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Clinical Trials |
Divisions of Experimental Oncology 1 [G. T., P. A., G. C., M. B.] and Medical Oncology [R. S., D. C., A. B., I. R., A. M. C.], Centro di Riferimento Oncologico, 33081 Aviano, and Pharmacia & Upjohn, 20152 Milan [F. S.], Italy
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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IDA therapy generally is well tolerated. The main IDA adverse effect is
myelosuppression. Gastrointestinal toxicity is also common. This
includes nausea, vomiting, and stomatitis of different WHO grades,
according to the IDA dose schedule used. G1-G2 diarrhea occurs
in 
10% of patients after a single i.v. dose (10–15
mg/m2) and in 10–30% of patients after oral
administration (40–45 mg/m2; Ref.
9
).
The pharmacokinetics of IDA have been evaluated in cancer patients after i.v. or oral administration (10 , 15) . IDA has a large volume of distribution, which probably indicates extensive tissue accumulation. IDA is metabolized, mainly in the liver after oral administration, to IDOL (10) . IDOL retains good cytotoxic activity in vitro (15) . Variability in oral absorption has been reported both between patients and within the same patient (10) .
IDA is the first anthracycline that can be given both p.o. and i.v. Oral IDA has been used in advanced breast cancer (11 , 16) . However, the role of oral IDA in this tumor needs to be better clarified. The oral route is useful in palliative treatment of patients with poor venous access and may be particularly appropriate for older patients (17) . Oral IDA in solid tumors was administered over 1, 3, or 5 days (9) . However, as demonstrated previously for other antineoplastic drugs (18 , 19) , the effectiveness of IDA might improve by low-dose continuous exposure. Although IDA is not a typical cell cycle phase-specific drug, it exerts some antitopoisomerase II activity (1) . It has been demonstrated that the commitment to cell killing by antitopoisomerase II agents predominantly occurs in S-phase cells (20) . Therefore, prolonged treatments with this drug increase the number of cells exposed to the drug during the most chemosensitive phase of the cell cycle. The increased ratio of IDOL/IDA AUC after oral compared with i.v. administration represents another advantage of prolonged low-dose treatments because IDA and its metabolite can cooperate in determining cytotoxic effects. Finally, the long plasmatic t1/2 of IDA and the longer t1/2 of IDOL (10) are pharmacological characteristics extremely favorable in protracted oral drug administration. In fact, they reduce the fluctuations in the plasmatic concentrations of the drug, allowing cells to be exposed to steadier drug concentrations, as with continuous i.v. infusion therapy.
To investigate a simple modality of IDA administration instead of the cumbersome and costly continuous i.v. infusion, a dose escalation of oral IDA was devised. The drug was given p.o. in hyperfractionated doses over a long period of time with the purpose of determining the MTD, toxicity profile, and pharmacokinetics of IDA this schedule.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The patients should not have received chemotherapy and/or radiation
within 4 weeks before IDA treatment and were not receiving concurrent
hormonal therapy. Patients with a history of cardiac disease were
excluded. Other inclusion/exclusion criteria were: normal baseline
(
50%) LVEF; life expectancy of at least 8 weeks; Eastern Cooperative
Oncology Group performance status of 0, 1, or 2; WBC count
4,000/µl; platelet count 150,000/µl; ANC 2,000/µl;
bilirubin level 
1.5 mg/dl; aspartate aminotransferase level
two times normal or lower, serum creatinine level 1.5 mg/dl, and
creatinine clearance 60 ml/min. Written informed consent was obtained
before study entry and the protocol was approved by the local Ethical
Committee.
Pretreatment and Treatment Evaluation.
Pretreatment evaluation included history and physical examination,
chest X-ray, liver ultrasound, electrocardiogram, determination
of resting baseline LVEF by echocardiography and computed tomography,
total body Tcm bone scan when clinically
indicated, full blood cell count, electrolytes, blood urea nitrogen,
creatinine clearance (24-h urinary collection), liver function tests,
prothrombin time-international normalized ratio (PT-INR), and partial
thromboplastin time (PTT). Laboratory tests were performed on a
weekly base. Toxicities were graded using the WHO criteria. The
compliance to therapy was assessed through weekly pill counts in
addition to a patient diary and evaluation was according to the
criteria of Miller et al. (21)
.
