Clinical Cancer Research Vol. 6, 4082-4090, October 2000
© 2000 American Association for Cancer Research
Molecular Oncology, Markers, Clinical Correlates |
Study of Dose Escalation and Sequence Switching of Administration of the Combination of Docetaxel and Doxorubicin in Advanced Breast Cancer
Kuniaki Itoh1,
Yasutsuna Sasaki,
Hirofumi Fujii,
Hironobu Minami,
Tomoko Ohtsu,
Hisashi Wakita,
Tadahiko Igarashi,
Yuko Watanabe,
Yusuke Onozawa,
Masaki Kashimura and
Yasuo Ohashi
Division of Oncology and Hematology, National Cancer Center Hospital East, Kashiwa 277-8577 [K. I., Y. S., H. F., H. M., T. O., H. W., T. I., Y. W., Y. On.]; Rhône-Poulenc Rorer Japan, Inc., Ibaraki 315 [M. K.]; and Epidemiology and Biostatistics, School of Health Sciences and Nursing, Faculty of Medicine, University of Tokyo, Tokyo 113-0033 [Y. Oh.], Japan
 |
ABSTRACT
|
|---|
The objectives
of the present study were to evaluate whether a schedule-dependent
pharmacokinetic and/or pharmacodynamic interaction exists between two
sequences of docetaxel and doxorubicin administration and to determine
the maximal tolerated dose (MTD) of this combination. Patients with
chemotherapy-naïve metastatic or recurrent advanced breast
cancer were enrolled. In the crossover design, tandem dose escalation
of docetaxel and doxorubicin was performed. Docetaxel, in doses ranging
from 50–70 mg/m2, was administered for 1 h by drip
infusion either just before or after a 5-min bolus i.v. injection of
doxorubicin at dosages from 40–50 mg/m2. The sequence of
drug administration was switched after the first course in each
patient, and the sequence of drug administration thereafter depended on
the patient’s choice. Twenty-five patients were initially
assessable for toxicity. The MTD in the sequence of doxorubicin after
docetaxel was 40 and 50 mg/m2, respectively, with the
dose-limiting toxicity of neutropenia. On the other hand, the MTD of
the sequence of docetaxel after doxorubicin was 70 and 50
mg/m2, respectively. The dose-limiting toxicities in this
sequence were neutropenia and diarrhea. Duration of grade 4 neutropenia
in the sequence of docetaxel followed by doxorubicin was significantly
longer than that in the alternate sequence (P =
0.0062). However, there was no difference in pharmacokinetic parameters
of docetaxel, doxorubicin, and doxorubicinol between the two sequences.
The sequence of 50 mg/m2 doxorubicin followed by 60
mg/m2 docetaxel is recommended for subsequent clinical
trials for practical reasons.
|
INTRODUCTION
|
|---|
Docetaxel has shown impressive antitumor activity in untreated and
pretreated patients with breast cancer in multiple Phase II clinical
trials and also in a variety of tumors, such as lung cancer, ovarian
cancer, head and neck cancer, and others (1)
. In Europe
and the United States, the recommended dose as a single agent was 100
mg/m2
every 3 weeks, and the recommended dose as
a single agent in Japan was 60 mg/m2
every 3–4
weeks. The response rate for patients with breast cancer who received
docetaxel as a first-line chemotherapy was 59%, and the response rate
for patients with breast cancer who received docetaxel as a second-line
chemotherapy was 41% (2)
. Anthracyclines are considered
the most effective agents for management of breast cancer, and the
inclusion of doxorubicin in a combination regimen increases the
response rate and duration of survival (3)
. Therefore, it
is logical and promising to choose doxorubicin as the agent to be used
in combination with docetaxel.
The sequence of drug administration has been worthy of study in cancer
chemotherapy. Rowinsky et al. (4)
reported that
the administration of cisplatin before paclitaxel induced significantly
more severe neutropenia than the opposite sequence in part because of
the lower paclitaxel
CL.2
Similarly,
drug-drug interaction was observed for cisplatin-topotecan
(5)
and paclitaxel-cyclophosphamide (6, 7, 8)
.
