OVERVIEW

Recent developments in breast-conserving surgery for breastcancer patients

F. Fitzal & O. Riedl & R. Jakesz

Received: 28 July 2008 /Accepted: 7 August 2008 /Published online: 10 September 2008# Springer-Verlag 2008

Abstract This invited review deals with the latest knowl-edge regarding breast conserving therapy in breast conserv-ing patients.

Keywords Breast conservation . Oncoplastic .

Resection margin . Perioperative management .

Breast surgery

Introduction

Local therapy for breast cancer is experiencing a renais-sance since the publication of a meta-analysis by the EarlyBreast Cancer Trialists’ Collaborative Group (EBCTCG)demonstrating that an absolute reduction of 5-year localrecurrence-free survival by 15% results in an absoluteimprovement in overall survival of 5% at 15 years [1, 2].This has been confirmed by other researchers [3]. In thisregard, surgery for breast cancer regains importance asit reduces the rate of local recurrence-free survival andsubsequently increases overall survival.

Breast-conserving therapy (BCT) developed over thepast 40 years [4]. The breakthrough publications were twoprospective randomized trials by Veronesi and Fisher [5, 6]showing that resection of the primary cancer with micro-scopically free margins yields 20-year disease-free andoverall survival outcomes similar to mastectomy. Severalother prospective studies confirmed these findings [7–10].Since that time, only minor improvements have been made,

and few novelties have emerged due to the lack ofprospective randomized trials and little financial supportfor surgical trials worldwide. Moreover, major internationalconferences rarely deal with surgical issues [11]. Thisreview explores surgical considerations for local control andsuggests new areas of research.

General considerations for local control

Studies revealed several prognostic factors for local recur-rence. In multivariate analyses margin status, age, lymphnode status, lymphovascular invasion, the omission ofradiotherapy, and extensive intraductal components (EIC=>25% DCIS from invasive component) independentlypredicted local recurrence [12–18], while tumor sizeapparently has no direct impact on local control [9, 19, 20].

Resection margins

There is still a dispute about the definition of negative andclose margins. While European physicians require largerdistances from cancer cells to the margin for a negativemargin, Americans are satisfied with at least 1 mm of freemargin [21]. However, most authors define a positive marginas less than 1 mm and a close margin as less than 2 mm ofnormal breast tissue between the resection margin and thenext cancer cell [22–24]. Recently, authors demonstrated thata negative resection margin below 3 mm is no guaranteefor the absence of cancer cells in the breast [17]. This issupported by the recent meta-analyses showing that radio-therapy improves local recurrence-free and overall survivalafter R0 resection [1].

Three prospective trials comparing BCT with mastecto-my from Milan [6], the National Cancer Institute (NCI) [8],

Langenbecks Arch Surg (2009) 394:591–609DOI 10.1007/s00423-008-0412-5

F. Fitzal :O. Riedl : R. Jakesz (*)Department of Surgery, Medical University Vienna,Vienna, Austriae-mail: raimund.jakesz@meduniwien.ac.at

and the European Organisation for Research and Treatmentof Cancer (EORTC) [9] showed that local recurrence-freesurvival was significantly worse after BCT. However, allthree trials included patients with cancer cells at the re-section margin. The other prospective trials did not find anysignificant difference in local recurrence-free survivalbetween BCT and mastectomy and included patients withresection-free margins only [5, 7, 10]. Veronesi demon-strated that positive resection margins increase local recur-rence rates significantly from 2% to 7% [25, 26].

Several retrospective analyses show that a resection-freemargin is arbitrative for any kind of BCT [24]. Horst et al.showed in their review that positive and close margins areassociated with increased local recurrence risk after BCT[24]. The authors of that report describe the results of 22studies with local recurrence data related to resectionmargin [22, 23, 27–46]. Positive margins increased the 5-to 10-year local recurrence rate significantly two to fivetimes with annual recurrence rates between 2% and 3%compared with annual recurrence rates of 0.2 to 0.4 inpatients with resection-free margins [44] (Table 1).

Resection-free margin, however, was not the only inde-pendent predictor of local recurrence. Authors also evaluatedthe size or number, respectively, of involved margins asrecurrence predictor. DiBiase et al. [33] reported the outcomeof 453 patients with a follow-up of 45 months. More thanone positive margin increased the 10-year local recurrencerate from 26% to 37%. Darvishian retrospectively analyzed50 patients and showed that extensive positive margins(more than 1 cm positive margins) significantly increased therisk for residual disease [47].

Multivariate analyses in these studies including age,tumor size, grading, and other prognostic factors for localrecurrence revealed that margin status was the single mostimportant factor for local recurrence rate. Thus, a resection-free margin of at least 1 mm distance between the lastcancer cell and the resection margin should be a standard inBCT, resulting in an annual local recurrence rate of 0.2%to 0.4% [44]. In the case of positive or close resectionmargins, systemic therapy may only delay local recurrence[23].

Radiotherapy

Several prospective trials clearly demonstrated that BCTwithout radiotherapy significantly increases the local re-currence rate [5, 48, 49]. Additionally, recent data alsosuggest that this increase in local recurrence rate reducesoverall and breast cancer-related survival significantly[1–3]. Thus, adjuvant radiotherapy is a standard procedurefor all patients after BCT. However, there is still thequestion whether radiotherapy may be omitted in somepatients with low-risk disease.

In 2004, the New England Journal of Medicinepublished two relevant prospective trials. Fyles et al.reported about patients 50 years or older under tamoxifenafter BCT with or without radiotherapy [50]. The localrecurrence rate increased from 0.6% to 7%, correspondingto a reduced 5-year survival of 91% compared with 84%.Hughes et al. compared radiotherapy with no radiotherapyin patients 70 years or older after BCT [51]. Radiotherapyimproved local recurrence rate significantly from 1% to4%. Patients with early breast cancer under 74 years of agewere randomly assigned to receive either radiotherapy ornot [52]. Similarly, this randomized trial demonstratedsignificantly improved local recurrence-free survival from4% to 14% with adjuvant radiotherapy. Local recurrencewas 23% after a median follow-up of 86 months, even invery low-risk patients (stage I) with resection-free marginsof at least 1 cm without extensive intraductal component(EIC) or nodal involvement [53]. The Austrian Breast andColorectal Cancer Study group (ABCSG) presented twoprospective trials at the San Antonio Breast CancerConference in 2005 [54]. Tumor size below 3 cm, postmen-opausal status, and lymph node-negative breast cancer wereinclusion criteria. Their data demonstrate that radiotherapysignificantly reduced local recurrence-free survival from3.19% to 0.24% (p=0.0008).

