BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin

Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4-21.6] versus 8.1 months (95% CI: 6.1-10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI: 32.5-indeterminate) versus 22.6 months (95% CI: 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.     

Effectiveness of a nursing support program for patients with recurrent ovarian cancer receiving pegylated liposomal doxorubicin (Caelyx/Doxil).

Pegylated liposomal doxorubicin (PLD) has become the preferred alternative for ovarian cancer patients who have failed platinum-based therapy, but side effects, such as palmar-plantar erythrodysesthesia (PPE), may lead to sub-optimal drug exposure and treatment discontinuation. A prospective Canadian multicentre open-label study evaluated the effects of a nurse-administered education and support program on treatment adherence and tolerability in 112 women with recurrent ovarian cancer. Subjects received an average of four four-week PLD cycles, the recommended number of courses required to evaluate the efficacy from PLD. Side effects were common, but 75% of patients were able to complete > 3 cycles and 59% completed > 4 cycles of PLD chemotherapy. With proactive nursing intervention, the incidence of PLD-associated grade three-four toxicities such as PPE and mucositis was substantially decreased. Nursing intervention may allow more patients to receive chemotherapy on schedule, thus reproducing the conditions of the clinical study in which the efficacy of the drug has been established.     

Direct 99mTc labeling of pegylated liposomal doxorubicin (Doxil) for pharmacokinetic and non-invasive imaging studies

Pharmacokinetic and organ distribution studies of liposomal drugs in humans are a challenge. A direct labeling method using (99m)Tc-N,N-bis(2-mercaptoethyl)-N',N'-diethyl-ethylenediamine (BMEDA) complex to label the commercially available pegylated liposomal doxorubicin, Doxil, has been introduced. Biodistributions of (99m)Tc-Doxil in normal rats were performed to evaluate the feasibility of using it for monitoring the pharmacokinetics of liposomes encapsulating drugs. Labeling efficiency of (99m)Tc-Doxil was 70.6 +/- 0.8% (n = 3). In vitro incubation of (99m)Tc-Doxil in 50% fetal bovine serum or 50% human serum at 37 degrees C showed good labeling stability with 72.3 +/- 3.6% or 78.6 +/- 1.8% of activity associated with Doxil at 24 h, respectively (n = 3). There was a two-phase blood clearance with half-clearance times of 2.2 and 26.2 h after bolus intravenous injection in normal rats. Distribution of (99m)Tc-Doxil at 44 h after injection had 19.8 +/- 1.3% of injected dose in blood, 14.1 +/- 1.7% in liver, 2.6 +/- 0.3% in spleen, 9.0 +/- 0.8% in bone with marrow, 6.0 +/- 0.5% in skin, and 15.3 +/- 4.3% in bowel (n = 5). Unencapsulated (99m)Tc-BMEDA had a very rapid blood clearance with a half-clearance time of only 0.12 h (n = 4). By using this (99m)Tc labeling method, biodistribution and pharmacokinetics of ammonium gradient liposomes encapsulating drugs can be determined by noninvasive scintigraphic imaging. This labeling method may be extended to (186)Re and (188)Re labeling to combine chemotherapy and radionuclide therapy for tumor treatment.     

Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy?

Rationally designed liposomes could improve the therapeutic indexes of chemotherapeutic drugs, which is due to alterations in the pharmacokinetics and biodistribution of encapsulated drugs. For traditional drug delivery systems, the accumulation of drugs in healthy and malignant tissues could be correlated with toxicity and efficacy. Some previous studies also indicate that the higher tumor AUC, the better therapeutic efficacy, suggestive of the possible existence of positive correlation. Are AUC values of liposomal drugs really predictive? For the purpose to address this question, we designed two pegylated liposomal doxorubicin formulations (PLD-75 and PLD-100), which had the same lipid/drug ratio and bilayer composition, but different size and internal ammonium sulfate concentration. In vitro drug retention experiments revealed that drug was released at a faster rate from PLD-75, a small size formulation. The plasma pharmacokinetics of PLD-75 was similar to that of PLD-100, regardless of whether the mice were tumor-free or not. It should be noted, though, that in tumor-bearing mice the plasma doxorubicin level in PLD-75 group was only about 59% of that in PLD-100 group at 48 h post injection. Furthermore, their biodistribution behavior in S-180 tumor-bearing KM mice was significantly different. Compared with animals receiving PLD-100, those receiving PLD-75 showed a 19.2%, 27.8%, and 23.5% decrease in liver (p<0.01), spleen (p<0.001) and lung (p<0.05) AUC, respectively. In other healthy tissues except kidney, the drug deposition also reduced by 10-15%, but the difference was not significant. The tumor AUC after administration of PLD-100 and PLD-75 were 1285.3 ugh/g and 762.0 ugh/g, respectively (p<0.001). Maximum drug levels achieved in the tumors were 33.80 microg/g (for PLD-100) and 20.85 microg/g (for PLD-75), and peak tumor concentration was achieved faster in PLD-75 group. However, enhanced drug accumulation does not mean increased antineoplastic effect, and at the same doxorubicin dose level, PLD-75 was more efficacious. As for toxicity studies, PLD-75 caused more rapid and severe body weight loss despite the fact that drug accumulation in healthy tissues was reduced. Our data indicate that liposomal systems are more complicated than conventional drug delivery systems, and it is hard to predict the toxicity and efficacy of liposomal drugs through the measure of liposomal drug accumulation.     

