Treatment of breast cancer in the elderly: A prospective, population-based Swiss study

J O U RN A L OF GE RI A TR IC O N CO LOG Y 4 ( 20 1 3 ) 3 9 – 47

Available online at www.sciencedirect.com

Treatment of breast cancer in the elderly: A prospective, population-based Swiss study M. Joergera, b,⁎, B. Thürlimannc , A. Savidana , H. Frickd , C. Ragethe , U. Lütolf f , G. Vlastosg , C. Bouchardyh , I. Konzelmanni , A. Bordonij , N. Probst-Henschk, l, m , G. Jundtn , S. Essa a

Cancer Registry St. Gallen-Appenzell, St.Gallen, Switzerland Department of Medical Oncology, Cantonal Hospital, St. Gallen, Switzerland c Breast Center, Cantonal Hospital, St. Gallen, Switzerland d Cancer Registry Grisons-Glarus, Chur, Switzerland e Brust-Zentrum Seefeld, Zurich, Switzerland f Department of Radio-Oncology, Zurich University Hospital, Zurich, Switzerland g Senology Unit, Geneva University Hospitals, Geneva, Switzerland h Geneva Cancer Registry, Geneva, Switzerland i Valais Cancer Registry, Sion, Switzerland j Ticino Cancer Registry, Locarno, Switzerland k Cancer Registry Zurich, Zurich, Switzerland l Swiss Tropical and Public Health Institute, Basel, Switzerland m University of Basel, Basel, Switzerland n Cancer Registry Basel, Basel, Switzerland b

AR TIC LE I N FO

ABS TR ACT

Article history:

Objectives: The primary objective of this population-based study is to describe the patterns of

Received 16 February 2012

care of elderly patients with breast cancer (BC), and evaluate potential causative factors for the

Received in revised form 16 June 2012

decrease in BC-specific survival (BCSS) in the elderly.

Accepted 3 August 2012

Patients and Methods: We included all or representative samples of patients with newly

Available online 24 August 2012

diagnosed BC from seven Swiss cancer registries between 2003 and 2005 (n = 4820). Surgical and non-surgical BC treatment was analyzed over 5 age groups (<65, 65 to < 70, 70 to < 75, 75

Keywords:

to <80 and ≥80 years), and the predictive impact of patient age on specific treatments was

Breast cancer

calculated using multivariate logistic regression analysis.

Elderly

Results: The proportion of locally advanced, metastatic and incompletely staged BC

Radiotherapy

increased with age. The odds ratio for performing breast-conserving surgery (BCS) in

Sentinel lymph node biopsy

stages I–II BC (0.37), sentinel lymph node dissection (SLND) in patients with no palpable

Chemotherapy

adenopathy (0.58), post-BCS radiotherapy (0.04) and adjuvant endocrine treatment (0.23) were all in disfavor of patients ≥ 80 years of age compared to their younger peers. Only 36% of patients ≥ 80 years of age with no palpable adenopathy underwent SLND. In the adjusted model, higher age was a significant risk factor for omitting post-BCS radiotherapy, SLND and adjuvant endocrine treatment. Conclusions: This study found an increase in incomplete diagnostic assessment, and a substantial underuse of BCS, post-BCS radiotherapy, SLND and adjuvant endocrine treatment

⁎ Corresponding author at: Department of Oncology & Hematology, Cantonal Hospital, Rorschacherstr. 95, 9007 St. Gallen, Switzerland. Tel.: + 41 71 4941111; fax: + 41 71 4942563. E-mail address: [email protected] (M. Joerger). 1879-4068/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jgo.2012.08.002

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JO U RN A L OF GE RI A TR IC O N COL O G Y 4 (2 0 1 3 ) 3 9 –4 7

in elderly patients with BC. There is a need for improved management of early BC in the elderly even in a system with universal access to health care services. © 2012 Elsevier Ltd. All rights reserved.

1.

