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Pegylated liposomal doxorubicin/carboplatin combination in ovarian cancer, progressing on single-agent pegylated liposomal doxorubicin  [cached]
Tal Grenader,Ora Rosengarten,Rut Isacson,Yevgeni Plotkin
World Journal of Clinical Oncology , 2012, DOI: 10.5306/wjco.v3.i10.137
Abstract: AIM: To assess the efficacy and safety of the combination of pegylated liposomal doxorubicin (PLD) and carboplatin in patients with recurrent epithelial ovarian carcinoma (ROC), following disease progression on single agent PLD. METHODS: An analysis of the medical records of 10 patients with ROC, treated in our institution with a combination of PLD and carboplatin following progression on single-agent PLD therapy was performed. The median age was 59.1 years (range, 45 to 77 years). All diagnoses were histological-proven. Eight of the 10 patients were platinum-resistant. Following disease progression on single-agent PLD treatment, carboplatin area under the curve (AUC)-5 was added to PLD in all 10 patients. In order to assess disease status, Ca-125 was assessed before each PLD/carboplatin treatment. Relative changes in Ca-125 values were calculated, and response defined as a greater than 50% reduction in Ca-125 from baseline. Radiographic studies were re-evaluated and responses to therapy based on computer tomography (CT) scans carried out on a regular basis every 2-3 mo in each patient. Statistical analysis was performed using SPSS (V19). RESULTS: A median of 10 cycles (range, 2-26) of the carboplatin-PLD combination was given. Of the 10 treated patients, 6 had > 50% reduction in Ca-125 levels from baseline, 4 of these had a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and the other 2 patients had no measurable disease. In a further 2 patients with a best response of disease stabilization and < 50% reduction of Ca-125 levels, one had progression of disease after 26 cycles, and the second progressed with brain metastases following 12 cycles. Seven of the eight patients who were platinum-resistant showed evidence of clinical benefit on carboplatin-PLD combination therapy; 5 of these had > 50% reduction in Ca-125 level, 4 also showed a partial response on CT scan. The treatment was generally well-tolerated by the patients. CONCLUSION: Addition of carboplatin to PLD, after disease progression on single-agent PLD therapy, is both effective and safe in patients with ROC, even in those with Platinum-resistant disease.
Pegylated liposomal doxorubicin: appraisal of its current role in the management of epithelial ovarian cancer  [cached]
Markman M
Cancer Management and Research , 2011,
Abstract: Maurie MarkmanCancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USAAbstract: Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. The drug is frequently employed as a single agent in the platinum-resistant setting, and recently reported data reveal the superiority of the combination of PLD plus carboplatin, compared with the platinum drug plus paclitaxel, in delaying the time to disease progression in women with recurrent (potentially platinum-sensitive) disease. Current research efforts involving PLD in ovarian cancer are focusing on adding novel targeted drugs to this cytotoxic agent. The utility of such approaches in the platinum-resistant population, compared with the sequential administration of single agents active in this setting, remains to be determined.Keywords: PLD, carboplatin, paclitaxel, platinum-sensitive, platinum-resistant
Pegylated liposomal doxorubicin in ovarian cancer  [cached]
Robert Strother,Daniela Matei
Therapeutics and Clinical Risk Management , 2009,
