Phase II to III Study Comparing Doxorubicin and Docetaxel With Fluorouracil, Doxorubicin, and Cyclophosphamide As First-Line Chemotherapy in
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《临床肿瘤学》
the Departments of Medical Oncology and Statistics, Erasmus University Medical Center, Daniel den Hoed Cancer Center
Ijsselland Hospital
Sint Clara Hospital, Rotterdam
Catharina Hospital, Eindhoven
Vlietland Hospital, Schiedam
Sint Franciscus Hospital, Roosendaal
Vlietland Hospital, Vlaardingen
Twee Steden Hospital, Tilburg
Van Weel Bethesda Hospital, Dirksland
Hospital Walcheren, Vlissingen
Aventis Pharma, Hoevelaken, the Netherlands
ABSTRACT
PURPOSE: To compare the efficacy and safety of doxorubicin and docetaxel (AT) with fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy for metastatic breast cancer (MBC).
PATIENTS AND METHODS: Patients (n = 216) were randomly assigned to either AT (doxorubicin 50 mg/m2 and docetaxel 75 mg/m2) or FAC (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); both regimens were administered on day 1, every 3 weeks.
RESULTS: A median number of six cycles was delivered in both arms, with a median relative dose-intensity of more than 98%. Median time to progression (TTP) and median overall survival (OS) were significantly longer for patients on AT compared with FAC (TTP: 8.0 v 6.6 months, respectively; P = .004; and OS: 22.6 v 16.2 months, respectively; P = .019). The overall response rate (ORR) was significantly higher in patients on AT compared with FAC (58% v 37%, respectively; P = .003). The ORR on AT was also higher in patients with visceral disease compared with FAC patients with visceral disease (59% v 36%, respectively; P = .003). There were no differences in grade 3 to 4 neutropenia and infections (AT 89% v FAC 84% and AT 12% v FAC 9%, respectively). Neutropenic fever was more common in AT-treated patients than FAC-treated patients (33% v 9%, respectively; P < .001). Grade 3 to 4 nonhematologic toxicity was infrequent in both arms. Congestive heart failure was observed in 3% and 6% of patients on AT and FAC, respectively.
CONCLUSION: In this phase II to III study, AT resulted in a significantly longer TTP and OS and a higher objective ORR than FAC. First-line AT is a valid treatment option for patients with MBC.
INTRODUCTION
Despite several decades of research, metastatic breast cancer (MBC) is still a virtually incurable disease. Therefore, the search for the optimal chemotherapy, which is aimed at palliating symptoms and prolonging survival, is an ongoing process. The anthracycline doxorubicin is an effective drug in the treatment of breast cancer, both as a single agent and as part of combination regimens.1,2 However, improvements in response rate and time to progression (TTP) have not translated into a statistically significant improvement in survival.
The taxane docetaxel, which was introduced in the 1990s, is also active in advanced breast cancer. Docetaxel is at least as effective as doxorubicin in single-agent studies, with response rates of 30% to 60%, depending on the population studied.3–7
Because both drugs are among the most efficacious drugs in the treatment of breast cancer, the combination of the two drugs in first-line therapy of metastatic disease is a logical step. In phase I studies, the combination of doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (AT) every 3 weeks proved feasible, with neutropenia and febrile neutropenia occurring as the main dose-limiting toxicities.8 Three randomized phase II or III studies compared the efficacy of an anthracycline/docetaxel combination with a standard anthracycline-containing regimen.9–11 In all three studies, the anthracycline/docetaxel combination showed a higher response rate, whereas TTP was significantly longer in two of the three studies. In one study, a longer overall survival (OS) time was also observed. In the present phase II to III study, we compared AT to a standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen as first-line chemotherapy for patients with MBC.
PATIENTS AND METHODS
Patient Population
Patients with histologically proven MBC were eligible for the study if they met the following inclusion criteria: female; age 18 to 70 years; WHO performance status of 0 to 2; measurable or assessable disease; WBC count more than 3 x 109/L; platelet count more than 100 x 109/L; bilirubin within normal limits; AST and ALT less than 2.5x the upper normal limit (UNL); alkaline phosphatase less than 5x UNL, unless in the presence of bone metastases and in the absence of any other liver disorder (patients were not eligible for the study in case of AST and/or ALT > 1.5x UNL associated with alkaline phosphatase > 2.5x UNL); and normal left ventricular ejection fraction (LVEF) 45%. Hormonal therapy had to be stopped before study entry. Previous radiation was allowed when applied more than 4 weeks before study entry, but indicator lesions should not have been previously irradiated. Prior adjuvant anthracycline chemotherapy was allowed provided that cumulative dosages of 240 mg/m2 of doxorubicin or 450 mg/m2 of epirubicin were not exceeded. Prior adjuvant chemotherapy should have been terminated 12 months before study entry. Patients were not eligible in case of previous chemotherapy for metastatic disease, known brain metastases or leptomeningeal involvement, other serious illness or medical condition, pregnancy, lactation, or nonadherence to contraceptive therapy. Initially, patients with lytic bone metastases as the only presentation of disease were eligible, but concomitant use of bisphosphonates was not allowed. An amendment approved in August 2000, after the enrollment of 140 patients, allowed for concomitant bisphosphonate treatment, thereby excluding patients with bone-only disease from the study. The protocol was approved by the medical ethical boards of all participating institutions. Informed consent was obtained from all patients before random assignment.
Treatment
Patients were treated with AT or FAC on day 1 every 3 weeks for a maximum of six cycles. In the AT arm, doxorubicin 50 mg/m2 was administered as an intravenous (IV) bolus injection, followed after 1 hour by docetaxel 75 mg/m2 as an IV infusion over 1 hour. In the FAC arm, doxorubicin 50 mg/m2 was administered as an IV bolus injection, followed by fluorouracil 500 mg/m2 as an IV bolus injection, after which cyclophosphamide 500 mg/m2 was administered as an IV infusion over 15 minutes. Docetaxel (Taxotere) was provided by Aventis (Hoevelaken, the Netherlands). Commercially available doxorubicin, fluorouracil, and cyclophosphamide were used.
