Determinants of outcome in elderly patients with positive sentinel lymph nodes

The American Journal of Surgery (2011) 201, 734 –740

Clinical Science

Determinants of outcome in elderly patients with positive sentinel lymph nodes Amer K. Karam, M.D.a, Meier Hsu, M.S.a, Sujata Patil, Ph.D.b, Michelle Stempel, M.S.a, Tiffany A. Traina, M.D.c, Alice Y. Ho, M.D.d, Hiram S. Cody, M.D.a, Monica Morrow, M.D.a, Mary L. Gemignani, M.D., M.P.H.a,* a

Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, Evelyn H. Lauder Breast Center, 300 E. 66th St, New York, NY 10065, USA; bDepartment of Biostatistics, Memorial Sloan-Kettering Cancer Center; cDepartment of Medicine, Memorial Sloan-Kettering Cancer Center; dDepartment of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA KEYWORDS: Elderly patients; Sentinel lymph nodes; Lymph nodes; Outcomes

Abstract BACKGROUND: Older women are less likely to receive standard of care treatment for breast cancer. METHODS: We examined variables that affected the outcome of elderly patients ⱖ70 years old among 1,470 patients with invasive cancer with positive sentinel lymph nodes (SLNs). RESULTS: Elderly patients were less likely to undergo mastectomy, completion axillary node dissection (ALND), adjuvant chemotherapy, and radiotherapy (RT) following breast-conserving therapy (BCT) compared with patients ⬍70 years old. The 5-year risk of disease progression and cumulative incidence of breast cancer–specific deaths were not significantly different for both groups. On multivariate analysis, hormone receptor–negative status, number of metastatic lymph nodes, high nuclear grade, and tumor size were the factors independently associated with increased risk of disease progression. CONCLUSIONS: Tumor factors were the primary determinants of breast cancer outcomes in our cohort. Elderly patients are less likely to receive aggressive surgical interventions and adjuvant therapy because of perceived life expectancy. © 2011 Elsevier Inc. All rights reserved.

Breast cancer is the most common non-skin cancer in women and the second leading cause of cancer deaths among women in the United States, with more than 180,000 new cases and 40,000 deaths in 2008.1 Improvements in medical care and prevention have led to a dramatic improvement in life expectancy in the United States; the number of Americans 65 years of age or older is expected to * Corresponding author. Tel.: ⫹1-646-888-5359; fax: ⫹1-646-8885365. E-mail address: [email protected] Manuscript received September 23, 2009; revised manuscript January 23, 2010

0002-9610/$ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.amjsurg.2010.02.005

reach 71 million, or roughly 20% of the population of the United States, by 2030.2 Moreover, a 65-year-old woman in the United States has an average life expectancy of over 19 years and will in all likelihood be faced with at least 1 chronic medical condition.3 The 2 leading causes of death in the elderly patient population are cardiovascular disease and cancer.4 Even though elderly patients over the age of 70 account for a substantial proportion of breast cancer cases and breast cancer-related deaths, there is substantial evidence that they are more likely to present with advancedstage disease and metastasis at diagnosis5 and that they are less likely to receive standard care therapy for their disease.6,7 In this study, we examined patients 70 years of age

A.K. Karam et al.

Determinants of outcome in node-positive elderly patients

or older with node-positive, operable breast cancer who were treated at our institution and compared their therapeutic regimens and outcomes to those of their younger counterparts. We focused our attention on elderly patients with positive sentinel lymph nodes (SLNs) because the algorithm for standard care in this population has not been clearly defined. In addition, a growing body of literature has been questioning the utility of completion axillary lymph node dissection (ALND) in certain subsets of SLN-positive breast cancer patients due to the absence of additional lymph node metastases in approximately 40% to 60% of patients8 and due to the minimal therapeutic benefit using adjuvant chemotherapy and radiation.9

