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Phase II Trial of Doxorubicin and Docetaxel Plus Granulocyte Colony-Stimulating Factor in Metastatic Breast Cancer: Eastern Cooperative Oncology Group Study E1196

From the Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Bronx, NY; Dana-Farber Cancer Institute, Boston, MA; Toledo Hospital, Toledo, OH; University of Pretoria, Pretoria, South Africa; and Emory University School of Medicine, Atlanta, GA.

Address reprint requests to Joseph A. Sparano, MD, Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center, Department of Oncology-2South, Room 52, 1825 Eastchester Rd, Bronx, NY 10461-2373.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The purpose of this multi-institutional phase II trial was to evaluate the efficacy and toxicity of doxorubicin and docetaxel plus granulocyte colony-stimulating factor (G-CSF) in patients with metastatic breast cancer. The primary objective was to determine whether the combination produced a response rate of at least 50%.

PATIENTS AND METHODS: Fifty-four patients with metastatic breast cancer received doxorubicin (60 mg/m² by intravenous [IV] injection) followed 1 hour later by docetaxel (60 mg/m² by IV infusion over 1 hour) every 3 weeks for up to eight cycles. All patients also received G-CSF.

RESULTS: Objective response occurred in 29 (57%) of 51 eligible patients (95% confidence interval [CI], 42% to 70%), including three patients who had a complete response (6%; 95% CI, 1% to 16%). The median response duration was 7 months (95% CI, 6.0 to 15.0 months), median time to treatment failure was 7.6 months (95% CI, 6.2 to 9.9 months), and the median survival was 27.5 months (95% CI, 21.5 months to upper limit not reached). The median cumulative doxorubicin dose was 395 mg/m² (range, 60 to 480 mg/m²). Fifteen patients (28%) were documented to have a decrease in the left ventricular ejection fraction below normal, and three patients (6%; 95% CI, 1% to 15%) developed congestive heart failure.

CONCLUSION: Using criteria that we had defined a priori, the doxorubicin-docetaxel regimen as used in this study was sufficiently active and tolerable to justify a phase III comparison with doxorubicin-cyclophosphamide in early-stage breast cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE ANTHRACYCLINES (eg, doxorubicin and epirubicin) and the taxanes (eg, paclitaxel and docetaxel) are the most active cytotoxic agents for the treatment of metastatic breast cancer.¹ A pooled analysis of randomized trials conducted in the pretaxane era demonstrated that doxorubicin-containing regimens resulted in a higher response rate and improved survival in patients with metastatic breast cancer.² Regarding early-stage disease, the Breast Cancer Trialists’ meta-analysis demonstrated a modest improvement in survival when doxorubicin was used as a component of adjuvant therapy.³ More recently, the taxanes have proven to be effective agents for patients with metastatic breast cancer who have failed doxorubicin-based therapy.^4,5 Furthermore, the addition of paclitaxel after doxorubicin-cyclophosphamide in early-stage disease significantly reduces the risk of relapse and improves survival.⁶

The anthracyclines and taxanes differ substantially in their mechanisms of action. The taxanes induce cytotoxicity by binding to tubulin, promoting microtubule assembly, and inhibiting microtubule depolymerization.⁷ In addition, they effect various other biologic processes that may contribute to their antineoplastic activity, such as inducing apoptosis⁸ and inhibiting angiogenesis,⁹ invasiveness,¹⁰ cell motility, and metalloproteinase production.¹¹ The anthracyclines, on the other hand, exert their cytotoxicity by inducing DNA damage through an inhibition of topoisomerase II. Given their efficacy, relative non–cross-resistance, partially nonoverlapping toxicities, and differing mechanisms of action, there is clear rationale for combining the anthracyclines and taxanes for the treatment of early- and advanced-stage breast cancer.

