Trabectedin Plus Pegylated Liposomal Doxorubicin in Recurrent Ovarian Cancer

Columbia University, New York, New York, United States
Journal of Clinical Oncology (Impact Factor: 18.43). 07/2010; 28(19):3107-14. DOI: 10.1200/JCO.2009.25.4037
Source: PubMed

ABSTRACT The objective of this study was to compare the efficacy and safety of trabectedin plus pegylated liposomal doxorubicin (PLD) with that of PLD alone in women with recurrent ovarian cancer after failure of first-line, platinum-based chemotherapy.
Women > or = 18 years, stratified by performance status (0 to 1 v 2) and platinum sensitivity, were randomly assigned to receive an intravenous infusion of PLD 30 mg/m(2) followed by a 3-hour infusion of trabectedin 1.1 mg/m(2) every 3 weeks or PLD 50 mg/m(2) every 4 weeks. The primary end point was progression-free survival (PFS) by independent radiology assessment.
Patients (N = 672) were randomly assigned to trabectedin/PLD (n = 337) or PLD (n = 335). Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65 to 0.96; P = .0190). For platinum-sensitive patients, median PFS was 9.2 months v 7.5 months, respectively (hazard ratio, 0.73; 95% CI, 0.56 to 0.95; P = .0170). Overall response rate (ORR) was 27.6% for trabectedin/PLD v 18.8% for PLD (P = .0080); for platinum-sensitive patients, it was 35.3% v 22.6% (P = .0042), respectively. ORR, PFS, and overall survival among platinum-resistant patients were not statistically different. Neutropenia was more common with trabectedin/PLD. Grade 3 to 4 transaminase elevations were also more common with the combination but were transient and noncumulative. Hand-foot syndrome and mucositis were less frequent with trabectedin/PLD than with PLD alone.
When combined with PLD, trabectedin improves PFS and ORR over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer.

