J O U R N A L O F G E R I A T R I C O N C O L O G Y X X ( 2 0 1 3 ) X X X – X X X

JGO-00140; No. of pages: 9; 4C:

Ava i l ab l e on l i ne a t www.sc i enced i r ec t . com

Adjuvant chemotherapy and differential invasive breast cancerspecific survival in elderly women☆,☆☆

Henry G. Kaplana,⁎, Judith A. Malmgrenb, c, Mary K. Atwooda

aSwedish Cancer Institute, Seattle, WA, USAbHealthStat Consulting Inc., Seattle, WA, USAcSchool of Public Health and Community Medicine, Department of Epidemiology, University of Washington, Seattle, WA, USA

A R T I C L E I N F O

☆ Supported by the Kaplan Cancer Researc☆☆ This research has been presented at the

⁎ Corresponding author at: 1221 E. MadisonE-mail address: hank.kaplan@swedish.o

1879-4068/$ – see front matter © 2013 Elseviehttp://dx.doi.org/10.1016/j.jgo.2012.12.007

Please cite this article as: Kaplan HG., etelderly women, J Geriatr Oncol (2013), http

A B S T R A C T

Article history:Received 28 August 2012Received in revised form18 October 2012Accepted 27 December 2012

Keywords:Breast neoplasm

Objective: To assess adjuvant chemotherapy recommendations, administration and disease-specific survival for invasive breast cancer (BC) among patients 75 years and older comparedwith that of younger women.Materials and methods: A cohort of patients with primary breast cancer, aged 65–94, stagesI–III from 1990 to 2010 was identified and tracked by our breast cancer registry (n=2329).Stage, treatment recommendations and outcomes were chart abstracted at diagnosis andfollow-up. Associations were tested with logistic regression and the Kaplan–Meier methodwas used for disease-specific survival (DSS).Results: Seventy-five percent of patients aged 75+ were seen by an oncologist comparedwith 78% aged 70–74 and 84% aged 65–69. Women aged 75+ seen by an oncologist weremore likely age 75–79, stage II/III, hormone receptor negative (HR−) or her-2/neu positive. Ofthese patients, age, stage and HR status were related to a chemotherapy recommendation.Of 106 patients recommended for chemotherapy, 18 refused (17%) and 24 did not completetreatment due to complications, patient choice, disease progression or death not related totreatment. DSS was equivalent for patients 75 and older with stage I BC compared to 65–74 year olds, but significantly worse in stage II and III patients, respectively (stage II 5 yearDSS 90% vs. 97%, stage III 5 year DSS 65% vs. 81%).Conclusion: Patients aged 75 and older with invasive breast cancer who were recommendedfor adjuvant chemotherapy have a high rate of refusal and complications from therapy. Theirdisease specificmortality disadvantage is restricted to stage II and III patients, a group in needof effective therapy to improve disease survival.

© 2013 Elsevier Ltd. All rights reserved.

ElderlyAdjuvant chemotherapySurvival analysisRisk modelingDisease specific survivalBreast cancer

1. Introduction

In 2007, women aged 75 in the United States had an averagelife expectancy of 12.5 years and comprised 7.5% of the femalepopulation [1]. In recent years twenty-one percent of incidentbreast cancer cases and thirty-eight percent of mortality frombreast cancer in the United States were women aged 75 and

h Fund and the Cancer SuSan Antonio Breast CancSt., Seattle, WA 98104, USrg (H.G. Kaplan).

r Ltd. All rights reserved.

al, Adjuvant chemothera://dx.doi.org/10.1016/j.jgo

older [2]. National Comprehensive Care Network (NCCN) guide-lines state that adjuvant chemotherapy recommendations donot extend to women over 70 years old as there are insufficientdata from randomized clinical trials and recommend thatindividualized treatment plans take into consideration thepatient's comorbid conditions [3]. These recommendationsare echoed in the International Society of Geriatric Oncology

rveillance System of the Fred Hutchinson Cancer Research System.er Symposium December 2010 as an abstract.A. Tel.: +1 206 386 2828; fax: +1 206 386 3782.

py and differential invasive breast cancer specific survival in.2012.12.007

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recommendations [4]. National data suggest that breast cancerdisease-specific survival in older women has not improved overtime in the same way it has for women younger than age 75,perhaps due to advances in treatment of limited applicability toolder women [5].

