- © 2001 by American Society of Clinical Oncology
Intensification of Adjuvant Chemotherapy: 5-Year Results of a Randomized Trial Comparing Conventional Doxorubicin and Cyclophosphamide With High-Dose Mitoxantrone and Cyclophosphamide With Filgrastim in Operable Breast Cancer With 10 or More Involved Axillary Nodes
- Pierre Fumoleau,
- Franck Chauvin,
- Moïse Namer,
- Roland Bugat,
- Michèle Tubiana-Hulin,
- Jean Paul Guastalla,
- Thierry Delozier,
- Pierre Kerbrat,
- Yves Devaux,
- Jacques Bonneterre,
- Annie Filleul and
- Michel Clavel
- From the Centre René Gauducheau, Nantes; Centre Antoine Lacassagne, Nice; Centre Claudius Regaud, Toulouse; Centre René Huguenin, Saint-Cloud; Centre Léon Bérard and Hôpital Edouard Herriot, Lyon; Centre François Baclesse, Caen; Centre Eugène Marquis, Rennes; Centre Oscar Lambret, Lille; and Wyeth-Lederle, Paris, France.
- Address reprint requests to Pierre Fumoleau, MD, Department of Medical Oncology, Centre René Gauducheau, Centre Regional de Lutte Contre le Cancer Nantes-Atlantique, 44805 Nantes-St Herblain, France; email: fumoleau{at}nantes.fnclcc.fr
Abstract
PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes.
PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m2 plus cyclophosphamide 600 mg/m2, with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates.
RESULTS: There were no significant differences in DFS (P = .44), DDFS (P = .67), or OS (P = .99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P = .01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P < .001).
CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m2 with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.
ADJUVANT chemotherapy is widely used for operable breast cancer and has been shown to improve both disease-free survival (DFS) and overall survival (OS). The benefit of such therapy was evaluated in the Early Breast Cancer Trialists’ Cancer Group meta-analysis.1 Although adjuvant chemotherapy generally benefits women with node-positive breast cancer, patients with 10 or more involved axillary nodes (N+ ≥ 10) have a poor prognosis.2 In such patients, the 5-year probability of DFS after surgery plus combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) or a similar regimen ranges from 20% to 30%.3 However, these results are no better than the 29% 5-year probability of DFS in patients treated with surgery alone.4 The addition of anthracyclines, such as doxorubicin, to standard-dose adjuvant chemotherapy results in only a small improvement.5,6 For example, the recent National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-22, which in one arm used standard doxorubicin and cyclophosphamide (AC) therapy, reported a 5-year DFS of 36% in a subgroup of 320 patients with 10 or more positive nodes.7
This high risk of recurrence and mortality and the arguments of Hryniuk and Bush8 regarding the importance of dose-intensity have encouraged single-arm studies using high-dose chemotherapy. Very high-dose chemotherapy has been administered using bone marrow support, and more recently, patients have been treated with peripheral-blood stem cells elicited using hematopoietic growth factors. Peters et al9 reported a 71% DFS and 78% OS at 5 years in 85 patients who received four cycles of cyclophosphamide, doxorubicin, and fluorouracil followed by high-dose chemotherapy with autologous marrow support. These results seem to be superior to those achieved in patients with 10 or more positive nodes in previous Cancer and Leukemia Group B (CALGB) adjuvant trials. Similarly, Gianni et al10 reported the 5-year probability of DFS and survival to be 57% and 70%, respectively, in 67 patients with 10 or more positives nodes who received high-dose sequential chemotherapy plus peripheral stem-cell support.
However, because patient selection may contribute to the apparently superior outcome reported for high-dose chemotherapy with hematopoietic support compared with standard adjuvant chemotherapy,11 prospective randomized trials comparing high-dose chemotherapy with bone marrow or stem-cell support to conventional treatment without such support are currently ongoing in North America and Europe.
The use of granulocyte colony-stimulating factor (G-CSF) offers an alternative method of increasing the dose-intensity of adjuvant chemotherapy, and adequate leukocyte recovery has been achieved in a significant number of patients.12-14 Mitoxantrone has been shown to have anthracycline-like antineoplastic effects in metastatic breast cancer, with a lower incidence of nonhematologic toxicities.15,16 Conventional dosages (12 mg/m2) result in acceptable hematologic toxicity, but more intensive dose levels cannot be routinely used in the adjuvant setting. Phase I studies of high-dose mitoxantrone demonstrated that a higher dose could be given if prophylactic G-CSF was administered.17-19 In addition, Catimel et al20 reported the feasibility of combining mitoxantrone 23 mg/m2 plus cyclophosphamide 600 mg/m2 and hematopoietic growth factor, every 3 weeks, as second-line chemotherapy for metastatic breast cancer.