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    • "The toxicity related to trabectedin plus PLD was acceptable. Benefits appeared more evident in the PS subset PFS (median PFS: 9.2 months vs. 7.5 months; p = 0.0170) and even more pronounced in patients with PPS disease with a PFI of 6–12 months PFS (median PFS: 7.4 months vs. 5.5 months; p = 0.0015) [19] [27] [68] [69]. It was the first positive randomized phase III trial in ROC that included a non-platinum and non-taxane combination. "
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    ABSTRACT: Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. In spite of high response rates to the standard front-line treatment for advanced disease with cytoreductive surgical debulking, followed by platinum/taxane-based chemotherapy, most patients eventually relapse developing drug-resistant disease. Owing to the molecular heterogeneity, genetic instability and mutagenicity of OC, increases in survival might be achieved by translating recent insights at the morpho-molecular levels to individual therapeutic strategies. Several emerging treatments have been shown to be active in platinum-sensitive (PS) recurrent OC (ROC), but an optimal strategy still has not been established. Based on the recent results, it is likely that the introduction of novel non-platinum based chemotherapies and molecular targeted therapies will have a major impact on the management of ROC. Some current strategies are focused on the extension of platinum-free interval (PFI) in patients with PS, particularly in those with partially PS disease. Apparently, the PFI extension by an effective non-platinum intervention, such as trabectedin plus pegylated liposomal doxorubicin (PLD), may reduce cumulative platinum-induced toxicities leading to longer survival after the reintroduction of subsequent platinum. The introduction of novel therapies, such as the antiangiogenic monoclonal antibody bevacizumab, opens a new field of targeted therapies in this indication. In this review, we aim to outline the therapeutic potential of new emerging approaches, particularly the role of non-platinum therapy with trabectedin in combination with PLD in patients with PS ROC.
    Cancer Treatment Reviews 08/2013; 40(3). DOI:10.1016/j.ctrv.2013.08.001
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    • "Although a PFI greater than 6 months predicts platinum sensitivity, within this group, patients with an interval greater than 12 months are considered fully sensitive and commonly retreated with platinum-containing regimens, whereas patients with a PFI between 6 and 12 months are believed to have partially platinumsensitive relapse. In this patient subset, both preclinical and clinical data suggest that the artificial prolongation of PFI with a nonplatinum-based therapy may be beneficial in reversing platinum resistance (Monk et al, 2010; Poveda et al, 2011). Conversely, patients who progress while receiving firstline therapy or within 6 months from its completion are considered to have refractory/resistant relapse, which is typically retreated with a monotherapy of nonplatinum agents, such as pegylated liposomal doxorubicin (PLD), gemcitabine, or topotecan, with a disappointing median survival of about 10 months from the time of recurrence (Rose et al, 2010). "
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    ABSTRACT: The NGR-hTNF (asparagine-glycine-arginine-human tumour necrosis factor) is able to promote antitumour immune responses and to improve the intratumoural doxorubicin uptake by selectively damaging tumour blood vessels. Patients progressing after ≥ 1 platinum/taxane-based regimen received NGR-hTNF 0.8 μg m(-2) and doxorubicin 60 mg m(-2) every 3 weeks. Primary endpoint was a Response Evaluation Criteria in Solid Tumors-defined response rate with a target of more than 6 out of 37 responding patients. A total of 37 patients with platinum-free interval lower than 6 months (PFI<6; n=25), or between 6 and 12 months (PFI=6-12; n=12) were enrolled. Median baseline peripheral blood lymphocyte count (PBLC) was 1.6 per ml (interquartile range, 1.2-2.1). In all, 18 patients (49%) received more than 6 cycles. Febrile neutropaenia was registered in one patient (3%). Among 35 assessable patients, 8 (23%; 95% CI 12-39%) had partial response (2 with PFI<6; 6 with PFI=6-12) and 15 (43%) had stable disease (10 with PFI<6; 5 with PFI=6-12). Median progression-free survival (PFS) was 5.0 months for all patients, 3.8 months for patients with PFI<6, and 7.8 months for patients with PFI=6-12. Median overall survival (OS) was 17.0 months. Patients with baseline PBLC higher than the first quartile had improved PFS (P=0.01) and OS (P=0.001). Tolerability and activity of this combination warrant further randomised testing in patients with PFI<6. The role of PBLC as a blood-based biomarker deserves further investigation.
    British Journal of Cancer 05/2012; 107(1):37-42. DOI:10.1038/bjc.2012.233
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    • "Combination therapies tend to be more toxic than monotherapies, especially with respect to myelotoxicity (Breidenbach et al. 2003). The current standard therapy for platinum-sensitive recurrent ovarian cancer (progress 6 months or later after the end of previous therapy) is platinum-based combinations with liposomal doxorubicin, gemcitabine, or paclitaxel (Pujade-Lauraine et al. 2010) and in case of contraindications for platinum the combination of trabectedin and liposomal doxorubicin (Monk et al. 2010). All these combination have a relatively high hematological or non-hematological toxicity in common. "
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    ABSTRACT: Treosulfan, an alkylating agent, has demonstrated activity in recurrent ovarian carcinoma. It is equieffective as oral (p.o.) and intravenous (i.v.) formulation. To explore the preference and compliance of elderly patients regarding p.o. or i.v. treosulfan for the treatment of relapsed ovarian carcinoma, women aged 65 years or older were included in this prospective multicenter study. Since elderly patients usually have several concomitant diseases and experience more treatment toxicity, an interim safety analysis was planned and performed after 25 patients finished therapy to assess the tolerability of the treatment regimens. Patients had a free choice of treosulfan i.v. (7,000 mg/m(2) day 1 of a 28-day cycle) or p.o. (600 mg/m(2) day 1-28 of a 56-day cycle) for a maximum of 12 cycles (i.v.) or 12 months (p.o.). Indecisive patients were randomized. Toxicity was evaluated according to the NCI-CTC version 2.0. Twenty-five of 51 recruited patients completed therapy at the time of the planned interim analysis (median age, 75 years; range, 70-82). Median ECOG was 1, and median number of prior chemotherapy regimens was 2. A median number of 4 cycles (range, 1-12) were administered per patient. Anemia was the most common hematological toxicity (88 % of patients). Most frequent non-hematological toxicities were nausea (76 %), constipation (68 %), and fatigue (64 %). Treatment was generally well tolerated despite the fact that most patients suffered from multiple comorbidities and were heavily pretreated. There were no unexpected hematological or non-hematological toxicities. Based on this safety analysis, the next step of study recruitment was continued.
    Journal of Cancer Research and Clinical Oncology 04/2012; 138(8):1413-9. DOI:10.1007/s00432-012-1221-3
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