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Dose-Escalation Study of Docetaxel in Combination With Mitoxantrone as First-Line Treatment in Patients With Metastatic Breast Cancer

From the Departments of Medical Oncology and Biostatistics, School of Medicine, University of Crete, Heraklion, Crete, Greece.

Address reprint requests to Vassilis Georgoulias, MD, Department of Medical Oncology, University General Hospital of Heraklion, P.O. Box 1352, 711.10 Heraklion, Crete, Greece; email georgsec@ danae.med.uch.gr.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To define the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of docetaxel in combination with mitoxantrone in patients with metastatic breast cancer (MBC).

PATIENTS AND METHODS: Forty-one chemotherapy-naive patients with MBC (median age, 61 years) were enrolled. Thirty-eight (93%) had performance status (World Health Organization [WHO]) 0, 29 (71%) were postmenopausal, and 21 (51%) had estrogen receptor–negative tumors. Patients received escalated doses of docetaxel (75 to 100 mg/m²) on day 1 and mitoxantrone (8 to 22 mg/m²) on day 8. Treatment was repeated every 3 weeks.

RESULTS: A total of 217 chemotherapy cycles were administered. Without recombinant human granulocyte colony-stimulating factor (rhG-CSF) support, the MTD1 occurred at the first dose level (docetaxel 75 mg/m² and mitoxantrone 8 mg/m²); DLTs were febrile neutropenia, grade 4 neutropenia lasting more than 5 days, and grade 3 diarrhea. With prophylactic rhG-CSF, the MTD2 was docetaxel 100 mg/m² and mitoxantrone 20 mg/m²; DLTs were febrile neutropenia and grade 4 neutropenia. Nine (22%) patients developed neutropenia after the first cycle of treatment. A total of 19 episodes of febrile neutropenia (9% of the cycles) occurred during the whole period of the study; there were no toxic deaths. At high docetaxel (100 mg/m²) and mitoxantrone (> 12 mg/m²) dose levels, a significant decrease of the absolute lymphocyte number was observed; immunophenotyping revealed that all lymphocyte subpopulations were reduced. Grades 2 and 3 neurosensory toxicity occurred in six patients (15%) and one patient (2%), respectively. No cardiac toxicity was observed. Nine complete responses (22%) and 23 partial responses (56%) were achieved (overall response rate, 78%; 95% confidence interval, 62.5% to 88.8%). The median duration of response was 12.5 months, and the median time to tumor progression was 14.5 months.

CONCLUSION: The reported combination of docetaxel and mitoxantrone with G-CSF support is a safe, intensified, well-tolerated, and effective regimen as first-line treatment in patients with MBC.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
DOSE AND SCHEDULE optimization are of great importance for the effectiveness of chemotherapy in metastatic breast cancer (MBC). Goldie and Coldman¹ proposed that chemotherapy-sensitive tumor cells become therapy-resistant through spontaneous somatic mutations, with a predictable frequency of one mutation per 10⁵ to 10⁶ cells. In addition, it was shown that some malignant cells are genetically more unstable than normal cells and give rise to various sublines resistant to treatment.² Both in vitro and in vivo studies suggest that drug resistance can be overcome by increasing the dose of the cytotoxic drugs.^3-7 However, other studies from the adjuvant setting of breast cancer have shown that increasing the dose-intensity or the total dose of cytotoxic drugs has failed to produce superior results.^8,9 Furthermore, the high-dose regimens have to be supported with hematopoietic growth factors, autologous bone marrow transplantation (ABMT), or peripheral-blood stem-cell (CD34⁺) transfusions.

