Safety Of Nonpegylated Liposomal Doxorubicin Research Articles

Efficacy and safety of non-pegylated liposomal doxorubicin in metastatic breast cancer therapy

Breast cancer is the most frequently diagnosed female cancer in Poland (over 17,500 women). Anthracyclines have become one of the most important drugs in breast cancer systemic treatment. In the treatment of metastatic disease combination chemotherapy with doxorubicin provides the objective response rate of 60–85%, and the median time of progression-free survival is about 12 months. Non-pegylated liposomal doxorubicin (NPLD) in combination with cyclophosphamide is associated with a lower risk of cardiotoxicity, higher efficacy and more favourable toxicity profile as compared with conventional anthracycline regimes. Two cases of females patients treated with NPLD described in this article demonstrate the importance of the choice of chemotherapy, professional monitoring, early detection and treatment of adverse effects. Non-pegylated liposomal doxorubicin ordained in systemic treatment of stage IV breast cancer prolongs survival and enhances the quality of life. It is a reasonable option for palliative therapy.

Nonpegylated Liposomal Doxorubicin as a Component of R-CHOP Is an Effective and Safe Alternative to Conventional Doxorubicin in the Treatment of Patients With Diffuse Large B-Cell Lymphoma and Preexisting Cardiac Diseases.

The aim of this retrospective analysis was to investigate the efficacy and safety of nonpegylated liposomal doxorubicin (NPLD) as part of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL) and preexisting cardiac diseases. Twenty-five patients were evaluated, median age was 73 (range 24-85) years, 23 patients received NPLD as part of their first-line therapy. Most patients suffered from more than 1 cardiac disease and in 14 patients left ventricular ejection fraction (LVEF) was reduced. One hundred nineteen cycles of NPLD were applied with a median of 5 (range 2-8) cycles per patient. Median dose per cycle was 95 mg (50 mg/m(2)). The overall response rate was 96% (44% complete remission, 52% partial remission). After a median follow-up of 23 months, 4 patients had disease relapse. Seven patients died, translating to an estimated 3-year progression-free and overall survival of 66% and 73%, respectively. Reasons for death were progressive disease or infection in 2 patients each and cardiovascular disease in 3 patients. After chemotherapy, LVEF decreased significantly in 28% and improved in 12% of patients, whereas median LVEF did not change (51% vs. 50%). No higher frequencies of decreased LVEF was observed in the group of patients with preexisting reduced LVEF. Five adverse events induced therapy termination: 2 myocardial infarctions, 2 pneumonias, and 1 reduced condition. No hand-foot-syndrome was observed. NPLD as a component of R-CHOP is an effective treatment in patients with DLBCL and preexisting cardiac diseases, whereas cardiac events were observed in 36% of patients in this cardiac high-risk group. However, these results need to be confirmed in a prospective randomized trial.

P3-16-13: Cardiac Safety of Non-Pegylated Liposomal Doxorubicin and Docetaxel as 1st Line Treatment in Metastatic HER2 Negative Breast Cancer (Myotax Study).

Abstract Background: Doxorubicin (DOX) is an effective, but cardiotoxic agent in metastatic breast cancer (BC). Incidence of heart failure (HF) is 2–4% and increases considerably with cumulative doses over 450–550 mg/m2. In Myocet® DOX is encapsulated in liposomes. It is delivered predominantly to areas with increased capillary permeability such as tumors and reduces cardiac exposure. We conducted an open non-comparative study to assess cardiac safety of Myocet® combined with docetaxel. Materials and methods: Females with locally advanced or metastatic HER2 negative BC. 6 cycles of Myocet® 60 mg/m2 and docetaxel 75 mg/m2 q3w as 1st line therapy. Left ventricular ejection fraction (LVEF) and disease status were assessed after cycle 2,4 and 6. Primary endpoint: signs and symptoms of HF (NYHA III-IV) or LVEF <50% and decrease ≥5% (with symptoms) or ≥10% (without symptoms). Results: 68 patients (pats) were included. Mean (sd;range) age 56,3 y (10,2;32-79), mean disease duration 5,5 y (5,1 y;1 mo-19 y), 31 pats had anthracyclines (AN) in the past. 49 pats completed all 6 cycles. Mean LVEF (%) over time are presented in table 1. 4 pats (3 AN pretreated) met the LVEF criteria for cardiotoxicity (no signs/symptoms of HF) after the 6th cycle. In 3 pats (all AN pretreated) a significant drop in LVEF was given as (one of the) reason(s) for premature discontinuation, but LVEF criteria for cardiotoxicity were not met. 73 grade ≥3 toxicities occurred in 32 pats; most frequent: neutropenia (±fever) 19 pats. Premature discontinuations (no. of pats): progressive disease 9, cardiotoxicity 3, other toxicity 4, death 2, other reason 1. In 10 pats the dose of Myocet was reduced. The best response was scored for 50 pats with at least 1 measurable lesion: CR 4, PR 28, SD 14, PD 4. Mean LVEF in the entire group decreased during the study from 63 to 59 (9,2) %. The decrease in the AN pretreated group was 7% and in the not pretreated pats 3%. 4 pats met the LVEF criteria for cardiotoxicity and 3 others were withdrawn for cardiotoxicity without meeting the criteria. 6 of these pats were AN pretreated. None of them had signs/symptoms of HF. PR or better was observed in 64% of pats. Conclusion: Liposomal DOX might provide more cardiac safety compared to conventional AN, but pats pretreated with conventional AN seem to be more prone to LVEF decrease. No signs or symptoms of HF have been observed. The combination of Myocet® and docetaxel is efficacious and sufficiently well tolerated and is currently investigated in combination with trastuzumab in HER2 positive pats. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-13.

