Dose-finding study of weekly docetaxel, anthracyclines plus fluoropyrimidines as first-line treatment in advanced breast cancer

O. Pagani1,*, C. Sessa1, F. Nolè2, E. Munzone2, D. Crivellari3, D. Lombardi3, B. Thürlimann4, D. Hess4, R. Graffeo1, M. Ruggeri1, S. Longhi1 and A. Goldhirsch1,2

1 Institute of Oncology of Southern Switzerland (IOSI), Ospedale S. Giovanni, Bellinzona, Switzerland; 2 Divisions of Medical Oncology, and Clinical Hemato-Oncology, Department of Medicine, European Institute of Oncology, Milan; 3 Divisione di Oncologia Medica C, Istituto Nazionale Tumori, Aviano, Italy; 4 Medizinische Klinik C, Kantonspital, St Gallen, Switzerland

* Correspondence to: Dr O. Pagani, Institute of Oncology of Southern Switzerland, Ospedale S. Giovanni, Bellinzona, Switzerland. E-mail: opagani{at}siak.ch


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: The efficacy and safety of prolonged fluoropyrimidines, either intravenously or orally, prompted their integration with taxanes and anthracyclines in the treatment of advanced breast cancer (ABC). We conducted three subsequent dose-finding studies on first-line chemotherapy in ABC with anthracyclines, either epirubicin (E) or doxorubicin (A), and docetaxel (T), both given on days 1 and 8 every 3 weeks, plus continuous infusion (CI) 5-fluorouracil (F) or capecitabine (X).

Patients and methods: Sixty-two patients (37% dominant visceral disease, 48% locally advanced disease, 45% two or more sites involved), received different doses of T (60–80 mg/m2), A (40–50 mg/m2) or E (60–90 mg/m2) and X (1650 and 2000 mg/m2), or CI F at a fixed daily dose of 200 mg/m2. Cardiac function was monitored at baseline and then every four cycles by echocardiography.

Results: The median number of cycles per patient with all regimens was four (range one to eight). Haematological and gastrointestinal toxicity defined the maximum tolerated doses, at T80/E90 mg/m2 with TEF, T70/A50/X2000 mg/m2 with TAX and T70/E80/X1650 mg/m2 with TEX. Two patients treated with TEF developed transient cardiac toxicity (dilatative cardiomyopathy and coronary subtotal stenosis requiring stenting) after cumulative E doses of 400 mg and 1100 mg/m2, respectively. Fifty-nine patients were evaluable for response; the overall response rates (ORR) were comparable between regimens (54% with TEF, 71% with TAX and 86% with TEX), with an 81% ORR in 31 patients with locally advanced disease.

Conclusions: The addition of fluoropyrimidines to weekly, intermittent ET is well tolerated and active in ABC.

Key words: advanced breast cancer, anthracyclines, docetaxel, fluoropyrimidines


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Clinical research in advanced breast cancer (ABC) during the last decade focused on new drugs, combinations and strategies to improve treatment cost-effectiveness. Taxanes and anthracyclines combinations have proved to be active and manageable as first-line therapy in several phase I/II trials [1Go–3Go]. Cytokinetic considerations suggest that weekly administration could prevent drug resistance, by avoiding re-growth of interval cancer cells [4Go]. Emerging data also suggest potential anti-angiogenic and apoptotic effects of taxanes, possibly related to timing of exposure and observed at concentrations and/or doses that are not directly cytotoxic [5Go]. In ABC, encouraging results have been obtained with weekly taxanes in both locally advanced and metastatic disease [6Go–9Go].

Low-dose, second- or third-line single-agent continuous infusion (CI) 5-fluorouracil (F) is associated with a 20%–30% overall response rate (ORR), with more than 40% subjective improvement [10Go], whereas an ORR exceeding 70% has been reported with CI F-containing regimens in metastatic or locally advanced disease [11Go, 12Go]. Capecitabine (X) mimics CI F and is activated preferentially at the tumour site [13Go]. Phase II studies have shown encouraging response rates (RRs) and a favourable safety profile, typical of infused fluoropyrimidines, in patients with taxane- and/or anthracycline-refractory ABC [14Go–16Go]. X and docetaxel (T) have demonstrated preclinical antitumour synergy, which is attributed to T-mediated upregulation of thymidine phosphorylase, an enzyme responsible for the relative tumour selectivity of X [17Go].

