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FORWARD I: a Phase III study of mirvetuximab soravtansine versus chemotherapy in platinum-resistant ovarian cancer.
Moore, KN, Vergote, I, Oaknin, A, Colombo, N, Banerjee, S, Oza, A, Pautier, P, Malek, K, Birrer, MJ
Future oncology (London, England). 2018;(17):1669-1678
Abstract
Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer. Patients will be randomized in a 2:1 ratio. The primary end point is progression-free survival, and key secondary objectives include comparison of overall response rates, overall survival and duration of response.
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Use of dairy products, lactose, and calcium and risk of ovarian cancer - results from a Danish case-control study.
Faber, MT, Jensen, A, Søgaard, M, Høgdall, E, Høgdall, C, Blaakaer, J, Kjaer, SK
Acta oncologica (Stockholm, Sweden). 2012;(4):454-64
Abstract
BACKGROUND A number of epidemiological studies have examined the association between use of dairy products and risk of ovarian cancer, but results are conflicting. Using data from a large Danish population-based case-control study we here further examined the association between dairy consumption, lactose, and calcium and risk of overall ovarian cancer and histological types of ovarian cancer. MATERIAL AND METHODS In the period 1995-1999 we included 554 women with epithelial ovarian cancer and 1554 randomly selected age-matched controls (35-79 years). All women participated in a detailed personal interview that included questions about dairy consumption. Data were analysed using multiple logistic regression models. RESULTS Total dairy intake was associated with ovarian cancer risk (OR = 1.11; 95% CI: 1.07-1.15 per 100 ml/day). The association was strongest for milk [OR = 1.14; 95% CI: 1.03-1.27 per glass (200 ml)/day], soured milk products [OR = 1.49; 95% CI: 1.22-1.81 per portion (250 ml)/day] and yoghurt [OR = 1.65; 95% CI: 1.22-2.23 per portion (250 ml)/day]. In contrast, intake of cheese was associated with a decreased risk [OR = 0.70; 95% CI: 0.55-0.89 for > 1 portion (100 ml)/day compared with no intake]. Intake of lactose, but not calcium, was also associated with an increased ovarian cancer risk (OR = 1.24; 95% CI: 1.10-1.40 per 10 g of lactose/day). Similar risk patterns were observed for the different histological types of ovarian cancer, indicating virtually identical aetiologies with regard to dairy intake, lactose, and calcium. CONCLUSIONS Our results indicate that intake of dairy products is associated with a modest increased risk of ovarian cancer. In addition, ovarian cancer development was associated with lactose intake.
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Comparison in purity and antitumor effect of brand and generic paclitaxel against human ovarian cancer cells by an in vitro experimental model.
Wang, KL, Yang, YC, Lai, JC, Tsai, TH, Lin, CP, Wu, YT, Chen, YY, Wang, SC, Chen, YJ
Drug development and industrial pharmacy. 2010;(10):1253-8
Abstract
CONTEXT The purity and the therapeutic effectiveness of the generic paclitaxel have not yet been examined and compared to the original brand form. OBJECTIVE This study aimed to compare the in vitro purity and biological effects of original brand form (Taxol) and a generic drug of paclitaxel. MATERIALS AND METHODS Purity was determined by high-performance liquid chromatography analysis, cell viability by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay, cell proliferation by clonogenic assay, morphology by Liu's staining, and cell cycle distribution by DNA histogram. RESULTS Taxol and generic paclitaxel shared similar high-performance liquid chromatography profiles with a major peak at the same retention time and ultraviolet spectrum. Generic paclitaxel inhibited the cell viability to an extent greater than Taxol. By assessing the IC(50), generic paclitaxel also exhibited a greater inhibitory activity on clonogenicity of human ovarian adenocarcinoma SKOV-3 cells. Although both generic paclitaxel and Taxol arrested SKOV-3 and ES-2 cells at G2/M phase with concurrent development of hypoploid and polyploid cells, Taxol treatment exhibited markedly less extent of these changes. Observation of cellular morphology revealed a greater amount of mitotic catastrophe-like and apoptotic cells in generic paclitaxel-treated cells than Taxol-treated cells. DISCUSSION AND CONCLUSION The results suggest that generic paclitaxel may possess a greater cell death inducing capacity and clonogenicity inhibitory activity against ovarian cancer cells than the original brand Taxol of the same purity. We conclude that this experimental model for assessing the difference between generic and brand name drugs might be considered as a reference while determining their interchangeability and could be easily established in a hospital-based laboratory.
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Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial.