盐酸拓扑替康联合顺铂治疗上皮性卵巢癌的临床研究

目的探讨盐酸拓扑替康联合顺铂治疗上皮性卵巢癌的疗效及毒副反应。方法将手术后经病理检查确诊为Ⅱ～Ⅳ期上皮性卵巢癌的68例患者按入选时间顺序分为2组:治疗组与对照组,每组34例。治疗组给予顺铂90 mg/m2,静脉滴注,d1;盐酸拓扑替康0.8 mg/m2,d1～5。对照组给予顺铂90 mg/m2静脉滴注,d1;环磷酰胺800 mg/m2静脉注射,d1。2组患者均以20 d为1疗程。5～7个疗程后评价疗效。结果临床疗效:治疗组完全缓解10例,部分缓解16例,有效率为76.5%;对照组完全缓解5例,部分缓解14例,有效率为55.8%。治疗组与对照组有效率比较差异有统计学意义(P<0.05)。毒副反应:发生Ⅲ～Ⅳ度骨髓抑制的患者,治疗组16例(47.1%),对照组为13例(38.2%),2组毒副反应发生率差异无统计学意义(P>0.05)。结论盐酸拓扑替康联合顺铂是治疗上皮性卵巢癌的有效方案,临床疗效较好,安全性高,其不良反应可控制,患者可耐受。     

Controlled application and removal of liposomal therapeutics: Effective elimination of pegylated liposomal doxorubicin by double‐filtration plasmapheresis in vitro

Introduction: Nanoscale particle‐based drug delivery systems like long circulating liposomal doxorubicin show unique pharmacokinetic properties and improved toxicity profiles. Liposomal doxorubicin accumulates in tumor tissue due to the enhanced permeation and retention effect, but only a small fraction of a total dose reaches the tumor site. Accumulation of liposomal doxorubicin is much faster in tumor sites than in certain organs where dose limiting adverse effects occur. Finding a way to detoxify the predominant part of a given dose, circulating in the blood after accumulation is completed, will presumably reduce severe side effects during chemotherapy. Methods: Elimination properties of therapeutic used pegylated liposomal doxorubicin (Doxil®/Caelyx®) and therapeutic used double‐filtration plasmapheresis systems were evaluated in vitro and in reconstituted human blood. Results: Liposomes can be filtered by appropriate membranes without leakage of doxorubicin up to a pressure of 1 bar. At higher pressures, liposomes (～85 nm) may squeeze through much smaller pores without significant leakage of doxorubicin, whereas decreasing pore size to ～8 nm leads to increased leakage of doxorubicin. With therapeutic used apheresis systems, liposomal doxorubicin can be efficiently eliminated out of buffer medium and reconstituted human blood. No leakage of doxorubicin was detected, even when liposomes were circulating for 48 h in human plasma before apheresis. Conclusions: Convenient apheresis techniques are capable of a safe and efficient elimination of therapeutic used liposomal doxorubicin in an experimental model system. J. Clin. Apheresis, 2010. © 2010 Wiley‐Liss, Inc.     

