Objective. Theaim of this prospective study was to evaluate the influence of secondary cytoreductive surgery on survival of patients with recurrent epithelial ovarian cancer.
Methods. Between June ...1993 and June 1999, 149 patients after primary treatment underwent secondary cytoreductive surgery: 69 (46.3%) had recurrence-free interval (RFI) 7–12 months, 59 (39.6%) RFI 13–24 months, and 21 (14.1%) RFI >24 months. Exclusion criteria included secondary cytoreduction during second-look laparotomy, interval cytoreduction, and palliative surgery in patients with intestinal obstruction or progressive disease.
Results. The median follow-up was 27 months. According to multivariate analysis, RFI groups, prior chemotherapy combination, and residual tumor after secondary surgery were associated independently with overall survival. Residual tumor after secondary surgery was by far the most strongly predictive factor for patient's survival (hazard ratio (HR) 2.65; 95% confidence interval (CI) 1.43–4.92). The 2-year survival rates were 22.3, 62.9, and 22.7%, respectively, for patients with RFI 7–12, 13–24, and >24 months. The 5-year survival was 29% for patients with RFI 13–24 months. No patients with RFI 7–12 and >24 months outlived the 4-year estimate. Unexpectedly, RFI >24 months was not correlated significantly with overall survival. However, 17 patients (81%) with RFI >24 months were heavily treated with chemotherapy before secondary surgery.
Conclusions. Patients who have documented gross disease preoperatively should be selected for a secondary debulking operation; the entity of surgical effort would be modulated in relation to previous treatment.
Atrial fibrillation (AF) is the most common cardiac arrhythmia that can potentially result in stroke. Vitamin K antagonists (VKA) like warfarin were for many decades the only oral anticoagulants ...available for stroke prevention in patients with non-valvular atrial fibrillation (AF) at high risk of stroke. Recently, new oral anticoagulants (NOACS) have been introduced that act via direct inhibition of thrombin (dabigatran) or activated factor X (edoxaban, rivaroxaban and apixaban). Unlike VKAs, these anticoagulants do not require routine INR monitoring and posses favorable pharmacological properties. NOACs act rapidly, and have a stable and predictable dose-related anticoagulant effect with few clinically relevant drug-drug interactions. Phase III trials comparing these agents to warfarin for stroke prevention in patients with non-valvular AF demonstrated that they are at least as efficacious and safe as warfarin. Evolution of clinical guidelines to incorporate the new anticoagulants for stroke prevention in non-valvular AF may result in a reduction in the incidence of AF-related strokes. Safe and effective use of these new drugs in clinical practice requires understanding of their distinct pharmacological properties.
Topotecan and paclitaxel were evaluated in a randomized, multicenter study of patients with advanced epithelial ovarian carcinoma who had progressed during or after one platinum-based regimen.
...Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 112) or paclitaxel (175 mg/m2) infused over 3 hours every 21 days (n = 114). Patients had bidimensionally measurable disease and were assessed for efficacy and toxicity.
Response rate was 23 of 112 (20.5%) in topotecan-treated patients and 15 of 114 (13.2%) in paclitaxel-treated patients (P = .138). Disease stabilization for at least 8 weeks was noted in 30% of patients with topotecan and 33% of patients with paclitaxel. Median durations of response to topotecan and paclitaxel were 32 and 20 weeks, respectively (P = .222) and median times to progression were 23 and 14 weeks, respectively (P = .002). Median survival was 61 weeks for topotecan and 43 weeks for paclitaxel (P = .515). Response rates for topotecan and paclitaxel were 13.3% versus 6.7% (P = .303) in resistant patients (not responded to prior platinum-based therapy or progressed within 6 months of an initial response) and 28.8% versus 20.0% (P = .213) in sensitive patients (progressed > 6 months after response). Neutropenia was significantly more frequent on the topotecan arm 79% versus paclitaxel arm 23% (P < .01). It was short-lasting and noncumulative in both arms. Nonhematologic toxicities were generally mild (grades 1 to 2) for both agents.
Topotecan has efficacy at least equivalent to paclitaxel manifested by the higher response rate and significantly longer time to progression.
