Available online at www.sciencedirect.com

The Breast 17 (2008) 367e371www.elsevier.com/locate/breast

Original article

Postmastectomy locoregional recurrence and distantmetastasis in breast carcinoma patients

Emin Yildirim*, Ugur Berberoglu

Department of Surgery, Ankara Oncology Training and Research Hospital, Konutkent-2, A-4 Blok 44, Ankara 06530, Turkey

Received 10 July 2007; received in revised form 12 November 2007; accepted 11 December 2007

Abstract

The aim of this study was to investigate predictive factors related to distant recurrence (DR) and to determine whether an association existsbetween locoregional recurrence (LRR) and DR in 956 patients. The multivariate time-dependent Cox regression analysis showed that tumorsize (>2 cm vs �2 cm; p< 0.0001; Hazard Ratio [HR], 3.7; 95% Confidence Interval [CI], 2.2e6.0), pN status (pN2/3 vs pN1; p< 0.0001;HR, 2.3; 95%CI, 1.7e3.1), lymphatic vascular involvement (yes vs no; p¼ 0.001; HR, 1.7; 95%CI, 1.2e2.3) and LRR (yes vs no; p¼0.001; HR, dependent on time) were the important prognostic factors for DR. This study confirms a time-dependent association betweenLRR and DR. A DR occurred immediately after LRR is strongly associated with the LRR, but this association decreases over time, and there-fore, a DR occurred lately after LRR is, possibly, not related to this LRR.� 2008 Elsevier Ltd. All rights reserved.

Keywords: Breast carcinoma; Prognosis; Local recurrence; Distant recurrence

Introduction

Breast carcinoma has been accepted as a systemic diseaseduring the recent decades, and locoregional recurrence(LRR) has been considered as an indicator but not as a sourcefor systemic dissemination.1 The results of a number ofrandomized clinical trials demonstrated a reduction in LRRbut no difference in overall survival by radiotherapy.2 Finally,the recent randomized trials showed that postoperative radio-therapy improved survival in women with node-positive breastcarcinoma who also received adjuvant systemic therapy.3e5

These studies supported the hypothesis that locoregional ther-apy might impact on overall survival, when systemic therapywas given to reduce the burden of micrometastatic disease.2

Therefore, a ‘‘spectrum hypothesis’’ that combined bothconflicting theses has been proposed by Hellman.6 It is consid-ered that breast carcinoma is not only a systemic disease as

* Corresponding author. Tel.: þ90 3122402951; fax: þ90 3123454979.

E-mail address: yildirimemin@yahoo.com (E. Yildirim).

0960-9776/$ - see front matter � 2008 Elsevier Ltd. All rights reserved.

doi:10.1016/j.breast.2007.12.005

proposed by the Fisher hypothesis but also behaves as local-ized disease as proposed by the Halstedian hypothesis.1

Because of the changing paradigm in breast carcinoma biol-ogy, there is an increasing interest about the impact of LRR onthe development of distant recurrence (DR). The aim of this studywas to investigate predictive factors related to DR and, to deter-mine whether an association exists between LRR and DR, ina group of breast carcinoma patients treated homogeneously.

Materials and methods

In this retrospective cohort study, the charts and final patho-logical reports of female patients who underwent modified rad-ical mastectomy for invasive breast carcinoma, from 1990 to2003 at Ankara Oncology Hospital, were reviewed. All patientshad complete axillary dissection and complete adjuvanttreatment if necessary according to the current guidelines.7,8

Pathological lymph node classification and tumor stagingwere done according to the UICC/AJCC criteria.9 Theendpoints of this study were LRR and DR. LRR was definedas the first site of tumor recurrence involving ipsilateral chest

Table 1

Patients’ characteristics

Features n %

Age group

>35 years 848 88.7

�35 years 108 11.3

Menopausal status

Postmenopausal 376 39.3

Premenopausal 580 60.7

Histological type

368 E. Yildirim, U. Berberoglu / The Breast 17 (2008) 367e371

wall and/or regional lymph node areas such as axillary, internalmammary or supraclavicular areas. Whereas LRRs as the firstevent in patients without evidence of DR for at least 6 monthsafter LRR was regarded as having an LRR, those with LRRthat occurred within 6 months before DR or occurred afterDR were censored for LRR. Information on the p53 and theHER2 was available only in a minority of patients, mostly thosetreated after the year 2001. Histologic grading was performedusing the criteria of Bloom and Richardson.10 Lymphaticvascular invasion (LVI) was defined as the presence of tumoremboli in peritumoral lymphatic spaces, capillaries or postca-pillary venules.11