In a recent phase III trial, XT significantly improved objective RR, time to disease progression, and overall survival compared with T in anthracycline-pretreated patients with ABC [18Go].

The International Breast Cancer Study Group conducted three multicentre dose-finding studies to develop the most safe, effective and convenient combination of one anthracycline, either epirubicin (E) or doxorubicin (A), together with T and fluoropyrimidines as first-line therapy in ABC.

These multicentre trials were designed as open-label, non-comparative, sequential dose-finding studies. The primary aim was to determine the maximum tolerated doses (MTDs) of the different combinations, and secondary aims were the evaluation of their toxicity profile and antitumour activity. Escalating doses of A or E and T were administered to consecutive groups of patients on days 1 and 8, in combination with one fluoropyrimidine (X or CI F), given on a 2-week schedule, every 3 weeks (or on full recovery) until the definition of MTD was reached. The TEF regimen was evaluated first because of the availability of toxicity data with ET [1Go], CEF [11Go] and TAF by intravenous (i.v.) bolus administration. X-containing regimens were tested subsequently, taking advantage of the toxicity data on TEF and the comparable safety profile of X and CI F. Starting doses were derived from previous studies with ET [19Go] and XT [20Go]. A standard daily dose of 200 mg/m2 CI F was given and kept unchanged. At least three patients, six in case of a dose-limiting toxicity (DLT) at the first cycle, had to be entered at each dose level. DLTs were defined as: an absolute neutrophil count (ANC) <0.5 x 109/l for more than 7 days, ANC <1 x 109/l on day 8, grade 4 thrombocytopenia, febrile neutropenia [ANC <1 x 109/l and single elevation in oral temperature to >38.5°C or National Cancer Institute Common Toxicity Criteria (NCI CTC) grade 3 infection] [21Go], grade ≥3 or persisting grade 2 non-haematological toxicity (excluding alopecia, vomiting, musculoskeletal pain) at the day of scheduled retreatment, grade 2 sensory motor neuropathy, and failure of ANC recovery on the day of retreatment. The MTD was reached when two or more out of six patients presented a DLT after the first cycle.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with documented metastatic or locally advanced breast cancer without prior chemotherapy for advanced disease were eligible. Neo/adjuvant chemotherapy completed at least 12 months prior to study entry was allowed; in the case of anthracycline-containing regimens the total cumulative dose of A or E could not exceed 240 or 430 mg/m2, respectively, using a cardiotoxicity conversion factor of 1.8 [22Go]. A maximum of two lines of prior endocrine therapy for advanced disease was allowed. Standard eligibility criteria included adequate haematological (ANC ≥2 x 109/l, platelet count ≥100 x 109/l) renal, hepatic (liver function tests currently recommended for treatment with T) [23Go] and cardiac function [left ventricular ejection fraction (LVEF) ≥50% by echocardiography], measurable or evaluable disease, and written informed consent.

Baseline evaluation (clinical, biochemical and radiological) had to be performed within a maximum of 2 weeks before study entry, in particular complete blood cell count (CBC) and biochemistry, echocardiography LVEF assessment, computed tomography (CT) or magnetic resonance imaging of indicator lesions and bone scan. CBC was repeated at least twice weekly and biochemistry before each cycle.

Cardiac function was assessed before each cycle (by ECG) and every four cycles (by LVEF). Treatment was discontinued in the case of congestive heart failure of any grade and/or of a ≥10% decrease in LVEF from baseline associated with a decline to ≤50%, confirmed 1 week later. Toxicity was recorded according to the NCI CTC version 2.0.

