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Journal of Clinical Oncology, Vol 22, No 13 (July 1), 2004: pp. 2587-2593
© 2004 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2004.08.125
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Multicenter Randomized Trial Comparing Sequential With Concomitant Administration of Doxorubicin and Docetaxel As First-Line Treatment of Metastatic Breast Cancer: A Spanish Breast Cancer Research Group (GEICAM-9903) Phase III Study

Emilio Alba, Miguel Martín, Manuel Ramos, Encarna Adrover, Ana Balil, Carlos Jara, Agustí Barnadas, Antonio Fernández-Aramburo, Pedro Sánchez-Rovira, Margarita Amenedo, Antonio Casado

From the Medical Oncology Department, Complejo Hospitalario Virgen de la Victoria, Málaga; Medical Oncology Department, Hospital Universitario San Carlos, and Medical Oncology Department, Fundación Hospital Alcorcón, Madrid; Medical Oncology Department, Centro Oncológico Regional, La Coruña; Medical Oncology Department, Hospital General Universitario, Alicante; Medical Oncology Department, Hospital Universitario Arnau de Vilanova, Lérida; Medical Oncology Department, Hospital Germans Trias i Pujol, Badalona; Medical Oncology Department, Complejo Hospitalario de Albacete, Albacete; and Medical Oncology Department, Complejo Hospitalario Ciudad de Jaén, Jaén, Spain

Address reprint requests to Emilio Alba, MD, PhD, Medical Oncology Service, Hospital Clínico Universitario Virgen de la Victoria, Colonia Santa Inés S/N, 29010 Málaga, Spain; e-mail: oncologia98{at}yahoo.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
PURPOSE: This randomized, multicenter, phase III trial evaluated whether sequential doxorubicin and docetaxel (A->T) reduced hematological toxicity, especially febrile neutropenia, compared with concomitant (AT) administration as first-line chemotherapy in metastatic breast cancer (MBC).

PATIENTS AND METHODS: One hundred forty-four patients were randomly assigned to receive three cycles of doxorubicin 75 mg/m2 every 21 days followed by three cycles of docetaxel 100 mg/m2, every 21 days (A->T) or six cycles of the combination doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (AT) every 21 days. Patients previously treated with anthracyclines received two cycles of doxorubicin followed by four cycles of docetaxel (A->T), or three cycles of AT followed by three cycles of docetaxel 100 mg/m2 every 21 days.

RESULTS: Febrile neutropenia was less common in the A->T arm (29.3% of patients, 6.9% of cycles) compared with the AT arm (47.8% of patients, 14.8% of cycles; P = .02 and P = .0004, respectively). Asthenia, diarrhea, and fever occurred more frequently in the AT arm. The overall responses rates were 61% in the A->T arm (95% CI, 50% to 72%) and 51% in the AT arm (95% CI, 39% to 63%). The median duration of response was 8.7 months (A->T) and 7.6 months (AT); the median time to progression was 10.5 months (A->T) and 9.2 months (AT); the median overall survival was 22.3 months (A->T) and 21.8 months (AT); and no significant differences were found.

CONCLUSION: A->T significantly reduced febrile neutropenia compared with AT in MBC patients and maintains comparable antitumoral efficacy. A->T represents a valid option for the treatment of MBC.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Metastatic breast cancer (MBC) is sensitive to a high number of cytotoxic drugs. Doxorubicin (A) is one of the most active single-agent chemotherapy treatments in MBC, with an overall response rate (ORR) in untreated patients of 35% to 50%.1 Docetaxel (T; Taxotere; Aventis Pharma SA, Antony Cedex, France), introduced in the 1990s for the treatment of advanced MBC, is the only chemotherapeutic agent that has shown a superior efficacy over doxorubicin in the first-line MBC setting, with a response rate of 48% (docetaxel: 100 mg/m2 every 21 days) versus 33% (doxorubicin: 75 mg/m2 every 21 days).2 Thus, both doxorubicin and docetaxel play major roles in the treatment of MBC.3