Several studies have evaluated the doxorubicin-paclitaxel combination in metastatic breast cancer. A phase III trial demonstrated the combination to be more effective than single-agent doxorubicin or paclitaxel with regard to objective response rate (47% for the combination v approximately 35% for the single agents) and median time to progression (8 months v 6 months), although the combination did not improve survival.¹² Other studies using a different schedule demonstrated high objective response rates (approximately 80% to 90%) and complete response rates (approximately 20% to 40%),^13,14 although the incidence of congestive heart failure (CHF) was substantially increased (approximately 20%) because of a paclitaxel-induced alteration in the pharmacokinetics of doxorubicin.¹⁵ Other studies failed to confirm the unusually high response rates initially reported by some for this combination, and cardiotoxicity remained prohibitive for use in the adjuvant setting.¹⁶

In the current trial that forms the basis for this report, we evaluated the efficacy of doxorubicin (60 mg/m²) and docetaxel (60 mg/m²) plus granulocyte colony-stimulating factor (G-CSF) in a phase II trial. The dose and schedule of the combination was based upon a phase I trial that identified two dosing schedules deemed suitable for phase II testing.¹⁷ The primary objective of this study was to determine whether the regimen produced an objective response rate of at least 50%. This was one of several phase II trials that the Breast Cancer Committee of the Eastern Cooperative Oncology Group (ECOG) had initiated to identify a suitable regimen for comparison with doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) in patients with early-stage breast cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients were required to have histologically confirmed adenocarcinoma of the breast with manifestations of progressive regional or metastatic disease that was measurable or assessable. Other requirements included the following: (1) age 18 years and 70 years; (2) ECOG performance status of 0, 1, or 2; (3) normal organ function (ie, normal total bilirubin and AST 2.5-fold the upper limits of normal, neutrophil count 1,500/µL, and 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 the diagnosis of metastatic disease; (7) normal left ventricular ejection fraction (LVEF) as measured by radionuclide angiography or echocardiography within 6 weeks of registration; (8) no risk factors of doxorubicin-associated cardiomyopathy (ie, atherosclerotic heart disease, congestive heart failure, irradiation to the mediastinum or left chest wall after mastectomy, and age > 70 years); (9) no history of irradiation to a field encompassing more than 25% of bone marrow; (10) no symptomatic or untreated brain metastases; (11) no history of thromboembolic disease; (12), not pregnant and using effective contraception if of childbearing potential; and (13) disease-free of prior invasive malignancies for at least 5 years with the exception of curatively treated squamous cell carcinoma-in-situ of the cervix. All patients were required to provide written informed consent, and the protocol was approved by the institutional review boards at each participating institution.

Treatment Plan
Patients received doxorubicin 60 mg/m² by intravenous (IV) bolus injection over 5 minutes. One hour after completion of the doxorubicin injection, patients received docetaxel (Taxotere; Rhone-Poulenc Rorer Pharmaceuticals, Inc, Collegeville, PA) (60 mg/m²) administered as a 1-hour IV infusion. Dexamethasone (8 mg orally twice daily) was given for 3 days beginning 1 day before each treatment cycle. G-CSF (Neupogen; Amgen, Inc, Thousand Oaks, CA) was given subcutaneously (5 mcg/kg) daily beginning on day 2 of therapy and continuing until the postnadir neutrophil count was at least 10,000/µL. Complete blood counts were obtained twice weekly beginning on day 8 of each cycle. Treatment was repeated every 3 weeks if the neutrophil count was 1,500/µL, platelets 100,000/µL, and the patient had recovered from all nonhematologic toxicity. The chemotherapy doses were reduced 25% if there was febrile neutropenia, grade 4 thrombocytopenia, or grade 3 nonhematologic toxicity (eg, mucositis). All toxicity (including cardiac toxicity) was graded according to the National Cancer Institute common toxicity criteria. Liver function was monitored at each cycle. The protocol specified removal from the study if the total bilirubin or AST increased by more than 1.5-fold and five-fold, respectively, above the upper limits of normal. If the total bilirubin was between 1.3- and 1.5-fold elevated or the AST was between 2.5- and five-fold elevated, both drugs were reduced by 50%. After completion of up to eight cycles of the combination, treatment continued with docetaxel alone (100 mg/m² via a 1-hour infusion every 3 weeks plus G-CSF) in those who had responding or stable disease. Treatment with docetaxel alone continued until two cycles beyond achieving a complete response, the development of progressive disease or prohibitive toxicity, or the patient’s or the physician’s discretion to stop. Neupogen and Taxotere were provided at no cost to patients participating in this trial by Amgen and Rhone-Poulenc Rorer, respectively.