In contrast, no sequence-dependent toxicity or sequence-dependent
pharmacokinetic interaction was reported in combinations of
paclitaxel-carboplatin (9)
and paclitaxel-topotecan
(10)
. However, there has been no report of an evaluation
of the sequence of administration of the combination of doxorubicin and
docetaxel. It was suggested that docetaxel is metabolized mainly by
liver cytochrome P450 isoenzymes of CYP3A and that doxorubicin inhibits
docetaxel metabolism in human hepatocytes (11)
. Therefore,
it is important to evaluate whether schedule-dependent differences in
toxicity and pharmacokinetics exist between two sequences of docetaxel
and doxorubicin administration.
The present Phase I study was conducted to determine the MTD of two
combinations of docetaxel and doxorubicin and to evaluate the
schedule-dependent pharmacokinetic and pharmacodynamic interactions of
these drugs in breast cancer patients with tumors that were estrogen
receptor negative or refractory to prior hormone therapy.
|
PATIENTS AND METHODS
|
|---|
Eligibility Criteria.
Patient eligibility criteria were as follows: (a) metastatic
or recurrent advanced breast cancer with histological or cytological
confirmation; (b) no prior chemotherapy except adjuvant
chemotherapy; (c) estrogen receptor negative or refractory
to prior hormone therapy; (d) age, 20–75 years; and
(e) good performance status (performance status of 0–2 by
Eastern Cooperative Oncology Group criteria). Other eligibility
criteria included a WBC count of 
4,000/µl, a neutrophil count of
2,000/µl, a platelet count of 100,000/µl, hemoglobin
9.5 grams/dl, serum albumin 3.0 grams/dl, total bilirubin
level 
1.5 mg/dl, AST and alanine aminotransferase levels 2.0 times the upper limit of the normal range, blood urea
nitrogen level within the normal limit,
PaO2 level 60 torr, normal
electrocardiography, and normal cardiac LVEF (50%). For
patients with liver metastasis of breast cancer, AST and alanine
aminotransferase values were required to be less than 3 times the upper
limit of the normal range. Written informed consent was obtained from
all patients. The institutional review board of the National Cancer
Center of Japan approved the protocol. This study was conducted
according to the guidelines of the Ministry of Health and Welfare of
Japan.
Treatment Plan.
All patients were treated while hospitalized until the second cycle was
completed. The study was designed as a prospective randomized crossover
trial. Study design is shown in Fig. 1
.
Consecutive patients were randomized to either the doxorubicin after
docetaxel sequence (docetaxel
doxorubicin sequence) or the docetaxel
after doxorubicin sequence (doxorubicindocetaxel sequence). There
was no time interval between the administration of doxorubicin and
docetaxel as described below. The sequence of drug administration was
switched for the second course. Namely, in the first and second cycle,
each patient received both sequences. If the patient responded to the
treatment or the disease was stable, treatment was repeated every 3 or
4 weeks after the WBC count recovered to 4000/µl until the total dose
of either docetaxel or doxorubicin reached 500
mg/m2
. The sequence of drug administration in the
third and subsequent cycles was chosen according to the toxicity and
the patient’s preference. Blood counts were monitored at least three
times per week until the second cycle was completed. Docetaxel was
administered by i.v. drip infusion over 1 h. Premedication by
corticosteroid hormone was not permitted in this trial because
corticosteroids contribute to leukocytosis and neutrophilia on the day
of chemotherapy and might affect the metabolism of docetaxel by liver
cytochrome P450. In addition, premedication of steroid hormones is not
regarded as standard treatment of docetaxel at the dose of 60
mg/m2
in Japan. Doxorubicin was
administered by a 5-min bolus i.v. injection just after or before the
administration of docetaxel. An initial dose of 50
mg/m2
docetaxel was adopted because the dose was
considered to be the minimal effective dose based on a Japanese Phase I
trial for breast cancer (12)
. The initial dose of
doxorubicin was determined by the minimal dose in the cyclophosphamide,
doxorubicin, and 5-fluorouracil combination.
Toxicity was evaluated for the first two cycles according to the
National Cancer Institute common toxicity criteria (13)
.