Our study aims to describe adjuvant chemotherapy treat-ment patterns, to test for factors associated with recommen-dations of treatment and compare outcomes by stage amongpatients aged 75 and older with primary invasive breastcancer to patients aged 65–74 with breast cancer.

2. Methods

We conducted a retrospective review of a prospective cohortof women aged 65 and older presentingwith biopsy confirmedstage I–III primary breast cancer from 1990 to 2010, identifiedand tracked by our dedicated breast cancer registry database.The registry of all patients seen at our institution aged 20–94was created in 1990 and contains detailed information onpatient characteristics, stage at diagnosis, and treatmentregimens. A total of 2776 cases were age 65–94 years andafter excluding stage 0 and IV cases, 2329 stage I–III patientsremained for the analytic group. The primary variables ofinterest in our study were ‘seen by an oncologist’, ‘chemo-therapy recommended yes or no’, ‘chemotherapy completedyes or no’, with reasons for ending treatment abstracted frompatient chart data. American Joint Committee on Cancer(AJCC) Cancer Staging Manual 7th edition categories anddefinitions were used for cancer staging [6]. Patient's TNMassignment using earlier staging was converted to the currentnomenclature for the purposes of this analysis. Estrogen andprogesterone receptor status was available on all patients buther-2/neu was tested and available only on patients diag-nosed after 1998.

Primary outcomes of interest were death from any causeand death from breast cancer with survival interval to event.Registry follow-up is updated annually with information onrecurrence, subsequent treatment and vital status from chartreview if the patient is still seen at the institution, or throughphysician directed follow-up letter if care is received else-where. If no response is received the institution's cancerregistry and the Surveillance Epidemiology and End Results(SEER) 9 Seattle-Puget Sound Registry are reviewed for thepatient's vital and disease status [7].

Chemotherapy regimenswere reviewed for each patient anddesignated as standard or non-standard protocol. Standardregimens included CMF (cyclophosphamide, methotrexate andfluorouracil given either weekly for 6 months or days 1 and 8 forsix cycles), CAF (cyclophosphamide, doxorubicin and fluoroura-cil given either every twenty-one days or days 1 and 8 everythree weeks for six cycles), AC (cyclophosphamide plus doxoru-bicin given every two or three weeks for four cycles), paclitaxelplus carboplatin (every 3 weeks for 4–6 cycles), CT (cyclophos-phamide plus docetaxel every 3 weeks for 4–6 cycles), and AC/T(doxorubicin plus cyclophosphamide for 4 cycles followed by ataxane either weekly or every two weeks). Due to age andpre-existing conditions, some chemotherapy patients weregiven non-standard treatment in the form of a reduced numberof treatments, non-standard agents or a reduction in the

Please cite this article as: Kaplan HG., et al, Adjuvant chemotheraelderly women, J Geriatr Oncol (2013), http://dx.doi.org/10.1016/j.jgo

number of agents as recorded in the chart notes. Trastuzumabwas not considered a chemotherapy drug in this analysis.

IBM SPSS Statistics v.18 was used for statistical analysis [8].Pearson chi-square tests were used for bivariate analysis ofdichotomous variables and analysis of variance for meancomparisons with two-tailed p values. Forward stepwiselogistic regression was used for multivariate modeling withchemotherapy given yes/no as the outcome. Disease-specificsurvival for patients aged 65–69 and 70–74 with breast cancerstages I–III in our registry did not differ significantly so theywere combined for comparison to patients aged 75+. Survivalanalysis with Kaplan–Meier plots was used for disease–specific survival (DSS), relapse free survival (RFS) (local,regional, distant or combined recurrence) and overall survival(OS) (death from any cause) with log-rank (Mantel–Cox)comparisons. Cox regression analysis was used to test theeffect of age related to disease-specific survival corrected forstage and treatment.

