VOLUME 23 NUMBER 25 SEPTEMBER 1 2005

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Weekly Paclitaxel Improves Pathologic Complete

Remission in Operable Breast Cancer When Compared
With Paclitaxel Once Every 3 Weeks
Marjorie C. Green, Aman U. Buzdar, Terry Smith, Nuhad K. Ibrahim, Vicente Valero,
Marguerite F. Rosales, Massimo Cristofanilli, Daniel J. Booser, Lajos Pusztai, Edgardo Rivera,
Richard L. Theriault, Cynthia Carter, Debra Frye, Kelly K. Hunt, W. Fraser Symmans, Eric A. Strom,
Aysegul A. Sahin, William Sikov, and Gabriel N. Hortobagyi
From The University of Texas M.D.
Anderson Cancer Center, Houston, TX;
and Brown University, Providence, RI.
Submitted June 30, 2004; accepted
April 23, 2005.
Supported in part by a research grant
from Bristol-Meyers Squibb.
Presented at the 37th Annual Meeting
of the American Society of Clinical
Oncology, San Francisco, CA, May
12-15, 2001; at the 38th Annual Meeting of the American Society of Clinical
Oncology, Orlando, FL, May 18-21,
2002; and in Green MC, Thomas E:
Preoperative systemic therapy for operable breast cancer, in Singletary E (ed):
Advanced Therapy of Breast Disease.
Hamilton, Ontario, Canada, BC Decker,
2004, pp 479-488.
Authors disclosures of potential conflicts of interest are found at the end of
this article.
Address reprint requests to Marjorie C.
Green, MD, The University of Texas
M.D. Anderson Cancer Center, 1515
Holcombe Blvd, Box 424, Houston, TX
77030; e-mail: mgreen@mdanderson.org.
2005 by American Society of Clinical
Oncology
0732-183X/05/2325-5983/$20.00
DOI: 10.1200/JCO.2005.06.232

Purpose
To determine the impact a change in schedule of paclitaxel administration from once every
3 weeks to frequent administration would have on the pathologic complete response (pCR)
rate in the breast and lymph nodes for patients with invasive breast cancer treated with
primary systemic chemotherapy (PST).
Patients and Methods
Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of
paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once
every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were
used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical
response and extent of residual disease in the breast and lymph nodes was assessed after
completion of all chemotherapy.
Results
A total of 258 patients were randomly assigned to receive doses of paclitaxel administered
either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients
had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly
paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel
followed by FAC was administered to 131 patients. Clinical response to treatment was similar
between groups (P .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%)
than patients treated with once-every-3-weeks paclitaxel (15.7%; P .02), with improved breast
conservation rates (P .05).
Conclusion
The change in schedule of paclitaxel from once every 3 weeks to a more frequent
administration significantly improved the ability to eradicate invasive cancer in the breast and
lymph nodes.
J Clin Oncol 23:5983-5992. 2005 by American Society of Clinical Oncology

INTRODUCTION

The use of anthracyclines in combination therapy is superior to the use of nonanthracyclinecontaining regimens. Anthracyclines have
become a key component of routine care for
patients with breast cancer.1 Paclitaxel induces

high response rates when administered once

every 3 weeks to treat metastatic breast cancer
(23% to 56%) and has a non cross-resistant
mechanism of action when compared with
anthracyclines.2-5 Several studies have evaluated the use of paclitaxel in the adjuvant
setting.6-9 The addition of paclitaxel to
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Green et al

anthracycline-based therapy improves both disease-free survival and overall survival for patients with node-positive earlystage breast cancer. Dose-dense paclitaxel (paclitaxel given on
a frequent or weekly schedule) has been shown to be a safe and
effective treatment of metastatic breast cancer, inducing tumor
responses in more than 50% of patients with metastatic breast
cancer.10,11 Recent retrospective data evaluating patients with
metastatic breast cancer has demonstrated that weekly administration of paclitaxel is associated with both improved response rate and time to tumor progression when compared
with the standard every-3-week paclitaxel.12 A phase II study
published in 199713 was among the first to demonstrate that
dose intensity as well as dose density of paclitaxel could have an
impact on response rate for patients with locally advanced or
metastatic breast cancer.
Our current study was designed to determine whether
a change in the schedule from administering paclitaxel once
every 3 weeks to once every week could impact the diseasefree survival rates for patients with early-stage breast cancer.
Another important end point was the determination of the
pathologic complete response (pCR) rate in the breast and
lymph nodes when patients with invasive breast cancer were
treated with primary systemic chemotherapy (PST). This
article presents the pathologic response data for this randomized phase III trial.
PATIENTS AND METHODS
Patients
All patients with histologically confirmed noninflammatory
clinical T1-3, N0-1, and M0 (including T1N0 and T0N1) invasive
carcinoma of the breast were eligible for this study. For patients
receiving PST, all patients had to have bidimensional measurable
locoregional disease and had to have not received local therapy for
their cancer. Patients were required to have adequate bone marrow function (peripheral granulocyte count of 1,500/mm3 and
platelet count 100,000/mm3). Adequate liver function with a
bilirubin within normal laboratory values was required. Serum
creatinine was required to be less than 2.5 mg/100 mL. Patients
with uncompensated congestive heart failure were excluded. Patients with a concomitant or prior history of other invasive carcinoma, except for localized squamous cell or basal cell carcinoma of
the skin or in situ squamous cell carcinoma of the cervix, were
excluded. Two institutions participated in this clinical study: The
University of Texas M.D. Anderson Cancer Center (Houston, TX)
and the Brown University Oncology Group (Providence, RI). The
institutional review boards of both institutions approved the study.
Patients were instructed regarding the investigational design of this
study and were required to sign a written institutional review board
approved informed consent form in compliance with institutional
and federal regulations.
Clinical, Radiologic, and Pathologic Evaluation
Before initiation of therapy, all patients underwent an evaluation that included a complete medical history and physical examination, a complete blood count, chemistry profile, chest radiograph,
liver ultrasound or computed tomography scan of the liver, and a
5984

