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Phase I Trial of Escalating Doses of Paclitaxel Plus Doxorubicin and Dexrazoxane in Patients With Advanced Breast Cancer

From the Eastern Cooperative Oncology Group Breast Cancer Committee, Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Bronx, NY; the Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, NY; Northwestern University School of Medicine, Chicago, IL; and the University of Maryland Greenebaum Cancer Center, Baltimore, MD.

Address reprint requests to Joseph A. Sparano, MD, Department of Oncology, Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, 2 South, Room 52, 1825 Eastchester Rd, Bronx, NY 10461-2373; email sparano{at}jimmy.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To determine the maximum-tolerable dose (MTD) of paclitaxel given as a 3-hour intravenous (IV) infusion that could be used in conjunction with doxorubicin and dexrazoxane, and to determine the effect of dexrazoxane on the pharmacokinetics of paclitaxel and doxorubicin.

PATIENTS AND METHODS: Twenty-five patients with advanced breast cancer received dexrazoxane (600 mg/m² by IV infusion over 15 minutes), followed 15 minutes later by doxorubicin (60 mg/m² IV), followed 15 minutes later by paclitaxel (150 or 175 mg/m² by IV infusion over 3 hours) in cohorts of three to six patients using a standard phase I design without (group A) and with (group B) granulocyte colony-stimulating factor (G-CSF). Treatment continued until there was a substantial decrease in the left ventricular ejection fraction (LVEF), congestive heart failure, progressive disease, or physician discretion to discontinue.

RESULTS: The MTD of paclitaxel was 150 mg/m², and adjunctive therapy with G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no significant effect on the pharmacokinetics of paclitaxel or doxorubicin. After a median cumulative doxorubicin dose of 360 mg/m² (range, 60 to 870 mg/m²), no patient developed congestive heart failure or had a decrease in LVEF below normal. An objective response occurred in all five patients with locally advanced breast cancer and in eight of 20 patients (40%; 95% confidence interval, 19% to 61%) with metastatic breast cancer.

CONCLUSION: When combined with doxorubicin (60 mg/m²) and dexrazoxane (600 mg/m²), paclitaxel given as a 3-hour infusion had an MTD of 150 mg/m², and G-CSF was required to prevent febrile neutropenia. Dexrazoxane had no effect on the pharmacokinetics of paclitaxel or doxorubicin. No patient in this trial had a decrease in the LVEF below normal, compared with about 20% to 50% of patients treated with doxorubicin and paclitaxel without dexrazoxane in other trials.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
DOXORUBICIN AND PACLITAXEL are among the most active cytotoxic agents for the treatment of metastatic breast cancer. Several randomized trials performed in the pre-taxane era showed that doxorubicin-containing chemotherapy regimens were associated with improved response and survival, compared with regimens that did not include doxorubicin.¹ Similar findings were noted in a pooled analysis of these randomized trials.² Given their single-agent activity, relative non–cross-resistance, partially non-overlapping toxicities, and different mechanisms of action, there is a clear rationale for combining the taxanes with doxorubicin in patients with advanced breast cancer.³ On the basis of these considerations, two separate groups performed phase I-II trials of the doxorubicin-paclitaxel combination in patients with metastatic breast cancer and independently reported very high response rates. Gianni et al³ reported a 94% response rate and 41% complete response (CR) rate in 32 assessable patients. Likewise, Dombernowsky et al⁴ reported an 83% response rate and 24% CR rate among 29 assessable patients. On the other hand, both trials were characterized by an unusually high rate of congestive heart failure (CHF) that occurred at cumulative doxorubicin doses not normally associated with this complication.⁵ For example, Gianni et al reported a 21% incidence of CHF after a median cumulative doxorubicin dose of 420 mg/m² (range, 120 to 480 mg/m²). Dombernowsky et al also noted a 20% incidence of CHF after a median cumulative doxorubicin dose of 369 mg/m² (range, 114 to 550 mg/m²). In both reports, CHF was defined as having grade 2/3 symptoms and objective signs using the New York Heart Association criteria. In addition, Dombernowsky et al reported that 50% of all patients had a decrease in the left ventricular ejection fraction (LVEF) below normal. In both trials, doxorubicin was given by slow intravenous (IV) bolus injection, followed 15 minutes later by paclitaxel given as a 3-hour IV infusion.