Abstract: Robert Strother1,2, Daniela Matei1–51Department of Medicine, 2Indiana University Melvin and Bren Simon Cancer Center, 3Department of Obstetrics and Gynecology, 4Department of Biochemistry and Molecular Biology, 5VA Roudebush Hospital Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN, 46202Abstract: The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Liposomal doxorubicin is devoid of the cardiac toxicity associated with doxorubicin, but is associated with predictable muco-cutaneous toxicity. The liposomal formulation leads to improved delivery to the target tumor tissue, allowing enhanced uptake by cancer cells. These properties translate into clinical utility in recurrent ovarian cancer as demonstrated by phase II and III trials, this proven clinical efficacy leading to FDA approval in second-line therapy for ovarian cancer. New combinations with cytotoxics, in particular with carboplatin, have demonstrated an acceptable toxicity profile and clinical utility in platinum-sensitive ovarian cancer. A favorable toxicity profile renders liposomal doxorubicin an ideal partner for combination regimens with other cytotoxics, and more recently with biological agents. Such combinations are the subject of ongoing clinical trials.Keywords: ovarian cancer, doxorubicin, liposomes, pegylated liposomal doxorubicin
Pegylated liposomal doxorubicin in ovarian cancer
Robert Strother, Daniela Matei
Therapeutics and Clinical Risk Management , 2009, DOI: http://dx.doi.org/10.2147/TCRM.S5148
Abstract: ylated liposomal doxorubicin in ovarian cancer Review (5710) Total Article Views Authors: Robert Strother, Daniela Matei Published Date August 2009 Volume 2009:5 Pages 639 - 650 DOI: http://dx.doi.org/10.2147/TCRM.S5148 Robert Strother1,2, Daniela Matei1–5 1Department of Medicine, 2Indiana University Melvin and Bren Simon Cancer Center, 3Department of Obstetrics and Gynecology, 4Department of Biochemistry and Molecular Biology, 5VA Roudebush Hospital Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN, 46202 Abstract: The encapsulation of doxorubicin in a pegylated liposomal matrix led to a reformulated agent with a different toxicity profile and improved clinical utility. Liposomal doxorubicin is devoid of the cardiac toxicity associated with doxorubicin, but is associated with predictable muco-cutaneous toxicity. The liposomal formulation leads to improved delivery to the target tumor tissue, allowing enhanced uptake by cancer cells. These properties translate into clinical utility in recurrent ovarian cancer as demonstrated by phase II and III trials, this proven clinical efficacy leading to FDA approval in second-line therapy for ovarian cancer. New combinations with cytotoxics, in particular with carboplatin, have demonstrated an acceptable toxicity profile and clinical utility in platinum-sensitive ovarian cancer. A favorable toxicity profile renders liposomal doxorubicin an ideal partner for combination regimens with other cytotoxics, and more recently with biological agents. Such combinations are the subject of ongoing clinical trials.
Pegylated liposomal doxorubicin: appraisal of its current role in the management of epithelial ovarian cancer
Markman M
Cancer Management and Research , 2011, DOI: http://dx.doi.org/10.2147/CMAR.S15558
Abstract: ylated liposomal doxorubicin: appraisal of its current role in the management of epithelial ovarian cancer Review (3389) Total Article Views Authors: Markman M Published Date June 2011 Volume 2011:3 Pages 219 - 225 DOI: http://dx.doi.org/10.2147/CMAR.S15558 Maurie Markman Cancer Treatment Centers of America, Eastern Regional Medical Center, Philadelphia, PA, USA Abstract: Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. The drug is frequently employed as a single agent in the platinum-resistant setting, and recently reported data reveal the superiority of the combination of PLD plus carboplatin, compared with the platinum drug plus paclitaxel, in delaying the time to disease progression in women with recurrent (potentially platinum-sensitive) disease. Current research efforts involving PLD in ovarian cancer are focusing on adding novel targeted drugs to this cytotoxic agent. The utility of such approaches in the platinum-resistant population, compared with the sequential administration of single agents active in this setting, remains to be determined.