bone scan. Bone scan and imaging studies of the liver for stage I
patients were optional.
Patients were diagnosed with invasive cancer by either core
biopsy or incisional biopsy. All tumors were evaluated by immunohistochemistry (IHC) for estrogen (ER) and progesterone (PR)
receptors as well as Her-2/neu by IHC and/or fluorescence in situ
hybridization (FISH). Patients were determined to have Her-2/neu
positive disease if they were either 3 by IHC or if they were determined to have gene amplification by FISH. Patients who underwent
incisional biopsy were required to have residual measurable disease
(either in the breast and/or axilla) in order to be included in the trial.
All patients had baseline bilateral mammogram and an ultrasound of
the affected breast and ipsilateral nodal basin.
Patients with lymph nodes that seemed palpable or abnormal
by ultrasound examination underwent fine needle aspiration
(FNA) to diagnose metastasis. Therefore, all patients assessed to
have node-positive disease had cytologic confirmation of lymph
node metastases.
Members of the medical, surgical, and radiation teams evaluated each patient. Tumor measurements were recorded in centimeters. Patients underwent clinical evaluation of the tumor before each
cycle of therapy. Patients also underwent mammogram and ultrasound evaluation of the breast and axilla after completion of both
paclitaxel and fluorouracil/doxorubicin/cyclophosphamide (FAC).
Guided by ultrasound, metallic coils were placed in the tumor bed to
indicate the primary tumor site for patients who might have breastconserving surgery at the completion of the chemotherapy.
Complete clinical response (CR) was defined as the clinical
absence of all evidence of active tumor in the breast and lymph
nodes. Partial response was defined as a 50% reduction in the
product of the perpendicular diameters of the measurable lesion(s) without progression of any lesion or appearance of any
new disease. Stable disease was defined as no change, or as a
decrease in tumor measurements insufficient to qualify as a partial
remission. Progression of disease was defined as a 25% increase in
size of (any) tumor and/or the appearance of new lesions. Combined clinical response included mammographic and ultrasound
evaluations combined with physical examination.
The breast and all excised axillary lymph nodes were fully
evaluated at the time of surgery. Residual gross tumor was measured in three dimensions. Specimens without a residual gross
tumor mass were sectioned and radiographed for comparison
with mammograms. The entire tumor bed was submitted for
histopathologic analysis. Axillary lymph nodes were entirely submitted for histopathologic analysis. Complete pathologic response
was defined as no histopathologic evidence of any residual invasive
cancer cells in the breast or axillary lymph nodes.
Treatment Plan
The overall treatment schema for patients treated with PST is
shown in Figure 1. All patients were prospectively registered for
the study in our online institutional research database, regardless
of the site of enrollment. Patients were stratified by age ( 50 years
or 50 years), tumor size, and by nodal status (N0 or N1).
Chemotherapy
Paclitaxel. The chemotherapy schema for paclitaxel is
shown in Figure 2. All chemotherapy was administered in the
outpatient setting. Patients assigned to the once-every-3-weeks
arm received paclitaxel 225 mg/m2 administered as a continuous
intravenous infusion over a period of 24 hours on day 1. Patients
received dexamethasone 20 mg, diphenhydramine 50 mg, and
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Weekly Paclitaxel Improves pCR Rate

Fig 1. Overall treatment schema: preoperative chemotherapy. ER,

estrogen receptor; PR, progesterone receptor; FAC, fluorouracil/doxorubicin/cyclophosphamide.

cimetidine 300 mg intravenously 30 minutes before chemotherapy. Therapy was given every 21 days for four cycles before receiving FAC.
Patients assigned to doses of weekly paclitaxel received different doses based on their nodal status because of the potential
toxicity associated with high-dose weekly paclitaxel. Patients
that were at a lower perceived risk of recurrence (node-negative)
received a more standard dose of weekly paclitaxel. Only patients
perceived to be at a higher risk of recurrence (node-positive)
received dose-intense weekly paclitaxel therapy. Patients who were
randomly assigned to weekly paclitaxel and had a lymph node
metastasis diagnosed by FNA initially received paclitaxel 175
mg/m2 given as a 3-hour intravenous infusion every week for 6
weeks followed by a 2-week break. This constituted one cycle of
therapy. Patients randomly assigned to this dose/schedule received two cycles of treatment. However, analysis of toxicity after
the first cohort of patients (n 13) revealed unacceptable levels of