Unusually high response rates and CR rates have also been reported by some^6,7 but not all^8-10 groups using the same or a similar dose and schedule of the combination. Gianni et al¹¹ have subsequently reported that paclitaxel perturbs the metabolism of doxorubicin, resulting in about a 30% increase in doxorubicin exposure. Others have reported a similar interaction if the drugs are given by a protracted infusion sequentially,¹² but not concomitantly.¹³ In addition, paclitaxel increases myocardial concentrations of both doxorubicin and epidoxorubicin in mice, an effect that occurs only if there is a relatively short interval between administration of the drugs.^14,15 Because the antitumor and cardiotoxic effects of doxorubicin are known to be dose dependent,¹⁶ this pharmacokinetic interaction provides a potential explanation for the therapeutic and toxic synergy observed with the combination. Indeed, some trials that used a longer interval between administration of the two drugs (or a more protracted infusion of paclitaxel) were associated with a lower risk of cardiomyopathy.^6,8 Clinically significant cardiotoxicity may be avoided, therefore, by altering the schedule of drug administration (ie, increasing the interval between administration of the two drugs or using a 24-hour rather than a 3-hour infusion of paclitaxel) or by limiting the cumulative dose of doxorubicin to 360 mg/m² (ie, six cycles of therapy).

Dexrazoxane is a bis-dioxopiperazine compound that has been shown to have a protective effect against doxorubicin-induced cardiomyopathy in women with metastatic breast cancer.^17-19 It is hydrolyzed to form a chelating agent that is similar in structure to EDTA, chelates with iron intracellularly, and inhibits the generation of free radicals that are responsible for the cardiotoxic effects of doxorubicin. Dexrazoxane results in near-complete protection against doxorubicin-induced cardiomyopathy and allows about one third of patients to receive at least 700 mg/m² of doxorubicin,^17-19 a cumulative dose at which about 20% of patients would be expected to develop CHF if dexrazoxane were not used.⁵

Given that the high activity of the doxorubicin-paclitaxel combination may be associated with an enhanced risk of cardiomyopathy, it was only logical to investigate the feasibility of combining the cardioprotective agent dexrazoxane with this regimen. Since the activity of doxorubicin is thought to be dose dependent,¹⁶ we chose to investigate a fixed dose of doxorubicin plus dexrazoxane and to escalate the dose of paclitaxel. The primary objective of our trial, therefore, was to determine the maximum-tolerable dose (MTD) of paclitaxel given as a 3-hour infusion that could be used with 60 mg/m² of doxorubicin plus dexrazoxane (600 mg/m², or a 10:1 ratio to doxorubicin dose). A secondary objective was to determine whether dexrazoxane had any influence on the pharmacokinetics of paclitaxel and doxorubicin.

	PATIENTS AND METHODS

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Patient Selection
Patients were required to have histologically confirmed adenocarcinoma of the breast that was either locally advanced (stage IIIB) or metastatic (stage IV) and to have disease that was measurable or assessable. Other requirements included (1) age at least 18 years and less than 70 years; (2) Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; (3) normal organ function (ie, normal total bilirubin and AST < twofold the upper limit of normal, neutrophil count > 1,500/µL, platelets > 100,000/µL); (4) no prior chemotherapy for metastases; (5) no prior adjuvant doxorubicin or taxane; (6) no adjuvant chemotherapy within 6 months of registration; (7) normal LVEF as measured by radionuclide angiography or echocardiography within 4 weeks of registration; (8) no risk factors of doxorubicin-associated cardiomyopathy (ie, no atherosclerotic heart disease, no hypertension requiring therapy within 3 months of registration, no irradiation to the mediastinum or left chest wall after mastectomy, and age < 70 years); (9) not taking drugs known to alter cardiac conduction (ie, digoxin, beta blockers, or calcium channel blockers); (10) no history of irradiation to a field encompassing more than 25% of bone marrow; and (11) no symptomatic or untreated brain metastases.