The activity of both drugs and the lack of complete cross-resistance between them provided the rationale for the development of a combination chemotherapy regimen with these agents.4 The concomitant use of doxorubicin and docetaxel achieved an ORR of 53% to 81%, but at the cost of a high rate of febrile neutropenia (36% to 40%).5-9 The concomitant use (AT regimen) of doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 every 21 days as first-line treatment of MBC, was compared with doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 21 days in a phase III trial.10 AT combination showed a high response rate (59% v 47%), but was accompanied by high incidence of hematological toxicity (febrile neutropenia in 33% of patients v 10% in the control group). Bone marrow toxicity and its complications, mainly febrile neutropenia, were the limiting toxicities of this combined chemotherapy.

The sequential administration of doxorubicin and docetaxel (A->T) might preserve antitumor efficacy and reduce the incidence and severity of toxicity. Several phase II studies have evaluated sequential doxorubicin (75 to 90 mg/m2) and docetaxel (100 mg/m2) for the treatment of early-stage and advanced breast cancer.11-15 In a previous phase II trial (Spanish Breast Cancer Research Group [GEICAM] 9801), we found that the sequential administration of doxorubicin (75 mg/m2 every 14 days with granulocyte colony-stimulating factor [G-CSF] support, or every 21 days without G-CSF) followed by docetaxel (100 mg/m2 every 21 days) conferred a 65% response rate, which was similar to that observed with the concomitant AT administration. However, this sequential approach seemed to have an improved toxicity profile, particularly with respect to febrile neutropenia, which was observed in 23% of patients when doxorubicin was administered every 2 weeks with G-CSF support, compared with a febrile neutropenia rate of 19% of patients, when doxorubicin was administered every 21 days.15

The present randomized, multicenter, phase III trial is the first to our knowledge to evaluate whether the A->T schedule reduced the incidence of hematological toxicity, especially the incidence of febrile neutropenia, compared with the concomitant administration of AT. Secondary end points of this phase III trial included ORR, time to disease progression, duration of response, overall survival, and overall toxicity profile.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Study Design
The study was designed as a phase III, randomized, open-label, prospective, multicenter clinical trial, and included 23 Spanish hospitals as active research centers. Random assignment was performed centrally at the GEICAM headquarters in Madrid. Patient recruitment began in December 1999 and concluded in December 2001. Good Clinical Practice principles (GCP-ICH) were applied to the study documents and procedures. The study was approved by independent ethics committees at each participating site, and the study protocol was submitted and approved by the National Health Authorities (Agencia Española del Medicamento, protocol 99-0380). All patients provided written informed consent. Clinical research forms were specifically designed to record the study data. Site monitoring was performed by GEICAM GCP Clinical Research Associates. Source data verification was performed on 100% of study information.

Patient Selection
The main eligibility criteria included women aged ≥ 18 years; with histologically confirmed MBC; measurable disease; Eastern Cooperative Oncology Group performance status ≤ 2; and normal bone marrow, renal, or hepatic function. Baseline laboratory study requirements included leukocytes greater than 4 x 109/L, neutrophils greater than 2 x 109/L, platelets greater than 100 x 109/L, hemoglobin greater than 10 g/dL, serum creatinine less than 2 mg/dL (with creatinine clearance > 45 mL/min), total bilirubin less than 1x upper normal limit (UNL), ALT and AST less than 2.5x UNL, and alkaline phosphatase less than 5x UNL. Patients with ALT and/or AST greater than 1.5x UNL concomitant with alkaline phosphatase higher than 2.5x UNL were excluded. Normal cardiac function was confirmed by left ventricular ejection fraction (LVEF; > 50%).

