Annals of Oncology 16: 247 252, 2005

doi:10.1093/annonc/mdi058

Original article

Evaluation of anemia, neutropenia and skin toxicities in

standard or dose-dense doxorubicin/cyclophosphamide (AC)
paclitaxel or docetaxel adjuvant chemotherapy in breast cancer
J. Schwartz*, S. M. Domchek, W.-T. Hwang & K. Fox
Hospital of the University of Pennsylvania, Philadelphia, PA, USA
Received 30 June 2004; revised 6 October 2004; accepted 11 October 2004

Introduction
Dose intensity, defined as the amount of drug delivered per
unit time (mg/m2/week), has been shown to correlate with outcome in adjuvant chemotherapy treatment of breast cancer [1].
However, attempts to capitalize on the dose-responsiveness by
escalating doses in standard schedules have so far not been
successful [2]. Dose-density refers to administration of drugs
with a shortened treatment interval [1]. This concept is
supported by the observation that breast cancer cells grow by
non-exponential Gompertzian kinetics, whereby tumor
regrowth is more rapid in a volume-reduced state, such as
between chemotherapy cycles [3, 5].
The CALGB 9741 trial was designed to test this concept
of dose-density and initial results were recently reported.
Patients were randomized to either concurrent doxorubicin/
cyclophosphamide (AC) paclitaxel (T) every 3-weeks,
sequential A ! T ! C every 3-weeks, dose-dense concurrent
AC paclitaxel, or dose-dense sequential A ! T ! C. The

*Correspondence to: Dr J. Schwartz, Women and Infants Hospital,

101 Dudley Street, Providence, RI 02905, USA. Tel: +1-401-274-1122;
E-mail: JSchwartz@wihri.org
q 2005 European Society for Medical Oncology

dose-dense arms were given with filgrastim. Results at 36

months follow-up showed a significant increase in overall and
disease-free survival for the dose-dense arms [4]. Standard
non-hematologic toxicity was reported for over 1900 patients.
However, data regarding dose modifications, delays, blood
transfusions and hospitalizations were reported for only 20%
of patients in the trial. The transfusion rate in the combination
dose-dense arm was high (13%) and no information was available concerning the use of recombinant erythropoietin (rhEpo)
products for anemia.
Docetaxel is frequently substituted for paclitaxel in adjuvant
3-weekly, non-dose-dense AC paclitaxel (NDD Pac) in clinical practice and there has been interest in the possibility of
substituting dose-dense AC docetaxel (DD Doc) for dosedense AC paclitaxel (DD Pac). Although no large studies of
dose-dense AC docetaxel exist, small trials of sequential
dose-dense doxorubicin/docetaxel indicate increased rates of
skin toxicity and anemia [6, 7].
The current evaluation was conducted to evaluate retrospectively the incidence and severity of certain toxicities of
dose-dense chemotherapy in clinical practice. In particular,
anemia, neutropenia and skin toxicities were evaluated in

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Background: Results of CALGB 9741 demonstrated that administering standard doxorubicin/

cyclophosphamide (AC) paclitaxel therapy for adjuvant therapy of breast cancer in a dose-dense
fashion with colony-stimulating factors increases efficacy, decreases severe neutropenia, but may
increase the need for blood transfusions. A chart review was performed to evaluate the rates of anemia, neutropenia and skin toxicities with dose-dense and traditional AC taxane chemotherapy.
Patients and methods: A total of 112 patients received one of four treatments: non-dose-dense
AC paclitaxel (NDD Pac), dose-dense AC paclitaxel (DD Pac), non dose-dense AC docetaxel
(NDD Doc), or dose-dense AC docetaxel (DD Doc).
Results: Transfusion rates were not increased in the dose-dense population; however, rates of grade
2 4 anemia (23% versus 0%, P = 0.029), as well as erythropoietin use (58% versus 0%, P <0.0001),
were significantly increased in the DD Pac group compared with the NDD Pac group. Grade 3 skin
toxicities were significantly increased in the DD Doc group compared with the NDD Doc group
(70% versus 11%, P <0.0001).
Conclusions: These results demonstrate that dose-dense AC taxane therapy may increase rates of
anemia and the need for erythropoietin, and decrease rates of neutropenia. The utility of DD Doc
appears limited by skin toxicities and its use outside of a clinical study should not be recommended.
Key words: anemia, breast cancer, docetaxel, dose-dense, doxorubicin, erythropoietin, hand foot
syndrome, neuropathy, paclitaxel

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patients receiving NDD Pac, DD Pac, standard AC docetaxel
(NDD Doc), and DD Doc at a single institution multidisciplinary breast center. Furthermore, consequences of toxicities
were evaluated, such as transfusions, use of rhEpo agents,
hospitalizations for febrile neutropenia, and dose delays or
reductions from the toxicities.

therapy of breast cancer from January 2002 to December 2003

as follows: NDD Pac, n = 20; DD Pac, n = 26; NDD Doc,
n = 56; DD Doc, n = 10. The DD Doc group was very small
because use was halted in early 2003 due to an increased rate
of unacceptable rate of skin toxicity, as described below.

