Centre for Developmental Cancer Therapeutics (CDCT), 1 Austin Hospital, 2 Western Hospital and 3 Royal Melbourne Hospital, Melbourne, Australia; 4 Aventis, Melbourne, Australia and Paris, France
Received 28 July 2003; revised 22 December 2003; accepted 31 December 2003
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ABSTRACT |
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Docetaxel is highly active in the treatment of patients with breast cancer. The principal dose-limiting toxicities of the 3-weekly regimen are neutropenia and febrile neutropenia. In a previous phase I dose-escalation study with granulocyte colony-stimulating factor (G-CSF) support, the recommended dose was determined to be docetaxel 160 mg/m2 3-weekly. The objectives of this phase II study were to determine the response rate and toxicity of this dose and schedule, given as first-line in patients with advanced breast cancer. Mobilisation of peripheral blood stem cells (PBSCs) was also investigated.
Patients and methods:
Eligible women had metastatic breast cancer and were aged 1875 years with ECOG performance status 2. Strict criteria for liver function were followed, and adjuvant chemotherapy must have been completed at least 6 months previously. Treatment was docetaxel 160 mg/m2 over 6090 min every 21 days with G-CSF 5 µg/kg/day until neutrophil recovery, for up to six cycles. A 3-day corticosteroid prophylaxis was given. Bloods samples to determine PBSC levels [CD34+, granulocytemacrophage colony-forming cells (GM-CFC) and burst-forming units-erythroid (BFU-E)] were taken on days 6, 8, 9 and 11 following docetaxel.
Results:
Twenty-five women with median age 50 years (range 3566) were included. Seventeen (68%) had previously received adjuvant chemotherapy. In total, 112 cycles were delivered (median four per patient), with dose reductions required in 12.5% of cycles. G-CSF was given for a median of 6 days. The median neutrophil nadir was 0.5 x 109/l and occurred a median 5 days after treatment. The median duration of grade 3 or 4 neutropenia was 2 days (range 17). Grade 4 neutropenia occurred in 44% of patients, but there was only one episode of febrile neutropenia. Five patients were taken off study due to toxicities that included oedema, neurosensory toxicity and asthenia. Confirmed partial response was seen in nine patients (37.5%; 95% confidence interval 19% to 59%). CD34+ cells, GM-CFC and BFU-E levels peaked at day 8 following docetaxel administration. The median CD34+ cell peak was 6.5 x 104/ml, with only 20% of patients <2 x 104/ml, a level below which leukapheresis is not usually attempted.
Conclusions:
Docetaxel 160 mg/m2 was delivered with G-CSF support with a very low rate of febrile neutropenia. Non-haematological toxicity was significant, causing five patients to go off study. Effective mobilisation of PBSCs was seen. The response rate of 37.5% was less than that obtained in first-line studies using standard-dose docetaxel 100 mg/m2, suggesting that there is no additional benefit in dose escalation of this cytotoxic agent in breast cancer patients using this schedule.
Key words: breast cancer, docetaxel, dose escalation, G-CSF, mobilisation, peripheral blood stem cells, phase II trial, toxicity
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Introduction |
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Docetaxel is the most active single agent in breast cancer, and at standard doses of 100 mg/m2 produces response rates of 4861% given first-line as a single agent [46], and 30%42% given second-line following anthracycline failure [79]. This study investigated whether escalated-dose docetaxel, given with G-CSF support to reduce neutropenia and febrile neutropenia, would result in higher response rates in patients treated first-line. In addition, we assessed toxicity and investigated the mobilisation of peripheral blood stem cells (PBSCs) with this regimen.
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Patients and methods |
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Women with histologically or cytologically proven breast cancer were eligible, aged 1875 years and with ECOG performance status (PS) 2. Baseline neurosensory changes were required to be grade
1, neutrophils
1.5 x 109/l, platelets
100 x 109/l, haemoglobin
10 g/dl and serum creatinine <1.5 times the institutional upper normal limit (UNL).
The eligibility criteria for hepatic function were as follows: total bilirubin 1x UNL, or
1.5x UNL if aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were normal; AST and ALT
2.5x UNL; and ALP
5x UNL (except in absence of liver metastases and presence of bone disease). Patients with both ALP >2.5x UNL and AST or ALT >1.5x UNL were not eligible.
Patients were allowed to have received adjuvant chemotherapy if it was completed at least 6 months previously, but were not to have received chemotherapy for advanced or metastatic disease. Patients were not to have received prior docetaxel or high-dose chemotherapy requiring haematopoietic progenitor support. Prior hormonal therapy or radiotherapy must have been completed at least 4 weeks previously, and total radiotherapy must have been to 30% of marrow-bearing areas. Patients with significant psychiatric or medical illnesses were not eligible. Patients gave written informed consent and the study was approved by the institutional ethics committees of participating hospitals.
At baseline the following investigations were undertaken: history and physical examination; electrocardiogram; complete blood count (CBC); electrolytes; renal and hepatic function; calcium; and random glucose. The CBC was checked three times per week from day 5 until neutrophil recovery, and then weekly. Baseline imaging investigations included a chest X-ray, a computed tomography scan of disease sites, and other imaging as required. Imaging of disease sites was repeated after three and six cycles. Objective responses were to be confirmed after at least 4 weeks.