Ductal 867 90.7

Lobular 89 9.3

Patient selection Tumor size (pT)

pT1a 11 1.2

pT1b 52 5.4

pT1c 244 25.5

pT2 546 57.1

pT3 103 10.8

Pathological lymph node status

pN0 361 37.8

pN1 298 31.2

Patient inclusion criteria for this retrospective cohort studywere as follows: being within clinically operable stages,having complete dissection of axillary lymph nodes, havingat least 10 lymph nodes on dissection material, having adju-vant treatment if necessary, no serious concomitant diseases,age less than 70 years, and no prior specific treatment. Ninehundred fifty-six eligible patients were included in the study.

pN2 86 9.0

pN3 211 22.1

Statistical analyses Pathological stage

Stage I 173 18.1

Stage II-A 267 27.9

Stage II-B 197 20.6

Stage III-A 109 11.4

Stage III-C 210 22.0

Extracapsular involvement in lymph node-positive patients

Yes 112 18.8

No 483 81.2

Histological grade

Grade I 81 12.7

Grade II 351 54.9

Grade III 207 32.4

Unknown 317 e

Lymphovascular involvement

No 752 78.7

Yes 204 21.3

Estrogen receptor status

Survival estimates were established using the KaplaneMeiermethod and differences in survivals were tested by the log-ranktest.12 All survival rates were presented with their standarderrors. Univariate and multivariate analyses of prognostic vari-ables for each endpoint were performed using Cox proportionalhazards (PH) model.13 The assumption of proportional hazardswas assessed by ln(�ln) survival curves. The effect of the prog-nostic factors except LRR did not vary significantly over time.Because there was a deviation from the PH model due to thetime dependency of LRR, a multivariate time-dependent Coxregression analysis was constructed and the ‘‘LRR� log(time)’’interaction term was included in the multivariate model forDR.14 Statistical tests were performed using the SPSS 13� statis-tical software package for Windows (SPSS Inc., Chicago, IL).

Results

Positive 436 54.8

Negative 360 45.2

Unknown 160 e

Study population

Progesterone receptor status

Positive 229 52.9

Negative 204 47.1

Unknown 523 e

p53 status

Positive 97 51.1

Negative 93 48.9

Unknown 766 e

HER2 status

Positive 65 25.5

Negative 190 74.5

Unknown 701 e

The median age was 46 (range 23e70) and median tumorsize was 3.0 cm (range 0.5e6.0). The median number of lymphnodes in dissection materials was 19 (range 10e53). Patients’characteristics were given in Table 1. Four hundred sixty-four(48.5%) patients were in stage II, whereas 210 (22.0%) patientswere in stage III-C because of having more than 10 positivenodes and/or positive nodes in the axillary level-III. Eighthundred forty-one patients (88.0%) accepted at high risk hadadjuvant combination chemotherapy (among these patients,487 (57.9%) received antracyclin-containing regimens andthe others received CMF, in ad hoc doses). ER and/or PRpositive 444 (46.4%) patients were given tamoxifen. Threehundred thirty-three (34.8%) patients had radiation therapy.

369E. Yildirim, U. Berberoglu / The Breast 17 (2008) 367e371

Clinical outcome

The median observation time was 72 (range 38e191)months for patients still alive at the follow-up cut-off date.Seventy-four (7.7%) patients died because of breast carci-noma-related reasons in the follow-up period. Thirty-seven(3.9%) patients had LRR and 182 (19.0%) patients had DR.Among 37 LRRs, 23 (62.2%) LRs were in chest wall, 1(2.7%) LRRs in axilla, 9 (24.3%) LRRs in supraclavicular fossaand 4 (10.8%) LRRs in internal mammary chain. Of patientsrecurred locally, 21 (56.8%) had DR after LR. In our database,whereas we observed no patient who had DR within 3 monthsafter LRR, three patients with simultaneously LRR and DR,and two patients who experienced DR within a period from 3to 6 months after LRR was not included in the study population,because of the inclusion criteria. In all patients, 10-year overallsurvival and DR-free survival rates were 87% (�0.01) and 76%(�0.02), respectively.

