant therapy. Noadditional benefit has been shown ifchemotherapy is given for more than6 months. The most popularregimen therefore includes six 3-weekly cycles of CMF. On theother hand, in spite of the long-term r isk of endometr ia lhype rp l a s i a and carcinoma forwomen taking tamoxifen, tamoxifenis s t i l l recommended since itsbenef ic ia l effect on breast cancer

significantly outweighs its minimalrisk on the uterus. Furthermore,using high doses of tamoxifen doesnot offer extra advantage. Until ananswer comes out from ongoingrandomised trials, the usualtamoxifen regimen is 20 mg daily for5 years.

The management algorithmdescribed is summarised in Figure 2.

Management of ductalcarcinoma in situ

Mastectomy has been the goldstandard in the treatment of DCISwith minimal local recurrence rates.With efficacy of breast conservationclearly demonstrated in invasivebreast cancer, recently there areincreasing numbers of women

undergoing wide local exc i s ionfollowed by intact breast irradiationfor DCIS. The selection criteria ofsmall tumour without demonstrablemult i focal i ty , as we l l as adequatehis to logica l margins should befol lowed. In genera l , a x i l l a r ysurgery is avoided due to the lowincidence of nodal invo lvement .When the diagnosis of DCIS isuncertain preoperatively, it isp robab ly j u s t i f i e d to performaxillary surgery at the t ime ofmastectomy. On the contrary, ifthe cancer is s u i t a b l e for breastconservation, it would be morereasonable to wait for the histologyresul ts pr ior to c o n t e m p l a t i n gaxi l la ry surgery via a differenti n c i s i o n . Ad juvan t systemictherapy is not i n d i c a t e d s inceDCIS has an excel lent prognos isafter adequate initial treatment.

Follow-up

The main aim of follow-up ofwomen after treatment of pr imarybreast cancer is to detect andoffer treatment to l o c o r e g i o n a lrecurrence, as well as contralateralbreast cancer, s ince the r i sk ofhaving a new pr imary increases ata rate of 1% per year. The follow-up schedule , therefore , i n v o l v e sregular physical examination,general ly at 6-monthly i n t e r v a lfor 5 years since most locoregionalrecurrence would have developedwi th in this per iod, together withscreening mammogram for theopposite breast or both breas tsin case of breast conservat ion, atan interval of 1-2 years (Table 2).

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Table 2: Follow-up algorithm for primary breast cancer

Method

Physical examination

Mammogram

Metastatic screening

Interval

6-monthly for 5 years, then yearly

Yearly for intact breast after irradiation

1-2 years for contralateral breast

Not indicated if asymptomatic

Routine metastatic screening isnot cost-effective since it could onlydetect less than 12% of metastasesat the asymptomatic stage, dependingon the nature of tests performed.1 6

Furthermore, at the t ime ofmetastases, the median survival is 2years and the objective of treatmentis to pa l l ia te symptoms and tomaintain the highest possible qualityof l i fe .1 0 The va lue of offeringtherapy in the absence of symptomsis therefore doubtful.

Figure 2: Management algorithm for invasive primary breast cancer

All

Choice oftreatment

I

Wide localexcision*

Intact breast

irradiation

NPI < 3.4

NPI > 3.4

Clinical/Radiological size > 3 cm ormultifocal disease on mammogram

i

Mastectomy*

t

Failed histological criteria(inadequate margins, lymphovascular permeation)

Flap irradiation for high risk groups(high grade, positive nodes,lymphovascular permeation)

No adjuvant systemic therapy

Premenopausal: CMF

Postmenopausal:ER positive - tamoxifenER negative - CMF

* All have axillary dissection.NPI = Nottingham prognostic indexER = Oestrogen receptorCMF = Cyclophosphamide, methotrexate and 5-fluorouracil

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1. Primary breast cancer can be effectively treated with either mastectomy or breast conservation followed

by radiotherapy, the choice of which does not affect the survival.

2. Excellent locoregional control is obtained by using strict selection criteria for breast conservation and

judicious addition of flap irradiation after mastectomy, as well as by carrying out axillary dissection.

3. Women undergoing mastectomy should be offered the choice of breast reconstruction.

4. Adjuvant systemic therapy is indicated when the chance of micrometastases is high, as reflected by the

nodal status, histological grade and size of the primary tumour. Conventional therapy includes chemo-

therapy or tamoxifen depending on the menopausal and oestrogen receptor status.

5. After the initial treatment of the primary cancer, women should be followed up by regular physical ex-

amination and mammogram.

6. Screening of breast cancer by mammogram is proven to produce a significant survival benefit in women

above the age of 50.

Conclusion and futuredirection

With more precise patientselection and choice of treatment,locoregional recurrence rate hasmarkedly decreased andu n c o n t r o l l a b l e gross locoregionalrecurrence has essent ia l ly beenabolished. On the other hand, theoutcome of breast cancer treatmentin terms of survival still depends onthe stage of the disease at the timeof diagnosis . This is beau t i fu l lyreflected by applying the NPI -only one-fourth of women withsymptomatic primary breast cancerbelong to the good prognostic group

and have su rv iva l comparable tonormal women. With the advent ofbreast cancer screening, theproport ion of good prognost iccancers has dramatically increased:good, moderate and poor prognosticgroups having a d i s t r i b u t i o n ofrespect ively 76%, 20% and 4%(Table 1),17 not to m e n t i o n theincreased proportion of women withDCIS. Mammographic screening forwomen above the age of 50 has beenproven to produce a survival benefitapproaching 40%,18,19 a gain whichis far better than that achieved byany regimen of adjuvant systemictherapy for cancers that arediagnosed at a late stage. The

feasibility of extending the benefit ofscreening to younger and other high-risk women should be explored.