Taxanes (paclitaxel and docetaxel) are the most active new drugs as first-line chemotherapy in patients with MBC; an overall response rate (ORR) ranging from 32% to 62% and a median response duration ranging from 7 to 16.4 months have been reported.^10-17 Taxanes also lack complete cross-resistance with anthracyclines.^18-21 Phase II studies have demonstrated that paclitaxel^22-24 and docetaxel²⁵ can be efficiently combined with anthracyclines to produce responses in 70% and 90% of patients, respectively. However, the combination of paclitaxel and doxorubicin is complicated by a relatively high incidence of cardiotoxicity.^22-24

Mitoxantrone is an anthracenedione that is structurally related to doxorubicin but lacks an aminosugar moiety. As first-line chemotherapy in patients with MBC, single-agent mitoxantrone showed 13% to 51% objective responses with a median duration of 2 to 39 months.^26,27 In addition, in vitro studies have revealed that mitoxantrone has a steeper dose-response effect than doxorubicin.²⁸ Randomized trials comparing mitoxantrone with doxorubicin, used either as single agents or in combination with cyclophosphamide and fluorouracil, failed to reveal statistically significant differences in the response rate (RR), response duration, time to tumor progression (TTP), and overall survival.^29,30 Only one study demonstrated a statistically significant difference in the ORR and overall survival in favor of doxorubicin-treated patients.³¹ However, in all of these studies, the mitoxantrone-based regimens had a significantly better toxicity profile than the doxorubicin-based regimens, especially in terms of alopecia, nausea, vomiting, and cardiomyopathy.^29-32

There is substantial evidence of a dose-response relationship in MBC.^33,34 Because of its favorable toxicity profile and the promising in vitro dose-response effect, mitoxantrone is frequently incorporated in high-dose chemotherapy regimens supported by either ABMT or peripheral-blood stem-cell transfusions.^7,35

We report here the results of a dose-finding trial for the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of an administration schedule of docetaxel and mitoxantrone given on days 1 and 8, respectively, every 3 weeks. This schedule was chosen for the following two reasons: (i) our intention was to administer the two drugs at their MTDs without ABMT or peripheral-blood stem-cell support; and (ii) in a pilot study, mitoxantrone (8 mg/m²) was administered on day 1 and docetaxel (75 mg/m²) on day 2 in six patients; all patients developed grade 4 neutropenia and/or febrile neutropenia. The prophylactic use of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in another three patients did not allow dose escalation because all patients developed DLTs. Finally, because previous studies have shown that treatment with taxanes is associated with decreased CD4⁺ cells,^36,37 an analysis of the absolute lymphocyte number and their phenotype was incorporated into the study.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection
Patients with histologically confirmed stage IV breast cancer were enrolled. Adjuvant chemotherapy was allowed, but disease recurrence had to have occurred at least 12 months after its completion and the received cumulative doxorubicin dose had to be less than 300 mg/m². No prior chemotherapy for metastatic disease was allowed. Other inclusion criteria were as follows: age 18 to 75 years; a World Health Organization (WHO) performance status (PS) of 0 to 2; measurable disease; a life expectancy of at least 3 months; adequate hematologic parameters, including an absolute neutrophil count (ANC) of more than 1,500/dL, a hemoglobin level of more than 8/dL, and a platelet count of more than 100,000/dL; and adequate hepatic (serum bilirubin, < 1.5 mg/dL), renal (serum creatinine, < 1.5 mg/dL), and cardiac (left ventricular ejection fraction [LVEF], 50%) function. Patients with brain metastases were eligible if they had been irradiated, the brain lesions were radiographically stable, and clinical improvement was evident. Patients were not eligible if they had a history of heart failure, uncontrolled angina, or coronary insufficiency in the past 6 months. Other exclusion criteria were radiation therapy within 4 weeks before initiation of treatment, irradiation of more than 25% of the bone marrow–containing bones,³⁸ severe infection or malnutrition, and the presence of a second primary tumor. The study was approved by the ethical and scientific committees of University General Hospital of Heraklion. All patients gave written informed consent and were registered with a central data management office.