On the basis of the above, this prospective study was designed to evaluate the potential benefit of dose intensification in patients with 10 or more positive nodes, using a randomized comparison between conventional adjuvant chemotherapy (doxorubicin and cyclophosphamide [AC]) and a high-dose, mitoxantrone-containing regimen. This article reports the 5-year results.
PATIENTS AND METHODS
Patients
Women aged 18 to 70 years with operable breast cancer and histologically proven involvement of 10 or more axillary lymph nodes were recruited from 12 centers in France. All patients had a performance status of less than 2, and negative preoperative staging including bilateral mammography, liver ultrasound, and radionuclide bone scan. Chest and liver computed tomographic (CT) scans and bone marrow biopsy were not mandatory.
Eligible patients had to have normal hematologic, hepatic, and renal functions and normal cardiac function (defined as baseline left ventricular ejection function [LVEF] ≤ 50%). Written informed consent was obtained from each patient.
Treatment Schedule
Within 28 days of surgery, patients were randomized to receive either intravenous (IV) doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days for four cycles (AC, arm A, the control group) or IV mitoxantrone 23 mg/m2 and cyclophosphamide 600 mg/m2 with filgrastim (G-CSF) 5 g/kg/d from day 2 to day 15, every 21 days for four cycles (arm B, the intensified group).
In arm A, a granulocyte count less than 1,500/mm3 and/or a platelet count less than 100,000/mm3 on day 21 necessitated a treatment delay of at least 1 week. If longer than 2 weeks was required for hematologic recovery, the patient was withdrawn.
In arm B, both nadir and hematologic counts at day 21 were considered. Retreatment was possible only if the granulocyte and platelet counts exceeded the limits defined above. In cases of granulocyte nadir less than 500/mm3 and hospitalization for treatment with antibiotics, or if the platelet nadir was less than 50,000/mm3, the dosage of mitoxantrone was decreased to 18 mg/m2 for subsequent courses.
Prophylactic antiemetics were administered to those patients who experienced nausea or vomiting after previous cycles of chemotherapy.
Hepatic and renal functions were assessed in all patients before each cycle of chemotherapy. Hematologic counts were performed on days 1, 4, 8, 15, and 21 in arm B and every 21 days in arm A. In both groups, LVEF was measured after the four treatment cycles and within 1 year of completing adjuvant chemotherapy.
Postmenopausal patients also received tamoxifen 20 mg/d for 5 years after completion of adjuvant therapy. For all patients, locoregional radiation therapy was started after completion of cytotoxic therapy.
Evaluation Criteria
Relapse was defined as evidence of local or distant recurrence diagnosed by a symptom or a systematic staging as defined in the follow-up procedures (every 4 months during the first 3 years and then once a year).
DDFS survival was defined as the interval from inclusion to evidence of metastatic involvement or death without relapse. DFS was defined as the interval from inclusion to evidence of relapse whatever the site. OS was defined as the time from inclusion to death (whatever the cause). Data on patients still alive or disease-free were censored at the time of last contact with the investigators.
Toxicity was evaluated according to World Health Organization criteria.
Randomization and Quality Control
After satisfying inclusion criteria, patients were randomly assigned to treatment using an independent computerized procedure managed by the coordinating center (unbalanced blocks). Monitoring was performed by on-site visits to investigating centers, and data were checked by computerized procedures. At the time of randomization, a stratification was performed on the investigating centers; no other factor was taken into account for stratification.
Statistical Analysis
The sample size was calculated on the basis of a 40% 5-year DFS in the conventional arm and an expected difference of 20%; alpha was chosen at the 5% level because beta was 20%, and 75 patients were needed in each arm for a one-sided comparison. Data were analyzed on intent-to-treat bases.21 Survival curves were calculated using the Kaplan-Meier method for both DFS and OS and were compared by using a log-rank test. Quantitative variables were compared using Student’s t test and qualitative variables using χ2 or Fisher’s exact test. Main prognostic factors (age, histologic grade, node involvement, receptor status) were analyzed as dummy variables based on usual thresholds both in univariate and multivariate analyses. Patients with missing data for these prognostic factors were excluded from multivariate analyses.