Other ongoing t r i a l s i n c l u d estudies to optimize treatment forsmall invasive cancer or DC1S. Canradiotherapy and/or a x i l l a r y surgerybe safely avo ided ? No loca lrecurrence was seen in 42 monthsafter t rea tment of DCIS by widelocal excision alone.20 Early resultsof p r imary systemic therapy areencouraging in increasing the rates ofbreast conservat ion 2 1 but whe the rsuch therapy w i l l have long-termsurv iva l benefi t needs to beelucidated. High-dose chemotherapy

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with stem cell support usingautologous bone marrow transplanthas been proposed as adjuvanttherapy for women with veryaggressive cancers. However this isan expensive treatment with definitemorbidity but unproven long-termbenefit. The results of randomisedcontrol trials must be awaited beforerecommending it as a conventionalmodality.22 •

References

1. Halsted WS. Operat ions for ca rc inomaof the breast . J Hopkins Hosp Rep1890-1; 2: 277-280.

2. Patey DH. Dyson WH. The prognos isof carc inoma of the breast in r e l a t i o nto the type of operat ions performed.Br J Cancer 1948; 2; 7-10.

3. Fisher B, Bauer M, Margolese R et al.Five-year results of a randomizedcl inical t r i a l compar ing totalmastectomy and segmcntalmastectomy w i t h or wi thou t r ad i a t i onin the t rea tment of breast cancer . NEngl J Med 1985; 312: 665-673.

4. Fisher B, Redmond C, Poisson R et al.Eight-year results of a randomizedclinical t r i a l comparing totalmastectomy and segmentalmastectomy w i t h or without r ad ia t ionin the treatment of breast cancer. NEngl J Med 1989; 320: 822-828.

5. Veronesi U, Salvadori B, Luini A et al.Breast conse rva t ion is a safe method inpat ients wi th smal l cancer of the breastLong-term results of three randomizedtr ia ls on 1,973 pat ients . Eur J Cancer1995. 3 1 A : 1574-1579.

6. Haffty BG, Wi lson LU, Smith R et al.Subareolar breast cancer : long- te rmresults in conservat ive surgery andr a d i a t i o n therapy. Int J Radiat OncolBiol Phys 1995; 33: 53-57.

7. Sibber ing DM, Galea MH, MorganDAI, et al. Safe selection cr i ter ia forbreast conservation wi thout r ad i ca le x c i s i o n in pr imary operable invasivebreast cancer. Eur j Cancer 1996.

8. C h e u n g KL, Blamey RW, RobertsonJFR et al. Subcu taneous mastectomyfor p r imary breast cancer or d u c t a lcarcinoma i n - s i t u . Eur J Surg Oncol( In press).

9. O' Rourke S, Galea MH, Morgan D etal. Local r e c u r r e n c e after s implemastectomy. Br J Surg 1994; 81: 386-389 .

10. Br i t i sh Surgeons Group of the Br i t i shAssociat ion of Surgical Oncology.G u i d e l i n e s for surgeons in themanagement of symptomatic breastdisease in the Uni ted Kingdom. Eur JSurg Oncol 1995; 21A.

1 1 . Weichse ibaum R, Merck A, Hel lman S.The role of postoperat ive i r r ad ia t ion incarcinoma of the breast. Cancer 1976;37: 2682-2690.

12. Fisher B. The evo lu t ion of paradigmsfor the management of breast cancer.A personal perspect ive. Cancer Res1992; 52: 2371-2383.

1 3 . Galea MH, Blarney RW, Elston CW etal. The Nottingham Prognostic Index

in p r imary breast cancer . BreastCancer Res Treat 1992; 22: 207 -219

I 4 . NIH Consensus S t a t e m e n t . Na t iona lIns t i t u t e s of H e a l t h C o n s e n s u sDevelopment Confe rence S t a t e m e n t :Treatment of ea r ly stage b r e a s tcancer . Bethesda MD: NIH 1990; J u n e1 8 - 2 1 .

15 W i l l i a m s MR, Walker KJ. T u r k e s A etal. The use of an LHRH a g o n i s t ( I C I118630, Z o l a d e x ) in advancedpremenopausa l breast cancer . Br JCancer 1986; 53: 629-636.

16. Lopr inz i CL. I t is now the age to def inethe appropr ia te f o l l o w - u p of p r i m a r ybreast cancer pa t i en t s J Cl Oncol1994: 12: 881-883.

17. E l l i s IO. Galea MH. L o c k e r A et al.E a r l y exper ience in breast cance rscreening: emphas i s on d e v e l o p m e n t ofprotocols for t r i p l e a s se s smen t . Breast1993; 2: 148-153.

18. Shapi ro S Evidence on sc reen ing forbreast cance r from a r a n d o m i z e d t r i a l .Cancer 1977; 39: 2772-2782.

19. Depa r tmen t of Hea l th & Soc ia lSecu r i t y . Breast cancer screening( C h a i r m a n : S i r Pa t r i ck For res t ) .London: HMSO, 1986.

20. S ibber ing DM, Obuszko 7. E l l i s 10 et al.Radio the rapy may be unneces sa ry afteradequate local exc i s ion of duc t a lcarc inoma in s i t u [Abstract ] . Breast1995; 4: 244,

21. Powles TJ, H i c k i s h TF, Makr i s A et al.Randomized t r ia l of c h e m o e n d o c r i n ethe rapy started before or af tersurgery for t r e a t m e n t of p r i m a r ybreas t cancer. J Clin Oncol 1995; 135 4 7 - 5 5 2 .

22. Baum M. New approach to breastcancer cure . Times 1995: 28 March .

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