Clinical Trials with Pegylated Liposomal Doxorubicin in the Treatment of Ovarian Cancer  [PDF]
Carmela Pisano,Sabrina Chiara Cecere,Marilena Di Napoli,Carla Cavaliere,Rosa Tambaro,Gaetano Facchini,Cono Scaffa,Simona Losito,Antonio Pizzolorusso,Sandro Pignata
Journal of Drug Delivery , 2013, DOI: 10.1155/2013/898146
Abstract: Among the pharmaceutical options available for treatment of ovarian cancer, increasing attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation prolongs the persistence of the drug in the circulation and potentiates intratumor accumulation. Pegylated liposomal doxorubicin (PLD) has become a major component in the routine management of epithelial ovarian cancer. In 1999 it was first approved for platinum-refractory ovarian cancer and then received full approval for platinum-sensitive recurrent disease in 2005. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Recent interest in PLD/carboplatin combination therapy has been the object of phase III trials in platinum-sensitive and chemona?ve ovarian cancer patients reporting response rates, progressive-free survival, and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. This paper summarizes data clarifying the role of pegylated liposomal doxorubicin (PLD) in ovarian cancer, as well as researches focusing on adding novel targeted drugs to this cytotoxic agent. 1. Introduction Ovarian cancer (OvCa) is the leading cause of death from gynaecological malignancies with an estimated 65697 new cases and 41448 deaths every year in Europe [1]. Approximately 15% of women present with disease localized in the ovaries and in this group surgery allows a 5-year survival in more than 90% of the cases. However, the majority of women present at the diagnosis with advanced disease (International Federation of Gynaecological Oncology (FIGO) stage III-IV) and their survival at 5 years is poor, currently less than 30% [2]. The main reasons for the high mortality rate are the lack of symptoms accompanying this tumor, in addition to the lack of an effective screening strategy for the overall population, and, lastly, the limited results obtained with standard medical treatments. The standard of care for the management of OvCa patients includes surgery for staging and optimal cytoreduction (no residual tumour) followed by a platinum/taxane chemotherapy combination [3, 4]. Recently bevacizumab has been approved in stage IIIb-IV cancer in combination and as a single-agent maintenance after carboplatin-paclitaxel [5, 6]. Although chemotherapy obtains high objective response rates even in patients with an advanced tumor stage, the vast majority of patients will experience tumor progression and require further therapy [7, 8]. Many strategies have been
Safety of a 3-weekly schedule of carboplatin plus pegylated liposomal doxorubicin as first line chemotherapy in patients with ovarian cancer: preliminary results of the MITO-2 randomized trial
Sandro Pignata, Giovanni Scambia, Antonella Savarese, Enrico Breda, Paolo Scollo, Rocco De Vivo, Emanuela Rossi, Vittorio Gebbia, Donato Natale, Filomena Del Gaizo, Emanuele Naglieri, Antonella Ferro, Pietro Musso, Alfonso D'Arco, Roberto Sorio, Carmela Pisano, Massimo Di Maio, Giuseppe Signoriello, Annalisa Annunziata, Francesco Perrone, the MITO Investigators (see appendix)
BMC Cancer , 2006, DOI: 10.1186/1471-2407-6-202
Abstract: Patients with ovarian cancer (stage Ic-IV), aged < 75 years, ECOG performance status ≤ 2, were randomized to carboplatin AUC 5 plus paclitaxel 175 mg/m2, every 3 weeks or to carboplatin AUC 5 plus pegylated liposomal doxorubicin 30 mg/m2, every 3 weeks. Treatment was planned for 6 cycles. Toxicity was coded according to the NCI-CTC version 2.0.The pre-planned safety analysis was performed in July 2004. Data from the first 50 patients treated with carboplatin plus pegylated liposomal doxorubicin were evaluated. Median age was 60 years (range 34–75). Forty-three patients (86%) completed 6 cycles. Two thirds of the patients had at least one cycle delayed due to toxicity, but 63% of the cycles were administered on time. In most cases the reason for