Dose-finding study of epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer (original) (raw)
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Clinical Breast Cancer, 2002
This randomized, double-blind, phase III trial compared granulocyte colony-stimulating factor (G-CSF; filgrastim) and leridistim (formerly myelopoietin), a chimeric dual agonist that binds both G-CSF and interleukin-3 receptors, for the prevention of neutropenic complications in patients with breast cancer receiving TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy. Patients with metastatic (44%) or localized breast cancer (56%) were randomized to G-CSF 5 μg/kg subcutaneously (s.c.) daily (n = 135), leridistim 5 μg/kg s.c. daily (n = 139), or leridistim 10 μg/kg s.c. every other day alternating with placebo (n = 139). Following administration of TAC (docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , cyclophosphamide 500 mg/m 2 ) on day 1, patients received growth factor beginning on day 2 until the postnadir absolute neutrophil count exceeded 1500 cells/μL. Chemotherapy cycles were repeated every 21 days. The incidence of febrile neutropenia was 7% in the G-CSF arm, 19% in the daily leridistim arm (P = 0.003 for comparison with G-CSF) and 22% in the alternate-day leridistim arm (P < 0.001 for comparison with G-CSF). There was no significant difference between treatment arms in the cumulative percentage of patients experiencing grade 4 neutropenia at some point during therapy (85%-88%). However, grade 4 neutropenia occurred in 53% of cycles in the G-CSF cohort, 61% of cycles in the daily leridistim group (P = 0.063 for comparison with G-CSF), and 63% of cycles in the alternate-day leridistim group (P = 0.015 for comparison with G-CSF). We conclude that G-CSF is superior to leridistim in the prevention of febrile neutropenia in patients with advanced breast cancer receiving TAC chemotherapy. The up-front prophylactic use of G-CSF is a reasonable supportive therapy for patients treated with docetaxel/anthracycline-based combination chemotherapy.
Cancer Control, 1996
Background Adjuvant chemotherapy for breast cancer is frequently accompanied by neutropenia requiring dose reduction or treatment delay that can potentially compromise therapeutic effectiveness. Recombinant granulocyte-colony stimulating factor (G-CSF) reduces the duration and severity of neutropenia. Methods Nineteen patients with newly diagnosed breast cancer receiving adjuvant systemic chemotherapy met criteria for dose reduction or treatment delay due to neutropenia. All were treated with G-CSF. The mean duration of G-CSF therapy was five days. Results An increase in mean absolute neutrophil count was seen in cycles with G-CSF. Chemotherapy treatment was delayed less often following the use of G-CSF. Conclusions Breast cancer patients receiving adjuvant chemotherapy who face treatment delays or dose reductions can continue on full-dose intensity therapy using supportive G-CSF. Prospective trials are needed to accurately measure the impact of G-CSF on dose intensity and long-term...
Annals of Oncology, 2000
Background; The combination of anthracyclines and taxanes is currently considered the first choice chemotherapy in advanced breast cancer (ABC) and considerable emphasis has been placed on programs exploring the safest and most efficient way to integrate these classes of drugs in both the metastatic and, more recently, the adjuvant setting. We report here the overall results of the combination of epidoxorubicin (E) 90 mg/m 2 and docetaxel (D) 75 mg/m 2 as first-line chemotherapy in ABC. Patients and methods; A total of 70 patients were entered in the initial dose-finding study (20 patients) and in the subsequent extended phase II trial (50 patients). Overall 54% of patients had dominant visceral disease and 57% had at least two metastatic sites. Adjuvant anthracyclines were allowed in the phase II part of the study based on the lack of cardiac toxicity observed in the phase I study at a median cumulative E dose of 480 mg/m 2. A maximum of eight cycles of the combination was allowed, and cardiac function was monitored at baseline and after every second course by echocardiography. Results: Overall, the median number of cycles administered with the combination was 4 (range 3-8). Neutropenia was confirmed to be the main haematological toxicity, with granulocyte colony-stimulating factor (G-CSF) support required in 44% of the cycles. Febrile neutropenia occurred in 12% of cycles of the combination but 52% of the episodes could be managed on an outpatient basis with oral antibiotics. Overall, the median cumulative dose of E, including prior adjuvant anthracyclines, was 495 mg/m 2 (range 270-1020 mg/irr). One patient who received adjuvant E together with radiotherapy to the left chest wall developed fully reversible clinical signs of cardiotoxicity and a significant decrease of LVEF to 35% after a cumulative E dose of 870 mg/m 2 , with four additional patients (6%) developing asymptomatic and transient decline of resting LVEF. The overall response rate (ORR) in 68 evaluable patients was 66% (95% confidence interval (95% CI): 54%-73%). A comparable antitumour activity of 71% was reported in the group of patients with a prior adjuvant chemotherapy with anthracyclines. After an overall median follow-up time of 22 months (range 4-39+), the median time to progression (TTP) was 4.5 months and the median duration of response was 8 months (range 3-16). No pharmacokinetic (Pk) interaction could be demonstrated between E and D when given simultaneously and sequentially with a one-hour interval. Conclusions: The combination of E and D in a multiinstitutional setting is an active and safe regimen in poorprognosis patients with ABC. New combinations and schedules are worth considering in an attempt to further improve disease response and long-term control of the disease.