Patients were excluded from the study if they had received prior chemotherapy for metastatic disease. However, previous neoadjuvant or adjuvant chemotherapy was allowed, provided that treatment had been completed at least 12 months before study entry. If a patient had been previously treated with an anthracycline, her cumulative anthracycline dose could not exceed 300 mg/m2 doxorubicin or the equivalent cumulative epirubicin dose. Hormone therapy for the adjuvant and/or metastatic setting was allowed, the last one only if the patient showed progressive disease at study entry. Prior radiotherapy was allowed at sites other than those used to assess response.

Further exclusion criteria included a history of malignancy other than breast cancer; however, patients with nonmelanoma skin cancer, in situ cervical carcinoma, or other cancer with no evidence of disease for ≥ 5 years were eligible. Patients were also excluded if they had known metastatic disease involving the CNS, pre-existing motor or sensory neurotoxicity more than grade 2, or a history of other serious illness (eg, congestive heart failure, angina pectoris, AIDS), uncontrolled infection, or if they showed contraindication for corticosteroid use, or were pregnant or lactating.

Chemotherapy Regimen
Eligible patients who had not previously been treated with anthracyclines were randomized to receive three cycles of doxorubicin 75 mg/m2 every 21 days followed by three cycles of docetaxel 100 mg/m2 every 21 days (A->T) or six cycles of combined doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 every 21 days (AT).

Eligible patients who had previously been treated with anthracyclines were randomized to receive two cycles of doxorubicin 75 mg/m2 every 21 days followed by four cycles of docetaxel 100 mg/m2 every 21 days (sequential treatment) or three cycles of AT 50 mg/m2 and 75 mg/m2, respectively, every 21 days, followed by three cycles of docetaxel 100 mg/m2 every 21 days (AT). Taking into account a maximum cumulative anthracycline dose of doxorubicin 300 mg/m2 in previous adjuvant treatments, and the doxorubicin 150 mg/m2 dose received during the present study both in the A->T arm (2 x 75 mg/m2) and in the concomitant AT arm (3 x 50 mg/m2), these patients never exceeded a maximum anthracycline dose of 450 mg/m2. Figure 1 summarizes the study treatment schedules.



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  		Fig 1. Design of the study and chemotherapy regimens scheduled. A, doxorubicin; T, docetaxel; R, random assignment.

 
All patients were given prophylactic corticosteroid premedication to decrease the incidence and severity of acute hypersensitivity reactions and chronic fluid retention; this consisted of the administration of oral dexamethasone (8 mg), methylprednisolone (40 mg), prednisone (50 mg), or prednisolone (50 mg) from the night before docetaxel administration and up to a maximum of 6 doses. Standard prophylactic antiemetic therapy was administered according to the investigator's criteria. G-CSF was not allowed as primary prophylaxis, but it was allowed after a first episode of febrile neutropenia.

Chemotherapy cycles were delayed 1 week for neutrophils less than 1,000/mm3 or platelets less than 100,000/mm3. If hematological values did not recover within 2 weeks, the patients were withdrawn from the study. Dose modifications were planned for severe toxicity. Patients who experienced febrile neutropenia (< 500 neutrophils/mm3 and ≥ 38.1°C body temperature) and required antibiotics and/or hospitalization had a 20% dose reduction for both drugs. Blood cell counts were measured twice every week until recovery. A second episode of febrile neutropenia implied a delay of 1 week, and after 2 weeks without recovering, the patients were withdrawn from the study. Both drug doses were also reduced by 20% in the event of grade 3 mucositis or skin toxicity ≥ grade 2, and after a second episode, the patients were withdrawn from the study. Any grade 4 toxicities implied the interruption of treatment. Other dose reductions were not allowed, and doses reduced for toxicity could not be re-escalated.