Blood for peripheral blood stem cell (PBSC) assays was taken during cycle 1, at baseline, and on days 6, 8, 9 or 10 and 11 following treatment. Assays of CD34+ cells, granulocytemacrophage colony-forming cells (GM-CFC) and burst-forming units-erythroid (BFU-E) were carried out as described previously [10].
Treatment and study design
The primary end point of the study was response rate, and secondary end points were toxicity and PBSC assays. A sample size of 25 patients was chosen for this exploratory study, to give preliminary information on response rate and to investigate whether this regimen could be delivered safely.
Patients received docetaxel 160 mg/m2 as a 1 h infusion every 3 weeks, for up to six cycles. The infusion duration was increased to 90 min where individual doses were >240 mg. A total of six doses of oral dexamethasone 8 mg were given at the following times: the evening prior to treatment; the morning of, and 1 h prior to, treatment; the evening after treatment; and the morning and evening of the next day.
Patients received G-CSF (lenograstim; Aventis, Paris, France) 5 µg/kg as a daily subcutaneous injection, commencing the day after chemotherapy and continuing until neutrophils were 1.0 x 109/l.
Toxicities were graded using the National Cancer Institute common toxicity criteria criteria, version 1.0. Docetaxel was administered every 21 days provided the neutrophil count was 1.5 x 109/l and platelets
100 x 109/l. Dose reductions of 20 mg/m2 were made for the following toxicities: febrile neutropenia persisting for
3 days despite intravenous antibiotics; platelet nadir <25 x 109/l; grade
3 skin toxicity or grade
2 neuropathy. Patients with persisting grade
2 skin or neurosensory toxicity after 1 weeks delay were to go off study. If grade
3 nausea, vomiting or diarrhoea occurred, patients received appropriate prophylaxis for the next cycle, and if grade
3 toxicity recurred a 20 mg/m2 dose reduction was made. If bilirubin became elevated above the baseline level, patients went off study if this did not recover to baseline by day 28. A 25% dose reduction occurred for abnormal hepatic function (AST and/or ALT
2.5x UNL or ALP
2.5x UNL) measured at the time treatment was due. With AST and/or ALT >5x UNL or ALP >5x UNL, 1 week was allowed for recovery to below these levels, after which time patients without recovery went off study. Other grade 3 or 4 toxicity required delay until recovery to grade
1, and a 10 mg/m2 dose reduction was subsequently made. No dose reductions were made for allergic reactions, peripheral oedema or effusions, or alopecia.
Complete and partial responses (PRs) were assessed using standard WHO criteria for bidimensional measurements. Response assessment was carried out by the investigators. Peak CD34+, GM-CFC and BFU-E cell levels from chemonaïve patients and those who had previously received chemotherapy were compared using the MannWhitney U-test.
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Results |
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Five patients (20%) discontinued treatment due to toxicity, with discontinuation after four cycles for four patients and after five cycles for one patient. Toxicity was grade 3 asthenia (one patient), grade 3 neurosensory (one patient), grade 3 peripheral oedema (one patient), grade 2 asthenia and grade 3 peripheral oedema (one patient), and grade 3 asthenia, neurosensory and neuromotor toxicity (one patient). There were no treatment-related deaths.
Haematological toxicity
G-CSF was administered for a median of 6 days (maximum 9 days). The median neutrophil nadir was 0.5 x 109/l (range 05.1), which occurred a median 5 days (range 56) after docetaxel administration. Eleven patients (44%) developed grade 4 neutropenia at some time during the course and an additional five patients (20%) developed grade 3 neutropenia (Table 2). The median duration of grade 3 or 4 neutropenia was 2 days. There was no grade 3 or 4 thrombocytopenia, and the median platelet nadir was 132 x 109/l, occurring at a median of 6 days after treatment. Anaemia was infrequent and no worse than grade 2, seen in two patients (8%), one of whom required transfusion. There was only one episode of febrile neutropenia. An additional two patients had grade 3 infection without neutropenia (Table 2).
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Antitumour efficacy
The median time to progression (TTP) was 163 days. Twenty-four patients were evaluable for efficacy. Confirmed PR was seen in nine patients [37.5%; 95% confidence interval (CI) 19% to 59%]. An additional two patients (8.3%) obtained an unconfirmed PR, for a combined confirmed and unconfirmed PR rate of 46% (95% CI 26% to 66%). Of the patients with PR or unconfirmed PR, eight patients (73%) had received prior adjuvant chemotherapy, compared with nine patients (64%) having received adjuvant chemotherapy in the non-responder group. Amongst responding patients, five patients (45%) had previously received adriamycin compared with seven (50%) of the non-responders.
PBSC assays
PBSC assay results were available for 20 patients. The results are shown in Table 3. Peak CD34+, GM-CFC and BFU-E cell levels occurred at day 8 following docetaxel and G-CSF.