Institutional review board (IRB) approved methods wereused for patient data entry and all registry data is storedin a password protected Health Insurance Portability andAccountability Act (HIPAA) compliant database. All analyseswere conducted using de-identified data as per IRB and HIPAAguidelines. This project was reviewed and approved by thelocal IRB with an informed consent waiver.

3. Results

Forty-one percent of female patients with stage I–III breastcancer over age 65 were 75 years or older (n=956) with a meanage of 80 years, and a range from 75 to 94 years. The majorityof the women 75 years and older were white (92%) and eithersingle or widowed (65%). Sixty percent had stage I tumors, 89%were estrogen receptor (ER) positive, and 75% were progester-one receptor (PR) positive. Of those tested after 1998, 9% wereher-2/neu positive and 5% were triple negative (ER, PR andher-2/neu negative). Initial treatment was 1) no surgery and noradiation (1%, n=7), 2) lumpectomywithout radiation (3%, n=21),3) lumpectomy with radiation (73%, n=698), 4) mastectomy withradiation (11%, n=108), and 5) mastectomy without radiation(13%, n=120). Seventy-one percent of the ER positive patientswere prescribed treatment with adjuvant hormonal therapywith 356 patients receiving estrogen receptor blockers and 269receiving aromatase inhibitor (AI) therapy.

Seventy-five percent of the patients were seen by anoncologist (n=716) with chemotherapy recommended to 106patients (11%). Patients seen by an oncologist were more oftenstage II or III (46%), but no difference was seen by race, maritalstatus, age, hormone receptor or her-2/neu status (Table 1).Chemotherapy was given to 88 patients with 18 of the 106recommended for therapy refusing treatment (17%). Of theeighteen patients refusing adjuvant chemotherapy treatment,thirteen received radiation therapy in addition to surgery.Fig. 1 contains the description of patient disposition catego-ries for analysis.

Of the 88 patients given chemotherapy, 74 were givenstandard chemotherapy and 14 were given non-standard che-motherapy due to age or comorbidity-related issues (Table 2). Ofthe 74 patients started on standard chemotherapy, eighteen

py and differential invasive breast cancer specific survival in.2012.12.007

Table 1 – Characteristics of women aged 75+years seenby an oncologist (n=956).

Not seenn (%)

(n=240, 25%)

Seenn (%)

(n=716, 75%)

Significance(p value)

Age75–79 122 (24%) 396 (76%) (n.s.)80–94 118 (27%) 320 (73%)

StageI 186 (32%) 389 (68%) (<0.001)II 45 (17%) 223 (83%)III 9 (8%) 104 (92%)

Hormone receptor statusPositive 207 (24%) 642 (76%) (n.s.)Negative 16 (19%) 70 (81%)

Adjuvant hormonal therapyHormone receptorpositive, adjuvanthormonal therapy=yes

91 (15%) 514 (85%) (<0.001)

Her-2/neu status (n=607, 63%)Positive 8 (14%) 48 (86%) (n.s.)Negative 68 (12%) 483 (88%)

HR/Her2 statusHR+/her2− 62 (12%) 444 (88%) (n.s.)HR+/her2+ 7 (16%) 37 (84%)HR−/her2− 6 (13%) 39 (87%)HR−/her2+ 1 (8%) 11 (92%)

n.s.: not significant; HR: hormone receptor.