Antiemetics for the FAC regimen were ondansetron 8 mg IV and dexamethasone 10 mg IV administered just before the doxorubicin infusion. Premedication for the AT regimen included dexamethasone 8 mg orally bid for 3 days, starting 24 hours before each docetaxel infusion, and ondansetron 8 mg IV before the chemotherapy infusion. After an amendment, patients included after July 8, 1997 received ciprofloxacin prophylaxis, 500 mg orally bid on days 4 to 15 after AT. Hematopoietic granulocyte growth factor treatment was advised as secondary prophylaxis after severe neutropenia to prevent treatment delays and dose reductions. Dose reductions (to 75% of starting dose) and/or treatment delays (up to a maximum of 2 weeks) were planned for severe nonhematologic toxicities, except alopecia and fluid retention, and persisting hematologic toxicities despite use of prophylactic measures. According to common practice, doxorubicin had to be stopped in patients who developed congestive heart failure (CHF) or when the absolute LVEF decreased to less than the lower limit of normal.
Assessments
Within 14 days before the start of study treatment, an evaluation was performed consisting of a medical history, physical and neurologic examination, performance status assessment, routine hematology and biochemistry parameters, ECG, LVEF (multiple-gated acquisition scan), and complete tumor assessment. Tumor assessment consisted of chest x-ray and abdominal ultrasound (in case of metastases, a computed tomography scan was required), a bone scintigraphy with additional x-rays or magnetic resonance imaging in case of bone metastases, and any other evaluation deemed necessary to evaluate tumor status. Up to a maximum of eight representable lesions were evaluated after cycles 2, 4, and 6 and then every 2 months for the first year and every 3 months thereafter, or at study discontinuation. Bone scintigraphy was performed before study entry and every 6 months thereafter.
Before each chemotherapy cycle, physical examination, performance status, weight, and biochemistry were assessed. Blood counts were performed weekly. LVEF was monitored by multiple-gated acquisition scan after cycles 4 and 6 and as clinically indicated. Neurologic examination was repeated every second course of therapy and during follow-up.
Toxicity was assessed before each new treatment cycle and graded according to the National Cancer Institute Common Toxicity Criteria (December 1994 version). Adverse events were graded as mild, moderate, or severe when National Cancer Institute criteria were not appropriate. WHO criteria were used to evaluate response to treatment. Responses had to be confirmed with a minimum of 4 weeks between the evaluations. Patients with disease progression after the second treatment cycle were classified as having progressive disease, and progression after the first cycle was classified as early progressive disease. All responses evaluated on radiologic studies were subjected to a blinded review by the principal investigator.
Study Design, Statistical Methodology, and Analysis
This was a randomized, nonblinded, multicenter, phase II to III study. Randomization (performed by calling a central telephone number) was stratified for center, prior chemotherapy (none v adjuvant), WHO performance status (0 v 1 to 2), and presence of bone metastases (yes v no). The study started as a randomized phase II study aiming for 30 patients on each of the two arms, with the primary objective being the reproduction of the estimation of the overall response rates (ORRs) in the two treatment arms. If response rates fulfilled prior defined criteria (ORR, 70% to 75% for AT and 50% to 55% for FAC), the study would continue to the phase III study as planned. Sample size for the phase II part was based on SEs of 9% and 8% for FAC and AT, respectively, for estimation of response rates. Significance testing was not performed at this phase of the study. Sample size for the phase III study was calculated on a difference in TTP. Assuming a median TTP of 8 months in the FAC arm and 12 months in the AT arm ( = .05, two sided, and ? = .2012), a total of 201 events were required, leading to a sample size of 260 patients.
The analysis of the study was performed at the Erasmus University Medical Center by a statistician and employee of this center (P.I.S.). For the analysis of the whole patient population, all comparisons were made using a two-sided = .05 for statistical significance. Comparisons between treatment groups for continuous or ordinal variables were assessed using the Mann-Whitney U test.
Time to events variables such as TTP, OS, and duration of response were analyzed using the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was used to adjust the treatment effect on TTP for prespecified prognostic factors. Ninety-five percent CIs for the relative hazard ratios (HRs) were calculated. Response rates between the treatment arms were compared using the 2 test.
The intent-to-treat population included all randomly assigned patients. Patients were assessable for response if they had received at least two treatment cycles with disease evaluation. Patients with early progressive disease within the period of two treatment cycles were also assessable for response. TTP was calculated from the date of random assignment to the date of progression, death, or withdrawal. Duration of response was calculated from the date of start of treatment until progression for the patients with a partial response and from the date of assessment of complete response until progression for the patients with a complete response. A separate per-protocol analysis for TTP and OS was performed excluding the group of patients with further anticancer therapy before progression, and a per-protocol analysis for ORR was performed excluding the 19 nonassessable patients.
Descriptive summary tables were made on safety parameters by treatment arm. Toxicity rates were compared between treatment arms using the 2 test or Fisher's exact test in case of small numbers. Analysis of LVEF changes was performed on patients with at least one assessment after baseline measurement.
RESULTS
Patient Population
After inclusion of the first 61 patients in the randomized phase II part of the study, the ORR was 60% in the AT arm (95% CI, 41% to 77%) and 45% in the FAC arm (95% CI, 27% to 64%). On the basis of these results, the study continued as a randomized phase III study. Between March 1997 and April 2002, a total of 216 patients were enrolled at 19 participating centers and randomly assigned to receive AT (109 patients) or FAC (107 patients). Patients were recruited in one academic hospital and 18 community hospitals in Southwest Netherlands. Because of slow accrual, a nonplanned interim analysis was performed in April 2002 to decide whether a significant difference in TTP could be anticipated with further accrual of the last 44 patients. With a median follow-up time of 8.7 months for the surviving patients, the results of the treatment of the first 151 patients for whom data were available were analyzed for TTP. One hundred forty-four of the 151 patients had experienced disease progression. Median TTP was 7.3 months for AT and 6.9 months for FAC (P = .18). An independent data monitoring committee determined that the chance of finding a statistical difference in TTP between the treatment arms had become so low that they recommended study closure. This recommendation was followed.
This article reports on all 216 included patients. Patient and tumor characteristics were balanced between the two treatment arms (Table 1). The median follow-up time was 27 months for survival and 14 months for progression (only for patients who did not reach the end point).
Treatment Administration
Overall, 215 patients were treated. One patient in the AT arm never started treatment. A total of 590 cycles of AT and 599 cycles of FAC were administered. The median number of cycles administered in both arms was six. Eighty-three percent of the patients on AT and 78% of the patients on FAC received the maximum number of six cycles. The median relative dose-intensity was 98% in both arms. The median cumulative dose of doxorubicin, including adjuvant anthracycline therapy, was 298 mg/m2 for patients on AT and 299 mg/m2 for patients on FAC. Reasons for treatment discontinuation were disease progression (AT, 5%; FAC, 11%), adverse events (AT, 9%; FAC, 5%), consent withdrawal (AT, 0%; FAC, 1%), and unknown (AT, 1%; FAC, 0%). Cardiotoxicity was the most frequently observed adverse event that resulted in treatment discontinuation (AT, 4%; FAC, 3%).