Schedule for Tumor Evaluation and Criteria for Response
All patients had all sites of measurable and/or assessable disease recorded within 2 weeks of registration, after cycle 4 and 8 of the combination, and then every 3 months thereafter until disease progression. Computerized tomography of the chest and abdomen, bone scan, and skeletal radiographs (if the bone scan was abnormal) were required at baseline in all patients. All studies were repeated at the indicated times if the baseline study demonstrated measurable and/or assessable disease. ECOG response criteria were used to define response.¹⁸ Response duration was measured from the day the patient first documented to have at least 50% tumor volume reduction until the time of disease progression. Time to treatment failure was defined as time from registration to tumor progression. Patients who died while on study without progression or shortly after going off study without progression were considered treatment failures. Patients without progression were censored at the last time known to be in remission or stable. Patients unassessable for response were censored at zero.

Monitoring for Cardiac Toxicity
All patients had an electrocardiogram, chest x-ray, and assessment of the LVEF (by radionuclide angiography or echocardiography) within 6 weeks before therapy and after cycles 6 and 8 of the combination. Patients with a prior history of left breast irradiation had a repeat LVEF assessment after cycle 4 (rather than cycle 6) and cycle 8. In addition, patients in whom the LVEF decreased by more than 10% and/or below the lower limits of normal were required to have a repeat measurement in 3 months. At each of these time points, a cardiac-specific history and physical examination were performed to evaluate for clinical signs and symptoms of CHF. CHF was defined as having at least two of the following features: (1) cardiomegaly on chest x-ray, (2) basilar rales, (3) an S3 gallop, and (4) dyspnea on exertion, orthopnea, or paroxysmal nocturnal dyspnea. This definition has previously been used in trials evaluating the cardioprotective agent dexrazoxane.¹⁹

Statistical Considerations
The primary objective of this study was to estimate the overall response rate of this regimen. It was anticipated that 50 patients would be accrued, of whom 45 would be eligible. The regimen would be considered promising and worthy of further testing if at least 23 (51%) of 45 eligible patients had an objective response. If the true response rate is 60%, the probability of observing fewer than 23 responses is .09. If the true response rate is only 40%, the probability of observing fewer than 23 responses is .91. A secondary end point was cardiac toxicity. With 50 patients assessable for toxicity, a toxicity observed in five patients (10%) would have a 90% confidence interval (CI) for the true incidence of between 4% and 20%. The expected incidence for congestive heart failure for patients prospectively monitored and using the criteria in this study is approximately 8% after a cumulative doxorubicin dose of between 400 and 450 mg/m².²⁰ The survival distributions for response duration, time to treatment failure, and overall survival were estimated using the Kaplan-Meier method.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Fifty-four patients were enrolled between December 1996 and July 1997. Three patients were considered ineligible because of failure to meet one of the eligibility criteria, including metastatic cancer arising from primary sites other than breast (n = 2) or prior left chest wall irradiation (n = 1). The characteristics of the remaining 51 eligible patients are listed in Table 1. The median age was 52 years (range, 20 to 70 years), 16 patients (31%) had bone metastases, 14 (27%) had liver metastases, 18 (35%) had at least three sites of metastases, and 12 (24%) had prior adjuvant chemotherapy.

