9
Clinical Breast Cancer February 2006 481 Interim Efficacy Analysis of BCIRG 006 Phase III Trail Compar- ing Trastuzumab-Based Adjuvant Treatment of HER2-Overexpressing Breast Cancer Overexpression of the HER2 protein is associated with poor prognosis, including increased risk of relapse and diminished survival compared with HER2-negative breast cancer. 1 Administration of the anti-HER2 monoclonal antibody trastuzumab with chemotherapy (dox- orubicin/cyclophosphamide [AC] or pacli- taxel) has been shown to significantly im- prove response rates (by approximately 20%) and prolong overall survival (OS; by nearly 5 months) for women with HER2- overexpressing metastatic breast cancer (MBC) but was associated with an in- creased incidence of cardiac dysfunction. 2 Recently, results from 3 randomized trials of adjuvant chemotherapy for breast can- cer, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31, North Central Cancer Treatment Group (NCCTG) N9831, and Breast Interna- tional Group (BIG) Herceptin® Adjuvant Trial (HERA), have demonstrated that the addition of trastuzumab improved survival when used subsequent to an- thracycline-based chemotherapy with or without a taxane but with an associated risk of cardiac toxicity. 3,4 Based on pre- clinical studies and phase II trials demon- strating the antineoplastic activity of nonanthracycline- based trastuzumab/do- cetaxel/platinum salt drug combination, the Breast Cancer International Research Group (BCIRG) 006 phase III trial was designed to evaluate the clinical benefit of including trastuzumab with a nonanthra- cycline platinum salt/taxane-based regi- men or the standard anthracycline-based regimen (Figure 1). 5,6 Slamon and col- leagues presented preliminary interim re- sults of the comparative benefits and risks (particularly cardiotoxicity) of this trial at the 28th Annual San Antonio Breast Cancer Symposium, held in De- cember 2005. 7 Eligible patients had fluorescence in situ hybridization–confirmed, HER2-ampli- fied, node-positive or high-risk node-neg- ative breast cancer. All eligible patients (N = 3222) were randomized to receive 1 of 3 regimens: (arm 1) AC (60 mg/m 2 and 600 mg/m 2 , respectively) every 3 weeks for 4 cycles followed by docetaxel (100 mg/m 2 ) every 3 weeks for 4 cycles; (arm 2) AC followed by docetaxel/trastuzumab for 1 year (weekly during treatment and every 3 weeks during follow-up); or (arm 3) concurrent docetaxel (75 mg/m 2 ) and carboplatin (area under the curve of 6) every 3 weeks for 6 cycles plus trastuzum- ab for 1 year. The primary endpoint of the study was disease-free survival (DFS), and secondary endpoints were OS and safety. Of the 3222 patients enrolled, 1073 highlights meeting Prepared by: Sabeeha Muneer, PhD; Aarati Ranganathan, PhD; Susan Peck, PhD; Latha Shivakumar, PhD Reviewed by: Joyce A. O’Shaughnessy, MD 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium San Antonio, TX December 2005 Figure 1: First Interim Analysis of BCIRG 006: Treatment Schema (n = 1075) Docetaxel 75 mg/m 2 plus Carboplatin AUC = 6 every 3 weeks for 6 cycles followed by Trastuzumab* (n = 1074) Doxorubicin 60 mg/m 2 plus Cyclophosphamide 600 mg/m 2 every 3 weeks for 4 cycles followed by Docetaxel 100 mg/m 2 every 3 weeks for 4 cycles plus Trastuzumab* (n = 1073) Doxorubicin 60 mg/m 2 plus Cyclophosphamide 600 mg/m 2 every 3 weeks for 4 cycles followed by Docetaxel 100 mg/m 2 every 3 weeks for 4 cycles *Weekly for 1 year during treatment and every 3 weeks during follow-up. Abbreviation: AUC = area under the curve; FISH = fluorescence in situ hybridization R A N D O M I Z E • HER2-overexpressing (FISH-confirmed) breast cancer • Node-positive or high-risk node-negative breast cancer • Hormone receptor–positive or –negative disease Eligibility Criteria: N = 3222

2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

Embed Size (px)

Citation preview

Page 1: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

Clinical Breast Cancer February 2006 • 481

Interim Efficacy Analysis of BCIRG 006 Phase III Trail Compar-ing Trastuzumab-Based AdjuvantTreatment of HER2-OverexpressingBreast CancerOverexpression of the HER2 protein is

associated with poor prognosis, includingincreased risk of relapse and diminishedsurvival compared with HER2-negativebreast cancer.1 Administration of theanti-HER2 monoclonal antibodytrastuzumab with chemotherapy (dox-orubicin/cyclophosphamide [AC] or pacli-taxel) has been shown to significantly im-prove response rates (by approximately20%) and prolong overall survival (OS; bynearly 5 months) for women with HER2-overexpressing metastatic breast cancer(MBC) but was associated with an in-creased incidence of cardiac dysfunction.2

Recently, results from 3 randomized trialsof adjuvant chemotherapy for breast can-cer, the National Surgical AdjuvantBreast and Bowel Project (NSABP) B-31,North Central Cancer Treatment Group(NCCTG) N9831, and Breast Interna-tional Group (BIG) Herceptin® AdjuvantTrial (HERA), have demonstrated thatthe addition of trastuzumab improvedsurvival when used subsequent to an-thracycline-based chemotherapy with orwithout a taxane but with an associatedrisk of cardiac toxicity.3,4 Based on pre-

clinical studies and phase II trials demon-strating the antineoplastic activity ofnonanthracycline- based trastuzumab/do-cetaxel/platinum salt drug combination,the Breast Cancer International ResearchGroup (BCIRG) 006 phase III trial wasdesigned to evaluate the clinical benefit ofincluding trastuzumab with a nonanthra-cycline platinum salt/taxane-based regi-men or the standard anthracycline-basedregimen (Figure 1).5,6 Slamon and col-leagues presented preliminary interim re-sults of the comparative benefits andrisks (particularly cardiotoxicity) of thistrial at the 28th Annual San AntonioBreast Cancer Symposium, held in De-cember 2005.7

Eligible patients had fluorescence in situ

hybridization–confirmed, HER2-ampli-fied, node-positive or high-risk node-neg-ative breast cancer. All eligible patients(N = 3222) were randomized to receive 1of 3 regimens: (arm 1) AC (60 mg/m2 and600 mg/m2, respectively) every 3 weeksfor 4 cycles followed by docetaxel (100mg/m2) every 3 weeks for 4 cycles; (arm 2)AC followed by docetaxel/trastuzumab for1 year (weekly during treatment andevery 3 weeks during follow-up); or (arm3) concurrent docetaxel (75 mg/m2) andcarboplatin (area under the curve of 6)every 3 weeks for 6 cycles plus trastuzum-ab for 1 year. The primary endpoint of thestudy was disease-free survival (DFS),and secondary endpoints were OS andsafety. Of the 3222 patients enrolled, 1073

highlightsmeeting

Prepared by: Sabeeha Muneer, PhD; Aarati Ranganathan, PhD; Susan Peck, PhD;Latha Shivakumar, PhDReviewed by: Joyce A. O’Shaughnessy, MD

