Phase I and pharmacokinetic study of docetaxel in combination with epirubicin and cyclophosphamide in advanced cancer: dose escalation possible with granulocyte colony-stimulating factor, but not with prophylactic antibiotics

D. Rischin1,5,+, S. P. Ackland2,5, J. Smith3, M. B. Garg2, S. Clarke4, M. J. Millward4, G. C. Toner1,5 and J. Zalcberg1

1 Division of Haematology and Medical Oncology and 3 Statistical Centre, Peter MacCallum Cancer Institute, Melbourne; 2 Newcastle Mater Hospital, Newcastle; 4 Sydney Cancer Centre, Sydney, Australia; 5 The Australian and New Zealand Breast Cancer Trials Group

Received 19 November 2001; revised 23 April 2002; accepted 13 May 2002;


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The objective of this phase I trial was to determine the maximally tolerated doses of the combination of docetaxel, epirubicin and cyclophosphamide.

Patients and methods:

Patients with advanced cancer, World Health Organization (WHO) performance status 0 to 2, who had received up to one prior chemotherapy regimen were treated with docetaxel, epirubicin and cyclophosphamide repeated every 21 days. The cyclophosphamide dose was fixed at 600 mg/m2 and the dose levels studied were: docetaxel/epirubicin; 60/60, 75/60, 75/75, 75/90, 85/90 and 85/105 mg/m2. There was provision for the addition of prophylactic ciprofloxacin and granulocyte colony-stimulating factor (G-CSF) in separate steps if dose-limiting toxicity (DLT) was neutropenia related.

Results:

Forty-three patients were entered and all were assessable for toxicity. Dose-limiting toxicity, predominantly febrile neutropenia, was surprisingly seen at the first dose level. The addition of prophylactic ciprofloxacin did not permit dose escalation, but dose escalation was possible with the addition of G-CSF. The highest administered dose level with G-CSF was docetaxel 85 mg/m2 and epirubicin 105 mg/m2 with DLTs in five of six patients. Treatment was well tolerated in 10 patients treated at the recommended dose level (85/90) with only one patient experiencing DLT. Responses were seen in a range of malignancies including breast and anaplastic thyroid cancers. No significant pharmacokinetic interaction was observed, but a transient increase in epirubicinol plasma concentration occurred during and after docetaxel infusion.

Conclusions:

The recommended dose level of docetaxel 85 mg/m2, epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 with G-CSF support has a favorable toxicity profile and is suitable for further investigation in phase II and III trials.

Key words: chemotherapy, cyclophosphamide, docetaxel, epirubicin, pharmacology, phase I trials


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Docetaxel has significant activity in a broad range of malignancies including breast, non-small-cell lung and ovarian cancers [13]. In breast cancer high response rates have been consistently observed in anthracycline pre-treated patients [1, 4]. Furthermore, randomized trials have demonstrated a superior response rate for single-agent docetaxel compared with doxorubicin in patients receiving first-line chemotherapy for metastatic breast cancer [5] and a survival advantage compared with vinblastine and mitomycin C as third-line chemotherapy [6].

As taxanes and anthracyclines are the most active drugs in breast cancer, there has been considerable interest in developing combination regimens. Initial trials of 3-h infusions of paclitaxel and doxorubicin reported high response rates with an increased risk of cardiac toxicity, which is at least in part due to a pharmacokinetic interaction resulting in increased levels of doxorubicin and doxorubicinol [7, 8]. In contrast, the combination of docetaxel and doxorubicin is not associated with any increased risk of cardiac toxicity or alteration of doxorubicin pharmacokinetics [9]. However, the plasma AUC (area under the concentration–time curve) of docetaxel is significantly increased by the prior administration of doxorubicin. In a preliminary report the combination of docetaxel and doxorubicin resulted in a superior response rate compared with the combination of doxorubicin and cyclophosphamide [10]. Doxorubicin and cyclophosphamide has been a commonly used regimen for breast cancer in both the adjuvant and advanced disease settings. Another approach to incorporating docetaxel into first-line combination regimens has been to add docetaxel to this combination, and high response rates have been reported [11]. Epirubicin has similar efficacy to doxorubicin in breast cancer, with less cardiac toxicity [12, 13]. In many countries epirubicin is often used instead of doxorubicin in the treatment of both early stage and advanced breast cancer [14, 15]. The Canadian trial which demonstrated the superiority of 5-fluorouracil, epirubicin and cyclophosphamide (FEC) over cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in node-positive breast cancer has led to a more widespread use of epirubicin in the adjuvant setting [15]. In this phase I study we have determined the maximally tolerated doses of the docetaxel, epirubicin and cyclophosphamide regimen.