DLT was determined by evaluation after the first cycle of therapy and
was defined as grade 4 neutropenia for 7 days or more, grade 4
neutropenia associated with infection for 3 days accompanied by fever
(>38°C), or any grade 3 or higher toxicity except anemia, alopecia,
anorexia, vomiting, and general malaise. If DLT occurred in one or two
of the first three patients at a specific dose level and sequence in
the first cycle, three additional patients were treated at that dose
level and sequence. The MTD was defined as the dose level and sequence
one level below that at which at least three of six patients developed
DLT in the first cycle. Once patients had a temperature of >38°C,
they were treated with broad spectrum antibiotics after blood culture
for a bacteriological survey. When neutropenia occurred as a DLT, the
use of G-CSF was permitted until the neutrophil count recovered to
2000/µl. Patients who vomited once after drug administration received
a serotonin antagonist, granisetron, and, in these cases, antiemetic
prophylaxis with granisetron was used for subsequent cycles. Patients
who experienced a DLT but were suspected of achieving a response were
allowed to receive retreatment at a reduction of one dose level. To
determine cardiotoxicity by combination of the two drugs, the LVEF was
determined at baseline and serially monitored before the second,
fourth, and sixth cycles and after the completion of treatment.
Relative dose intensity of docetaxel and doxorubicin per week was
calculated by dividing the administered dose at each level by the
actual dose of level one for each drug. If the relative dose intensity
did not increase, the dose level of the highest intensity was
considered to be the recommended dose for the combination.
Patients with measurable lesions were evaluated for antitumor response
to the combination. Complete response was defined as the disappearance
of all measurable or assessable disease and all signs and symptoms of
disease for at least 4 weeks. Partial response was defined as a
reduction of 50% or greater in the sum of the products of the
perpendicular diameters of all measurable lesions and the appearance of
no new lesions for at least 4 weeks. Stable disease was defined as a
less than 50% reduction or a less than 25% increase in the sum of the
products of two perpendicular diameters of all measurable lesions and
the appearance of no new lesions. Progressive disease was defined as an
increase of 25% in the size of any lesion or the development of any
new lesions. A breast surgeon and physician not related to this study
reviewed the evaluation of responses.
Pharmacokinetic Sampling.
To study pharmacokinetics, blood samples in all patients were obtained
from venous catheters placed in the arm contralateral to the drug
infusion. In the doxorubicindocetaxel sequence, blood samples were
collected before the infusion; immediately after completion of the
infusion of doxorubicin; at 15 and 30 min during the infusion of
docetaxel; immediately after the end of the infusion of docetaxel; 5,
20, and 35 min after the end of the infusion of docetaxel; and 1, 3, 4,
7, 24, 48, and 72 h after the end of the infusion of docetaxel. In
the opposite sequence, that of docetaxeldoxorubicin, blood samples
were collected before treatment; 30 min after the start of the
docetaxel infusion; just after the end of docetaxel infusion; just
after the infusion of doxorubicin; at 15, 30, and 55 min after the
infusion of doxorubicin; and at 2 h and 55 min, 3 h and 55
min, 6 h and 55 min, 23 h and 55 min, 47 h and 55 min,
and 71 h and 55 min after the end of the infusion of
doxorubicin. Heparinized plasma obtained from patients was
stored at -20°C until analyzed.
HPLC Determination.
Frozen plasma samples were thawed at ambient temperature and then
vortexed and centrifuged for 5 min at 3000 rpm to remove fibrous
materials that can clog extraction columns. The assay was carried out
at the Ibaraki Laboratory of Rhône-Poulenc Rorer Japan.
Docetaxel concentrations in plasma were determined by HPLC (reverse
phase) using the Inertsil ODS 2 column (5 µm; 4.6 x 250 mm; GL
Sciences, Tokyo, Japan) with UV detection (14)
. The method
involves a solid-phase extraction (Bond Elut C2; Varian, Harbor, CA).
Docetaxel and the internal standard were determined by an UV detector
adjusted at 225 nm, and peak height was used for quantification. The
lower limit of the assay was 7.5 ng/ml, and the linearity was confirmed
up to 4000 ng/ml in plasma.