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were switched to non-standard treatment because they couldnot tolerate standard therapy. Incomplete adjuvant therapy wasdue to complications (n=17), patient choice (n=3), unknown(n=2), disease progression (n=1), and non-treatment related

Fig. 1 – CONSOR

Please cite this article as: Kaplan HG., et al, Adjuvant chemotheraelderly women, J Geriatr Oncol (2013), http://dx.doi.org/10.1016/j.jgo

death (n=1) (Table 3). For all patients started on standard therapytreatment but excluding patients discontinued due to non-complication issues (death, disease progression, personal choiceand unknown) the completion rate was 81% (55/68). Treatmentcompletion rates were 69% for patients on initial non-standardtherapy and 28% for patients started on standard therapy butswitched to non-standard therapy due to complications. Treat-ment ending complications (n=17) included thrombocytopenia(n=1), neuropathy (n=2), neurotoxicity (n=2), neutropenia (lowwhite count) (n=5), neutropenic fever (n=1), rash (n=1), pulmo-nary complications (n=1), hyponatremia (n=3), and general drugintolerance due to age (n=1). There were no treatment relateddeaths. Thirty-eight of the chemotherapy patients were givengranulocyte colony-stimulating factor (GCSF), 33 were not and 17were unknown (Table 2). GCSF administration was not signifi-cantly associated with completion of chemotherapy.

Therapy completion rate excluding non-completion dueto patient choice, disease recurrence or death, by regimenwas the following: CMF=61% (n=23); AC/T, AT, or CAF/T=90%(n=20); AC or CAF=100% (n=8); CT=100% (n=11); carboplatinplus taxane=67% (n=6); andnon-standard regimen=69% (n=13).In these cases incompletion was due to treatment relatedcomplications. Non-standard regimens were the following:1) AC/carboplatin-paclitaxel/CMF pre-op, carboplatin/paclitaxelpost-op, 2) anastrozole only pre-op, single agent cyclophospha-mide post-op changed to paclitaxel, discontinued due toneutropenia, 3) CMF weekly times three months (n=2), 4)cyclophosphamide–paclitaxel–carboplatin weekly times three,5) low dose doxorubicin weekly times 25 weeks, 6) single agenttaxane, and 7) single agent capecitabine pre-op.

The majority of the chemotherapy recommended patientswere younger (age 75–79=77%), had larger tumor size, weremore often lymph node positive, stage II or III (84%), andhormone receptor negative, her-2/neu negative, or her-2/neupositive (Table 3). In a forward stepwise logistic regressionmodel with chemotherapy recommended as the outcome,order of entry of variables was: 1) stage [stage II odds ratio

T diagram.

py and differential invasive breast cancer specific survival in.2012.12.007

Table 2 – Chemotherapy characteristics: women aged75+years (n=956).

n (%)

Chemotherapy dispositionNot seen by oncologist 240 (25.1%)Seen by oncologist:No chemotherapy recommended

610 (63.8%)

Chemotherapy recommended 106 (11.1%)

Chemotherapy givenYes 88 (83.0%)Patient refused treatment 18 (17.0%)Neoadjuvant therapy 14 (13.2%)

GCSF therapyYes 38 (43.2%)No 33 (37.5%)Unknown 17 (19.3%)

Chemotherapy completed (n=88)Yes 64 (72.7%)No, complications 17 (19.3%)No, expired 1 (1.1%)No, disease progression 1 (1.1%)No, patient choice 3 (3.4%)Unknown if completed 2 (2.3%)

Chemotherapy completionrates by category (n=88)

% completed w/ocomplications ⁎

Standard therapy (not switched) 54 (61.4%) 100%Switched to non-standard therapydue to complications

18 (20.5%) 28%

Non-standard therapy 14 (15.9%) 69%Unknown number of cycles 2 (2.3%) –

Chemotherapy completionrates by regimen (n=81) a

% completed w/ocomplications ⁎⁎

Carboplatin+taxane 6 (7.4%) 67%AC, CAF ⁎ 8 (9.9%) 100%AC/taxane, AT, CAF/taxane ⁎⁎ 20 (24.7%) 90%CMF 23 (28.4%) 61%cyclophosphamide+taxane 11 (13.6%) 100%Non-standard regimen 13 (16.0%) 69%

A=doxorubicin, C=cyclophosphamide, F=5 fluorouracil, M=methotrexate, Carbo=carboplatin, T= taxane.⁎ p<0.001.⁎⁎ p=0.030

a Includes patients that completed chemotherapy (n=64) andthose who discontinued standard therapy due to complications(n=17) (total n=81).