Introduction

Over 40% of patients with breast cancer (BC) are diagnosed above the age of 65 years, and the incidence and mortality of BC in the elderly is still growing in developed countries.1 At the same time, treatment according to international recommendations2 is less often provided to the elderly patient with BC, and this concerns primary surgery3–5 as well as adjuvant radiotherapy3 and systemic therapy.3,6 Despite competing mortality from noncancer disease in the elderly, undertreatment of BC has been linked to higher rates of disease recurrence and BC-specific mortality, particularly in the oldest patients with BC.7 The reasons for undertreating elderly patients with BC are various, including comorbidity,8 the perception that elderly patients have a more favorable risk profile, concerns about treatment compliance, tolerability and limited life expectancy. Accounting for these aspects, guidelines have been published by the International Society of Geriatric Oncology (SIOG) to support decision taking and individualization of treatment in the elderly patient with BC.2 These guidelines emphasize the value of breast surgery in operable patients, axillary lymph node dissection in clinical node-positive BC, sentinel lymph node dissection (SLND) in patients with clinically node-negative BC and post-BCS (breastconserving surgery) radiotherapy or adjuvant endocrine treatment in estrogen receptor (ER)-positive BC.2 The decision to give adjuvant chemotherapy in early BC should not be an age-based decision, but rather be based on the individual biology of the disease, the estimated life expectancy, treatment tolerance and patient preferences. Controversy exists with regard to the use of adjuvant chemotherapy in postmenopausal ER-positive BC patients, and treatment benefits and risks have to be outweighed carefully.9 Until recently, few trials specifically evaluated problems in the elderly BC patient with regard to surgery,10 endocrine treatment,11,12 adjuvant chemotherapy,13 and adjuvant radiotherapy,14–16 and extrapolation from these trials to the entire elderly population must not be done without great caution, as study patients often are less frail than the average patient. This study prospectively looked at unselected elderly patients to assess their characteristics, describe clinical management of BC and evaluate potential causative factors for the decrease in BC-specific survival (BCSS) in the elderly.

2.

Methods

2.1.

Study Design and Data Collection

Patients with a diagnosis of BC between January 2003 and December 2005 were identified from 7 population-based cancer registries. Detailed methodology of the study has been reported previously.17,18 Patient data were abstracted from medical charts. To complete information on therapies, questionnaires were sent to family doctors or treating gynecologists, allowing a high completeness of information on BC treatment (>95%). Five

registries (Geneva, Valais, Ticino, St. Gallen-Appenzell and Grisons-Glarus) collected information on all cases between 2003 and 2005, 2 registries (Basel and Zurich) collected information on a representative sample of 505 randomly selected cases. Socioeconomic covariates included age, nationality (as proxy for migrant), region of residence, urban/suburban versus rural residence, affluence categorized into quartiles of median income and level of education (tertiary education versus other). Provider characteristics included patient discussion at a perioperative multidisciplinary tumor conference (MDTC) as described previously,17 involvement of the team in clinical research and estimated number of patients with breast cancer per surgeon and year. Breast cancer staging used the 6th edition of the American Joint Committee on Cancer staging criteria.19 The study was approved by the Institutional Review Board (IRB) of the Cantonal Hospital St. Gallen, where the study center is located.

2.2.

Tumor Characteristics and Provider-Related Items

Patients were grouped into age groups <65, 65 to <70, 70 to <75, 75 to <80 and ≥80 years. The following clinico-pathological and socio-economic parameters were compared across the age groups: estrogen receptor (ER) expression (<10%, 10–50%, >50%, unknown), HER2-status, histological grading, tumor stage (pTNM-stage in case tumorectomy was performed, cTNM otherwise), nodal status, lymphovascular invasion (positive lymphovascular invasion versus no invasion), MDTC and treatment within an institute participating in clinical research. Patient, tumor and provider-related characteristics were compared across the 5 age groups using the Wilcoxon trend test and the χ2-test where appropriate. As information on provider characteristics was lacking for the region of Ticino, and caseload per surgeon was partially lacking for the region of Basel, these data could not be used for multivariate data analysis.

2.3.