grade 3 neurotoxicity (76.9%), and the dose of paclitaxel was

therefore reduced to 150 mg/m2, maintaining the same schedule.
Evaluation of the second cohort of patients treated with
high-dose paclitaxel at 150 mg/m2 (n 14) showed a reduction in
grade 3 neurotoxicity (50%) but that an increasing number of
patients had delay in delivery of their dose at week 4 due to
neutropenia.14 Therefore, the schedule of paclitaxel was changed
for this group. The remainder of the patients treated with highdose weekly paclitaxel (n 29) received 150 mg/m2 over a period
of 3 hours every week for 3 weeks, followed by a one-week rest.
This constituted one cycle of therapy. Four cycles of paclitaxel
were administered at this dose and schedule to the remainder of
the patients with lymph node involvement who were randomly
assigned to receive weekly paclitaxel therapy. Patients receiving
high-dose weekly paclitaxel received dexamethasone 20 mg intravenously 30 minutes before chemotherapy. Diphenhydramine 50
mg and cimetidine 300 mg were optional.
The clinically N0 patients randomly assigned to the weekly
schedule received paclitaxel 80 mg/m2 administered as an intravenous infusion over a period of 1 hour every week for 12 weeks.
Dexamethasone 10 mg was given intravenously 30 minutes before paclitaxel for the first three doses. If the patient had no
symptoms or signs of allergic reaction to paclitaxel, then the dose
of dexamethasone was decreased to 5 mg intravenously 30 minutes before chemotherapy.
FAC. FAC chemotherapy consisted of fluorouracil 500
mg/m2 administered intravenously on days 1 and 4; cyclophosphamide 500 mg/m2 administered intravenously on day 1; and doxorubicin 50 mg/m2 administered as a 72-hour continuous intravenous
infusion through a central catheter. FAC was administered every 21
days for four cycles to all patients after completion of all doses of
paclitaxel. All chemotherapy (paclitaxel 4 and FAC 4) was given
before locoregional therapy.
Dose modification criteria. National Cancer Institute toxicity
criteria version 2.0 was used to assess all treatment-related toxicities. Of the patients receiving low-dose weekly paclitaxel (80 mg/
m2/wk), the dose of paclitaxel was reduced by 25% for those
patients with neurotoxicity of NCI grade 3 or higher. Of the

Fig 2. Paclitaxel chemotherapy plan.

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Green et al

patients receiving high-dose weekly paclitaxel (175 or 150 mg/m2),

if they developed grade 3 NCI neurotoxicity, the paclitaxel dose
was stopped until the neurotoxicity diminished to grade 2 or
lower, and then paclitaxel was resumed at 80 mg/m2 for the remainder of the cycles. If a patient receiving high-dose weekly
paclitaxel had NCI grade 2 neurotoxicity on the day therapy was
due to be administered, the paclitaxel dose was reduced to 80
mg/m2 for the remaining doses. If the dose of paclitaxel was
reduced to 80 mg/m2, the doses were delivered weekly without any
breaks. The dose of weekly paclitaxel was reduced by 20% for other
nonhematologic NCI grade 3/4 organ toxicities. While receiving
FAC, the dose of FAC was reduced by 20% for nonhematologic
toxicities that were NCI grade 3 or higher, if not controlled by
conservative management. Patients did not receive routine hematopoietic growth factor (granulocyte colony stimulating factor). If
a patient experienced neutropenic fever, granulocyte colony stimulating factor was prescribed.
Statistical Considerations
This report focuses on the neoadjuvant arm of a larger trial of
480 patients that will assess the impact of different schedules of
paclitaxel, given as either PST or adjuvant therapy, on disease-free
survival. The initial trial design anticipated that at least 220 of the
480 patients would present with intact tumors and therefore they
would receive PST. This would thereby provide 80% power for a
further objective to detect an 18% difference in clinical CR rates
between groups treated with weekly or once-every-3-weeks paclitaxel schedules (two-sided type 1 error .05). Because pCR is now
recognized as a more reproducible measure of response and a
better predictor of long-term patient outcomes, the analysis of
results focuses on pathologic results, although clinical response
results are also presented. pCR was defined as the absence of
invasive cancer cells in both the breast and the lymph nodes. This
definition allowed residual noninvasive breast cancer. The data
presented here is defined as per the American Joint Committee on
Cancer staging guidelines published in 2002.15
Clinical response was determined by physical examination.
Combined clinical response was calculated by combining physical
examination with mammogram and ultrasound. For patients randomly assigned to receive PST, but who received therapy in the
adjuvant setting or for whom data was not sufficient for analysis of
clinical response, clinical response was described as not assessable.
Tabulated response results were compared using the 2 test, or
Fishers exact test in the case of some small subsets. Results were
compared separately for patients with N0 disease and those with N1
disease, and then combined using the Mantel-Haenszel method.
Compliance With Treatment
Of the 258 patients, one patient randomly assigned to receive
paclitaxel once every 3 weeks and three patients randomly assigned to
receive paclitaxel weekly chose to have surgery before receiving PST.
In order to include all randomly assigned patients, the response results determined at the time of surgery for these patients were included, even though these patients had not had benefit from
chemotherapy at that time. These patients received chemotherapy
according to the randomized assignment, after surgery.
For another nine patients, surgical pathology results were not
available. For six of these nine patients who were randomly assigned to once-every-3-weeks paclitaxel, reasons for unavailability
were the following: treated at outside facility with no pathology
report available (three patients), disease progression (two patients), and death secondary to sepsis (one patient). For three of
5986

these nine patients who were randomly assigned to weekly paclitaxel,

reasons for unavailability were the following: treated at outside facility
with no pathology report available (one patient), patient refused
surgery (one patient), and disease progression (one patient). All of
the nine patients were included in the totals as not achieving pCR
in tabulations for the primary analyses, but were omitted from the
tabulations regarding size of tumor involvement in breast and nodes
if data were not sufficient for analysis.
RESULTS