Treatment Duration and Reasons for Discontinuing Therapy
Forty-two patients (78%) completed at least four cycles of treatment, 35 patients (65%) completed at least six cycles, and 30 patients (56%) completed the maximum of eight cycles. The median cumulative doxorubicin dose was 395 mg/m² (range, 60 to 480 mg/m²). For the 24 patients who received less than eight cycles of the combination, reasons for discontinuation of the combination included progressive disease (n = 12), toxicity (n = 6), patient refusal or withdrawal (n = 4), administration of nonprotocol therapy (n = 1), or withdrawal from the study because of ineligibility (n = 1). Of the six patients who discontinued the combination because of toxicity, only one discontinued because of cardiac toxicity (asymptomatic decrease in LVEF from 72% to 50%). For the 12 patients who received less than four cycles of the combination, only four patients discontinued treatment because of toxicity.

Cardiac Toxicity
A total of 40 patients had at least two measurements of the LVEF performed (Table 3). Of these patients, 11 had grade 1 toxicity (LVEF decreased 10% but < 20% from baseline and no symptoms), eight had grade 2 toxicity (LVEF decreased by 20% from baseline and no symptoms), and 15 had a documented decrease in the LVEF below normal (all listed in Table 4). Of the 15 patients in whom the LVEF decreased below normal (Table 4), the median cumulative doxorubicin dose was 450 mg/m² (range, 120 to 480 mg/m²); in 11 of these 15 patients, the decrease was within 10% (absolute value) of the lower limits of normal.

Other Toxicity
Among all 54 patients who were treated, a total of 323 cycles of the doxorubicin-docetaxel combination and 116 cycles of single-agent docetaxel were given. The proportion of patients with toxicity by worst grade experienced is listed in Table 5. Severe (grade 3) or life-threatening (grade 4) toxicities that occurred in at least 10% of patients included granulocytopenia (76%), thrombocytopenia (16%), infection (15%), and nausea (13%). Other grade 3 or 4 toxicities that occurred in less than 10% of patients included anemia (9%), vomiting (9%), glucose intolerance (7%), fatigue (6%), stomatitis (6%), cardiac toxicity (6%), diarrhea (4%), neurosensory toxicity (4%), neuromotor toxicity (4%), pulmonary toxicity (2%), edema (2%), hypersensitivity reaction (2%), phlebitis (2%), hypertension (2%), and febrile neutropenia (2%).

There were two treatment-associated deaths, and both occurred in patients who had liver metastases and impaired hepatic function. The protocol required a normal total bilirubin and AST to be less than 2.5-fold elevated above the upper limits of normal within 2 weeks of registration. In addition, liver function was monitored at each cycle, and the protocol specified removal from the study if the total bilirubin or AST increased by more than 1.5-fold and five-fold, respectively, above the upper limits of normal. If the total bilirubin was between 1.3- and 1.5-fold elevated or the AST was between 2.5- and five-fold elevated, both drugs were reduced by 50%. One patient (no. 51) was a 57-year-old woman who died of septic shock associated with neutropenia and progressive disease 7 days after the second cycle of therapy. Both cycles were given at full dose, which was consistent with the protocol-specified guidelines. The total bilirubin was normal on the first day of therapy, and the AST and alkaline phosphatase were elevated 1.7- and 1.5-fold, respectively, above the upper limits of normal. The first cycle was uncomplicated. Just prior to the second cycle, the total bilirubin was normal, and the AST and alkaline phosphatase had increased to 2.1- and 2.2-fold, respectively, above the upper limits of normal. The second patient (no. 42) was a 57-year-old woman who died of septic shock associated with severe neutropenia, gastrointestinal hemorrhage, and progressive disease 8 days after the third cycle of therapy. The total bilirubin was normal, and the AST was 1.5-fold elevated 14 days before registration. On the first day of treatment, however, the AST and alkaline phosphatase were elevated 3.9-fold and 4.3-fold, respectively. Although the AST decreased to normal and the alkaline phosphatase improved (to 1.4-fold elevated), the total bilirubin increased from a normal level (0.9 mg/dL) to an elevated level (1.7 mg/dL, or 1.7-fold above normal) before the third cycle, which was given at full dose (which was not consistent with the protocol guidelines).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We performed a multi-institutional phase II trial of doxorubicin (60 mg/m²) and docetaxel (60 mg/m²) plus G-CSF in 54 patients with metastatic breast cancer. The dose and schedule used in this study was based upon one of two schedules identified in a previous phase I trial, the other being 50 mg/m² of doxorubicin and 75 mg/m² of docetaxel.¹⁷ We chose the schedule used in the current trial because we were interested in developing a regimen for early-stage breast cancer that could be compared with doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) in a phase III trial. Based upon the efficacy of the safety of the doxorubicin-docetaxel regimen observed in the study and in other trials, the United States Breast Cancer Intergroup has initiated and completed a phase III trial comparing four cycles of doxorubicin (60 mg/m²) plus either cyclophosphamide (600 mg/m²) or docetaxel (60 mg/m²) in patients with early-stage breast cancer. The only variable in this trial, therefore, is the substitution of docetaxel for cyclophosphamide.