Anti-Cancer Drugs, 2005
This phase II trial evaluated the efficacy and toxicity of vinorelbine 25 mg/m 2 plus docetaxel 60 mg/m 2 administered on day 1, every 2 weeks with granulocyte colony-stimulating factor support (G-CSF, 5 lg/kg/day, days 3-7) as primary prophylaxis in patients with histologically confirmed metastatic breast cancer (MBC) and previously treated with anthracyclines in the adjuvant or in the first-line setting. A total of 48 patients received 352 cycles (median 8, range 2-10). All patients were included in the efficacy and safety evaluation on an intent-to-treat analysis. Eight patients (17%) showed a complete response and 14 patients (29%) showed a partial response. Overall response rate was 46% [95% confidence interval (CI) 33-60]. The median duration of response was 10.0 months. With a median follow-up of 18.0 months, the median time to progression was 11.9 months and the median overall survival was 27.1 months. The most frequently reported grade 3/4 hematological toxicity was neutropenia (19% of patients, 4% of cycles). Febrile neutropenia was reported in six patients (13%) and 7 cycles (2%), but no toxic deaths were reported. The most common grade 3/4 non-hematological toxicity was asthenia (17% of patients, 6% of cycles) and nail toxicity (15% of patients, 3% of cycles). In conclusion, biweekly docetaxel plus vinorelbine with G-CSF support is active and well tolerated as chemotherapy for patients with MBC resistant to anthracyclines. G-CSF support is recommended for lowering the incidence and severity of neutropenia and febrile neutropenia. Anti-Cancer Drugs
Annals of Oncology, 2002
Background: The objective of this phase I trial was to determine the maximally tolerated doses of the combination of docetaxel, epirubicin and cyclophosphamide. Patients and methods: Patients with advanced cancer, World Health Organization (WHO) performance status 0 to 2, who had received up to one prior chemotherapy regimen were treated with docetaxel, epirubicin and cyclophosphamide repeated every 21 days. The cyclophosphamide dose was fixed at 600 mg/m 2 and the dose levels studied were: docetaxel/epirubicin; 60/60, 75/60, 75/75, 75/90, 85/90 and 85/105 mg/m 2. There was provision for the addition of prophylactic ciprofloxacin and granulocyte colony-stimulating factor (G-CSF) in separate steps if dose-limiting toxicity (DLT) was neutropenia related. Results: Forty-three patients were entered and all were assessable for toxicity. Dose-limiting toxicity, predominantly febrile neutropenia, was surprisingly seen at the first dose level. The addition of prophylactic ciprofloxacin did not permit dose escalation, but dose escalation was possible with the addition of G-CSF. The highest administered dose level with G-CSF was docetaxel 85 mg/m 2 and epirubicin 105 mg/m 2 with DLTs in five of six patients. Treatment was well tolerated in 10 patients treated at the recommended dose level (85/90) with only one patient experiencing DLT. Responses were seen in a range of malignancies including breast and anaplastic thyroid cancers. No significant pharmacokinetic interaction was observed, but a transient increase in epirubicinol plasma concentration occurred during and after docetaxel infusion. Conclusions: The recommended dose level of docetaxel 85 mg/m 2 , epirubicin 90 mg/m 2 and cyclophosphamide 600 mg/m 2 with G-CSF support has a favorable toxicity profile and is suitable for further investigation in phase II and III trials.