Treatment
Docetaxel (Taxotere; Rhone-Poulenc Rorer, Collegeville, PA) in 150 mL of normal saline was administered as a 1-hour infusion on day 1. All patients received a standard premedication regimen with oral dexamethasone 12 hours and 4 hours before docetaxel administration and for 3 days after treatment.³⁹ Mitoxantrone (Novantrone; Lederle-Wyeth, Indianapolis, IN) in 50 mL of normal saline was administered as a 15-min infusion on day 8. All patients received standard antiemetic treatment with ondansetron (16 mg intravenously before the administration of cytotoxic drugs, and 8 mg orally for 2 consecutive days after chemotherapy). Treatment was given on an outpatient basis and was repeated every 3 weeks if the ANC was greater than 1,500/dL and the nonhematologic toxicities, except alopecia, had been resolved. The starting dose level for docetaxel was 75 mg/m², escalated by increments of 25 mg/m² to 100 mg/m²; the starting dose for mitoxantrone was 8 mg/m², escalated by increments of 2 mg/m² to 22 mg/m². There was no intrapatient escalation, and at least three patients were treated at each dose level. The DLT was defined as the occurrence of one of the following: grade 4 neutropenia or thrombocytopenia lasting more than 5 days; ANC less than 1,000/dL and temperature higher than 38.5°C for more than 48 hours (febrile neutropenia); and any grade 3 or higher nonhematologic toxicity, except alopecia, nausea, and vomiting. The dose level at which grade 4 neutropenia lasting more that 5 days or febrile neutropenia occurred was repeated, with prophylactic administration of rhG-CSF (5 µg/kg/d subcutaneously; Granocyte; Rhone-Poulenc Rorer) from day 2 to day 6 and from day 9 to day 19. The MTD was defined as the dose at which two or more out of three patients or three or more out of six patients developed DLT. The recommended dose for further studies was defined as one dose level below the dose that caused DLT.

Dose-adjustment criteria were as follows: The docetaxel dose was reduced by 20% in subsequent cycles in case of grade 3 or 4 neutropenia occurring from day 2 to day 8 of the cycle; a similar dose reduction for mitoxantrone was performed in patients with grade 3 or 4 neutropenia occurring from day 9 to day 20. In addition, grade 3/4 thrombocytopenia, grade 2 or higher mucositis, and febrile neutropenia necessitated a 20% dose reduction of both drugs. A 25% reduction of the docetaxel dose was performed in cases of grade 2/3 diarrhea.

Patient Evaluation
Baseline evaluations included the following: patient history, physical examination, chest x-rays, complete blood count with differential and platelet count, blood chemistry, ECG, and echocardiography or multigated angiogram scan with LVEF measurement. Computed tomography scans of the chest, abdomen, pelvis, and brain were performed when clinically indicated. Complete blood counts with differential and platelet counts were performed twice weekly or daily in patients with grade 3/4 neutropenia or thrombocytopenia or febrile neutropenia; blood chemistry analyses and physical examinations were performed every 3 weeks. Toxicities were recorded according to the WHO criteria.⁴⁰ Cardiac monitoring consisted of pertinent history, physical examination, and ECG every 3 weeks; echocardiograms or multigated angiogram scans were performed after the third and the sixth chemotherapy cycles and then every 3 months, for a maximum of 9 months after treatment completion.

Responses were evaluated according to WHO response criteria.⁴⁰ Patients were evaluated before each cycle for lesions assessable by physical examination or chest x-rays; otherwise, response to treatment was evaluated by imaging studies after every three chemotherapy cycles. Patients who achieved a complete response (CR) received three additional cycles of chemotherapy; patients with a partial response (PR) or stable disease received a maximum of six chemotherapy cycles. Patients who experienced progressive disease during the treatment were withdrawn from the study.