Efficacy
All randomly assigned patients were evaluated for ORR, TTP, and OS according to the intent-to-treat principle. Objective overall responses were documented in 63 (58%) of 109 patients on AT and in 40 (37%) of 107 patients on FAC. This difference in response is statistically significant (P = .003; Table 2). In the AT arm, four patients (4%) achieved a complete response and 59 patients (54%) achieved a partial response. In the FAC arm, one patient (1%) achieved a complete response and 39 patients (36%) achieved a partial response. The median duration of overall response was 10.0 months in the AT arm (95% CI, 7.2 to 17.3 months) and 9.7 months in the FAC arm (95% CI, 6.9 to 15.4 months; P = .98). When clinical benefit (stable disease of 6 months) is included, responses were observed in 82 patients (75%) on AT and in 66 patients (62%) on FAC (P = .03).
In addition, in patients with a poor prognosis, AT seemed to be more effective than FAC (Table 3). The ORR for the AT arm versus the FAC arm was 59% v 36%, respectively, in patients with visceral disease (P = .003); 59% v 36%, respectively, in patients with lung/liver involvement (P = .006); and 64% v 40%, respectively, when three organs were involved (P = .02).
TTP was analyzed after a median follow-up time of 14 months. The median TTP for patients on AT (8.0 months; 95% CI, 6.6 to 8.8 months) was significantly longer than the median TTP for patients on FAC (6.6 months; 95% CI, 6.1 to 7.2 months; P = .004; Fig 1). The HR for FAC versus AT was 1.50 (95% CI, 1.13 to 1.98; P = .004).
Survival analysis was performed at 27 months, when 84 patients (77%) on AT and 93 patients (87%) on FAC had died. Median OS was significantly longer for patients treated with AT (22.6 months; 95% CI, 17.1 to 27.9 months) than for patients on FAC (16.2 months; 95% CI, 13.8 to 17.9 months; P = .019; Fig 2). The HR for FAC versus AT was 1.43 (95% CI, 1.06 to 1.92; P = .019).
Multivariate Cox regression model was used to evaluate the impact of prognostic factors on TTP and OS. Factors analyzed were prior adjuvant chemotherapy, performance status (WHO 0 v 1 and 2), presence of bone metastases, visceral disease, three organs involved, and disease-free interval. For TTP, the unadjusted HR for FAC versus AT was 1.50 (95% CI, 1.13 to 1.98; P = .004), and the adjusted HR was 1.52 (95% CI, 1.15 to 2.01; P = .004). For OS, the unadjusted HR for FAC versus AT was 1.43 (95% CI, 1.06 to 1.92; P = .019), and the adjusted HR was 1.43 (95% CI, 1.06 to 1.94; P = .019). This confirms the statistically significant treatment effect of AT versus FAC for TTP and OS. Poststudy taxane therapy was administered to 25 patients (23%) treated with AT and 72 patients (67%) treated with FAC.
A total of 31 patients (17 patients on AT and 14 patients on FAC) received further therapy before progression. This treatment consisted of hormonal therapy (AT, 10%; FAC, 7%), radiotherapy (AT, 1%; FAC, 2%), or other chemotherapy (AT, 5%; FAC, 5%). Analysis of TTP and OS excluding the group of patients with further therapy before progression showed no major changes in the results. AT still resulted in a significantly longer TTP of 7.0 months compared with 6.4 months for FAC (P = .004) and a significantly longer OS of 22.1 months compared with 16.1 months for FAC (P = .041). When the 19 patients who were not assessable for response were excluded, the ORR was significantly higher in AT compared with FAC (ORR, 63% v 41%, respectively; P = .002).
Safety
All but one patient (n = 215) were assessable for toxicity (Table 4). On study, there were two toxic deaths in the AT arm. One of these patients died of a proven septicemia. The most frequent grade 3 to 4 toxicity was neutropenia, which occurred in 89% of AT patients and 84% of FAC patients (P = .11). Neutropenic fever, which was defined as fever greater than 38.5°C associated with grade 4 neutropenia requiring IV antibiotic treatment, and grade 3 to 4 infections were more frequently observed in patients treated with AT. Thirty-six patients (33%) in the AT arm and 10 patients (9%) on FAC experienced neutropenic fever. The number of courses complicated with neutropenic fever was 44 (7%) in the AT arm compared with 11 (2%) in the FAC arm. In 23 (64%) of the 36 patients who experienced neutropenic fever, the fever was observed in the first course of therapy. Neutropenic fever on FAC was not related to the first course of therapy. Eight patients on AT experienced two episodes of neutropenic fever. Granulocyte colony-stimulating factor (G-CSF) was administered as secondary prophylaxis in 22 (61%) of the 36 patients with neutropenic fever on AT. Of the 14 patients not treated with G-CSF, two patients experienced a second episode of neutropenic fever. Grade 3 to 4 infections were observed in 12% of the patients on AT and in 9% of the patients on FAC (P = .66.)
As expected, grade 3 to 4 neurotoxicity was more frequently observed in AT-treated patients than FAC-treated patients and consisted of neurosensory (2% v 0%, respectively) and neuromotor toxicity (5% v 0%, respectively), but the frequency was low. Patients on AT experienced more grade 3 to 4 stomatitis than patients on FAC (7% v 2%, respectively), but FAC-treated patients reported more grade 3 to 4 vomiting than AT-treated patients (14% v 7%, respectively).
Two patients died of cardiac failure 12 and 13 months after study entry. One of these two patients had been treated with prior adjuvant doxorubicin and cyclophosphamide (AC), and the other patient was re-treated with FAC after progression. There was no significant difference in cardiotoxicity between the two treatment groups. A decrease in the LVEF of 20% from baseline value was observed in 22% of AT patients and 15% of FAC patients (P = .32) A decrease in LVEF to less than the institutional lower normal limit (< 45%) was observed in 17% and 14% of the patients in AT and FAC arms, respectively (P = .58). Three patients on AT and six patients on FAC experienced CHF, which was manageable in all but one patient. Of these nine patients, five had been treated with adjuvant anthracycline therapy. In four of these nine patients, CHF occurred 12, 26, 27, and 30 months after study entry, when subsequent (potential) cardiotoxic treatment for progressive disease could have played a role.