Patient and Treatment Evaluation
Prestudy evaluations included a medical history review and physical examination, tumor measurements, cardiac function tests (LVEF by echocardiography and ECG), hematology and biochemistry tests, and other examinations as clinically indicated. All patients were evaluated before each cycle of treatment (including physical examination, hematology, and biochemistry tests) and on completion of the treatment schedule. Tumor measurements were repeated after three and six cycles. Response was evaluated after a minimum of three cycles (three doxorubicin cycles in the A->T schedule [two doxorubicin cycles and one docetaxel cycle in case of prior anthracyclines], or three combined AT cycles in the AT schedule) according to WHO criteria.16 Complete response (CR; no detectable tumor, including bone), partial response (PR; ≥ 50% reduction), and stable disease were determined by two observations not less than 4 weeks apart. All toxicities were documented and graded according to the National Cancer Institute Common Toxicity Criteria.17 The patients were monitored for clinical and laboratory toxicity and were asked to report the occurrence of adverse experiences to the investigator.

Data Analysis
Sample size calculations required 72 patients in each treatment arm to ensure 80% power (one-sided {alpha} = .05) to detect a reduction of febrile neutropenia in the sequential treatment arm from 36% to 19%.

Toxicity analyses were performed on patients who received at least one cycle (safety population). Clinical efficacy, defined as response rates (CR, PR, and ORR [CR+PR]), duration of response, time to progression, and survival, was considered a secondary objective. All efficacy analyses were conducted on the intent-to-treat population. The duration of the response for responding patients (CR or PR) dated from the date of first objective response until the time of progression. The time to progression was defined as from the date of randomization to the date of first documented progression. Survival was calculated from the date of randomization to death by any cause. Log-rank tests and Kaplan-Meier estimations were performed for duration of response, time to progression, and survival. Objective response rates were calculated with 95% CIs. {chi}2 test or Fisher's exact test when suitable were used to compare response or toxicity in both treatment arms. Differences were assumed to be significant when P < .05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
Patient Characteristics
A total of 144 patients were enrolled from December 1999 to December 2001. Seventy-five patients were randomized to A->T treatment arms, whereas 69 patients were randomized to AT treatment arms. The patients were stratified prospectively based on the previous administration of anthracyclines and the study center.

The two treatment arms were balanced with respect to all major prognostic factors; there were no significant differences with respect to age, performance status, menopausal status, estrogen receptors status, disease-free interval, tumor load, and the presence of visceral disease, as well as prior chemotherapy, hormonal therapy, or radiation therapy (Table 1). Although a greater number of patients had received previous anthracycline treatment in the A->T arm (28%) than in the AT arm (22%), this difference was not statistically significant.


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  		Table 1. Patient and Disease Characteristics at Baseline

 
Treatment
Eighty-one percent of the patients in A->T arm completed the six cycles, versus only 67% in the AT arm (Table 2). The higher rate of withdrawal found in the AT arm was mainly due to adverse events (Table 3). The relative dose-intensity was greater than 95% in all patients allocated to the A->T arm, but less than 95% in the AT treatment arm (Table 2).


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  		Table 2. Treatment Administration

 

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  		Table 3. Early Study Withdrawal: Reasons

 
Hematological Toxicity
We defined febrile neutropenia as fever ≥ 38.1°C concomitant with an absolute neutrophil count lower than 500/mm3, and requiring antibiotic intravenous administration and/or hospitalization. Febrile neutropenia was the most frequent hematological toxicity occurring in both treatment arms. In the A->T treatment arm, febrile neutropenia was reported in 29.3% of patients and 6.9% of cycles, versus 47.8% of patients and 14.8% of cycles in the AT treatment arm (Table 4). AT administration alone added up to 16.1% of cycles with febrile neutropenia and 9.6% of cycles requiring G-CSF administration. Occurrence of febrile neutropenia and subsequent administration of G-CSF was statistically higher in AT cycles than in doxorubicin or docetaxel cycles (Table 4). No significant differences between both treatment arms were found in other hematological toxicities (Table 5).