2005Highlights From:

The 28th Annual San Antonio Breast Cancer Symposium

San Antonio, TXDecember 2005

Figure 1: First Interim Analysis of BCIRG 006: Treatment Schema

(n = 1075)Docetaxel 75 mg/m2 plus

Carboplatin AUC = 6 every 3 weeks for 6 cycles followed by

Trastuzumab*

(n = 1074)Doxorubicin 60 mg/m2 plus

Cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles followed by

Docetaxel 100 mg/m2 every 3 weeks for 4 cycles plus

Trastuzumab*

(n = 1073)Doxorubicin 60 mg/m2 plus

Cyclophosphamide 600 mg/m2 every 3 weeks for 4 cycles followed by

Docetaxel 100 mg/m2 every 3 weeks for 4 cycles

*Weekly for 1 year during treatment and every 3 weeks during follow-up.Abbreviation: AUC = area under the curve; FISH = fluorescence in situ hybridization

RANDOMIZE

• HER2-overexpressing(FISH-confirmed)

breast cancer• Node-positive or high-risknode-negative breast cancer• Hormone receptor–positive

or –negative disease

Eligibility Criteria:

N = 3222

Page 2: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

482 • Clinical Breast Cancer February 2006

Meeting Highlights

patients were randomized to arm 1, 1074patients were assigned to arm 2, and 1075patients were assigned to arm 3. The me-dian patient age was 53 years, 62% of pa-tients underwent mastectomy, and 59%received radiation therapy. One third ofpatients had node-negative disease, 39%had 1-3 positive nodes, and 54% had hor-mone receptor–positive tumors.At a median follow-up of 23 months (322

events) at the first planned interimanalysis, the estimated DFS was signifi-cantly increased from 73% in the stan-dard AC followed by docetaxel arm to 84%in the AC followed bydocetaxel/trastuzumab arm (hazard ratio[HR], 0.49; P < 0.0001) and 80% in thedocetaxel/carboplatin/ trastuzumab(TCH) arm (HR, 0.61; 95% confidenceinterval, 0.47-0.79; P = 0.0002). Nostatistically significant difference hasbeen observed between the 2trastuzumab-containing arms (P =0.16). To date, insufficient events pre-clude evaluation of the secondary end-point of OS at this time. All 3 regimens were well tolerated, with

no statistically significant differences inhematologic or nonhematologic toxicities,including febrile neutropenia, in any ofthe 3 treatment arms. However, a signifi-cantly higher incidence of cardiac events(Table 1),7 defined by congestive heartfailure, grade 3/4 arrhythmias, or is-chemia/myocardial infarctions, was ob-served in arm 2 compared with arm 1(2.34% vs. 0.95%; P = 0.016), whereas theincidence of cardiac events in the TCHand AC followed by docetaxel arms werestatistically similar (1.33% vs. 0.95%;P = 0.54). Moreover, more patients in theAC followed by docetaxel/trastuzumab

arm experienced a > 10% decrease in leftventricular ejection fraction comparedwith those in the AC followed by docetax-el arm (17.3% vs. 9%; P = 0.002) or theTCH arm (17.3% vs. 8%; P < 0.0001).

Clinical RelevanceResults of the first interim analysis of

this trial at a median follow-up of 23months confirm that trastuzumab in com-bination with chemotherapy (anthracy-cline- or nonanthracycline-based) signifi-cantly improves DFS compared with an-thracycline/cyclophosphamide/taxanechemotherapy alone in patients withHER2-overexpressing breast cancer. No-tably, the study results confirm earlier re-ports demonstrating that inclusion of ataxane plus trastuzumab after anthracy-cline-based chemotherapy increases therisk of cardiac toxicity. Considering thatthe nonanthracycline-based TCH regimenis associated with lower cardiotoxicity andprovides an improved DFS benefit com-pared with AC followed by docetaxel with-out trastuzumab, the trastuzumab/carbo-platin/taxane regimen appears to be a rea-sonable treatment option for patients withbreast cancer who are at an increased riskof cardiac dysfunction.

Adjuvant Docetaxel or Vinorelbineplus 5-Fluorouracil/Epirubicin/ Cy-clophosphamide, with or Without Trastuzumab, in HER2-Overexpressing Early-Stage Breast Cancer: FinHer TrialTrastuzumab, an anti-HER2 mono-

clonal antibody, is approved for use as a

single agent or in combination for thetreatment of patients with HER2-over-expressing MBC. However, trastuzumabin combination with anthracycline-based chemotherapy is associated with ahigher incidence of cardiac dysfunctionand is therefore contraindicated.8

Recently, interim results from 4 phaseIII trials comparing the efficacy andsafety of trastuzumab in combinationwith standard chemotherapy regimensfor the adjuvant treatment of HER2-overexpressing breast cancer were re-ported. All the trials showed a signifi-cant increase in DFS with trastuzumab(NSABP B31 and NCCTG N9831 com-bined report: HR, 0.48; P < 0.0001,with a 33% reduction in the risk ofdeath [P = 0.015]; BIG HERA trial:HR, 0.54; P < 0.0001; and BCIRG 006trial: HR, 0.49; P < 0.0001 when com-paring AC followed bydocetaxel/trastuzumab with AC fol-lowed by docetaxel, and HR, 0.61; P =0.0002 when comparing TCH with ACfollowed by docetaxel).9-11 However, inthese trials, there was a higher inci-dence of cardiac-related events (grade3/4 congestive heart failure, cardiac is-chemia/infarction, or arrhythmias andcardiac death) in the trastuzumab-con-taining regimens compared withchemotherapy alone, except for theTCH arm of BCIRG 006, which showedno increase in cardiac events cmoparedwith AC followed by docetaxel alone.Thus, the evaluation of alternative

trastuzumab-combination regimens thatmight offer the same or improved effica-cy while reducing cardiotoxicity is a clin-ical priority. The optimal duration oftreatment with trastuzumab is alsobeing investigated. A phase III study wasdone to evaluate the efficacy and safetyof docetaxel or vinorelbine followed by 5-fluorouracil/epirubicin/cyclophos-phamide (FEC) with or withouttrastuzumab, administered for 9 weeksconcomitantly in patients with HER2-overexpressing disease as adjuvant ther-apy in early-stage breast cancer (FinHertrial).12 The interim analysis reportfrom this study was presented by Joen-suu at the 2005 Annual San AntonioBreast Cancer Symposium. This study enrolled 1010 patients (aged

≤ 65 years) with node-positive or node-negative (tumor size > 2 cm and prog-

Table 1: First Interim Analysis of BCIRG 006: Cardiac Toxicities7

Congestive Heart Failure

Cardiac Ischemia/Infarction

Arrhythmias

Total Cardiac Events*

> 10% LVEF Decrease†

Grade 3/4 Toxicity

Number of Patients (%)

AC Followed byDocetaxel(n = 1050)

3

0

7

10 (1)

91/1012 (9)

AC Followed byDocetaxel/

Trastuzumab(n = 1068)

17

4

4

25 (2)

180/1040 (17.3)