DISCUSSION
This is the first randomized phase II to III trial comparing AT with standard FAC as first-line chemotherapy in patients with MBC. The patients were recruited through one academic hospital and 18 community hospitals, thus permitting true practice evaluation of this new regimen. AT proved to be significantly superior to FAC for the three efficacy parameters of ORR, TTP, and OS. Also, in patients with poor prognostic features (ie, visceral disease or more than three organs involved), AT showed a higher ORR. A survival benefit is seldomly reported in trials assessing treatment of MBC. To clarify, we put our current results into perspective of the anthracycline/docetaxel combination in general by critically reviewing our data and comparing the results with the data obtained in similar trials.
Eight randomized trials comparing the efficacy of an anthracycline/taxane combination with a standard anthracycline-containing regimen have been reported.9–11,13–19 In the four anthracycline plus paclitaxel studies, the combination of doxorubicin/paclitaxel or epirubicin/paclitaxel was compared with AC, FAC, or epirubicin/cyclophosphamide.13–16 In three of these four trials, equivalence between the study arms for TTP, OS, and ORR was suggested. Only one study favored the paclitaxel-containing arm for ORR, TTP, and OS.13
Four trials, including ours, compared combination chemotherapy containing an anthracycline plus docetaxel with a standard anthracycline-containing regimen (Table 5). 9–11 In all four studies, ORR was significantly higher in the patients treated with the anthracycline/docetaxel combination. Furthermore, TTP was significantly longer for in three of the four studies. OS was longer for the anthracycline/taxane regimen in our study and in the study by Tubiana-Hulin et al,11 but OS was equal for the two regimens tested in the studies of Nabholtz et al9 and Mackey et al.10
Median OS for the patients on FAC in our study was 16.2 months. This seems to fall into the range of OS times as reported in six other randomized trials (OS: range, 12.7 to 22 months; median, 18.2 months) in which FAC was one of the treatment arms.10,13,20–23 In addition, the survival advantage observed for AT does not seem to be related to an imbalance in prognostic factors to the disadvantage of the FAC group. In univariate analysis, treatment seemed to be a candidate for the multivariate model testing. In the multivariate analysis using the prognostic factors of prior adjuvant chemotherapy, performance status of 0 v 1 to 2, visceral disease, three organs involved, the presence of bone metastases, and median disease-free survival, treatment remained an independent parameter.
Other factors that could have affected the duration of survival are dose-intensity and additional treatment after study medication. Dose-intensity was more than 98% in the two treatment arms and cannot account for the difference in OS. In the FAC arm, 67% of the patients were additionally treated with taxanes, and 23% of the patients on AT had a second taxane exposure in the course of the disease (data not shown). Taxane application in the FAC-treated patients was frequent, and the difference in survival cannot be explained by the fact that the patients in the FAC arm were withheld from taxane therapy. Because half of the patients in our trial had liver disease and 76% had visceral involvement, we hypothesized that FAC (with doxorubicin 50 mg/m2) may be insufficient treatment for this relatively poor prognostic group. To assess this hypothesis, we compared the prognostic factors of the FAC-treated patients in our study with the factors in the patients on FAC in the studies of Mackey et al10 and Jassem et al,13 which used the same FAC regimen. In our study, 80% of the patients in the FAC arm had visceral disease. In the other two studies, these percentages were 71% and 68%. Fifty-one percent of our patients on FAC had liver involvement, compared with 44% of patients in the study of Mackey et al10 and 33% in the study of Jassem et al.13 Compared with these studies, we may have accrued a poorer prognostic group of patients. However, it will require a formal meta-analysis to elucidate whether the combination of an anthracycline with a taxane results in a better survival for (a subgroup of) patients with MBC.
The AT regimen was generally well tolerated. Despite the prophylactic use of ciprofloxacin, neutropenic fever occurred frequently and at a rate comparable to the results from the Nabholtz et al9 study, which did not use this prophylaxis. Two patients died during neutropenia. In one patient, sepsis was proven. Neutropenic fever during AT treatment was mostly observed in the first treatment cycle (64%). Four patients treated with secondary G-CSF prophylaxis experienced a second neutropenic event. However, the number of patients with a second neutropenic event during G-CSF prophylaxes is too small to draw any conclusions. In the early analyses of studies Breast Cancer International Research Group 001 and Spanish Breast Cancer Research Group 9805, both secondary and primary prophylaxis with G-CSF resulted in a decrease in neutropenic events during taxane-containing therapy.24,25
There was no significant difference in cardiac toxicity between the two treatment regimens. Severe cardiotoxicity with clinically relevant CHF occurred in three patients on AT and six patients on FAC. Of these nine patients experiencing CHF, five had been treated previously with adjuvant AC, and the mean cumulative anthracycline dose in these five patients was 512 mg/m2 (range, 440 to 540 mg/m2). Two patients died of CHF (12 and 13 months after study entry). One of these two patients was re-treated with FAC at disease progression, and the second patient had been treated with adjuvant AC and received a cumulative dose of 540 mg/m2 of doxorubicin. Other nonhematologic toxicities were usually mild, with no significant difference between the study arms.
In conclusion, our phase II to III study showed that AT is feasible in the community practice. The regimen is usually well tolerated, with neutropenic fever as the main adverse event. Prophylaxis with ciprofloxacin is unable to reduce the episodes of neutropenic fever. AT was more effective than standard FAC with respect to ORR, TTP, and OS. AT seems to be a valid option for first-line therapy in patients with MBC, especially for patients with rapidly advancing visceral disease.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank the participation of the following principal investigators of the Clinical Trial Group of the Comprehensive Cancer Center, Rotterdam, the Netherlands: A.G.P.M. van Reisen, Terneuzen; J.M.L. Stouthart, Rotterdam; D.J. de Gooyer, Roosendaal; J. van den Bosch, E. Trommel, D.R. Halkema, H.W.A. Berenschot, G.H.M. van der Linden, F.H.W. Kauw, Dordrecht; F.L. Waltman, Goes; M.G.A. Baggen, M.P.C. Middelkoop, Rotterdam; M.B. van Hennik, W.H. van Vliet, Gorinchem; F.A.A. Valster, Bergen op Zoom; A.C. Dullemond-Westland, Dirksland; and J.J.M. van der Hoeven, Amstelveen, the Netherlands.
NOTES
Supported by Aventis Pharma, Hoevelaken, the Netherlands.