Population

Patients and methods

Potential patients were identified using computerized pharmacy usage lists
of the relevant chemotherapy agents from January 2002 to December
2003 in our outpatient breast center. Medical records were identified for
patients who received NDD Pac, DD Pac, NDD Doc or DD Doc as adjuvant therapy for primary operable breast cancer. The initial doses utilized
were doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2, paclitaxel
175 mg/m2 and docetaxel 100 mg/m2.

As this was a descriptive analysis utilizing all available patients, no power

analysis was performed. Statistical analysis using Fishers exact test was
used when indicated. The University of Pennsylvania IRB approved this
study. All patients signed a chemotherapy consent prior to receiving any chemotherapy, and if patients were identified as having a skin toxicity from the
chart review, they signed an additional Institutional Review Board approved
informed consent before completing the skin questionnaire.

Anemia
Only two patients in our population received transfusions, one
in DD Pac and one in DD Doc. RhEpo products were started
in the DD groups soon after the Hg fell below 11 mg/dl. The
DD Pac group in our study had a higher rate of grade 24
anemia (23% versus 0%, P = 0.029) and a significantly greater
rate of rhEpo use (58% versus 0%, P < 0.0001) compared with
NDD Pac. In contrast, 21% of the NDD Doc and 20% of the
DD Doc groups received rhEpo (see Table 2).

Neutropenia
As expected, the standard use of filgrastim or pegfilgrastim
with the DD Pac and DD Doc regimens decreased the rates of
grade 34 neutropenia and hospitalizations for febrile neutropenia compared with the non dose-dense groups (see Table 3).

Results

Dose delaysneutropenia

In total, 112 patients were identified by medical records as having received one of the aforementioned regimens for adjuvant

The number of patients requiring dose delays secondary to

neutropenia was significantly decreased in the DD Pac group

Table 1. Patient population

Node positive

NDD Pac (n = 20)

DD Pac (n = 26)

NDD Doc (n = 56)

15 (75)

23 (89)

49 (87)

DD Doc (n = 10)
7 (70)

Node negative

5 (25)

3 (11)

7 (13)

3 (30)

Premenopausal

9 (45)

19 (73)

33 (59)

7 (70)

Postmenopausal

11 (55)

7 (27)

23 (41)

3 (30)

ER (+)

15 (75)

16 (62)

39 (70)

4 (40)

10 (38)

17 (30)

Median age, years (range)

ER ( )

51 (3669)

5 (25)

46 (2955)

47 (3075)

46 (2661)

Median weight, kgs (range)

64 (53126)

70 (51120)

68 (55117)

63 (55105)

Percentages given in parentheses.

6 (60)

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A retrospective chart review was performed to evaluate the main outcomes of anemia, neutropenia and skin toxicities. Laboratory data (hemoglobin and absolute neutrophil count) and skin reaction information, such
as location, symptoms, severity and treatment, were collected and toxicity
graded using the National Cancer Institute Common Toxicity Criteria
(NCI CTC) version 3.0. Ramifications of the toxicities were also collected,
such as dose delays, reductions and discontinuations, hospitalizations for
febrile neutropenia, and treatments such as transfusions, colony stimulating factors and rhEpo. Dose delay, for any reason, was also collected.
Baseline demographic information, such as age, weight, allergies, medications, menopausal and nodal status, was collected to evaluate for possible risk factors for toxicity. Also, if a patient was identified as having a
NCI CTC grade 24 skin, or grade 23 nail toxicity, the patient was contacted for a brief questionnaire to obtain additional information about the
toxicity, such as activities of daily living affected by the reaction, exacerbating factors, treatments that provided relief and date of final resolution.

In our population, all regimens were used in both nodenegative and node-positive, ER(+)/ER( ), and pre- and postmenopausal women. Both dose-dense regimens were used in
primarily premenopausal women. Most women were node
positive (84%). All node-negative patients were considered
high risk by one or more of the following: tumor size greater
than 2 cm, high grade, ER negativity, or age <35 years. All
node-negative patients who received dose-dense therapy were
ER-negative plus one or more of the other aforementioned
high-risk variables. Sixty-seven per cent (four of six) of the
node-negative dose-dense patients were premenopausal (see
Table 1).