Treatment Plan.
IDA was provided by Pharmacia Upjohn (Milan, Italy) in powder oral
capsules of 1 and 5 mg. Each therapy course was administered for 21
days every 28 days, The starting dose of 1 mg was taken around either
8.30 a.m. or 8.30 p.m. In the subsequent cycles, the dose was
increased by 1 mg/day (with the larger dose given in the evening) until
disease progression, refusal, or DLT. The 1-mg capsule to be added was
given alternatively in the morning or in the evening. Patients had a
standard meal 20 min before intake of IDA. Supportive care was
administered when necessary. DLT was defined as G4 hematological
toxicity or any other toxicity of G3 or higher, and MTD was the dose
level at which two DLT events occurred. Antiemetics were used in the
presence of vomiting of G2 or higher, whereas hematological growth
factors were administered in the presence of G4 hematological toxicity.
To achieve a safe treatment, the protocol was planned to start with a very low dosage but permitting dose escalation within the individual patient to better evaluate cumulative toxicity of IDA and duration of response. We planned to enroll cohorts of five patients at each dose level. The dose was escalated by 1 mg/day only if G2 toxicity was not exceeded. If patients had G3 hematological toxicity, they were re-treated at the same dose level. If a patient experienced DLT, the next 5-patient cohort started at the same dose level (for a total of 10 patients), and the patient who had developed DLT was re-treated at 50% of the dose level. If two patients of a cohort of at least five patients experienced DLT, no additional cohort was enrolled and MTD was established.
Patients who needed 2 weeks instead of 1 to recover from toxicity were
re-treated at the same dose level. If patients did not recover from
toxicity after 2 weeks, they were dismissed from the study. Patients
were also dismissed from the study if during the 21 days of IDA intake
they had a neutrophil count 1,000/µl and/or platelet count
50,000/µl for >1 week, or cardiac events (congestive heart
failure, reduction of LVEF 20%). In those cases, patients were
replaced with new patients entered at the same dose level. Patients
with progressive disease at the end of a specific dose level were taken
off the study and replaced with new patients. Assessment of toxicity
included all treated patients, whereas only those patients who received
at least one 28-day course of IDA were assessable for response.
Drug Assay and Pharmacokinetic Analysis.
Blood samples for drug assay were taken on day 21 at 0 (immediately
before drug intake), 1, 2, 3, 4, 6, 12, 24, 48, and 72 h after the
last oral IDA dose. Blood samples were also collected at 0, 1, 2, 3,
and 4 h on day 1, and at 0 h on days 8 and 15. Blood samples
were picked up in lithium heparinate tubes and centrifuged immediately;
the plasma was stored at -20°C until analysis.
IDA and its metabolite IDOL were measured using a reversed-phase high-performance liquid chromatography method with fluorescence detection, as reported by Zanette et al. (22) with slight modifications. Plasma IDA and IDOL concentrations were quantified using the internal standard method and a calibration curve ranging between 0.10 and 10 ng/ml. The limit of quantification was 0.10 ng/ml. Doxorubicin was used as the internal standard within this range of concentrations. The within- and between-day precision was <10% (as the coefficient of variation) for both IDA and IDOL.
Pharmacokinetic parameters were calculated using a noncompartmental model. Estimates of pharmacokinetic parameters and the numerical validation of the model were obtained by the PCNONLIN 4.0, a nonlinear regression program. The Cmax and corresponding time to maximum concentration were determined from the experimental data. AUC was calculated by the trapezoidal rule from time 0 to 12 h (AUC0–12 h). AUC0–24 h was obtained by multiplying AUC0–12 h by 2. The apparent CL (CLapp, in liters/h) was calculated as the ratio of daily IDA dose (in micrograms), and AUC0–24 h. t1/2 (in hours) was determined by regression analysis of the log concentration versus time data in the elimination phase of both the parent compound and its metabolite. The apparent Vd (Vd app, in liters) was calculated as the ratio of clearance and elimination rate (in inverse hours), which is the slope of the log-linear terminal phase. CLapp and Vd app for IDOL were obtained with the same dose used for IDA calculations. An approximation would be introduced depending on the proportion of absorbed IDA that was not converted to IDOL and on the rate at which the parent drug was converted to its metabolite.