Presented in part at the 12th European Conference of Clinical Oncology, Copenhagen, Denmark, September 21-25, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Bennett JM, Muss HB, Doroshow JH, et al: A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast cancer. J Clin Oncol 6:1611-1620, 1988
Marin M, Pienkowski T, Mackey J, et al: TAC improves DFS and OS over FAC in node-positive early breast cancer patients, BCIRG001. San Antonio Breast Cancer Conference, San Antonio, TX, December 3-6, 2003 (abstr 35)
Martin M, Lluch A, Sequi MA, et al: Prophylactic growth factor (GF) support with adjuvant docetaxel, doxorubicin and cyclophosphamide (TAC) for node-negative breast cancer (BC): An interim safety analysis of GEICAM9805 study. J Clin Oncol 22:32, 2004 (suppl, abstr 620)(Marijke Bontenbal, Geert-)
Ijsselland Hospital
Sint Clara Hospital, Rotterdam
Catharina Hospital, Eindhoven
Vlietland Hospital, Schiedam
Sint Franciscus Hospital, Roosendaal
Vlietland Hospital, Vlaardingen
Twee Steden Hospital, Tilburg
Van Weel Bethesda Hospital, Dirksland
Hospital Walcheren, Vlissingen
Aventis Pharma, Hoevelaken, the Netherlands
ABSTRACT
PURPOSE: To compare the efficacy and safety of doxorubicin and docetaxel (AT) with fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line chemotherapy for metastatic breast cancer (MBC).
PATIENTS AND METHODS: Patients (n = 216) were randomly assigned to either AT (doxorubicin 50 mg/m2 and docetaxel 75 mg/m2) or FAC (fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); both regimens were administered on day 1, every 3 weeks.
RESULTS: A median number of six cycles was delivered in both arms, with a median relative dose-intensity of more than 98%. Median time to progression (TTP) and median overall survival (OS) were significantly longer for patients on AT compared with FAC (TTP: 8.0 v 6.6 months, respectively; P = .004; and OS: 22.6 v 16.2 months, respectively; P = .019). The overall response rate (ORR) was significantly higher in patients on AT compared with FAC (58% v 37%, respectively; P = .003). The ORR on AT was also higher in patients with visceral disease compared with FAC patients with visceral disease (59% v 36%, respectively; P = .003). There were no differences in grade 3 to 4 neutropenia and infections (AT 89% v FAC 84% and AT 12% v FAC 9%, respectively). Neutropenic fever was more common in AT-treated patients than FAC-treated patients (33% v 9%, respectively; P < .001). Grade 3 to 4 nonhematologic toxicity was infrequent in both arms. Congestive heart failure was observed in 3% and 6% of patients on AT and FAC, respectively.
CONCLUSION: In this phase II to III study, AT resulted in a significantly longer TTP and OS and a higher objective ORR than FAC. First-line AT is a valid treatment option for patients with MBC.
INTRODUCTION
Despite several decades of research, metastatic breast cancer (MBC) is still a virtually incurable disease. Therefore, the search for the optimal chemotherapy, which is aimed at palliating symptoms and prolonging survival, is an ongoing process. The anthracycline doxorubicin is an effective drug in the treatment of breast cancer, both as a single agent and as part of combination regimens.1,2 However, improvements in response rate and time to progression (TTP) have not translated into a statistically significant improvement in survival.
The taxane docetaxel, which was introduced in the 1990s, is also active in advanced breast cancer. Docetaxel is at least as effective as doxorubicin in single-agent studies, with response rates of 30% to 60%, depending on the population studied.3–7
Because both drugs are among the most efficacious drugs in the treatment of breast cancer, the combination of the two drugs in first-line therapy of metastatic disease is a logical step. In phase I studies, the combination of doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (AT) every 3 weeks proved feasible, with neutropenia and febrile neutropenia occurring as the main dose-limiting toxicities.8 Three randomized phase II or III studies compared the efficacy of an anthracycline/docetaxel combination with a standard anthracycline-containing regimen.9–11 In all three studies, the anthracycline/docetaxel combination showed a higher response rate, whereas TTP was significantly longer in two of the three studies. In one study, a longer overall survival (OS) time was also observed. In the present phase II to III study, we compared AT to a standard fluorouracil, doxorubicin, and cyclophosphamide (FAC) regimen as first-line chemotherapy for patients with MBC.
PATIENTS AND METHODS
Patient Population
Patients with histologically proven MBC were eligible for the study if they met the following inclusion criteria: female; age 18 to 70 years; WHO performance status of 0 to 2; measurable or assessable disease; WBC count more than 3 x 109/L; platelet count more than 100 x 109/L; bilirubin within normal limits; AST and ALT less than 2.5x the upper normal limit (UNL); alkaline phosphatase less than 5x UNL, unless in the presence of bone metastases and in the absence of any other liver disorder (patients were not eligible for the study in case of AST and/or ALT > 1.5x UNL associated with alkaline phosphatase > 2.5x UNL); and normal left ventricular ejection fraction (LVEF) 45%. Hormonal therapy had to be stopped before study entry. Previous radiation was allowed when applied more than 4 weeks before study entry, but indicator lesions should not have been previously irradiated. Prior adjuvant anthracycline chemotherapy was allowed provided that cumulative dosages of 240 mg/m2 of doxorubicin or 450 mg/m2 of epirubicin were not exceeded. Prior adjuvant chemotherapy should have been terminated 12 months before study entry. Patients were not eligible in case of previous chemotherapy for metastatic disease, known brain metastases or leptomeningeal involvement, other serious illness or medical condition, pregnancy, lactation, or nonadherence to contraceptive therapy. Initially, patients with lytic bone metastases as the only presentation of disease were eligible, but concomitant use of bisphosphonates was not allowed. An amendment approved in August 2000, after the enrollment of 140 patients, allowed for concomitant bisphosphonate treatment, thereby excluding patients with bone-only disease from the study. The protocol was approved by the medical ethical boards of all participating institutions. Informed consent was obtained from all patients before random assignment.
Treatment
Patients were treated with AT or FAC on day 1 every 3 weeks for a maximum of six cycles. In the AT arm, doxorubicin 50 mg/m2 was administered as an intravenous (IV) bolus injection, followed after 1 hour by docetaxel 75 mg/m2 as an IV infusion over 1 hour. In the FAC arm, doxorubicin 50 mg/m2 was administered as an IV bolus injection, followed by fluorouracil 500 mg/m2 as an IV bolus injection, after which cyclophosphamide 500 mg/m2 was administered as an IV infusion over 15 minutes. Docetaxel (Taxotere) was provided by Aventis (Hoevelaken, the Netherlands). Commercially available doxorubicin, fluorouracil, and cyclophosphamide were used.