Docetaxel/Carboplatin/Trastuzumab(n = 1056)

4

1

9

14 (1)

82/1029 (8)

*P = 0.016 for AC→ T vs. AC → TH; P = 0.54 for AC → T vs. TCH; P = 0.11 for AC → TH vs. TCH.†P = 0.002 for AC → T vs. AC → TH; P = 0.493 for AC → T vs. TCH; P < 0.0001 for AC → TH vs. TCH. Abbreviations: H = trastuzumab; LVEF = left ventricular ejection fraction; T = docetaxel

Page 3: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

Clinical Breast Cancer February 2006 • 483

Meeting Highlights

esterone receptor–negative) breast can-cer. Patients who had experienced anydegree of cardiac failure, severe cardiacdisease, or hypertension were ineligible.All patients were randomized to receivedocetaxel (100 mg/m2) every 3 weeksfor 3 cycles or vinorelbine (25 mg/m2)every week for 8 cycles, followed by FEC(600 mg/m2, 60 mg/m2, and 600 mg/m2,respectively) every 3 weeks for 3 cycles.Patients with HER2-overexpressingdisease were further randomized to re-ceive trastuzumab (4 mg/kg first dosefollowed by 2 mg/kg weekly for 9 weeks)only versus not, concomitantly with doc-etaxel or vinorelbine. The primary objec-tive was to determine recurrence-freesurvival (RFS). Secondary objectiveswere OS, toxicity, and cardiac function. Of the 1010 patients enrolled in the

study (23% with HER2-overexpressingdisease), 1 patient was excluded, 502 pa-tients received docetaxel/FEC, and 507patients received vinorelbine/FEC.Tumor size distribution was significant-ly different between the 2 arms (tumorsize ≤ 10 mm: 6% in the docetaxel/FECarm vs. 10% in the vinorelbine/FECarm; and tumor size > 20 mm: 59% inthe docetaxel/FEC arm vs. 53% in the vi-norelbine/FEC arm; P = 0.02). There

was no significant difference in otherstratification variables.At a median follow-up of 3 years, there

was a significant improvement in RFSwith docetaxel/FEC compared with vi-norelbine/FEC (91.3% vs. 86.4%; HR,0.58; P = 0.005). Recurrence-free sur-vival was significantly improved withthe addition of trastuzumab (89.3% vs.77.6%; HR, 0.42; P = 0.01). Overall sur-vival was not significantly different be-tween chemotherapy regimens (96.4%with docetaxel/FEC vs. 95.5% with vi-norelbine/FEC; HR, 0.66; P = 0.15), al-though there was a trend toward in-creased survival with the addition oftrastuzumab in the HER2-overexpress-ing population (96.3% vs. 89.7%; HR,0.41; P = 0.07; Table 2).12

The major grade 3/4 adverse events ob-served with docetaxel/FEC were neu-tropenia (98%) and neutropenic fever(24%). In comparison, 58% of patients ex-perienced neutropenia and 3% of patientshad neutropenic fever withvinorelbine/FEC. Adverse events weresimilar with trastuzumab plus vinorel-bine/FEC compared with vinorelbine/FEC alone (Table 3).12 The toxicity pro-file of trastuzumab plus docetaxel/FECversus docetaxel/FEC was not reported.

Among the HER2-overexpressing popula-tion, no patients in the trastuzumab armexperienced cardiac failure comparedwith 1% in the control group. Left ven-tricular ejection fraction decrease (> 15%from baseline) was seen in 3% versus 6%of the patients in the trastuzumab andcontrol arms, respectively.

Clinical RelevanceAdjuvant combination chemothera-

py with docetaxel/FEC significantlyimproved RFS compared with vinorel-bine/FEC in early-stage breast cancer(HR, 0.58; P = 0.005), though therewas no difference in OS. However,treatment with docetaxel/FEC was as-sociated with more serious adverseevents, primarily neutropenia and neu-tropenic fever. In addition, short-term ad-ministration of trastuzumab concomi-tantly with docetaxel or vinorelbine for9 weeks increased RFS in patients withHER2-overexpressing breast cancer(HR, 0.42; P = 0.01) compared with thesame chemotherapy regimens with notrastuzumab, with a trend toward im-proved OS. At a median 3-year follow-up, no severe cardiac-related toxicitywas observed with trastuzumab. Basedon these preliminary results, largerphase III studies are needed to definethe optimal duration of adjuvanttrastuzumab therapy in patients withearly-stage breast cancer.

MA.17 Post-Unblinding Updateand Treatment Duration Analysis For women with hormone receptor–pos-

itive early-stage breast cancer, approxi-mately 50% of relapses will occur afterthe completion of 5 years of tamoxifentherapy.13 However, extending tamoxifentherapy beyond 5 years has not beenshown to improve survival and is associ-ated with an increased risk of serious ad-verse events, such as endometrial cancerand thromboembolic events.14 TheMA.17 trial was designed to investigatewhether extending adjuvant endocrinetherapy by following the initial 5 years oftamoxifen with an additional 5 years ofthe aromatase inhibitor letrozole couldreduce the risk of these late recurrencesand further improve patient survival.15

A total of 5187 postmenopausal women

Table 2: Trastuzumab with Docetaxel/FEC or Vinorelbine/FEC in HER2-OverexpressingBreast Cancer: Efficacy12

Recurrence-Free Survival Overall Survival

Percentof Patients

91.3

86.4

89.3

77.6

HR

0.58

0.42

P Value

0.005

0.01

Percentof Patients

96.4

95.5

96.3

89.7

HR

0.66

0.41

P Value

0.15

0.07

Median follow-up was 3 years.*These patients did not receive trastuzumab.

All Patients (N = 1010; 1009 Evaluable)

Docetaxel/FEC (n = 502)

Vinorelbine/FEC (n = 507)

Patients with HER2-Overexpressing Disease (n = 232; 231 Evaluable)

Trastuzumab (n = 115)

Control* (n = 116)

Table 3: Trastuzumab with Docetaxel/FEC or Vinorelbine/FEC in HER2-OverexpressingBreast Cancer: Toxicities12

Neutropenia

Neutropenic Fever

Cardiac Arrhythmia

Grade 3/4Toxicity

All Patients (N = 1010;1009 Evaluable)

Patients with HER2-OverexpressingDisease (n = 232; 231 Evaluable)

Docetaxel/FEC

98

24

Vinorelbine/FEC

58

3

Vinorelbine/FEC

58

2

1

Vinorelbine plusTrastuzumab/FEC

56

5

0

Values are percentages.