Immunofluorescence Studies
Peripheral blood (5 ml) in EDTA was obtained before treatment and on day 1 of the second cycle before chemotherapy administration for phenotypic analysis of lymphocytes. The manufacturer's recommended volumes of the appropriate monoclonal antibodies (mAbs) were aliquoted in individual tubes. One hundred microliters of peripheral blood were added directly to each tube, vortexed, and incubated for 20 minutes at 4°C. After the addition of fluorescent-activated cell-sorting lysing solution (Immunoprep kit; Coulter, Miami, FL), samples were washed twice with phosphate-buffered saline containing azide (0.1% v/v) and stored in phosphate-buffered saline containing paraformaldehyde (1% v/v). Cells were stained with the following mAbs: anti-CD3 (IOT3), anti-CD4 (IOT4), anti-CD8 (IOT8), anti-CD20 (IOT20), and anti-CD56 (IOT56). Irrelevant murine mAbs of the immunoglobulin (Ig) G1, IgG2a, and IgG2b subclasses were used to define background staining of negative controls. All mAbs were coupled with fluorescein isothiocyanate and obtained from Immunotech (Lumigny, France). Flow cytometry analysis was performed on an Elite scan apparatus (Coulter) equipped with Elite Software 4.1. A minimum of 10,000 cells, contained within the lymphocyte gate, were analyzed. A control sample obtained from normal blood donors was also analyzed concurrently with each experimental sample.

Statistical Analysis
The duration of response was measured from the first documentation of response to disease progression. Overall survival was measured from study entry to death. Actuarial probability of survival was estimated using the Kaplan-Meier method.⁴¹ Qualitative factors were compared by the Pearson's ² contingency table analysis,^42,43 and confidence intervals for RRs were calculated using methods for exact binomial confidence intervals.⁴⁴

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
A total of 41 patients with MBC were enrolled onto the study, and their characteristics are listed in Table 1. The median age was 61 years, and 38 patients (93% ) had PS 0; twenty-nine patients (71%) were postmenopausal and 21 patients (51%) had estrogen receptor–negative tumors. Twenty-one patients (51%) had not received prior chemotherapy, whereas 11 patients (27%) had received prior adjuvant chemotherapy with a doxorubicin-containing regimen (cyclophosphamide, doxorubicin, and fluorouracil). Twenty-nine (71%) patients had visceral metastases.

Dose Escalation
Table 2 shows dose-limiting events observed during dose escalation. At dose level 1, four out of six patients developed DLTs (febrile neutropenia, one patient; grade 4 neutropenia, two patients; grade 4 neutropenia associated with grade 3 diarrhea, one patient), which indicates that at this dose level, without G-CSF support, the MTD1 of the combination was reached. The addition of rhG-CSF permitted the dose escalation of docetaxel to 100 mg/m² and of mitoxantrone to 22 mg/m². At this dose level, three out of five patients developed DLTs (febrile neutropenia, one patient; grade 4 neutropenia lasting more than 5 days, two patients; Table 2), which indicates that the MTD2 was reached. Therefore, the recommended dose for further phase II studies was docetaxel 100 mg/m² on day 1 and mitoxantrone 20 mg/m² on day 8 with rhG-CSF support.

Hematologic Toxicity
A total of 217 chemotherapy cycles were administered, and toxicity data were available from all cycles. Patients received a median of five chemotherapy courses (range, one to nine), and 13 patients (32%) received a median of six or more (range, six to nine). The median cumulative dose administered was 53 mg/m² (range, 10 to 171 mg/m²) for mitoxantrone and 450 mg/m² (range, 74 to 818 mg/m²) for docetaxel. Four patients discontinued treatment after the first course because of toxicity and one because of deterioration of PS. Myelosuppression was dose limiting at all dose levels. Six (15%) and nine (22%) patients developed grade 3 and 4 neutropenia, respectively, after the first cycle of treatment (Table 3); three of them (8%) developed febrile neutropenia requiring hospitalization. All patients were treated uneventfully, with a median duration of hospitalization of 3 days (range, 3 to 5 days). In addition, 16 second or subsequent chemotherapy cycles, corresponding to six patients (15%), were complicated by grade 4 neutropenia and fever (a total of 19 febrile episodes [9%] during the whole study period; Table 4 ). There were no toxic deaths caused by sepsis. Table 4 also shows that reductions in docetaxel and mitoxantrone dose due to neutropenia were required in 50 (23%) and 31 (14%) of the cycles, respectively. In 15 cycles (7%), docetaxel was reduced after the first cycle, whereas in the remaining 35 cycles (16%), it was reduced after the second or subsequent chemotherapy cycles. Similarly, in 14 cycles (6%), mitoxantrone was reduced after the first cycle, whereas in 17 cycles (8%), it was reduced after the second or subsequent cycles. Hematologic toxicity was not cumulative (Table 4).