Doxorubicin and doxorubicinol, which is the major metabolite of
doxorubicin in plasma, were determined by HPLC (reverse phase) using
the Bondapak Phenyl column (10 µm; 3.9 x 300 mm; Waters,
Milford, MA) with fluorescence detection (15)
. The method
involves a solid-phase extraction (Bond Elut C2; Varian). Doxorubicin,
doxorubicinol, and the internal standard (daunorubicin) were determined
by a fluorescence detector adjusted at Ex 470 nm and Em
565 nm, and the peak height was used for quantification. The lower
limit of the assay was 5 ng/ml for doxorubicin and 4.4 ng/ml for
doxorubicinol, and linearity was confirmed up to 2000 ng/ml for
doxorubicin and 262.5 ng/ml for doxorubicinol in plasma.
Pharmacokinetic parameters were calculated using the MULTI program
described by Yamaoka et al. (16)
.
Cmax was taken from the actual value.
The terminal rate constant (k) was determined by log-linear
regression analysis of the terminal phase of the plasma
concentration-time courses. The t1/2
values were calculated by the equation
t1/2 = 0.693/k. The
AUC0
was calculated
by the linear trapezoidal rule up to the last measurable data point
with extrapolation to infinity. CL was calculated by dividing the dose
of docetaxel or doxorubicin received by the AUC.
Vss was calculated by the equation
CL x (mean residual time) - [infusion time (h)/2].
Pharmacodynamic Parameter Calculation.
The neutrophil counts and the time under the curve were drawn, and the
area under the grade 2 (<1500/µl), grade 3 (<1000/µl), and grade
4 (<500/µl) time curve was calculated by the trapezoidal rule,
respectively. Regression curves for the relationship between AUC or CL
and the area under the grade 2, 3, and 4 neutropenia time curves or the
nadir of the neutrophil count for each sequence were made and compared,
respectively.
|
RESULTS
|
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Between November 13, 1995 and May 14, 1998, 25 patients were
enrolled into the study. All patients were assessable for toxicity. The
median number of cycles administered per patient was five (range, one
to nine). Two of four patients treated with the doxorubicindocetaxel
sequence in the first cycle preferred the same sequence in the third
and subsequent cycles. However, four of six patients who were given the
docetaxeldoxorubicin sequence in the first cycle were treated with
the opposite sequence in the third and subsequent cycles because of
patient preference in one patient and toxicities in three patients.
Patient characteristics are shown in Table 1
. The median time from the last adjuvant
chemotherapy was 16.1 months, with a range of 1–197 months. The median
number of metastatic disease sites for all patients was two sites, with
a range of one to five sites.
Hematological Toxicity.
The major toxicity of the combination was grade 4 neutropenia. One
patient receiving the doxorubicindocetaxel sequence at dose level 1
experienced febrile neutropenia for 1 day. All three patients receiving
the docetaxeldoxorubicin sequence at dose level 2 experienced grade
4 neutropenia for more than 7 days, but the neutropenia in all patients
resolved without G-CSF, and the MTD in this sequence was 50
mg/m2
docetaxel and 40
mg/m2
doxorubicin (level 1). Therefore, the
doxorubicindocetaxel sequence was administered subsequently through
level 4, reaching dosages of 50 mg/m2
doxorubicin
and 70 mg/m2
docetaxel. Duration of grade 4
neutropenia of all patients is shown in Table 2
. Duration of grade 4 neutropenia at
dose level 2 was significantly longer with the docetaxeldoxorubicin
sequence than with the opposite sequence (P = 0.0062).