Treatment of Early Breast Cancer

Minimum treatment was defined as local surgery of any type (if operable, not metastatic or locally advanced) or endocrine therapy (if ≥ 10% ER-expression and non minimalrisk BC as defined previously,20) and analyzed over the age groups. Subsequently, the following surgical and non-surgical treatment options of BC were similarly analyzed over the age groups: (1) type of final breast surgery in stages I–II BC <30 mm diameter, (2) application of any axillary surgery in stages I–II BC, (3) application of axillary surgery in clinically node-positive BC, (4) SLND in clinically node-negative BC, (5) post-BCS radiotherapy, (6) post-mastectomy (MX) radiotherapy if recommended, (7) endocrine therapy in ER-positive (≥10% ER-expression), non minimal-risk BC, and (8) chemotherapy in ER-negative, nodepositive or locally-advanced (cT3–4) BC. The predictive impact of patient age was calculated for performing post-BCS radiotherapy and adjuvant endocrine treatment in patients with ERpositive, non minimal-risk BC using multivariate logistic

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J O U RN A L OF GE RI A TR IC O N CO LOG Y 4 ( 20 1 3 ) 3 9 – 47

regression analysis. Finally, the impact of any potential underuse of adjuvant endocrine treatment in patients ≥65 years of age with ER-positive, non minimal-risk BC was assessed using the simulated 10-year benefit from endocrine treatment in the individual patient from Adjuvant! Online (www.adjuvantonline. com). Adjuvant! Online predicted 10-year outcome was separately calculated for BC relapse and overall survival rate. Similarly, the impact of any potential underuse of postoperative chemotherapy in patients ≥65 years of age with ER-negative, node-positive or locally advanced BC was assessed using the simulated 10-year benefit from chemotherapy from Adjuvant! Online.

were compared across age groups in patients with metastatic breast cancer (MBC). All tests of significance were two-sided; p < 0.05 was considered significant. All statistical analyses were performed using STATA 11.0 software (STATA Corp., College Station, Texas, U.S.).

3.

Results

3.1.

Tumor Characteristics and Provider-Related Items

A total of 4820 patients were included into the study. We excluded 187 patients with early BC but not treated in a curative intention, and 36 patients with non-epithelial histology of BC. From these patients, 57% were ≥65 years of age, 13% ≥80 years of age. The proportion of patients with primary metastatic BC and locally-advanced or unstaged BC increased with age (Table 1). ER-expression <10% decreased with age (21% in patients <65 years, 10% in patients ≥80 years of age). Poor histological differentiation decreased with age, but this was not true for welldifferentiated BC. The proportion of patients with node-positive

2.4. Neoadjuvant Treatment and Treatment of Stage IV Breast Cancer The use of neoadjuvant chemotherapy and endocrine treatment was compared between patients of different ages using logistic regression analysis, adjusting for tumor stage, grading, nodal status, HER2 expression and lymphovascular invasion. Additionally, endocrine receptor status and histological grading

Table 1 – Patient and tumor characteristics.

ER-expression < 10% 10–50% > 50% Unknown HER2-status Negative Positive Unknown Histological grading 1 2 3 Tumor size ≥ 30 mm No Yes Stage I II III IV Unknown Nodal status Negative Positive Unknown MDTC No Yes Clinical research No Yes

65 to <70 years (n = 588)

70 to <75 years (n = 477)

75 to < 80 years (n = 382)

N

(%)

N

(%)

N

(%)

N

%

N

%

578 287 1832 54

(21) (10) (67) (2)

102 42 433 11

(17) (7) (74) (2)

57 32 379 9

(12) (7) (79) (2)

54 23 290 15

(14) (6) (76) (4)

65 23 438 96

(10) (4) (70) (15)

1828 439 484

(66) (16) (18)

376 88 124

(64) (15) (21)

316 49 112

(66) (10) (24)

198 41 143

(52) (11) (37)

256 49 317

(41) (8) (51)

551 1348 751

(21) (51) (28)

129 288 141

(23) (52) (25)

81 281 95

(18) (61) (21)

76 203 76

(21) (57) (22)

95 305 118

(18) (59) (23)

2236 365

(86) (14)

478 74

(87) (13)

355 85

(81) (19)

276 64

(81) (19)

311 140

(69) (31)

1039 1091 445 140 36

(38) (40) (16) (5) (1)

249 216 69 43 11

(42) (37) (12) (7) (2)

183 182 72 29 11

(39) (38) (15) (6) (2)

116 156 60 27 23

(30) (41) (16) (7) (6)

114 226 122 56 104

(18) (36) (20) (9) (17)

1479 1215 57

(54) (44) (2)

347 218 23

(59) (37) (4)

281 177 19

(59) (37) (4)

202 148 32

(53) (39) (8)

294 193 135

(47) (31) (22)

1080 1128

(49) (51)