Predictive factors for distant recurrence in all patients

The univariate Cox regression analysis demonstrated thatpatient age, menopausal status, tumor size, pathological lymphnode status, extent of nodal involvement, histological grade,extracapsular involvement, lymphatic vascular invasion(LVI), estrogen receptor (ER) status, progesterone receptor(PR) status, HER2 status and presence of LRR were statisti-cally significant prognostic factors for DR (Table 2). SinceHER2 status was known in only 255 patients, HER2 statuswas not included in the multivariate analysis.

The multivariate time-dependent Cox analysis showed thattumor size, extent of positive nodes and LVI were the mostimportant predictors of DR (Table 3). This analysis also

Table 2

The results of univariate Cox regression analysis for distant recurrence in all

patients

Features p-Value HR 95%CI

Age group (�35 years vs >35 years) 0.009 1.7 1.2e2.5

Menopausal status (premenopausal

vs postmenopausal)

0.008 1.5 1.2e2.1

Histological type (ductal vs lobular) NS

Tumor size (>2 cm vs �2 cm) <0.0001 5.3 3.2e8.7

Pathological lymph node status

(positive vs negative)

<0.0001 2.3 1.6e3.3

Extent of nodal involvement

(pN2/3 vs pN1)

<0.0001 3.6 2.7e4.9

Extracapsular involvement (yes vs no) 0.03 1.5 1.1e2.3

Histological grade

(grade II/III vs grade I)

0.01 2.1 1.2e3.8

Lymphatic vascular involvement

(yes vs no)

<0.0001 2.6 2.0e3.6

Estrogen receptor status

(negative vs positive)

<0.0001 1.8 1.3e2.5

Progesterone receptor status

(negative vs positive)

<0.0001 2.1 1.4e3.3

p53 status (positive vs negative) NS

HER2 status (positive vs negative) <0.0001 3.1 1.9e5.2

LRRa (yes vs no) <0.0001 3.9 2.5e6.1

a Locoregional recurrence.

demonstrated that there was an important association betweenLRR and DR. The ‘‘LRR� log(time)’’ interaction termremained significant in the model and this approved thatLRR violated the assumption of the PH model. The‘‘LRR� log(time)’’ interaction term’s coefficient had a nega-tive value, indicating a greater early effect of LRR on the rateof distant recurrence, with a diminishing effect over time(data not shown in the Table).

Predictive factors in 255 patients whoseHER2 status are known

The results of univariate Cox and the multivariate time-dependent Cox analysis were given in Table 4. The multivar-iate analysis in this subgroup of patients showed that tumorsize, extent of positive nodes, LVI, ER status, HER2 statusand LRR were the most important predictors of DR. Therewas a time-dependent association between LRR and DRwith an early effect of LRR on DR, as seen in the multivariateanalysis on all patients.

Discussion

The rates of locoregional recurrence after mastectomy forinvasive breast carcinoma vary widely, from 5% up to 40%in the literature,3e5,15 and this wide range is possibly due topotential bias because of inadequate axillary sampling, incom-plete surgical technique, and suboptimal systemic therapy.16

Two recent studies showed an LRR rate of 9% after mastec-tomy.16,17 In the presented study, an LRR rate of 3.9%,possibly due to homogeneous surgical technique with a mediannumber of 19 lymph nodes dissected and also adjuvant

Table 3

The result of multivariate time-dependent Cox regression analysis for distant

recurrence (DR) in all patients

Features p-Value HR 95%CI

Tumor size (>2 cm vs �2 cm) <0.0001 3.7 2.2e6.0

Extent of nodal involvement

(pN2/3 vs pN1)

<0.0001 2.3 1.7e3.1

Lymphatic vascular involvement

(yes vs no)

0.001 1.7 1.2e2.3

LRRa (yes vs no) 0.001 2.3 1.5e3.7

(at time zero) (at time zero)

LRR� log(time)b 0.01 Dependent on time

Pathological lymph node status

(positive vs negative)

NS

Age group (�35 years vs >35 years) NS

Menopausal status (premenopausal

vs postmenopausal)

NS

Extracapsular involvement

(yes vs no)

NS

Estrogen receptor status

(negative vs positive)

NS

Progesterone receptor status

(negative vs positive)

NS

Histological grade (II/III vs I) NS

a Locoregional recurrence.b Interaction term because of the time-dependent nature of association

between LRR and DR.

