1 University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven; 2 H. Hartziekenhuis Hospital, Roeselare, Belgium; 3 University Hospital of Heraclion, Crete, Greece; 4 University of Graz, Graz, Austria; 5 University Hospital of Gent, Gent, Belgium; 6 University of Vienna, Vienna; 7 General Hospital Salzburg, Salzburg, Austria; 8 Academic Hospital Groningen, Groningen, The Netherlands; 9 Aventis Pharma Inc., Antony, France
Received 15 May 2002; revised 7 October 2002; accepted 30 October 2002
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Abstract |
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This phase II study evaluated the feasibility and efficacy of alternating and sequential regimens of docetaxel and doxorubicin as first-line chemotherapy for metastatic breast cancer (MBC).
Patients and methods:
Women with MBC requiring first-line chemotherapy for progressive disease (n = 106) were randomized and received 3-weekly monotherapy with docetaxel (T, 100 mg/m2, 1-h i.v. infusion) and doxorubicin (A, 75 mg/m2, 2030-min i.v. infusion) either on a cycle-by-cycle alternating basis (ATATATAT, n = 51) or sequentially each for four cycles (TTTTAAAA, n = 55).
Results:
For both regimens, the median number of cycles administered was the maximum of eight. The alternating and sequential groups achieved similar objective tumor response rates (60% and 67%, respectively) and similar median duration of response (47 and 44 weeks, respectively). With a median follow-up of 31 months, median survival times were estimated at 20 and 26 months in the alternating and sequential groups, respectively. No unexpected toxicities were reported. Compared with alternating therapy, patients receiving sequential therapy were more likely to complete the planned eight chemotherapy cycles (69% versus 63%), and had a lower incidence of febrile neutropenia (2% versus 14%).
Conclusions:
Alternating and sequential docetaxeldoxorubicin regimens are viable alternatives to simultaneous combination therapy in MBC, with sequential therapy achieving slightly higher response rates and improved tolerability compared with alternating therapy.
Key words: alternating, breast cancer, chemotherapy, docetaxel, doxorubicin, sequential
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Introduction |
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The taxanes, paclitaxel and docetaxel, are a newer class of chemotherapeutic agents that block tubulin depolymerization and thereby disrupt mitosis. They are among the most active cytotoxic agents available for the treatment of MBC [6] and have already led to improved therapeutic results in this disease, both in the palliative and adjuvant settings [713]. Docetaxel (Taxotere®), a semi-synthetic taxoid, has produced impressive response rates (4868%) as single-agent first-line chemotherapy for MBC [12, 1416], and achieved the highest activity, to date, in women with disease resistant to anthracyclines [1719]. Furthermore, in patients with prior exposure to alkylating-agent-based chemotherapy, docetaxel 100 mg/m2 was shown to produce statistically superior response rates compared with doxorubicin 75 mg/m2 (48% versus 33%; P = 0.008) [16].
To further improve response rates and time to progression, combination regimens based on docetaxel and anthracyclines are being evaluated [2022]. For example, in a phase II study, first-line docetaxel and doxorubicin combination therapy produced a high objective response rate of 76% [21]. However, to date, the best strategy for combining taxanes and anthracyclines (i.e. sequential versus concomitant versus alternating) has not been established by a single completed phase III study in patients with MBC, although this is an area of active investigation [2325].
Doses in combination regimens are generally limited by the combined toxicity profiles of the agents. The recommended combination doses for docetaxel and doxorubicin of 75 mg/m2 and 50 mg/m2, respectively, are somewhat lower than those recommended for single-agent chemotherapy (100 mg/m2 and 75 mg/m2, respectively), and have been defined based on grade 3 infection (the dose-limiting toxicity for this combination). Alternative strategies to deliver high doses of multiple chemotherapeutic agents in women with MBC are therefore currently being explored. Goldie and Coldman hypothesized that, since treatment failure is largely due to resistance to chemotherapy, and resistance develops by spontaneous random mutation at a rate proportional to the number of dividing cells, administering high doses of chemotherapy would rapidly reduce the number of dividing cells, thereby preventing resistance [26, 27]. Alternating high doses of non-cross-resistant agents on a cycle-by-cycle basis would minimize the emergence of double resistance.