Methods This study was a review of our institutional prospective SLN database. We identified patients with invasive breast cancer who were treated at Memorial Sloan-Kettering Cancer Center (MSKCC) between July 1997 and July 2003, and who were SLN-positive by intraoperative frozen-section analysis (FS) or on final pathological examination by hematoxylin and eosin (H&E) and/or immunohistochemical (immunohistochemistry [IHC]) analysis using cytokeratin stains. Standard pathological examination for SLNs that were negative on FS included an FS control (recorded as “routine H&E”) and 2 adjacent sections: 1 stained with H&E and the other with anticytokeratin (AE1:AE3) IHC taken from the paraffin block at each of 2 levels, 50 ␮m apart (recorded as “serial sections/IHC”). A median of 5 slides were examined per SLN. Non-SLNs were examined with routine single-section H&E stains. ALND was defined on the basis of surgeon intent and not the number of nodes removed. We excluded all patients with stage 4 breast cancer or bilateral breast cancer, and patients with a history of cancer in the preceding 5 years (except for nonmelanoma skin cancer and noninvasive cervical cancer), as well as patients receiving neoadjuvant chemotherapy, to obtain a homogeneous primary operative cohort. During this time period, 4,446 patients underwent surgery and SLN biopsy for invasive breast cancer at our institution. From this group, we were able to identify 1,470 patients with positive SLNs who met our inclusion criteria. Institutional review board approval was obtained to retrospectively review their medical charts to obtain clinical, operative, pathological, and follow-up data. Elderly patients were defined as those age 70 years or older. Comorbid medical conditions were classified according to the validated Adult Comorbidity 27 system described by Piccirillo et al.10 Briefly, the diseases and conditions affecting each patient were divided into 1 of 3 levels (mild, moderate, or severe) according to the severity of individual organ decompensation. An overall comorbidity score (none; mild; moderate; severe) was assigned based on the highest-ranked single ailment. When 2 or more moderate ailments occurring in different organ systems or

735

disease groupings were noted, the overall comorbidity score was designated as severe. Immediate completion ALND was defined as those patients undergoing axillary clearance at the time of breast surgery. Delayed ALND was defined as those patients who had a return to the operating room on a separate occasion for axillary clearance.

Statistical analysis Patient age at the time of SLN biopsy was categorized as elderly (ⱖ70 years) and nonelderly (⬍70 years). Comorbidity scores were divided into 2 categories: none to mild (0 –1), versus moderate to severe.2,3 Fisher exact or Wilcoxon rank-sum tests were used to compare elderly patients to nonelderly patients on demographic and pathological characteristics, as well as on therapeutic regimens. All survival endpoints were measured starting from the date of SLN biopsy. Overall survival time ended with date of death due to any cause, or last follow-up date if the patient was still alive. Five-year survival rates for elderly and nonelderly patients were estimated by methods of Kaplan–Meier and compared by log-rank test. Breast cancer– specific deaths were evaluated by methods of competing risk, with death of other causes (DOC) accounted for as a competing risk factor. Gray test was used to compare differences in deaths due to disease by age group. Dates and cause of death were obtained by reviewing the patient’s medical record, contacting the patient’s doctor, or accessing the Social Security Death Index. Another endpoint of interest was risk of disease progression. Disease progression time ended with date of locoregional or distant recurrence, or last follow-up if the patient did not recur. There were 4 patients (1 patient with stage IV presentation, 1 patient with new primary tumor, and 2 patients with no recurrence information listed) who were all deemed to have died of disease; they were included as events on their dates of death. With DOC as the competing factor, competing risk regression modeling was performed to examine factors associated with disease progression and to evaluate the effect of age after adjusting for covariates. With the exception of hormone therapy, all factors with univariate P values ⬍.20 were entered into the multivariable model. Aside from retaining the elderly and ALND variables, the model was reduced until only those factors with a P value ⬍.05 remained. Hormone therapy was not examined in multivariable models due to its close association with hormone receptor positivity. Age was included as the main variable of interest, and ALND was retained because of its relevance to the treatment of SLN patients. Nuclear grades I and II were combined as a reference group to compare with grade III for the analysis. The final multivariable model is a complete case analysis and is based on 1,305 patients with complete data. Competing risk analyses were performed using R statistical software version 2.3 (The R Foundation for Statistical Computing, Vienna, Austria) using the crr and cuminc func-

736 tions within library cmprsk. All other statistical analyses were performed using SAS 9.1 (SAS Institute, Cary, NC).