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Patients were required to have histologically proven cancer, but patients with hematological malignancies, non-small-cell lung cancer and squamous cell carcinoma of the head and neck were excluded. Patients may have received up to one prior chemotherapy regimen. No prior taxane chemotherapy was permitted. Prior anthracycline dose had to be <=300 mg/m2 of doxorubicin or <=540 mg/m2 epirubicin. Prior radiotherapy to <30% of the marrow bearing areas was permitted. Prior chemotherapy or radiotherapy must have been completed at least 4 weeks prior to study entry. With regard to hepatic function, bilirubin had to be within normal limits, transaminases <=2.5 x upper limit of normal (ULN) and alkaline phosphatase <=5 x ULN (if liver disease present). However, if the level of alkaline phosphatase was >2.5 x ULN, transaminases had to be <=1.5 x ULN. Other eligibility criteria were as follows: age from 18 to 75 years, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, absolute neutrophil count >=2.0 x 109/l, platelet count >=100 x 109/l, serum creatinine <=1.5 x normal and left ventricular ejection fraction measured by radionuclide ventriculography >= lower limit of normal. Written informed consent was obtained from all patients and the protocol was approved by the Institutional Ethics Committee.

Patients were excluded from the trial for any of the following: uncontrolled angina, hypertension, arrhythmias, cardiac failure, myocardial infarction within the preceding 12 months, active infection, any contraindication for the use of dexamethasone, brain metastases as the only known site of disease or if uncontrolled, pre-existing peripheral neuropathy grade >=2 by the National Cancer Institute-Common Toxicity Criteria (NCI-CTC), and pregnancy or lactation.

Pretreatment and follow-up evaluations
Before enrolment all patients underwent a full history, physical examination, complete blood count (CBC) with differential, electrolytes, liver function tests, creatinine, ECG, gated cardiac scan, chest X-ray and imaging of known sites of disease. While on study patients were clinically assessed for toxicity weekly during the first cycle then every 3 weeks subsequently. Complete blood count including differential was performed three times a week during the first cycle then twice a week, and electrolytes, creatinine and liver function tests were performed weekly during the first cycle and then every 3 weeks. ECG was performed every 3 weeks. Computed tomography (CT) scanning and imaging of known sites of disease were performed every two cycles, as were gated cardiac scans.

Grading of toxicity from treatment was according to NCI-CTC. Anti-tumor activity was assessed according to the World Health Organization (WHO) response criteria. Response duration was calculated from the date of treatment commencement.

Treatment plan
Drug administration
Docetaxel (TaxotereTM) was supplied by Aventis (Sydney, Australia) and epirubicin (Pharmorubicin) was obtained from Pharmacia-Upjohn (Sydney, Australia). Epirubicin was administered first over 15 min followed immediately by cyclophosphamide over 15 min. There was a 45 min interval between the end of the cyclophosphamide infusion and the commencement of the 1-h docetaxel infusion. Dexamethasone 8 mg orally was taken 13, 7 and 1 h prior to docetaxel and 12, 24 and 36 h after docetaxel. Prophylactic anti-emetic treatment was to be given to all patients. Prophylactic recombinant granulocyte colony stimulating factor (G-CSF) support was only permitted at the designated dose levels where it was being added to determine whether this would permit further dose escalation. G-CSF (Granocyte) was supplied by Amrad Pharmaceuticals (Melbourne, Australia).