Page 4: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

484 • Clinical Breast Cancer February 2006

Meeting Highlights

with early-stage breast cancer who hadcompleted 4.5-6 years of adjuvant ta-moxifen therapy were randomized to re-ceive letrozole (2.5 mg per day orally; n= 2593) or placebo (n = 2594) for an ad-ditional 5 years. Analysis at a medianfollow-up of 30 months demonstratedthat patients on the letrozole arm expe-rienced a significant improvement inDFS (HR, 0.58; P < 0.001) and distantDFS (HR, 0.60; P = 0.002). AlthoughOS was similar between arms (HR, 0.82;P = 0.3), subset analysis revealed a sig-nificant survival advantage for patientswith node-positive disease (HR, 0.61; P =0.04) with letrozole treatment. Based onthe clear efficacy benefits of letrozoletherapy observed at the time of the firstprespecified interim analysis, the studywas unblinded to allow women on theplacebo arm the option of initiatingtherapy with letrozole. Results from an analysis of the out-

comes of patients initially on placebowho elected to receive letrozole therapyafter unblinding were presented byGoss et al at the 2005 San AntonioBreast Cancer Symposium.16 A total of1655 women on the placebo arm electedto receive letrozole therapy, whereas613 patients chose to continue withoutfurther treatment. Patients who optedfor letrozole therapy were generallyyounger (aged < 70 years; 80% vs. 66%;P < 0.01) with a poorer performancestatus (Eastern Cooperative OncologyGroup performance status of 0; 92% vs.96%; P < 0.01) and were less likely to

have node-negative disease (49% vs.57%; P < 0.01) and more likely to havereceived previous chemotherapy (49%vs. 33%; P < 0.01) than those remainingoff treatment. Initiating letrozole thera-py a median of 2.5 years after stoppingtamoxifen was associated with a signifi-cant improvement in DFS (HR, 0.31;P < 0.0001) as well as with improved dis-tant DFS (HR, 0.28; P = 0.002), OS (HR,0.53; P = 0.05), and decreased risk ofcontralateral breast cancer (HR, 0.23;P = 0.017) in an analysis conducted 2years after patients began letrozole(Table 4).16 However, letrozole therapywas associated with a significantly high-er rate of new osteoporosis diagnoses(3.9% vs. 1.6%; P = 0.007) but no signif-icant difference in the incidence of clini-cal fractures (3.2% vs. 2.8%; P = 0.6),and there was no significant difference inincidence of cardiac disease (2.8% vs.2.9%; P = 0.84).In addition, Ingle et al presented re-

sults of an analysis of hazard ratios forrecurrence versus duration of letro-zole treatment performed on the ini-tial randomized study population ofMA.17.17 A nonparametric kernelmethod was used to estimate hazardrates over time, and a Cox model with atime-dependent covariate was used totest the decreasing trend of HRs overtime. The HR for DFS progressively de-creased over time in favor of letrozoleversus placebo, from 0.52 at 12 months to0.19 at 48 months after randomization(P < 0.0001; Table 5).17 Hazard ratiosfor distant DFS comparing letrozole withplacebo also decreased over time, from0.43 at 12 months to 0.21 at 48 months(P = 0.0013), but OS, though alwaystrending toward improvement withletrozole, did not reach significance inthe overall treated population (P = 0.33).In the node-positive population, a

similar decrease in HRs was observedfor DFS (P = 0.0004), distant DFS(P = 0.0005), and OS (P = 0.038; Table6),17 but trends in the node-negativepopulation were not significant.

Clinical RelevanceThe patients initially on the placebo

arm of MA.17 who elected to receive letro-zole therapy after unblinding demonstrat-ed a significant reduction in recurrencerisk and an improvement in OS despitean average of 2.5 years between comple-tion of tamoxifen treatment and initiationof therapy with the aromatase inhibitor.This suggests that patients with a highrisk of recurrence can still receive benefitfrom extended adjuvant therapy withletrozole even if years have passed sincecompletion of tamoxifen. In addition, al-though the analysis of HRs over time doesnot answer questions regarding the opti-mal duration of letrozole therapy, the re-sults suggest that clinical benefits in-crease with increased duration of treat-ment, up to the present analysis done with48-months follow-up.

E1199, A Phase III Study ComparingAdjuvant Paclitaxel with DocetaxelGiven Weekly or Every 3 Weeks Paclitaxel and docetaxel are approved

for the adjuvant treatment of node-negative breast cancer.18,19 Adding pa-clitaxel to AC was found to increase 5-year RFS from 65% to 70% and OSfrom 77% to 80% in patients withnode-positive breast cancer.20 Previousstudies have shown that paclitaxel 80mg/m2 administered weekly has ahigher objective response rate (ORR)and longer time to progression (TTP)than the standard every-3-week regi-men as treatment for MBC.21,22

E1199, a large, randomized, phase IIIstudy, was initiated to compare the effi-cacy of docetaxel and paclitaxel given

Table 4: MA.17 Post-Unblinding Analysis: Efficacy and Safety16

Efficacy

DFS

Distant DFS

OS

ContralateralBreast Cancer

Safety

Clinical BoneFracture

New Osteoporosis

CardiovascularDisease

Hazard Ratio* Outcome

0.31

0.28

0.53

0.23

PlaceboFollowed byLetrozole vs.Placebo (%)

3.2 vs. 2.8

3.9 vs. 1.6

2.8 vs. 2.9

P Value

< 0.0001

0.002

0.05

0.017

P Value

0.6

0.007

0.84

*Placebo followed by letrozole versus no treatment.

Table 5: Hazard Ratio Versus Duration of Treatment17

12

24

36

48

DFS HR(Overall

Population)

Months AfterRandomization

(Letrozole vs. Placebo)

0.52

0.45

0.35

0.19

P Value

< 0.0001

*Placebo followed by letrozole versus no treatment.

Table 6: Hazard Ratio Versus Duration of Treatment17

DFS

Distant DFS

OS

Hazard Ratio Trend, P Value* Outcome

0.0004

0.0005

0.038

*The hazard ratio decreased over time.

Page 5: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

Clinical Breast Cancer February 2006 • 485

Meeting Highlights

weekly or every 3 weeks in terms ofDFS and to compare various dosingschedules for the taxanes in patientswith stage II/III breast cancer who havereceived previous AC treatment. Theresults of this study were presented bySparano et al at the 2005 San AntonioBreast Cancer Symposium.23

A total of 5052 patients with ≥ 1 positiveaxillary lymph node or with high-risknode-negative disease were enrolled inthe E1199 trial between October 1999and January 2002. The median age of pa-tients was 51 years. Patients were ran-domized to receive treatment with 4 cy-cles of AC (60 mg/m2 and 600 mg/m2, re-spectively) every 3 weeks followed by 4 cy-cles of paclitaxel 175 mg/m2 every 3weeks, 12 doses of paclitaxel 80 mg/m2

weekly, 4 cycles of docetaxel 100 mg/m2

every 3 weeks, or 12 doses of docetaxel35 mg/m2 weekly (Figure 2).23 Themaximum planned total doses of thetaxanes were 700 mg/m2 (every-3-weekpaclitaxel), 960 mg/m2 (weekly pacli-taxel), 400 mg/m2 (every-3-week doc-etaxel), and 420 mg/m2 (weekly docetax-el). The majority of the patients receivedall doses of weekly and every-3-week pa-clitaxel (88% vs. 95%, respectively) or do-cetaxel (77% vs. 87%, respectively) as perthe study design. The median follow-uptime was 46.5 months.The primary endpoint was DFS, with a

secondary endpoint of OS. Paclitaxel anddocetaxel were found to have a similarimpact on DFS and OS after AC treat-ment in patients with operable breast