The doxorubicin-docetaxel regimen evaluated in this study resulted in an objective response rate of 57% (95% CI, 42% to 70%), median response duration of 7 months, and median time to treatment failure of 7.6 months. Among 39 eligible patients who had no prior adjuvant chemotherapy, objective response occurred in 67% (95% CI, 50% to 80%). Although severe granulocytopenia (< 1,000/µL) occurred in 76% of patients despite the use of G-CSF, serious infection occurred in 15% of patients and febrile neutropenia in only 2%. Two patients died of treatment-related complications, both of whom had extensive liver metastases and an elevated AST and alkaline phosphatase, features known to be associated with an increased risk of life-threatening docetaxel-associated toxicity.²¹ In fact, it is now recommended that patients with liver metastases who have either an elevated bilirubin or at least a 1.5-fold elevation in the AST (or ALT) and a 2.5-fold elevation in the serum alkaline phosphatase not receive docetaxel.²²

Our findings are nearly identical with the results of a phase III trial that compared a slightly different dose of doxorubicin (50 mg/m²) and docetaxel (75 mg/m²) (AT) with doxorubicin (60 mg/m²) and cyclophosphamide (600 mg/m²) (AC) for a maximum of eight cycles in 423 patients with metastatic breast cancer.²³ The docetaxel-containing arm, compared with the AC arm, was associated with a significantly improved response rate (60% v 47%, respectively; P = .012) and median time to progression (37.1 v 31.9 weeks, respectively; P = .0153). Although no difference in survival was observed at the time of this analysis, the median survival had not yet been reached. There was no significant difference in the incidence of CHF (2% for AT v 4% for AC), although patients treated with docetaxel received less doxorubicin (median cumulative dose of 378 mg/m² for AT v 420 mg/m² for AC). Likewise, there was no significant difference in the incidence of treatment-associated death between the two arms (2% for AT v 4% for AC). Although the incidence of febrile neutropenia was significantly higher for AT (31% for AT v 10% for AC), G-CSF was not used. Other groups have likewise found the doxorubicin-docetaxel combination to be a highly active and tolerable regimen for patients with metastatic²⁴ and stage II/III breast cancer.²⁵

Unlike the doxorubicin-paclitaxel regimen, the combination of doxorubicin and docetaxel is not associated with an increased risk of cardiotoxicity. Paclitaxel has been shown to alter the plasma disposition of doxorubicin and its major metabolite (doxorubicinol), resulting in approximately a 30% increase in exposure to doxorubicin and its active metabolite.¹⁵ This interaction is highly sequence- and schedule-dependent and is observed if there is a relatively short (15-minute) interval between administration of the drugs or with relatively short (3-hour) paclitaxel infusions.²⁶ Docetaxel, on the other hand, has been found to have no effect on the pharmacokinetics of doxorubicin when docetaxel is given as a 1-hour infusion either 1 hour or 15 minutes after an injection of doxorubicin.^27,28 Paclitaxel also increases the plasma concentration time curves for the 7d-Aone and glucuronidated metabolites of epirubicin to a significantly greater extent than docetaxel.²⁹ These findings provide a potential explanation for the enhancement of cardiotoxicity when doxorubicin is used with paclitaxel but not docetaxel. It is noteworthy, however, that doxorubicin increases the plasma concentration curve of docetaxel by approximately 30%.²⁷ It is likely that the effect of doxorubicin on the disposition of docetaxel is accentuated in patients with liver disease because the anthracyclines are also known to be metabolized by the liver.³⁰ This may provide an explanation for the two toxic deaths observed in our study in patients who had liver metastases and impaired liver function and points out the need to continually monitor liver function in patients with liver metastases treated with this combination.