Dose levels
The starting dose level (level 1) was epirubicin 60 mg/m2, cyclophosphamide 600 mg/m2 and docetaxel 60 mg/m2. These doses were chosen based on the preliminary results that had been reported with doxorubicin, cyclophosphamide and docetaxel. The cyclophosphamide dose was fixed at 600 mg/m2 for subsequent dose levels defined in advance as: level 2, epirubicin 60 mg/m2 and docetaxel 75 mg/m2; level 3, epirubicin 75 mg/m2 and docetaxel 75 mg/m2; level 4, epirubicin 90 mg/m2 and docetaxel 75 mg/m2; level 5, epirubicin 90 mg/m2 and docetaxel 85 mg/m2 and level 6, epirubicin 105 mg/m2 and docetaxel 85 mg/m2. If the predominant dose-limiting toxicity (DLT) was febrile neutropenia or prolonged neutropenia then there was provision for further attempted dose escalation with the addition of prophylactic ciprofloxacin 500 mg twice a day from day 5 until neutrophils were >=1.0 x 109/l. If prophylactic ciprofloxacin did not permit further dose escalation, then further dose escalation with G-CSF without ciprofloxacin was to be attempted. If ciprofloxacin permitted dose escalation and the DLT remained neutropenia related then further dose escalation with G-CSF and ciprofloxacin would be investigated. G-CSF 33.6 million units (263 µg) was administered subcutaneously daily commencing on the day after chemotherapy and continued until neutrophils were >=1.0 x 109/l. Cycles were repeated every 3 weeks. Dose escalation was not permitted in individual patients and the minimum interval between treatment cycles was 21 days. Epirubicin was to be ceased after a cumulative dose of 900 mg/m2 had been reached. Patients with progressive disease were taken off the study.

At least three patients were entered at each dose level. If DLT occurred during the first cycle up to six patients were treated at that dose level. Dose-limiting toxicity was defined as febrile neutropenia (grade 4 neutropenia with fever >38.5°C or >38°C on three separate occasions in a 24 h period), grade 4 neutropenia >=7 days, grade 4 thrombocytopenia, grade 4 nausea/vomiting, grade 2 sensory or motor neuropathy or grade 3 or 4 non-hematological toxicity excluding alopecia and anemia. If three patients or more experienced DLT during the first cycle enrolment at this dose level was ceased and the preceding dose level was deemed to be the dose recommended for phase II trials.

Dose modification for toxicity
Dose reductions were defined for hematological and non-hematological toxicities. Epirubicin and docetaxel doses were reduced by 25% for febrile neutropenia, nadir neutrophil count <0.5 x 109/l for >=7 days, or nadir platelet count <50 x 109/l. No dose modification was made for uncomplicated neutrophil count <0.5 x 109/l for <7 days. If the day 21 neutrophil count was <1.5 x 109/l, or the platelet count <100 x 109/l, further treatment was delayed 1 week until recovery. WHO grade 3 or 4 non-hematological toxicity were generally managed by a 25% dose reduction of both drugs. However, patients could be managed by symptomatic treatment alone or removal from the study at the investigator’s discretion. Clinically significant hypersensitivity reactions (defined as hypotension that required therapy, angioedema, respiratory distress requiring bronchodilator therapy or generalized urticaria) required cessation of the docetaxel infusion and appropriate supportive measures.

Pharmacokinetics
In view of unexpected toxicities seen at dose levels 1a and 1b, the protocol was amended to investigate docetaxel and epirubicin pharmacokinetics. Blood was collected for pharmacokinetics of docetaxel and epirubicin from at least one patient at every dose level. Heparinized venous blood samples (10 ml) were obtained prior to the start of epirubicin infusion and then at 16 time points in the following 73 h [at the end of the 15 min epirubicin infusion; then 5, 15 and 30 min after epirubicin infusion; at the start of the docetaxel infusion (60 min after the start of the epirubicin infusion); 30 min after the start of the docetaxel infusion; and the end of the infusion; then 15 min, 30 min and 1, 2, 4, 8, 24, 48 and 72 h post-infusion]. Blood samples were kept on ice, centrifuged within 15 min and plasma was stored at –80°C until analysis.

