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doi:10.1093/annonc/mdi058
Original article
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
248
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.
Population
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
Node positive
DD Pac (n = 26)
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)
ER ( )
51 (3669)
5 (25)
46 (2955)
47 (3075)
46 (2661)
64 (53126)
70 (51120)
68 (55117)
63 (55105)
6 (60)
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).
249
Table 2. Anemia (Hb)a and associated complications
NDD Pac DD Pac P
(n = 20)
(n = 26) value
Skin toxicities
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)
0.075 23 (41)
1 (10)
0.08
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)
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
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).
250
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
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
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-
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.
References
1. Gianni AM, Piccart MJ. Optimizing chemotherapy dose density and
dose intensity: new strategies to improve outcomes in adjuvant
therapy for breast cancer. Eur J Cancer 2000; 36: S1 S3.
2. 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 2003; 21:
976 983.
3. Norton L. Evolving concepts in the systemic drug therapy of breast
cancer. Semin Oncol 1997; 24 (Suppl. 10): S3 S10.
4. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dosedense 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
2003; 21: 14311439.
5. Piccart MJ. Mathematics and oncology: a match for life? J Clin
Oncol 2003; 21: 14251428.
6. DiLeo A, Crown J, Nogaret JM et al. A feasibility study evaluating
docetaxel-based sequential and combination regimens in the adjuvant
therapy of node-positive breast cancer. Ann Oncol 2000; 11:
169 175.
7. Miller KD, McCaskill-Stevens W, Sisk J et al. Combination versus
sequential doxorubicin and docetaxel as primary chemotherapy for
breast cancer: a randomized pilot trial of the Hoosier oncology
group. J Clin Oncol 1999; 17: 30333037.
8. von Minckwitz G, Costa SD, Raab G et al. Dose-dense doxorubicin,
docetaxel, and granulocyte colony-stimulating factor support with or
without tamoxifen as preoperative therapy in patients with operable
carcinoma of the breast: a randomized, controlled, open phase IIb
study. J Clin Oncol 2001; 19: 35063515.
9. Jackisch C, von Minckwitz G, Eidtmann H et al. Dose-dense
biweekly doxorubicin/docetaxel versus sequential neoadjuvant chemotherapy with doxorubicin cyclophosphamide/docetaxel in operable
breast cancer: second interim analysis. Clin Breast Cancer 2002; 3:
276 280.
10. Zimmerman GC, Keeling JH, Burris HA et al. Acute cutaneous reactions to docetaxel, a new chemotherapeutic agent. Arch Dermatol
1995; 131: 202206.
11. Holmes FA, Rowinsky EK. Pharmacokinetic profiles of doxorubicin
in combination with taxanes. Semin Oncol 2001; 28: 814.
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
252
12. Eich D, Scharffetter-Kochanek K, Eich HT et al. Acral erythrodysesthesia syndrome caused by intravenous infusion of docetaxel in
breast cancer. Am J Clin Oncol 2002; 25: 599602.
13. Vukelya S, Baker W, Burris HA 3rd, Keeling JH, Von Hoff D.
Pyridoxine therapy for palmar-plantar erythrodysesthesia associated
with taxotere. J Natl Cancer Inst 1993; 85: 14321433.
14. Scotte F, Tourani JM, Banu E et al. Assessment of frozen glove use
in the prevention of docetaxel induced onycholysis and cutaneous