Phase II study of deoxyspergualin in metastatic breast cancer
Kapil DhingraVicente ValeroLia GutiérrezRichard L. TheriaultDaniel J. BooserFrankie A. HolmesAman U. BuzdarGiuseppe FraschiniGabriel N. Hortobágyi
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Detection of neutropenia depends on the white cell count and the differential count, both of which involve considerable error. Pathogenetically, neutropenia can be attributed one of the following mechanisms: insufficient (or inefficient) formation, enhanced destruction or utilization, or--rarely--shift to the marginal pool. Isolated neutropenia should be distinguished from neutropenia combined with anemia and/or thrombocytopenia. The latter is usually due to bone marrow failure, whereas the former depends on peripheral mechanisms. Drug induced neutropenia may appear either as unforeseen acute agranulocytosis (aminophenazone type), depending on preceding sensitization, or as a slowly developing, dose-dependent cytopenia. Gradually developing neutropenia is an early stage of a general disease (collagen diseases, leukemia and other neoplasias, infections).
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Background: This multicenter phase II trial was conducted to analyze the clinical activity and toxicity of the combination of pegylated liposomal doxorubicin and vinorelbine as first-line treatment in elderly patients with metastatic breast cancer. Patients and Methods: From August 2002 to August 2004, 42 patients with metastatic breast cancer were recruited for treatment with pegylated liposomal doxorubicin 40 mg/m2 intravenously (i.v.) on day 1 and vinorelbine 30 mg/m2 i.v. on days 1 and 15 every 4 weeks. Results: The median age of the patients in this trial was 68 years (range 60–82). 40% of patients had 2 or more sites of metastasis, 33 (78%) had predominantly visceral metastasis, and 7 (16%) mostly bone metastasis. Just 2 (5%) patients had only lymphogenous or soft tissue metastasis. All patients had an ECOG performance status of 0–1, but 70% of the patients had relevant comorbidities. In an intention-to-treat analysis, the overall clinical response rate was 36%, the complete response rate was 2%, and the rate of partial remissions was 34%; stable disease occurred in 30%, and progressive disease was observed in 36%. Median duration of response was 10 months. Median time to progression was 4 months, and median overall survival time was 24 months. Conclusion: The combination of pegylated liposomal doxorubicin and vinorelbine is an active and well tolerated regimen in elderly patients with metastatic breast cancer in first-line treatment.
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Abstract Neutropenia is a decrease in the number of neutrophilic leucocytes in the blood. Neutropenia is defined as an absolute neutrophil count or ANC (total white blood cells per litre multiplied by the percentage of neutrophils) more than two standard deviations below the normal mean. The ANC is usually more than 2.0 × 10 9 L −1 . Neutropenia is graded as mild, moderate or severe; severe is less than 0.5 × 10 9 L −1 . Severe neutropenia predisposes to a high risk of bacterial and fungal infections. Neutropenia occurs both as an acquired and as an inherited disorder. Drugs and autoimmune diseases are the common causes of acquired neutropenia. There are many hereditary causes of neutropenia; all of these are rare conditions, but some are quite severe. Proper treatment depends on understanding the cause of neutropenia and its expected duration. Short periods of neutropenia can be managed with careful observation or antibiotics. Patients with severe chronic neutropenia benefit from long‐term treatment with granulocyte colony‐stimulating factor (G‐CSF). Key Concepts Neutrophils are critical for normal defence from infections by bacteria on body surfaces. Blood neutrophil levels below normal, that is, neutropenia, predispose to bacterial and fungal infections. The bone marrow produces neutrophils from haematopoietic stem cells through an orderly process that takes about 10–14 days. Neutropenia is usually due to acquired or intrinsic/hereditary disorders affecting bone marrow production of these cells. When neutrophil production is interrupted by drugs or diseases recovery often takes several days. The risk of infection in patients with neutropenia depends on the severity of neutropenia and its duration. With a brief period, that is, 1–3 days, the risk is relatively low. Severe neutropenia lasting longer is associated with a steadily increasing risk of severe infection and even death. Proper management of neutropenia requires understanding its cause and the expected duration of neutropenia. When it is due to drugs, either cancer chemotherapy or as an idiosyncratic reaction to other drugs, the duration is usually relatively brief and can be managed with observation or antibiotics. Neutropenia lasting more than about 5–7 days and more chronic neutropenia predispose patients to a much higher risk of bacterial and fungal infections. These patients benefit from treatment with granulocyte colony‐stimulating factor (G‐CSF). It is now possible to identify the genetic cause for severe chronic neutropenia in many patients through deoxyribonucleic acid (DNA) sequencing studies. Understanding of the molecular and cellular basis for these disorders is growing rapidly.