Statistical analysis was performed with software SAS system 6.12, 1989–1995 (SAS Institute Inc., Cary, NC). Correlation between kinetic and dynamic parameters was performed by the linear regression analysis. Regression analysis of multiple parameters against a single variable, to determine independently predictive parameters, was performed using a stepwise regression analysis. The Wilcoxon test was used for statistical evaluation of paired data when two groups of parameters were compared. The significance of the coefficients of the correlation found was determined as reported elsewhere (23) .
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). Three patients did not complete even
a single 21-day therapy cycle. One of them refused to continue therapy
after 5 days at 5 mg/day because of psychological problems. The other
two patients had neutrophils count <1000/µl for >7 days at the dose
level of 7 mg/day and were taken off study on day 17 of therapy. In
both patients, neutrophils (2000/µl) spontaneously recovered in 1
week.
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, 3
, and 4
. Overall, IDA was well tolerated. Hematological toxicity was the
most common. Generally, the ANC nadir decreased with the increase in
IDA dose with a statistically significant correlation
(P = 0.00019; r = -0.44). At the
highest dose level of IDA (10 mg/day), the median ANC was 850/µl
(min, <100/µl; max, 1500/µl; mean, 870 ± 430/µl). However,
a single patient experienced G4 neutropenia at a dose level of 3
mg/day. Such a toxicity occurred when the dose was escalated from 2 to
3 mg/day; to further explore treatment safety, we treated two
additional patients at 2 mg/day. Thus, 5 patients had the dose
escalated from 2 to 3 mg/day and a total of 10 patients were treated
with 3 mg/day. No DLT was observed in these 10 patients.
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2000/µl) within 7
days from the end of IDA administration. Seven patients recovered
within 2 weeks and thus were re-treated with the same dose: three, one,
one, and two patients were re-treated at the dose levels of 6, 7, 9,
and 10 mg/day, respectively. Among these patients, two had three cycles
(one patient at 6 mg/day and one patient at 10 mg/day, respectively;
Table 1
). Only two patients did not recover adequate neutrophil counts
within 14 days and were dismissed from the study. One of these patients
had an ANC nadir of 1000/µl at 7 mg/day and completely recovered from
toxicity in 29 days. The other patient had an ANC nadir of 1555/µl at
3 mg/day and recovered in 35 days. Both these patients had been
pretreated with chemotherapy (FEC). One patient developed a G4 hematological toxicity (DLT) at 10 mg/day. The ANC nadir was <100/µl, platelets were <10,000/µl, erythrocytes were 2.07 x 106/µl, and hemoglobin was 6.2 g/dl. Erythrocyte and platelet transfusion, together with granulocyte colony-stimulating factor rescue, was performed. The toxicity resolved completely in 21 days. It must be considered that in this patient’s ANC was 4400/µl on day 14.
Analysis of the neutrophil nadir over multiple courses of IDA showed no evidence of cumulative hematological toxicity.
Concerning nonhematological toxicity, diarrhea occurred in few patients
and at doses 9 mg/day. (Table 3)
. G1-G2
diarrhea was observed in four different patients. One patient had G3
diarrhea (DLT) when treated at 10 mg/day. Diarrhea started on day 17 of
IDA intake and was maximum on day 21; it needed 1 week for resolution.
Two patients experienced DLT (G4 hematological toxicity and G3 diarrhea) at 10 mg/day, and MTD was defined at this dose level. The median dose intensity at 10 mg/day, as defined by the amount of drug delivered per week, was 44.7 mg (range, 35–52.5 mg; mean, 44.9 ± 7.5 mg).