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Table 2. Anemia (Hb)a and associated complications
NDD Pac DD Pac P
(n = 20)
(n = 26) value

Skin toxicities

NDD Doc DD Doc P

(n = 56)
(n = 10) value

Anemia (Hb) 0 (0)

G2-4

6 (23)

0.029

8 (14)

4 (40)

0.02

Transfusions

0 (0)

1 (4)

0 (0)

1 (10)

0.152

RhEpo

0 (0)

15 (58)

2 (20)

0.644

<0.0001 12 (21)

NCI CTC worst grade experienced per patient.

Percentages given in parentheses.
Hb, hemoglobin.

Table 3. Neutropenia (ANC)a and associated complications

NDD Pac DD Pac P
NDD Doc DD Doc P
(n = 20)
(n = 26) value (n = 56)
(n = 10) value
0 (0)

0.075 23 (41)

1 (10)

0.08

Hosp. Feb. NTP 2 (10)

0 (0)

0.184 11 (20)

0 (0)

0.192

Dose reductions

0 (0)

0 (0)

NA

0 (0)

Dose delays

5 (25)

Discontinuations 0 (0)

5 (9)

0 (0)

0.011 18 (32)

1 (10)

0.26

0 (0)

NA

0 (0)

1 (2)

NCI CTC worst grade experienced per patient.

Percentages given in parentheses.
ANC, absolute neutrophil count; Hosp. Feb NTP, hospitalizations for febrile neutropenia; NA, not available.

Table 4. Dose delays

NDD Pac DD Pac P
NDD Doc DD Doc P
(n = 20)
(n = 26) value (n = 56)
(n = 10) value
Total dose
delays

8 (40)

6 (23)

0.22

25 (45)

2 (20)

0.17

Neutropenia
5 (25)
delays (also
listed above)

0 (0)

0.011 18 (32)

1 (10)

0.26

Neuropathy
delays

3 (15)

6 (23)

0.49

6 (11)

0 (0)

0.28

Skin toxicity
delays

0 (0)

0 (0)

NA

1 (2)

1 (10)

0.282

Percentages given in parentheses.

NA, not available.

compared with the NDD Pac group (0% versus 25%,

P = 0.011). Thirty-two per cent of patients in the NDD Doc
group experienced a dose delay due to neutropenia, and overall 45% experienced any dose delay in the NDD Doc group.
The median number of days of the dose delays was 7 days in
all treatment groups (range 310) (see Table 4).

Dose delaysneuropathy
There was a trend towards increased delays due to neuropathy
in the DD Pac group compared with the NDD Pac group
(23% versus 15%, P = 0.49). The median number of days of
the dose delays was 7 days in all treatment groups (range
310) (see Table 4).

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ANC grade 34 3 (15)

The DD Doc group was found to have an unacceptably high

rate of skin toxicities, and its use was stopped after a total of
10 patients were treated. The total rate of any grade 3 skin toxicity, including nail toxicity (onycholysis), skin rash, or hand
foot syndrome, was 80% compared with 11% in the NDD Doc
group (P <0.0001). One other DD Doc patient had grade 2
skin/nail toxicity for a 90% (nine of 10) rate of skin toxicity in
our DD Doc population. All 10 DD Doc patients were premedicated with dexamethasone 8 mg twice daily for 3 days. In
addition, two patients in the DD Pac group experienced hand
foot syndrome during the end of the AC portion of therapy.
A case report of one of the nine DD Doc patients who
experienced severe skin toxicity is presented below, as an
example of the nature and progression of the skin toxicities.
A 44-year-old premenopausal woman with a T3, node-negative, ER( ) breast cancer was given adjuvant AC docetaxel
on a dose-dense schedule. After the first cycle of docetaxel,
the patient noted transient pruritis of the cheeks and hands.
One day after the second cycle of docetaxel, a tingling, painful, pruritic erythema of the hands, feet and face was noted.
Both sides of the hands and feet were red with large darker
red plaques. The pain worsened after the third dose of docetaxel and desquamation started soon after. The patient also
reported very painful nail beds and hands, which made daily
activities challenging, onycholysis, itchy/watery eyes, which
sometimes inhibited her vision, and tenderness of the soles,
which made walking uncomfortable for 23 weeks. Methylprednisolone dose packs were given after the third and fourth
cycles of docetaxel dose with little relief, but the patient did
report that soaking her hands in Epsom salts, using moisturizers, and artificial tears did improve her symptoms. No cycles
of docetaxel were held or delayed. The patient reported that
the pain and tingling decreased 2 weeks after the final docetaxel dose, the desquamation resolved over 1 month after docetaxel, and after 6 months a remaining reddish appearance
and mild tingling of the face, hands and feet resolved.
In summary, DD Doc caused a severe hand foot syndrome
sometimes accompanied by a rash in the face or extremities,
onycholysis and increased lacrimation, which sometimes
impaired vision in the majority of patients. The median time
to skin toxicity was 1 day after the second dose of docetaxel
or 15 days after the first dose of docetaxel, and the median
time to onycholysis was 6 weeks after the first docetaxel dose.
The reaction of the hands and feet was associated with a painful burning or stinging sensation, which inhibited the activities
of daily living of the affected patients for, on average, 2
weeks, before a gradual resolution in the form of desquamation over a period of 23 months. The reactions started
immediately after the first docetaxel dose, worsened with each
docetaxel cycle, and started to resolve only after the docetaxel
was discontinued. Sixty per cent of patients had therapy discontinued prematurely due to these reactions. Oral and topical
steroids and antihistamines had little success in providing
relief for patients. Most patients did, however, report relief
with use of moisturizers. There was no correlation between