Treatment Plan
Patients received dexrazoxane (600 mg/m²) by IV infusion over 15 minutes. Fifteen minutes after completion of the infusion, patients received doxorubicin 60 mg/m² by IV bolus injection over 5 minutes. Fifteen minutes after completion of the doxorubicin injection, patients received paclitaxel administered as a 3-hour IV infusion. The dose of paclitaxel was assigned at the time of registration and was intended to be 150, 175, or 200 mg/m². If neutropenia was found to be dose limiting, the protocol called for continued dose escalation of paclitaxel in conjunction with granulocyte colony-stimulating factor (G-CSF). For those patients assigned to receive G-CSF, it was given as a subcutaneous daily dose of 5 µg/kg/d beginning about 24 hours after completion of the chemotherapy. G-CSF was discontinued when the postnadir neutrophil count was at least 10,000/µL. Complete blood cell counts were obtained twice weekly beginning on day 8 of each cycle. The doses of all drugs were reduced 25% if the patient had febrile neutropenia, grade 4 thrombocytopenia, or grade 3 or higher nonhematologic toxicity (eg, mucositis). All toxicity was graded according to the National Cancer Institute common toxicity criteria. All patients were treated on a protocol that was reviewed and approved by the National Cancer Institute (protocol T95-0054) and by the institutional review boards at each participating institution. Participating centers included the Albert Einstein Comprehensive Cancer Center (four patients), Kaplan Comprehensive Cancer Center (16 patients), and Northwestern University Medical Center (five patients).

Dose-Escalation Schema
Patients were treated in cohorts of three to six per group. If none of three patients had dose-limiting toxicity (DLT), the paclitaxel dose was escalated. If one of three had DLT, then three additional patients were treated at the same dose level, and further escalation was permitted if one of six had DLT. The MTD was considered to be one dose level below which at least two of three patients, or at least two of six patients, had DLT. DLT was defined as febrile neutropenia, grade 4 thrombocytopenia, or grade 3 or higher nonhematologic toxicity. For patients who were treated without G-CSF, the definition of DLT also included a neutrophil count of less than 500/µL for more than 3 days, because this would identify a patient at high likelihood of developing febrile neutropenia in subsequent cycles or if further dose escalation occurred. Dose escalation was initially performed without G-CSF (group A). When neutropenia was found to be dose limiting, dose escalation continued with G-CSF (group B). After the MTD had been identified, 10 additional patients were treated at the MTD (group C). Patients in group C received doxorubicin and paclitaxel in cycle 1, and then dexrazoxane, doxorubicin, and paclitaxel in cycle 2. For patients in group C, multiple blood samples were drawn during cycles 1 and 2 for measurement of plasma concentrations of paclitaxel, doxorubicin, and dexrazoxane (see Results, under Pharmacokinetics).

Duration of Therapy and Schedule for Cardiac Evaluation
Patients underwent repeat radionuclide angiography after cycles 4, 6, and 8, and then every cycle thereafter. Patients continued therapy until one of the following events occurred: (1) disease progression; (2) CHF (defined as having at least two of the following: cardiomegaly, basilar rales, an S3 gallop, and dyspnea on exertion, orthopnea, or paroxysmal nocturnal dyspnea); (3) a substantial decrease in the LVEF of at least 20 percentage points from baseline, or by at least 10 percentage points from baseline and below normal, or by more than five percentage points below the lower limit of normal; (4) toxicity that in the judgment of the investigator was prohibitive and poorly tolerated; or (5) the patient's refusal to continue treatment or the investigator's belief that it was in the patient's best interest to stop therapy (eg, achievement of maximum response and proceeding to alternative therapy such as mastectomy or high-dose therapy plus stem-cell transplantation).

Criteria for Response and Schedule for Tumor Evaluation
ECOG response criteria were used to define response.²⁰ Tumor evaluation occurred after cycle 4, after an additional two cycles of therapy, and then every 4 months if a response occurred.

Pharmacokinetic Sampling and Analysis
Multiple plasma samples were drawn in 10 patients treated in group C for measurement of paclitaxel, doxorubicin, and dexrazoxane blood levels. During cycle 1, samples were drawn at 15 minutes before the doxorubicin infusion and at 0, 15, 30, 60, and 90 minutes and 2, 3, 4, 6, 12, 24, and 48 hours after initiation of the paclitaxel infusion. For cycle 2, samples were drawn at the same time points plus four additional time points, including just before the dexrazoxane infusion, 7.5 minutes and 15 minutes after initiation of the dexrazoxane infusion, and 72 hours after initiation of the paclitaxel infusion. At each time point, 10 mL of blood was drawn into a heparinized tube, centrifuged for 5 minutes at 1,000 x g with collection of the plasma in cryovials, and stored at -20°C until packed in dry ice for shipment to the analysis site.