Table 3 – Patient/tumor characteristics of women aged75+years recommended for chemotherapy vs. notrecommended for chemotherapy (n=716).

Variable Chemorecommended

Chemo notrecommended

p value

(n=106) (n=610)

Age75–79 82 (20.7%) 314 (79.3%) <0.00180–94 24 (7.5%) 296 (92.5%)

RaceWhite 93 (14.4%) 552 (85.6%) n.s.Asian 9 (20.9%) 34 (79.1%)Black 4 (22.2%) 14 (77.8%)Other 0 10 (100.0%)

Marital statusMarried 40 (15.4%) 220 (84.6%) n.s.Single/divorced 16 (18.0%) 73 (82.0%)Widowed 50 (13.7%) 315 (86.3%)

Tumor size in centimeters (cm)3.34 cm 1.99 cm <0.001

Positive lymph nodesYes 70 (32.7%) 144 (67.3%) <0.001

TNM stageI 17 (4.4%) 372 (95.6%) <0.001II 37 (16.6%) 186 (83.4%)III 52 (51.0%) 50 (49.0%)

Hormone receptor (HR) statusHR positive 72 (11.2%) 570 (88.8%) <0.001HR negative 34 (48.6%) 36 (51.4%)

ER/PR/Her2 statusHR+/her2− 50 (11.3%) 394 (88.7%) <0.001HR+/her2+ 11 (29.7%) 26 (70.3%)HR−/her2− 19 (48.7%) 20 (51.3%)HR−/her2+ 8 (72.7%) 3 (27.3%)

n.s.: not significant.

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(OR)=4.98 (95%confidence interval (CI)=2.58, 9.59), stage III OR=28.15 (95% CI=13.97, 56.73)], 2) hormone receptor status [HRnegative OR=8.62 (95% CI=4.51, 16.47)], 3) age 75–79 [OR=4.48(95% CI=2.50, 8.03)], and 4) race=Asian compared with white[OR 3.11 (95% CI=1.18, 8.22)] (n=716) (Table 4). In a sub-analysisof patients with her-2/neu status testing (1999–2010), order ofentry was: 1) stage, 2) HR/her-2/neu status, and 3) age (n=529)(Table 4). Both models were highly predictive of chemotherapyrecommended with total predictive ability of 87.6% each andsimilar order of entry into the model with stage, hormonereceptor orhormone receptor andher-2/neustatus andyoungerrelative age contributing to significant prediction.

Please cite this article as: Kaplan HG., et al, Adjuvant chemotheraelderly women, J Geriatr Oncol (2013), http://dx.doi.org/10.1016/j.jgo

Comparing patients 75 years and older to patients 65–69and 70–74 years of age, fewer patients were either her-2/neupositive or ER negative but race, stage and tumor sizedistribution were not different. Significantly more womenaged 65–74 years received adjuvant chemotherapy (65–69=34%, 70–74=20%, and 75+=9%; p<.001) with higher comple-tion rates (65–69=91%, 70–74=84%, 75+=73%; p<.001). Treat-ment ending complications increased with age with thehighest rate among patients aged 75 and older (19%) (Table 5).

Average length of follow-up for patients diagnosed before2009 was 7.35 years (range 1.46 to 20.76 years). Forty-sixpercent of the patients aged 75 years and older were alivewith no evidence of disease (NED) at follow-up, 33% died withno evidence of disease, and 18% were either alive with diseaseor died from disease. Overall and disease-free survival rateswere stratified by stages I, II and III (Figs. 2 and 3). Comparingpatients aged 75+ with patients aged 65–74, OS and DSS werenot significantly different for stage I but were for stage II andapproached significance for stage III (Fig. 4). Five year DSS for

py and differential invasive breast cancer specific survival in.2012.12.007

Table 4 – Forward stepwise logistic regression model forpatients seen by an oncologist: chemotherapyrecommended yes/no.