Multivariate analyses were performed by using a proportional hazards model.22 To estimate the therapeutic effect of dose intensification according to node involvement, an interaction factor between node involvement (< 15 or ≥ 15 positive nodes) and treatment arm was tested in the multivariate analysis. A hazard rate ratio for this interaction factor statistically different from 1 indicates that the treatment effect differs between the two subgroups independently of prognostic factor effect. In such multivariate analyses, treatment effect was estimated as adjusted on remaining covariables. Moreover, the stability of the model has been tested for estimating the interaction factor by successively removing cofactors.
RESULTS
Patients
From January 1992 to April 1995, 150 patients, who fulfilled the eligibility criteria, from 12 French centers were entered onto this prospective clinical trial and were randomly assigned to receive either conventional chemotherapy (arm A, n = 74) or intensive chemotherapy (arm B, n = 76). Baseline patient characteristics are listed in Table 1; there were no statistically significant differences between the two groups. The mean number of surgically removed axillary nodes was 19 in both groups, and the mean number of histologically involved lymph nodes was 14 (arm A) and 15 (arm B). The type of surgery was well balanced between groups; 54% of patients in arm A and 51% in arm B had undergone mastectomy. All 150 patients were included in the analysis; the median follow-up time was 60 months (range, 41 to 79 months) and follow-up was available for each patient.
Baseline Patient Characteristics
Treatment Administration
Treatment administration data are listed in Table 2. Patients in arm A received a total of 287 courses; 241 cycles (84%) were on-schedule, 43 were delayed by 1 week, and three were delayed by 2 weeks. The mean relative dose-intensity was 18.8 mg/m2/wk for doxorubicin and 186 mg/m2/wk for cyclophosphamide. Four patients discontinued treatment: two because of persistent neutropenia, one patient refused treatment after two cycles, and one because of impaired LVEF (examination omitted at baseline and performed after one cycle).
Treatment Administration
A total of 294 cycles of high-dose mitoxantrone and cyclophosphamide were administered to patients in arm B; 252 cycles (86%) were delivered on schedule, and 31 and 11 were delayed for 1 or 2 weeks, respectively. The normalized dose-intensity was 7.3 mg/m2/wk for mitoxantrone and 190 mg/m2/wk for cyclophosphamide. The median duration of G-CSF treatment was 14 days (range, 9 to 17 days), and the mean and median daily doses were 320 g and 300 g, respectively. Five patients withdrew before completing four cycles of chemotherapy (persistent hematologic toxicity in three and febrile neutropenia in two).
Outcome
At the cutoff date for analysis, 5-year DDFS was 45% (range, 34.3% to 58%) in arm A and 50% (range, 38.6% to 62%) in arm B (P = .67) ( Fig 1). Five-year DFS was 41% in arm A versus 49% in arm B (P = .44) ( Fig 2).
Fig 1. Five-year probability of DDFS in 74 patients who received AC (arm A) and 76 patients who received mitoxantrone plus cyclophosphamide with filgrastim (MC + G-CSF).
Fig 2. Five-year probability of DFS in 74 patients who received AC (arm A) and 76 patients who received MC + G-CSF (arm B).
OS rates at 5 years were 61% and 60% in arms A and B, respectively (P = .83), with 54 deaths at time of analysis (26 in arm A and 28 in arm B) ( Fig 3). Confidence intervals are graphed.
Fig 3. Five-year probability of OS in 74 patients who received AC (arm A) and 76 patients who received MC + G-CSF (arm B).
A subanalysis of patients with 15 or more positive nodes revealed significant differences in DDFS (19% v 49%, P = .01) ( Fig 4) and DFS (19% [7.8% to 38.8%] v 49% [31.5% to 66.1%], P = .02) ( Fig 5). This finding was confirmed by multivariate analysis, in which the interaction factor for treatment with AC (arm A) was statistically significant in patients with 15 nodes (hazard ratio rate, 3.09, P = .03; 95% confidence interval, 1.09 to 8.79), which indicates a significantly higher probability of relapse in this subgroup for patients receiving AC ( Table 3). For OS, there was a nonsignificant trend in favor of intensive chemotherapy (40% v 52%, P = .13).
Fig 4. Five-year probability of DDFS in a subanalysis of patients with ≥ 15 positive nodes (28 patients who received AC and 31 patients who received MC + G-CSF).