Both the doxorubicin and dexrazoxane plasma assays (performed by L.L., S.M., and D.F.) used solid-phase extraction with the addition of appropriate internal standards for control of drug recovery. The doxorubicin assay used methods previously described for epirubicin, with the substitution of 500-mg C-8 solid-phase extraction columns (Varian Associates, Palo Alto, CA),^21,22 whereas the dexrazoxane assay was simplified from that previously used²² to include a single solid-phase extraction step and detection at 214 nm without use of the column switching technique. Estimates of plasma pharmacokinetic parameters used nonlinear modeling (WINONLIN, version 1.5; Scientific Consulting, Inc, Apex, NC). For IV dosing, a short-infusion two-compartment model was used. The area under the plasma concentration versus time curve was calculated both as model specific and by a model-independent trapezoidal rule determination. The distribution and elimination half-lives, total body clearance, and maximum concentration were also tabulated. Concentrations of paclitaxel in plasma were measured (by R.S. and M.J.E.) by high-performance liquid chromatography using methods previously described.²³

The pharmacokinetics of paclitaxel was evaluated by both noncompartmental and model-dependent (compartmental) methods. For the compartmental analysis, a previously described three-compartment, nonlinear model using Bayesian estimation and the ADAPT II pharmacokinetic software program²⁴ was fit to the plasma paclitaxel concentration versus time profile for each patient. Furthermore, because plasma paclitaxel concentrations were measured at intervals too widely spaced to allow precise definition of duration at or above given thresholds (for example, above 0.05 µM plasma paclitaxel concentration), the time spent at or above various plasma paclitaxel concentrations was determined from concentration versus time profiles simulated for each patient. This was accomplished with patient-specific pharmacokinetic parameter estimates and the SIM module in the ADAPT II program. Area under the concentration versus time curve was calculated with log-trapezoidal rule and with LaGrange function²⁵ as implemented by the LAGRAN program.²⁶ A comparison of the pharmacokinetic parameters for cycle 1 and cycle 2 was performed using the Wilcoxon signed rank test.

	RESULTS

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Patient Characteristics
Twenty-five patients were accrued onto this trial between April 1996 and April 1997. The characteristics of the patient population are listed in Table 1. One patient in group C was considered ineligible because of prior left chest wall irradiation. This patient, who progressed after three cycles of therapy, was included in the analyses of response, toxicity, and pharmacokinetics.

Results of Dose Escalation
The results of dose escalation are shown in Table 2. At the first paclitaxel dose level of 150 mg/m² without G-CSF (group A), two of three patients had severe neutropenia (< 500/µL) that lasted more than 3 days and that was not associated with fever. Accrual continued at the same paclitaxel dose level—therefore, after addition of G-CSF (group B). One of six patients treated with 150 mg/m² of paclitaxel plus G-CSF had febrile neutropenia. One patient treated in this cohort erroneously received 175 mg/m² during the first cycle. This patient did not have febrile neutropenia, however, and received 150 mg/m² during subsequent cycles. After escalation of the paclitaxel dose to 175 mg/m² plus G-CSF, two of six patients had febrile neutropenia. Ten additional patients were then treated at the MTD of paclitaxel (group C), which was defined as 150 mg/m². Patients in group C received doxorubicin and paclitaxel plus G-CSF in cycle 1, then dexrazoxane, doxorubicin, and paclitaxel plus G-CSF in cycle 2 and all subsequent cycles. No patient treated in group C had DLT during cycle 1 or cycle 2.

Cardiac Toxicity
The median cumulative doxorubicin dose was 360 mg/m² (range, 60 to 870 mg/m²). Nine patients (36%) received at least 420 mg/m² of doxorubicin. The LVEF was measured pre- and posttherapy in 23 of 25 patients. In these 23 patients, there was no significant difference in the mean LVEF pretherapy (65.5% ± 6.5%), compared with posttherapy (63.0% ± 5.9%). In no patient did the LVEF decrease to below normal. In addition, no patient developed CHF or was withdrawn from the study for cardiac toxicity.