Table 4

The results of Cox regression analyses for distant recurrence (DR) in 255 patients whose HER2 status are known

Features Univariate Cox

regression analysis

Multivariate time-dependent

Cox regression analysis

p-Value p-Value HR 95%CI

Tumor size (>2 cm vs �2 cm) 0.003 <0.0001 3.5 2.1e5.8

Extent of nodal involvement (pN2/3 vs pN1) <0.0001 <0.0001 2.5 1.8e3.3

Lymphatic vascular involvement (yes vs no) <0.0001 0.001 1.7 1.3e2.4

Estrogen receptor status (negative vs positive) 0.001 0.004 1.7 1.2e2.2

HER2 status (positive vs negative) <0.0001 0.001 2.0 1.2e3.9

LRRa (yes vs no) <0.0001 0.03 3.6

(at time zero)

1.3e9.9

(at time zero)

LRR� log(time)b e 0.05 Dependent on time

Pathological lymph node status (positive vs negative) 0.01 NS

Progesterone receptor status (negative vs positive) 0.05 NS

Age group (�35 years vs >35 years) NS e

Menopausal status (premenopausal vs postmenopausal) NS e

Extracapsular involvement (yes vs no) NS eHistological grade (II/III vs I) NS e

a Locoregional recurrence.b Interaction term because of the time-dependent nature of association between LRR and DR.

370 E. Yildirim, U. Berberoglu / The Breast 17 (2008) 367e371

treatments, was better than the other studies.3e5,16,17 LRRafter mastectomy reflects either growth of tumor cells left inthe mastectomy area or spread to the regional nodes.18,19

LRR after mastectomy may occur in two situations: in the firstsituation, LRR includes LRR without DR or LRR conse-quently with DR; and in the second situation, LRR occurs asa part of systemically metastasized disease.20 It is currentlydifficult to precisely distinguish a true, isolated LRR fromsystemic disease, except for a criterion related to time betweenLRR and DR if occurred. In the literature, the definition ofisolated LRR is not standard, and the time to DR after LRRvaries from 1 to 6 months, in different studies evaluatedLRR.3,4,16,21e24 And also, a recent large study indicated thatan LRR was considered isolated, if no DR was observed fora period of 2 years after the LRR occurred, whereas an LRRwas accepted non-isolated, if DR was observed before orconcomitantly with the LRR, or within a period of 2 years af-ter the occurrence of the LRR.25 In the presented study, wetook into consideration only patients without evidence of DRfor at least 6 months after LRR, so that the result could notbe confused. Inasmuch as we aimed to evaluate the potentialassociation between the true LRR and further DR, it wasassumed that patients with a DR within 6 months after theLRR were likely to have already a systemic disease. There-fore, the source of LRRs in these patients might be relatedto the systemic disease, and if these patients were includedin the study, the effect of LRR on DR might be overestimated.

On the other hand, the most important prognostic factorsfor DR in primary breast carcinoma are histopathologicalfeatures of the primary tumor and the regional nodes, becausethese characteristics reflect the biology of the disease.18 In ourstudy, whereas for all patients tumor size, extent of nodalinvolvement and the presence of lymphatic vascular invasionwere the most important predictors of DR after mastectomy,for subgroup of patients whose HER2 status was known,several factors, including tumor size, extent of nodal involve-ment, the presence of lymphatic vascular invasion, estrogen

receptor and HER2 status found to affect DR, as similar tothe literature.18,26 This study also indicates the high predictivevalue of LVI and HER2 status for a tumor’s high metastaticpotential, in addition to the classical markers such as tumorsize and nodal status, in accordance with some reports.7,11

The relationship between LRR and subsequent DR iscontroversial, and many studies in the literature reported theimportance of locoregional control and its impact on diseaseoutcome. Although the predominating assumption was thatLRR is an independent prognostic factor associated witha poor outcome, there is no prospective study on the clinicalcourse of LRR, and most of our knowledge on the importanceof locoregional control derives from prospective or meta-analysis studies in primary breast carcinoma that haveevaluated the effect of postoperative radiotherapy.3,27e31 TheDanish and British Columbia trials revealed that adjuvantradiotherapy was mandatory to obtain the best locoregionaltumor control in breast carcinoma patients.3e5 The EarlyBreast Cancer Trialists’ Collaborative Group demonstrateda two-thirds reduction in LRR with radiotherapy comparedwith surgery alone.28 The reduction in LRR decreased theDR rate by avoiding secondary dissemination.32 It was indi-cated that one breast carcinoma death over the next 15 yearscould be avoided for every four LRRs avoided.29 WhileLRR is an independent prognostic indicator for DR in somestudies, it is not known whether the relationship betweenLRR and DR is coincidental or causal.33 Our study demon-strated an independent and causal association between bothoutcomes of breast carcinoma, and this association was thetime-dependent. There was a greater early effect of LRR onthe risk of DR, with diminishing impact over time, in consis-tent with some studies.17,32,34 This result suggested that a shorttime to DR after an LRR might be an indicator of a biologicalaggressive tumor, and in these patients, the biology of the dis-ease might ultimately dictate outcome.16,17 This finding mayalso explain partly a different subset of patients with breastcarcinoma in whom more aggressive locoregional treatment