Between November 1998 and July 2001, of the 480 patients

enrolled onto the study, 258 patients with intact breast cancer

Table 1. Pretreatment Patient and Tumor Characteristics

Once-Every3-Weeks
Paclitaxel
(n 127)
Characteristic
Clinical tumor status
T0
T1
T2
T3
T4
Nodal status
N0
N1
Clinical stage
I
IIA
IIB
IIIA
IIIB
Age, years
50
50
Median
Range
Ethnicity
White
Black
Hispanic
Other
Estrogen (and/or progesterone) receptor
Positive
Negative
Unknown
Her-2/neu
Positive
Negative
Unknown
Nuclear grade (Blacks)
I (well differentiated)
II (moderately differentiated)
III (poorly differentiated)
Data not available

Weekly
Paclitaxel
(n 131)

No. of
Patients

No. of
Patients

2
21
89
14
1

2
16
70
11
1

0
22
92
16
1

0
17
70
12
1

73
54

57
43

72
59

55
45

10
69
38
9
1

8
54
30
7
1

11
65
45
9
1

8
50
34
7
1

60
67

47
53

66
65

50
50

50
27-73

49
25-76

94
15
13
5

74
12
10
4

104
8
15
4

80
6
11
3

83
44
2

65
35
2

95
31
5

72
24
4

31
94
2

24
74
2

24
104
3

18
79
2

6
57
60
4

5
45
47
3

8
54
65
4

6
41
50
3

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Weekly Paclitaxel Improves pCR Rate

received PST with either weekly or once-every-three-weeks

doses of paclitaxel. The remaining patients enrolled onto the
study received therapy in the adjuvant setting. Data regarding
these patients will be described in a separate article. One hundred ten patients were documented to have axillary lymph
node involvement after FNA of suspected lymph nodes. Of
these 110 patients, 54 received paclitaxel once every 3 weeks
and 56 patients received paclitaxel on a weekly schedule. One
hundred forty-eight patients had normal appearing lymph
nodes, based on physical examination and ultrasound.
Seventy-three of these 148 patients received paclitaxel once
every 3 weeks and 75 patients received paclitaxel on a weekly
schedule. Table 1 lists the pretreatment patient and tumor
characteristics. Approximately 70% of all patients had T2 tumors. Approximately 40% or more of all patients had cytologically proven lymph node involvement. More than half of all
patients enrolled had hormone-receptorpositive tumors (ER

and/or PR) and more than 70% of patients were Her-2/neu

negative by either IHC (0, 1, or 2) or FISH.
Table 2 lists clinical response and combined clinical
response to PST based on treatment schedule, as well as on
the method of local therapy. The combined clinical response includes physical examination as well as mammogram/ultrasonography. Twenty-four percent of patients
receiving paclitaxel once every 3 weeks obtained a clinical
CR after completion of paclitaxel administration. Four patients receiving once-every-3-weeks paclitaxel had progression of disease on therapy, including one patient who
progressed before receiving any therapy. Thirty-four percent of patients receiving weekly paclitaxel obtained a
clinical CR after completion of paclitaxel. One patient developed metastatic progression on weekly paclitaxel therapy. There was no statistical difference in clinical response
based on treatment schedule (P .25). Breast-conserving

Table 2. Clinical Response to Therapy and Method of Surgical Management

Once-Every-3Weeks Paclitaxel
(n 127)
Characteristic
Clinical response after paclitaxel
CR
PR
Stable disease
Progressive disease
Not assessable
Overall response after paclitaxel
CR
PR
Stable disease
Progressive disease
Not assessable
Clinical response after all PST (includes US/MMG)
CR
PR
Stable disease
Progressive disease
Not assessable
Overall response after all PST (includes US/MMG)
CR
PR
Stable disease
Progressive disease
Not assessable
Local therapy/type of surgery
Modified radical mastectomy/axillary dissection or sentinel node biopsy
Segmental mastectomy/axillary dissection or sentinel node biopsy
Segmental mastectomy alone
Axillary dissection alone
None
Unknown

No.

Weekly Paclitaxel
(n 131)
No.

P
.25

30
59
27
4
7

24
47
21
3
6

45
56
17
4
9

34
43
13
3
7

10
68
41
5
3

8
54
32
4
2

14
72
35
4
5

11
55
27
3
4

50
58
10
2
7

39
46
8
2
6

73
39
10
1
8

56
30
8
1
6

30
75
15
4
3

24
59
12
3
2

46
65
14
1
5

35
50
11
1
4

73
48
0
1
3
2

57
38
0
1
2
2

65
61
2
0
2
1

50
47
1
0
1
1

.94

.05

Abbreviations: CR, complete response; PR, partial response; PST, primary systemic chemotherapy; US/MMG, ultrasound/mammogram.