Background: Combination chemotherapy yields better response rates which do not always lead to a survival advantage. The aim of this study was to investigate whether the reported differences in the ...efficacy and toxicity of monotherapy with doxorubicin (DOX) versus combination therapy with cisplatin (CDDP) in endometrial adenocarcinoma lead to significant advantage in favour of the combination. Patients and methods: Eligible patients had histologically-proven advanced and/or recurrent endometrial adenocarcinoma and were chemo-naïve. Treatment consisted of either DOX 60 mg/m2 alone or CDDP 50 mg/m2 added to DOX 60 mg/m2, every 4 weeks. Results: A total of 177 patients were entered and median follow-up is 7.1 years. The combination DOX–CDDP was more toxic than DOX alone. Haematological toxicity consisted mainly of white blood cell toxicity grade 3 and 4 (55% versus 30%). Non-haematological toxicity consisted mainly of grade 3 and 4 alopecia (72% versus 65%) and nausea/vomiting (36 % versus 12%). The combination DOX–CDDP provided a significantly higher response rate than single agent DOX (P <0.001). Thirty-nine patients (43%) responded on DOX–CDDP 13 complete responses (CRs) and 26 partial responses (PRs), versus 15 patients (17%) on DOX alone (8 CR and 7 PR). The median overall survival (OS) was 9 months in the DOX–CDDP arm versus 7 months in the DOX alone arm (Wilcoxon P = 0.0654). Regression analysis showed that WHO performance status was statistically significant as a prognostic factor for survival, and stratifying for this factor, treatment effect reaches significance (hazard ratio = 1.46, 95% confidence interval 1.05–2.03, P = 0.024). Conclusions: In comparison to single agent DOX, the combination of DOX–CDDP results in higher but acceptable toxicity. The response rate produced is significantly higher, and a modest survival benefit is achieved with this combination regimen, especially in patients with a good performance status.
A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer showed that these two compounds have similar activity. ...In this study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa. We therefore were able to assess the degree of non-cross-resistance between these two compounds.
Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy.
Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients).
Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival. We demonstrated that the two drugs have a degree of non-cross-resistance. Thus, there is a good rationale for incorporating these drugs into future first-line regimens.
This study is aimed at investigating the novel use of minocycline for cardiac protection during ischemia/reperfusion (I/R) injury, as well as its mechanism of action.
Minocycline is a tetracycline ...with anti-inflammatory properties, which is used clinically for the treatment of diseases such as urethritis and rheumatoid arthritis. Experimentally, minocycline has also been shown to be neuroprotective in animal models of cerebral ischemia and to delay progression and improve survival in mouse models of neurodegenerative diseases.
We studied 62 rat intact hearts exposed to I/R and cell cultures of neonatal and adult rat ventricular myocytes.
Minocycline significantly reduced necrotic and apoptotic cell death, both in neonatal and adult myocytes, not only when given prior to hypoxia (p < 0.001), but also at reoxygenation (p < 0.05). Moreover, in the intact heart exposed to I/R, in vivo treatment with minocycline promoted hemodynamic recovery (p < 0.001) and cell survival, with reduction of infarct size (p < 0.001), cardiac release of creatine phosphokinase (p < 0.001), and apoptotic cell death (p < 0.001). In regard to its antiapoptotic mechanism of action, minocycline significantly reduced the expression level of initiator caspases, increased the ratio of XIAP to Smac/DIABLO at both the messenger RNA and protein level, and prevented mitochondrial release of cytochrome c and Smac/DIABLO (all, p < 0.05). These synergistic actions dramatically prevent the post-ischemic induction of caspase activity associated with cardiac I/R injury.
Because of its safety record and multiple novel mechanisms of action, minocycline may be a valuable cardioprotective agent to ameliorate cardiac dysfunction and cell loss associated with I/R injury.
Apoptosis, a genetically programmed form of cell death, contributes to myocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion ...injury. The apoptotic program is complex, involving both pro- and anti-apoptotic proteins, and apoptosis occurs when the equilibrium between these opposing factors is perturbed. Some of these factors are intrinsic to the apoptotic pathway, such as the pro- and anti-apoptotic members of the Bcl2 family. Other, extrinsic, cellular factors can also modify the outcome of the response to an apoptotic stimulus. In this review, we have focused on some of these extrinsic factors, such as STAT-1 as a pro-apoptotic agent and the urocortins and Bag-1 as anti-apoptotic factors, since these may be potential therapeutic targets. In addition, we discuss the profound cytoprotective effects of the antibiotic, minocycline.
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