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  		Table 4. Febrile Neutropenia Pattern

 

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  		Table 5. Grade 3/4 Toxicity per Patient

 
Nonhematological Toxicity
Only asthenia, diarrhea, and fever (without neutropenia) occurred more frequently in the AT treatment arm (Table 5). Cardiovascular toxicity was reported by three patients, who experienced thrombosis or embolism events, and two patients who suffered from mesenteric ischemia. The latter ones, both assigned to the AT treatment arm, died and were reported as toxic deaths.

Clinically relevant congestive heart failure occurred in two patients included in the AT treatment arm, but one of these events was secondary to an anthracycline overdose. The other patient experienced a significant reduction in the LVEF twice during the treatment, but the researcher judged it appropriate to continue treatment; a partial response was found in this patient.

Response to Treatment
Both therapeutic regimens showed similar antitumor efficacy. The ORR found was 61% (46 patients; 95% CI, 50% to 72%) in the A->T arm and 51% (35 patients; 95% CI, 39% to 63%) in the AT arm (Table 6). No significant differences between treatments in the ORR were found (P = .20). Nine patients (12%) showed a complete response in the A->T arm versus four patients (6%) in the AT arm. The median time to response was 2.32 months in the A->T arm and 2.17 months in the AT arm. Despite the low number of patients treated, an analysis of ORR according to prior anthracycline administration was done; there were no significant differences in ORR between the groups because of prior anthracyclines.


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  		Table 6. Response Rate (intent-to-treat population)

 
The median duration of response was 8.7 months (95% CI, 6.5 to 10.8) in the A->T arm and 7.6 months (95% CI, 4.8 to 10.4) in the AT arm. The median time to progression was 10.5 months in the A->T arm and 9.2 months in the AT arm (Fig 2). No significant differences between treatments were found (P = .87). With regard to overall survival, 60 events were reported after a median follow-up of 17.5 months (27 events in the A->T arm v 33 events in the AT arm). The median overall survival was 22.3 months in the A->T arm and 21.8 months in the AT arm. No significant differences between treatments were found (P = .41).



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  		Fig 2. Time to progression (intent-to-treat population). A, doxorubicin; T, docetaxel.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Authors' Disclosures of...
 REFERENCES
 
In patients with metastatic disease, the survival benefit associated with treatment is generally modest at best: MBC is largely incurable,1,18 and few (< 10%) patients remain disease-free beyond 5 years.19,20 Therefore, the maintenance of quality of life by reducing toxic side effects assumes a great relevance in the treatment of MBC patients.21 Combination or sequential single agents have been used to improve the antitumor response in first-line MBC chemotherapy, and among the most active first-line combination regimens for MBC is AT.10 The main goal of this study was, therefore, to determine if administering sequential A->T chemotherapy could maintain antitumoral efficacy, while reducing the incidence of toxicity, particularly the febrile neutropenia reported with the concomitant AT schedule.

We observed febrile neutropenia in 47.8% of patients treated with AT. This incidence of febrile neutropenia seems to be quite higher than that reported in previous studies.5-15 The range of febrile neutropenia incidence in the literature is 10% to 40% with the concomitant treatment5-10 and 0% to 23% with the sequential schedules.11-15 Nevertheless, most of these studies were phase II or pilot clinical trials, and in some of them, the use of primary prophylactic ciprofloxacin and/or G-CSF was allowed.8,10-12,15

A->T administration notably reduced the incidence of febrile neutropenia from 47.8% (AT) to 29.3% of patients (A->T). This incidence is higher than previously reported by our study group in a phase II trial using the same A->T schedule (19% of patients).15 This is probably related to the poor diagnostic characteristics of the patients enrolled in the present study, in which more than 70% of them presented with visceral disease, and 56% presented with three or more metastatic locations. However, in the present study, not only were fewer patients on A->T affected by febrile neutropenia when compared with patients on AT, but there were also fewer cycles with febrile neutropenia (6.9% v 14.8%), which translated into a decreased use of G-CSF. All these findings confirm a significant reduction of the main limiting hematological toxicity with A->T administration of doxorubicin and docetaxel compared with the AT administration. Overall, a better toxicity profile allowed a lower withdrawal rate and a higher relative dose-intensity with the A->T schedule. Paridaens et al22 reported a low incidence (2% of patients) of febrile neutropenia in patients treated with A->T, doxorubicin and docetaxel, using prophylactic G-CSF. These authors commented that no patients required G-CSF support after the first cycle. However, the use of prophylactic G-CSF should be recommended in special groups of patients treated with the A->T schedule (eg, those showing a high risk for developing myelosupression).