A phase I/II trial of non-pegylated liposomal doxorubicin, docetaxel and trastuzumab as first-line treatment in HER-2-positive locally advanced or metastatic breast cancer

AimTo assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC). Patients and methodsThe maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6–8 cycles of Myocet® 50mg/m2 (day 1), docetaxel 30mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4mg/kg followed by 2mg/kg/week) every 21d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF). ResultsThe overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9months (C.I. 8.7–15.0). Median overall survival was not reached. The most frequent grade 3–4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3–4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline >15%. LVEF median values remained stable from baseline to the end of the study (60%). ConclusionsThe combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC.

Nonpegylated liposomal doxorubicin (Myocet™) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EUR018 trial

BackgroundTo evaluate the activity and safety of nonpegylated liposomal doxorubicin (Myocet™) when substituted for doxorubicin in the R-CHOP regimen (R-COMP). Patients and methodsSeventy-five elderly patients with diffuse large B-cell lymphoma (DLBCL) were studied. Only patients with left ventricular ejection fraction (LVEF) ≥50% were allowed. R-COMP regimen was administered every 3 weeks for three cycles, followed by additional five cycles in case of complete response (CR) or partial response. ResultsFrom November 2002 to April 2005, 75 patients were registered, of which 72 were evaluated. Median age was 72 years (range 61–83); 56% of patients had high or high–intermediate International Prognostic Index score. Median LVEF at baseline was 61%. Thirty-eight patients had history of abnormal cardiovascular conditions. The overall response rate was 71%, with a CR rate of 57%. After a median follow-up of 33 months, the 3-year overall survival, failure-free survival, and progression-free survival rates were 72%, 39%, and 69%, respectively. Neutropenia (54%) was the most frequent grade 3–4 adverse event (AE); 21% of patients experienced cardiac AEs, graded as 3–4 in 4% of the cases. ConclusionR-COMP is an effective regimen for the treatment of DLBCL in elderly patients, with an acceptable tolerability profile.

Cardiac safety of nonpegylated liposomal doxorubicin in patients with advanced breast cancer treated with myocet plus vinorelbine or myocet plus cyclophosphamide in a randomized phase II trial.

1119 Background: Treatment with nonpegylated liposomal doxorubicin (Myocet, M) has already shown a reduced level of cardiotoxicity as compared to traditional doxorubicin. We are reporting the cardiac safety of M evaluated in a multicenter randomized phase II trial comparing M plus vinorelbine (V) versus M plus cyclophosphamide (C). Methods: Patients must have LABC or MBC, PS (ECOG≤ 2) and measurable disease. Previous anthracyclines as adjuvant, or endocrine therapy for advanced disease were allowed. They received M 60 mg/m2 plus C 600 mg/m2 iv on day1 of a 21 day cycle (arm A), or M 50 mg/m2 plus V 25 mg/m2 iv on day 1 and V 60 mg/m2 orally on day 8 of a 21 day cycle. Primary objective was ORR, secondary endpoint was safety. Cardiotoxicity was monitored by echocardiogram, performed every 3 cycles for the first 6 cycles and every other cycle afterwords. Results: Between July 2006 and November 2009 178 women were enrolled, 137 are actually evaluable for efficacy and safety (41 pts too early). Patient charac...

5068 Cardiac safety of non-pegylated liposomal doxorubicin in combination with docetaxel as 1st line treatment in locally advanced or metastatic HER2 negative breast cancer (MYOTAX study)

Immune deficiency and bacterial infection have been suggested to play a role in the pathophysiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Zoledronate was previously found to promote THP-1 cell death. To examine this hypothesis with all commonly prescribed bisphosphonates, we tested the effect of (nitrogen-containing) ibandronate, risedronate, alendronate, pamidronate, and (non–nitrogen-containing) clodronate on macrophagic THP-1 cells.Activated THP-1 cells were exposed to .5 to 50 μM of nitrogen-containing bisphosphonates and .5 to 500 μM of clodronate. Cell adherence and survival were assessed in vitro using the xCELLigence real-time monitoring system. Results were confirmed histologically and verified with Live/Dead staining.All bisphosphonates inhibited THP-1 cell adherence and survival dose and time dependently, significant for zoledronate, alendronate, pamidronate, and clodronate in high concentrations (50 μM and 500 μM; P < .05). Low concentrations (0.5 μM) of risedronate, alendronate, and pamidronate prolonged the inflexion points of THP-1 cell survival compared with controls (P < .05). THP-1 cells exhibited no cytomorphologic changes at all concentrations.Commonly prescribed bisphosphonates inhibit the survival of macrophagic THP-1 cells dose-dependently without altering morphology. This may suggest a local immune dysfunction reflective of individual bisphosphonate potency leading to the pathogenesis of BRONJ.