cancer regardless of the dosing schedule(Table 7).23 The HRs for DFS were 0.985(P = 0.83) when comparing the 2 taxanesand 1.043 (P = 0.54) when comparing theweekly and every-3-week schedules. The4-year DFS rates were 80.6%, 83.5%,83.1%, and 80.5%, respectively, for theevery-3-week and weekly paclitaxel or do-cetaxel arms. The 4-year OS rates weresimilar in the 4 treatment arms (88.8%,91.7%, 89.3%, and 88.9%). In an ex-ploratory analysis, weekly paclitaxel wasfound to show a trend toward improvedDFS compared with the standard pacli-taxel arm (HR, 1.2; P = 0.06). In theweekly and every-3-week docetaxel arms,the DFS rates compared with the every-3-week paclitaxel arm were: HR, 1.13, P =0.2 in the weekly docetaxel arm and; HR,1.03, P = 0.78 in the every-3-week doc-etaxel arm. The overall incidence of grade 3/4 ad-

verse events was similar among the 4treatment arms with the exception ofgrade 4 toxicities in the every-3-week do-

cetaxel arm (24% and 6% vs. 24% and 4%vs. 21% and 50% vs. 39% and 6%, respec-tively, for the every-3-week and weeklypaclitaxel or docetaxel arms). However,weekly administration of docetaxel led tosubstantial reduction of grade 3/4 neu-tropenia (3% vs. 46%), febrile neutrope-nia (1% vs. 16%), and grade 3/4 infection(5% vs. 13%) compared with every-3-week docetaxel (Table 8).23 The inci-dence of grade 3/4 neuropathy, which was5% with the every-3-week paclitaxel, in-creased to 8% with weekly paclitaxel.

Clinical RelevanceThe results from E1199 demonstrate

that paclitaxel and docetaxel have similarefficacy in terms of DFS and OS, regard-less of the dosing schedules, when givenafter AC in patients with operable breastcancer. Weekly paclitaxel and every-3-week docetaxel showed a trend towardimproved DFS compared with paclitaxelgiven every 3 weeks—results foreshad-owed by 2 randomized trials in MBC.22,24

Every-3-week docetaxel was associatedwith more grade 3/4 adverse events com-pared with paclitaxel. Because paclitaxeland docetaxel have similar efficacy afterAC as adjuvant therapy for patients withearly-stage breast cancer, the choice of tax-ane for each patient can be made on thebasis of its safety profile.

Phase III Trial of Docetaxel/ Cyclophosphamide Versus Doxorubicin/Cyclophosphamide as Adjuvant Chemotherapy forBreast CancerIn recent years, the use of a taxane as

a single agent or in combination withother active agents for MBC has shownsuperior response rates when compared

Figure 2: E1199 Trail: Treatment Schema23

RANDOMIZE

• T1-3, N1/2, or T2/3 N0Invasive breast cancer

•Treated by lumpectomy ormastectomy plus

negative sentinel node biopsy• ≤ 12 Weeks since final

surgical procedure• Negative surgicalmargin (≥ 1 mm)

Paclitaxel 175 mg/m2

every 3 weeks for 4 cyclesMaximum total dose:

700 mg/m2 (n = 1261)

Paclitaxel 80 mg/m2 weeklyfor 12 cycles

Maximum total dose:960 mg/m2 (n = 1239)

Docetaxel 35 mg/m2 weekly for 12 cyclesMaximum total dose:

420 mg/m2 (n =1245)

Docetaxel 100 mg/m2 every3 weeks for 4 cyclesMaximum total dose:

400 mg/m2 (n = 1243)

HormonalTherapy

RadiationTherapy

N = 5052

Eligibility Criteria:

ACA: 60 mg/m2

C: 600 mg/m2

every 3 weeks

Table 7: E1199 Trial: Survival23

HR Disease-Free Survival

0.985

1.043

P Value

0.83

0.54

88.8

91.7

89.3

88.9

Paclitaxel vs. Docetaxel

Every-3-Week vs.Weekly Schedules

4-Year Overall Survival Rate (%)

Every-3-week paclitaxel

Weekly paclitaxel

Every-3-week docetaxel

Weekly docetaxel

Table 8: E1199 Trial: Grade 3/4 Adverse Events23

Every-3-Week

PaclitaxelEvent Weekly

Paclitaxel

Every-3-Week

Docetaxel

WeeklyDocetaxel

Neutropenia

FebrileNeutropenia

Infection

Fatigue

Neuropathy

4

< 0.5

3

2

5

2

1

4

3

8

46

16

13

9

4

3

1

5

11

6

All numbers are percentages.

Page 6: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

486 • Clinical Breast Cancer February 2006

Meeting Highlights

with nontaxane regimens. Comparingsingle-agent docetaxel with doxorubicinin MBC, a randomized phase III trialshowed an increased ORR (48% vs.33.3%; P = 0.008) and longer medianTTP (26 weeks vs. 21 weeks) in favor ofdocetaxel.25 The main cumulative toxici-ties were different for these agents: car-diac toxicity was predominant with dox-orubicin, and fluid retention was treat-ment-limiting with docetaxel. Two multi-center phase III trials comparing a tax-ane-containing regimen (doxorubicin pluspaclitaxel or docetaxel) to one without ataxane (5-fluorouracil/doxorubicin/cy-clophosphamide [FAC] or AC) as first-linetherapy for MBC reported significantlybetter ORR (P ≤ 0.032) and median TTP(P ≤ 0.034) in the doxorubicin plus pacli-taxel or docetaxel arms.26,27 The studycomparing doxorubicin/paclitaxel withFAC also reported significantly increasedOS (23.3 months vs. 18.3 months; P =0.013) with doxorubicin/paclitaxel. Fur-ther-more, a phase II study has shownpromising results with the combination ofdocetaxel/cyclophosphamide (TC) as first-line therapy in MBC.28 The ORR was65%, median TTP was 6 months, and me-dian OS was 22 months.The observed activity and toxicity pro-

file of docetaxel provide the rationalefor evaluating this agent in early-stagebreast cancer.29 Jones and colleaguesdesigned a randomized phase III trialto compare the efficacy and safety ofTC with AC in early-stage breast can-cer. The results from the final analysiswere presented at the 2005 Annual San

Antonio Breast Cancer Symposium.This study enrolled patients with stage

I/II or operable stage III invasive breastcancer. Patients with invasive cancer > 7cm or < 1 cm, those who had undergoneprevious neoadjuvant chemotherapy forbreast cancer, or who had been treatedwith chemotherapy or radiation therapyfor any other malignancy within 3 yearswere excluded. Eligible patients wererandomized to receive 4 cycles of AC (60mg/m2 and 600 mg/m2, respectively) ver-sus TC (75 mg/m2 and 600 mg/m2, re-spectively), intravenously on day 1 every21 days. Chemotherapy preceded anyradiation therapy, and/or tamoxifen wasadministered to patients with estrogenreceptor–positive cancer afterchemotherapy. The primary endpoint ofthis study was DFS, and the secondaryendpoints were OS and toxicity. Of the 1016 patients in the trial begin-

ning in 1997, 506 were randomized to theTC arm and 510 were assigned to the ACarm. The median age of the patients was52 years, and the prognostic features werewell balanced between the 2 arms. Pa-tients were stratified based on age (< 50years or ≥ 50 years) and lymph node sta-tus (0, 1-3, or ≥ 4 positive nodes). In botharms, approximately 70% of the patientshad hormone receptor–positive breast can-cer, and > 80% had an unknown HER2status. Forty seven percent of the patientsin the TC arm and 49% in the AC arm hadnode-negative disease; approximately 40%in both arms had 1-3 positive nodes.