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Table 5. Skin toxicitiesa and associated complications

Rash grade 3

NDD Pac
(n = 20)

DD Pac
(n = 26)

P value

0 (0)

0 (0)

NA

Rash grade 23

2 (10)

8 (31)

0.15

Handfoot grade 3

0 (0)

1 (4)

Handfoot grade 23

0 (0)

2 (8)

Nails grade 23

0 (0)

2 (8)

0.498

Total grade 3 skin/nail

0 (0)

1 (4)

Dose reductions

0 (0)

0 (0)

Dose delays

0 (0)

Discontinuations

0 (0)

NDD Doc
(n = 56)

DD Doc
(n = 10)

P value

2 (4)

2 (20)

0.106

15 (27)

6 (60)

0.062

2 (4)

6 (50)

0.001

3 (5)

7 (70)

<0.0001

11 (20)

7 (70)

0.03

6 (11)

8 (80)

<0.0001

NA

0 (0)

0 (0)

NA

0 (0)

NA

1 (2)

1 (10)

0.282

0 (0)

NA

1 (2)

6 (60)

<0.0001

NCI CTC worst grade experienced per patient.

Percentages given in parentheses.
NA, not available.

Discussion
The purpose of this evaluation was to quantify and describe
the skin and hematologic toxicities seen in non-dose-dense
and dose-dense adjuvant therapies for breast cancer that were
already in use at our institution. We report a high rate of
severe skin and nail toxicities with dose-dense AC docetaxel.
Overall, 90% of patients reported either nail toxicity, rash or
hand foot syndrome, with 80% of patients experiencing a
grade 3 toxicity. Previous small pilot trials have shown that
dose-dense doxorubicin and docetaxel can be given concurrently successfully, but certain toxicities increase when these
agents are given sequentially in a dose-dense fashion as adjuvant therapy. In two studies which examined sequential versus
concurrent dose-dense doxorubicin and docetaxel, grade 3 4
hand foot or skin toxicity was seen in 30% 40% of sequential versus 0% of concurrent patients [6, 7]. Our evaluation
provided detailed descriptions of the skin toxicities from
sequential dose-dense treatment, which are consistent with the
other reports in the literature [6, 7, 10]. Several other trials
have successfully given concurrent dose-dense doxorubicin
plus docetaxel without an increase in skin toxicities,
suggesting that sequential therapy with dose-dense doxorubicin and then docetaxel causes an increase in certain toxicities
[8, 9].
The exact mechanisms by which a sequential rather than
concurrent schedule of dose-dense doxorubicin/docetaxel
causes an increase in severe skin reactions are unknown.
Although docetaxel has been reported to cause isolated cases
of mild hand foot syndrome in other settings, the increased
rate of severe reactions with biweekly dosing was not
expected. Paclitaxel causes hand foot syndrome with less fre-