chemotherapy delay was neutropenia or other hematological toxicity. No delay due to palmar-plantar erythrodysesthesia (PPE) was recorded. No toxic death was recorded. Reported hematological toxicities were: grade (G) 3 anemia 16%, G3/G4 neutropenia 36% and 10% respectively, G3/4 thrombocytopenia 22% and 4% respectively. Non-haematological toxicity was infrequent: pulmonary G1 6%, heart rhythm G1 4%, liver toxicity G1 6%, G2 4% and G3 2%. Complete hair loss was reported in 6% of patients, and G1 neuropathy in 2%. PPE was recorded in 14% of the cases (G1 10%, G2 2%, G3 2%).This safety analysis shows that the adopted schedule of carboplatin plus pegylated liposomal doxorubicin given every 3 weeks is feasible as first line treatment in ovarian cancer patients, although 37% of the cycles were delayed due to haematological toxicity. Toxicities that are common with standard combination of carboplatin plus paclitaxel (neurotoxicity and hair loss) are infrequent with this experimental schedule, and skin toxicity appears manageable.Ovarian cancer has the highest mortality rate of all gynaecologic neoplasms. The high mortality rate may be explained by the lack of symptoms accompanying early disease, resulting in patients being diagnosed
A randomized phase II study of carboplatin plus pegylated liposomal doxorubicin versus carboplatin plus paclitaxel in platinum sensitive ovarian cancer patients: a Hellenic Cooperative Oncology Group study
Dimitrios Bafaloukos, Helena Linardou, Gerasimos Aravantinos, Christos Papadimitriou, Aristotelis Bamias, George Fountzilas, Haralabos P Kalofonos, Paris Kosmidis, Eleni Timotheadou, Thomas Makatsoris, Epaminondas Samantas, Evangelos Briasoulis, Christos Christodoulou, Pavlos Papakostas, Dimitrios Pectasides, Athanasios M Dimopoulos
BMC Medicine , 2010, DOI: 10.1186/1741-7015-8-3
Abstract: Patients with histologically confirmed recurrent OC, at the time of or more than 6 months after platinum-based chemotherapy, were randomized to six cycles of CP (carboplatin AUC5 + paclitaxel 175 mg/m2, d1q21) or CLD (carboplatin AUC5 + pegylated LD 45 mg/m2, d1q28).A total of 189 eligible patients (CP 96, CLD 93), with a median age of 63 years, median Performance Status (PS) 0 and a median platinum free interval (PFI) of 16.5 months, entered the study. Discontinuation due to toxicity was higher in the CP patients (13.5% versus 3%, P = 0.016). The overall response rate was similar: CP 58% versus CLD 51%, P = 0.309 (Complete Response; CR 34% versus 23%) and there was no statistical difference in time-to-progression (TTP) or overall survival (OS; TTP 10.8 months CP versus 11.8 CLD, P = 0.904; OS 29.4 months CP versus 24.7 CLD, P = 0.454). No toxic deaths were recorded. Neutropenia was the most commonly seen severe toxicity (CP 30% versus CLD 35%). More frequent in CLD were severe thrombocytopenia (11% versus 2%, P = 0.016), skin toxicity and Palmar-plantar erythrodysesthesia (PPE) grade 1-2 (38% versus 9%, P< 0.001), while grade 3 neurotoxicity and alopecia were higher in CP (7% versus 0%, P = 0.029, 20% versus 5%, P = 0.003). PS and PFI were independent prognostic factors for TTP and OS.The combination of pegylated LD with carboplatin is effective, showing less neurotoxicity and alopecia than paclitaxel-carboplatin. It thus warrants a further phase III evaluation as an alternative treatment option for platinum-sensitive OC patients.Australian New Zealand Clinical Trials Registry: ACTRN12609000436279Ovarian cancer (OC) remains the leading cause of death due to gynaecological malignancies [1]. The standard first-line treatment is a platinum-paclitaxel combination, achieving complete response rates of up to 50%. However, despite progress in first-line therapy, more than 60% of patients relapse and die from chemoresistant disease [2-4]. Therefore, the majority of patient
Phase II study of the combination carboplatin plus celecoxib in heavily pre-treated recurrent ovarian cancer patients
Francesco Legge, Amelia Paglia, Marco D'Asta, Gilda Fuoco, Giovanni Scambia, Gabriella Ferrandina
BMC Cancer , 2011, DOI: 10.1186/1471-2407-11-214