Docetaxel and epirubicin/epirubicinol were measured by methods previously described [16, 17]. In brief, after solid phase extraction of plasma, samples were analysed by two different HPLC methods with UV detection at 227 nm (docetaxel) using paclitaxel as an internal standard, and fluorescence detection (epirubicin and epirubicinol) using doxorubicin as an internal standard. The lower limit of detection for docetaxel is 5 ng/ml using 1 ml of plasma, and 2 ng/ml for epirubicin and epirubicinol. Concentrations were estimated by reference to a standard curve made during each chromatographic run.

Pharmacokinetic parameters were estimated from plasma concentration data using both non-compartmental and compartmental methods (WinNonLin Ver. 1.5). For non-compartmental analyses a constant infusion was assumed and a log/linear trapezoidal method was used for calculations of AUC. Terminal half-life was calculated by extrapolation from the last 3–4 time points (24, 48 and 72 h post-infusion). A three-compartment model was used for epirubicin, as previous studies had shown that this provided the best description of the data [17]. A three-compartment model was also used for docetaxel. For both three-compartment models a constant infusion with no lag time and first-order elimination was assumed. Concentrations were weighted as 1/Y2. The Nelder–Mead method of minimization was used for modeling. AUC to infinity was calculated by the log trapezoidal method. Terminal half-life was calculated as ln(2)/{gamma}, where {gamma} is the terminal first-order elimination rate constant. Total body clearance was calculated as the ratio of the delivered dose to the AUC (to infinity) for each drug.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
The details of the 43 patients enrolled on this study are given in Table 1. One patient with non-small-cell lung cancer was inadvertently treated, but has been included in the analysis as the patient met all other eligibility criteria. The number of patients entered at each dose level is given in Table 2.


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Table 1. Patient characteristics (n = 43)
 

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Table 2. Dose-limiting toxicity (first cycle)
 
Toxicity
All patients were evaluable for toxicity. The number of patients experiencing DLT in the first cycle at each dose level is given in Table 2. All three patients treated at dose level 1a experienced DLT. Two patients experienced febrile neutropenia, in one case also associated with grade 3 diarrhea and in the other associated with grade 4 neutropenia for >=7 days. The third patient had a fever associated with grade 4 neutropenia but was started on intravenous antibiotics prior to meeting the strict criteria for febrile neutropenia in this protocol. This patient was treated on the second cycle with the same doses and experienced grade 3 diarrhea. Although this patient did not meet the strict criteria for DLT, it was thought that she should be considered as having experienced DLT. Hence, we decided to enrol patients on dose level 1b with the same doses and prophylactic ciprofloxacin, rather than expanding the initial 1a dose level. At dose level 1b, three of five patients experienced febrile neutropenia, and accrual was hence ceased before a sixth patient was enrolled. One of these patients on dose level 1b with recurrent nasopharyngeal carcinoma and a bulbar palsy died following cycle 1 from aspiration pneumonia associated with grade 4 neutropenia.

As febrile neutropenia was the predominant toxicity, we explored dose level 1c with the same doses and G-CSF but no ciprofloxacin. This dose level was well tolerated with no DLT. At dose level 2 there was one febrile neutropenia in the first three patients, and the dose level was expanded. An additional two patients were treated without DLT, but one of these patients was inadvertently treated at the doses for level 3. As there was a delay in accruing the sixth patient, and an additional patient would not have influenced the decision to go up to the next dose level, we proceeded to dose level 3 and included the patient treated who had already received the dose level 3 doses. At dose level 3 one of six patients had febrile neutropenia, at dose level 4 two of six patients had febrile neutropenia and no DLT was observed in the initial three patients treated on dose level 5. No non-hematological DLTs were seen at dose levels 1c–4. At dose level 6, five of six patients experienced DLT, febrile neutropenia in three, one patient had grade 3 fatigue and one patient experienced grade 4 vomiting and grade 3 diarrhea. Hence, dose level 6 was the highest administered dose and dose level 5 is the recommended dose level. As stipulated in the protocol we then expanded dose level 5 to a total of 10 patients. Only one of 10 patients treated on the recommended dose level experienced a DLT, febrile neutropenia and grade 3 stomatitis.