Other Toxicity
A total of 156 assessable treatment cycles were administered. The median number of treatment cycles administered was six (range, one to 17). Only four patients (16%) required dose modification for toxicity; all of these patients required a 25% dose reduction for febrile neutropenia. Noncardiac toxicity is summarized in Table 3. The most common severe toxicity was leukopenia. Severe thrombocytopenia was uncommon. There were no grade 4 nonhematologic events. Stomatitis was relatively uncommon and usually mild or moderate. About one third of patients developed neuropathy, but it usually did not require dose modification of paclitaxel. Reasons for discontinuing therapy included achievement of maximal response and cross-over to nonprotocol therapy (n = 10; 40%), disease progression (n = 9; 36%), patient withdrawal (n = 3; 12%), or physician discretion (n = 3; 12%).

Pharmacokinetics
The results of the pharmacokinetic analysis are shown in Table 4. An additional 10 patients, who were treated at the MTD of 150 mg/m² of paclitaxel, underwent pharmacokinetic evaluation (group C). Data regarding paclitaxel are available for nine patients, and data for doxorubicin and dexrazoxane are available for 10 patients. During cycle 1, patients received doxorubicin and paclitaxel plus G-CSF. During cycle 2, patients received the same regimen plus dexrazoxane. When comparing cycle 1 and 2, there was no significant difference for either paclitaxel or doxorubicin in any of the pharmacokinetic parameters that were evaluated, including area under the curve, half-life, maximum concentration, or clearance. Likewise, there was no significant difference between cycle 1 and 2 in the median time that the paclitaxel concentration was more than 0.05 µM. With regard to dexrazoxane, the pharmacokinetic parameters were not significantly different when compared with findings in a prior study that evaluated the pharmacokinetics of dexrazoxane (comparative data not shown),²² suggesting that the use of paclitaxel did not affect the pharmacokinetics of dexrazoxane.

Response and Survival Data
All five patients with stage IIIB disease had an objective clinical response to therapy, although all three who underwent mastectomy had persistent microscopic disease. These patients received a median of seven cycles of therapy (range, three to seven cycles) before receiving local therapy. Three of five patients with stage IIIB disease progressed after a median of 5 months (range, 4 to 5 months), with the remaining two disease free at 15 and 19 months. Of the remaining 20 patients with metastatic disease, eight patients (40%; 95% confidence interval, 19% to 61%) had an objective response to therapy, including one CR and seven partial responses. The median response duration was 3 months (range, 1 to 11 months), and median survival has not yet been reached after a median follow-up of 12 months (range, 2 to 21 months).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We performed a phase I trial in which we sought to determine the MTD of paclitaxel that could be used in combination with 60 mg/m² of doxorubicin and 600 mg/m² of the cardioprotective agent dexrazoxane. Paclitaxel was given as a 3-hour IV infusion beginning 15 minutes after doxorubicin in a manner identical to that initially reported by Gianni et al³ and Dombernowsky et al.⁴ The MTD of paclitaxel by our criteria was 150 mg/m², and adjunctive therapy with G-CSF was required to prevent an unacceptably high rate of febrile neutropenia.

None of the 25 patients treated with a median cumulative doxorubicin dose of 360 mg/m² in this trial had a decrease in the LVEF below normal or developed CHF. In three other trials that evaluated the doxorubicin-paclitaxel combination without dexrazoxane in which cardiac toxicity was carefully monitored, between 20% and 50% of patients had a decrease in the LVEF below normal after median cumulative doxorubicin doses ranging from 240 mg/m² to 420 mg/m² (Table 5). In addition, about 20% of patients developed clinical evidence of CHF if the median cumulative doxorubicin dose exceeded 360 mg/m².^3,4 In one of these trials performed by the ECOG, the incidence of CHF was only 2% because the cumulative doxorubicin dose was restricted to less than 360 mg/m².¹⁰ Comparison of the LVEF data from the ECOG study with data from the current study demonstrates that patients treated with dexrazoxane were significantly less likely to have a decrease in the LVEF below normal (10 of 52 patients v zero of 25 patients; P < .03) and had a significantly smaller decrease in the mean LVEF after therapy (mean decrease of 7.3% v 2.5%; P = .036, paired t test). This occurred despite the fact that patients treated with dexrazoxane in the current study actually received a substantially greater cumulative dose of doxorubicin (median of 360 mg/m²), compared with those who did not receive dexrazoxane in the ECOG study (median of 240 mg/m²).¹⁰ In addition, it is unlikely that the lesser cardiac toxicity associated with dexrazoxane was attributable to the lower paclitaxel dose used in this study (150 to 175 mg/m²) compared with the ECOG study (200 mg/m²), because paclitaxel-induced perturbation in doxorubicin metabolism has been reported at these lower doses of paclitaxel.¹¹ Although we recognize the limitations of comparing toxicity data from two separate trials, this indirect comparison nevertheless suggests that dexrazoxane may be useful in preventing the cardiomyopathy associated with the doxorubicin-paclitaxel combination. Further study will be required to confirm this observation.