212 234

(48) (52)

207 181

(53) (47)

129 153

(46) (54)

268 202

(57) (43)

1705 1046

(62) (38)

397 191

(68) (32)

315 162

(66) (34)

267 115

(70) (30)

492 130

(79) (21)

p-Value a

<.001

.027

.049

<.001

<.001

.005

.012

<.001

N = number of patients, ER = estrogen receptor status, MDTC = multidisciplinary tumor conference. Wilcoxon test for trend for > 2 categories, χ2-test for 2 categories.

a

≥80 years (n = 622)

<65 years (n = 2751)

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JO U RN A L OF GE RI A TR IC O N COL O G Y 4 (2 0 1 3 ) 3 9 –4 7

BC decreased with age, but there was a high proportion of unknown nodal status in patients ≥80 years of age (22%). The proportion of patients being discussed at a MDTC and treated in institutions participating in clinical research both decreased with age. The proportion of patients participating in a clinical study decreased from 123 (7.5%) in those <65 years of age to 31 (2.9%) in those ≥65 years of age (p <0.001).

3.2.

patients (19%) <65 years of age, but only 2 out of 51 patients (4%) ≥80 years of age. The rate of surgical staging of the axilla decreased with age in both patients with stages I–II BC and in those with clinically node-positive BC. Similarly, the rate of SLND as the only axillary procedure in patients with clinically node-negative BC decreased with age (Table 2), and the OR for performing SLND showed an approximate linear decrease in patients ≥70 years of age (Fig. 1B). The administration of postBCS radiotherapy and post-MX radiotherapy (when indicated) both decreased with age; patients ≥80 years of age received post-BCS and post-MX radiotherapy 32% and 11% of the time, respectively. The administration of adjuvant endocrine treatment in patients with ER-positive, non minimal-risk BC also decreased with age (Table 2), and the OR for endocrine treatment decreased at age 70 (Fig. 1C). When using “Adjuvant! Online” to estimate the potential benefit of applying adjuvant endocrine treatment in these patients, there was an absolute 10-year benefit for relapse-free survival of 5.2%, and an absolute benefit for overall survival of 1.8%. Finally, the use of adjuvant chemotherapy in patients with ER-negative, node-positive or locally-

Treatment of Early Breast Cancer

Overall, 40 women (1.1%) with stage I or II BC did not receive minimum treatment as defined above, but this proportion was markedly higher in patients ≥80 years of age (28 out of 340 women, 8.2%). The proportion of patients with stage I or II BC receiving breast surgery was 99% in patients <80 years of age and 84% in patients ≥80 years of age (p< 0.001). In stage I-II BC <30 mm in diameter, the proportion of BCS versus MX decreased with age (Table 2), and the odds ratio (OR) for performing BCS showed a marked drop at the age of 75 years (Fig. 1A). Breast reconstruction following MX was performed in 35 out of 188

Table 2 – Treatment of patients with early breast cancer.

Final SX in stages I–II BC <30 mm diameter and no previous BC BCS MX MX with reconstr. Any axilla SX in stages I–II No Yes Axilla staging in cN + BC No Yes SLND only in cN0 BC No Yes RX after BCS No Yes RX following MX c No Yes Endocrine therapy d No Yes Chemotherapy e No Yes

OR (95%-CI) b

<65 years (n = 2575) a

65 to <70 years (n = 534) a

70 to <75 years (n = 437) a

75 to <80 years (n = 332) a

≥80 years (n = 462) a

N

(%)

N

(%)

N

(%)

N

%

N

%

1218 153 35

(87) (11) (2)

287 33 3

(89) (10) (1)

204 33 2

(85) (14) (1)

129 37 1

(77) (22) (1)

118 49 2

(70) (29) (1)

0.37 (0.26–0.53) Ref.