371E. Yildirim, U. Berberoglu / The Breast 17 (2008) 367e371

does not result in better survival, despite improved locore-gional control.30 Maybe, the technologies of genomics andproteomics may have a predictive role for determining of thesebiologically aggressive tumors in the future.

In conclusion, the patients only who had adjuvant treat-ments, if necessary according to the current guidelines, wereincluded in our study, lest the patients without these treatmentsin spite of necessity should not confuse with the result. Theresults indicated a time-dependent association between LRRand DR, and LRR following mastectomy was frequently, butnot always, the cause of systemic disease. A DR occurredimmediately after LRR was strongly associated with theLRR, but this association decreased over time, and therefore,a DR occurred lately after LRR was, possibly, not related tothis LRR. Since the application of new technologies as predic-tive or prognostic tools are not likely to be utilized in thecurrent practice nowadays, every effort should be made todecrease the local failure rate, mainly by a good surgicaltechnique and possibly by adjuvant treatments.

Conflict of interest statement

None declared.

References

1. Dunst J, Steil B, Furch S, Fach A, Lautenschlaeger C, Diestelhorst A,

et al. Prognostic significance of local recurrence in breast cancer after

postmastectomy radiotherapy. Strahlenther Onkol 2001;177:504e10.

2. Whelan TJ, Julian J, Wright J, Jadad AR, Levine ML. Does locoregional

radiation therapy improve survival in breast cancer? A meta-analysis.

J Clin Oncol 2000;18:1220e9.

3. Ragaz J, Olivotto IA, Spinelli JJ, Phillips N, Jackson SM, Wilson KS,

et al. Locoregional radiation therapy in patients with high-risk breast

cancer receiving adjuvant chemotherapy: 20-year results of the British

Columbia randomized trial. J Natl Cancer Inst 2005;97:116e26.

4. Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F,

et al. Postoperative radiotherapy in high risk premenopausal women

with breast cancer who receive adjuvant chemotherapy: Danish Breast

Cancer Cooperative Group 82b Trial. N Engl J Med 1997;337:949e55.

5. Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M,

et al. Postoperative radiotherapy in high risk postmenopausal breast cancer

patients given adjuvant tamoxifen. Danish Breast Cancer Cooperative

Group 82c randomised trial. Lancet 1999;353:1641e8.

6. Hellman S. Stopping metastases at their source. N Engl J Med 1997;337:

996e7.

7. Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ,

panel members. Meeting highlights: international expert consensus on the

primary therapy of early breast cancer 2005. Ann Oncol 2005;16:1569e83.

8. Recht A, Edge SB, Solin LJ, Robinson DS, Estabrook A, Fine RE, et al.

Postmastectomy radiotherapy: clinical practice guidelines of the Ameri-

can Society of Clinical Oncology. J Clin Oncol 2001;19:1539e69.

9. Greene FL, Page DL, Fleming ID, Fritz AG, Balch CM, Haller DG, editors.

AJCC cancer staging manual. 6th ed. New York: Springer-Verlag; 2002.

10. Bloom HJG, Richardson VW. Histologic grading and prognosis in breast

cancer. Br J Cancer 1957;11:359e77.

11. Schoppmann SF, Bayer G, Aumayr K, Taucher S, Geleff S, Rudas M,

et al. Prognostic value of lymphangiogenesis and lymphovascular invasion

in invasive breast cancer. Ann Surg 2004;240:306e12.

12. Kaplan EL, Meier P. Nonparametric estimation for incomplete observa-

tions. J Am Stat Assoc 1958;53:457e81.

13. Cox DR. Regression models and life tables. J R Stat Soc 1972;B34:

187e220.

14. Kleinbaum DG. Survival analysis. New York: Springer; 1996.

15. Clemons M, Hamilton T, Goss P. Does treatment at the time of locore-

gional failure of breast cancer alter prognosis? Cancer Treat Rev 2001;

27:83e97.