This was one of several trials initiated by the Breast Cancer Committee of the ECOG whose primary purpose was to determine a doxorubicin-taxane combination that would be suitable for comparison with doxorubicin-cyclophosphamide in early-stage breast cancer. We were encouraged to see that the doxorubicin-paclitaxel combination had significantly improved response and time to disease progression in metastatic disease in trial E1193,¹² thereby providing a sound rationale for this strategy. We reasoned that the improved control of macroscopic disease in patients with clinically evident metastases would likely translate into improved eradication of microscopic disease and improved survival in early-stage disease. The doxorubicin-paclitaxel regimen used in E1193 was not practical for use in the adjuvant setting, however, because of the 4-hour interval between administration of the two drugs and the 24-hour infusion of paclitaxel. Therefore, we performed a phase II trial of doxorubicin (60 mg/m²) followed 15 minutes later by paclitaxel (200 mg/m²) given as a 3-hour infusion in 52 patients with metastatic breast cancer, a regimen that has previously been shown to produce a very high response rate (approximately 80% to 90%) and incidence of CHF (approximately 20%).^13,14 To reduce the risk of CHF, we restricted the maximum cumulative doxorubicin dose to 360 mg/m² (or six cycles of therapy). The objective response rate of 57% was comparable with our previous experience with a different schedule of the combination in E1193 and ruled out, with a reasonable degree of certainty, that the true response rate exceed 70%.¹⁶ Furthermore, 23% of assessable patients had a decrease in the LVEF below normal and 6% developed CHF (despite receiving a median cumulative doxorubicin dose of only 240 mg/m²). In our judgement, the relatively high degree of cardiac toxicity observed with only four to six cycles of the combination rendered it unsuitable for further testing in the adjuvant setting. In another trial performed by our group, we demonstrated that the cardioprotective agent dexrazoxane greatly diminished the cardiotoxicity of this same doxorubicin-paclitaxel regimen, although the response rate was only 40% and median response duration was only 3 months.³¹ This raised concern about using dexrazoxane in the adjuvant setting, particularly because one previous study demonstrated a significantly lower response rate when dexrazoxane was used in conjunction with doxorubicin-based therapy for metastatic disease.²⁰ In our most recent trial that forms the basis for this report, the doxorubicin-docetaxel combination produced a relatively high objective response rate that exceeded the 50% rate that we had determined a priori to be sufficiently encouraging for further investigation in an adjuvant trial. Although 28% of all patients had a decrease in the LVEF below normal (including 6% who developed CHF), the median cumulative doxorubicin dose (395 mg/m²) far exceeded the dose that would be used in the adjuvant setting (240 mg/m²) and is consistent with previous reports for patients treated with a comparable doxorubicin dose.²⁰ In addition, although there were two treatment-associated deaths, both patients had extensive liver metastases with hepatic dysfunction, features that would not be applicable to use of this regimen in the adjuvant setting (so long as there was no other cause for liver disease). Finally, the results of the phase III trial reported by Nabholtz et al²³ demonstrating a higher response rate and comparable safety for AT compared with AC in metastatic disease provides further rationale for choosing a docetaxel-based regimen for further study in the adjuvant setting.

