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Sandra M. Swain, Gong Tang, Charles E. Geyer Jr, Priya Rastogi, James N. Atkins, Paul P. Donnellan,
Louis Fehrenbacher, Catherine A. Azar, Andr ́e Robidoux, Jonathan A. Polikoff, Adam M. Brufsky,
David D. Biggs, Edward A. Levine, John L. Zapas, Louise Provencher, Donald W. Northfelt, Soonmyung
Paik, Joseph P. Costantino, Eleftherios P. Mamounas, and Norman Wolmark
Journal of Clinical Oncology VOL 31 NUM 26 SEPTEMBER 10 2013
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Adjuvant anthracycline- and taxane- based chemotherapy provides
substantial benefits for women diagnosed with node-positive, early-stage
breast caner
However, a significant proportion of women treated with adjuvant
chemotherapy still develop disease recurrence, which necessitates
additional studies that evaluate alternative treatment strategies.
Doxorubicin(A) and cyclophosphamide(C) followed by paclitaxel(P) on a
dose-dense schedule(DD AC→P) is considered an optimal Paclitaxelbased adjuvant regimen for node-positive primary breast cancer.
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The addition of Gemcitabine(G) to paclitaxel has shown improved
outcomes in women with metastatic breast cancer.
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Therefore in NSABP B-38 trial they chose to test whether the addition of a
fourth agent, Gemcitabine, to DD AC→P would provide a disease-free
survival benefit in the adjuvant setting.
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Because docetaxel(T), A, and C (TAC) is also considered an optimal
docetaxel-based adjuvant regimen, They designed this trial to also compare
TAC with the investigational dose-dense AC→PG regimen.
Gemcitabine
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Patients
◦ Women with histologically proven node-positive invasive breast cancer who had
undergone primary surgery with a total mastectomy or lumpectomy with clear
margins of resection.
◦ Primary tumor stage pT1, pT2, or pT3
◦ Ipsilateral lymph node stage pN1, pN2a, pN3a, or pN3b
◦ Exclusive criteria
 Contralateral breast cancer, a prior history of breast cancer ductal carcinoma in situ
 Cardiac disease that precluded the use of anthracyclines, grade 2 or greater peripheral
neuropathy and pregnant
 HER-2-positive tumor
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Study design
◦ Patients were stratified according to the number of positive lymph node(1 to 3, 4
to 9, or ≥ 10)
◦ Hormone receptor status(ER- and PR-, ER+ and/or PR+)
◦ Type of surgery and planned radiotherapy
◦ After stratification, patients were randomly assigned by using a biased-coin
minimization algorithm
◦ Three treatment regimens
 DD AC→P : four cycles of A 60 mg/m2 plus C 600 mg/m2 every 2 weeks followed by
four cycles of P 175 mg/m2 every 2 weeks
 DD AC→PG : four cycles of A 60 mg/m2 plus C 600 mg/m2 every 2 weeks followed
by four cycles of P 175 mg/m2 plus G 2,000 mg/m2 every 2 weeks
 TAC : six cycles of concurrently administered A 50 mg/m2 plus C 500 mg/m2 plus
docetaxel 75 mg/m2 every 3 weeks
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Statistical Analysis
◦ The primary end point
 Disease-free survival
 Local, regional, or distant breast cancer recurrence, second primary cancer
 Death as a result of any cause that occurred before these other events
◦ Secondary end point
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Overall survival
Death as a result of any cause; recurrence-free interval
Time to first local, regional, or distant recurrence; distant recurrence-free interval
Time to distant disease recurrence only
Toxicities of the drug regimens
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Patients
◦ November 3 2004~ May 3 2007
◦ 4894 women were randomly assigned
 TAC : 1630
 DD AC→P : 1634
 DD AC→PG : 1630
◦ 4859 had follow-up
◦ Baseline charateristics
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Efficacy
◦ After median follow-up of 64months 941 DFS events had been reported
 TAC : 327, DD AC→P : 294, DD AC→PG : 320
◦ At the time of this analysis, 540 of the 4859 patients had died
 TAC : 185, DD AC→P : 188, DD AC→PG : 188
◦ Results from multiple Cox proportional
hazards models, adjusting age at study entry,
number of positive lymph nodes, estrogen
receptor status, and radiation therapy and
type of surgery did not show significant
differences in DFS or OS among the three
treatment arms
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Safety
◦ Toxicity from protocol therapy was
acceptable for the adjuvant setting and
typical for the regimens used.
◦ There were 25 deaths on treatment:
13 in the TAC arm, five in the DD
AC→P arm, and seven in the DD
AC→PG arm (P=0.2)
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Use of ESA
◦ Among 4,841 patients with follow-up data, 2,149 (44.4%) received an ESA
(epoetin alfa or darbepoetin alfa)
◦ Patients who received ESAs had similar incidences of second primary cancer
compared with those who did not receive ESA support (4.3% v 3.8%; P=0.35).
◦ ESA use showed no association with risk of DFS events after adjusting for
treatment, age, tumor size, number of positive nodes, and surgery type
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Anthracyclines and taxanes are among the most active and commonly used
chemotherapeutic agents for the treatment of early-stage breast cancer
On the basis of the findings of the Cancer and Leukemia Group B 9741
trial, which demonstrated significantly improved DFS and OS with dosedense regimens over conventionally scheduled regimens ‘DD AC→P’ is
considered to be one of the most effective P-based adjuvant chemotherapy
regimens
In this study, the addition of G to DD AC→P did not improve outcomes
and no significant differences in efficacy end points were identified between
the investigational arm DD AC→PG and TAC
The future lies in studies that will help us determine appropriate treatments
based on tumor biology(gene expression, hormonal therapy, endocrine
therapy).