Cost-minimization analysis of piperacillin/tazobactam versus imipenem/cilastatin for the treatment of serious infections: a Canadian hospital perspective

BACKGROUND: In 1998 we reported the first Canadian double-blind, randomized, clinical trial involving a comparison of piperacillin/tazobactam (P/T) with imipenem/cilastatin (I/C). The present study was conducted to determine the feasibility of replacing I/C at our institution. OBJECTIVE: To describe the outcome of a pharmacoeconomic analysis of the clinical trial from the perspective of a tertiary acute-care institution. METHODS: A total of 150 consenting adults originally prescribed I/C were randomly assigned to receive either P/T 4.5 g i.v. (n = 75) or I/C 500 mg i.v. (n = 75) every six hours. Actual direct medical resources used in relation to the treatment of bacterial infections were prospectively assessed during a clinical trial; these included cost of study and ancillary antibiotics, hospitalization, diagnostic testing (radiology, laboratory assessments), and labor, as well as treatment of adverse drug reactions, antibiotic failures, and superinfections. RESULTS: While costs for successful treatment courses were similar across treatment arms, hospitalization costs for treatment course failures were higher for P/T recipients. Direct medical costs for treatment courses associated with a superinfection were also higher in the P/T arm. Overall costs for treatment failures with either study drug were at least twofold those observed for successful treatment courses. Mean total management cost per patient in the P/T group was $15,211 ($ CDN throughout) (95% CI $11,429 to $18,993), compared with $14,232 (95% CI $11,421 to $17,043) in the I/C group (p = 0.32), resulting in a mean cost difference of $979. Sensitivity analyses revealed that the superiority of I/C over P/T for successful treatment of serious infections was sensitive to changes in the cost of hospitalization and drug efficacy for either drug. CONCLUSIONS: Based on the results of the clinical trial, P/T and I/C offer similar clinical, microbiologic, and toxicity outcomes in hospitalized patients with serious infections. Under base-case conditions, our pharmacoeconomic analysis showed that I/C was a cost-effective alternative to P/T at the dosage regimens studied. However, this finding was sensitive to plausible changes in both clinical and economic parameters.     

Delineating the anti-metastatic potential of pentoxifylline in combination with liposomal doxorubicin against breast cancer cells

Breast cancer remains the second most prevalent cancer worldwide. Several anticancer drugs are being currently used in the treatment of breast cancer. However, owing to high cytotoxicity, induced resistance and cost ineffectiveness, there is an urgent need to develop newer therapeutic regimens that limit the current problems. One of the approaches in this regard is the formulation of combination therapies whereby multiple drugs are being delivered at relatively lesser dose that surely confines the aforesaid problems. In this purview, we had evaluated the effects of pentoxifylline, a methylxanthine derivative and liposomal doxorubicin (Lipodox), an anthracycline in combination to evaluate their anti-metastatic activities both in vitro and in vivo against breast cancer cells. The combination regime exhibited synergistic activity and inhibited cellular proliferation to a greater extent with regard to each drug used alone.     

Cost-minimization analysis of simvastatin versus atorvastatin for maintenance therapy in patients with coronary or peripheral vascular disease

BACKGROUND: Previous health economic studies have demonstrated the cost-effectiveness of simvastatin in the treatment of coronary heart disease (CHD) based on clinical results of the Scandinavian Simvastatin Survival Study. A prior analysis evaluated the "cost of getting to goal," but ignored all costs after titration. However, when evaluating the cost-effectiveness of long-term therapies, it is important to consider the maintenance costs as well. OBJECTIVE: The purpose of this study was to evaluate the maintenance costs of treatment with simvastatin versus that of treatment with another more recently available statin, atorvastatin, in a European context. METHODS: We assessed the long-term maintenance cost of simvastatin versus atorvastatin in terms of the cost of reducing low-density lipoprotein cholesterol (LDL-C) levels to the recommended goals based on a previously published clinical trial in patients with CHD. The analysis focused on the patients in the original clinical trial who were randomized to treatment with simvastatin or atorvastatin. Patients began therapy with 10 mg of simvastatin or atorvastatin; the dose of study drug was titrated every 12 weeks up to 40 mg simvastatin or 80 mg atorvastatin, with the addition of up to 8 g/d of cholestyramine until a modified European Atherosclerosis Society LDL-C goal (<2.84 mmol/L) was reached. As there was no significant difference between the 2 groups in resource utilization for adverse events, only drug costs were included. The calculated average annual maintenance cost was based on the distribution of the final daily dosing regimens and the public drug prices for each regimen. Individual country analyses were conducted using each local currency. RESULTS: There was no significant difference between groups in the percentage of patients reaching their LDL-C goal over the study period (80% for simvastatin-treated pa- tients vs 89% for atorvastatin-treated patients, P = 0.135). However, the cost of maintaining a similar percentage of patients at their appropriate LDL-C levels was significantly lower in the simvastatin group compared with the atorvastatin group in 13 of the 17 countries assessed. In the remaining 4 countries, there was a cost advantage for simvastatin, but it did not reach statistical significance. CONCLUSIONS: Across Europe there was a significant reduction in the cost of maintaining patients at their appropriate LDL-C levels with simvastatin versus atorvastatin. The results of this analysis, along with the proven clinical benefits of simvastatin, support the use of this drug as the treatment of choice in the secondary prevention of CHD.     