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e11050 Background: Pegylated liposomal doxorubicin (PLD) has demonstrated equivalent antitumor activity to conventional doxorubicin and a significantly lower risk of cardiotoxicity when given as single agent or in combination with cyclophosphamide, but there is limited experience with the combination of PLD and vinorelbine. This phase II study was performed to evaluate the efficacy and safety of the PLD and vinorelbine in patients with metastatic breast cancer. Methods: From August 2004 to August 2007, 51 patients with metastatic breast cancer were treated with PLD (35 mg/m2) and vinorelbine (25 mg/m2 D1, 8) in 3-weeks intervals for up to eight cycles. Results: The overall response rate was 50% and 78% of patients derived a clinical benefit. Median time to progression and overall survival were 10.0 months (95% CI, 6.9-13.1 months) and 25 months (95% CI, 22.1-29.8 months), respectively. Median duration of response was 12.0 months (95% CI 7.1-16.9). A total of 408 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients and 3 patients, respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases and one case, whereas grade 3 and 4 mucositis occurred in six cases and two cases, respectively. Grade 2 cardiac toxicity was observed in only one case. Conclusions: The combination of pegylated liposomal doxorubicin and vinorelbine is an active and well-tolerated regimen in patients with metastatic breast cancer. No significant financial relationships to disclose.
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Many phase II trials investigated the combination of Gemcitabine (G) and Vinorelbine (V) in the treatment of metastatic breast cancer (MBC) with variable outcomes. This study was conducted to explore whether this combination was effective and tolerable in MBC patients who were heavily pretreated with anthracyclines and taxanes.A phase I study was conducted first to establish the maximum tolerated dose (MTD) of the G and V combination in MBC patients. Then, a phase II study evaluated the response rates, the median time to progression (TTP), the overall survival (OS) as well as the toxicities resulting from this combination at the MTD.Nine patients were enrolled in the phase I study. The MTD was identified as 700mg/m(2) of G on days 1 and 8 in combination with 15 mg/m(2) of V on days 2 and 9, every 21 days. Twenty-one of 25 patients involved in the phase II study were evaluable for response. No complete or partial responses were achieved; 6 patients (24.0%) had stable disease and 15 (60.0%) progressed. The median TTP was 2 months and the median OS 10 months. Grade 3/4 Neutropenia was the major hematologic toxicity, occurring in 52% of the cycles. The most common non-hematologic grade 3/4 toxicities were fatigue (18%), myalgias (17%) and arthralgias (13%).In heavily pretreated patients with MBC, the combination of G and V at the doses stated above was ineffective as it did not induce partial or complete responses. Other chemotherapy agents or combinations should be evaluated in future studies.