Tumour response was defined according to WHO criteria [24Go, 25Go] with the exception that osteolytic lesions were considered evaluable. Response was initially assessed after the first two cycles in the absence of signs of early progression, and every two cycles thereafter. Response duration was calculated from first demonstration of response to documented progressive disease (PD), and time to disease progression was dated from initial treatment to progression, last contact or start of further antitumour therapy. Responders could receive a maximum of eight cycles of the combination or, in case of previous anthracyclines, up to a total cumulative dose of 480 mg/m2 of A and 860 mg/m2 of E: treatment could then be continued with T and the allocated fluoropyrimidine until relapse or unacceptable toxicity.

T (Taxotere®) and X (Xeloda®) for clinical use were supplied by Aventis and Roche, respectively. E and A were administered i.v. as a 15-min infusion followed, after a 1 h interval, by T given as a 1-h infusion on days 1 and 8. CI F was administered through a portable pump, connected to a subcutaneously implanted central i.v. line. Both CI F and X were given on an intermittent 2-week treatment schedule followed by 1 week pause.

Patients received prophylactic dexamethasone (4 mg), orally 12 h and 30 min before and 12 h after T. Prophylactic antiemetics, oral antibiotics and growth factors [granulocyte colony-stimulating factor (G-CSF)] were given according to investigators' routine practice. Therapy was administered in the outpatient clinic on days 1 and 8 every 3 weeks, provided that the ANC was ≥2 x 109/l and the platelet count was ≥100 x 109/l. If haematological recovery had not occurred after a maximum delay of 3 weeks patients were withdrawn from the study.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
From March 1999 to July 2002 a total of 62 patients with metastatic or locally advanced breast cancer were treated with TEF (30 patients), TAX (24 patients) or TEX (eight patients). The median follow-up time is 22 months (range 3–45+). Patients' characteristics were similar in the three groups with regards to median age, estrogen receptor status and prior adjuvant treatment (Table 1). A significant proportion of patients treated with TEF had visceral/liver involvement (50%) and at least two metastatic sites (57%), compared with the majority of patients treated with the X-containing regimens, who had locally advanced disease only (50% in TAX and 63% in TEX).


View this table:
[in this window]
[in a new window]
 
Table 1. Baseline characteristics of the patients

 
A total of 305 cycles of therapy were administered (Table 2), of which 294 (96%) were given without G-CSF support and evaluable for haematological toxicity. The median number of cycles per patient with all regimens was four (range one to eight).


View this table:
[in this window]
[in a new window]
 
Table 2. Dose levels

 
At the three lowest dose levels of TEF (T 30–35 mg/m2 and E 30–40 mg/m2), one patient each at the first and second level (T30/E30 mg/m2 and T35/E30 mg/m2) experienced a DLT (grade 4 diarrhoea) after the first cycle (Table 2). At the fourth dose level (T35/E45 mg/m2), three of seven patients developed a haematological DLT (two with failure of ANC recovery on day 21 and one with ANC <1 x 109/l on day 8). At the fifth level (T40/E45 mg/m2), eight of nine patients suffered a DLT (five with failure of ANC recovery on day 21, one with grade 3 mucositis and two with ANC <0.5 x 109/l for more than 7 days), thus the MTD was defined with this combination.

One of three patients per level treated at the first and second level of TAX (T30/A20/X1650 mg/m2 and T40/A20/X1650 mg/m2) experienced a DLT (failure of ANC recovery on day 21 with grade 3 liver toxicity and failure of ANC recovery at day 21, respectively). After reducing the dose of T at the subsequent level (T35/A25/X1650 mg/m2), two of seven patients suffered a DLT (one with grade 3 mucositis and one with febrile neutropenia). At the fourth level (T35/A25/X2000 mg/m2), five of six patients developed a DLT (three with febrile neutropenia, one with grade 3 bloody diarrhoea requiring inpatient hydration and febrile neutropenia and one with failure of ANC recovery on day 21). The MTD was achieved and five additional patients were treated at the recommended phase II dose (T35/A25/X1650 mg/m2), with one additional patient experiencing a DLT (febrile neutropenia).

