Cardiac safety profile of prolonged (≥6 cycles) pegylated liposomal doxorubicin administration in patients with gynecologic malignancies

Abstract Pegylated liposomal doxorubicin, (CAELYX; Schering Plough) was introduced because of its low or totally absent cardiotoxicity and greater penetration in tumor tissue. Based on differences in clinical pharmacokinetics and clinical studies, the dose for PLD is lower than the standard dose for doxorubicin and epidoxorubicin. This feature makes it suitable for use in older patients and/or those with previous heart disease suffering from diffuse large B-cell NHL, by including Caelyx in 30 mg/mq doses in the classic CHOP regimen, in place of conventional doxorubicin. In this single-centre study, the endpoint were the therapeutic response and the incidence of cardiotoxicity, assessed by means of echocardiogram (LVEF),before and after chemotherapy and at a later stage following the last chemotherapy cycle. Pegylated liposomal doxorubicin was administered in a dose of 30 mg/mq in association with standard doses of Cyclophosphamide 750 mg/mq, Vincristine 1,4 mg/mq, Prednisone 100 mg/mq p.o. day 1–5, and Rituximab 375 mg/mq at 21 day intervals.The trial enrolled 24 patients, aged between 65 and 83 (average age 75 years), in stage II-IV (15 patients in stage IV, 6 in stage III and 3 in stage II); in 65% of the patients, the International Prognostic Index was high-intermediate. An average of six chemotherapy cycles were administered per patients. No dose-limiting cumulative toxicity was observed. The objective responses observed were 85%, with 70% complete responses and 15% partial responses. The average duration of the response was 14 months (1.7–41.5 months). There was no decrease in LVEF associated with administration of pegylated liposomal doxorubicin. Pegylated liposomal doxorubicin in combination with Cyclophosphamide, Vincristine and Prednisone in addition to Rituximab, was found to be active and safe in this series of patients with diffuse large B-cell lymphoma with complete remission in 70% of the cases, without this affecting cardiac safety.

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Cardiac safety of trabectedin monotherapy and in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.11547 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 11547-11547

Author(s):

Robin Lewis Jones ◽

Thomas J. Herzog ◽

Shreyaskumar Patel ◽

Margaret von Mehren ◽

Scott Schuetze ◽

...

Keyword(s):

Ovarian Cancer ◽

Multivariate Analysis ◽

Liposomal Doxorubicin ◽

Safety Data ◽

Pegylated Liposomal Doxorubicin ◽

Cardiac Safety ◽

Phase 3 ◽

Increased Risk ◽

Cardiac Medication ◽

Clinical Awareness

11547 Background: Trabectedin (T) is an established option as monotherapy for advanced soft tissue sarcomas (STS; Leiomyosarcomas and Liposarcomas in the USA) and in combination with pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer (ROC). This retrospective analysis evaluated the cardiac safety profile in over 1500 patients (pts) from clinical trials administering T monotherapy for STS or in combination with PLD (T+PLD) for ROC. Methods: Integrated cardiac safety data was analyzed from ten Phase 2 trials and one Phase 3 trial in STS (T) and two Phase 3 ROC trials (T+PLD). Cardiac-related treatment-emergent adverse events (TEAEs) were summarized using MedDRA terminology and by Kaplan-Meier analysis for time-to-event variables. Subgroup analyses were performed for cardiac-related TEAEs, including any significant decrease in LVEF. Results: Integrated data on T monotherapy included 982 pts (Table). Of these, 110 (11.2%) pts who received ≥1 dose of T experienced a cardiac-related TEAE, including tachycardia (3.1%), palpitations (1.5%), LVEF decrease (1.3%), sinus tachycardia (1.0%), and/or congestive cardiac failure (1.0%). A multivariate analysis revealed factors associated with increased risk to be cardiovascular medical history (risk ratio [RR]: 1.90; 95% CI: 1.24-2.91; p = 0.003) and age > 65 years (RR: 1.78; 95% CI: 1.12,2.83; p = 0.014). Cardiac-related TEAEs were reported in 78 (12.6%) of 619 pts receiving T+PLD (Table). Incidence of cardiac-related TEAEs was greater with T+PLD compared with PLD monotherapy (12.6% vs 5.6%). A multivariate analysis showed that pts were at increased risk for experiencing cardiac-related TEAEs when treated with T+PLD compared to PLD monotherapy (RR: 2.70; 95% CI: 1.75,4.17; p < 0.0001) and when there was a history of prior cardiac medication (RR: 1.88; 95% CI: 1.16,3.05; p = 0.010). Conclusions: Although infrequent, patients receiving T after prior anthracyclines or in combination with PLD are at risk for cardiac dysfunction, and appropriate clinical awareness and monitoring is encouraged to optimize patient outcomes. [Table: see text]

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Safety Profile of Trabectedin in Combination With Liposomal Pegylated Doxorrubicin in Relapsed Ovarian Carcinoma: Considerations for Optimal Management

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e318217b360 ◽

2011 ◽

Vol 21 (Supp 1) ◽

pp. S6-S8 ◽

Cited By ~ 4

Author(s):

Antonio González Martín

Keyword(s):

Safety Profile ◽

Older Patients ◽

Liposomal Doxorubicin ◽

Pegylated Liposomal Doxorubicin ◽

Optimal Management ◽

Toxicity Profile ◽

Hand Foot Syndrome ◽

Clinical Consequences ◽

Health Status Score

The toxicity profile of trabectedin in the OVA-301 trial, that combined trabectedin with pegylated liposomal doxorubicin for the treatment of patients with ovarian cancer, has shown to be predictable and manageable. No unexpected toxicities were found, with neutropenia and transient increase in transaminases as the most common adverse events reported. The elevation in transaminases appeared early and generally decreased in incidence and intensity over subsequent cycles, with no major clinical consequences. A similar safety profile was seen in the analysis of the older patients in the trial. There were no detrimental effects in quality of life with the combination. Moreover, the Global Health Status score was better for the combination arm in those patients with a PFI of 6 to 12 months that were in response after 5 cycles. Trabectedin with pegylated liposomal doxorubicin is not associated with cumulative end-organ toxicities (renal, cardiac, or neurological toxicities). The toxicity profile is different from other second-line strategies without the presence of inconvenient side effects, such as alopecia, hypersensitivity reactions, hand-foot syndrome, or mucositis.

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