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1040 Background: UTD1, a genetically engineered epothilone analog, is a microtubule stabilizing agent that showed promising activities in phase I trials. In this report, two open-label, multicenter phase II studies of UTD1 alone or UTD1 plus capecitabine (CAP) were carried out to evaluate its efficacy and safety in metastatic breast cancer (MBC) patients (pts). Methods: In both studies, MBC patient who was pretreated with taxanes, anthracyclines and/or CAP received UTD1 at a dose of 40mg/m2/d intravenously on day 1 to day 5 or at 30mg/m2/d (d1-d5) in combination with CAP (2000mg/m2/d, orally) on d1-d14, every 21 days until disease progression or unacceptable toxicity occurred for a maximum of 6 cycles. The primary endpoint was objective response rate (ORR) and the secondary endpoints were toxicity and progression-free survival (PFS) for the combination. Results: 25 pts received a total of 128 cycles in the combination with a median of 6 cycles (range 1-6 cycles) per patient. Among 24 pts who were evaluable for efficacy, responses included one complete response (CR), 11 partial responses (PR), 9 stable diseases (SD), and a median PFS of 7.5 months. In the UTD1 monotherapy, 34 pts received a median of 4 cycles of UTD1 and 30 pts were evaluable for efficacy. One patient had a confirmed CR, 7 had PR and 13 had SD. Peripheral neuropathy (PN) was the major adverse event associated with UTD1 toxicity in both studies, but was manageable. 40% of pts in the combination had grade 3 PN or/and foot syndrome compared to 11% in the monotherapy. One patient was removed from the monotherapy after the first cycle because of grade 3 neurotoxicity, which was reversed after 3 weeks. There were no drug-related deaths in the two studies. Other grade 3 toxicities included neutropenia (12% vs 3%, combination vs monotherapy), diarrhea (4% vs 3%), myalgia/arthralgia (8% vs 0%), dizziness (4% vs 0 %). Conclusions: UTD1 was well-tolerated in both studies with the primary toxicity being PN, and demonstrated notable antitumor activities in MBC pts. 27% of ORR was seen for the monotherapy or 50% of ORR and a median PFS of 7.5 months for the combination. A multicenter, phase III study of UTD1 plus CAP vs CAP alone in MBC is underway. Clinical trial information: TRC-13004205.
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Summary Neutropenia is linked to the development of invasive candidiasis/candidaemia, for which micafungin has demonstrated efficacy, but evidence in patients with neutropenia is limited. The aim of this study was to evaluate the efficacy of micafungin for the treatment of invasive candidiasis/candidaemia in patients with neutropenia (<500 neutrophils/μL) and without neutropenia. This pooled, post hoc analysis of 2 Phase 3 trials compared micafungin 100 mg/d (adults) and 2 mg/kg/d (paediatrics) with L‐AmB 3 mg/kg/d ( NCT 00106288) and micafungin 100 mg/d and 150 mg/d with caspofungin 70 mg/d followed by 50 mg/d (adults) ( NCT 00105144); treatment duration 2‐4 weeks (≤8 weeks for chronic disseminated candidiasis). Effects of neutropenia duration and Candida spp. on efficacy outcomes (treatment success, clinical and mycological response) were examined. Of 685 patients, 77 had neutropenia. The most common infection in patients with/without neutropenia was due to C. tropicalis (31/77) and C. albicans (295/608) respectively. Overall success was numerically lower in patients with vs without neutropenia (63.6% vs 72.9%). Clinical and mycological response was similar between groups. Neutropenia duration or Candida spp. did not impact micafungin's overall success rate. This analysis supports evidence that micafungin is effective against invasive candidiasis/candidaemia in patients with neutropenia, irrespective of neutropenia duration or Candida spp., although overall success may be lower than in patients without neutropenia.
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Second-line treatment of patients with metastatic breast cancer resistant to anthracyclines is an important clinical issue. The aim of the present two-stage phase II study was to evaluate activity and toxicity of vinorelbine + mitomycin C (VM) in such patients. Fifty-five patients were entered and received vinorelbine 30 mg/m<sup>2</sup> on days 1 and 8 + mitomycin C 10 mg/m<sup>2</sup> on day 1, every 4 weeks, up to 9 cycles. Two complete and 23 partial responses were observed for an overall response rate of 45.4% (95% CI 32.0–59.4). Median survival was 13 months and probability of surviving after a 1-year follow-up was 58%. Toxicity was never life-threatening, but G-CSF was used in 45% of cycles to contrast neutropenia that was the most frequent side effect. These results are consistent with previous studies and strongly support VM being considered among the optimal polychemotherapy regimens for second-line treatment of metastatic breast cancer in clinical practice; for clinical research aims, VM should be used as control arm for randomized trials evaluating the activity of new drugs against breast cancer.
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