The MTD of paclitaxel in this trial was 15% to 25% lower than the MTD of paclitaxel in other trials of the doxorubicin-paclitaxel combination that used similar criteria for defining DLT.^3,4 Febrile neutropenia was the DLT. There was no evidence for a pharmacokinetic interaction between dexrazoxane and paclitaxel or doxorubicin to account for this observation. Furthermore, although the trial was not designed to assess the effect of paclitaxel on the pharmacokinetics of dexrazoxane, the pharmacokinetic profile of dexrazoxane in this study seems comparable to that reported in other studies evaluating the pharmacokinetics of dexrazoxane used in conjunction with doxorubicin (without paclitaxel).²² Dexrazoxane is known to be myelosuppressive when used as a single agent^27-29 and results in more neutropenia when combined with fluorouracil, doxorubicin, and cyclophosphamide¹⁷ without altering the pharmacokinetics of doxorubicin.²² In another phase I trial evaluating the combination of dexrazoxane, doxorubicin, and paclitaxel, neutropenia was also found to be dose limiting at the initial paclitaxel dose level of 125 mg/m², although most patients in this trial had received prior chemotherapy for metastatic disease (P. Ravdin, personal communication, December 1998). Taken together, these findings suggest that dexrazoxane is myelosuppressive and may have compromised our ability to use a higher dose of paclitaxel. On the other hand, there is at best only a modest dose-response relationship for the dose range of paclitaxel used in our trial,³⁰ and recent evidence suggests no dose-response relationship at higher doses of the drug.³¹

An issue of concern is whether dexrazoxane impairs the antineoplastic activity of chemotherapy. The objective response rate was significantly lower for patients treated with dexrazoxane in one of three trials that compared fluorouracil, doxorubicin, and cyclophosphamide given with and without dexrazoxane.¹⁸ Time to progression and survival were not different in the two arms, however. In addition, no difference in response rate, time to progression, or survival was observed in two other trials.^17,18 Because of these concerns, dexrazoxane is not recommended for use as a component of initial therapy of metastatic breast cancer, but rather is recommended for patients who have received a cumulative doxorubicin dose of at least 300 mg/m² and who would benefit from continued therapy in the judgment of the treating physician. Our trial was not designed to assess whether dexrazoxane impairs the antitumor activity of the doxorubicin-paclitaxel regimen. The level of activity that we observed in our trial is lower than that reported by some groups^3,4,6,7 but is consistent with the findings reported by other groups.^8-10

In conclusion, we determined that the MTD of paclitaxel given as a 3-hour infusion was 150 mg/m² when combined with doxorubicin (60 mg/m²) and dexrazoxane (600 mg/m²), and adjunctive therapy with G-CSF was required to prevent an unacceptably high rate of febrile neutropenia. In addition, dexrazoxane had no significant effect on the pharmacokinetics of paclitaxel or doxorubicin. The efficacy of the regimen was within the range of activity that had previously been reported for the doxorubicin-paclitaxel combination. Finally, in contrast to other reports of the doxorubicin-paclitaxel combination, patients treated with dexrazoxane in this trial had no cardiac toxicity, suggesting that dexrazoxane may be useful in ameliorating the cardiac toxicity associated with this specific dose and schedule of the combination.

	ACKNOWLEDGMENTS

 
Supported by the Department of Health and Human Services, National Cancer Institute, Bethesda, MD (grant no. P30CA13330), and by grants from Bristol-Myers, Inc, and Pharmacia, Inc.

We thank Dr. Jeffrey Abrams and Dr. Susan Arbuck of the National Cancer Institute for their support and their helpful recommendations in the design and conduct of this study.

	NOTES

 
Presented in part on December 5, 1997, at the 20th Annual San Antonio Breast Cancer Symposium, San Antonio, TX.

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Submitted July 21, 1998; accepted November 3, 1998.

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