Antiemetics for the FAC regimen were ondansetron 8 mg IV and dexamethasone 10 mg IV administered just before the doxorubicin infusion. Premedication for the AT regimen included dexamethasone 8 mg orally bid for 3 days, starting 24 hours before each docetaxel infusion, and ondansetron 8 mg IV before the chemotherapy infusion. After an amendment, patients included after July 8, 1997 received ciprofloxacin prophylaxis, 500 mg orally bid on days 4 to 15 after AT. Hematopoietic granulocyte growth factor treatment was advised as secondary prophylaxis after severe neutropenia to prevent treatment delays and dose reductions. Dose reductions (to 75% of starting dose) and/or treatment delays (up to a maximum of 2 weeks) were planned for severe nonhematologic toxicities, except alopecia and fluid retention, and persisting hematologic toxicities despite use of prophylactic measures. According to common practice, doxorubicin had to be stopped in patients who developed congestive heart failure (CHF) or when the absolute LVEF decreased to less than the lower limit of normal.
Assessments
Within 14 days before the start of study treatment, an evaluation was performed consisting of a medical history, physical and neurologic examination, performance status assessment, routine hematology and biochemistry parameters, ECG, LVEF (multiple-gated acquisition scan), and complete tumor assessment. Tumor assessment consisted of chest x-ray and abdominal ultrasound (in case of metastases, a computed tomography scan was required), a bone scintigraphy with additional x-rays or magnetic resonance imaging in case of bone metastases, and any other evaluation deemed necessary to evaluate tumor status. Up to a maximum of eight representable lesions were evaluated after cycles 2, 4, and 6 and then every 2 months for the first year and every 3 months thereafter, or at study discontinuation. Bone scintigraphy was performed before study entry and every 6 months thereafter.
Before each chemotherapy cycle, physical examination, performance status, weight, and biochemistry were assessed. Blood counts were performed weekly. LVEF was monitored by multiple-gated acquisition scan after cycles 4 and 6 and as clinically indicated. Neurologic examination was repeated every second course of therapy and during follow-up.
Toxicity was assessed before each new treatment cycle and graded according to the National Cancer Institute Common Toxicity Criteria (December 1994 version). Adverse events were graded as mild, moderate, or severe when National Cancer Institute criteria were not appropriate. WHO criteria were used to evaluate response to treatment. Responses had to be confirmed with a minimum of 4 weeks between the evaluations. Patients with disease progression after the second treatment cycle were classified as having progressive disease, and progression after the first cycle was classified as early progressive disease. All responses evaluated on radiologic studies were subjected to a blinded review by the principal investigator.
Study Design, Statistical Methodology, and Analysis
This was a randomized, nonblinded, multicenter, phase II to III study. Randomization (performed by calling a central telephone number) was stratified for center, prior chemotherapy (none v adjuvant), WHO performance status (0 v 1 to 2), and presence of bone metastases (yes v no). The study started as a randomized phase II study aiming for 30 patients on each of the two arms, with the primary objective being the reproduction of the estimation of the overall response rates (ORRs) in the two treatment arms. If response rates fulfilled prior defined criteria (ORR, 70% to 75% for AT and 50% to 55% for FAC), the study would continue to the phase III study as planned. Sample size for the phase II part was based on SEs of 9% and 8% for FAC and AT, respectively, for estimation of response rates. Significance testing was not performed at this phase of the study. Sample size for the phase III study was calculated on a difference in TTP. Assuming a median TTP of 8 months in the FAC arm and 12 months in the AT arm ( = .05, two sided, and ? = .2012), a total of 201 events were required, leading to a sample size of 260 patients.
The analysis of the study was performed at the Erasmus University Medical Center by a statistician and employee of this center (P.I.S.). For the analysis of the whole patient population, all comparisons were made using a two-sided = .05 for statistical significance. Comparisons between treatment groups for continuous or ordinal variables were assessed using the Mann-Whitney U test.
Time to events variables such as TTP, OS, and duration of response were analyzed using the Kaplan-Meier method and the log-rank test. The Cox proportional hazards model was used to adjust the treatment effect on TTP for prespecified prognostic factors. Ninety-five percent CIs for the relative hazard ratios (HRs) were calculated. Response rates between the treatment arms were compared using the 2 test.
The intent-to-treat population included all randomly assigned patients. Patients were assessable for response if they had received at least two treatment cycles with disease evaluation. Patients with early progressive disease within the period of two treatment cycles were also assessable for response. TTP was calculated from the date of random assignment to the date of progression, death, or withdrawal. Duration of response was calculated from the date of start of treatment until progression for the patients with a partial response and from the date of assessment of complete response until progression for the patients with a complete response. A separate per-protocol analysis for TTP and OS was performed excluding the group of patients with further anticancer therapy before progression, and a per-protocol analysis for ORR was performed excluding the 19 nonassessable patients.
Descriptive summary tables were made on safety parameters by treatment arm. Toxicity rates were compared between treatment arms using the 2 test or Fisher's exact test in case of small numbers. Analysis of LVEF changes was performed on patients with at least one assessment after baseline measurement.
RESULTS
Patient Population
After inclusion of the first 61 patients in the randomized phase II part of the study, the ORR was 60% in the AT arm (95% CI, 41% to 77%) and 45% in the FAC arm (95% CI, 27% to 64%). On the basis of these results, the study continued as a randomized phase III study. Between March 1997 and April 2002, a total of 216 patients were enrolled at 19 participating centers and randomly assigned to receive AT (109 patients) or FAC (107 patients). Patients were recruited in one academic hospital and 18 community hospitals in Southwest Netherlands. Because of slow accrual, a nonplanned interim analysis was performed in April 2002 to decide whether a significant difference in TTP could be anticipated with further accrual of the last 44 patients. With a median follow-up time of 8.7 months for the surviving patients, the results of the treatment of the first 151 patients for whom data were available were analyzed for TTP. One hundred forty-four of the 151 patients had experienced disease progression. Median TTP was 7.3 months for AT and 6.9 months for FAC (P = .18). An independent data monitoring committee determined that the chance of finding a statistical difference in TTP between the treatment arms had become so low that they recommended study closure. This recommendation was followed.
This article reports on all 216 included patients. Patient and tumor characteristics were balanced between the two treatment arms (Table 1). The median follow-up time was 27 months for survival and 14 months for progression (only for patients who did not reach the end point).
Treatment Administration
Overall, 215 patients were treated. One patient in the AT arm never started treatment. A total of 590 cycles of AT and 599 cycles of FAC were administered. The median number of cycles administered in both arms was six. Eighty-three percent of the patients on AT and 78% of the patients on FAC received the maximum number of six cycles. The median relative dose-intensity was 98% in both arms. The median cumulative dose of doxorubicin, including adjuvant anthracycline therapy, was 298 mg/m2 for patients on AT and 299 mg/m2 for patients on FAC. Reasons for treatment discontinuation were disease progression (AT, 5%; FAC, 11%), adverse events (AT, 9%; FAC, 5%), consent withdrawal (AT, 0%; FAC, 1%), and unknown (AT, 1%; FAC, 0%). Cardiotoxicity was the most frequently observed adverse event that resulted in treatment discontinuation (AT, 4%; FAC, 3%).