Not assessable includes patients for whom data describing physical examination was not adequate to determine response, including patients treated in the
adjuvant setting.

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Table 3. Median Cumulative Dose of Paclitaxel and Relative Dose Intensity As Delivered
Once-Every-3-Weeks Paclitaxel
(n 127)

Weekly Paclitaxel
(n 131)

Node-Positive Patients
(n 54)

Node-Negative Patients
(n 73)

Node-Positive Patients
(n 56)

Node-Negative Patients
(n 75)

900 mg/m2
75 mg/m2/wk

900 mg/m2
75 mg/m2/wk

1,380 mg/m2
86.3 mg/m2/wk

960 mg/m2
80 mg/m2/wk

Median cumulative dose

Dose intensity

therapy was completed for 48 patients who received paclitaxel once every 3 weeks compared with 61 patients who
received paclitaxel on a weekly schedule (P .05).
Table 3 lists the median cumulative dose of paclitaxel
received per treatment arm as well as the relative median
dose intensity per treatment arm calculated based on the
cumulative dose/duration of therapy (weeks).
The pathologic response to therapy based on examination of the breasts and lymph nodes is listed in Tables 4 and
5. The pCR in the breast alone is listed in Table 6. Six
patients who received once-every-3-weeks paclitaxel had
measurable disease only in the axilla before chemotherapy
(five patients status after excisional biopsy; one patient T0).
Ten patients who received weekly paclitaxel had undergone
excisional biopsy and had measurable disease only in the
axillae before chemotherapy. All of these patients were included in the intent-to-treat analysis.
After completion of once-every-3-weeks paclitaxel and
FAC, 15.7% of patients had no residual disease in the breast
and axillae. For those patients who received weekly paclitaxel followed by FAC, 28.2% of patients obtained a pathologic complete response in the breast and axillae (P .02;
Fig 3). The magnitude of response was similar for patients
receiving paclitaxel once every 3 weeks, regardless of nodal
status. For patients receiving differing doses of weekly paclitaxel, the magnitude of pCR was also similar.
An unplanned analysis of pCR in the breast and lymph
nodes based on ER/PR status is listed in Table 7. Patients
with ER/PRnegative tumors, as well as those with ERand/or PR-positive tumors, receiving weekly paclitaxel had
increased pCR rates compared with those receiving onceevery-3-weeks paclitaxel (P .007). Patients with ER/PR

negative tumors had a higher pCR rate compared with those

patients with ER- and/or PR-positive tumors, regardless of
the paclitaxel schedule administered. However, the magnitude of benefit observed with the use of weekly paclitaxel
was increased in patients with ER- and/or PR-positive tumors (pCR, 22%) compared with those patients receiving
once-every-3-weeks paclitaxel (pCR, 11%).
Toxicities of both treatment schedules are listed in
Table 8. Patients initially randomly assigned to receive paclitaxel at a dose of 175 mg/m2 had an unacceptable level of
grade 3 neurotoxicity (76.9%). With reduction of the dose
of weekly paclitaxel to 150 mg/m2, neurotoxicity was reduced to 45.5%. Of the patients receiving weekly paclitaxel
at a dose of 80 mg/m2/wk, 13.5% developed grade 3 neurotoxicity. The rate of infection was low for patients receiving
weekly paclitaxel regardless of the dose of paclitaxel used.
DISCUSSION

Paclitaxel, when given on a standard once-every-3-weeks

schedule following or preceding an anthracycline-containing
regimen, improves disease-free and overall survival in patients
with lymph-nodepositive breast cancer.7,8,9 The activity of
paclitaxel is directly related to the cell cycle. It is hypothesized
that administration of paclitaxel on a more frequent or continuous schedule will improve the efficacy of this agent. Paclitaxel given on a frequent basis also potentially exhibits
antiangiogenic and pro-apoptotic effects, thereby enhancing
the efficacy of this schedule.16-18 For example, Symmans et al19
found that the apoptotic response to paclitaxel was almost
complete within 4 days, suggesting that more frequent dosing

Table 4. Pathologic Response to Chemotherapy According to Nodal Status (paclitaxel and FAC)
Once-Every-3-Weeks Paclitaxel
(n 127)
Node-Positive
Patients
(n 54)

pCR, breast and axillae

Weekly Paclitaxel
(n 131)

Node-Negative
Patients
(n 73)

Node-Positive
Patients
(n 56)

Node-Negative
Patients
(n 75)

No.

No.

No.

No.

17

11

15

16

29

21

28

.02

Abbreviations: FAC, fluorouracil/doxorubicin/cyclophosphamide; pCR, pathologic complete response.

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Weekly Paclitaxel Improves pCR Rate

Table 5. Overall Pathologic Response

Once-Every-3-Weeks Paclitaxel
(n 127)

Weekly Paclitaxel
(n 131)

No. of Node-Positive Patients

(n 54)

No. of Node-Negative Patients

(n 73)

No. of Node-Positive Patients

(n 56)

No. of Node-Negative Patients

(n 75)

10
5
13
20
3
3

9
3
24
30
1
6

15
4
9
21
4
3

18
3
15
36
1
2

16
23
11
3
1

51
11
4
1
6

31
16
6
1
2

59
11
4
0
1

Breast
No invasive disease
In situ only
1 cm
1-5 cm
5 cm
Not measurable
Lymph nodes
0
1-3
4-10
10
Not measurable

This includes patients with T0 or TX tumors, patients without pathology, or patients who had persistent disease that could not be accurately measured.