At a median follow-up of 66 months, the5-year DFS was significantly different(86% with TC vs. 80% with AC; HR, 0.67;P = 0.015). With TC, there were 2 deathson treatment (< 1%; 1 cardiac toxicityand 1 with sepsis and neutropenia). Incomparison, no deaths on treatment oc-curred in the AC arm. Although therewas a trend toward improved 5-year OS,this difference was not statistically signif-icant (90% for TC vs. 87% for AC; HR0.76; P = 0.131; Table 9).29

The adverse event profiles were differentbetween the 2 treatment groups. A signif-icantly higher number of patients treatedwith TC developed grade 3/4 neutropenicfever compared with those administeredAC (6% vs. 3%; P = 0.03). Grade 3/4 nau-sea (2% vs. 7%; P < 0.01) and vomiting(< 1% vs. 5%; P < 0.01) were more fre-quent in the AC arm (Table 10).29 No in-stances of coronary heart failure were re-ported in either treatment group.

Clinical RelevanceThe results of this phase III trial indi-

cate that adjuvant chemotherapy withTC was associated with a significant im-provement in DFS (HR, 0.67; P = 0.015) at5 years and a trend toward improved OSwhen compared with the standard ACregimen in patients with early-stagebreast cancer. The regimens differed sig-nificantly in their safety profiles, withmore pronounced gastrointestinal symp-toms on the AC arm and a somewhatmore frequent incidence of neutropenic

Table 9: Phase III Trial of TC Versus AC as Adjuvant Chemotherapy for Breast Cancer: Efficacy29

TC (n = 506)

Treatment Regimen

Event AC (n = 510)

5-Year DFS

5-Year OS

Local or Distant Relapseor Secondary Cancer

Death (All Causes)

Death (Without Relapse)

Death on Treatment

86%

90%

59 (12)

55 (11)

7 (1)

2 (< 1)*

80%

87%

80 (16)

71 (14)

12 (2)

0

Values in parentheses are percentages.Median follow-up was 66 months. DFS (TC vs. AC): HR, 0.67; P = 0.015.OS (TC vs. AC): HR, 0.76; P = 0.131.*One with cardiac toxicity and 1 with sepsis and neutropenia.

Table 10: Phase III Trial of Docetaxel/Cyclophosphamide Versus Doxorubicin/ Cyclophosphamide as Adjuvant Chemotherapy for Breast Cancer: Toxicities29

Toxicity Docetaxel/Cyclophosphamide Doxorubicin/Cyclophosphamide

All Grades

63

53

16

35

33

24

0

59

6

2

< 1

< 1

1

1

0

Grade 3/4

Treatment Regimen

All Grades

58

81

43

2

17

15

0

Grade 3/4

55

3

7

5

< 1

< 1

1

0

Values are percentages.*P = 0.03.†P < 0.01.

Hematologic Toxicity

Neutropenia

Neutropenic Fever*

Nonhematologic Toxicity

Nausea†

Vomiting†

Edema†

Myalgia†

Arthralgia†

Coronary Heart Failure

Page 7: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

Clinical Breast Cancer February 2006 • 487

fever on the TC arm. Based on these re-sults, TC is a reasonable alternative as anonanthracycline-based adjuvant regi-men for operable breast cancer.

Long-Term Follow-up of Intergroup Trial C9741: Dose-Dense Chemotherapy for Adjuvant Treatment of Early-StageBreast CancerPrevious phase III trials have found that

chemotherapy regimens containing ACand a taxane are superior to AC alone inthe treatment of early-stage breast can-cer.30 In an effort to improve the effec-tiveness of adjuvant chemotherapy forbreast cancer, other treatment parame-ters such as dose intensity, dose density,duration, and sequence have been exten-sively evaluated. Dose-dense schedulingrefers to the administration ofchemotherapy at standard doses but witha shortened intertreatment interval.Based on the Norton-Simon hypothesis,dose-dense scheduling postulates thatmore frequent cytotoxic therapy will re-sult in greater cell-kill by decreasing timefor tumor regrowth and allowing forgreater eradication of residual disease.31

Pilot studies have demonstrated thatdose-dense chemotherapy is safe and fea-sible with hematopoietic growth factorsupport. A phase III trial, IntergroupC9741, was designed to evaluate the effi-cacy of dose-dense versus standard sched-uling and to compare sequential doxoru-bicin followed by paclitaxel followed bycyclophosphamide versus concurrent ACfollowed by paclitaxel for the adjuvanttreatment of node-positive early-stage

breast cancer.32-34 At the 2005 San Anto-nio Breast Cancer Symposium, Hudis etal presented the final efficacy and safetyresults with 6.5 years of follow-up as wellas exploratory subset analyses on behalfof the US Intergroup investigators.35

A total of 1972 patients with resectednode-positive breast cancer were ran-domized with a 2 × 2 factorial designto receive 1 of 4 adjuvant therapies:(regimen 1; n = 501) concurrent AC(60 mg/m2 and 600 mg/m2, respective-ly) followed by paclitaxel (175 mg/m2)each for 4 cycles every 3 weeks; (regi-men 2; n = 495) concurrent AC fol-

lowed by paclitaxel each for 4 cyclesevery 2 weeks (dose-dense); (regimen3; n = 488) 4 cycles each of doxoru-bicin, paclitaxel, and cyclophos-phamide administered sequentiallyevery 3 weeks; (regimen 4; n = 493)the same sequence for 4 cycles eachevery 2 weeks (dose-dense; Figure3).35 All patients who received dose-dense chemotherapy received filgrastimsupport. Study stratifications includedthe number of positive nodes, tumor size,estrogen receptor status, and tamoxifentreatment. Patient characteristics werewell balanced among all arms. The medi-

Meeting Highlights

Figure 3: INT C9741: Treatment Schema35

Arm 1Concurrent/standard AC → T every 3 weeks (21 weeks total)

Arm 2Concurrent/dose-dense AC → T every 2 weeks (14 weeks total)*

Arm 3Sequential/standard A → T → C every 3 weeks (33 weeks total)

Arm 4Sequential/dose-dense A → T → C

every 2 weeks (22 weeks total)*

(N = 1972)

*With filgrastim support (5 μg/kg, 7 doses).Abbreviations: A = doxorubicin 60 mg/m2; C = cyclophosphamide 600 mg/m2; ER = estrogen receptor; T = paclitaxel 175 mg/m2

RANDOMIZE

•Node-positive breast cancer• ER-positive or ER-negative

disease•Completion of primary

treatment (surgery)

Eligibility Criteria:

Table 11: Intergroup Trial C9741: Clinical Outcome at 6.5-Year Median Follow-up35