These data demonstrate that even in low-risk patientswith resection-free margins of more than 1 cm, radiotherapyis effective in improving??? local recurrence-free survival.However, if one looks behind the curtain, recurrence ratesbetween 3% and 7% in patients without radiotherapy are stillexcellent. Thus, these trials also demonstrate that omittingradiotherapy in highly selected patients may yield satisfac-tory local recurrence rates.

Age/menopausal status

Age has been demonstrated to be a predominant risk factorfor local recurrence [13, 16, 55, 56]. Several authorsshowed an increase in local recurrence rate with ageyounger than 45, 40, or 35; however, there is no clearcutoff [28, 32, 36, 37, 40, 43, 49] (Table 2). Aftermultivariate correction with other factors such as marginstatus, age remained a significant prognostic factor for localrecurrence development. This may be due to an increasedrate of EIC or other aggressive tumor biological character-istics in young patients, resulting in increased risk ofpositive resection margins [13, 16, 55, 56].

Others indicate that the increased risk of local recurrenceis not associated with age but rather with menopausal status[38, 57] and found no difference in known prognosticfactors between younger and older patients despite the factthat survival was poorer in younger patients. As chemo-oophorectomy compared with chemotherapy reduces risk

592 Langenbecks Arch Surg (2009) 394:591–609

for local recurrence by 50%, circulating estrogens may beadversely related to local relapse in young patientssupporting the menopause hypothesis [58].

Although retrospective analyses showed an increasedrisk of local relapse, the data are inconclusive. Prospectivestudies comparing BCT with mastectomy did find anincreased risk for local recurrence in younger patients afterBCT but not after mastectomy [6, 9, 59]. Keeping in mindthat younger patients bare an increased risk of having EICand resection-free margins were not required in these two

prospective studies, the increased local failure rate mayactually be based on increased rates of positive resectionmargins in younger women. However, age below 35 wasseen to be a risk factor for local recurrence in otherprospective trials including only patients with resection-freemargins [60, 61]. In contrast to these studies, the EORTCstudy by van Dongen showed no increase for localrecurrence in younger patients after BCT [9]. Theincreased risk for local recurrence in younger women didnot yield an increased risk of death, as shown in a

Table 1 Retrospective trials analyzing the local recurrence risk (LRR) comparing positive (<1 mm) versus negative (>1 mm) resection margins

Author Institute City Pub

date

Journal Period Number (n) LRR in % Median p

Positive

margin

Negative

margin

Follow-up

(years)

Smitt Stanford University

Medical C

Stanford 2003 Int J Radiat Oncol

Biol Phys

1972–1996 535 18 3 6 0.0001

Park Dana-Farber Cancer

Institute

Boston 2000 J Clin Oncol 1968–1987 533 27 7 8 0.007

Peterson University of

Pennsylvania

Philadelphia 1999 Int J Radiat Oncol

Biol Phys

642 10 8 8 0.2

Freedman Fox Chase Cancer

Center

Philadelphia 1999 Int J Radiat Oncol

Biol Phys

1979–1992 1262 12 7 10 0.04

DiBaise Thomas Jefferson

University

Philadelphia 1998 Cancer 1978–1994 453 31 13 10 0.047

Wazer New England Medical

Center

Boston 1998 Int J Radiat Oncol

Biol Phys

1982–1994 509 17 6 10 0.01

Kini William Beaumont

Hospital

Royal Oak 1998 Cancer 1980–1987 400 17 6 10 0.018

Pierce University of Michigan Ann Arbor 1997 Int J Radiat Oncol

Phys

1984–1995 429 10 3 5 0.04

Gage Harvard, Medical School Boston 1996 Cancer 1976–1986 343 16 2 5 <0.05

Heimann University of Chicago Chicago 1996 Cancer 1984–1994 852 11 2 5 0.01

Burke Queensland Radium

Institute

Brisbane 1995 Int J Radiat Oncol

Biol Phys

1982–1989 512 15 2 5 0.01

Laborgne Hospital Pereira Rossell Montevidoe 1995 Int J Radiat Oncol

Phys

1973–1990 796 9 6 9 <0.05

Veronesi European Institute of

Oncology

Milan 1995 Eur J Cancer 1973–1989 1973 17 9 5–7 <0.05

Dewar Gustav Roussy Paris 1995 Cancer 1970–1982 757 14 6 9 0.02

Mansfield Thomas Jefferson

University

Philadelphia 1995 Cancer 1982–1994 263 20 5 10 0.03

Smitt Stanford University

Medical C

Stanford 1995 Cancer 1972–1992 289 9 2 5 0.0001

Borger Netherland Cancer

Institute

Amsterdam 1994 J Clin Oncol 1979–1988 723 16 2 5 <0.05

Slotman Free University Hospital Amsterdam 1994 Radiother Oncol 1980–1998 508 10 3 5 <0.05

VanDongen Netherland Cancer

Institute

Amsterdam 1992 Eur J Cancer 1980–1986 902 20 9 8 <0.05

Basterlink Netherlands Cancer

Institute

Amsterdam 1988 Radiother Oncol 1979–1984 585 7 2 6 <0.05

Clarke Gustav Roussy Paris 1985 Int J Radiat Oncol

Biol Phys

1970–1981 436 9 4 5 <0.05

Patients with positive resection margins have an increased risk of local recurrence rate.