Analysis of the absolute lymphocyte number (ALN) demonstrated a significant reduction of the ALN after the third dose level. The phenotypic analysis of peripheral-blood lymphocytes on day 0 and day 22 also revealed a significant decrease of CD3⁺ cells at dose levels 4, 5, 6, and 9; CD4⁺ cells at dose levels 4, 5, and 9; CD8⁺ cells at dose levels 4, 5, 6, and 9; CD20⁺ at dose levels 4, 5, 6, 7, and 9; and CD56⁺ at dose levels 4, 5, 6, and 7. For example, at dose level 9, the phenotypic analysis on days 0 and 22 revealed CD3⁺ cells (1,304 ± 101 v 352 ± 386; P < .001), CD4⁺ cells (774 ± 75 v 186 ± 199; P < .01), CD8⁺ cells (490 ± 75 v 176 ± 214; P < .05), and CD20⁺ cells (202 ± 84 v 42 ± 35; P < .01).

Seventeen (8%) and 74 (34%) cycles required treatment delays at day 1 and day 8 of the cycle, respectively. The reasons for these delays were neutropenia (81 cycles), thrombocytopenia (five cycles), diarrhea (two cycles), allergic reaction (two cycles), and nonneutropenic infection (one cycle). In all cases, symptoms were resolved within 5 days from the planned day of chemotherapy and treatment was continued uneventfully. There was no significant difference in the time intervals between cycles for the different dose levels (Table 4); however, at some dose levels, the intervals between cycles were prolonged for some days (ie, dose levels 3 and 8; Table 4). Because treatment delays at day 1 resulted in dose reductions for mitoxantrone and delays at day 8 caused reductions for docetaxel, overall, docetaxel and mitoxantrone could be given at the planned doses and scheduled intervals in 77% and 86% of the courses, respectively.

Cardiac Toxicity and Other Nonhematologic Toxicities
The median LVEF was 58% at baseline (range, 54% to 67%), 55% after three courses (n = 32; range, 52% to 65%), and 53% after six courses (n = 29; range, 51% to 59%). No patient developed clinical congestive heart failure or had to be removed from the study because of decreased LVEF less than 50%.

Nonhematologic toxicity was relatively mild (Table 5). Severe alopecia was observed in almost all patients. Grade 2 nausea and vomiting was reported in 15 patients (36%) and grade 2 mucositis in 13 (32%). Grade 3 diarrhea occurred in four patients (10%) (one episode occurred during the first cycle). Grades 2 and 3 neurosensory toxicity were observed in six patients (15%) and one patient (2%), respectively; neurotoxicity seemed to be cumulative because it was always observed after the third cycle of treatment. Moderate and severe fatigue occurred in nine (22%) and three (7%) patients, respectively. Mild peripheral edema occurred in five patients (12%), but it was easily manageable with oral diuretics. The low incidence of peripheral edema was observed despite the median cumulative docetaxel dose of 450 mg/m², probably because of the prophylactic use of dexamethasone. Moderate and severe nail modifications were observed in 10 (24%) and three (7%) patients, respectively; severe nail changes were associated with complete and painful nail destruction. This onycholysis was reversible 2 to 3 months after the discontinuation of docetaxel. Hypersensitivity reactions in the form of localized or generalized skin rash occurred in 15 patients (36%) during docetaxel infusion; these reactions were relatively severe in five patients (12%) who experienced chest tightness and/or shortness of breath that required stopping the infusion and administration of corticosteroids before restarting the infusion. In all patients, treatment was reinstituted a few hours later without additional problems.