16. Buchanan CL, Dorn PL, Fey J, Fey C, Giron G, Naik A, et al. Locore-

gional recurrence after mastectomy: incidence and outcomes. J Am Coll

Surg 2006;203:469e74.

17. Carreno G, del Casar JM, Corte MD, Gonzales LO, Bongera M,

Merino AM, et al. Local recurrence after mastectomy for breast cancer:

analysis of clinicopathological, biological and prognostic characteris-

tics. Breast Cancer Res Treat 2007;102:61e73.

18. Kamby C, Sengelov L. Survival and pattern of failure following locore-

gional recurrence of breast cancer. Clin Oncol 1999;11:156e63.

19. Fernando IN. The role of radiotherapy in patients undergoing mastectomy

for carcinoma of the breast. Clin Oncol 2000;12:158e65.

20. Horiguchi J, Koibuchi Y, Yoshida T, Takata D, Kikuchi M, Rokutanda N,

et al. Significance of local recurrence as a prognostic factor in the treat-

ment of breast cancer. Anticancer Res 2006;26:569e74.

21. Schmoor C, Sauerbrei W, Bastert G, Schumacher M, for the German

Breast Cancer Study Group. Role of isolated locoregional recurrence of

breast cancer: results of four prospective studies. J Clin Oncol 2000;18:

1696e708.

22. Jagsi R, Raad RA, Goldberg S, Sullivan T, Michaelson J, Powell SN, et al.

Locoregional recurrence rates and prognostic factors for failure in node-

negative patients treated with mastectomy: implications for postmastec-

tomy radiation. Int J Radiat Oncol Biol Phys 2005;62:1035e9.

23. Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M,

Costantino JP, et al. Low locoregional recurrence rate among node-nega-

tive breast cancer patients with tumors 5 cm or larger treated by mastec-

tomy, with or without adjuvant systemic therapy and without

radiotherapy: results from five national surgical adjuvant breast and bowel

project randomized clinical trials. J Clin Oncol 2006;24:3927e32.

24. Livi L, Saieva C, Detti B, Meattini I, Susini T, Paiar F, et al. Loco-regional

recurrence in 2064 patients with breast cancer treated with mastectomy

without adjuvant radiotherapy. Eur J Surg Oncol 2007;33:977e81.

25. de Bock GH, van der Hage JA, Putter H, Bonnema J, Bartelink H, van

de Velde CJ. Isolated loco-regional recurrence of breast cancer is more

common in young patients and following breast conserving therapy:

long-term results of European Organisation for Research and Treatment

of Cancer Studies. Eur J Cancer 2006;42:351e6.

26. Cianfrocca M, Goldstein LJ. Prognostic and predictive factors in early-

stage breast cancer. Oncologist 2004;9:606e16.

27. Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfav-

ourable effects on long-term survival of radiotherapy for early breast

cancer: an overview of the randomised trials. Lancet 2000;355:1757e70.

28. Early Breast Cancer Trialists’ Collaborative Group. Effects of chemother-

apy and hormonal therapy for early breast cancer on recurrence and

15-year survival: an overview of the randomised trials. Lancet 2005;

365:1687e717.

29. Early Breast Cancer Trialists’ Collaborative Group. Effects of radiother-

apy and of differences in the extent of surgery for early breast cancer

on local recurrence and 15-year survival: an overview of the randomised

trials. Lancet 2005;366:2087e106.

30. van der Hage JA, Putter H, Bonnema J, on behalf of the EORTC Breast

Cancer Group. Impact of locoregional treatment on the early-stage breast

cancer patients: a retrospective analysis. Eur J Cancer 2003;39:2192e9.

31. de Steene JV, Soete G, Storme G. Adjuvant radiotherapy for breast cancer

significantly improves overall survival: the missing link. Radiother Oncol

2000;55:263e72.

32. Arriagada R, Rutqvist LE, Mattsson A, Kramar A, Rotstein S. Adequate

locoregional treatment for early breast cancer may prevent secondary

dissemination. J Clin Oncol 1995;13:2869e78.

33. Clemons M, Danson S, Hamilton T, Goss P. Locoregionally recurrent

breast cancer: incidence, risk factors and survival. Cancer Treat Rev2001;27:67e82.

34. Willner J, Kiricuta IC, Kolbl O. Locoregional recurrence of breast cancer

following mastectomy: always a fatal event? Results of univariate and

multivariate analysis. Int J Radiat Oncol Biol Phys 1997;37:853e63.