Langenbecks Arch Surg (2009) 394:591–609 593

retrospective analysis of 9,000 women with 700 patients<45 years. The increase in local recurrence rate was similarfor invasive and intraductal carcinoma [62, 63]. A recentanalysis of women younger than 50 years comparing BCTwith mastectomy showed no significant difference in local,distant recurrence, and overall survival for this selectedgroup [64].

To prevent the increased risk for local failure after BCT inyounger women, a resection-free margin of at least 2 mmshould be warranted as in this population the increased riskfor local recurrence was not statistically significantly differentcompared with older patients [65]. Also, a boost dose ofradiation and tamoxifen in women with ductal carcinoma insitu (DCIS) reduces the risk, indicating that mastectomy isnot necessary if adjuvant treatment is appropriate.

Size

Concerning size, the six prospective studies comparingBCT with mastectomy included patients with tumordiameters of up to 5 cm [5–10]. Retrospective analysesindicated that tumor diameter is no predictive factor forlocal recurrence-free survival [28] [22, 35, 37, 40, 43,66]. Thus, tumor size up to 5 cm may be treated withBCT.

Only two retrospective analyses showed that even inpatients with tumor diameter above 5 cm, BCT may beoncologically feasible if cosmetic outcome is satisfactory(depending on breast/tumor size relation) [19, 20]. Howev-er, resection-free margins and adjuvant radiotherapy shouldbe provided. The introduction of neoadjuvant systemictherapy and the increased early detection rate reduced thenumber of T3 cancers; thus, only a minority of patients willhave to face this issue. Prospective studies will not beperformed due to ethical reasons.

General considerations for perioperative management

Intraoperative frozen section analyses

Frozen section analysis (FSA) guides the surgeon duringBCT to perform primary tumor resection with clear marginsand yields an accuracy of 97% [67, 68]. Furthermore, “corecut” FSA results may inform the surgeon immediatelyabout the necessity to perform surgical axillary lymph nodedissection in cases of an intraoperatively diagnosed inva-sive breast cancer. Subsequently, a second operation (two-stage procedure) may be avoided in a considerable numberof patients [69, 70]. The false-negative rate and the numberof two-stage procedures, respectively, have been reported torange between 0% and 19% after FSA [67, 68, 70–72].Without the use of FSA, a two-stage procedure may becomeT

able

2The

localrecurrence

rate

(LRR)in

patientscomparing

youn

gwith

olderageshow

ingasign

ificantly

increasedLRRforyo

ungerpatients

Autho

rInstitu

teCity

Pub

date

Journal

Years

Num

bers

(n)

LRRin

%Age

(cutoff;years)

Median

pValue

You

ngage

Older

age

Follow-up(years)

Kini

William

Beaum

ontHospital

Roy

alOak

1998

Cancer

1980

–198

740

025

735

100.00

4Pierce

University

ofMichigan

Ann

Arbor

1997

IntJRadiatOncol

BiolPhy

s19

84–199

542

915

435

50.00

01

Veron

esi

Europ

eanInstitu

teof

Oncolog

yMilan

1995

Eur

JCancer

1973

–198

919

736

155

5–7

<0.05

Dew

arGustavRou

ssy

Paris

1995

Cancer

1970

–198

275

714

740

90.02

Leborgn

eHospitalPereira

Rossell

Mon

tevido

e19

95IntJRadiatOncol

BiolPhy

s19

73–199

079

636

2340

100.00

01

Borger

NetherlandCancerInst

Amsterdam

1994

JClin

Oncol

1979

–198

872

38

640

5<0.05

594 Langenbecks Arch Surg (2009) 394:591–609

necessary in up to 38% to 54% of patients undergoing simplelumpectomy [73, 74]. Multiple re-excisions during BCT donot increase the local recurrence rate [75].

While the accuracy, sensitivity, and specificity rates arebetween 95% and 99% [67, 69, 76], several authors raisedconcerns regarding the use of FSA for nonpalpable lesions,tumors below 1 cm in diameter, and pure microcalcifications[68, 71, 77–81]. As a consequence, physicians have beenconcerned about reduced diagnostic accuracy particularlyin such lesions. In addition, pathologists have reported onfreezing artifacts, which may cause difficulties in determin-ing both final tumor staging and the smallest free resectionmargin, thus interfering with tailoring adequate adjuvanttherapy and deteriorating oncological outcome. Other argu-ments like economic and logistic considerations have alsobeen addressed. Thus, several breast cancer units have beenshifting their policy not to apply FSA on a routine basis [71].

Intraoperative FSA of breast specimens reduces the needfor secondary surgery in 20% to 40% [69, 70, 82–85] andrapidly achieves optimal oncologic results with clear margins[86]. These results suggest a reduction of two-stage pro-cedures by the use of FSA comparing with reports on BCTwithout the use of FSA [73, 74].

Unpublished data of a retrospective analysis at ourinstitution regarding the use of FSA demonstrated, in amultivariate model, that the use of neoadjuvant therapy, theabsence of preoperative sure cut biopsy, and the necessityof preoperative stereotactic-guided breast biopsy reducedthe accuracy of intraoperative FSA. However, small tumorsize or low-grade differentiation were not independentvariants for a false-negative FSA. The use of FSA resultedin a two-stage operation in only 9% of all patients (submittedto Eur J Surg Oncol 2008).

Biopsy

Diagnostic breast biopsy is indicated in BIRADS IV lesionsand helps the surgeon to plan the operation in BIRADS Vlesions [87]. The concern about needle track seeding duringcore needle biopsy of breast cancer is not completely un-founded. In the literature, several case reports demonstratedneedle track seeding after core biopsy [88–92]. Histologicalproof has been reported recently of tumor cell displacementwithin the needle track after fine needle biopsy in sixpatients [88].

Available data demonstrate that the local recurrencerate in patients with preoperative fine needle biopsy orcore biopsy is between 2% and 6% [93–96] with amedian follow-up of 5 years. This recurrence rate issimilar to that reported in many clinical studies for breastcancer patients without preoperative core needle biopsy.Chen et al. [93] showed no difference in the rates of localrecurrence-free survival between breast cancer patients

with or without preoperative core biopsy. Another studywith 398 patients supported this hypothesis [94]. In aretrospective analysis at our institution, the use ofpreoperative core needle biopsy did not increase the localrecurrence rate [97]. Thus, displaced tumor cells seem toplay no critical role for local recurrence after BCT andadjuvant radiotherapy.

