Platinum retreatment of platinum-resistant ovarian cancer after nonplatinum therapy
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States Gynecologic Oncology
(Impact Factor: 3.77).
11/2003; 91(1):123-9. DOI: 10.1016/S0090-8258(03)00464-5
The objective was to determine the response rate to platinum retreatment of "platinum-resistant" ovarian cancer after intervening nonplatinum therapy.
We retrospectively identified 30 patients with platinum-resistant ovarian cancer who received nonplatinum chemotherapy for recurrent epithelial ovarian cancer prior to additional platinum therapy. All patients were treated between July 1, 1997, and June 30, 2001. Platinum resistance was defined as less than a partial response to platinum therapy or progression within 6 months of the last platinum therapy.
Overall, 7 of 30 patients experienced an objective response to platinum therapy (partial response, 23%; complete response, 0%) based on CT scan (2/21) and/or CA-125 (5/9) criteria. The median time to progression for the group was 17 weeks (range, 4-59 weeks). Several predictive factors were identified. The interval since the last platinum treatment did not appear to be predictive in this group. Only 1 of 16 patients who did not have an objective response to the most recent platinum-based therapy responded to platinum rechallenge. Similarly, no patient who received more than three intervening nonplatinum treatments responded to additional platinum therapy (0/10).
Our small retrospective series suggest that the platinum-resistant category is heterogenous and includes patients who may respond to retreatment with platinum-based agents. This group includes the patients with prior platinum responses and early progression. However, patients without an objective response to the last prior platinum therapy or more than three intervening treatments are unlikely to respond to subsequent platinum therapy.
Available from: Sheng Yu
- "Epithelial ovarian cancer (OC) is the leading cause of death from gynecologic malignancies. OC is mostly asymptomatic at early-stage, and most of the cases are diagnosed when the tumor has established regional or distant metastases . "
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ABSTRACT: Recently, there have been a number of studies on the association between MDM2 (Murine Double Minute 2) 309 polymorphism and ovarian cancer risk. However, the results of previous reports remain controversial and ambiguous. Thus, we performed a meta-analysis to explore more precisely the association between MDM2 309 polymorphism and the risk of ovarian cancer.
A meta-analysis was performed to examine the association between MDM2 309T>G polymorphism and ovarian cancer risk. Odds ratio (OR) and its 95% confidence interval (CI) were used for statistical analysis.
Our publication search identified a total of 6 studies with 1534 cases and 2211 controls. No significant association was found between MDM2 309T>G polymorphism and ovarian cancer risk in total population analysis. In the subgroup meta-analysis by ethnicity, a negative association was shown in Asian subgroup (G vs. T OR = 0.774, 95% CI = 0.628-0.955, P = 0.017, P(het) = 0.327; GG vs. TT: OR = 0.601, 95% CI = 0.395-0.914, P = 0.017, P(het) = 0.417; dominant model TG+GG vs. TT: OR = 0.661, 95% CI = 0.468-0.934, P = 0.019, P(het) = 0.880), and no significant association in any genetic models among Caucasians was observed.
This meta-analysis provides evidence for the association between MDM2 309 polymorphism and ovarian cancer risk, supporting the hypothesis that MDM2 SNP309 G allele acts as an important ovarian cancer protective factor in Asians but not in Caucasians.
Available from: Leggy A Arnold
- "Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. Early-stage cancers are mostly asymptomatic, and most of the diagnoses at presentation detect established regional or distant metastases . The majority of the patients will experience recurrent disease, as well as resistance to chemotherapeutic agents. "
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ABSTRACT: Numerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models.
Antitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c-VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein.
Antitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis.
Available from: Amelia Paglia
- "The response rates were found not to be significantly associated with the grade of platinum-resistance, thus suggesting a potential influence of celecoxib in favourably modulating the susceptibility to platinating agents. One could argue that the activity documented in platinum-resistant and relatively sensitive subgroups is comparable to the amount of responses reported for platinum reinduction in these specific populations [5,7,30-32]. However, so far, it is difficult to directly compare our results with previously published studies due to the retrospective design of these series [5,7,30-32], the type of response assessment (i.e. "
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ABSTRACT: Cyclooxygenase-2 overexpression is associated with poor outcome and resistance to platinum-based chemotherapy in ovarian cancer. We evaluated the antitumor activity and safety of the combination carboplatin plus the COX-2 inhibitor celecoxib in recurrent heavily-treated OC patients.
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).
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