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
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Abstract |
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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 (6080 mg/m2), A (4050 mg/m2) or E (6090 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
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Introduction |
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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 [10], whereas an ORR exceeding 70% has been reported with CI F-containing regimens in metastatic or locally advanced disease [11
, 12
]. Capecitabine (X) mimics CI F and is activated preferentially at the tumour site [13
]. 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 [14
16
]. 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 [17
].
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 [18].
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 [1], CEF [11
] 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 [19
] and XT [20
]. 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] [21
], 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.
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Patients and methods |
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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 [24, 25
] 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.
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Results |
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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 34 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.
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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).
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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%).
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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 12107). 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.
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Discussion |
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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. [26] 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. [27
] 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.
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Overall, the antitumour activity in the present study is comparable to that of combination regimens [30]. 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. [31
] 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. [32
] 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).
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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.
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Acknowledgements |
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Received for publication January 16, 2005. Revision received March 9, 2005. Revision received April 12, 2005. Accepted for publication May 10, 2005.
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References |
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