One patient had a LVEF fall of 30%, with bradycardia and
hypotension, during the second cycle with IDA at 7 mg/day. However, it
should be considered that this patient was concomitantly treated with
radiotherapy in the mediastinum (5000 rads). Despite the previous,
large doses of anthracyclines, no additional patient had cardiovascular
toxicity. The median LVEF was 62.5% (range, 40–67%; mean, 61 ±
7.1%) with no significant (P not significant by Wilcoxon
test) difference with the basal value.
An attempt to calculate toxicities versus IDA dose expressed
in mg/m2/day instead of mg/day was made. The
results are shown in Table 4
. The two
patients that experienced DLT at the dose of 10 mg/day received an IDA
dose >5.5 mg/m2/day. The G4 hematological
toxicity occurred in a patient treated with 6.85
mg/m2/day IDA, and the G3 diarrhea was observed
in a patient treated with 5.65 mg/m2/day IDA.
Overall, in our study, four patients (for a total of five courses) had
an IDA dose of >5.5 mg/m2/day. All of these
patients were in the cohort of five patients treated with 10 mg/day
IDA.
The response evaluation was performed in 21 patients. A partial
response was observed in three patients (14.3%) treated with doses
from 2 to 6 mg/day, from 7 to 9 mg/day, and from 8 to 10 mg/day,
respectively. The response duration was 3–8 months, and the number of
therapy cycles was four to six. These three patients previously had
received anthracyclines as postoperative adjuvant treatment and
had relapsed 11, 29, and 35 months, respectively, from the end of
adjuvant chemotherapy. Six patients (28.6%) had stabilization of
disease for 2–6 months (median, 4.0 months). Among these, five
patients (83%) had progressed previously with an i.v.
epirubicin-containing chemotherapy regimen. Twelve patients (57%) had
disease progression. Among these latter, five had early disease
progression after the first course of therapy and were dismissed from
the study. Finally, 10 patients were not evaluable for response (Table 5)
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summarizes the IDA and IDOL
pharmacokinetics as determined by serial blood sampling performed on
the last day of IDA administration (day 21) in 27 patients and on day
17 in 2 patients who had no further therapy. Both IDOL and IDA
exhibited linear pharmacokinetics over the dose range studied (Fig. 1)
. The concentrations of IDOL in plasma
exceeded those of IDA immediately after the start of treatment and
remained higher over the 21 days of treatment (Fig. 1
and Table 7
).
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). Intraday variations of IDOL were 19.3
± 9.4% (median, 18.0%; range, 9.9–40.9%). Sampling
performed on days 8, 15, and 21 indicated that both IDA and IDOL
maintained a relatively constant steady-state levels throughout the
course of drug administration (Table 7)
.
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. A highly significant correlation was observed between IDA
AUC and IDOL AUC (P < 0.000001; r =
0.83).
No evidence of accumulation of plasma IDA and IDOL and no
significant differences in IDA and IDOL AUC occurred during subsequent
cycles with the same dose level in the six patients investigated. In a
single patient treated with 2 and 3 mg/day, the plasma level of IDOL
was 6-fold higher than the median value. The IDOL AUC was 152.2 and
201.7 µg·h/liter at the doses of 2 and 3 mg/day, respectively,
whereas the IDA AUC was within the range observed in the other patients
treated with the same doses. This patient had severe G4 neutropenia at
the dose of 3 mg/day and was dismissed from the study because of
disease progression. She was receiving, in addition to IDA, quinidine,
paracetamol, codeine, and diclofenac.
A relationship between plasma IDA and IDOL and toxicity was
investigated. By univariate analysis, significant associations (Fig. 3)
were observed between ANC at nadir and
IDA AUC (P = 0.022; r = -0.33), IDA
Cmax (P = 0.0067;
r = -0.38), IDOL AUC (P = 0.0009;
r = -0.43), and IDOL Cmax
(P = 0.0016; r = -0.41). By stepwise
linear regression multivariate analysis that included the IDA AUC, IDOL
AUC, IDA Cmax, and IDOL
Cmax in the model, the strongest and only
significant determinant of ANC was IDA Cmax.