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Discussion |
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Despite widespread usage in breast and other malignancies, the potential for dose escalation of docetaxel has not been explored systematically. We previously reported a dose-escalation study in patients with a range of malignancies, where docetaxel was escalated in 10 mg/m2 increments with G-CSF support. DLTs were skin and neurosensory, and the recommended dose for phase II studies was 160 mg/m2 given every 3 weeks [3].
In the current study, docetaxel was administered at 98% of the planned dose intensity. Dose reductions were required in only 12.5% of cycles, and only 7% of cycles were delayed. These data confirm that it is feasible to deliver docetaxel 160 mg/m2 with G-CSF support to this patient population. The current study was notable for a very low level of febrile neutropenia, with only one episode of febrile neutropenia when prophylactic G-CSF is given. This confirms the results of our previous phase I study, where only two of 29 patients developed febrile neutropenia. In the current study, although 11 patients (44%) had grade 4 neutropenia, the median duration was only 2 days. The duration of neutropenia is known to be a significant factor in the risk for developing infection [15]. Studies of standard-dose docetaxel with G-CSF in a range of malignancies have also generally shown a low rate of febrile neutropenia [16, 17], although in one study of 60 patients with lung cancer a febrile neutropenia rate of 30% was seen [18].
The pattern of non-haematological toxicity was similar to that seen for patients treated at standard doses and similar to the profile seen in our previous phase I trial [3]. Peripheral oedema and asthenia were the most troublesome toxicities, and led to cessation of treatment in four patients. These toxicities became more apparent with multiple cycles. Three patients had grade 3 neurosensory toxicity, leading to cessation in two patients. Toxicity to nails was frequent and consisted of marked discolouration and onycholysis. Cutaneous toxicity was frequent and seen in 72% of patients, which was higher than in some studies of standard-dose docetaxel [8]. However, severe cutaneous toxicity did not occur, which is also usually the case with standard dose docetaxel [8]. This is interesting, as cutaneous toxicity was dose-limiting in the phase I study of this regimen [3].
Overall, 37.5% (95% CI 19% to 59%) of patients had objective responses, which were all PRs. An additional 8.3% of patients had unconfirmed PRs. Prior adjuvant chemotherapy, with or without adriamycin, did not appear to influence the response rate. The response rate is less than the 5461% response rate obtained in phase II studies of docetaxel 100 mg/m2 in first-line treatment of advanced breast cancer [4, 5]. It is also less than the 48% response rate to docetaxel 100 mg/m2 obtained in a randomised trial reported by Chan et al. [6] comparing docetaxel with doxorubicin in a population previously treated with alkylating agents, 49% of whom had received chemotherapy for metastatic disease. There was also no improvement in TTP seen with escalation of the dose of docetaxel. The TTP was 23 weeks in the current study, compared with 26 weeks in the study by Chan et al. [6].
Paclitaxel shares a similar cytotoxic mechanism with docetaxel and is active against a similar spectrum of malignancies. Dose escalation of paclitaxel in breast and other malignancies has sometimes improved response rates, but without clear improvement in survival or other end points. In a randomised study, Winer et al. [19] assigned 325 women with metastatic breast cancer to paclitaxel 135, 210 or 250 mg/m2 over 3 h. No difference was seen in response rate or overall survival. Similarly, in a study of 471 women randomised to paclitaxel 135 or 175 mg/m2 over 3 h, no significant difference in response rate or survival was seen [20]. In ovarian cancer, increases in paclitaxel dose from 135 to 175 mg/m2 [21] or 135 to 250 mg/m2 [22] have resulted in small increases in response rate, but no improvement in survival. Likewise, escalation of paclitaxel from 135 to 250 mg/m2, in combination with cisplatin, did not improve response rate or survival in patients with non-small-cell lung cancer [23].
Previous studies have reported mobilisation of PBSC using docetaxel 100 mg/m2 [24, 25] or 100120 mg/m2 [26] along with G-CSF 10 µg/kg/day. In a study of docetaxel 100 mg/m2 and G-CSF 10 µg/kg/day, the kinetics of PBSC mobilisation were similar to the current study, with peak CD34+ cell levels occurring on days 8 and 9 [24]. In the current study, 80% of patients achieved a peak CD34+ cell level >2 x 104/ml, a level that is associated with sufficient PBSC collection at leukapheresis [11, 12]. Peak levels of GM-CFC and BFU-E were similar to those obtained from our institution following cyclophosphamide 2 g/m2 and G-CSF as a mobilising regimen, using the same techniques in the same laboratory (data not shown).
In this study of patients with breast cancer treated first-line, docetaxel 160 mg/m2 was safely delivered every 3 weeks with G-CSF support. Febrile neutropenia was infrequent, but non-haematological toxicities, especially peripheral oedema and asthenia, were significant for some patients. The response rate of 37.5% was less than that seen in phase II and III studies of standard-dose 3-weekly docetaxel given first-line. These results suggest that escalation of the dose of docetaxel to 160 mg/m2 using this schedule is unlikely to improve patient outcomes.
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Acknowledgements |
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FOOTNOTES |
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