Among eight patients treated with TEX (T35/E40/X1650 mg/m2), five developed a DLT (one with grade 3 liver toxicity, two with failure of ANC recovery on day 21 and one with febrile neutropenia). One patient, treated with neo-adjuvant TEX, died of drug-related toxicity 3 weeks after the first TE administration, because of probable cerebral bleeding while pancytopenic. This patient developed early uncontrolled gastrointestinal (GI) toxicity 4 days after starting treatment, which required X discontinuation and hospitalisation for supportive treatment, which was followed by severe prolonged bone marrow suppression. Renal, liver and coagulation tests were within normal limits. A post mortem examination was not performed.

Dose reductions not related to DLTs were applied to nine patients (28%) treated with TAX and TEX as a consequence of either haematological toxicity (two patients) or in combination with GI toxicity (seven patients). Overall, seven patients (11%) discontinued treatment due to toxicity, mainly of the GI tract, which seemed to be dose- and drug-unrelated: one patient at the first level of TEF (T30/E30 mg/m2) developed grade 4 diarrhoea during the first cycle while receiving concomitant antalgic radiotherapy to the spine; one patient at the fourth level of TAX (T35/A25/X1650 mg/m2) developed grade 4 mucositis after the second cycle requiring inpatient nutrition and hydration; and two patients at the highest level of TAX (T35/A25/X2000 mg/m2) developed recurrent diarrhoea and mucositis despite X dose reduction and definitively stopped treatment after three and four cycles, respectively. One additional patient with lung involvement, at the first level of TEF (T30/E30 mg/m2) stopped CI F after two cycles due to grade 3 diarrhoea and mucositis and went off study after a total of five cycles due to acute dyspnoea and lung interstitial fibrosis; no signs of PD or infection were detected (CT scan, bronchoscopy with bronchial lavage) and the event was considered as possibly related to T. Another patient at the highest level of TEF (T40/E45 mg/m2) and one patient at the highest level of TAX (T35/A25/X2000 mg/m2) stopped treatment due to haematological toxicity (febrile neutropenia after the third cycle and cumulative grade 3 anaemia requiring blood transfusion, respectively).

Overall, treatment delays occurred in about one-third of cycles of TEF and TAX (13 and 12 patients, 70% and 54% at the highest dose levels) and mainly because of haematological toxicity (96% and 83%, respectively). Forty-four per cent (four patients) of the TEX cycles were delayed because of haematological toxicity.

Fluoropyrimidine doses were reduced and/or discontinued in 14 patients (47%) treated with TEF and in seven patients (22%) treated with X, owing to GI toxicity, while both T and the anthracycline were reduced in one patient treated with TEF due to grade 2 liver toxicity and in one patient treated with TAX due to long-lasting grade 4 neutropenia.

Overall, G-CSF was given during 3% of cycles in five patients treated either with TAX (three patients) or TEX (two patients), mainly because of delayed recovery from myelotoxicity.

Haematological toxicity
Each cycle was fully evaluable for haematological toxicity if at least a twice weekly CBC was available. Overall, neutropenia grade 3–4 was dose-related in TEF and TAX and was associated with febrile neutropenia in 4% of cycles (Table 3); seven episodes (58%) occurred after cycle 1, three under prophylactic antibiotics and four patients developed concomitant grade ≥2 GI toxicity. Prophylactic antibiotics were given in 14% of cycles and the majority of the febrile episodes (54%) were treated outpatient with oral antibiotics.


View this table:
[in this window]
[in a new window]
 
Table 3. Overall neutropenia and related complications

 
It appears that the replacement of F by X and the subsequent dose escalation of X and T was associated with a lower ANC nadir and a higher incidence of febrile neutropenia, but did not affect nadir duration, whereas the myelotoxicity profile of the three regimens was not influenced by the given anthracycline (Table 4).


View this table:
[in this window]
[in a new window]
 
Table 4. Overall neutropenia and related complications according to equivalent doses of anthracyclines and fluoropyrimidines

 
Grade 3 anaemia and grade 4 thrombocytopenia were rare (4% of TAX cycles and one patient receiving TEX, respectively).