38 2090

(2) (98)

8 457

(2) (98)

21 343

(6) (94)

28 244

(10) (90)

140 198

(41) (59)

Ref. 0.04 (0.03–0.06)

51 638

(7) (93)

16 96

(14) (86)

20 97

(17) (83)

15 70

(18) (82)

54 88

(38) (62)

Ref. 0.18 (0.12–0.27)

707 753

(48) (52)

179 161

(53) (47)

147 115

(56) (44)

105 68

(61) (39)

93 52

(64) (36)

Ref. 0.58 (0.41–0.82)

94 1689

(5) (95)

28 372

(7) (93)

38 256

(13) (87)

51 146

(26) (74)

136 64

(68) (32)

Ref. 0.04 (0.03–0.06)

99 234

(30) (70)

14 31

(31) (69)

25 34

(42) (58)

27 21

(56) (44)

89 11

(89) (11)

Ref. 0.06 (0.03–0.12)

117 1567

(7) (93)

21 345

(6) (94)

33 316

(9) (91)

36 231

(13) (87)

111 307

(27) (73)

Ref. 0.23 (0.18–0.30)

6 260

(2) (98)

4 34

(11) (89)

3 14

(18) (82)

10 12

(45) (55)

24 5

(83) (17)

Ref. 0.01 (0–0.4)

N = number of patients, SX = surgery, BC = breast cancer, BCS = breast conserving surgery, ER = estrogen receptor status, RX = radiotherapy, MX = mastectomy, cN+ (node-positive) = patients with palpable adenopathy, cN0 (node-negative) = patients with no palpable adenopathy, Ref. = reference. a All patients with early (stages I–III) BC. b Odds ratio and 95% confidence interval for the comparison of patients ≥ 80 years of age with patients < 80 years of age. c In patients with locally advanced disease or positive margins. d In patients with endocrine-sensitive, non minimal-risk early breast cancer. e In patients with ER-negative, nodal-positive or locally-advanced (T3–T4), non metastatic BC.

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Fig. 1 – Forest plots showing the use of breast-conserving surgery versus mastectomy over age in stages I–II breast cancer <30 mm (1A), sentinel lymph node biopsy only (1B), adjuvant endocrine treatment in breast cancer with ER-expression >10% and non-minimal risk features (1C) and chemotherapy in patients with hormone receptor negative breast cancer (1D). Patients <65 years of age are taken as the reference (OR = 1).

advanced (T3–T4) BC decreased with age (Table 2), and the OR for chemotherapy showed a marked drop already at the age of 65 years (Fig. 1D). In patients ≥ 65 years of age with early-stage ER-negative, non minimal-risk BC, 8% did not receive postoperative chemotherapy as indicated, corresponding to

a maximum absolute loss of 3.5% for 10-year relapse-free survival and 1.5% for 10-year overall survival when simulating clinical outcome according to “Adjuvant Online”. The specific chemotherapy regimens across age groups are outlined in Table 3. Patients ≥ 65 years of age were significantly more

Table 3 – Chemotherapy regimens used in patients with early breast cancer. Chemotherapy regimen

b

6 cycles of CMF 4 cycles of anthracyclines c > 4 cycles of anthracyclines d Anthracyclines + taxanese

<65 years

65 to <70 years

70 to <75 years

75 to < 80 years

N

(%)

N

(%)

N

(%)

N

%

101 441 522 225

(7.8) (34.2) (40.5) (17.5)

23 50 52 11

(16.9) (36.8) (38.2) (8.1)

10 24 19 9

(16.1) (38.7) (30.7) (14.5)

5 7 1 0

(38.5) (53.8) (7.7) (0)

OR (95%-CI) a

1.60 (1.08–2.37) 0.69 (0.53–0.90) 0.46 (0.35–0.61) 0.33 (0.20–0.53)

N = number of patients, C = cyclophosphamide, M = methotrexate, F = 5-fluorouracil. a Odds ratio and 95% confidence interval for the comparison of patients ≥ 65 years of age versus patients < 65 years of age. b Cyclophosphamide in combination with doxorubicin (A) or epirubicin (E). c One of the following: 6 cycles of AC, CAF, CEF, FEC100 or FAC; 4 cycles of AC followed by 4 cycles of CMF. d One of the following: 3 cycles of (F)EC followed by 3 cycles of docetaxel (T); 6 cycles of TAC or AT; 4 cycles of AC followed by 12 weekly administrations of paclitaxel; 4 cycles of AT.

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likely to receive CMF (cyclophosphamide, methotrexate, and fluorouracil) chemotherapy (OR = 1.60, 1.08–2.37), and significantly less likely to receive anthracyclines or anthracycline/ taxane combinations (OR = 0.33, 0.20–0.53).