Neoadjuvant therapy

The use of neoadjuvant therapy has been introduced asstandard treatment for locally advanced breast cancerpatients since prospective trials demonstrated that breastconservation rates were increased with this treatment optionwhile having similar overall survival rates when comparedwith adjuvant treatment [98–101].

However, some prospective and retrospective datasuggest that patients with BCT after neoadjuvant therapymay have an increased risk for the development of a localrecurrence [102]. Van der Hage [103] demonstrated thatBCT after neoadjuvant therapy for patients primarilyplanned for mastectomy significantly deteriorated overallsurvival. Thus, there is evidence that resection margins afterneoadjuvant therapy should be the same as before therapy.If this were true, there would be no further advantage ofneoadjuvant therapy, and this treatment option could bequestioned at all. Recent meta-analyses support these data[104].

The reason for an increased local recurrence rate may bethe possibility of leaving some cancer cells in the breastafter BCT due to a scattering rather than a concentricshrinkage of the primary cancer after neoadjuvant therapy.Singletary et al. demonstrated that there are several risk factorsfor the existence of scattered residual cancer cells afterneoadjuvant therapy such as skin edema, persistent tumorsize >4 cm, and intramammary lymphatic invasion [105].

Looking closer at the meta-analyses of nine prospectivetrials suggesting that BCT is related to an increase in localrecurrence rate after neoadjuvant therapy, [104] it becomesevident that several trials included patients with resection-positive margins after BCT or even without any surgeryafter neoadjuvant treatment [104]. Excluding these patients,loco-regional recurrence is similar between BCT with andwithout neoadjuvant therapy.

Fisher demonstrated that the local recurrence rate afterneoadjuvant therapy followed by BCT did not differ signif-icantly compared with the local recurrence rate of patientsafter BCTand adjuvant chemotherapy (10% versus 7% after amedian follow-up of 9.5 years) [106]. However, for patientsinitially considered for mastectomy and treated with BCTafter neoadjuvant therapy, the local recurrence rate wassignificantly increased compared with those who wereinitially candidates for BCT (15.9% versus 9.9% p=0.04).

Langenbecks Arch Surg (2009) 394:591–609 595

This compares well with the data by van der Hage mentionedabove [103]. However, the worse outcome may be attributedto a difference in tumor stage between the two groups andmay thus, in fact, reflect worse tumor biology in the groupwith initially planned mastectomy [107]. In a retrospectiveanalysis from Milan in 195 patients treated with BCT afterneoadjuvant therapy, the local recurrence rate was 6% after amedian follow-up of 41 months which is similar to the rateseen in patients without neoadjuvant therapy and BCT [108].

Predictors for local failure after neoadjuvant therapyinclude lymph node status, lymphovascular invasion,multifocal pattern of disease, and residual disease largerthan 2 cm after therapy [109]. None or two of these factorswere associated with 3% to 12% of 5-year local recurrencerate, whereas the presence of three factors was associatedwith an 18% local recurrence rate at 5 years. Initial tumorsize did not correlate with local recurrence rate. However,clinical response did. In this regard, BCT is indicated afterneoadjuvant therapy after careful selection. Risk factors andresponse to therapy by magnetic resonance imaging (MRI)should be evaluated before surgery. Better MRI techniquesshould be evaluated to assess whether the cancer decreasedconcentrically or in a scattered pattern.

Future directions for breast surgery

The biology of local recurrence

Fowble et al. reported on 1,030 patients operated between1978 and 1986 with a local recurrence rate of 6% at10 years. Fifty percent of the recurrences were detected byclinical examination, 30% by mammography alone, and20% by both. Fifteen percent were synchronously metasta-sized. The median recurrence-free interval was 34 months.Sixty-five percent were within the former tumor bed. Themedian survival for recurrent patients was 33 months,reflecting an increased risk of distant metastases [110].These patterns changed only marginally [111].

In general, local recurrences after BCT have favorableoutcomes compared with local recurrences after mastecto-my [112]. The median time to local recurrence ranges from30 to 70 months. Recent data suggest that there are differentbiological types of local recurrence. This topic is so farmarginally explored and hypothetical. However, some dataindicate that there seems to be a true recurrence (TR)compared with a new primary cancer (NP).

Authors differentiate between TR and NP by locationand tumor biology. Komoike et al. showed that TR had34% positive lymph nodes and a median disease-free survivalof 46 months, while NP had 8% positive lymph nodes and amedian survival of 62 months. Risk factors for TR and NPwere similar and included age, positive resection margins,

omission of radiotherapy, and lymph node positivity; howev-er, the 5-year survival rate differed significantly (TR=71%versus NP=94%) [113]. Smith included flow cytometrychanges to distinguish between TR and NP [114] andreported on 136 local recurrences. Sixty percent had NPwith a significantly longer period to breast relapse from thefirst BCT (3.7 versus 7.3 years) and were significantlyyounger than patients with TR. During the first 8 years afterBCT, similar frequency of NP and TR were observed, whilethereafter, the rate of NP increased to 13% compared with6% of TR. Ten-year overall survival differed significantlybetween NP and TR (75% versus 55%). Similarly, out of 126recurrences, Huang et al. demonstrated that time to recur-rence differed between TR (5 years) and NP (7 years) withan improved 10-year survival rate for the NP compared withTR (77% versus 46%). Salvage treatment resulted in betterlocal control for NP than for TR (2% versus 18%). In thisregard, earlier publications already showed that time to localrecurrence is one of the most important prognostic factors forfurther oncologic outcome [18, 113–118].

In conclusion TR defined as “in-bed” recurrencesindicate a worse prognosis or poor surgery, yielding a highdistant recurrence rate and worse prognosis compared withNP which are defined as breast recurrence outside the formertumor bed. NP show an improved overall survival ratecompared with TR. However, to date, standard treatmentdoes not differ between NP and TR. In this regard, furtherstudies are warranted.