Two hundred and six cycles of treatment (median 5, range 1–10) were given to 43 patients. Twenty patients required a dose reduction during their treatment. Neutropenia was the predominant hematological toxicity with grade 4 neutropenia occurring in 95% of cycles. Grade 4 neutropenia lasting >=7 days occurred in three patients treated on dose levels 1a and 1b, but not in any patients who received G-CSF. Twenty-seven cycles (13%) in 17 patients were complicated by febrile neutropenia. Significant thrombocytopenia was uncommon with grade 2 thrombocytopenia in 9% of patients and grade 3 in 14%; no grade 4 thrombocytopenia was observed. Grade 3 or 4 non-hematological toxicities were infrequent (Table 3).


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Table 3. Toxicity (206 evaluable cycles)
 
Five cycles in five patients were delayed for 3 or more days owing to drug-related toxicity. At the recommended dose level nine patients received >=95% of the planned epirubicin, cyclophosphamide and docetaxel doses per cycle, and one patient received 90% of the planned doses per cycle. The median dose intensity, calculated as received mg/m2/day relative to the protocol-defined dose intensity, at the recommended dose level was 99% for each of the three drugs. At the recommended dose level, the mean time between cycles was 21 days for seven patients and 22, 23 and 25 days in the other three patients.

Responses
Seventeen (44%, 95% CI 25% to 56%) of 39 evaluable patients achieved an objective response, with three complete and 14 partial responses. Of the 11 evaluable breast cancer patients there was one CR and five PRs (55% response rate, 95% CI 23% to 83%). Median duration of response in the breast cancer patients was 10.9 months (range 8.4 to >25.5). Eight of the breast cancer patients were treated on dose level 1, and there were no breast cancer patients treated on dose levels 5 and 6. Responses were also seen in the following tumors: endometrium, two; anaplastic thyroid, two; soft tissue sarcoma, two; unknown primary, two; and one each of non-small-cell lung cancer, esophageal cancer and squamous cell carcinoma of the skin. There was one responder on dose level 1a, two on dose level 1b, two on dose level 1c, one on dose level 2, three on dose level 3, four on dose level 4, two on dose level 5 and two on dose level 6.

Pharmacokinetics
Docetaxel
In the compartmental analysis, all patients fitted a three-compartment model except for one patient, where a two-compartment model provided an adequate fit. Similar estimates were derived for non-compartmental analysis as for compartmental analysis. There was no correlation between docetaxel dose and either mean AUC or Cmax for the small number of dose levels examined (Table 4; compartmental analysis). Similarly, there was no alteration in clearance with increasing docetaxel dose. These data are not significantly different from previous reports of pharmacokinetics of docetaxel as a single agent [18].


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Table 4. Docetaxel pharmacokinetic parameters
 
Epirubicin and epirubicinol
The dose of epirubicin administered ranged from 95 to 185 mg, with the infusion duration ranging from 0.2 to 0.42 h (12–25 min). In the compartmental analysis, all patients fitted a three-compartment model. Pharmacokinetic parameters by this analysis were the same as by non-compartmental analysis. For epirubicin there was a trend to increased AUC with increased dose. Epirubicin Cmax also showed a trend to increase with dose (Table 5). However, the small number of subjects and the wide interpatient variation means that this trend is not statistically significant. There was no alteration in clearance or mean terminal half-life with increasing epirubicin dose. Epirubicin and epirubicinol pharmacokinetic parameters were not significantly different from previous reports (Tables 5 and 6) [19].