Although both error of intrapatient variability (P =
0.0224) and the cycle effect (P = 0.0226) were
significant, the crossover design in this study was considered to be
valid for evaluation (Table 3)
. G-CSF was
used for 3 days in one patient at level 3 who experienced grade 4
neutropenia for 9 days. Two patients at level 4 experienced DLT; one
patient experienced grade 4 neutropenia for more than 7 days, and G-CSF
was administered for 1 day, and one patient experienced febrile
neutropenia for more than 3 days, and G-CSF was administered for 2
days. The other three patients at level 4 experienced febrile
neutropenia for 1 day. Although the incidence of DLT at level 4 (DLT
was seen in two of six patients at this level) did not fulfil the
definition of MTD in the original protocol, further dose escalation was
stopped because the relative dose intensity was not increased despite
the dose escalation as described below. We concluded that level 4 was
the MTD in the doxorubicindocetaxel sequence. There was no
documented sepsis. G-CSF was used in eight patients during 14 different
cycles of administration of the doxorubicindocetaxel sequence. Delay
of subsequent cycles was observed in two patients at level 2 and three
patients at level 4.
One patient experienced grade 3 anemia and another 20 patients
experienced grade 1 or 2 anemia in the first cycle. Thrombocytopenia
was not observed in the first cycle. Grade 1 and grade 2
thrombocytopenia were observed in three patients during the subsequent
cycles.
Nonhematological Toxicity.
Nonhematological toxicities in the first cycle are shown in Table 4
. One patient at dose level 1
experienced an allergic reaction. Although the patient was able to
complete the first cycle of the combination after the i.v.
administration of 20 mg of dexamethasone, 5 mg of chlorpheniramine
maleate, and 20 mg of famotidine, she was not assessable for the second
cycle of chemotherapy because she was removed from the study due to an
allergic reaction before completion of the second cycle, despite
premedication. One patient at level 4 experienced severe systemic skin
eruption due to allergy just after the beginning of docetaxel
administration and was removed from the study. One patient receiving
the doxorubicindocetaxel sequence at dose level 3 experienced
reversible grade 3 diarrhea without abdominal pain, and no recurrences
were observed on retreatment at a one-dose level reduction. Fifteen
patients experienced grade 1 or 2 diarrhea during the subsequent
cycles. Nausea and vomiting were mild and generally well controlled
after a prophylactic serotonin antagonist was used. Grade 1 and 2 oral
mucositis was observed in 13 patients at all cycles. One patient
experienced grade 3 elevated AST, and another 10 patients experienced
grade 1 or 2 liver damage at all cycles. Fluid retention was not noted
in the absence of corticosteroid premedication. All patients developed
alopecia, which was generally complete by the end of the second cycle.
With regard to cardiotoxicity, despite the median cumulative
doxorubicin dose being 220 mg/m2
(range, 40–360
mg/m2
), no congestive heart failure was
observed. No patient had a LVEF decrease of more than 20%, with the
exception of one patient whose LVEF decreased from 82% to 65% after
six cycles of chemotherapy.
Relative Dose Intensity.
Relative dose intensity of each level in the doxorubicindocetaxel
sequence is shown in Table 5
. Although
two of six patients at dose level 4 experienced DLT, this dose level
was considered to be the MTD of the doxorubicindocetaxel sequence
because the relative dose intensity of level 4 was not increased in
contrast with that of level 3 (Table 5)
. Therefore, the determination
of the MTD in the doxorubicindocetaxel sequence was not based on
observation of the DLT but on relative dose intensity.
Pharmacokinetics.
Pharmacokinetic parameters of docetaxel, doxorubicin, and doxorubicinol
in the first and second cycles at all dose levels are shown in Table 6
. There were no significant differences
in the pharmacokinetic parameters of docetaxel, doxorubicin, and
doxorubicinol between the two sequences at dose levels 1 and 2.
Pharmacokinetics of a representative case at dose level 2 are
shown in Fig. 2
.
Pharmacodynamics.
The area under the grades 2, 3, and 4 neutropenia-time curve and
nadir count of neutrophils at levels 1 and 2 are shown in Table 7
. There was a significant difference
between the two sequences in the correlation between the AUC of
docetaxel and the area under the grade 4 neutropenia-time curve at
levels 1 and 2, or when levels 1 and 2 were considered together
(P = 0.0354). However, no significant differences were
found between the two sequences in correlation between AUC, CL of
docetaxel and nadir counts of neutrophils or area under the
neutropenia-time curve of grade 2 and grade 3 at dose levels 1 and 2 or
when dose levels 1 and 2 were considered together. Similarly, there
were no significant differences between the two sequences with respect
to correlations between the AUC, CL of doxorubicin and nadir counts of
neutrophils or the area under the neutropenia-time curve of grades 2,
3, and 4 at dose levels 1 and 2 or the combination of levels 1 and
2. Furthermore, there was no significant correlation between the
AUC of doxorubicinol and those values.