Salvage surgery after local recurrence

Salvage surgery for local relapse after primary BCT ormastectomy in patients with comparable breast cancerbiology yields similar overall survival curves [43]. Thequestion is whether these patients may undergo a secondBCT. There are only a few retrospective studies regardingtherapy of local recurrence. Current standard treatment oflocal breast recurrence after BCT and adjuvant radiotherapyis mastectomy. Local control at 5 years may be achieved in70% to 95% of patients after salvage mastectomy [110,119, 120]. However, a second BCT attempt may be possiblein several patients from a surgical standpoint.

Kurtz et al. published their data about BCT after localrecurrence as early as 1988 [121]. Out of 118 patients withlocal recurrence after BCT, 52 were treated with an additionalwide resection. After a median follow-up of 6 years, the 5-year local recurrence rate was 21% with a cancer-specificsurvival percentage of 79% at 5 years. Cox regressionanalyses demonstrated that margin status and disease-freeinterval influenced local control after local recurrence [18].Komoike identified a second local recurrence after salvageBCT in 30%. Overall and disease-free survival did not differbetween salvage mastectomy and BCT comparing 41 patients

596 Langenbecks Arch Surg (2009) 394:591–609

[122]. Young age below 35 years was an independentprognostic factor for a second local relapse. Salvadoricompared 134 patients with salvage mastectomy with 57patients after a second wide resection for ipsilateral breasttumor recurrence following primary BCT and radiotherapy[123]. Similarly, there was no difference between the twogroups as to disease-free survival; however, the second localrecurrence rate at 5 years was higher in patients after salvageBCT (19% versus 4%). After a median follow-up of 13 yearsAlpert et al. compared salvage BCT with mastectomy in 146patients. Ten-year overall (58% versus 65%), distant (24%versus 32%), and local disease-free survival (6% versus 6%)did not differ between the two groups. However, in bothgroups, there were several patients with positive resectionmargins, and mastectomized patients had significantly worseprognostic factors making interpretation difficult.

To improve oncologic outcome after salvage BCT, asecond period of radiotherapy may be applied. However,only a few studies investigate repeated irradiation aftersalvage BCT. Resch et al. reported on 17 patients treatedwith pulse dose rate brachytherapy after lumpectomy oflocal recurrence [124]. Twenty-three percent had a secondlocal recurrence treated with mastectomy and only moderategrade 1–2 side effects were reported. Deutsch et al.retrospectively examined 39 patients after BCT and repeatedradiotherapy for treatment of local recurrence [125]. Inanalogy, 23% had a secondary local recurrence. Side effectsand cosmetic outcome were only marginally assessed.Recently, Wahl et al. reported on 5% 3–4 toxicity sideeffects in repeat irradiation patients after surgical therapy forlocal recurrence [126]. Galper et al. demonstrated thatmastectomy is superior to BCT and radiotherapy regardingdistant metastases, second non-breast malignancy and death[127]. In turn, Komoike et al. recently showed no differencein overall survival between BCT and mastectomy with alocal recurrence rate of 20% after repeated BCT [113].

The use of BCT with repeated radiotherapy has beenreported by Voogd et al. Of 360 local-recurrent breast cancerpatients, 36% had synchronous distant disease. The remaining266 had a 10-year overall survival rate of 39% and a distantdisease-free survival rate of 36% with a local control rate of68%. Significant prognostic factors in multivariate analysesfor overall survival after local recurrence were tumor size ofthe recurrence, lymph node status of the primary tumor, modeof recurrence detection, and vascular invasion [111]. Thissuggests that the addition of radiotherapy is feasible but doesnot improve overall survival. Early detection of localrecurrence may increase oncologic outcome. The addition ofsystemic to loco-regional therapy showed only marginaloncologic improvements and is still a matter of debate [128].

In conclusion, salvage mastectomy is still the standardtreatment for locally recurrent breast cancer after BCT.Repeated conservation followed by repeated radiotherapy

may be used after informed patient consent and shouldoptimally be done in trials. Young age, G3, invasive versusintraductal recurrence, and time to first recurrence as well asrecurrence size are factors which may guide the physician todecide about local therapy.

Synchronous metastasized patients

Overall survival for patients with metastasized breast cancer(stage IV) is limited. Most recent data report on mediansurvival between 11 and 23 months depending on prognosticfactors and systemic therapy [129–134]. As cancer cellshave already spread throughout the systemic circulation instage IV breast cancer, it is generally believed that systemictherapy may be the only life-prolonging treatment. Even instage I and II breast cancer patients, more aggressive localtherapy did not improve overall survival [5, 6]

The first clinical evidence that local therapy may be ofbenefit in stage IV disease arises from renal-cell cancerpatients. Case reports about metastasis shrinkage after primarytumor resection in those patients were followed by tworandomized trials demonstrating that removal of the primarytumor in metastasized renal-cell cancer significantly improvedsurvival [135, 136].

Regarding stage IV breast cancer patients, Khan et al.[132] evaluated 9,162 patients accounting for 4.1% of allbreast cancer patients entered into the National Cancer DataBase (NCDB) between 1990 and 1993. Forty-three percenthad systemic treatment only, while 57% underwent addi-tional local surgery due to salvage treatment, patient’s wish,or local complications. Local therapy consisted of partial ortotal mastectomy with or without axillary surgery. The useof radiotherapy has not been evaluated due to lack of data.Patients with surgical removal of the primary tumor had asignificantly increased 3-year survival rate (17% versus35%) with a hazard ratio of 0.61. Similarly, the GenevaCancer Registry report by Rapiti et al. [133] demonstrated a40% reduced risk of death with the surgical removal of theprimary tumor in 300 stage IV breast cancer patients. Asignificant improvement in progression-free survival withthis treatment has been demonstrated in 224 patients withstage IV breast cancer at the MD Anderson Cancer Center,[129], and Blanchard et al. [130] showed a significantincrease in median survival from 17 to 27 months for thesurgical removal of the primary in 427 stage IV breast cancerpatients at the Baylor College of Medicine. A retrospectiveanalysis of the Surveillance, Epidemiology and End Results(SEER) program data of 9,734 patients also demonstrated a37% improvement for overall survival in patients with stageIV breast cancer and removal of the primary tumor [134](Table 3).