Supportive Cancer Therapy, 2004
Objective. Patients receiving chemotherapy are prone to neutropenic infections presenting with non-specific symptoms such as a high fever and elevated inflammation parameters. Large-vessel vasculitis (LVV) may have a similar clinical presentation and should be included in differential diagnostics. Few published case reports and adverse event reports suggest a causal association between LVV and the use of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. Our objective was to evaluate the relationship between LVV, G-CSF and chemotherapy. Methods. Between 2016-2018, we identified six patients in Finland with probable drug-induced LVV associated with G-CSF and chemotherapy. All 6 patients had breast cancer. A systematic literature review was performed according to PRISMA guidelines using comprehensive search terms for cancer, chemotherapy, G-CSF and LVV. Results. The literature search identified 18 similar published case reports of which most were published after year 2014. In all patients combined (n=24), the time delay from the last drug administration to the LVV symptoms was on average 5 days with G-CSF (range=1-8 days) and 9 days with chemotherapy (range=1-21 days). Common symptoms were fever (88%), neck pain (50%) and chest pain (42%). Based on imaging, 17/24 (71%) had vascular inflammation in the thoracic aorta and supra-aortic vessels, but 5/24 (21%) had reportedly inflammation limited to the carotid area. Conclusion. This review suggests that LVV may be a possible serious adverse event associated with G-CSF and chemotherapy. Successful management of drug-induced LVV requires early identification, through diagnostic imaging, and discontinuation of the drug.
Breast Cancer Research and Treatment, 1995
Mitoxantrone (MTZ) and vinorelbine (VNR) have shown a good efficacy in advanced breast cancer. We conducted a phase I-II trial to determine the MTDs and best schedule of these drugs, in advanced breast cancer patients, when granulocyte-colony stimulating factor (G-CSF) support was given. The starting dose-intensity level was MTZ 3 mg/m2/week + VNR 15 mg/m2/week; dose was escalated at each step by 1 mg/mZ/week for MTZ and 5 mg/m;/week for VNR, until dose limiting toxicity (DLT) developed in 33 % or more of the patients at the first course. G-CSF 5 gg/kg/day d 3-13 was administered at each cycle from dose level 2 on. For each dose step we planned 3 different schedules (a = total dose of MTZ on day 1; b = total dose d 1 and 8; c = weekly schedule). At the time of this analysis (December 1993) 43 patients with locoregionally advanced or metastatic breast cancer have entered this study, 23 of whom had received prior chemotherapy other than adjuvant. Toxicity has been primarily hematologic. Non hematologic toxicity never caused interruption of dose escalation. Overall 8 patients developed DLT at the first course. Dose escalation was stopped at level 3 in patients receiving schedules a or b, and in those receiving schedule c the dose was escalated until level 5. The MTD was MTZ 6 mg/m 2 and VNR 30 mg/m 2 weekly. Age, dose level, and PS were found to be correlated with neutrophil and platelet nadirs, but dose level was the only independent variable predictive of myelotoxicity at multiple regression analysis. Forty-one patients were evaluable for response. Five complete and 16 partial responses were recorded for a 51% [35-67] overall response rate. This was 67% (12/18) in chemotherapy naive patients as compared to 39% (9/23) in those who had been pretreated. Seven of 21 (33%) patients receiving dose level i and 2 responded as compared to 14/20 (70%) patients who received higher dose-intensity (p = 0.02). Dose level and pretreatment were the only variables significantly associated with response rate at multiple logistic analysis. The median TTP was 9.5 months for the entire group. It was significantly better in patients who received a dose level > 2 (15 vs. 7; p-0.015). However, the chemotherapy dose level did not significantly predict outcome after correction for pretreatment (yes vs. no), at multivariate Cox analysis. In conclusion, G-CSF support allows us to achieve a high dose-intensity of MTZ and VNR. Weekly administration of mitoxantrone is recommended to achieve the maximum dose level.