Response.
Although the present study was carried out in a Phase I setting and two
patients were unable to complete the treatment due to an allergic
reaction, response was evaluated in all patients on the basis of
intention to treat. Ten of 25 patients had a partial response. The
response rate was 40% (95% confidence interval, 21–61%). Median
progression-free survival from the initial day of this
combination chemotherapy was 6 months, with a range of 1.3–12 months.
|
DISCUSSION
|
|---|
Docetaxel and doxorubicin are considered to be two of the most
effective anticancer agents against breast cancer. Chemotherapy with a
combination of both drugs has been considered to have promise.
Therefore, this Phase I trial of docetaxel and doxorubicin in
combination was conducted in breast cancer patients who were estrogen
receptor negative or refractory to prior hormone therapy because these
patients were considered to be the most suitable population for
anticancer chemotherapy. In addition, our study was conducted to
evaluate the effect of the sequence of administration of docetaxel and
doxorubicin. The MTD in the docetaxeldoxorubicin sequence was 50 and
40 mg/m2
, respectively, and the MTD in the
alternative doxorubicindocetaxel sequence was 50 and 70
mg/m2
, respectively. The duration of grade 4
neutropenia was significantly longer in patients treated with the
docetaxeldoxorubicin sequence than in patients treated with the
opposite sequence (P = 0.0062). Therefore, it was
suggested that the sequence of administration of these drugs affected
myelosuppression.
Concerning interactions between drugs, there have been reports which
have evaluated the effects of the order of administration of two drugs,
especially with regard to paclitaxel and doxorubicin. In a study of the
combination of a 24-h infusion of paclitaxel and bolus injection of
doxorubicin either 4 h before or 4 h after the infusion of
paclitaxel, Sledge et al. (17)
reported that
toxicity manifested by mucositis appeared more severe when paclitaxel
preceded doxorubicin compared with the reverse sequence. In the
simultaneous 72-h continuous infusion of both drugs, a greater
concentration of doxorubicinol was shown with this combination in
comparison with the administration of doxorubicin alone
(18)
. The sequence of paclitaxel given over 24 h
followed by doxorubicin given over 48 h was associated with
greater toxicity and increased maximal plasma concentration and AUC of
doxorubicin as reported by Holmes et al. (19)
.
In these studies, the sequence of paclitaxel followed by doxorubicin
was suggested to be more toxic, possibly because of pharmacokinetic
interaction. In contrast, there was no sequence-dependent toxicity and
pharmacokinetic difference between two sequences of 3-h paclitaxel
infusion and bolus injection of doxorubicin (20)
. The
present study is the first report of a prospective analysis of the
pharmacodynamics and pharmacokinetics of drug interaction according to
the order of administration of doxorubicin and docetaxel. Although
there was no pharmacokinetic difference according to drug sequence in
our study, and docetaxel may differ from paclitaxel in its
pharmacokinetic interaction with doxorubicin, our results, which showed
that the docetaxeldoxorubicin sequence was more toxic, might be
reasonable from the viewpoint of findings of studies of paclitaxel and
doxorubicin.
The effect of the sequence of administration on drug to drug
interaction was evaluated for the combination of docetaxel with
cisplatin or ifosfamide (21)
. Pronk et al.
(22)
found no significant differences in pharmacodynamics
and pharmacokinetics between two schedules of docetaxel and
cisplatin, but there appeared to be a trend toward a higher incidence
of grade 3 and grade 4 leukocytopenia when the administration of
cisplatin was followed by that of docetaxel. Similarly, toxicity was
reduced when docetaxel preceded ifosfamide (21)
. Moreover,
Baille et al. (23)
indicated no pharmacokinetic
interaction between docetaxel and several anticancer drugs from the
review of results in Phase I trials. In our study, there was no
significant difference in pharmacokinetic parameters of docetaxel,
doxorubicin, and doxorubicinol between the two sequences. Similarly,
Bellott et al. (24)
reported that docetaxel did
not change the pharmacokinetic profile of doxorubicin or its
metabolite, doxorubicinol, in the pharmacokinetic study in which 75
mg/m2
docetaxel was administered immediately
after or 1 h after bolus infusion of 50
mg/m2
doxorubicin. D’Incalci et al.