(such as the weekly dose we tested in our study) of paclitaxel might be beneficial to maintain continued apoptotic
response. A preclinical study20 also demonstrated that tumoral apoptotic response after paclitaxel treatment is associated with a significant decrease in interstitial pressure, and
with vasodilatation and increased endothelial surface area.
This decompression in the tumor continues for several days
after the apoptotic response, so in humans, by day 7 there
is probably still a period of favorable intratumoral perfusion
and drug delivery to the cancer cells. Our prospective clinical
trial was planned to evaluate whether the schedule of paclitaxel
treatment affects the in vivo response to PST, as defined by the
pathologic response in the breast and lymph nodes.
PST has many theoretical benefits. However, the timing of chemotherapy has not demonstrated definitively an
impact on overall survival.21,22 The ability of a chemotherapy regimen to eradicate invasive breast cancer in the breast
(and lymph nodes) has been retrospectively correlated with
long-term survival.21-24 It can be hypothesized that any
regimen that improves the pCR rate when compared with a
known standard will likely be able to improve overall survival.25 Therefore, pCR may be a biologic surrogate to
disease-free survival and overall survival. This feature of
neoadjuvant chemotherapy is being studied prospectively

in several randomized trials, including National Surgical

Adjuvant Breast and Bowel Project (NSABP) B-27.26
Several published studies have evaluated the use of
taxanes as a component of PST. The majority of these are
phase II studies evaluating anthracycline- and taxane-based
therapy in the preoperative setting for locally advanced
breast cancer with a wide range of pCR rates (8% to 22%) in
a heterogeneous group of patients.27-29 The largest phase III
study, NSABP B-27, compared patients receiving docetaxel
once every 3 weeks for four cycles after four cycles of doxorubicin and cyclophosphamide (AC) with patients who
only received four cycles of AC. Patients receiving AC

Table 6. Pathologic Complete Response in the Breast Alone

pCR, breast

Once-Every-3-Weeks Paclitaxel
(n 127)

Weekly Paclitaxel
(n 131)

21.3%

30.5%

.2

Abbreviation: pCR, pathologic complete response.

Fig 3. Overall pathologic response. pCR, pathologic complete response.

5989

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Green et al

Table 7. pCR by Schedule of Paclitaxel According to ER/PR Status

Once-Every-3-Weeks Paclitaxel
(n 127)
ER- and/or PRPositive Patients
(n 83)

pCR, breast and axillae

ER- and PRNegative Patients

(n 44)

Weekly Paclitaxel
(n 131)

No.

No.

UNK
(n 2)

11

10

23

ER- and/or PRPositive Patients

(n 95)

ER and PR
Negative Patients
(n 31)

No.

No.

UNK
(n 5)

21

22

15

48

.007

Abbreviations: pCR, pathologic complete response; ER, estrogen receptor; PR, progesterone receptor; UNK, unknown.

followed by docetaxel achieved a pCR of 25.6% in the breast

alone compared with a pCR of 13.7% for patients receiving
only AC.26 In our study, the pCR in the breast alone was
21.2% for patients receiving once-every-3-weeks paclitaxel
followed by FAC versus 31% for those patients receiving
weekly paclitaxel followed by FAC. As our study was designed to evaluate both the breast and lymph nodes, direct
comparisons across studies should be done with caution.
Many studies evaluating PST present the data regarding pCR in reference to the breast alone, as in NSABP B-27;
however, residual disease in the axilla can negatively predict
survival.24,30 Our study evaluates the pCR in the breast and
axillae. When evaluated on an intent-to-treat basis, we have
shown that changing the schedule of paclitaxel results in
significantly improved ability to eradicate invasive cancer in
both the breast and lymph nodes. If patients treated in the
adjuvant setting despite being randomly assigned to PST are
excluded from analysis, the results reveal that the pCR is still
increased for patients receiving weekly paclitaxel (29%)
compared with those receiving paclitaxel once every 3
weeks (16%). In addition, the difference in magnitude of

pCR is maintained in both hormone-receptorpositive and

negative patients receiving weekly paclitaxel, with 22% of
patients with ER- and/or PR-positive patients obtaining a
pCR in the breast and lymph nodes compared with 11% for
those patients treated with once-every-3-weeks paclitaxel
and FAC.
Toxicities were not the same in the treatment groups.
Patients randomly assigned to receive high-dose weekly
paclitaxel had significant neurotoxicity limiting the usefulness of this dose for routine clinical use. Paclitaxel administered at a lower dose of 80 mg/m2 was very well tolerated,
with a reduced risk of neutropenic fever and grade 3 neuropathy, compared with once-every-3-weeks paclitaxel.
This is in keeping with the results of a randomized trial
comparing weekly paclitaxel at low and high doses in the
metastatic setting.31 One patient died of a treatment-related
septic episode during the FAC portion of chemotherapy.
This patient had been randomly assigned to receive the
standard once-every-3-weeks paclitaxel followed by FAC.
Recent data from the Cancer and Leukemia Group B
(CALGB) demonstrated that chemotherapy administered