Abbreviations: ER = estrogen receptor; G-CSF = granulocyte colony-stimulating factor; NS = not significant

Every-3-Week

Schedule

77%

83%

79%

71%

Dose-DenseSchedule

(with G-CSF)P Value

0.012

0.049

NS

0.014

72%

79%

80%

61%

DFS

OS

DFS: Subset Analysis

ER-PositiveTumors

ER-NegativeTumors

Table 12: Intergroup Trial C9741: Major Toxicities35

Toxicity

Regimen IDoxorubicin/

Cyclophosphamide → Paclitaxel

Every-3-WeekSchedule

Regimen IIDoxorubicin/

Cyclophosphamide → Paclitaxel Every-2-Week

Schedule(with G-CSF)

Regimen IIIDoxorubicin→

Paclitaxel→Cyclophosphamide

Every-3-WeekSchedule

Regimen IVDoxorubicin→

Paclitaxel→Cyclophosphamide

Every-2-WeekSchedule

(with G-CSF)

Numbers are percentages unless otherwise indicated. Abbreviations: AML = acute myelogenous leukemia; G-CSF = granulocyte colony-stimulating factor; MDS = myelodysplasia

Number Treated

Grade 4 Neutropenia

Febrile Neutropenia(Patients Hospitalized)

Red Blood Cell Transfusion

Grade 3/4 Neurotoxicity

Long-Term Toxicities (6.5 Years)

Second Breast Cancer

AML/MDS

Grade 3 Cardiac Events

501

43

5

3

3.9

3

1

2.5

495

9

2

13

4.5

1

0.4

1

488

24

3

0

1.9

5

0.4

2.5

493

3

2

2

1.9

1

1

1.5

Page 8: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

488 • Clinical Breast Cancer February 2006

Meeting Highlights

1. Slamon DJ, Clark GM, Wong SG, et al.Human breast cancer: correlation of relapseand survival with amplification of the HER-2/neu oncogene. Science 1987; 235:177-182.

2. Slamon DJ, Leyland-Jones B, Shak S, et al.Use of chemotherapy plus a monoclonal an-tibody against HER2 for metastatic breastcancer that overexpresses HER2. N Engl JMed 2001; 344:783-792.

3. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvantchemotherapy in HER2-positive breast can-cer. N Engl J Med 2005; 353:1659-1672.

4. Romond EH, Perez EA, Bryant J, et al.Trastuzumab plus adjuvant chemotherapyfor operable HER2-positive breast cancer. NEngl J Med 2005; 353:1673-1684.

5. Pegram MD, Konecny GE, O’Callaghan C, etal. Rational combinations of trastuzumabwith chemotherapeutic drugs used in thetreatment of breast cancer. J Nat CancerInst 2004; 96:739-749.

6. Pegram MD, Pienkowski T, Northfelt DW, etal. Results of two open-label, multicenterphase II studies of docetaxel, platinum salts,and trastuzumab in HER2-positive ad-vanced breast cancer. J Nat Cancer Inst2004; 96:759-769.

7. Slamon D, Eiermann W, Rober N, et al. PhaseIII trial comparing AC-T with AC-TH andwith TCH in the adjuvant treatment ofHER2 positive early breast cancer patients:first interim efficacy analysis. Breast CancerRes Treat 2005; 94(suppl 1):S5 (Abstract #1).

8. Slamon DJ, Leyland-Jones B, Shak S, et al.

Use of chemotherapy plus a monoclonal an-tibody against HER2 for metastatic breastcancer that overexpresses HER2. N Engl JMed 2001; 344:783-792.

9. Romond EH, Perez EA, Bryant J, et al.Trastuzumab plus adjuvant chemotherapyfor operable HER2-positive breast cancer. NEngl J Med 2005; 353:1673-1684.

10. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvantchemotherapy in HER2-positive breast can-cer. N Engl J Med 2005; 353:1659-1672.

11. Slamon D, Eiermann W, Robert N, et al.Phase III trial comparing AC followed by Twith AC followed by TH and with TCH inthe adjuvant treatment of HER2 positiveearly breast cancer patients: first interim ef-ficacy analysis. Presented at: the 28th An-nual San Antonio Breast Cancer Sympo-sium; December 8-11, 2005; San Antonio,TX. Abstract #1.

12. Joensuu H, Kellokumpu-Lehtinen P-L, BonoP, et al. Trastuzumab in combination withdocetaxel or vinorelbine as adjuvant treat-ment of breast cancer: the FinHer trial. Pre-sented at: the 28th Annual San AntonioBreast Cancer Symposium; December 8-11,2005; San Antonio, TX. Abstract #2.

13. Early Breast Cancer Trialists’ CollaborativeGroup. Effects of chemotherapy and hor-monal therapy for early breast cancer on re-currence and 15-year survival: an overviewof the randomised trials. Lancet 2005;365:1687-1717.

14. Fisher B, Dignam J, Bryant J, et al. Five ver-

sus more than five years of tamoxifen forlymph node-negative breast cancer: updatedfindings from the National Surgical Adju-vant Breast and Bowel Project B-14 ran-domized trial. J Natl Cancer Inst 2001;93:684-690.

15. Goss PE, Ingle JN, Martino S, et al. Ran-domized trial of letrozole following tamox-ifen as extended adjuvant therapy in recep-tor-positive breast cancer: updated findingsfrom NCIC CTG MA.17. J Natl Cancer Inst2005; 97:1262-1271.

16. Goss PE, Ingle JN, Palmer MJ. Updatedanalysis of NCIC CTG MA.17 (letrozole vs.placebo to letrozole vs placebo) post un-blinding. Breast Cancer Res Treat 2005;94(suppl 1):S10 (Abstract #16).

17. Ingle JN, Goss PE, Tu D. Analysis of dura-tion of letrozole extended adjuvant therapyas measured by hazard ratios of disease re-currence over time for patients on NCICCTG MA.17. Breast Cancer Res Treat 2005;94(suppl 1):S11 (Abstract #17).

18. Paridaens R, Biganzoli L, Bruning P, et al. Pa-clitaxel versus doxorubicin as first-line sin-gle-agent chemotherapy for breast cancer: aEuropean Organization for Research andTreatment of Cancer randomized study withcross-over. J Clin Oncol 2000; 18:724-733.

19. van Oosterom AT. Docetaxel (Taxotere): aneffective agent in the management of sec-ond-line breast cancer. Semin Oncol 1995;22(suppl 13):22-28.