quency than docetaxel in the literature; however, there were

two cases of hand foot syndrome in the DD Pac group.
Whether this phenomenon with dose-dense doxorubicin and
docetaxel is due to a unique dose or sequence-dependant interaction is unclear. Pharmacokinetic analyses available in the
literature do not indicate a significant interaction when doxorubicin and docetaxel are given sequentially. However, these
analyses were based on single-dose studies and not extended
dosing durations [11]. Moreover, there is no current evidence
to suggest that colony-stimulating factors contribute to these
particular toxicities. One theory is that an interaction between
doxorubicin and docetaxel that is specific to dose-dense
sequential therapy does exist. Alternatively, the more frequent
dosing and size of the doses may saturate the metabolic
capacity of the liver, and the resultant increase in drug serum
levels may cause more pronounced toxicities of docetaxel,
which is reported to cause hand foot syndrome, or even doxorubicin, which can also cause hand foot syndrome when
body exposure time (AUC) is increased, such as with liposomal doxorubicin. This increased AUC of doxorubicin, as well
as skin toxicity related to paclitaxel, may be two of the
reasons why hand foot syndrome was seen with DD Pac and
not just during DD Doc.
Risk factors predicting populations at higher risks of these
toxicities, as well as successful prevention strategies for
docetaxel-induced skin toxicities, have not been found so
far. While premedication with steroids successfully prevents
hypersensitivity and edema in several trials, we did not find
that steroids reliably protect against or treat docetaxel-induced
skin reactions, which has been corroborated by other studies
[15]. Dose reduction has been reported to occasionally prevent
skin toxicities in further cycles. However, in our study the
reactions continued to worsen with each successive cycle in
all affected patients [7]. Pyridoxine has been tried with some
success in a small study, and recently reported data suggest
that acral cooling may be an effective prevention strategy
for docetaxel-related skin toxicity [1214]. Our current

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patient demographics such as age, weight, allergies,

medications, menopausal or nodal status and the rate of skin
reactions in our population (see Table 5).

251
rhEpo associated with dose-dense therapy, with the possible
decrease in hospitalizations for febrile neutropenia and inconvenient cycle delays. This information, in addition to qualityof-life data, would assist clinicians in individualizing therapy
for breast cancer patients by utilizing additional risk/benefit
information for the dose-dense therapy.
Our evaluation also adds to the existing data, which indicate
that dose-dense sequential AC docetaxel causes severe and
unacceptable skin toxicities, and its use should not be recommended outside a clinical trial until a mechanism to reduce
the toxicity is elucidated.

Acknowledgements
We would like to thank Kamakshi Rao for her guidance with
this manuscript.

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evaluation similarly did not find any patient risk factors for
toxicity such as weight, age or menopausal status, and the
only treatment found to give relief for skin toxicities in our
experience, albeit small, were moisturizing products.
RhEpo products were used more frequently in the dosedense setting than in the standard dose setting at our institution. This may reflect increased hematopoeitic toxicity, a
lower threshold of clinicians to institute prophylactic use
given the transfusion rates in CALGB 9741 or, most likely, a
combination of these two factors. Although this evaluation
had a small sample size, the fact that there was only one red
blood cell transfusion in the DD Pac group is probably due to
the frequent rhEpo use, and provides some evidence that transfusions may be prevented by rhEpo use in the dose-dense
setting.
Our study did support the conclusions of CALGB 9741 in
regards to dose-dense regimens reducing the rates of grade 4
neutropenia and febrile neutropenia, probably due to the
consistent use of colony-stimulating factors with dose-dense
therapy. Neutropenia was measured in this evaluation similar
to CALBG 9741, with blood counts obtained on the day of
each chemotherapy cycle, and to assess possible febrile
neutropenia. Although the dose-dense therapies do seem to
decrease the rate of dose delays from neutropenia, which may
improve dose intensity, there was an increased rate of dose
delays from neuropathy, although treatment still occurred
within a median of 7 days.
This evaluation also provided some information about the
differences in toxicities between the standard NDD Pac and
NDD Doc, although this was not the main outcome of the
evaluation, and was not compared statistically. NDD Doc did
tend towards increased anemia, rhEpo use and febrile neutropenia compared with NDD Pac. Although the rates of neuropathy are generally lower with docetaxel than paclitaxel, our
NDD Doc population still experienced some dose delays from
neuropathy and had more total dose delays than NDD Pac.
The frequency of dose delays in both the NDD Pac and Doc
groups was surprising. However, the differences in toxicities
and delays between the AC-taxanes will become more evident
when ongoing large studies of these regimens are published in
the future.
This evaluation is limited by its retrospective, non-randomized, and single-center nature; our results, however, provide
some interesting directions for further research. AC docetaxel
should not be used in a dose-dense fashion unless studies can
identify safe and effective dosages of the agents as well as
toxicity prevention strategies. Since this study was not
designed to grade neuropathy, the incidence and dose delays
from neuropathy should be prospectively studied in patients
receiving dose-dense therapies. Differences in neuropathy may
become significant if studied in a larger setting.
The interim results of CALGB 9741 did show dose-dense
AC paclitaxel to be an effective and improved therapy for
breast cancer patients, and the use of this regimen will certainly increase. A cost-effectiveness analysis would be useful
to balance the increased use of colony-stimulating factors and

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