Controlled targeting of liposomal doxorubicin via the folate receptor in vitro.

Differential expression of folate receptor has been exploited to target liposomes to tumors. Astrogliomas express low folate receptor levels and are typically surrounded by normal cells expressing little or no folate receptors. While targeting cells with high over-expression of folate receptor (KB and HeLa) has been demonstrated, it is unclear whether targeting tumors expressing low levels of folate receptor is possible. In this study, it was demonstrated that optimizing the number of targeting ligands (folic acid) enables differential liposomal doxorubicin uptake in C6 glioma while sparing healthy cortical cells. By micellization of folate conjugates and their controlled insertion into pre-formed liposomes, tight control over the number of targeting ligands per liposome was demonstrated. Doxorubicin uptake in KB and C6 cells was dependent on the number of targeting ligands, while cortical cells showed increasing non-specific uptake with ligand number. Co-culture of C6 glioma with cortical cells confirmed preferential uptake in C6 glioma relative to cortical cells. A cell kill experiment showed that folate-targeted liposomal doxorubicin is cytotoxic and slows proliferation of KB and C6 cells with minimal effect on cortical cells. Therefore modulation of targeting ligand number enables significant differential uptake of doxorubicin in cells with low levels of folate receptor.     

Cost-minimization analysis of low-molecular-weight heparin (dalteparin) compared to unfractionated heparin for inpatient treatment of cancer patients with deep venous thrombosis

Goals Low-molecular-weight heparin (LMWH) has shown to be as effective as unfractionated heparin (UFH) in the treatment of deep venous thrombosis (DVT). Although the acquisition cost of LMWH is significantly greater than that of UFH, we hypothesized that once-daily dalteparin, a LMWH, could reduce treatment costs of cancer patients with DVT by eliminating anticoagulation monitoring and shortening hospitalization.Patients and methods We developed a cost-minimization model by using outcomes and resource utilization data from two retrospective matched cohorts of cancer patients who, between 1994 and 1999, were hospitalized at our comprehensive cancer center for treatment of DVT with either LMWH (n=21) or UFH (n=168). We assumed all LMWHs and UFH to be equally effective. The total costs for the dalteparin strategy and the UFH strategy were calculated in year 2003 U.S. dollars, from the providers perspective, by multiplying the number of resources used for inpatient treatment of DVT by their unit costs.Results The mean total cost for inpatient care was $3,383 (95% CI= $2,683– $4,083) for dalteparin and $4,952 (95% CI=$4,718–$5,185) for UFH. Substantial savings resulted from shorter hospitalization among the dalteparin-treated patients (mean 3.19 versus 5.22 days). Sensitivity analysis did not change the conclusion that dalteparin is less expensive than UFH.Conclusions Savings realized from less anticoagulant monitoring and shorter hospitalization offset the higher acquisition cost of dalteparin. The dalteparin strategy is less expensive than the UFH strategy for the inpatient treatment of DVT among cancer patients.Presented in part at the 3rd Annual Houston Area Health Services & Outcomes Research Conference, Houston, TX, USA, November 25, 2002     

Implementation of intraperitoneal chemotherapy for the treatment of ovarian cancer

In January 2006, a clinical announcement made by the National Cancer Institute suggested that intraperitoneal chemotherapy become standard care for patients with newly diagnosed stage III, optimally debulked epithelial ovarian cancer. Intraperitoneal chemotherapy is new to many healthcare providers (i.e., physicians, nurses, and pharmacists). This article will discuss how to implement intraperitoneal chemotherapy in practice. Education and experience are the keys to successful implementation.     

吉西他滨联合卡铂治疗复发性上皮性卵巢癌临床分析

目的 探讨吉西他滨(Gem)联合卡铂治疗复发性上皮性卵巢癌的有效性和不良反应.方法 采用随机对照研究的方法,将2008-08-2010-12间在川北医学院附属医院收治的48例复发性上皮性卵巢癌患者随机分为研究组(Gem联合卡铂)和对照组(紫杉醇联合卡铂),对其疗效及不良反应进行比较.结果 对照组和研究组完全缓解率(CR)分别为12.5％和29.17％,总有效率分别为45.83％和79.17％,不良反应分别提高54.17％和25.00％.研究组CR和总有效率明显高于对照组(P＜0.01),研究组治疗后不良反应明显低于对照组(P＜0.01).结论 Gem联合卡铂治疗复发性上皮性卵巢癌的临床疗效较好,不良反应较低.     