A trial conducted by the United States Intergroup (C9344) recently demonstrated that the addition of four cycles of paclitaxel (175 mg/m² over 3 hours every 3 weeks) after four cycles of AC reduced the risk of recurrence and death by approximately 20% in patients with axillary node–positive breast cancer.²³ Although the data from the Oxford overview suggests that the benefit from adjuvant chemotherapy is similar amongst different risk groups,³ the benefit of adjuvant taxane therapy for node-negative disease remains to be established. Furthermore, there are many important questions regarding the optimal integration of taxane therapy in the adjuvant setting, most of which will be addressed in cooperative groups studies that are either ongoing or in development. The question remains open as to whether the taxanes are best used sequentially or in combination with doxorubicin, the optimal duration of adjuvant therapy, and whether there is a selective advantage for a specific taxane (docetaxel or paclitaxel) or taxane schedule (every 3 weeks or weekly).^32,33 The role for trastuzumab³⁴ in her2/neu-expressing tumors also represents an important research question for early-stage disease. Completion of these carefully designed trials should provide answers for these important questions.

	ACKNOWLEDGMENTS

 
Supported in part by Public Health Service grant nos. CA14958, CA23318, CA21692, and CA21115 from the National Cancer Institute, National Institutes of Health, and the Department of Health and Human Services.

We thank Dianne Ingersoll for her expert data management, Amgen for supplying Neupogen, and Rhone-Poulenc Rorer Pharmaceuticals for supplying Taxotere for this study.

	NOTES

 
Presented at the Twenty-First Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 15, 1998.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Honig SF: Treatment of metastatic disease: Hormonal and chemotherapy, in Harris JR, Lippman ME, Morrow M, et al (eds): Diseases of the Breast. Lippincott-Raven, Philadelphia, PA, 1996, pp 669-734

2. A’Hern RPA, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67:801-805, 1993[Medline]

3. Early Breast Cancer Trialists’ Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[Medline]

4. Bissery MC, Nohynek G, Sandernink GJ, et al: Docetaxel: A review of preclinical and clinical experience—Part I. Clinical experience. Anti-Cancer Drugs 6:1943-1951, 1995

5. Rowinsky EK, Donehower RC: Drug therapy: Paclitaxel. N Eng J Med 332:1004-1014, 1995[Free Full Text]

6. Henderson IC, Berry D, Demetri G, et al: Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive breast cancer. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 390)

7. Sparreboom A, van Tellingen O, Nooijen WJ, et al: Preclinical pharmacokinetics of paclitaxel and docetaxel. Anti-Cancer Drugs 9:1-17, 1998[Medline]

8. Haldar S, Chintapalli J, Croce C: Taxol induces bcl-2 phosphorylation and death of prostate cancer cells. Cancer Res 56:1253-1255, 1996[Abstract/Free Full Text]

9. Belotti D, Vergani V, Drudis T, et al: The microtubule drug paclitaxel has antiangiogenic activity. Clin Cancer Res 2:1843-1849, 1996[Abstract]

10. Verschueren H, Dewit J, DeBraekeller J, et al: Motility and invasive potency of murine T-lymphoma cells: Effect of microtubules inhibitors. Cell Biol Int 128:11-19, 1994

11. Stracke ML, Soroush M, Liotta LA, et al: Cytoskeletal agents inhibit motility and adherence of human tumor cells. Kidney Int 43:151-157, 1993[Medline]

12. Sledge GW Jr, Neuberg D, Ingle J, et al: Phase III trial of doxorubicin versus paclitaxel versus doxorubicin plus paclitaxel as first-line therapy for metastatic breast cancer: An intergroup trial. Proc Am Soc Clin Oncol 16:1a, 1997 (abstr 2)

13. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol 13:2688-2699, 1995[Abstract]

14. Dombernowsky P, Gehl J, Boesgaard M, et al: Doxorubicin and paclitaxel: A highly active combination in the treatment of metastatic breast cancer. Semin Oncol 23:23-27, 1996 (suppl 11)[Medline]

15. Gianni L, Bigano L, Locatelli A, et al: Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer. J Clin Oncol 15:1906-1915, 1997[Abstract/Free Full Text]