3.3. Predictors for the Use of Post-BCS Radiotherapy and Adjuvant Endocrine Treatment Higher age was the strongest and independent negative predictor for performing post-BCS radiotherapy (OR=0.11, 95%-CI 0.07–0.17 for patients ≥80 years of age) (Table 4). Each category of increasing age was associated with a higher risk for omitting post-BCS radiotherapy. Stage III BC was the strongest predictor for performing post-BCS radiotherapy (OR=3.19, 95%-CI 1.50–6.75 for patients ≥80 years of age), while other risk factors such as ERnegativity, HER2-positivity, poor histological grading or nodepositivity did not predict the use of post-BCS radiotherapy. Higher age was also the strongest and independent negative predictor for performing adjuvant endocrine treatment (OR=0.23, 95%-CI 0.16–0.33 for patients ≥80 years of age) (Table 5). Each category of increasing age was associated with a higher risk for omitting adjuvant endocrine treatment. Treatment in an institution

Table 4 – Predictors for performing adjuvant radiotherapy following breast-conserving surgery (multivariate analysis). Odds ratio Patient age < 65 years 65 to <70 years 70 to <75 years 75 to <80 years ≥ 80 years ER-status < 10% 10–50% > 50% Unknown HER2-status Negative Positive Unknown Histological grading 1 2 3 Stage I II III IV Nodal status Negative Positive Unknown MDTC No Yes Clinical research No Yes

Ref. 0.71 0.37 0.29 0.11 Ref. 0.86 0.79 1.42

95% CI

Log-rank p

0.40–1.24 0.22–0.61 0.17–0.50 0.07–0.17

0.23 < 0.001 < 0.001 < 0.001

Table 5 – Predictors for performing adjuvant endocrine treatment when recommended (multivariate analysis). Odds ratio Patient age < 65 years 65 to <70 years 70 to <75 years 75 to <80 years ≥ 80 years ER-status < 10% 10–50% > 50% HER2-status Negative Positive Unknown Histological grading 1 2 3 Stage I II III IV Nodal status Negative Positive Unknown MDTC No Yes Clinical research No Yes

95% CI

Log-rank p

Ref. 1.10 0.81 0.53 0.23

0.68–1.79 0.52–1.28 0.33–0.87 0.16–0.33

0.69 0.38 0.01 <0.001

Ref. 0.80 1.56

0.49–1.29 1.09–2.22

0.36 0.01

Ref. 1.16 1.53

0.78–1.73 1.10–2.13

0.47 0.01

Ref. 0.48 0.44

0.30–0.75 0.26–0.74

0.001 0.002

Ref. 0.61 0.53 0.34

0.42–0.89 0.31–0.90 0.18–0.64

0.01 0.02 0.001

Ref. 1.36 1.42

0.95–1.95 0.50–4.04

0.09 0.51

Ref. 1.72

1.30–2.29

<0.001

Ref. 2.47

1.80–3.39

<0.001

ER = estrogen receptor status, MDTC = multidisciplinary tumor conference. 0.41–1.80 0.48–1.31 0.33–6.08

0.69 0.37 0.63

Ref. 0.73 1.05

0.44–1.21 0.72–1.52

0.23 0.81

Ref. 1.85 1.41

1.26–2.73 0.86–2.32

0.002 0.17

Ref. 1.60 3.19 0.42

1.02–2.51 1.50–6.75 0.21–0.84

0.04 0.002 0.01

Ref. 0.92 0.28

0.57–1.48 0.11–0.73

0.72 0.009

Ref. 1.28

0.92–1.79

0.15

Ref. 1.58

1.10–2.27

0.01

ER = estrogen receptor status, MDTC = multidisciplinary tumor conference.

participating in clinical research was the strongest predictor for performing adjuvant endocrine treatment (OR = 2.47, 95%-CI 0.18–3.39). ER-status, histological grading and tumor stage were all significant and independent predictors for performing adjuvant endocrine treatment following breast surgery. Higher age was also an independent negative predictor for doing SLND in patients with no palpable adenopathy (OR=0.62, 95%-CI 0.39–1.00 for patients ≥80 years of age). The OR for doing SLND in patients with no palpable adenopathy decreased with increasing patient age. Treatment in an institution participating in clinical research was the strongest predictor for doing SLND in these patients (OR=1.59, 95%-CI 1.29–1.97).