Results The median age at diagnosis for our entire study population was 53 years (range 21– 89 years), with 1,265 (86%) patients under the age of 70 years and 205 (14%) patients age 70 years and above. The median follow-up period for the entire cohort of survivors was 67 months (range 0 –124 months); the median follow-up period was 69 months (range 0.7–124.0 months) for survivors under 70 years of age; and the median follow-up period was 57 months (range 0 –117 months) for survivors 70 years of age and older. Two elderly patients did not have further follow-up at MSKCC. Table 1 demonstrates the demographic and pathological variables examined for our study population of breast cancer patients with positive SLNs at MSKCC. The median pathological size of the tumors in our patient population was 1.6 cm (range 0.1–11.0 cm). As expected, most tumors were of ductal origin (1,290 [87.8%] infiltrating ductal carcinoma vs 180 [12.2%] infiltrating lobular carcinoma), estrogen receptor (ER)-positive (81.2%) and HER2 normal (86.4%). Information about the adjuvant therapy patients received postoperatively is also detailed in Table 1. As expected, most patients received chemotherapy postoperatively (86.9%) with a median number of 8 chemotherapy cycles (range 0 – 68), and almost all patients with hormone-responsive disease received adjuvant anti-estrogen therapy (97.5%). Only 63 (4.6%) patients received dedicated radiation therapy (RT) to the axilla. As expected, the number of positive lymph nodes correlated very strongly with FS positivity; 99% of patients with positive frozen sections had 1 or more positive lymph nodes. Table 1 examines the variables compared in the subset groups in our study population. On univariate analysis, patients 70 years of age or older were more likely to have moderate to severe comorbidities than their younger counterparts (46% vs 11%, P ⬍ .0001). Elderly patients were less likely to receive completion ALND than their younger counterparts (73% vs 89%, P ⬍ .0001), even though the number of positive SLNs was not statistically different for both groups. Additionally, elderly patients were more likely to undergo breast-conserving therapy (BCT) than nonelderly patients (67% vs 59%, P ⫽ .03). This finding likely reflects a trend for less aggressive surgical management in elderly patients. Among the pathological variables examined, lower nuclear grade (I and II) tumors and the absence of lymphovascular invasion were the only factors that were significantly more likely to be present in elderly patients compared with younger patients (65% vs 54%, P ⫽ .008; and 69% vs 59%, P ⫽ .009, respectively). Table 1 also demonstrates the adjuvant therapy variables examined in our study groups. Postoperatively, elderly patients were less likely to receive chemotherapy (43% vs 94%, P ⬍ .0001) and breast RT (82% vs 90%, P ⫽ .008),

The American Journal of Surgery, Vol 201, No 6, June 2011 but more likely to receive axillary RT (8% vs 4%, P ⫽ .02) when compared with younger patients. Interestingly, elderly patients who received chemotherapy had fewer cycles of chemotherapy prescribed than their younger counterparts (7.5 planned cycles vs 9.0, respectively; P ⫽ .004), but were just as likely to complete their assigned treatment course (percent cycles completed: 97% vs 98%, respectively; P ⫽ .34). However, elderly patients were just as likely to receive anti-estrogen therapy as their younger counterparts (83% vs 79%, P ⫽ .2). On univariate analysis of disease progression, hormone receptor–negative and HER2/neu overexpressed/overamplified tumors, as well as increasing tumor size, nuclear grade, number of metastatic lymph nodes, the presence of lymphovascular invasion, and ALND were all associated with a significantly increased risk of disease progression. Controlling for factors independently associated with disease progression and for differences in receipt of completion ALND associated with age, our multivariable model revealed no detectable difference in risk of disease progression between elderly and younger patients (Table 2). Elderly patients consistently did not show a statistically significant difference in the cumulative incidence of breast cancer–specific deaths at 5 years compared with younger patients (6.4% vs 4.9%, P ⫽ .77) (Fig. 1).