Variable Odds ratio (95% confidenceinterval)

Women aged 75+ with hormone receptor status results (n=716)Stage I Reference categoryStage II 4.98 (2.58, 9.59)Stage III 28.15 (13.97, 56.73)Hormone receptor negative 8.62 (4.51, 16.47)Ages 75–79 compared with 80+ 4.48 (2.50, 8.03)Race=white Reference categoryAsian (n=41) 3.11 (1.18, 8.22)Black (n=18) 0.97 (0.22, 4.23)Marital status: widowed,married, single

Not significant

Women aged 75+ with HR and her2neu status results (n=529)Stage I Reference categoryStage II 4.93 (2.40, 10.15)Stage III 35.38 (15.41, 81.25)HR+/her2− Reference categoryHR+/her2+ 4.51 (1.75, 11.67)HR−/her2− 9.63 (4.12, 22.52)HR−/her2+ 39.92 (8.20, 194.44)Ages 75–79 compared with 80+ 6.34 (3.22, 12.51)Race: white, Asian, black Not significantMarital status: widowed,married, single

Not significant

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stage I breast cancer was 99% for age 65–74 and 99.5% for age75+; 97% for stage II age 65–74 vs. 90% for age 75+; and 81% forstage III age 65–74 vs. 65% for age 75+. In a Cox regressionmodel corrected for stage and treatment by radiation andadjuvant chemotherapy, patients with breast cancer aged 75

Table 5 – Chemotherapy characteristics of women aged 65–69,

65–69(n=734)n (%)

Chemotherapy dispositionNot seen by oncologist 119 (16.2%)Consult only 356 (48.5%)Chemo recommended 259 (35.3%)

Chemotherapy givenYes 246 (95.0%)Recommended, patient refused 13 (5.0%)Chemotherapy given 245 (33.5%)Neoadjuvant therapy given 27 (10.4%)GCSF therapy received 103 (60.9%)

103/169

Chemotherapy completedYes 223 (91.0%)No, expired 0No, patient health issues 1 (0.4%)No, disease progression 1 (0.4%)No, patient choice 2 (0.8%)No, complications 15 (6.1%)No, reason unknown 2 (0.8%)Unknown if completed 1 (0.4%)

n.s.: not significant.

Please cite this article as: Kaplan HG., et al, Adjuvant chemotheraelderly women, J Geriatr Oncol (2013), http://dx.doi.org/10.1016/j.jgo

and older had a significantly increased risk of disease specificmortality (OR 1.69, 95% CI=1.13, 2.54).

4. Discussion

Our studydescribes oncologic practice and treatment ofwomen75 years and older, a population rarely included in clinical trialsdue to a high prevalence of comorbid conditions and increasedmortality from all causes. We found that a substantial numberof women with higher stage disease were seen by oncologistsbut patients in this age group were more likely to refusetreatment and had higher rates of non-completion due tocomplications. Patients on an initial reduced or non-standardtreatment regimen had a 69% completion rate and manypresumably healthier patients starting on standard chemother-apy regimens had to be switched to a reduced regimen orstopped therapy due to complications. Patients started onstandard therapy but switched to a non-standard regimen hada low completion rate (28%).

A significantly smaller percentage of female patients withbreast cancer aged 75 years and older were seen by oncologistscompared to patients aged 65 to 74. A smaller percentage ofpatients 75 years and older with breast cancer had adjuvantchemotherapy treatment and the ones that did were likely toget treatment ending non-neutropenic complications meaningthe majority of patients that had treatment ending complica-tions did not have complications that affected their white bloodcell counts. GCSF was administered as often as in youngerpatients. For specific therapies, we observed that CMF had ahigher rate of treatment ending complications compared withother regimens including those containing doxorubicin. Whilesurprising, in a review of SEER Medicare data Barcenas et al.