Response to Treatment and Survival
All patients were assessable for response. CR was documented in nine patients (22%) and PR in 23 (56%) for an ORR of 78% (95% confidence interval, 62.5% to 88.8%). Stable disease and progressive disease were observed in five (12%) and four (10%) patients, respectively. Responses were observed mainly during the first three chemotherapy courses, but three patients with PR by the third cycle experienced a CR by the sixth cycle. Responses were observed at all dose levels (RR according to tumor localization was 89% for locoregional tumors, 80% for lymph nodes, 64% for lung tumors, 67% for liver tumors, and 57% for pleural tumors). The median duration of response was 12.5 months (range, 1 to 19.5 months), and the median TTP was 14.5 months (range, 2.5 to 21.5 months). After a median follow-up of 18 months (range, 2 to 21.5 months), 12 patients (29%) are progression-free and 31 (75.6%) are alive. The median survival time has not yet been reached (range, 2 to 21.5 months).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This dose-finding study is the first reported in the literature to demonstrate that docetaxel can be safely combined with high-dose mitoxantrone in an alternate administration schedule. On the basis of this schedule, the recommended dosages for further phase II studies are docetaxel 100 mg/m² on day 1 and mitoxantrone 20 mg/m² on day 8 with G-CSF support. The main objective of this schedule design was to evaluate the feasibility of an intensified regimen without ABMT or peripheral-blood stem-cell support. Therefore, the initial hypothesis was that administration of docetaxel on day 1 with G-CSF support could permit the recovery of neutropenia in less than 8 days; similarly, the administration of mitoxantrone on day 8 with G-CSF support could permit the recovery of neutrophils in less than 15 days, thus permitting the administration of the next cycle every 3 weeks. In addition, in a pilot study, we observed that the administration of lower doses of mitoxantrone (8 mg/m² on day 1) and docetaxel (75 mg/m² on day 2) with G-CSF support was not feasible because of excessive toxicity. Similarly, mitoxantrone dose escalation above 14 mg/m² could not be achieved when the drug was combined with paclitaxel on the same day.^45,46 Conversely, the alternate schedule, reported in this study, permitted the administration of docetaxel at its MTD,^10,11 whereas mitoxantrone could be administered at a dosage that was 43% to 67% higher than the usual mitoxantrone doses (12 mg/m² to 14 mg/m²) used in combination regimens.^30,32,47,48 Nevertheless, this dose is about 50% lower than the MTD of mitoxantrone when it is used as a single agent with G-CSF support.⁴⁹ Because doxorubicin and mitoxantrone are considered to have an equivalent activity and myelotoxicity at a dose ratio of 5:1, the equivalent dose for doxorubicin would be 100 mg/m², a dose that cannot be given easily because of major and severe adverse events.

The DLT of the present regimen was mainly grade 4 neutropenia occurring in nine (22%) of 41 patients during the first chemotherapy cycle. It is interesting that the incidence of febrile neutropenia was relatively low, occurring in only 8% of the patients during the first cycle of treatment and in 9% of the administered cycles during the whole study period. This may be attributed to the use of G-CSF, the lack of severe mucositis, and the short duration of neutropenic episodes (median, 3 days; range, 3 to 6 days). Although, myelotoxicity was not cumulative, it was the reason for docetaxel and mitoxantrone dose reduction in 20% and 10% of the second and subsequent cycles, respectively. In addition, day 8 was delayed in 34% of the first chemotherapy cycles, whereas day 1 was delayed in 8% of the subsequent cycles. These observations suggest that docetaxel was the main reason of myelotoxicity. Moreover, the pharmacokinetic data of Schiller et al⁴⁹ demonstrated that the mean area under the curve and the peak of mitoxantrone levels are not correlated with the duration of grade 4 neutropenia; this could probably explain the low incidence of mitoxantrone dose reduction and treatment delays on day 1 of the second or subsequent cycles.