Comments Elderly women likely present with larger tumors because many patients in this age group do not undergo regular mammographic screening. They are more likely to be undertreated because of the bias that treatment may be too toxic and will not benefit the patient.11,12 The number of coexisting medical conditions, which tend to increase with advancing age, and declining functional status may also account for the nonparticipation of elderly patients in screening programs and clinical trials, and for the perceived lack of benefit from standard care therapy.13–16 Even though few patients older than 70 years of age were accrued to chemotherapy trials, a population-based observational study described a survival benefit from adjuvant chemotherapy in patients 66 years of age or older with endocrine unresponsive disease. These findings likely reflect the increase in overall benefit derived from treatment of patients with node-positive disease.17 Similarly, the efficacy of various adjuvant chemotherapy regimens in nodepositive older patients was analyzed in a recent review of 4 randomized Cancer and Leukemia Group B (CALGB) trials. Although the efficacy of the various regimens did not differ across the age groups, older patients had worse overall survival because of competing causes of death, and they had higher rates of treatment-related mortality. In addition, the number of patients 70 years of age or older represented only 2% of the patients examined; they were also highly selected and therefore not likely to reflect the average elderly patient population.18

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Table 1 Univariate comparison of demographic, pathological, and adjuvant therapy variables in our elderly (age ⱖ70 years) and nonelderly (age ⬍70 years) patients with positive sentinel lymph nodes Variable Comorbidities None to mild Moderate to severe No. of surgeries 1 2 3 or more Operation type Conservation Mastectomy Completion ALND No Yes Positive FS No/not done Yes No. of positive LNs IHC only One or more Chemotherapy No Yes Hormone therapy No Yes Breast RT for BCT patients None XRT or IORT Axillary RT None XRT Histological grade I II III Nuclear grade I II III ER Negative Positive PR Negative Positive HER2 Negative Positive ER- or PR-positive ER-negative/PR-negative ER-positive and/or PR-positive LVI No Yes Multifocality No Yes Tumor size T1a,b T1c T2–T3

All

Age ⬍70

Age ⱖ70

P

1,233 (84.0%) 235 (16.0%)

1,124 (89%) 141 (11%)

109 (54%) 94 (46%)

⬍.0001

544 (37.6%) 659 (45.6%) 243 (16.8%)

429 (34%) 601 (48%) 235 (19%)

115 (64%) 58 (32%) 8 (4%)

⬍.0001

878 (59.7%) 592 (40.3%)

741 (59%) 524 (41%)

137 (67%) 68 (33%)

.03

198 (13.5%) 1,272 (86.5%)

143 (11%) 1,122 (89%)

55 (27%) 150 (73%)

⬍.0001

599 (40.7%) 871 (59.3%)

500 (40%) 765 (60%)

99 (48%) 106 (52%)

.02

183 (12.4%) 1,287 (87.6%)

154 (12%) 1,111 (88%)

29 (14%) 176 (86%)

.43

181 (13.1%) 1,202 (86.9%)

72 (6%) 1,120 (94%)

109 (57%) 82 (43%)

⬍.0001

278 (20.4%) 1,084 (79.6%)

247 (21%) 932 (79%)

31 (17%) 152 (83%)

.24

89 (10.9%) 730 (89.1%)

66 (10%) 625 (90%)

23 (18%) 105 (82%)

.008

1,309 (95.4%) 63 (4.6%)

1,138 (96%) 48 (4%)