70–74, & 75+years.

70–74(n=639)n (%)

75+(n=956)n (%)

p value

138 (21.6%) 240 (25.1%) <0.001350 (54.8%) 610 (63.8%)151(23.6%) 106 (11.1%)

129 (85.4%) 88 (83.0%) <0.00122 (14.6%) 18 (17.0%)127 (20.2%) 88 (9.2%) <0.00117 (11.3%) 14 (13.2%) n.s.48 (58.5%)48/82

38 (53.5%)38/71

n.s.

106 (83.5%) 64 (72.7%) <0.0010 1 (1.1%)2 (1.6%) 00 1 (1.1%)4 (3.1%) 3 (3.4%)12 (9.4%) 17 (19.3%)1 (0.8%) 02 (1.6%) 2 (2.3%)

py and differential invasive breast cancer specific survival in.2012.12.007

Fig. 2 – Overall survival post breast cancer diagnosis by stage of patients aged 75+ (n=830).

Fig. 3 – Disease free survival post breast cancer diagnosis by stage of patients aged 75+ (n=812).

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Please cite this article as: Kaplan HG., et al, Adjuvant chemotherapy and differential invasive breast cancer specific survival inelderly women, J Geriatr Oncol (2013), http://dx.doi.org/10.1016/j.jgo.2012.12.007

Fig. 4 – DSS for stage II and III patients aged 75+ compared to patients age 65–74.

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found favorable adherence of older women to adjuvant doxoru-bicin,with the caveat of less adherence to doxorubicin regimensamong women 75 years and older [9]. Ibrahim et al. observedthat doxorubicin treatment was well tolerated among patients65 and older with similar disease free survival compared to thatof younger patients [10]. Nuzzo et al. evaluated the use ofdocetaxel versus CMF in elderly patients recently and notedbetter tolerance to docetaxel than CMF [11].

Stage I patients' rate of survival was excellent and complete-ly comparable if not superior to women aged 65 to 74 years(99.5% DSS at 5 years). The majority of stage I cases receivedeither no adjuvant systemic therapy or hormone only adjuvanttherapy. This is consistent with the results of the widelyreported ATAC trial [12]. Stage II and III breast cancer was lessprevalent but those patients with higher stage breast cancer

Please cite this article as: Kaplan HG., et al, Adjuvant chemotheraelderly women, J Geriatr Oncol (2013), http://dx.doi.org/10.1016/j.jgo

had a significantly worse disease specific survival than patientswith the same stage (II and III) breast cancer among 65 to74 year olds. Overall survival was particularly poor in womenaged 75 and older reflecting the significant force of mortalitypresent with advanced age. Van der Water et al. have reportedthat older women have a poorer survival with advancing ageeven with hormone receptor positive disease, and that trendwas significantly associated with tumor size and nodal status[13]. It would appear that theworse disease-specific survival weobserved in patients aged 75 and older with stages II and IIIbreast cancer is related to the lower rate of treatment of thesepatients with adjuvant chemotherapy as they had equivalentsurgical and radiation treatments to younger women and asubstantial number were seen by an oncologist. Our observa-tions are in linewith national statistical findings ofworse breast

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cancer specific survival in older women and it appears that thismay be related to limited applicability of adjuvant chemother-apy for higher stage disease in women 75 years and older [5].

Our analysis of a prospective registry cohort is the largestsingle institution patient population of women aged 75 andolder in theUnited States reported to date.Wedonot have exactchemotherapy dosages for all patients in our cohort, but we dohave all information on agents given, timing of treatment andcomplications of treatment. The question of undertreatmentcannot be fully addressed by our study as we do not havemeasures of comorbid conditions. As this is not a randomizedclinical trialwe canonlymake observationsof utility of differentagents and are not able to test their effect on recurrence orsurvival.