Antitumoral efficacy was measured as a secondary end point, and this study was not powered to detect modest advantages of one regimen over the other. Overall, A->T and AT administration showed similar efficacy, both in terms of tumor response and survival. The overall response rate with A->T was 61% (nine complete responses) and 51% with AT (four complete responses), consistent with the 65% previously reported with the A->T schedule15 or the 59% found with the AT schedule.10 The response rates found here were also similar to those reported with the sequential but inverse (T->A) schedule (67%)22 or with the AT schedule using a low dose of docetaxel (70%).9 Moreover, the response rate found with the A->T schedule (61%) was higher than the 48% found with docetaxel monotherapy.2

In conclusion, we found in this randomized phase III trial a remarkable reduction of febrile neutropenia with A->T schedule as first-line chemotherapy in MBC patients. Moreover, the sequential A->T schedule showed a comparable incidence for other toxicities, and maintained a similar high antitumoral efficacy than that usually reported with the concomitant AT chemotherapy. Therefore, the sequential A->T schedule is a safe, manageable, and viable alternative to the simultaneous combination therapy (AT) in the first-line setting of MBC.


   Authors' Disclosures of Potential Conflicts of Interest
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
REFERENCES
 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Miguel Martin, Aventis, Bristol-Meyers Squibb, Roche, Novartis, Pfizer. Received more than $2,000 a year from a company for either of the last 2 years: Miguel Martin, Aventis, Bristol-Meyers, Roche, Novartis, Pfizer.


   Acknowledgment
 
We acknowledge María Escudero and Esther Mahillo for statistical analysis and quality control in the study, Vicente Alfaro for assistance in article redaction, and the general coordination of Aventis Pharma, Spain.


   NOTES
 
Supported by Aventis Pharma SA.

The results of this study were presented as oral communication at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003 (Abstract 27).

Authors' disclosures of potential conflicts of interest are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Authors' Disclosures of...
 REFERENCES
 
1. Ellis MJ, Hayes DF, Lippman ME: Treatment of metastatic breast cancer, in Lippman ME, Morrow M, Osborne CK (eds): Diseases of the Breast. Philadelphia, PA, Lippincott, 2000, pp 749-797

2. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer: The 303 Study Group. J Clin Oncol 17:2341-2354, 1999[Abstract/Free Full Text]

3. Valero V, Hortobagyi GN: Are anthracycline-taxane regimens the new standard of care in the treatment of metastatic breast cancer? J Clin Oncol 21:959-962, 2003[Free Full Text]

4. Nabholtz JM, Riva A: Taxane/anthracycline combinations: Setting a new standard in breast cancer? Oncologist 6:5-12, 2001[Abstract/Free Full Text]

5. Dieras V, Barthier S, Beuzeboc P, et al: Phase II study of Taxotere (T) in combination with doxorubicin (A) as first-line chemotherapy of metastatic breast cancer. Breast Cancer Res Treat 50:262, 1998 (abstr 226)

6. Misset JL, Dieras V, Gruia G, et al: Dose-finding study of docetaxel and doxorubicin in first-line treatment of patients with metastatic breast cancer. Ann Oncol 10:553-560, 1999[Abstract/Free Full Text]