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Table 5. Epirubicin pharmacokinetic parameters
 

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Table 6. Epirubicinol pharmacokinetic parameters as a function of epirubicin dose
 
On close inspection of the plasma concentration–time profiles of epirubicin and epirubicinol, there was clearly an effect of docetaxel infusion on the profile of epirubicinol but not on epirubicin. In 11 of 18 cases, the plasma concentration of epirubicinol increased during the docetaxel infusion, and after infusion epirubicinol levels resumed a relatively normal decrement from a higher base (Figure 1). The median increase in epirubicinol concentration from the start to the end of docetaxel infusion was 10% (range 1–49%). In the other seven cases there was a flattening of the curve during infusion, with a median fall from start to end of infusion of only 7% (range 0–11%). In these cases the fall during infusion was less than expected from the pre-docetaxel epirubicinol plasma concentration–time curve.



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Figure 1. Plasma epirubicin and epirubicinol concentration–time profiles of one patient. Epirubicinol concentration increased from 6.0 ng/ml at the start of the docetaxel infusion to 7.7 ng/ml at the end of the docetaxel infusion (a 28% increase).

 

    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
In this trial we found that the combination of docetaxel, epirubicin and cyclophosphamide with G-CSF support is a well tolerated and active regimen, with recommended doses of docetaxel 85 mg/m2, epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2. However, we unexpectedly observed DLT at the first dose level tested, docetaxel 60 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 600 mg/m2, when given without G-CSF. In current phase II and III trials a TAC regimen using doses of docetaxel 75 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 is being investigated [11]. At dose levels 1a and 1b (same doses as 1a with prophylactic antibiotics), six of eight patients experienced febrile neutropenia during the first cycle, precluding further dose escalation. In phase I trials of epirubicin and docetaxel without cyclophosphamide the recommended doses of epirubicin/docetaxel without G-CSF were 90/75, 60/80 and 75/80 mg/m2, and with G-CSF the recommended doses were 125/85 and 90/90 mg/m2 [2022].

The choice of a recommended dose level in a phase I trial must always be interpreted with caution in view of the limited patient numbers, variability in the criteria used to determine the maximum tolerated dose and also the fact that decisions about dose escalation are often made on the basis of toxicity experienced during the first cycle only. In our trial, there was more febrile neutropenia seen at dose level 4 than at dose level 5, the recommended dose level (Table 3). However, it is reassuring that although dose level 5 was expanded to 10 patients only two patients experienced an episode of febrile neutropenia, with only one occurring during the first cycle. Furthermore, we found that it was possible to maintain dose intensity at this dose level, with median dose intensity relative to the protocol-defined dose intensity of 99% for each of the three drugs.

In view of the unexpected toxicity seen at dose levels 1a and 1b, with six patients with febrile neutropenia and two cases of grade 3 diarrhea, we investigated the pharmacokinetics of docetaxel and epirubicin. However, the pharmacokinetics appear to be similar to that observed in previous trials of epirubicin and docetaxel separately or together [23, 24]. We did observe a transient increase in epirubicinol levels during and shortly after docetaxel infusion. These data suggest that docetaxel or the diluent polysorbate decreased epirubicinol distribution or clearance, or both. Alternatively, docetaxel may have temporarily halted glucuronidation of epirubicin and epirubicinol, leading to diversion of epirubicin metabolism towards reduction. This explanation seems unlikely since there was no concomitant change in epirubicin levels during docetaxel infusion.

Esposito et al. [23] compared the effects of paclitaxel and docetaxel on epirubicin pharmacokinetics in breast cancer patients. This study showed that paclitaxel significantly increased and docetaxel slightly increased epirubicinol plasma levels and AUC in the first 24 h after dosing, and that both taxanes increased 7-deoxy-aglycone concentrations in plasma, suggesting that docetaxel transiently decreases clearance of epirubicin metabolites. These effects, however, are small in comparison to the effects of paclitaxel on doxorubicin pharmacokinetics, where a 30% increase in exposure to doxorubicin and its metabolite doxorubicinol has been shown [8]. In the absence of an apparent pharmacokinetic explanation there is no obvious explanation for our inability to escalate to equivalent doses achieved with the TAC regimen without G-CSF. In this regard it is noteworthy that we did not see any effect of epirubicin on docetaxel pharmacokinetics, in contrast to studies of doxorubicin effect on docetaxel exposure, where a 30% increase in AUC of docetaxel has been observed [9]. If these apparent differences in the effect of the two anthracyclines on docetaxel metabolism are true, we may have expected to be able to escalate doses in our study to well above the TAC equivalents. However, high febrile neutropenia rates have been reported in previous trials with docetaxel and anthracyclines [11, 25]. A phase II trial of the TAC regimen reported febrile neutropenia in 34% of patients [11] and trials of docetaxel and doxorubicin have reported febrile neutropenia rates of 31% and 42% without G-CSF [10, 25].