Efficacy
All randomly assigned patients were evaluated for ORR, TTP, and OS according to the intent-to-treat principle. Objective overall responses were documented in 63 (58%) of 109 patients on AT and in 40 (37%) of 107 patients on FAC. This difference in response is statistically significant (P = .003; Table 2). In the AT arm, four patients (4%) achieved a complete response and 59 patients (54%) achieved a partial response. In the FAC arm, one patient (1%) achieved a complete response and 39 patients (36%) achieved a partial response. The median duration of overall response was 10.0 months in the AT arm (95% CI, 7.2 to 17.3 months) and 9.7 months in the FAC arm (95% CI, 6.9 to 15.4 months; P = .98). When clinical benefit (stable disease of 6 months) is included, responses were observed in 82 patients (75%) on AT and in 66 patients (62%) on FAC (P = .03).
In addition, in patients with a poor prognosis, AT seemed to be more effective than FAC (Table 3). The ORR for the AT arm versus the FAC arm was 59% v 36%, respectively, in patients with visceral disease (P = .003); 59% v 36%, respectively, in patients with lung/liver involvement (P = .006); and 64% v 40%, respectively, when three organs were involved (P = .02).
TTP was analyzed after a median follow-up time of 14 months. The median TTP for patients on AT (8.0 months; 95% CI, 6.6 to 8.8 months) was significantly longer than the median TTP for patients on FAC (6.6 months; 95% CI, 6.1 to 7.2 months; P = .004; Fig 1). The HR for FAC versus AT was 1.50 (95% CI, 1.13 to 1.98; P = .004).
Survival analysis was performed at 27 months, when 84 patients (77%) on AT and 93 patients (87%) on FAC had died. Median OS was significantly longer for patients treated with AT (22.6 months; 95% CI, 17.1 to 27.9 months) than for patients on FAC (16.2 months; 95% CI, 13.8 to 17.9 months; P = .019; Fig 2). The HR for FAC versus AT was 1.43 (95% CI, 1.06 to 1.92; P = .019).
Multivariate Cox regression model was used to evaluate the impact of prognostic factors on TTP and OS. Factors analyzed were prior adjuvant chemotherapy, performance status (WHO 0 v 1 and 2), presence of bone metastases, visceral disease, three organs involved, and disease-free interval. For TTP, the unadjusted HR for FAC versus AT was 1.50 (95% CI, 1.13 to 1.98; P = .004), and the adjusted HR was 1.52 (95% CI, 1.15 to 2.01; P = .004). For OS, the unadjusted HR for FAC versus AT was 1.43 (95% CI, 1.06 to 1.92; P = .019), and the adjusted HR was 1.43 (95% CI, 1.06 to 1.94; P = .019). This confirms the statistically significant treatment effect of AT versus FAC for TTP and OS. Poststudy taxane therapy was administered to 25 patients (23%) treated with AT and 72 patients (67%) treated with FAC.
A total of 31 patients (17 patients on AT and 14 patients on FAC) received further therapy before progression. This treatment consisted of hormonal therapy (AT, 10%; FAC, 7%), radiotherapy (AT, 1%; FAC, 2%), or other chemotherapy (AT, 5%; FAC, 5%). Analysis of TTP and OS excluding the group of patients with further therapy before progression showed no major changes in the results. AT still resulted in a significantly longer TTP of 7.0 months compared with 6.4 months for FAC (P = .004) and a significantly longer OS of 22.1 months compared with 16.1 months for FAC (P = .041). When the 19 patients who were not assessable for response were excluded, the ORR was significantly higher in AT compared with FAC (ORR, 63% v 41%, respectively; P = .002).
Safety
All but one patient (n = 215) were assessable for toxicity (Table 4). On study, there were two toxic deaths in the AT arm. One of these patients died of a proven septicemia. The most frequent grade 3 to 4 toxicity was neutropenia, which occurred in 89% of AT patients and 84% of FAC patients (P = .11). Neutropenic fever, which was defined as fever greater than 38.5°C associated with grade 4 neutropenia requiring IV antibiotic treatment, and grade 3 to 4 infections were more frequently observed in patients treated with AT. Thirty-six patients (33%) in the AT arm and 10 patients (9%) on FAC experienced neutropenic fever. The number of courses complicated with neutropenic fever was 44 (7%) in the AT arm compared with 11 (2%) in the FAC arm. In 23 (64%) of the 36 patients who experienced neutropenic fever, the fever was observed in the first course of therapy. Neutropenic fever on FAC was not related to the first course of therapy. Eight patients on AT experienced two episodes of neutropenic fever. Granulocyte colony-stimulating factor (G-CSF) was administered as secondary prophylaxis in 22 (61%) of the 36 patients with neutropenic fever on AT. Of the 14 patients not treated with G-CSF, two patients experienced a second episode of neutropenic fever. Grade 3 to 4 infections were observed in 12% of the patients on AT and in 9% of the patients on FAC (P = .66.)
As expected, grade 3 to 4 neurotoxicity was more frequently observed in AT-treated patients than FAC-treated patients and consisted of neurosensory (2% v 0%, respectively) and neuromotor toxicity (5% v 0%, respectively), but the frequency was low. Patients on AT experienced more grade 3 to 4 stomatitis than patients on FAC (7% v 2%, respectively), but FAC-treated patients reported more grade 3 to 4 vomiting than AT-treated patients (14% v 7%, respectively).
Two patients died of cardiac failure 12 and 13 months after study entry. One of these two patients had been treated with prior adjuvant doxorubicin and cyclophosphamide (AC), and the other patient was re-treated with FAC after progression. There was no significant difference in cardiotoxicity between the two treatment groups. A decrease in the LVEF of 20% from baseline value was observed in 22% of AT patients and 15% of FAC patients (P = .32) A decrease in LVEF to less than the institutional lower normal limit (< 45%) was observed in 17% and 14% of the patients in AT and FAC arms, respectively (P = .58). Three patients on AT and six patients on FAC experienced CHF, which was manageable in all but one patient. Of these nine patients, five had been treated with adjuvant anthracycline therapy. In four of these nine patients, CHF occurred 12, 26, 27, and 30 months after study entry, when subsequent (potential) cardiotoxic treatment for progressive disease could have played a role.