These data together strongly suggest an important rolefor local therapy in stage IV cancer disease. However, this

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has to be proven in prospective studies. Furthermore, therationale for a life-extending role of local therapy inmetastasized patients is unclear. Theoretically, there aresome unproven speculative explanations. The primary tumormay act as a source for ongoing systemic spread ofchemoresistant cancer cells (circulating tumor cells, stemcells) [137–140] or metastases proliferation factors(TGFbeta [141–143], VEGF [144–149]) supporting sys-temic tumor growth and further metastases proliferation.Resection of the primary tumor may thus down-regulate theconstant release of circulating tumor cells/stem cells, and/orproliferating factors [150, 151] reducing the capacity toproduce new metastases and decreasing proliferation ofmetastases. The reduction of chemoresistant systemic stemcells by resection of the primary tumor may render metastaticcells chemosensitive. Clinically there is evidence that resec-tion of the primary tumor may enhance the response tosystemic therapy [136, 152, 153].

Prospective trials have to answer this question, and twotrials have already been started. The first in India started inFebruary 2005 (NCT00193778), and the second in Turkeystarted in November 2007 (NCT00557986). The Indiantrial first starts with palliative chemotherapy and random-izes patients only after response, the Turkish trial random-izes immediately. However, beside the question of thetiming of surgery, it is not known whether axillaryclearance and radiotherapy must be provided. Retrospec-tive analyses of available data show that patients withradiotherapy and axillary surgery seem to have improvedsurvival [132–134].

Oncoplastic surgery

Oncoplastic surgery defines the appropriate adequate sur-gery to extirpate a cancer in the breast combined with partialor total reconstruction as well as immediate or delayedreconstruction with access to a full range of techniques tocorrect excision defects [154]. There are several different

newly developed techniques (Fig. 1) used for immediatereconstruction of partial breast defects [155–161].

Indication

Oncoplastic techniques may be used during any kind ofbreast-conserving surgery for breast cancer. However, withregard to breast reduction techniques there are severalindications and contraindications.

Breast/tumor size relation The breast volume excised playsa central role for breast cosmesis after BCT. In patients withan expected volume reduction of more than 10%, surgeonsshould think about the use of oncoplastic surgery [162–164] as cosmetic outcome may significantly be impaired.The breast volume reduction of more than 10% reduced thecosmetic result by 50% [163]. This is especially true formultifocal lesions where resection volumes may be 25% of

Table 3 Retrospective analyses of stage IV breast cancer patients comparing local surgery of the primary tumor versus no surgery

Study Number (n) T1/2 (%) Median survival HR p Value

OP No OP

NCDB 16,024 45 25.3 11.6 0.61 0.0001SEER 9,734 41 36 21 0.58 0.001Geneve 300 31 25 18 0.60 0.001MD Anderson 224 38 Not reached Not reached n.s. n.s.Baylor 427 – 27 16 – 0.0014Dana Farber 170 – 48 25 – 0.02

Local resection improved the overall survival significantly.NCDB National Cancer Data Base, SEER: surveillance, epidemiology, and end results, HR hazard ratio, n.s. not significant

50

60

70

80

90

100

'00 '01 '02 '03 '04 '05

breast conserving surgery

YEAR

% 75 7479

82 82

92

Fig. 1 The percentage rate of breast conservation during the last yearsat the Medical University Vienna, Department of General Surgery.The increase in the last year may be explained by increased finding ofsmaller invasive and intraductal carcinomas and the increased use ofbreast conservation due to oncoplastic techniques

598 Langenbecks Arch Surg (2009) 394:591–609

the breast or larger as one quadrant at least has to beresected. Patients with microcalcifications and suspectedDCIS are also good candidates for oncoplastic surgery asDCIS is often multifocal.

Tumor location Cosmetic results after breast-conservingsurgery for breast cancer in the medial, central, or lowerquadrant yields worse results compared with other locations[165, 166]. Concerning central nipple involvement, it isclear that central lumpectomy without any reconstruction ofthe nipple-areola complex will reduce the cosmetic out-come. Regarding the inner quadrant, scar formation andloss of décolleté in the upper part are hardly tolerated bywomen. In the lower quadrant, the defect is easily visiblecompared to the other side. However, in the upper lateralquadrant, the gravity of the breast parenchyma may stretchthe skin over the defect and may improve cosmesis withoutusing a local oncoplastic technique.

Macromastia and Ptosis In patients with a mild to severeptosis, even in smaller breasts, oncoplastic techniques byusing breast-lifting methods may be of advantage for thegeneral cosmesis by lifting the nipple in the right place andkeeping the scar around the areola. Although simplelumpectomy in macromastia (cup-D size or larger) patientsmay reach good cosmetic results, breast reduction of bothsides improve symptoms such as back and shoulder painand may thus improve the quality of life. Moreover, thehomogeneity of radiation dose distribution may be alteredin large breasts [167], thus, breast reduction may improveadjuvant radiotherapy effects.

Contraindications for oncoplastic techniques

Contraindications for oncoplastic surgery are generallydefined by contraindications for BCT. These includemulticentric disease, inflammatory carcinoma, progressivedisease after neoadjuvant therapy, and patients’ wish [168,169]. Furthermore, if microscopically negative margins arenot achieved, oncoplastic surgery in terms of BCT anddefect replacement or displacement is also contraindicated.Only with a few exceptions, neither oncoplastic surgery norBCT should be performed without the use of adjuvantradiotherapy [1, 48, 170].