The possibility of undertreatment in this age group has beenraised by numerous authors [14–19].We observed a higher rate ofadjuvant hormonal therapy among patients with hormonereceptor positive breast cancer seen by an oncologist (80%) versusthose not seen by an oncologist (44%) indicating possible under-treatment when patients are not seen by an oncologist. Weobserved a very low incidence of lumpectomywithout additionalradiation treatment in our cohort (3%). In an analysis of SEER-Medicare data Albert et al. found that 88% of early stage lumpec-tomy patients aged 70–79 received radiation treatment with 91%among patients aged 70–74 and 84% among patients aged 75–79[20]. The authors found receipt of radiation treatment was asso-ciated with an absolute reduction in risk of subsequent mastec-tomy, a surrogate endpoint for local recurrence, but no benefitregarding mastectomy rates for patients over age 75 unless theyhad high grade tumors with pathologic lymph node assessment.Survivalwasnot addressed. Othershave commentedon the goodprognosis of stage I patients in this age group, even withoutradiation. Hughes et al. have noted that older women treatedwith tamoxifen without radiation for stage I disease have asomewhat higher local recurrence rate but unchanged survivalcompared with those who received radiation [21,22].

Since the majority of the patients with stage II and IIIbreast cancer were seen by oncologists, we assume that thelow rate of chemotherapy recommendations for higher stagecancer was due to comorbid conditions and the pending forceof mortality from conditions other than breast cancer withadvancing age. The low number of women aged 75 and oldergiven chemotherapy (17% among stage II and 50% amongstage III) and the high rate of incompletion due to complica-tions for patients that did receive chemotherapy support theview that current chemotherapy regimens are often notcompatible with advanced age. It is important to point outthat no patients in our cohort died from complications relatedto treatment, suggesting that if flexibility is used severecomplications of therapy can be avoided or at least mitigated.

In a study byOladipo et al. dosing andagent informationwerereviewed to calculate percent of patients aged 65 to 78 yearsreceiving 85% of initial therapy [23]. A significant portion ofpatients achieved intended dose intensity with manageabletoxicity levels. However, 24% required hospitalization for com-plications from treatment. The possibility of using capecitabineas a single agent in older women rather than standard therapyhas been examined [24,25]. Unfortunately, capecitabine provedinferior as a means of disease control while standard therapypatients had twice as many moderate-to-severe toxic effects. In

Please cite this article as: Kaplan HG., et al, Adjuvant chemotheraelderly women, J Geriatr Oncol (2013), http://dx.doi.org/10.1016/j.jgo

France, Laki et al. did not find any difference in cause-specificsurvival for patients with operable breast cancer between 70–75,75–80 and ≥80 years of age [26]. Very few women were treatedwith chemotherapy (3.7%) with most receiving surgery andradiotherapy,whichwould be consistentwith our experience instage I disease. In a review of SEER linkedMedicare datawomenaged 70 and older with lymph node positive, ER-negativebreast cancer had a significant reduction in disease relatedmortality associatedwith chemotherapy [27]. In a reviewof fourrandomized controlled trials, equivalent survival was observedbetween older and younger age groups for equivalent chemo-therapy given but with higher treatment related mortalityrelated to older age [28].

Differential disease-specific survival exists betweenwomen 65–74 years and 75 years and older for higher stagedisease but survival among patients with stage I breast cancer75 years and older is equivalent to younger patients. Womenlower stage disease in this older age group are able to receiveadequate and appropriate therapy independent of comorbidconditions. However, older women with aggressive or ad-vanced stage disease require therapy that is difficult toadminister safely. There is a distinct need to find effectivetreatment that can be tolerated by older adults to bring thestage II and III disease-specific survival rates into line withthose of the younger age groups.

Funding

The study was funded by the Kaplan Cancer Research Fund.

Conflict of Interest

The authors have no conflicts of interest to report.

Author Contribution

Concept and design: HGK, JAM, Data collection: MKA, Analysisand interpretation of data: HGK, JAM,MKA,Manuscript drafting:HGK, JAM, Discussion and final approval: HGK, JAM, MKA.

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