(25)
also indicated that a 1-h interval between the
administration of docetaxel and doxorubicin did not change the AUC data
compared with the immediate administration of the second agent.
However, they described the important finding that docetaxel did not
alter doxorubicin AUC, but doxorubicin increased the docetaxel AUC
compared with the AUC of each drug administered singly. Moreover, it
was reported that docetaxel increased doxorubicin levels in mice not
only in many tissues but also in serum at 24 h (26)
.
It was unknown whether these results were related to the
pharmacodynamic differences found in our study. No active metabolites
of docetaxel and doxorubicin were identified, and the observation that
there were no significant differences in pharmacokinetics between the
two sequences suggested that the difference might be related to factors
such as cellular pharmacokinetics rather than the plasma concentration
of the drugs or that the sequence of drug administration might affect
the sensitivity of myeloid progenitor cells in bone marrow.
The French study, in which doxorubicin was given first as an i.v.
15-min bolus injection followed 1 h later by docetaxel as a 1-h
infusion, indicated that the recommended dose for the combination of
both drugs was either 75 mg/m2
docetaxel plus 50
mg/m2
doxorubicin or 60
mg/m2
of both drugs (27
, 28)
.
Kennedy et al. (29)
also reported that the MTD
for doxorubicin and docetaxel was 40 and 60
mg/m2
, respectively, with the same schedule as
the French study (27
, 28)
. The MTD in our study, which seemed to
be a little low, might have been affected by the avoidance of the
standard use of corticosteroid premedication with docetaxel. However,
similar doses in the doxorubicindocetaxel sequence in our study
suggested that there were no ethnic differences in the pharmacokinetics
of docetaxel in agreement with population pharmacokinetic studies
(30
, 31)
. In fact, the difference in recommended dose for
docetaxel between Japan and the United States and Europe was due to the
criterion for DLT, that is, the duration of grade 4 neutropenia.
Moreover, the French study (27
, 28)
recently reported that
excellent response rates of 66% and 90% were achieved with the
combination of docetaxel and doxorubicin in previously untreated
metastatic breast cancer. The response rate in our study, which was
similar to those with the single administration of docetaxel, might be
due to bias in patient selection; however, the present study was
performed in a Phase I setting, and the response rate was not the
primary end point.
We concluded that a sequence-dependent toxicity of docetaxel and
doxorubicin on neutropenia was suggested but that there was no
pharmacokinetic sequence interaction between the two drugs. The
sequence of 50 mg/m2
doxorubicin followed by 60
mg/m2
docetaxel is recommended for practical
reasons for subsequent clinical trials, and the Phase II study is
ongoing in Japan. It would be of interest to evaluate that sequence in
comparison with the sequence of 50 mg/m2
docetaxel followed by 40 mg/m2
doxorubicin to
evaluate whether the latter schedule, which has the same toxicity but
at a lower dosage, would be associated with a higher or lower response
rate.
|
FOOTNOTES
|
|---|
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 To whom requests for reprints should be
addressed, at Division of Oncology and Hematology, National Cancer
Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, 277-8577, Japan.
Phone: 81-471-331111; Fax: 81-471-346922; E-mail: kaito{at}east.ncc.go.jp 
2 The abbreviations used are: CL, clearance; MTD,
maximal tolerated dose; AST, aspartate aminotransferase; DLT,
dose-limiting toxicity; G-CSF, granulocyte colony-stimulating factor;
LVEF, left ventricular ejection fraction; HPLC, high-performance liquid
chromatography; Cmax, peak plasma
concentration; t1/2, terminal half-life;
AUC, area under the plasma concentration-time curve;
Vss, volume of distribution at steady
state.
Received 3/13/00;
revised 7/ 6/00;
accepted 7/14/00.
|
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