3.4. Neoadjuvant Treatment and Treatment of Stage IV Breast Cancer Neoadjuvant endocrine treatment was more often administered to elderly patients with BC ≥65 years of age compared to patients <65 years of age, after adjusting for tumor-related risk factors (OR 1.54, 95%-CI 1.02–2.35; p= 0.04). By contrast, neoadjuvant chemotherapy was less often administered to elderly patients with BC compared to young patients (OR 0.23, 95%-CI 0.14–0.37; p< 0.001) after adjusting for tumor-related risk factors. Metastatic

J O U RN A L OF GE RI A TR IC O N CO LOG Y 4 ( 20 1 3 ) 3 9 – 47

breast cancer was more frequently found to be ER-positive in patients 65 years of age or older compared to patients <65 years of age (80% vs. 66%, p =0.01), but there was no difference in the proportion of poor histological differentiation in MBC between elderly and young patients (49% vs. 40%, p =0.16). Breast surgery in MBC was performed in 54% of patients <65 years of age compared to 32% in patients ≥80 years of age (p= 0.04), and there was no statistical difference in the type of breast surgery (BCS versus MX). The rate of endocrine treatment in patients with ER-positive MBC decreased from 91% in patients <65 years of age to 78% in patients ≥80 years of age (p =0.07). Statistical analysis of chemotherapy in patients with stage IV BC was not reliable due to small patient numbers.

4.

Discussion

The present study provides evidence for incomplete staging and a substantial underuse of BCS versus MX, post-BCS radiotherapy and adjuvant endocrine treatment in elderly patients with early BC. No uniform “threshold” could be defined for patient age at which the rate of non-standard treatment increased in the elderly. For example, the use of post-BCS radiotherapy decreased in patients ≥75 years of age, while the use of adjuvant endocrine treatment decreased in patients ≥70 years of age, and the use of adjuvant chemotherapy began to drop in patients ≥55 years of age. Breast cancer will increasingly affect the lives of older women, especially in more developed countries, with BC prevalence approaching 7% in patients ≥70 years of age.21 Accordingly, the absolute incidence and prevalence of BC will increase most remarkably in the oldest women, and it will become increasingly important to ensure high-quality treatment in these patients. This is of particular importance as more elderly women will have no or only minor health problems. In 2007, the International Society of Geriatric Oncology published a position paper on the diagnosis and treatment of BC in elderly women.2 The authors recommend surgery not to be denied to patients with BC who are ≥70 years of age, and to use the same procedures as used in younger patients, unless patient preference dictates otherwise. Furthermore, endocrine treatment should also be offered to older women who are candidates for endocrine treatment. According to the recommendations of the International Society of Geriatric Oncology, adjuvant chemotherapy should not be an age-based decision, but should take into account the patient's life expectancy, potential benefit from treatment and patient preferences.2 Prospective, randomized trials have demonstrated that BCS with or without ALND followed by local radiotherapy is equivalent to MX in terms of overall survival and disease-free survival for patients with earlystage BC.22,23 Nonetheless, BCS remains underutilized in women of all ages and particularly in elderly women,24 and there are elderly women who do not receive any BC surgery according to an international comparison.5 In this study, virtually all women did undergo surgery for early BC, but with a substantial decrease in the proportion of elderly women receiving BCS instead of MX. Besides patient age, there are other reasons for the underuse of BCS, such as socioeconomic factors,25 geographic or access barriers,25–28 and physician attitudes towards treatment and patient involvement in treatment decisions.29,30 Even though