Non-haematological toxicity
All patients were evaluable for non-haematological toxicity, which was generally moderate (Table 5). Grade 2 alopecia developed in 72% of patients, and was unrelated to dose and schedule. Grade ≥2 neurotoxicity was present in 11% of cycles. No clinically relevant fluid retention, arthralgia and/or myalgia were reported with all combinations. Asthenia was occasionally severe and apparently more common with X-containing combinations (26% and 22% as compared with 5% with TEF). Overall, X increased the incidence of diarrhoea while mucositis, nausea and vomiting appeared dose-dependent across the different regimens, as expected. Grade 2 liver toxicity was quite common with all treatment regimens (17% and 21% of patients with TEF and TAX and 13% with TEX), fully recovered in all but two patients (one treated with TEF and one treated with TAX) and was not related to dose or liver tumour involvement. A total of three patients developed transient grade 3 liver toxicity (two treated with TAX and one with TEX).


View this table:
[in this window]
[in a new window]
 
Table 5. Major grade ≥2 non-haematological toxicities (% patients)

 
Cardiac toxicity
Overall, there was no difference among the three regimens in the median anthracycline cumulative dose, including prior adjuvant treatment (range 178–220 mg/m2) or in the median baseline LVEF (>60%). The echocardiography was repeated at the end of treatment in 58% of all patients without changes in the median determinations (66%).

Two patients treated with TEF (7%) experienced severe cardiac toxicity. The first had symptomatic coronary subtotal stenosis and required a stent implant 6 months after having completed four cycles at the first dose level (T30/E30 mg/m2, total cumulative E dose of 400 mg), with complete clinical and functional recovery. The patient's predisposing cardiac risk factors included hyperlipaemia and left chest wall irradiation (60 Gy), completed 2 months earlier. The second patient developed congestive heart failure shortly after the eighth cycle at T40/E45 mg/m2: echocardiography showed dilatative cardiomyopathy with significant LVEF reduction (from 60% at baseline to 35%). Both the clinical picture and LVEF recovered under medical treatment. This patient received prior adjuvant anthracyclines to a cumulative E dose of 1100 mg/m2.

Antitumour activity
Three of 62 patients were not evaluable for response after the first cycle either because of treatment refusal (two patients with TEF) or because of toxic death (one patient with TEX). The ORRs were comparable among the three regimens and ranged from 54% with TEF (95% confidence interval 34% to 72%) to 71% with TAX (95% confidence interval 49% to 87%) and 86% with TEX (95% confidence interval 42% to 99%), with no differences in RR among the different dose levels (Table 6). A clinical complete response (cCR) was documented in one patient with lung and soft tissue involvement treated with TAX (4%) and in two patients with locally advanced disease treated with TEX (29%).


View this table:
[in this window]
[in a new window]
 
Table 6. Antitumour activity

 
Overall, the median time to best response was comparable between the different regimens (range 87–93 days). Overall duration of response was censored in the majority of responders (33 patients) owing to the addition of different surgical or chemo-endocrine maintenance therapies, and was comparable between the different schedules in the remaining five patients (range 2–12 months).

Adjuvant chemotherapy did not affect antitumour activity: the ORR was 75% in the 12 patients who completed adjuvant treatment at least 12 months before on-study treatment (median 33 months; range 12–107). Four of the six patients who received prior anthracyclines achieved a partial response and one a stable disease, for an ORR of 67%. All sites of disease responded to treatment, irrespective of dose (Table 7); the ORR in visceral disease ranged from 40% with TEF to 50% with TAX and 67% with TEX. In the 31 patients with locally advanced diseases, the ORR was 70% with TEF and 86% with TAX, with all four patients treated with TEX achieving a response; no pCRs were reported.


View this table:
[in this window]
[in a new window]
 
Table 7. Tumour response by disease site

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In a previous multicentre phase I–II study of 92 patients, we showed that first-line chemotherapy of ABC with single dose ET every 3 weeks is well tolerated and active, with an ORR of 66% [1Go].