Fig 5. Five-year probability of DFS in a subanalysis of patients with ≥ 15 positive nodes (28 patients who received AC and 31 patients who received MC + G-CSF).
Hazard Rate Ratios of Main Prognostic Factors and Interaction Factor for DDFS
Toxicity
The main toxicities in both treatment arms are listed in Table 4. Hematologic toxicity by cycle for high-dose mitoxantrone is listed in Table 5.
Incidence of Main Hematologic and Nonhematologic Adverse Effects (according to WHO criteria)
Hematologic Toxicities by Cycle in the Intensified Treatment Arm B
Hematologic counts were not mandatory between courses in arm A but were performed at days 4, 8, and 15 in arm B. Febrile neutropenia was observed in one (0.3%) of 287 cycles in arm A and 10 (3%) of 294 cycles in arm B (involving eight patients). Neutropenia was slightly cumulative in arm B; the incidence of grade 3 to 4 neutropenia was 36% at cycle 1, 38% at cycle 2, 43% at cycle 3, and 48% at cycle 4 (Table 5). In addition, the median nadir platelet counts and hemoglobin levels slowly decreased from cycle 1 to cycle 4.
Most patients (90% in arm A and 87% in arm B) were treated with concomitant 5-hydroxytryptamine-3 antagonists, and nausea and vomiting were moderate in both groups (grade 2 or 3, 22% v 20%, respectively). Alopecia was significantly less common in arm B than in arm A (grade 2 or 3, 33% v 71%; P < .001). No other severe side effects were reported and there were no acute toxic deaths.
With a 5-year follow-up, no clinical cardiac toxicity occurred and three late hematologic toxicities possibly related to chemotherapy occurred in arm B (acute myelomonocytic leukemia, myelodysplasia with blast crisis, and refractory anemia with excess of blasts in one patient each).
DISCUSSION
Retrospective analysis suggests a dose-response relationship for chemotherapy in the treatment of both metastatic and stage II breast cancer.23,24 In vitro studies with human cell lines have shown a clear dose-response relationship for alkylating agents, anthracyclines, and mitoxantrone.25,26 Dose intensification can be achieved by using (1) moderately escalated doses without hematopoietic growth factor support; (2) high-dose chemotherapy with hematopoietic growth factor (G-CSF or granulocyte-macrophage CSF) support; or (3) very high-dose chemotherapy, the ultimate dose intensification, which necessitates the use of autologous stem-cell bone marrow transplantation or peripheral stem-cell infusion.
Doxorubicin is a logical agent to intensify in patients with breast cancer because of its single-agent efficacy in this disease.27 However, severe stomatitis was reported in the majority of patients treated with up to double the conventional dose of this agent (120 mg/m2 v 60 mg/m2).28 Single-agent mitoxantrone administered at a dose of 12 mg/m2 every 3 weeks is also effective in the primary treatment of metastatic breast cancer.29 Moreover, the incidence of alopecia, mucositis, nausea/vomiting, and cardiomyopathy with mitoxantrone was significantly lower than that reported with anthracyclines.15,16 Furthermore, the dosage of single-agent mitoxantrone can be increased up to 90 mg/m2 when combined with autologous stem-cell support,30 and a four-fold dose escalation is feasible when mitoxantrone is combined with hematopoietic growth factors including filgrastim.17,18 Two studies have demonstrated the feasibility of escalating the dose of mitoxantrone in combination with cyclophosphamide when hematopoietic growth factor is used19,20; the recommended doses were mitoxantrone 28 mg/m2 and cyclophosphamide 600 mg/m2,19 and mitoxantrone 23 mg/m2 and cyclophosphamide 600 mg/m2.20
Patients with at least 10 involved axillary nodes have a poor prognosis, with a projected 5-year survival of approximately 30%,4 and the use of CMF and anthracyclines results in little improvement. The high risk of recurrence and mortality has therefore encouraged single-arm studies using high-dose chemotherapy with hematopoietic support.
When our study was initiated in January 1992, no randomized study specifically designed for patients with at least 10 involved axillary nodes had been published. Preliminary results of single-arm trials in this setting using very high-dose chemotherapy with autologous stem-cell support suggested significant benefit.9,10 Because of the activity demonstrated in studies NSABP B-1531 and NSABP B-16,32 adjuvant AC (four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) was selected as one standard for adjuvant therapy in node-positive breast cancer and formed the conventional arm in our randomized study. Treatment in the intensified arm was based on the study by Catimel et al20 that recommended doses of mitoxantrone 23 mg/m2 and cyclophosphamide 600 mg/m2 plus filgrastim every 3 weeks. Thus, the cyclophosphamide dose was the same in both arms.