A second strategy is to administer multiple agents sequentially. A model proposed by Norton and Simon argued that rate of tumor regression is directly related to tumor growth rate [28, 29], and that in a heterogeneous tumor, faster dividing cell populations would regress more quickly in response to chemotherapy than slower dividing cell populations. Norton and Simon hypothesized that the best management strategy would be to treat the faster dividing cell populations first, and then the slower dividing cell populations. This would be accomplished most efficiently by sequential chemotherapy with multiple cycles of one agent followed by multiple cycles of a second agent devoid of cross-resistance with the first. Support for sequential chemotherapy can be found in a randomized study conducted in women with breast cancer who had more than three positive lymph nodes. The study found that patients receiving sequential doxorubicin then CMF (cyclophosphamide, methotrexate and 5-fluorouracil) had significantly (P = 0.002) improved survival and relapse-free survival rates 10 years post-surgery compared to those treated with alternating doxorubicin and CMF [4].
In this paper, we report the results of an open-label randomized phase II study conducted to evaluate the feasibility, activity and tolerability of alternating and sequential regimens of docetaxel and doxorubicin administered as first-line chemotherapy for MBC.
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Patients and methods |
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Inclusion/exclusion criteria
The study was open to women aged 1875 years with histologically or cytologically proven breast cancer requiring first-line chemotherapy for progressive metastatic disease. Patients with a single metastatic lesion required histological or cytological proof of metastasis at study entry. Further inclusion criteria were: at least one bidimensionally measurable lesion, World Health Organization (WHO) performance status 2, normal hematology values (neutrophils
2 x 109/l, platelets
100 x 109/l, hemoglobin
10 g/dl), normal hepatic function [total bilirubin
1.25 times the upper limit of the institutional normal range (N), alanine and aspartate aminotransferases
2.5N, alkaline phosphatase
5N], normal renal function (creatinine
140 µmol/l and creatinine clearance
60 ml/min), and normal cardiac function as confirmed by measurement of left ventricular ejection fraction (LVEF) by echography or MUGA scan.
Patients were excluded if they had previously received chemotherapy for metastatic disease. Neoadjuvant or adjuvant chemotherapy was permitted, although prior anthracyclines were allowed only if the cumulative dose of doxorubicin or anthracycline equivalent was 240 mg/m2 and a 12-month interval had elapsed since the last anthracycline adjuvant dose. Prior taxane treatment was not permitted. Hormonal therapy may have been given as adjuvant therapy or for metastatic disease provided the patient had progressive disease on study entry. Radiation therapy was allowed at sites other than those used to assess response in the study, provided a 4-week interval had elapsed since the last session. Patients must have fully recovered from any toxic effects of previous antitumor therapy.
Further exclusion criteria were a history of prior malignancies (other than curatively treated non-melanoma skin cancer or excised carcinoma in situ of the uterine cervix), known brain or leptomeningeal involvement, symptomatic grade 2 peripheral neuropathy, or a history of other serious illnesses or medical conditions.
Treatment schedule
Prior to randomization, which was conducted centrally using a block design method, patients were stratified for visceral involvement. Patients were randomized on study entry to receive either (i) alternating doxorubicin (A) and docetaxel (T) on a cycle-by-cycle basis for eight cycles (ATATATAT) or (ii) sequential administration of docetaxel for four cycles followed by doxorubicin for four cycles (TTTTAAAA). Docetaxel was given at 100 mg/m2 by 1-h i.v. infusion. Doxorubicin was given at 75 mg/m2 by 2030-min i.v. infusion. Eight cycles were administered (unless progression or unacceptable toxicity occurred earlier), one every 3 weeks. All patients received prophylactic oral dexamethasone (8 mg) at 13, 7 and 1 h before, and 12, 24 and 36 h after each docetaxel infusion.