The present dose-finding study evaluated the feasibility of integrating fluoropyrimidines into a weekly, intermittent ET regimen: the three combinations tested (TEF, TAX, TEX) compared favourably with single dose ET, resulting in a significantly lower incidence of grade 4 neutropenia and febrile neutropenia than with every 3 weeks ET, for which the MTD was E90/T75 mg/m2 and G-CSF support was required in 44% of cycles. In contrast, with the weekly regimens G-CSF was introduced, according to local clinical practice, in only 3% of cycles. The MTDs of the different combinations were reached at T40/E45/F200 mg/m2 for TEF, T35/A25/X2000 mg/m2 for TAX and T35/E40/X1650 mg/m2 for TEX: the recommended doses were T35/E45/F200 mg/m2 for TEF and T35/A25/X1650 mg/m2 for TAX.

In a dose-finding study of every 3 weeks E (50 mg/m2), dose-escalating T and CI F (200 mg/m2), Humphreys et al. [26Go] stopped dose escalation at the first dose level (T50 mg/m2) due to the occurrence of febrile neutropenia in 39% of patients; the ORR was 64% in 51 evaluable patients. In a recently published phase I/II trial by Wenzel et al. [27Go] in 33 patients with stage III/IV disease receiving weekly ET for six consecutive weeks followed by 1 week rest, the MTD was T40/E35 mg/m2, neutropenic fever being the DLT.

Our data further confirm that an intermittent weekly schedule allows higher total doses of ET to be delivered, irrespective of the chosen fluoropyrimidines. On the other hand, treatment delays (one-third of cycles overall) and fluoropyrimidine discontinuation occurred in a significant proportion of patients, with 22% and 47% of patients discontinuing the fluoropyrimidine due to GI toxicity in the X-containing regimens and in TEF, respectively.

The toxicity profile seems to be drug- and dose-dependent, as expected. Although comparative analysis was not a predefined objective of the studies and despite the limited number of patients treated at each dose level, the replacement of CI F by X, together with increasing doses of T, apparently affects the ANC nadir and the incidence of febrile neutropenia, but not the median duration of severe neutropenia (Table 4). On the other hand, when non-haematological toxicity is considered, at equivalent dose levels of T and X, a trend towards an increased incidence of mucositis and diarrhoea with A than with E emerged (Table 8). The lack of escalating dose levels of TEX prevents further speculation on whether the type of anthracycline plays a role on the development of GI toxicity.


View this table:
[in this window]
[in a new window]
 
Table 8. Major grade ≥2 non-haematological toxicity according to equivalent doses of anthracyclines and fluoropyrimidines (% cycles)

 
At a median anthracycline cumulative dose of ~200 mg/m2 only two patients treated with TEF developed severe cardiac impairment. The first patient suffered from coronary subtotal stenosis after a low E dose (400 mg total dose) and had, as predisposing risk factors, a personal history of hyperlipaemia and a recent left chest wall irradiation. The clinical picture is consistent with the well-known F cardiac toxicity, whose possible underlying mechanisms are myocyte damage or vasospasms [28Go]. Coronary disease has been so far anecdotally reported with X [29Go], but its expanding indication as adjuvant and palliative treatment should encourage a careful cardiac monitoring. The second patient developed a classic anthracycline cardiomyopathy after eight cycles of treatment at the highest dose level (T40/E45/F200 mg/m2), which resolved completely after medical treatment.

Overall, the antitumour activity in the present study is comparable to that of combination regimens [30Go]. The different distribution of organ involvement within the individual regimens and the small number of patients treated in each subgroup makes any comparison merely speculative. Nevertheless, the X-containing regimens, where a significant proportion of patients had locally advanced disease, appear to be associated with a better RR (54% versus 74%), especially when used as neo-adjuvant treatment (70% versus 89%), and an increased CR rate, irrespective of the type of antracycline administered and of the dose of T (Table 9). Our data are in line with those of other groups: Venturini et al. [31Go] reported an ORR of 67% and 97% in 67 patients with stage III and IV disease treated every 3 weeks with ET (75 mg/m2 each) in association with X (1000 mg/m2), and Baltali et al. [32Go] achieved an ORR of 95% (cCR 25%) in 63 patients with locally advanced disease treated every 3 weeks with T (80 mg/m2), E (60 mg/m2) and F (500 mg/m2).