In view of the profound but brief neutropenia that occurs with docetaxel there has been interest in the possible role of prophylactic antibiotics in reducing the risk of febrile neutropenia. Nabholtz et al. [11] have suggested that the addition of ciprofloxacin to a regimen of docetaxel, doxorubicin and cyclophosphamide may have led to a reduced incidence of febrile neutropenia. Other investigators including ourselves have used prophylactic antibiotics with docetaxel-based regimens, despite the lack of randomized data confirming benefit [26]. One of the novel aspects of the current trial was to add ciprofloxacin as part of the dose escalation strategy if neutropenia-related DLT was observed. However, this did not permit dose escalation, with three of five patients on dose level 1b experiencing febrile neutropenia. A similar approach was reported by Ardizzoni et al. [27] in which they added ciprofloxacin to a regimen of cyclophosphamide, doxorubicin and etoposide given with G-CSF in patients with small-cell lung cancer. In that phase I trial the addition of ciprofloxacin to a G-CSF-containing regimen allowed them to escalate the doses by one dose level. While it is not possible to draw any definite conclusions about the role of prophylactic antibiotics in patients receiving docetaxel-containing regimens based on the small number of patients treated in our trial, it does suggest that the routine use of prophylactic antibiotics in this setting should be questioned. A randomized trial of prophylactic antibiotics in patients receiving docetaxel is required to determine whether this approach does in fact reduce the incidence of febrile neutropenia. It is of interest that Tjan-Heijnen et al. [28] recently reported the results of a randomised trial that found that prophylactic ciprofloxacin and roxithromycin reduced the febrile neutropenia rate in patients with small-cell lung cancer receiving cyclophosphamide, doxorubicin and etoposide chemotherapy with or without G-CSF.

Activity was observed in a broad range of cancers, including a 55% response rate in breast cancer. The partial responses observed in two of three patients with anaplastic thyroid cancer are noteworthy. Anaplastic thyroid cancer has a dismal prognosis with median survival of <8 months in most series [29]. Chemotherapy is not widely used due to the limited activity of currently available drugs. Although doxorubicin is generally regarded as the most active single agent, a disappointing response rate of 5% was achieved in a small randomized trial [30]. Response rates of 33% and 14% have been reported in small series for the combination of doxorubicin and cisplatin [30, 31]. Further investigation of our docetaxel-based regimen in this disease should be considered.

In conclusion, the regimen of docetaxel, epirubicin and cyclophosphamide with G-CSF support was well tolerated, and exhibited activity in several tumor types. At the recommended dose level febrile neutropenia and grade 3 or 4 non-hematological toxicity were infrequent. No significant pharmacokinetic interaction was observed with this schedule, but a transient increase in epirubicinol plasma concentration occurred during and after docetaxel infusion. The requirement for G-CSF in order to escalate to moderate doses of docetaxel and epirubicin may limit the utility of this regimen for advanced breast cancer. However, this would be a suitable regimen to compare to the FEC regimen in node-positive breast cancer [15].


    Acknowledgements
 
This trial was supported by The Australian and New Zealand Breast Cancer Trials Group, Aventis and Pharmacia.


    Footnotes
 
+ Correspondence to: Dr D. Rischin, Division of Hematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag No 1, A’Beckett St, Melbourne 8006, Australia. Tel: +61-3-9656-1804; Fax: +61-3-9656-1408; E-mail: drischin{at}petermac.unimelb.edu.au Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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