20. Henderson IC, Berry DA, Demetri GD, et al.Improved outcomes from adding sequential

References

an age was 50 years, 65% of patients hadestrogen receptor–positive tumors, 70%of patients received tamoxifen treatment,the median number of positive lymphnodes was 3, and 12% of patients had ≥10 involved axillary lymph nodes. At a median follow-up of 6.5 years, there

was no significant difference in the pri-mary endpoint of DFS (P = 0.65) or sec-ondary endpoint of OS (P = 0.496) be-tween the sequential or concurrent regi-mens (Table 11).35 Comparing the 2 dose-dense versus the 2 standard schedulingarms, DFS (77% vs. 72%; P = 0.012) andOS (83% vs. 79%; P = 0.049) rates weresignificantly prolonged for the dose-densecompared with the 3-weekly regimens.Exploratory subset analyses showed im-proved DFS (71% vs. 61%; P = 0.014) andOS (75% vs. 68%; P = 0.039) rates in pa-tients with estrogen receptor– and prog-esterone receptor–negative disease withdose-dense chemotherapy comparedwith the 3-week schedule, whereasthere was no significant difference inDFS or OS rates with dose-dense sched-

uling in patients with hormone recep-tor–positive disease compared with con-ventional scheduling. Patients who received standard every-

3-week scheduling (sequential or concur-rent) had a higher incidence of grade 4granulocytopenia compared with thoseon the dose-dense regimens (33% vs. 6%;P < 0.0001), with 2% of patients in thedose-dense arm versus 4% in the 3-week-ly arm hospitalized for febrile neutrope-nia (Table 12).35 Of note, 13% of patientson the dose-dense AC followed by pacli-taxel schedule had ≥ 1 red blood celltransfusion compared with < 3% in theother arms. Long-term toxicities weresimilar between the 4 treatment groupswith regard to the incidence of acutemyelogenous leukemia or myelodyspla-sia (0.7% in both dose-dense and stan-dard every-3-week arms), occurrence ofsecond breast cancer (1.2% in the dose-dense arm vs. 3.6% in the every-3-weekarm), and grade 3 cardiac events (1.2%in the dose-dense arm vs. 2.5% in theevery-3-week arm).

Clinical RelevanceThe results of this final report of Inter-

group trial C9741 demonstrate that every-2-week dosing of AC followed by paclitax-el or sequential doxorubicin/ cyclophos-phamide/paclitaxel significantly improvesDFS compared with standard every-3-week scheduling in node-positive breastcancer. Although dose-dense chemothera-py was generally tolerable and neutrope-nia was manageable with the use of fil-grastim, there was an increased need forred blood cell transfusions. However, therisk of long-term toxicities, such as the de-velopment of acute myelogenous leukemia,myelodysplasia, or cardiac events, wassimilar between the dose-dense and stan-dard schedules. Sequential doxorubicin/cyclophosphamide/paclitaxel chemothera-py provided a similar survival benefitcompared with concurrent AC followed bypaclitaxel. In conclusion, dose-densechemotherapy is a superior therapeutic op-tion for node-positive breast cancer, partic-ularly for hormone receptor–negativebreast cancers.

Page 9: 2005 Highlights From: The 28th Annual San Antonio Breast Cancer Symposium; San Antonio, TX December 2005

Clinical Breast Cancer February 2006 • 489

Meeting Highlights

paclitaxel (T) but not from escalating dox-orubicin (A) dose in an adjuvant chemother-apy regimen for patients with node-positiveprimary breast cancer (BC). J Clin Oncol2003; 21:976-983.

21. Seidman AD, Hudis CA, Albanel J, et al.Dose-dense therapy with weekly 1-hour pa-clitaxel infusions in the treatment ofmetastatic breast cancer. J Clin Oncol 1998;16:3353-3361.

22. Seidman AD, Tiersten A, Hudis C, et al.Phase II trial of paclitaxel by 3-hour infu-sion as initial and salvage chemotherapy formetastatic breast cancer. J Clin Oncol 1995;13:2575-2581.

23. Sparano JA, Wang M, Martino S, et al.Phase III study of doxorubicin-cyclophos-phamide followed by paclitaxel or docetaxelgiven every 3 weeks or weekly in patientswith axillary node-positive or high-risknode-negative breast cancer: results ofNorth American Breast Cancer Intergrouptrial E1199. Breast Cancer Res Treat 2005;94(suppl 1): (Abstract #48).

24. Jones SE, Erban J, Overmoyer B, et al. Ran-domized phase III study of docetaxel com-pared with paclitaxel in metastatic breast can-cer. J Clin Oncol 2005; 23:5542-5541.

25. Chan S, Friedrichs K, Noel D, et al. Prospec-tive randomized trial of docetaxel versusdoxorubicin in patients with metastaticbreast cancer. J Clin Oncol 1999; 17:2341-

2354.26. Jassem J, Pienkowski T, Pluzanska A, et al.

Doxorubicin and paclitaxel versus fluo-rouracil, doxorubicin, and cyclophos-phamide as first-line therapy for womenwith metastatic breast cancer: final resultsof a randomized phase III multicenter trial.J Clin Oncol 2001; 19:1707-1715.

27. Nabholtz JM, Falkson C, Campos D, et al. Do-cetaxel and doxorubicin compared with dox-orubicin and cyclophosphamide as first-linechemotherapy for metastatic breast cancer:results of a randomized, multicenter, phase IIItrial. J Clin Oncol 2003; 21:968-975.

28. Trent JC, Valero V, Booser DJ, et al. A PhaseI study of docetaxel plus cyclophosphamidein solid tumors followed by a phase II studyas first-line therapy in metastatic breastcancer. Clin Cancer Res 2003; 9:2426-2434.

29. Jones S, Savin MA, Holmes FA, et al. Finalanalysis: TC (docetaxel/cyclophosphamide, 4cycles) has a superior disease-free survivalcompared to standard AC (doxorubicin/ cy-clophosphamide) in 1016 women with earlystage breast cancer. Presented at: the 28thAnnual San Antonio Breast Cancer Sympo-sium; December 8-11, 2005; San Antonio, TX.Abstract #29.

30. Henderson IC, Berry DA, Demetri GD, et al.Improved outcomes from adding sequentialpaclitaxel but not from escalating doxoru-bicin dose in an adjuvant chemotherapy regi-

men for patients with node-positive primarybreast cancer. J Clin Oncol 2003; 21:976-983.

31. Norton L, Simon R. The Norton-Simon hy-pothesis revisited. Cancer Treat Rep 1986;70:163-169.

32. Hudis C, Seidman A, Baselga J, et al. Se-quential dose-dense doxorubicin, paclitaxel,and cyclophosphamide for respectable high-risk breast cancer: feasibility and efficacy. JClin Oncol 1999; 17:93-100.

33. Fornier MN, Seidman AD, Theodoulou M, etal. Doxorubicin followed by sequential pacli-taxel and cyclophosphamide versus concur-rent paclitaxel and cyclophosphamide: 5-year results of a phase II randomized trial ofadjuvant dose-dense chemotherapy forwomen with node-positive primary breastcancer. Clin Cancer Res 2001; 7:3934-3941.

34. Citron ML, Berry DA, Cirrincione C, et al.Randomized trial of dose-dense versus con-ventionally scheduled and sequential versusconcurrent combination chemotherapy aspostoperative adjuvant treatment of node-positive primary breast cancer: first reportof Intergroup trial C9741/Cancer andLeukemia Group B trial 9741. J Clin Oncol2003; 21:1431-1439.

35. Hudis C, Citron M, Berry D, et al. Five yearfollow-up of INT C9741: dose-dense (DD)chemotherapy (CRx) is safe and effective.Breast Cancer Res Treat 2005; 94(suppl1):S20 (Abstract #41).