Abstract: Patients were administered oral celecoxib (400 mg/day) in combination with intravenous carboplatin (AUC5, q28). A Simon's two-stage design was employed.45 patients were enrolled: 23 (51.1%) presented platinum-resistance, and 27 (60%) had received at least 3 prior regimens for recurrence. The response rate was 28.9% with 3 complete and 10 partial responses (median duration of response = 6 months). Only one (0.4%) G4 non-febrile neutropenia was observed; G3 neutropenia, anemia, or thrombocytopenia, were observed in 2.5%, 1.7%, and 1.7% of the cycles, respectively. G3-4 vomiting was reported in only 1.7%, and 0.4% of the cycles were associated with G3 dyspepsia or diarrhea or constipation. Only one patient experienced G3 hypertension associated to G2 hypersensitivity reaction. No differences in baseline versus post-treatment Quality of Life scores were observed. Median progression free survival and overall survival were 5 and 13 months, respectively.Celecoxib combined with carboplatin showed promising activity and it is well tolerated in heavily-treated recurrent ovarian cancer patients.NCT01124435 (ClinicalTrials.gov Identifier) and 935/03 (study ID numbers).Most ovarian cancer (OC) patients experience recurrence of disease within 2 years from initial treatment, and typically are re-treated with platinum-based combinations, if considered platinum-sensitive (interval to recurrence/progression longer than 6 months) [1,2] or with non-platinum agents, such as liposomal doxorubicin, gemcitabine, topotecan, if considered platinum-resistant (interval to recurrence/progression less than 6 months from the completion of primary treatment) [3,4]. However, going on to receive multiple lines of chemotherapy, platinum re-treatment is very often attempted, also after the administration of several non-platinum drugs, and shows response rates ranging from 6 to 23% [5-7]. Given the palliative intent of any medical treatment of recurrent OC [8,9], the integration of non-cytotoxic drugs
Pegylated liposomal doxorubicin in the management of ovarian cancer
Gabriella Ferrandina, Giacomo Corrado, Angelo Licameli, et al
Therapeutics and Clinical Risk Management , 2010, DOI: http://dx.doi.org/10.2147/TCRM.S3348
Abstract: ylated liposomal doxorubicin in the management of ovarian cancer Review (5006) Total Article Views Authors: Gabriella Ferrandina, Giacomo Corrado, Angelo Licameli, et al Published Date September 2010 Volume 2010:6 Pages 463 - 483 DOI: http://dx.doi.org/10.2147/TCRM.S3348 Gabriella Ferrandina1,2, Giacomo Corrado1, Angelo Licameli1, Domenica Lorusso2, Gilda Fuoco1, Salvatore Pisconti3, Giovanni Scambia2 1Gynecologic Oncology Unit, Department of Oncology, Catholic University of Campobasso, Campobasso, Italy; 2Gynecologic Oncology Unit, Catholic University of Rome, Rome, Italy; 3Salvatore Pisconti, Oncology Unit, Taranto Hospital, Taranto, Italy Abstract: Among the pharmaceutical options available for treatment of ovarian cancer, much attention has been progressively focused on pegylated liposomal doxorubicin (PLD), whose unique formulation, which entraps conventional doxorubicin in a bilayer lipidic sphere -surrounded by a polyethylene glycol layer, prolongs the persistence of the drug in the -circulation and potentiates intratumor drug accumulation. These properties enable this drug to sustain its very favorable toxicity profile and to be used safely in combination with other drugs. PLD has been already approved for treatment of advanced ovarian cancer patients failing first-line platinum-based treatment. Moreover, phase III trials have been already completed, and results are eagerly awaited, which hopefully will expand the range of PLD clinical application in this neoplasia both in front-line treatment, and in the salvage setting in combination with other drugs. Moreover, attempts are continuing to enable this drug to be combined with novel cytotoxic drugs and target-based agents. This review aims at summarizing the available evidence and the new perspectives for the clinical role of PLD in the management of patients with epithelial ovarian cancer.
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