View this table:
[in this window]
[in a new window]
 
Table 9. Tumour response according to equivalent doses of anthracyclines and fluoropyrimidines

 
In conclusion, X represents a well tolerated and active alternative to CI F in combination with weekly anthracyclines and T in ABC, particularly when given as neo-adjuvant treatment for locally advanced disease. The development of effective combinations to be used for a limited period of time in this subset of patients could be of particular interest and worth exploring.

The toxicity profile of the three weekly combination regimens explored and the equivalent every 3 weeks schedules appears to be different, the first being associated with increased GI toxicity and the latter with dose-limiting haematological toxicity and febrile neutropenia. On the other hand, antitumour activity is substantially comparable: additional comparative evaluation of quality of life, including frequency of hospital visits, and financial considerations (i.e. inpatient management of febrile neutropenia and G-CSF support) would therefore be helpful in selecting, among the different regimens currently available, the most cost-effective approach in the individual patient.

The actual role of triplets, as compared with alternating and sequential schedules, should be also re-discussed in the management of ABC.


    Acknowledgements
 
We thank the patients who participated, the nurses and the data managers who contributed their technical expertise to the conduct of the study. This study was supported by Aventis, Antony, France and Pharmacia & Upjohn, Milan, Italy.

Received for publication January 16, 2005. Revision received March 9, 2005. Revision received April 12, 2005. Accepted for publication May 10, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
1. Pagani O, Sessa C, Nole F et al. Epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer: a multicentric phase I–II study. Ann Oncol 2000; 11: 985–991.[Abstract]

2. Viens P, Roche H, Kerbrat P et al. Epirubicin–docetaxel combination in first-line chemotherapy for patients with metastatic breast cancer: final results of a dose-finding and efficacy study. Am J Clin Oncol 2001; 24: 328–335.[CrossRef][ISI][Medline]

3. Venturini M, Michelotti A, Papaldo P et al. Identification of the highest dose of docetaxel associable with active doses of epirubicin. Results from a dose-finding study in advanced breast cancer patients. Ann Oncol 2001; 12: 1097–1106.[Abstract]

4. Gilewski T, Norton L. Cytokinetics and breast cancer chemotherapy. In Harris JR, Lippman ME, Morrow M et al. (eds): Diseases of the Breast. Philadelphia, PA: Lippincott-Raven 1996; 751–768.

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

6. Baselga J, Tabernero JM. Weekly docetaxel in breast cancer: applying clinical data to patient therapy. Oncologist 2001; 6 (Suppl 3): 26–29.[Abstract/Free Full Text]

7. Burstein HJ, Manola J, Younger J et al. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol 2000; 18: 1212–1219.[Abstract/Free Full Text]

8. Seidman D, Berry D, Cirrincione C et al. CALGB 9840: Phase III study of weekly (W) paclitaxel (P) via 1-hour (h) infusion versus standard (S) 3h infusion every third week in the treatment of metastatic breast cancer (MBC), with trastuzumab (T) for HER2 positive MBC and randomized for T in HER2 normal MBC. Proc Am Soc Clin Oncol 2004; 14: 457 (Abstr 512).

9. Crown J, O'Leary M, Ooi WS. Docetaxel and paclitaxel in the treatment of breast cancer: a review of clinical experience. Oncologist 2004; 9 (Suppl 2): 24–32.[Abstract/Free Full Text]

10. Regazzoni S, Pesce G, Marini G et al. Low-dose continuous intravenous infusion of 5-fluorouracil for metastatic breast cancer. Ann Oncol 1996; 7: 807–813.[Abstract]

11. Eisen T, Smith IE, Johnston S et al. Randomized phase II trial of infusional fluorouracil, epirubicin, and cyclophosphamide versus infusional fluorouracil, epirubicin, and cisplatin in patients with advanced breast cancer. J Clin Oncol 1998; 16: 1350–1357.[Abstract/Free Full Text]

12. Smith IE, A'Hern RP, Coombes GA et al. A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial. Ann Oncol 2004; 15: 751–758.[Abstract/Free Full Text]

13. Wagstaff AJ, Ibbotson T, Goa KL. Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer. Drugs 2003; 63: 217–236.[ISI][Medline]