Advantages of oncoplastic techniques

Several authors reported on advantages of oncoplasticsurgery. These include the increase of resection volume,[157, 171, 172] leading to larger resection-free margins[173–175] which may have an impact on oncologic

outcome. However, to date, no prospective randomized orretrospective trial comparing lumpectomy and oncoplasticsurgery has been performed to demonstrate a difference inlocal recurrence-free survival. Results of prospective andretrospective analyses suggest that there is no benefit forresection-free margins of >2 mm compared with <2 mm,[24]; thus, there is only little evidence that oncoplasticsurgery may in fact improve oncologic results. However,the possibility of increased resection volume plays a centralrole in raising the rate of BCT. This may, in fact, reduce thenecessity of performing neoadjuvant therapy in severalpatients with a large breast cancer or an unfavorable breast/tumor size relation and thus improve quality of life.

Disadvantages of oncoplastic techniques

Beside the prolongation of operative time, oncoplastictechniques my increase local morbidities [176–178]. Skinnecrosis and wound dehiscence are the most often reportedcomplications after oncoplastic surgery. Obese patients,smokers, and patients with diabetes bear an increased riskto develop local complications [176].

13 years of BCT at a single cancer center

We retrospectively analyzed all patients operated at theMedical University of Vienna, Department of Surgery, from1995 until 2007. Of 2,705 patients 77% underwent BCT.The demographics are listed in Table 4. After a medianfollow-up of 61 months, we saw 7% local recurrences withan overall survival rate of 95%. The use of BCT increasedover time from 70% to 93% as seen in Fig. 1.

Sentinel lymph node biopsy

Knowledge of the existence of lymph node metastases inpatients with invasive breast cancer is mandated to evaluatetheir prognosis, tailor adjuvant therapy, and to improvelocoregional recurrence-free survival. In this regard, axil-lary staging is necessary. The anatomy of lymphaticmapping was published by Estourgie et al. in 2004 in 691patients with radionucleid dye. Between 88% (innerquadrant) and 97% (outer quadrant) are drained throughthe axillary lymph nodes, while 14% (outer quadrant) to37% (inner quadrant) drain via the mammaria lymph nodes.Here we will discuss only the axillary staging procedure bysentinel node biopsy (SNB).

SNB has replaced axillary dissection of level I and II inbreast cancer patients with clinically and pathologicallynegative lymph nodes. The first SNB for breast cancer

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patients was performed in the early 1990s [179]. Ametanalysis by Kim et al. demonstrated an accuracy of92% with a median false-negative rate of 7% [180].Radionucleid [181] and/or methylene blue dye [182] mayboth be used for the detection of the sentinel node.

Detection method

Although their seems to be no significant difference, someinvestigators showed that the radionucleid method has anaccuracy of 89% while the methylene blue dye methodreaches 83% (p=0.007). The combination of both increasesthe detection rate up to 92% [180, 183] with a falsenegative rate of 5% for dual-agent injection versus 11% forsingle-agent injection [184]. The advantage of the radio-nucleid technique is the possible detection of extra-axillarylymph nodes which may be seen in 7% [181]. However,time consumption, the necessity of a nuclear medicaldepartment and costs are disadvantages associated with thismethod. Thus, blue dye detection is still preferred in severalbreast cancer centers. A recent report in Lancet Oncologybased on 5536 patients demonstrated an overall accuracy of97% and a false-negative rate of 9% for the blue dyemethod [185] and 0.7% of all patients showed an allergicreaction.

Injection site

The correct dye injection site has been investigated inseveral trials. While some authors show the highest detectionrate with peritumoral injection or dermal injection, othersshow that the surgeon performing the technique is crucialrather than the technique itself [186, 187]. The importance ofa trained surgeon rather than the injection site or thetechnique used has been demonstrated by others [188].

In this regard, increased experience reduces the falsenegative rate after SNB and increases the accuracy of thistechnique [189, 190]. Thirty cases should be performedunder the observation of a senior surgeon until a false-negative rate of 5% and an accuracy of 90% has beenreached [191]. Others demonstrated that four to six casesmay be enough [189].

Oncologic safety

Prospective data

Oncologic safety has been demonstrated by Veronesi et al.in the first prospective trial comparing SNB with axillarydissection [192] with 3 year’s follow-up. There were noaxillary recurrences in either arm, while morbidity wasimproved in patients after SNB. A second randomized trialhas been published in 2008 by Zavagno et al. showing asimilar disease-free survival (87% vs 89%) rate in patientsafter SNB compared with axillary dissection after a follow-up of 56 months [193]. The data of the NSABP-B32 studycomparing SNB with axillary clearance have not yet beenpublished.

Retrospective data

The Swedish multicenter cohort study with 3,534 patientsdemonstrated that patients after a negative SNB (n=2246)had an axillary recurrence in 0.6% after a follow-up of37 months [194]. A 7-year follow-up of 953 patients afterSNB demonstrated that only three developed axillarymetastases and were treated with axillary dissection. The5-year overall survival rate was 98% in this population[195]. The Minneapolis cancer registry data published in2005 demonstrated an axillary recurrence rate of 0.6%in 700 node-negative patients after SNB with a medianfollow-up of 33 months [196]. Similar results were publishedby the Roswell Park Cancer Institute in Buffalo [197].Interesting overall survival data from a Netherland group inNijemen demonstrated an improved outcome for 880 node-negative SNB patients compared with 1681 node-negativeaxillary dissection patients with a hazard ratio of 1.2 aftercorrection for other confounding factors [198]. Patients(n=4008) have been followed up for 31 months showing

Table 4 Demographs of 2081 patients after BCT at a single cancercenter (Medical University Vienna, General Surgery)

Parameter Valuen=2081

Mean age 58 aPremenopausal 25%pTis 11%pT1a 5%pT1b 13%pT1c 37%pT2 23%pT3 1%pN1 20%G1/2 52%G3 26%Er and Pr neg 20%Radiotherapy 73%Antihormontherapy 70%Neoadjuvant therapy 12%Chemotherapy 29%LRFS 7%OS 95%BCRD 1.2%Median FU 61 months

Er Estrogen receptor, Pr progesterone receptor, LRFS local recurrencefree survival, OS overall survival, BCRD breast cancer-related death,FU follow-up

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only 0.25% of axillary recurrence at the Memorial Sloan-Kettering Cancer Center [199]. The most recent paper fromKorea demonstrated an axillary recurrence rate after negativeSNB of 0.4% in 720 patients with a median follow-up of40 month and a median harvest of two sentinel nodes [200].