Dyspnea during thalidomide treatment for advanced ovarian cancer

OBJECTIVE: To detail the dyspnea encountered in women receiving thalidomide as therapy for advanced ovarian cancer. CASE SUMMARIES: Eight of 18 (44%) patients with recurrent ovarian cancer developed dyspnea while receiving thalidomide 200 mg daily as part of a prospective Phase II study. Dyspnea was evaluated with pulse oximetry, chest X-ray and, if indicated, spiral computed tomography scan. Four patients had abnormal chest X-ray findings (1 pleural effusion, 1 pneumonia, 2 mild congestive heart failure), and one of these patients also had a pulmonary embolus. The other 4 patients had no objective test findings to explain their dyspnea. Five patients had resolution of symptoms when thalidomide was discontinued and, when the drug was resumed at a 50% dose reduction, experienced no further shortness of breath. DISCUSSION: While dyspnea in association with thalidomide has not previously been reported as a common adverse event, it was a frequent complaint of patients receiving this drug as part of a Phase II study. Comorbid conditions causing dyspnea were evaluated since they are common in this patient population; however, half of our patients had no objective evidence of such conditions. The Naranjo probability scale indicated a probable relationship between dyspnea and thalidomide therapy in the patients with no objective evidence of comorbidity. We advocate discontinuation of thalidomide until symptoms have resolved, at which time reintroduction of thalidomide at a reduced dose may be considered. CONCLUSIONS: Patients receiving thalidomide may develop dyspnea as an adverse effect of the drug. In selected patients, thalidomide may be safely reintroduced once symptoms resolve.     

Liposome co-encapsulation of synergistic combination of irinotecan and doxorubicin for the treatment of intraperitoneally grown ovarian tumor xenograft

Liposome co-encapsulation of synergistic anti-cancer drug combination is an emerging area that has demonstrated therapeutic benefit in clinical trials. Remote loading of two or more drugs into a single liposome constitutes a new challenge that calls for a re-examination of drug loading strategies to allow the loading of the drug combination efficiently and with high drug content. In this study, the Mn^2 + gradient coupled with A23187 ionophore was applied in the sequential co-encapsulation of doxorubicin and irinotecan, as this drug loading method is capable of remotely loading drugs by apparently two different mechanisms, namely, coordination complexation and pH gradient. Doxorubicin and irinotecan could be co-encapsulated into liposomes in a wide range of drug-to-drug ratios, with encapsulation efficiencies of > 80%. The total encapsulated drug content was non-linearly correlated with increases in the intraliposomal Mn^2 + concentration, with a maximum total drug-to-lipid molar ratio of 0.8:1 achieved with 600 mM Mn^2 +. This high encapsulated drug content did not affect the stability of the co-encapsulated liposomes upon storage for six months. Regardless of the encapsulated drug amount, the liposomes did not exhibit the fiber bundle precipitate morphology but rather an undefined structural organization in the aqueous core. The co-encapsulated liposome formulation was further tested in an intraperitoneally grown, human ovarian tumor xenograft model, and was shown to significantly improve the survival of the tumor-bearing animals. The improvement in therapeutic efficacy was possibly due to the increase in systemic drug exposure, with the maintenance of the synergistic molar drug ratio of 1:1 in circulation.     

三苯氧胺治疗乳腺癌引发卵巢囊肿的临床分析

目的 探讨乳腺癌患者服用三苯氧胺后卵巢囊肿的发生情况。方法 93例服用三苯氧胺的乳腺癌患者为观察组，23例未服用三苯氧胺患者为对照组。结果 观察组发现卵巢囊肿18例，发生率19．35％，明显高于对照组，随访中囊肿缩小或停药后缩小。未绝经和绝经不足1年的患者，其卵巢囊肿发生率为38．5％，月经规律患者发生率为68．2％。对照组无卵巢囊肿发生。结论 卵巢囊肿是乳腺癌患者服用三苯氧胺的常见副作用，主要发生于尚未绝经或绝经不足1年的患者，囊肿能自行消失或停药后消失。