Patients who experienced febrile neutropenia (grade 4 neutropenia with grade 2 fever requiring i.v. antibiotics and/or hospitalization), grade 4 neutropenia lasting >7 days or a documented infection were given prophylactic lenograstim [granulocyte colony-stimulating factor (G-CSF)] in subsequent cycles: 150 µg subcutaneously daily from the day following chemotherapy until neutrophils rose to >1 x 109/l. In cases of febrile neutropenia developing in the next cycle (despite the prophylactic measure), and/or important non-hematologic toxicities (see below), dose reductions were planned: docetaxel was reduced to 75 mg/m2 and then, if necessary, to 55 mg/m2; doxorubicin was reduced to 60 mg/m2 and then, if necessary, to 50 mg/m2. If, at scheduled retreatment time, neutrophils were <1.5 x 109/l or platelets were <100 x 109/l, the next chemotherapy cycle was delayed for up to 2 weeks until recovery; patients who did not recover within this period were removed from the study.
Standard anti-emetic and antidiarrhea therapy was allowed on a prophylactic or treatment basis, as needed. Patients who, nevertheless, developed grade 3/4 nausea, vomiting or severe mucositis underwent dose reduction in the next cycle (as described above). For other grade 3 toxicity (except alopecia and anemia), treatment was generally delayed until recovery to grade 1 (maximum 2 weeks) and restarted at a lower dose (de-escalation scheme described above). Patients with grade 3/4 peripheral neuropathy or other grade 4 toxicity (except alopecia and anemia) were withdrawn from the study.
Patients in the alternating arm who progressed after the first cycle (doxorubicin) received salvage treatment with single-agent docetaxel, and those who progressed after the second cycle (docetaxel) received further chemotherapy at the discretion of the investigator. In the sequential arm, patients who developed unacceptable toxicity or refused treatment during the first part of treatment (docetaxel) could proceed to the second part of treatment (doxorubicin) provided all acute toxicity had reversed.
Efficacy and safety evaluations
Baseline and study evaluations included medical history, physical examinations, radiology assessments (including homolateral mammography, chest X-ray or CT scan, abdominal ultrasound or CT scan, bone scan, and other examinations as clinically indicated), complete blood counts, assessments of liver and renal function, and cardiac monitoring by LVEF. LVEF was determined by MUGA scan or echocardiography. Tumor measurements were made at least every two cycles and responses were classified according to WHO/UICC criteria [30]. A complete response (CR) was defined as disappearance of all known disease, while a partial response (PR) was a 50% decrease in the size of all lesions. Complete and partial responses had to be confirmed at two evaluations not <4 weeks apart. Progressive disease (PD) was defined as a
25% increase in the size of at least one measurable lesion or the appearance of a new lesion. Responses were reviewed by two independent radiologists.
Patients were asked to report the occurrence of any adverse event to the investigator and were monitored at least every 3 weeks (on the day before study drug infusion) for clinical and laboratory toxicity. The incidence of neuropenia was evaluated at nadir. Toxicity was graded according to National Cancer Institute Common Toxicity Criteria [31]. Complete blood counts were made weekly or every day in cases of febrile neutropenia or infection until recovery (neutrophils >1 x 109/l and fever grade 0/1). LVEF was monitored after a cumulative 300 mg/m2 dose of doxorubicin or anthracycline equivalent, and before every cycle on reaching a cumulative dose of 450 mg/m2. Irrespective of the reason for discontinuation, all patients were to be monitored during the first month after the last study drug infusion and followed up every 2 months until death to monitor tumor progression and survival.