Our study failed to demonstrate a significant benefit in 5-year OS for intensified chemotherapy. DFS rate was 41% in the conventional arm and 49% in the intensified arm, and the DDFS rate was 45% versus 50%; neither difference was significant (P = .44 and .67, respectively). This result was irrespective of the fact that an intent-to-treat analysis was performed. Compliance was excellent in both arms, with relative dose intensities of 94% for doxorubicin and 93% for cyclophosphamide in arm A and of 95% for both mitoxantrone and cyclophosphamide in arm B. Thus, the failure to note any difference in outcome between the two treatment groups was clearly not related to any difference in relative dose-intensity. There was also no intergroup difference between the number of delayed cycles (46 in arm A v 42 in arm B). Considering the initiation date of this study, any new biologic predictive factor, such as Her2/neu, has been taken into account.
Regarding the apparently small number of patients (n = 150) enrolled, the sample size was calculated on the basis of 40% DFS at 5 years in the control arm. After the encouraging results of two single-arm trials using high-dose chemotherapy with autologous stem-cell support,9,10 an expected difference of 20% was chosen (alpha, 5%; beta, 20%). Over a period of 39 months, 150 patients from 12 centers were enrolled onto this study, which was specifically designed for patients with 10 involved axillary nodes. In the CALGB 8541 trial,33 which began in January 1985 and enrolled 1,572 women with node-positive stage II breast cancer, the number of patient with N+ ≥ 10 was approximately 50 per arm (v 75 in our study). The published NSABP B-22 trial,7 which enrolled 2,305 patients with positive axillary nodes from July 1989 to May 1991, had 106, 106, and 108 patients with at least 10 positive nodes in the three arms. Since 1990, it has been difficult to increase the size of this subgroup of patients with N+ ≥ 10 without significantly lengthening studies. The number of positive nodes strongly correlates with tumor size; many patients with T3 tumors now receive neoadjuvant chemotherapy and screening has decreased tumor size.
At the time of randomization, stratification was only performed on the investigating centers; no other factor was considered. Nevertheless, the difference in DDFS for patients with at least 15 positive nodes (5-year DDFS was 49% for the intensified arm v only 19% in the conventional arm) deserves comment. Despite the small number of patients in this subgroup (28 in arm A and 31 in arm B), the difference was significant (P = .01). The significant value of the interaction factor suggests that intensification decreases the probability of relapse only in the subgroup with 15 or more positive nodes because no effect of intensification is observed in the subgroup with 10 to 15 positive nodes. Nevertheless, this result could be cautiously considered, as this subgroup analysis was not planned in the study design.
Our study should be compared with randomized trials reporting the effects of dose intensification using moderately escalated doses without G-CSF support. The CALGB 8541 trial33 compared three dose levels of cyclophosphamide, doxorubicin, and fluorouracil in women with node-positive breast cancer. The total dose in the low-dose arm was half that in the other two arms; after a median follow-up of 3.4 years, patients treated with the high or moderate dose had significantly longer DFS (P < .001) and OS (P = .004) than those who received the low dose in three-way log-rank comparisons. The difference between the low-dose and high-dose groups was significant for the subgroup with N+ ≥ 10 (hazard rate ratio, 1.63; P = .038). Indeed, the investigators correctly concluded that chemotherapy doses should not be reduced below the minimum shown to be beneficial.
The NSABP trial B-22,7 in which 2,305 node-positive patients received randomly either standard-dose AC (60 mg/m2 and 600 mg/m2, respectively) for four cycles, dose-intensified AC (60 mg/m2 for four cycles and 1,200 mg/m2 for two cycles), or dose-intensified and increased AC (60 mg/m2 for four cycles and 1,200 mg/m2 for four cycles), failed to show any improved outcome with higher cyclophosphamide doses. There were no differences in 5-year DFS or OS among the three arms. There was also no difference for the N+ ≥ 10 subgroup, in which 5-year DFS was approximately 40% and OS was approximately 60%. These results are similar to those reported in our trial.
In 1990, the French Adjuvant Study Group initiated a study to investigate the effects of increasing the dose of epirubicin in fluorouracil, epirubicin, and cyclophosphamide (FEC) from 50 to 100 mg/m2.34 With a median follow-up of 5 years, results suggest that FEC 100 mg/m2 significantly improves DFS and OS compared with FEC 50 mg/m2 in patients with resectable, high-risk, node-positive breast cancer.