Predicting positive lymph nodes

Lymphovascular invasion has been demonstrated to be thestrongest single predicting factor for a positive sentinellymph node in multiple analyses of two studies with morethan 4,000 patients each [201, 202].

Morbidity data

Improvements in morbidity have recently been demonstrat-ed in a prospective trial by Mansel et al. [203], demon-strating a reduced number of lymphedema, drain usage,length of hospital stay, and time to resumption of normaleveryday activities after surgery in the SNB group. Thishas been supported by others [193, 195]. However, theimproved morbidity by SNB seems to be abrogated afterlonger follow-up [204].

Number of nodes

Jeruss showed that by harvesting a median number of twosentinel nodes, the axillary local recurrence rate in node-negative patients was 0.32%. Others suggest that threelymph nodes should at least be harvested as authorsdemonstrated a reduced false-negative rate compared with1 or 2 lymph node harvesting [185]. In a retrospective studywith 1,287 patients, the false-negative rate was reducedfrom 14% to 4% after SNB by harvesting more than onenode [205]. The number of lymph nodes examined in node-negative breast-conserved patients with adjuvant radiother-apy had no impact on disease-free survival, while in themastectomy cohort, the number of lymph nodes in node-negative patients significantly correlated with disease-freesurvival [206], suggesting an understaging in this specialpatient cohort. However the numbers were too small todraw a definitive conclusion. Ninety-nine percent of positivenodes were found in the first five nodes sampled at the MDAnderson in more than 40,000 patients, as reported at theSan Antonio conference in 2006 and published in 2008[207]. Schrenk et al., however, demonstrated an accuracy of99% by harvesting two nodes [208].

Multifocality and multicentricity

Multifocal and multicentric breast cancer are no exclusioncriteria, although there is only little evidence supporting therole of SNB in these patients. In Austria, Schrenk et al.

were the first to demonstrate that 19 patients with multi-centric cancer had no false-negative sentinel node (axillarydissection controlled) [209]. A 96% rate of accuracy and a8% false-negative rate in 70 multicentric/multifocal breastcancer patients has been published by Tousimis et al. [210].In 127 multifocal breast cancer patients, the accuracy andfalse negative rate were 97% and 7%, respectively [211],with a mean number of 2.6 nodes sampled in Korea whichdid not differ from patients with unifocal breast cancer[212]. In Milano, 42 multicentric breast cancer patients hada 100% identification rate of the sentinel node without anyaxillary metastases after 24 months [213]. Another axillarycontrolled trial of 31 multifocal/multicentric patients dem-onstrated an accuracy of 96% and a false negative rate of7% similar to non-multicentric disease patients [214].

SNB and neoadjuvant chemotherapy

Several studies addressed the question whether SNB maybe possible after neoadjuvant chemotherapy. A meta-analysisof these studies was published in 2006 [215]. Twenty-onestudies investigating SNB with axillary surgery as controland including 1,273 patients were analyzed. The reportedpooled detection rate was 90% and the pooled sensitivity89% with an accuracy rate of 94%. These investigatorsconcluded that SNB may be an accurate method to detectaxillary lymph node metastases in clinical node-negativebreast cancer patients after neoadjuvant therapy.

Micrometastasis

The use of SNB increased the detection rate for smallcancer cells in the lymph nodes due to increased histolog-ical sections. In this regard, cancer cells visualized withhematoxylin/eosin (HE) below 0.2 mm are called isolatedtumor cells, cancer cells between 0.2 and 2 mm are micro-metastases, which may be detected with HE or immunohis-tochemistry. A remarkable overview by Rutgers at the SanAntonio Breast Cancer Conference in 2006 is available on theinternet (http://209.196.53.174/2006_webcast/ day 3 plenarylecture 3). In general, there is substantial risk (20%) ofhaving additional lymph node metastasis in HE-detectedmicrometastases and less risk in immunohistochemistry-detected micrometastases (9%) [216]. The occurrence of amicrometastasis does not impair disease-free or overallsurvival. In this regard, other prognostic factors such aslymph vessel invasion, young age, and grading showed to beincluded into the question, whether axillary dissectionshould be performed in patients with micrometastases.Veronesi et al. started a randomized trial comparing axillarydissection versus nil in this patient subgroup. The resultsshould be available in the next years. Until that time, cancercells in the lymph node should be followed by axillary

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dissection, regardless of the detection rate [217]. Isolatedtumor cells should be, however, regarded as pN0.

Re-SNB after SNB

Prior breast and/or axillary surgery are still a contraindica-tion for SNB. However, there are several interesting articlesthat report very low local recurrence rates after the use of are-SNB in locally recurrent breast cancer and prior breastand/or axillary surgery [218–222]. The largest series wasreported by Port et al. [220] with 117 recurrent breastcancer patients. While SNB was successful in only 55%,the use of dye did not help to detect the sentinel lymphnode (dye detection rate 6%, isotope detection rate 45%;dye and isotope detection rate 44%). Sixteen percent had apositive re-SNB, and in 91% of these, the sentinel was theonly site of cancer spread. Previous axillary clearanceinstead of SNB reduced the success of re-SNB from 74% to36%. After 2 years, there were no local recurrences in thepatients undergoing a re-SNB. The authors concluded that are-SNB may be feasible. However, prospective studies haveto be performed to further investigate this issue. So far, itmay be said that blue dye may not be used and re-SNB afteraxillary clearance may not be feasible.

Conclusion

Recent developments demonstrated that local therapy forbreast cancer patients is gaining increased importance. Newmethods such as oncoplastic techniques have been devel-oped recently, improving quality of life and cosmeticoutcome. Local therapy is one of the main treatmentmodalities for early and locally advanced breast cancer.Whether local therapy will also be an important treatmentoption for metastasized patients has to be elucidated inprospective trials.

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