Statistical analysis
The primary end point was determination of CR rates. Comparison of the safety profiles of the two schedules was also considered a major end point. Secondary end points were overall response rates, duration of response, time to progression, and survival. The planned sample size of 41 patients per arm was determined according to Flemings two-stage design. It was assumed that neither treatment schedule would be of further interest if the CR rate was <5%. The sample size allowed for testing of the Null hypothesis (H0; the true CR rate is <5%) versus the Alternative hypothesis (HA; the true CR rate is >20%). As observation of a significant difference in CR rate was considered unlikely (due to the sample size), the safety comparison would assist in determining which of the two schedules would be of further interest.
Efficacy analyses, except survival, were performed on evaluable populations (patients who received at least two chemotherapy cycles and had at least one complete post-baseline tumor assessment). The overall survival analysis was performed on the intention-to-treat population [patients who had started at least one infusion of the study drug(s)]. KaplanMeier estimation was performed for duration of response, time to progression and survival. The duration of objective response was calculated in complete and partial responders from the start of study treatment to the time of first progression. The time to progression was determined in all patients from the start of study treatment to the time of first progression, last contact or further treatment. Survival was dated from the start of study treatment to the time of death by any cause. In case of further antitumor treatment before disease progression, time to progression was censored at the date of the last tumor assessment.
All treated patients were included in the safety analyses. Hematological analyses considered patients with at least one blood count between days 2 and 19.
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Results |
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The two groups had similar demographics and tumor characteristics at baseline (Table 1). In the intention-to-treat population, patients had a median age of 55 years, and 89% were of WHO performance status 0/1. Visceral, liver and bone involvement was reported in 82%, 51% and 47% of patients, respectively. No patients presented only bone lesions. Overall, 39% had received prior neoadjuvant or adjuvant chemotherapy but only three patients had received prior anthracyclines.
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The incidence of grade 4 neutropenia and associated toxicity is summarized in Table 4. The majority of patients (87% overall) experienced grade 4 neutropenia, for a median of 7 days in each group (range 121 days in the alternating group; 114 days in the sequential group). Febrile neutropenia (grade 4 neutropenia concomitant with grade 2 fever) was more common with alternating therapy than with sequential therapy. Infection was rare (six patients had a grade 3 infection; no patient experienced a grade 4 infection). No grade 4 anemia occurred, and only one patient in the alternating group experienced grade 4 thrombocytopenia.
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Discussion |
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The response rates observed in the present study are in line with those reported previously in studies examining the activity of docetaxel and doxorubicin as combination therapy. In phase I/II studies employing a dose of docetaxel 75 mg/m2 and doxorubicin 50 mg/m2, response rates of at least 75% and 2-year survival rates of 50% were achieved, with excellent results observed even in patients who had received prior adjuvant therapy, or who had liver involvement or multiple sites of disease [3234]. Furthermore, results from a recent phase III international study (TAX 306) in women with MBC reported that the combination of docetaxel 75 mg/m2 plus doxorubicin 50 mg/m2 achieved significantly higher response rates (60% versus 47%; P = 0.012) and a significantly longer time to disease progression (P = 0.015) compared with combination therapy with doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 [35]. These results are particularly impressive considering that the doxorubicin dosage was 20% lower in the docetaxel arm than in the cyclophosphamide arm.
The response rates achieved in the present trial with sequential and alternating docetaxeldoxorubicin regimens also compare favorably with those achieved with other anthracycline-containing combination regimens commonly used in women with first-line MBC [3638]. However, in the absence of a well-designed phase III study of sequential and alternating docetaxeldoxorubicin therapy, caution must be employed when comparing the results of the present study with those obtained with other treatment regimens and strategies.