However, it accounted for only 14% of ANC variance
(P = 0.01; R2 = 0.14).
By univariate analysis, significant associations between ANC at nadir
and IDA CLapp (P = 0.0018;
r = 0.48) were also observed.
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-glutamyltransferase, respectively, or with
performance status and patient age. |
DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The predominant nonhematological toxicity was diarrhea. However, it was
generally mild, in agreement with a previous study (4)
in
which IDA produced severe or moderate diarrhea only in 5% of
patients. Diarrhea was strictly dose dependent and was observed only at
a dose 9 mg/day in 3 of 10 patients.
We determined the MTD of IDA in this schedule to be 10 mg/day. Neutropenia and diarrhea were the DLTs. The two patients that experienced DLT at the dose level of 10 mg/day received an IDA dose >5.5 mg/m2/day. This represents a 2–3-fold enhancement of dose intensity compared with the standard schedule of oral IDA administration (30–45 mg/m2 every 3 weeks). The clinical toxicity/dose relationship for this schedule appears to be steep, and dramatic increases in toxicity were observed when passing from 9 to 10 mg/day or when using IDA doses >5.5 mg/m2/day, although the percentage of difference between these dosages is little. Therefore, caution has to be observed when doses approximate the total dose/day MTD or 5.5 mg/m2/day. On the basis of these findings, we believe that a total dose of 8 mg/day (4 mg every 12 h for 21 days every 28 days) with a dosage <5 mg/m2/day could be given safely with this schedule, and it could represent the recommended phase II study dose.
In our study, hospitalization was required only for the patients who
developed DLTs; with these exceptions, no hematological growth factors
or antiemetics were required. Generally, patients recovered adequate
neutrophil counts (2000/µl) for recycle within 1 week, and only two
patients were dismissed from the study for inadequate neutrophil count
for >2 weeks. Concerning cardiac adverse events, chronic IDA
administration was safe. This was probably due to the lower
cardiotoxicity of IDA compared with other anthracycline analogues
(12)
and to the prolonged continuous administration
(24)
. Concerning the reduction of 20% in LVEF observed
in one patient, this must be ascribed to an extenuating circumstance
(concomitant salvage-radiotherapy with 5000 rads in the mediastinum).
In the clinical practice, drug dose is calculated as a function of body-surface area, but recently this method has been questioned (25) . Moreover, because of the standard commercial formulation of oral antineoplastic drugs, it is difficult to adapt the precise dosage to the body surface area. In the present study, we used the IDA dose per day instead of dose/m2/day because previously reported data on oral IDA suggested a great variability in the bioavailability (10) and such variations in bioavailability could be greater than interpatient variations in body surface. However, we also investigated the relationship between toxicity and daily dose adjusted to the body surface area. In particular, the finding that MTD occurred in patients treated with an IDA dose >5.5 mg/m2/day strongly suggests that this dose/m2/day represents the limit for MTD.
The intrapatient dose escalation adopted in this study does not allow definitive conclusions about cumulative toxicity for a specific dose level. However, cumulative IDA exposure does not appear to be a predisposing factor to myelosuppression because toxicity was not related to the number of cycles administered to each patient. No patient re-treated with the same dose level developed cumulative toxicity, and in addition, the two DLTs were observed during the first course of IDA.
After chronic oral IDA administration, the pharmacokinetic parameters
of IDA and IDOL (t1/2, CL, and
Vd) were consistent with those
described previously (26)
, assuming a bioavailability of
10–30% for IDA and a metabolized amount of 80% for IDOL
(27)
. The plasma levels of IDOL rapidly exceeded those of
the parental compound and remained higher throughout the treatment,
indicating a substantial first-pass conversion of IDA to IDOL during
absorption from the gastrointestinal tract. The ratio IDOL/IDA AUC was
stable across the dose range, suggesting that reduction of IDA to IDOL
by aldoketoreductase was not saturated with the schedule used in this
study.