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BCS has become more frequent in elderly women with early BC since the mid-1990s,31 we found that the proportion of women receiving post-BCS radiotherapy decreased substantially in women ≥75 years of age (74% of patients 75 to <80 years and 32% of patients ≥80 years of age). The data as found in the Swiss population are comparable to what has been described in other European countries and the U.S.5,32 In fact, omission of post-BCS radiotherapy puts patients at increased risk for local and systemic relapse, and has been shown to result in reduced BCspecific survival in women ≥75 years of age.33 Recently, SLND instead of ALND has been shown to be a safe strategy in patients with BC with no palpable adenopathy (node-negative), even in the presence of 1 to 2 SLN containing metastases in frozen sections,34 and has the potential to improve the quality of life in elderly women. In the present study, the proportion of patients receiving SLND as a sole surgical procedure to local lymph nodes was 52% in younger patients and decreased to 36% in patients ≥80 years of age. Clearly, this shows potential improvements in surgical treatment, as the avoidance of axilla surgery contributes significantly to the quality of life in BC patients, and this may be of special value to the elderly. In a small retrospective study, Hamaker and colleagues looked at the individual motivation for guideline deviation in 166 elderly patients with BC ≥70 years of age.35 In total, 122 (74%) patients were diagnosed and treated according to national guidelines. Guideline deviation was motivated in 18 patients (comorbidity in 11, patient preferences in 5, age in 2 patients), unmotivated in 18 and undeliberate in 8 patients. In 2003, Bouchardy and colleagues reviewed clinical files of 407 patients with BC ≥80 years of age recorded at the Geneva Cancer Registry between 1989 and 1999.7 When compared with international treatment recommendations, roughly half of the elderly patients with BC were found to be undertreated, which resulted in a decreased 5-year BC-specific survival. Similar results were reported more recently by Hancke and colleagues, who enrolled 1922 women aged ≥50 years treated at a single center between 1992 and 2005.3 Women >70 years received BCS less often than their younger peers (>79 years: 54%; 70–79 years: 74%–83%; <70 years: 93%). Non-adherence to the guidelines on radiotherapy (70 years: 9%; 70–79 years: 14%–27%; >79 years: 60%) and chemotherapy (<70 years: 33%; 70–79 years: 54%–77%; >79 years: 98%) increased with age. When performing similar studies, it is important to exclude clinically relevant comorbidity that may have precluded breast surgery or adjuvant chemotherapy, and has also been shown to be an important surrogate for death without BC recurrence.36 In the present study, the analysis of early BC was limited to patients treated with curative intent. Furthermore, the adequacy of a respective treatment was individually judged by taking into account the tumor characteristics such as tumor stage or ER-status, and correcting for the fact that adjuvant chemotherapy might not be feasible in patients ≥75 years of age. In the future, wider use of gene microarray tests such as Oncotype DX® may exclude lower risk patients from the use of adjuvant chemotherapy. However, such tests have not been used at the time of patient accrual, and are only infrequently used in Switzerland at present. The strengths of this study include the population-based nature and prospective planning of data analysis, registrybased case identification that enabled us to study patients in

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the community setting, and avoidance of a systemic bias in patient accrual by central planning and structured patient inclusion. Also, the proportion of missing data is low and the number of variables collected is large as compared with other population-based studies. Our study is limited by the retrospective data collection, the lack of outcome data and the fact that missing data cannot be considered at random. Our observations nevertheless are population-based and reflect clinical practice in a community setting. By including all types of providers, identification of patients through cancer registries, and achieving a large and very complete data set, potential selection bias was substantially reduced. Another limitation is the fact that we did not assess all potentially interacting comorbidities, although patients not treated in a curative intention were excluded from the analysis of early BC treatment. In conclusion, this study found an increase in incomplete diagnostic assessments, and a substantial underuse of BCS, post-BCS radiotherapy, SLND and adjuvant endocrine treatment in elderly patients with BC. There is a need for improved management of early BC in the elderly even in a system with universal access to health care services.

Disclosures and Conflict of Interest Statements All authors confirm that this paper has not been published previously, is not under consideration for publication elsewhere, and will not be published elsewhere in the same form, in English or in any other language, without the written consent of the publisher. None of the authors has a conflict of interest or financial disclosure to declare. The study has been funded by the Swiss Cancer League (KLS 01766-08-2005).

Author Contributions Concept and design: B. Thürlimann, S. Ess, U. Lütolf. Data collection: A. Savidan, H. Frick, C. Rageth, G. Vlastos, C. Bouchardy, I. Konzelmann, A. Bordoni, N. Probst-Hensch, G. Jundt, S. Ess. Analysis and interpretation of data: M. Joerger, B. Thürlimann, S. Ess. Manuscript writing and approval: M. Joerger, B. Thürlimann, A. Savidan, H. Frick, C. Rageth, U. Lütolf, G. Vlastos, C. Bouchardy, I. Konzelmann, A. Bordoni, N. Probst-Hensch, G. Jundt, S. Ess.

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