Table 8. Toxicities of Paclitaxel Treatment

% Distribution
Toxicity
Neutropenic fever
Neutropenic infection
Non-neutropenic infection, grade 2-3
Myalgias
Grade 2
Grade 3
Allergic reaction, grade 2-3
Stomatitis, grade 3
Nausea, grade 3
Vomiting, grade 3
Diarrhea, grade 3

Paresthesias
Grade 2
Grade 3

5990

Once-Every-3-Weeks Paclitaxel
(n 127)

Weekly Paclitaxel
(n 131)

19.7
9.5
23.7

3.1
1
18.1

50.4
29.9
4.7
2.4
3.1
1
5.5

39.7
19.1
3.9
0
3.1
0
5.3

37
14.2

175 mg/m2

150 mg/m2

80 mg/m2

15.4
76.9

38.6
45.5

23
13.5

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Weekly Paclitaxel Improves pCR Rate

on a more dose-dense schedule (every 2 weeks) resulted

in improved disease-free and overall survival compared
with therapy given on a standard once-every-3-weeks
schedule.8 It is possible that the main determinant of this
difference in survival is the administration of paclitaxel on a
more frequent schedule. This advantage is consistent with
the results of our current study. We demonstrate a significant therapeutic improvement with weekly paclitaxel. This
is possibly because a more frequent schedule is favorably
aligned with the timing of pathophysiologic responses to
paclitaxel in the tumor. In that circumstance, the advantages obtained from frequent administration of paclitaxel
may outweigh the effects of higher dose. Although the ideal

dose of weekly paclitaxel is not defined,; doses between 80

and 100 mg/m2 have demonstrated safety in the metastatic
setting. Whether increasing, or even decreasing, the dose of
paclitaxel will result in a superior outcome is to be determined. However, the high-dose weekly paclitaxel schedule
in this study seems to not have had an impact on the
magnitude of benefit, but the toxicity of the higher dose
limits its utility. Additional follow-up will be needed in
order to determine whether the change in schedule of paclitaxel improves survival for patients with operable breast
cancer, and if so, whether dose intensity adds any benefit to
the schedule change.

Authors Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following authors or their immediate family members
indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the
investigation. For a detailed description of the disclosure categories, or for more information about ASCOs conflict of interest
policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Authors

Employment

Leadership

Consultant

Stock

Marjorie C. Green

Honoraria

Research Funds

Testimony

Other

Bristol (A)

Aman U. Buzdar

AstraZeneca (A)

Pfizer (C);
Genentech (C);
Roche (C);
Bristol (C)

Nuhad K. Ibrahim

Novartis (B)

Eli Lilly (B);

Biomera (B)

Richard L. Theriault

National
Comprehensive
Cancer Network
(A)

William Sikov

Bristol-Myers
Squibb Oncology
(A)
Dollar Amount Codes

REFERENCES
1. Early Breast Cancer Trialists Collaborative
Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet
352:930-942, 1998
2. Holmes FA, Walters R, Theriault RL, et al:
Phase II trial of taxol, an active drug in the
treatment of metastatic breast cancer. J Natl
Cancer Inst 83:1797-1805, 1991
3. Seidman AD, Reichman BS, Crown JP, et
al: Paclitaxel as second and subsequent therapy
for metastatic breast cancer: Activity independent of prior anthracycline response. J Clin Oncol
13:1152-1159, 1995
4. Abrams JS, Vena DA, Baltz J, et al:
Paclitaxel activity in heavily pretreated breast
cancer: A National Cancer Institute Treatment
Referral Center trial. J Clin Oncol 13:20562065, 1995
5. Nabholtz JM, Gelmon K, Bontenbal M, et
al: Multicenter, randomized comparative study of
two doses of paclitaxel in patients with metastatic
breast cancer. J Clin Oncol 14:1858-1867, 1996

(A) $10,000

(B) $10,000-99,999

Bristol-Myers
Squibb Oncology
(B)
(C) $100,000

6. Mamounas EP, Bryant J, Lembersky BC,

et al: Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for
node-positive breast cancer: Results from
NSABP B-28. Proc Am Soc Clin Oncol 22:4, 2003
(abstr 12)
7. Henderson IC, Berry DA, Demetri GD, et
al: Improved outcomes from adding sequential
paclitaxel but not from escalating doxorubicin
dose in an adjuvant chemotherapy regimen for
patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003
8. Citron ML, Berry DA, Cirrincione C, et al:
Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative
adjuvant treatment of node-positive primary breast
cancer: First report of Intergroup Trial C9741/
Cancer and Leukemia Group B Trial 9741. J Clin
Oncol 21:1431-1439, 2003
9. Buzdar AU, Singletary SE, Valero V, et al:
Evaluation of paclitaxel in adjuvant chemotherapy for patients with operable breast cancer:
Preliminary data of a prospective randomized
trial. Clin Cancer Res 8:1073-1079, 2002

Bristol-Myers
Squibb Oncology
(A)