171 (92%) 15 (8%)

.02

44 (3.5%) 394 (31.0%) 832 (65.5%)

36 (3%) 333 (30%) 730 (66%)

8 (5%) 61 (36%) 102 (60%)

.20

42 (3.4%) 652 (52.6%) 546 (44.0%)

38 (4%) 546 (51%) 488 (46%)

4 (2%) 106 (63%) 58 (35%)

.01

250 (18.8%) 1,081 (81.2%)

223 (20%) 917 (80%)

27 (14%) 164 (86%)

.09

487 (36.8%) 837 (63.2%)

410 (36%) 724 (64%)

77 (41%) 113 (59%)

.26

1,011 (86.4%) 159 (13.6%)

866 (86%) 145 (14%)

145 (91%) 14 (9%)

.06

218 (16.4%) 1,112 (83.6%)

193 (17%) 946 (83%)

25 (13%) 166 (87%)

.21

894 (60.8%) 576 (39.2%)

752 (59%) 513 (41%)

142 (69%) 63 (31%)

.009

1033 (70.3%) 437 (29.7%)

877 (69%) 388 (31%)

156 (76%) 49 (24%)

.06

237 (16.4%) 651 (45.1%) 555 (38.5%)

200 (16%) 559 (45%) 484 (39%)

37 (18%) 92 (46%) 71 (36%)

.54

ALND ⫽ axillary lymph node dissection; BCT ⫽ breast-conserving therapy; ER ⫽ estrogen receptor; FS ⫽ frozen section; IHC ⫽ immunohistochemistry; IORT ⫽ intraoperative radiation therapy; LN ⫽ lymph node; LVI ⫽ lymphovascular invasion; PR ⫽ progesterone receptor; RT ⫽ radiation therapy; XRT ⫽ external radiation therapy.

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The American Journal of Surgery, Vol 201, No 6, June 2011

Table 2 Competing risk-regression analysis for risk of disease progression in breast cancer patients with positive sentinel lymph nodes at Memorial Sloan-Kettering Cancer Center Univariate Variable Age (y) ⬍70 ⱖ70 Comorbidities None–mild Moderate–severe Completion ALND No Yes Pathological size T1 T2 T3 No. of positive LNs IHC only 1–3 Positive LNs ⱖ4 Positive LNs LVI No Yes Multifocality No Yes Histological grade I II III Unknown Nuclear grade I or II III Unknown ER- and/or PR-positive No Yes HER2 Negative Positive Unknown Chemotherapy No Yes RT BCT no RT BCT with RT Mastectomy no RT Mastectomy with RT RT to axilla No Yes Hormone therapy* No Yes

Multivariate

N

Recurred

HR

95% CI

P

HR

95% CI

1,265 205

173 16

1.0 .67

(.40–1.12)

.13

1,233 235

160 28

1.0 1.0

(.67–1.50)

.99

198 1,272

9 180

1.0 2.86

(1.46–5.61)

888 509 46

79 94 12

1.0 2.31 3.14

183 1,021 266

11 109 69

894 576

P

1.0 .98

(.58–1.67)

.95

.002

1.0 1.96

(.81–4.73)

.14

(1.71–3.12) (1.71–5.76)

⬍.0001 .0002

1.0 1.84 1.73

(1.32–2.58) (.85, 3.53)

.0004 .13

1.0 1.99 5.02

(1.08–3.67) (2.67–9.42)

.03 ⬍.0001

1.0 1.99 3.84

(.89–4.45) (1.68–8.80)

.09 .002

82 107

1.0 2.10

(1.58–2.80)

⬍.0001

1,033 437

133 56

1.0 1.01

(.74–1.38)

.94

44 394 832 200

2 26 142 19

1.0 1.44 3.98 2.05

(.34–6.04) (.99–16.10) (.48–8.78)

.62 .05 .33

694 546 230

50 115 24

1.0 3.26 1.44

(2.35–4.54) (.89–2.33)