Our study is the third to report the effects of dose intensification of adjuvant therapy using G-CSF to reduce the duration of nadir counts. In the NSABP B-25 trial,35 which accrued 2,545 node-positive women and closed in February 1994, patients were randomized to receive AC adjuvant chemotherapy: either doxorubicin 60 mg/m2 for 4 days and cyclophosphamide 1,200 mg/m2 for 4 days plus G-CSF, or doxorubicin 60 mg/m2 for 4 days and cyclophosphamide 2,400 mg/m2 for 2 days plus G-CSF, or doxorubicin 60 mg/m2 for 4 days and cyclophosphamide 2,400 mg/m2 for 4 days plus G-CSF. This trial was not specifically designed for N+ ≥ 10 patients. Like NSABP B-22, NSABP B-25, although not followed for as long, is thus far reported as negative.
The aim of the CALGB 9344 trial36 was to test whether dose escalation of doxorubicin (60 mg/m2, 75 mg/m2, or 90 mg/m2) or the addition of paclitaxel after four courses of AC could improve results. This study accrued patients with node-positive primary breast cancer, and the higher dosage of doxorubicin (90 mg/m2) was given with G-CSF. With a short follow-up (18 months), no advantage has been found using either of the higher doses. However, this trial was not specifically designed for N+ ≥ 10 patients, and in the latter two arms, doxorubicin total doses were given on two consecutive days.
Several single-arm trials, using very high-dose chemotherapy with autologous stem-cell support for patients with 10 or more involved axillary nodes, have suggested significant survival benefit.9,10,37 These results have not yet been confirmed by the two small but properly randomized adjuvant trial published in 1998.38,39 In addition, the results of two large clinical trials40,41 have been recently reported and have not yielded clear-cut evidence of the superiority of this therapy compared with conventional treatment.
Our study investigated the feasibility of administering mitoxantrone 23 mg/m2 plus cyclophosphamide 600 mg/m2 and G-CSF every 3 weeks for four cycles in the adjuvant setting. It is difficult to compare the incidence of neutropenia and thrombocytopenia because hematologic counts were performed every 3 weeks in the conventional arm but on days 1, 4, 8, 15, and 21 in the intensified arm. Nonetheless, the number of cycles delayed due to hematologic dysfunction at day 21 was similar (39 in the conventional arm v 33 in the intensified arm). The incidence of febrile neutropenia was low in both arms, occurring in 0.3% of cycles in arm A and 3% in arm B. Mild cumulative neutropenia, thrombocytopenia, and anemia were observed in the intensified arm, but there was no decrease in dose-intensity. Most patients received 5-hydroxytryptamine-3 antagonists, and the incidence of nausea and vomiting was moderate and similar in both treatment arms. The incidence of alopecia was significantly lower (P < .001) in patients who received high-dose mitoxantrone compared with those treated with AC.
No other severe adverse events were reported, and there was no acute or delayed cardiac toxicity. No acute toxic deaths occurred.
In the intensified arm, three late toxicities possibly related to chemotherapy were reported. Myelodysplasia with blast crisis has previously been described after conventional-dose and escalated-dose adjuvant chemotherapy with alkylating agents.42 Acute myelomonocytic leukemia may occur after a relatively short latency period (10 to 18 months) after treatment with topoisomerase II inhibitors.41,43 The updated results of NSABP B-2544 show an increased risk of myelodysplasia and acute myeloid leukemia in comparison with previous NSABP studies. In the NSABP B-25 study, the initial cases are similar to those associated with topoisomerase II inhibitors (AML subtype M4 or M5), and more recent cases have some characteristics similar to those described after alkylator therapy (AML subtype M1 or M2).
In conclusion, this study, designed to evaluate high-dose chemotherapy in N+ ≥ 10 patients, has demonstrated the feasibility of escalating the dose of mitoxantrone up to 23 mg/m2 in combination with cyclophosphamide 600 mg/m2 when used in conjunction with filgrastim. Although there was no significant difference between treatment groups at 5 years, the results suggest that intensified treatment may decrease the risk of relapse compared with AC therapy in the N+ ≥ 15 subgroup.
Acknowledgments
Supported by Amgen-Roche and Wyeth-Lederle, Paris, France.
- Received October 22, 1999.
- Accepted September 13, 2000.