DISCUSSION
This is the first randomized phase II to III trial comparing AT with standard FAC as first-line chemotherapy in patients with MBC. The patients were recruited through one academic hospital and 18 community hospitals, thus permitting true practice evaluation of this new regimen. AT proved to be significantly superior to FAC for the three efficacy parameters of ORR, TTP, and OS. Also, in patients with poor prognostic features (ie, visceral disease or more than three organs involved), AT showed a higher ORR. A survival benefit is seldomly reported in trials assessing treatment of MBC. To clarify, we put our current results into perspective of the anthracycline/docetaxel combination in general by critically reviewing our data and comparing the results with the data obtained in similar trials.
Eight randomized trials comparing the efficacy of an anthracycline/taxane combination with a standard anthracycline-containing regimen have been reported.9–11,13–19 In the four anthracycline plus paclitaxel studies, the combination of doxorubicin/paclitaxel or epirubicin/paclitaxel was compared with AC, FAC, or epirubicin/cyclophosphamide.13–16 In three of these four trials, equivalence between the study arms for TTP, OS, and ORR was suggested. Only one study favored the paclitaxel-containing arm for ORR, TTP, and OS.13
Four trials, including ours, compared combination chemotherapy containing an anthracycline plus docetaxel with a standard anthracycline-containing regimen (Table 5). 9–11 In all four studies, ORR was significantly higher in the patients treated with the anthracycline/docetaxel combination. Furthermore, TTP was significantly longer for in three of the four studies. OS was longer for the anthracycline/taxane regimen in our study and in the study by Tubiana-Hulin et al,11 but OS was equal for the two regimens tested in the studies of Nabholtz et al9 and Mackey et al.10
Median OS for the patients on FAC in our study was 16.2 months. This seems to fall into the range of OS times as reported in six other randomized trials (OS: range, 12.7 to 22 months; median, 18.2 months) in which FAC was one of the treatment arms.10,13,20–23 In addition, the survival advantage observed for AT does not seem to be related to an imbalance in prognostic factors to the disadvantage of the FAC group. In univariate analysis, treatment seemed to be a candidate for the multivariate model testing. In the multivariate analysis using the prognostic factors of prior adjuvant chemotherapy, performance status of 0 v 1 to 2, visceral disease, three organs involved, the presence of bone metastases, and median disease-free survival, treatment remained an independent parameter.
Other factors that could have affected the duration of survival are dose-intensity and additional treatment after study medication. Dose-intensity was more than 98% in the two treatment arms and cannot account for the difference in OS. In the FAC arm, 67% of the patients were additionally treated with taxanes, and 23% of the patients on AT had a second taxane exposure in the course of the disease (data not shown). Taxane application in the FAC-treated patients was frequent, and the difference in survival cannot be explained by the fact that the patients in the FAC arm were withheld from taxane therapy. Because half of the patients in our trial had liver disease and 76% had visceral involvement, we hypothesized that FAC (with doxorubicin 50 mg/m2) may be insufficient treatment for this relatively poor prognostic group. To assess this hypothesis, we compared the prognostic factors of the FAC-treated patients in our study with the factors in the patients on FAC in the studies of Mackey et al10 and Jassem et al,13 which used the same FAC regimen. In our study, 80% of the patients in the FAC arm had visceral disease. In the other two studies, these percentages were 71% and 68%. Fifty-one percent of our patients on FAC had liver involvement, compared with 44% of patients in the study of Mackey et al10 and 33% in the study of Jassem et al.13 Compared with these studies, we may have accrued a poorer prognostic group of patients. However, it will require a formal meta-analysis to elucidate whether the combination of an anthracycline with a taxane results in a better survival for (a subgroup of) patients with MBC.
The AT regimen was generally well tolerated. Despite the prophylactic use of ciprofloxacin, neutropenic fever occurred frequently and at a rate comparable to the results from the Nabholtz et al9 study, which did not use this prophylaxis. Two patients died during neutropenia. In one patient, sepsis was proven. Neutropenic fever during AT treatment was mostly observed in the first treatment cycle (64%). Four patients treated with secondary G-CSF prophylaxis experienced a second neutropenic event. However, the number of patients with a second neutropenic event during G-CSF prophylaxes is too small to draw any conclusions. In the early analyses of studies Breast Cancer International Research Group 001 and Spanish Breast Cancer Research Group 9805, both secondary and primary prophylaxis with G-CSF resulted in a decrease in neutropenic events during taxane-containing therapy.24,25
There was no significant difference in cardiac toxicity between the two treatment regimens. Severe cardiotoxicity with clinically relevant CHF occurred in three patients on AT and six patients on FAC. Of these nine patients experiencing CHF, five had been treated previously with adjuvant AC, and the mean cumulative anthracycline dose in these five patients was 512 mg/m2 (range, 440 to 540 mg/m2). Two patients died of CHF (12 and 13 months after study entry). One of these two patients was re-treated with FAC at disease progression, and the second patient had been treated with adjuvant AC and received a cumulative dose of 540 mg/m2 of doxorubicin. Other nonhematologic toxicities were usually mild, with no significant difference between the study arms.
In conclusion, our phase II to III study showed that AT is feasible in the community practice. The regimen is usually well tolerated, with neutropenic fever as the main adverse event. Prophylaxis with ciprofloxacin is unable to reduce the episodes of neutropenic fever. AT was more effective than standard FAC with respect to ORR, TTP, and OS. AT seems to be a valid option for first-line therapy in patients with MBC, especially for patients with rapidly advancing visceral disease.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following author or immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We thank the participation of the following principal investigators of the Clinical Trial Group of the Comprehensive Cancer Center, Rotterdam, the Netherlands: A.G.P.M. van Reisen, Terneuzen; J.M.L. Stouthart, Rotterdam; D.J. de Gooyer, Roosendaal; J. van den Bosch, E. Trommel, D.R. Halkema, H.W.A. Berenschot, G.H.M. van der Linden, F.H.W. Kauw, Dordrecht; F.L. Waltman, Goes; M.G.A. Baggen, M.P.C. Middelkoop, Rotterdam; M.B. van Hennik, W.H. van Vliet, Gorinchem; F.A.A. Valster, Bergen op Zoom; A.C. Dullemond-Westland, Dirksland; and J.J.M. van der Hoeven, Amstelveen, the Netherlands.
NOTES
Supported by Aventis Pharma, Hoevelaken, the Netherlands.
Presented in part at the 12th European Conference of Clinical Oncology, Copenhagen, Denmark, September 21-25, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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