16. Sparano JA, Hu P, Rao RM, et al: Phase II trial of doxorubicin and paclitaxel plus granulocyte-colony stimulating factor in metastatic breast cancer: An Eastern Cooperative Oncology Group study (E4195). J Clin Oncol 17:3828-3834, 1999[Abstract/Free Full Text]

17. Misset JL, Dieras V, Bozec L, et al: Long-term follow-up of the phase I/II study of docetaxel and doxorubicin as first line chemotherapy of metastatic breast cancer. Proc Am Soc Clin Oncol 17:160a, 1998 (abstr 612)

18. Oken MM, Creech RH, Tormey DC, et al: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982[Medline]

19. Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15:1318-1332, 1997[Abstract/Free Full Text]

20. Swain S: Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Sem Oncol 25:43-47, 1998 (suppl 10)[Medline]

21. Bruno R, Hille D, Riva A, et al: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 16:187-196, 1998[Abstract/Free Full Text]

22. Physician’s Desk Reference (ed 53). Montvale, NJ, Medical Ecomics Company Inc, 1999, pp 2609-2614

23. Nabholtz JM, Falkson G, Campos D, et al: A phase III trial comparing doxorubicin and docetaxel to doxorubicin and cyclophosphamide as first line therapy for metastatic breast cancer. Proc Am Soc Clin Oncol 18:127a, 1999 (abstr 485)

24. Nabholtz JM, Mackey JR, Smylie M, et al: Phase II study of Taxotere (docetaxel), doxorubicin, and cyclophosphamide (TAC) in the treatment of metastatic breast cancer. Proc Am Soc Clin Oncol 16:148a, 1997 (abstr 518)

25. Von Minckwitz G, Costa SD, Eiermann W, et al: Maximized reduction of primary breast tumor size using preoperative chemotherapy with doxorubicin and docetaxel. J Clin Oncol 17:1999-2005, 1999[Abstract/Free Full Text]

26. Sparano JA: Use of dexrazoxane and other strategies to prevent cardiomyopathy associated with doxorubicin-taxane combinations. Sem Oncol 25:66-71, 1998 (suppl 10)

27. Bellot R, Robert J, Dieras V, et al: Taxotere does not change the pharmacokinetic profile of doxorubicin and doxorubicinol. Proc Am Soc Clin Oncol 17:221a, 1998 (abstr 853)

28. Schuller J, Czejka M, Kletzl H, et al: Doxorubicin and Taxotere: A pharmacokinetic study of the combination in advanced breast cancer. Proc Am Soc Clin Oncol 17:205a, 1998 (abstr 790)

29. Esposito M, Venturini M, Vannozzi MO, et al: Comparative effects of paclitaxel and docetaxel on the metabolism and pharmacokinetics of epirubicin in breast cancer patients. J Clin Oncol 17:1132-1140, 1999[Abstract/Free Full Text]

30. Robert J, Gianni L: Pharmacokinetics and metabolism of anthracyclines. Cancer Surv 17:219-252, 1993[Medline]

31. Sparano JA, Speyer J, Gradishar WJ, et al: Phase I trial of escalating doses of paclitaxel plus doxorubicin and dexrazoxane in patients with advanced breast cancer. J Clin Oncol 17:862-869, 1999[Abstract/Free Full Text]

32. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16:3353-3361, 1998[Abstract]

33. Burstein JH, Younger J, Bunnell CA, et al: Weekly docetaxel (Taxotere) for metastatic breast cancer: A phase II trial. Proc Am Soc Clin Oncol 18:127a, 1999 (abstr 484)

34. Slamon D, Leyland-Jones B, Shak S, et al: Addition of Herceptin (humanized anti-her2 antibody) to first line chemotherapy for her2-overexpressing metastatic breast cancer markedly increased anticancer activity: A randomized, multinational controlled phase III trial. Proc Am Soc Clin Oncol 17:98a, 1998 (abstr 377)

Submitted August 10, 1999; accepted February 22, 2000.

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