(N/R) Not Required

10. Seidman AD, Hudis CA, Albanel J, et al:

Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic
breast cancer. J Clin Oncol 16:3353-3361,
1998
11. Perez EA, Vogel CL, Irwin DH, et al: Multicenter phase II trial of weekly paclitaxel in
women with metastatic breast cancer. J Clin
Oncol 19:4216-4223, 2001
12. Seidman AD, Berry D, Cirrincione C, et al:
CALGB 9840: Phase III stud of weekly (W)
paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3h infusion every third week in the
treatment of metastatic breast cancer (MBC),
with trastuzumab (T) for HER2 positive MBC and
randomized for T in HER2 normal MBC. Proc Am
Soc Clin Oncol 22:6s, 2004 (suppl; abstr 512)
13. Sikov WM, Akerley W, Cummings F, et al:
Weekly high-dose paclitaxel in locally advanced
and metastatic breast cancer. Breast Cancer Res
Treat 46:95, 1997 (abstr 412)
14. Green MC, Buzdar AU, Hortobagyi GN:
Reduction of neurotoxicity from schedule modification of dose-dense paclitaxel. Breast Cancer
Res Treat 64:86, 2000 (abstr 343)

5991

www.jco.org

Downloaded from jco.ascopubs.org on September 10, 2016. For personal use only. No other uses without permission.
Copyright 2005 American Society of Clinical Oncology. All rights reserved.

Green et al

15. Singletary SE, Allred C, Ashley P, et al:

Revision of the American Joint Committee on
Cancer staging system for breast cancer. J Clin
Oncol 20:3628-3636, 2002
16. Milross CG, Mason KA, Hunter NR, et al:
Relationship of mitotic arrest and apoptosis to
antitumor effect of paclitaxel. J Natl Cancer Inst
88:1308-1314, 1996
17. Lau DH, Xue L, Young LJ, et al: Paciltaxel
(Taxol): an inhibitor of angiogenesis in a highly
vascularized transgenic breast cancer. Cancer
Biother Radiopharm 14:31-36, 1999
18. Belotti D, Vergani V, Drudis T, et al: The
microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res 2:1843-1849, 1996
19. Symmans WF, Volm MD, Shapiro RL, et
al: Paclitaxel-induced apoptosis and mitotic arrest assessed by serial fine-needle aspiration:
Implications for early prediction of breast cancer
response to neoadjuvant chemotherapy. Clin
Cancer Res 6:4610-4617, 2000
20. Griffon-Etienne G, Boucher Y, Brekken C,
et al: Taxane-induced apoptosis decompresses
blood vessels and lowers interstitial fluid pressure in solid tumors: Clinical implications. Cancer
Res 59:3776-3782, 1999
21. Wolmark N, Wang J, Mamounas E, et al:
Preoperative chemotherapy in patients with oper-

5992

able breast cancer: Nine-year results from National

Surgical Adjuvant Breast and Bowel Project B-18.
J Natl Cancer Inst Monogr 30:96-102, 2001
22. van der Hage JA, van de Velde CJ, Julien
JP, et al: Preoperative chemotherapy in primary
operable breast cancer: Results from the European Organisation for Research and Treatment
of Cancer trial 10902. J Clin Oncol 19:4224-4237,
2001
23. Feldman LD, Hortobagyi GN, Buzdar AU,
et al: Pathological assessment of response to
induction chemotherapy in breast cancer. Cancer
Res 46:2578-2581, 1986
24. Kuerer HM, Sahin A, Hunt KK, et al: Incidence and impact of documented eradication of
breast cancer axillary lymph node metastases
before surgery in patients treated with neoadjuvant chemotherapy. Ann Surg 230:72-78,
1999
25. Fisher B, Bryant J, Wolmark N: Effect of
preoperative chemotherapy on the outcome of
women with operable breast cancer. J Clin Oncol 16:2672-2685, 1998
26. Bear H, Anderson S, Brown A, et al: The
effect on tumor response of adding sequential
preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: Preliminary results
from National Surgical Adjuvant Breast and

Bowel Project Protocol B-27. J Clin Oncol 21:

4165-4174, 2003
27. ORegan R, Malik U, Sparano JA, et al:
Neoadjuvant docetaxel followed by adjuvant doxorubicin and cyclophosphamide for stage III breast
cancer: Clinical response and long-term survival.
Proc Am Soc Clin Oncol 22:41, 2003 (abstr 163)
28. Valero V, Esteva FE, Rosales M, et al: Phase
II trial of primary chemotherapy with docetaxel and
doxorubicin in locally advanced breast cancer: Clinical and pathological results. Proc Am Soc Clin
Oncol 19:132a, 2000 (abstr 519)
29. Garcia-Mata J, Calvo L, Mel JR, et al:
Concomitant administration of doxorubicin plus
docetaxel (AT) as neoadjuvant treatment of
stage IIB and III breast cancer (BC). Proc Am Soc
Clin Oncol 22:63, 2003 (abstr 253)
30. McCready DR, Hortobagyi GN, Kau S, et
al: The prognostic significance of lymph node
metastases after preoperative chemotherapy for
locally advanced breast cancer. Arch Surg 124:
21-25, 1989
31. Sikov WM, Akerley W, Kahanic S, et al:
Multicenter, 3-arm randomized study of highdose weekly paclitaxel (HDWP) versus standarddose weekly paclitaxel (SDWP) for metastatic
breast cancer (MBC). Proc Am Soc Clin Oncol
21:34a, 2002 (abstr 134)

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