⬍.0001 .14

2.27 1.25

(1.53–3.36) (.75–2.11)

⬍.0001 .39

218 1,112

56 118

1.0 .35

(.25–.48)

⬍.0001

1.0 .57

(.39–.83)

1,011 159 300

122 31 36

1.0 1.77 .80

(1.19–2.64) (.54–1.19)

.005 .27

181 1,202

17 170

1.0 1.28

(.78–2.12)

.33

89 730 490 87

17 85 63 22

1.0 .51 .60 1.24

(.30–.87) (.35–1.04) (.64–2.37)

.01 .07 .53

1,309 63

174 10

1.0 1.26

(.67–2.36)

.48

278 1,084

72 115

1.0 .34

(.25–.46)

⬍.0001

.004

HR ⫽ hazards ratio; CI ⫽ confidence interval; ALND ⫽ axillary lymph node dissection; LN ⫽ lymph node; IHC ⫽ immunohistochemistry; LVI ⫽ lymphovascular invasion; ER ⫽ estrogen receptor; PR ⫽ progesterone receptor; RT ⫽ radiation therapy; BCT ⫽ breast-conserving therapy. *Hormone therapy and ER/PR positivity are closely associated; to reduce collinearity, only ER/PR positivity was included in the multivariable model.

It is well-established that postoperative breast irradiation decreases locoregional recurrence.19,20 A recent study noted that the frequency of breast irradiation following BCT in-

creased with advancing age and that the omission of RT was associated with significantly reduced locoregional control, as well as with breast cancer–specific and overall survival.21

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Determinants of outcome in node-positive elderly patients

739

The limitations of our study include its retrospective design, the relatively small number of patients in the elderly and moderate-to-severe comorbidities groups, and the inability to determine whether treatment decisions were made based on physician recommendations, patient preferences, or both. In addition, the data are derived from a tertiary care center and do not take into account the geographic variability in patterns of care. In conclusion, we were able to illustrate in our study that among patients with node-positive breast cancer, patients 70 years of age or older differed from their younger counterparts in their initial surgical management, as well as in choice of adjuvant therapy. The limited life expectancy and significant comorbidities seen in a significant proportion of patients 70 years of age or older may help justify the current treatment modalities for breast cancer of the elderly, including less-aggressive therapy. Our data highlight the need for additional research regarding the impact of treatment decisions in elderly patients 70 years of age or older. Figure 1 Breast cancer–specific deaths by age group among patients with positive sentinel lymph nodes.

In addition, 2 randomized control trials evaluated the role of breast irradiation in older women who underwent BCT. In both trials, breast irradiation was associated with a significantly lower risk of locoregional recurrence.22,23 The univariate results of our study are consistent with those reported previously showing that elderly women 70 years of age or older are more likely to receive less aggressive primary therapy, including fewer surgical procedures, axillary dissections, chemotherapy cycles, and propensity to omit postoperative RT.21,24,25 Similarly, elderly patients with node-positive breast cancer were significantly less likely to receive adjuvant chemotherapy.26,27 Interestingly, this disparity in breast cancer therapy did not translate into a difference in disease progression after multivariable-adjusted modeling or breast cancer–related deaths in our study. Moreover, the small number of patients who did not receive adjuvant cytotoxic chemotherapy likely represents the small subset of patients with favorable disease characteristics receiving adjuvant endocrine therapy with a limited life expectancy and moderate-to-severe comorbidities for whom the benefits of chemotherapy are hard to validate. Extermann et al calculated that for a 1% decrease in mortality at 10 years if using cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy, a healthy 75-yearold woman with hormone receptor-positive early-stage breast cancer would require a 22% risk of relapse at 10 years. An equivalent improvement in breast cancer mortality in older and/or sicker patients would require a much higher risk of relapse.13 This is illustrated in our study by the significant association of age, comorbidity, and nodal disease burden with the odds of receiving chemotherapy (results not shown).

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