7. Sparano JA, O'Neill A, Schaefer PL, et al: Phase II trial of doxorubicin and docetaxel plus granulocyte colony-stimulating factor in metastatic breast cancer: Eastern Cooperative Oncology Group Study E1196. J Clin Oncol 18:2369-2377, 2000[Abstract/Free Full Text]

8. Lembersky BC, Anderson R, Smith A, et al: Phase II trial of doxorubicin and docetaxel for locally advanced and metastatic breast cancer: Preliminary results of NSABP BP-57. Proc Am Soc Clin Oncol 19:104a, 2000 (abstr 403)

9. Aihara T, Takatsuka Y, Itoh K, et al: Phase II study of concurrent administration of doxorubicin and docetaxel as first-line chemotherapy for metastatic breast cancer. Oncology 64:124-130, 2003[CrossRef][Medline]

10. Nabholtz JM, Falkson C, Campos D, et al: Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: Results of a randomized, multicenter, phase III trial. J Clin Oncol 21:968-975, 2003[Abstract/Free Full Text]

11. Miller KD, McCaskill-Stevens W, Sisk J, et al: Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group. J Clin Oncol 17:3033-3037, 1999[Abstract/Free Full Text]

12. Schwartzberg L, Birch R, Weaver C, et al: Randomized trial of simultaneous (SIM) vs. sequential (SEQ) doxorubicin (A) and docetaxel (T) in patients (Pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 19:72a, 2000 (abstr 278)

13. Cresta S, Grasselli G, Martoni A, et al: A randomized phase II study of alternating (AA) vs sequential (SS) vs the combination (CC) of doxo-rubicin (A) and docetaxel (T) as 1st line CT in MBC pts. Proc Am Soc Clin Oncol 20:48a, 2001 (abstr 190)

14. Koroleva I, Wojtukiewicz M, Zaluski J, et al: Preliminary results of a phase II randomized trial of taxotere (T) and doxorubicin (A) given in combination or sequentially as first-line chemotherapy (CT) for metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 20:30a, 2001 (abstr 117)

15. Alba E, Ribelles N, Anton A, et al: Sequential doxorubicin and docetaxel as first-line treatment in metastatic breast cancer: A GEICAM-9801 phase II study. Breast Cancer Res Treat 77:1-8, 2003[CrossRef][Medline]

16. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline]

17. National Cancer Institute: Guidelines for the Reporting of Adverse Drug Reactions. Bethesda, MD, Division of Cancer Treatment, National Cancer Institute, 1988

18. Hortobagyi GN: Chemotherapy of breast cancer: A historical perspective. Semin Oncol 24:11-14, 1997 (suppl 17)

19. Greenberg PA, Hortobagyi GN, Smith TL, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14:2197-2205, 1996[Abstract]

20. Schneeweiss A, Hensel M, Sinn P, et al: Characteristics associated with long-term progression-free survival following high-dose chemotherapy in metastatic breast cancer and influence of chemotherapy dose. Ann Oncol 13:679-688, 2002[Abstract/Free Full Text]

21. Miles D, von Minckwitz G, Seidman AD: Combination versus sequential single-agent therapy in metastatic breast cancer. Oncologist 7:13-19, 2002 (suppl 6)[Abstract/Free Full Text]

22. Paridaens R, Van Aelst F, Georgoulias V, et al: A randomized phase II study of alternating and sequential regimens of docetaxel and doxorubicin as first-line chemotherapy for metastatic breast cancer. Ann Oncol 14:433-440, 2003[Abstract/Free Full Text]

Submitted August 18, 2003; accepted April 15, 2004.


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Achievements in Systemic Therapies in the Pregenomic Era in Metastatic Breast Cancer
Oncologist, March 1, 2007; 12(3): 253 - 270.
[Abstract] [Full Text] [PDF]

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J. O'Shaughnessy
Extending Survival with Chemotherapy in Metastatic Breast Cancer
Oncologist, October 1, 2005; 10(suppl_3): 20 - 29.
[Abstract] [Full Text] [PDF]

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