The AUCs for IDA and IDOL showed interpatient variations at selected
dose levels. However, the IDA and IDOL AUCs generally showed a good
correlation. We think that this could reflect interpatient variations
in IDA absorption rather than IDA metabolism, as also suggested by
Schleyer et al. (27)
. On the contrary,
individual abnormalities in IDA metabolism should be considered a very
rare event with chronic oral IDA administration because only one
patient had an IDOL/IDA ratio 6-fold higher than that observed in
the remaining patients. The abnormal IDOL plasma level in this patient
was associated with increased IDOL
t1/2 and reduced IDOL
CLapp. The liver function test and creatininemia
for this patient were within the normal range, and at present, we
cannot conclude that some drugs taken by this patient (i.e.,
quinidine) during IDA therapy may have influenced the elimination
pathway of IDOL. Quinidine is a substrate for P-gp and could compete
with IDOL. P-gp is expressed in the liver at the luminal surfaces of
bile canaliculi (28)
and probably facilitates the biliary
excretion of IDOL more than IDA, whose transport is less affected by
P-gp activity (15)
.
At present, few data are available regarding the relationship between
oral IDA pharmacokinetics and toxicity (5
, 13
, 29)
. We
found that the nadir granulocyte count correlated, by univariate
analysis, with the IDA AUC, IDOL AUC, IDA Cmax,
and IDOL Cmax. This strict association could
suggest that even the interpatient variability observed in the plasma
drug level at selected dose levels is of clinical interest.
Multivariate regression analysis identified IDA
Cmax as the strongest determinant of ANC at nadir
and the most significantly predictive variable independent from IDOL
Cmax, IDA Cmax, IDOL AUC,
and IDA AUC, which were entered into the stepwise regression equation.
However, IDA Cmax accounted for only 14% of
variance of ANC, and this does not allow definitive conclusions on the
identification of the best variable for the prediction of IDA
myelosuppression. Nevertheless, the pharmacodynamic correlations
indicate that hyperfractionated oral IDA, by reducing the plasma IDA
Cmax, could contribute to reduced
hematological toxicity.
This study was not intended to demonstrate an effectiveness of hyperfractionated oral IDA in breast cancer. However, 3 of the 21 patients (14.3%) evaluable for response did have objective responses, and 6 patients (28.6%) showed stable disease. These results could be promising for further phase II studies. The limited sample size precluded conclusions regarding a relationship between response and dose.
In conclusion, chronic oral administration of IDA is easily administered and well tolerated by outpatients. This schedule allows greater dose intensity compared with conventional schedules, and IDOL appears to have some pharmacological effects. Whether chronic oral IDA administration offers advantages over a conventional schedule will require formal phase II studies. However, the activity and toxicity profiles of IDA observed with this schedule may be promising.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by a grant from the Ministry
of Health ("Ricerca Finalizzata" FSN 1997). 
2 To whom requests for reprints should be
addressed, at Centro di Riferimento Oncologico, Via Pedemontana
Occidentale 12, 33081 Aviano (PN), Italy. Phone: 39-0434-659300; Fax:
39-0434-659428; E-mail: mboiocchi{at}ets.it
3 The abbreviations used are: IDA, idarubicin;
DAU, daunorubicin; IDOL, idarubicinol
(4-demethoxy-13-dihydrodaunorubicin); AUC, area under the curve;
t1/2, half-life; MTD, maximum tolerated
dose; FEC, fluorouracil-epirubicin- cyclophosphamide; LVEF, left
ventricular ejection fraction; ANC, absolute neutrophil count; DLT,
dose-limiting toxicity; Cmax, maximum plasma concentration;
CL, clearance; Vd, volume of distribution;
P-gp, P-glycoprotein.
Received 12/30/99; revised 2/29/00; accepted 3/ 1/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), 5 (
), and
10 (•) mg/day are shown; bars, SD.