Markman, M, Liu, PY, Moon, J, Monk, BJ, Copeland, L, Wilczynski, S, Alberts, D
Gynecologic oncology. 2009;(2):195-8
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Abstract
OBJECTIVES A SWOG/GOG phase 3 trial exploring the impact of 12-monthly cycles of paclitaxel given to patients with advanced ovarian cancer who achieved a complete response to primary chemotherapy was discontinued by the Data Safety and Monitoring Committee when a prospectively defined interim analysis revealed a highly statistically significant improvement in progression-free survival (PFS). At study closure, it was too early to assess the impact on overall survival. METHODS Patients (n=296) received either 3 or 12 monthly cycles of paclitaxel (175 mg/m(2) over 3 h). RESULTS Of the 146 patients on the 3-cycle arm, 9 (6%) received >3 cycles. Median (12 versus 3 cycles; intention-to-treat analysis) updated PFS (all pts) 22 versus 14 months, p=0.006; overall survival (all pts) 53 versus 48 months, p=0.34. CONCLUSION Twelve cycles of single agent maintenance paclitaxel significantly improves PFS. Explanations for the lack of a favorable influence on overall survival include: (a) treatment at relapse equalized outcome; (b) the sample size was insufficient to reveal a difference; (c) "crossover" of patients from 3 cycles to longer treatment masked a potential difference. An ongoing phase 3 trial will hopefully provide a definitive answer to the question of the impact of this maintenance strategy on overall survival.
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Lack of reliability of CA125 response criteria with anti-VEGF molecularly targeted therapy.
Azad, NS, Annunziata, CM, Steinberg, SM, Minasian, L, Premkumar, A, Chow, C, Kotz, HL, Kohn, EC
Cancer. 2008;(8):1726-32
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Abstract
BACKGROUND CA125 is an accepted indicator of epithelial ovarian cancer (EOC) response and is used to monitor patients treated with cytotoxic chemotherapy. It is uncertain how CA125 is affected by molecularly targeted drugs. In this pilot study, the authors analyzed the utility of CA125 to predict disease behavior in patients who were receiving sorafenib, a Raf-kinase/VEGFR2 inhibitor, and bevacizumab, an anti-VEGF monoclonal antibody. METHODS Fifteen of 42 patients had recurrent EOC. Patients received sorafenib 200 mg orally twice daily or D1-5 of 7 and bevacizumab 5 mg/kg to 10 mg/kg intravenously every 2 weeks for 28-day cycles. Computed tomography (CT) scans were performed every 2 cycles for restaging, and CA125 was measured monthly. CA125 concentrations were retrospectively analyzed as a function of clinical behavior. RESULTS Fourteen of 15 patients had abnormal CA125 concentrations at study entry (median 1056 U/mL; range, 67 U/mL to 9813 U/mL). Seven (47%) patients had partial response by imaging criteria. Five of these 7 patients had partial response by CA125 criteria (71% sensitivity). Eight (53%) patients would have had partial responses if CA125 criteria were used; only 5 were confirmed by CT (63 % specificity). Imaging and CA125 criteria combined yielded a higher total response rate of 10 of 15 (67%). Three patients with objective partial response by imaging lasting >20, >22, and >24 cycles would have terminated treatment prematurely if CA125 had been used. CONCLUSIONS CA125 changes may not correspond to imaging response criteria for EOC patients who are receiving sorafenib and bevacizumab. Caution is recommended when using CA125 as a response criterion of molecularly targeted agents until prospective studies validate CA125 changes with objective imaging response results.
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Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum.
Rosenberg, P, Andersson, H, Boman, K, Ridderheim, M, Sorbe, B, Puistola, U, Parö, G
Acta oncologica (Stockholm, Sweden). 2002;(5):418-24
Abstract
The aim of this study was to evaluate the efficacy and toxicity of paclitaxel given at the same dose intensity and administered weekly (arm A) or every 3 weeks (arm B). and to assess the safety of intravenous steroids versus standard peroral premedication. Two hundred and eight patients with advanced ovarian cancer previously treated with no more than one platinum-containing regimen were randomized to receive either a weekly infusion of paclitaxel or an infusion every 3 weeks. The median delivered dose intensity was 77.6 mg/m2/week in the weekly arm, and 72.7 mg/m2/week in the every 3 weeks arm. WHO grade 3-4 hematological and non-hematological toxicity occurred more frequently in arm B. No difference in number of severe events of hypersensitivity, response rate, time to progression or survival between arms was observed. Weekly paclitaxel at a dose of 67 mg/m2/week was found to have a better safety profile and seemed to be as effective as the equivalently dosed schedule every 3 weeks. Intravenous steroids are a safe alternative to oral steroids.