14. Reichardt P, Von Minckwitz G, Thuss-Patience PC et al. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 2003; 14: 1227–1233.[Abstract/Free Full Text]

15. Seidman AD, O'Shaughnessy J, Misset JL. Single-agent capecitabine: a reference treatment for taxane-pretreated metastatic breast cancer? Oncologist 2002; 7 (Suppl 6): 20–28.[Abstract/Free Full Text]

16. Fumoleau P, Largillier R, Clippe C et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40: 536–542.[CrossRef][ISI][Medline]

17. Nadella P, Shapiro C, Otterson GA et al. Pharmacobiologically based scheduling of capecitabine and docetaxel results in antitumor activity in resistant human malignancies. J Clin Oncol 2002; 20: 2616–2623.[Abstract/Free Full Text]

18. O'Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol 2002; 20: 2812–2823.[Abstract/Free Full Text]

19. Pagani O, Sessa C, Martinelli G et al. Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer. Ann Oncol 1999; 10: 539–545.[Abstract]

20. Pronk LC, Vasey P, Sparreboom A et al. A phase I and pharmacokinetic study of the combination of capecitabine and docetaxel in patients with advanced solid tumours. Br J Cancer 2000; 83: 22–29.[CrossRef][Medline]

21. Pizzo P. Management of fever in patients with cancer and treatment-induced neutropenia. N Engl J Med 1993; 328: 1323–1332.[Free Full Text]

22. Theodoulou M, Seidman AD. Cardiac effects of adjuvant therapy for early breast cancer. Semin Oncol 2003; 30: 730–739.[ISI][Medline]

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

24. Miller AB, Hoogstraten B, Staquet M et al. Reporting results of cancer treatment. Cancer 1981; 47: 207–214.[ISI][Medline]

25. James K, Eisenhauer E, Christian M et al. Measuring response in solid tumors: unidimensional versus bidimensional measurement. J Natl Cancer Inst 1999; 91: 523–528.[Abstract/Free Full Text]

26. Humphreys AC, Dent J, Rodwell S et al. Phase II study of docetaxel in combination with epirubicin and protracted venous infusion 5-fluorouracil (ETF) in patients with recurrent or metastatic breast cancer. A Yorkshire breast cancer research group study. Br J Cancer 2004; 90: 2131–2134.[ISI][Medline]

27. Wenzel C, Locker GJ, Pluschnig U et al. Phase I/II trial of weekly epidoxorubicin and docetaxel (wED) in the neoadjuvant and palliative treatment of patients with breast cancer. Cancer Chemother Pharmacol 2002; 50: 155–159.[CrossRef][ISI][Medline]

28. Wacker A, Lersch C, Scherpinski U et al. High incidence of angina pectoris in patients treated with 5-fluorouracil. A planned surveillance study with 102 patients. Oncology 2003; 65: 108–112.[CrossRef][ISI][Medline]

29. Frickhofen N, Beck FJ, Jung B et al. Capecitabine can induce acute coronary syndrome similar to 5-fluorouracil. Ann Oncol 2002; 13: 797–801.[Abstract/Free Full Text]

30. Esteva FJ, Valero V, Pusztai L et al. Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond. Oncologist 2001; 6: 133–146.[Abstract/Free Full Text]

31. Venturini M, Durando A, Garrone O et al. Capecitabine in combination with docetaxel and epirubicin in patients with previously untreated, advanced breast carcinoma. Cancer 2003; 97: 1174–1180.[CrossRef][ISI][Medline]

32. Baltali E, Altundag MK, Onat DA et al. Neoadjuvant chemotherapy with Taxotere–epirubicin–5-fluorouracil (TEF) in local-regionally advanced breast cancer: a preliminary report. Tumori 2002; 88: 474–477.[ISI][Medline]





This Article
Abstract
Full Text (PDF)
All Versions of this Article:
16/10/1609    most recent
mdi308v1
E-letters: Submit a response
Alert me when this article is cited
Alert me when E-letters are posted
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Pagani, O.
Articles by Goldhirsch, A.
PubMed
PubMed Citation
Articles by Pagani, O.
Articles by Goldhirsch, A.