By adopting a sequential or alternating strategy, we were able to use the highest feasible dosages of docetaxel and doxorubicin recommended for single-agent chemotherapy (100 mg/m2 and 75 mg/m2, respectively), without any apparent cumulative dose-limiting toxicity. Indeed, the median number of chemotherapy cycles administered was the intended maximum of eight, and the overall median dose intensity was high in both groups. The sequential regimen appeared to be better tolerated than the alternating regimen, with slightly more patients in this group completing the planned eight chemotherapy cycles (69% versus 63%). As expected, the majority of patients experienced grade 4 neutropenia. However, in common with previous studies of single-agent docetaxel chemotherapy [1216] and combination docetaxel and doxorubicin chemotherapy [21], neutropenic episodes were usually short-lived and recovery to grade 0/1 was generally in time for the next cycle. Febrile neutropenia occurred more frequently in patients belonging to the alternating group than in those from the sequential group (14% versus 2%), although the incidence was considerably lower than that previously observed with doxorubicindocetaxel combination chemotherapy (36%) [21]. From the first cycle, no patient required G-CSF treatment.
Both regimens in this study also had good non-hematological toxicity profiles. Severe adverse events were rare in both groups and there were no unexpected adverse events. Only one case of severe fluid retention was noted, and did not result in discontinuation of therapy. There were no clinical episodes of heart failure in the study, and asymptomatic absolute LVEF decreases of 10% were relatively uncommon (<8% of patients), despite a cumulative doxorubicin dose of 294 mg/m2 and 300 mg/m2 in the alternating and sequential groups, respectively. This finding is particularly encouraging given that paclitaxel (given by short infusion) reduces liver clearance of doxorubicin, increasing doxorubicin exposure and thereby leading to high levels of congestive heart failure (>20% in phase II trials). In contrast, docetaxel does not appear to have any effect on doxorubicin pharmacokinetics or augment anthracycline cardiotoxicity [35].
After the initiation of this study, several other phase I/II studies evaluating the efficacy and feasibility of sequential administration of docetaxel and doxorubicin as neoadjuvant or adjuvant therapy in women with breast cancer have been reported [3942]. Khayat et al. [42] found that administration of four cycles of docetaxel (100 mg/m2 every 3 weeks) followed by four cycles of doxorubicin and cyclophosphamide (60/600 mg/m2 every 3 weeks) resulted in a 71% overall response rate, with a median duration of response of 53 weeks. Another study of neoadjuvant therapy with sequential doxorubicin 75 mg/m2 then docetaxel 100 mg/m2 each for three cycles versus combination docetaxel 56 mg/m2 and doxorubicin 75 mg/m2 for four cycles found both regimens to be well tolerated and produce a high objective response rate (89% and 81%, respectively) [41]. Cresta et al. [25] recently reported results from a randomized phase II study that compared alternating, sequential and simultaneous combination of docetaxel and doxorubicin as first-line chemotherapy in 121 patients with MBC. The overall response rate (57%, 67% and 66%, respectively) and time to disease progression (34, 33 and 36 weeks, respectively) were similar across all three treatment arms. Interestingly, the response rate for the sequential arm is identical to that obtained in the sequential arm of our study (67%), and further mirrors the present study in that it was slightly higher than the rate obtained for the alternating arm (60% for the current study and 57% for the study of Cresta et al. [25]). Febrile neutropenia (22%), grade 34 infections (2%) and grade 34 stomatitis (12%) were more common with the combination regimen. In addition, four episodes of congestive heart failure occurred in the combination arm, attributed to the higher cumulative dose of doxorubicin (480 mg/m2). Cresta et al. concluded that either the sequential or alternating schedules were viable first-line treatments for MBC [25]. A number of randomized phase III trials are now underway to further define the role of sequential docetaxeldoxorubicin chemotherapy in early breast cancer patients, and their results are eagerly awaited.
In conclusion, the efficacy and tolerability of simultaneous combination therapy with docetaxel plus doxorubicin in MBC is well established. The present phase II study suggests that alternating and sequential regimens of these two cytotoxic agents are viable alternatives to simultaneous combination therapy in this setting, with the sequential regimen achieving slightly higher response rates and improved tolerability compared with the alternating regimen. Phase III studies are warranted to validate these findings.
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Acknowledgements |
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Footnotes |
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References |
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