It is of interest that the docetaxel-mitoxantrone regimen induced a significant decrease of the ALN at escalated dose levels. The decrease of the ALN was associated with a significant decrease of all lymphocyte subsets, despite the heterogeneity observed at some dose levels. However, since lymphopenia was always observed above the fourth dose level, it is reasonable to assume that it is dose-related; moreover, this observation further excludes the possibility that lymphopenia is due to the prophylactic use of corticosteroids, which was the same at all dose levels. Previous studies have also described important CD4⁺ lymphopenia in patients treated with various types of intensive chemotherapy,⁵⁰ as well as with paclitaxel³⁶ or docetaxel and radiotherapy.³⁷ Therefore, chemotherapy-induced lymphopenia seems to correlate with the intensity of the regimen and is not limited to the administration of taxanes. Additional phenotypic studies of peripheral-blood lymphocytes during the whole period of treatment with the docetaxel-mitoxantrone regimen is needed to define more precisely its long-term effects on lymphocyte subsets. It is obvious that such quantitative lymphocyte abnormalities may have severe consequences for the patient's humoral and cell-mediated immunity, including immunity against cancer; an older study by Hortobagyi et al⁵¹ has demonstrated the prognostic value of delayed-type hypersensitivity responses to common antigens in the survival of patients with MBC.

Nonhematologic toxicity was mild or moderate; neurotoxicity, fatigue, and nail changes, which were the most serious and frequent among the patients' complaints, were cumulative, usually occurring after the fourth chemotherapy cycle. In addition, the alternate administration schedule of docetaxel and mitoxantrone was not associated with congestive heart failure or decreased LVEF, even in nine patients who received a cumulative mitoxantrone dose of more than 80 mg/m². This observation suggests that this schedule is safe in terms of cardiotoxicity for patients with normal baseline cardiac function.

Mitoxantrone has an established activity against breast cancer that is quite similar to that of doxorubicin. Randomized studies comparing the two drugs either as single agents or in combination with cyclophosphamide and fluorouracil (cyclophosphamide, doxorubicin, and fluorouracil v cyclophosphamide, mitoxantrone, and fluorouracil) have not shown significant differences in the RR, duration of response, and survival.^28-32,45-47 Although efficacy was not the primary objective of this trial, the achieved 22% CR and 78% ORR with the alternate administration of docetaxel and mitoxantrone are among the highest reported in the literature with conventional chemotherapy without ABMT. In addition, the median duration of response was 12.5 months, the median TTP was 14.5 months, and 75% of the enrolled patients were alive after a median follow-up period of 18 months. Taken together, these observations strongly suggest that the combination of docetaxel and mitoxantrone, in the schedule used in this study, is a highly effective regimen in MBC. This high efficacy compares favorably with other taxane-anthracycline combinations^22,25 and may be attributed to the steep dose-response curve of mitoxantrone.²⁸ An important question is whether high doses of mitoxantrone are more effective in solid tumors than the conventional ones. A trial of high versus standard doses of single-agent mitoxantrone is in progress to answer this question.

In conclusion, the alternate administration of docetaxel and mitoxantrone with G-CSF support can be considered an intensified and highly effective chemotherapy regimen that can be used as first-line treatment in patients with MBC without the need for ABMT or peripheral-blood CD34⁺ cell support.

	ACKNOWLEDGMENTS

 
Supported in part by a grant from the Cretan Association for Biomedical Research (CABR).

	REFERENCES

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Submitted August 19, 1998; accepted November 24, 1998.

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