Carboplatin In Ovarian Cancer Patients Research Articles

Effect of CX3CL1/CX3CR1 gene polymorphisms on the clinical efficacy of carboplatin therapy in Han patients with ovarian cancer.

Gene polymorphisms have a close relationship with the clinical effects of carboplatin for ovarian cancer. Here, we investigated the relationship between CX3CL1 and CX3CR1 genotypes and the clinical efficacy of carboplatin in ovarian cancer, thereby clarifying the unidentified genetic factors that influence the efficacy of carboplatin in ovarian cancer. Based on the above purposes, we used Sequenom Mass ARRAY technology to detect CX3CL1 and CX3CR1 gene polymorphisms in 127 patients with carboplatin-treated ovarian cancer. We performed various statistical analyses to evaluate the effects of CX3CL1 and CX3CR1 genetic variants, demographic data, and clinical characteristics on the effect of carboplatin therapy. The results show that the CX3CL1 genotypes rs223815 (G>C) and rs682082 (G>A) will significantly affect the clinical efficacy of carboplatin for ovarian cancer (p < 0.05), while the other six genotypes and all CX3CR1 genotypes have no significant effect (p > 0.05). In addition, only one population factor, age, had a significant effect on the clinical efficacy of carboplatin-treated ovarian cancer (p < 0.05). Based on the above research results, we concluded that the clinical efficacy of carboplatin in ovarian cancer patients was significantly correlated with age and CX3CL1 polymorphism factors; however, more in-depth effects and mechanisms need to be explored by large-scale, multicenter studies.

Psoas muscle volume as a predictor of peripheral neurotoxicity induced by primary chemotherapy in ovarian cancers.

Low skeletal muscle mass (sarcopenia) has been reported to have an influence on survival and toxicities of chemotherapy in several solid tumors. The impact of sarcopenia on the treatment of ovarian cancers has not been determined. The present study aimed to evaluate correlation between sarcopenia and toxicities of chemotherapy in ovarian cancers. Medical charts of the ovarian cancer patients that received chemotherapy with paclitaxel and carboplatin at our hospital between 2010 and 2015 were retrospectively reviewed. Muscle areas of bilateral psoas major muscles at the fifth lumbar vertebra were measured using images obtained by computed tomography. The volume of muscle and clinicopathological factors were evaluated for toxicities of chemotherapy. The protocol of the present study was approved by the institutional review board of our institution. A total of 76 patients with ovarian cancers were identified, and enrolled in the present study. Median psoas index (PI, the psoas muscle major cross-sectional area divided by the height squared) was 583mm2/m2 (range 326-999). The patients with low PI developed peripheral neuropathy more frequently compared with those with high PI (32 vs. 11%; P=0.047). PI value was not associated with other toxicities such as neutropenia and thrombocytopenia. PI value was associated with grade 2 or higher peripheral neuropathy in univariate analysis (OR=3.92; 95% CI 1.21-15.32; P=0.02) and multivariate analysis (OR=3.93; 95% CI 1.17-15.87; P=0.03). PI value was significantly associated with peripheral neuropathy induced by combination therapy with paclitaxel and carboplatin in ovarian cancer patients. Although further studies are needed to confirm the results, the volume of skeletal muscle mass could be a potential biomarker to predict toxicities in ovarian cancer patients.

A comparison of measured and estimated glomerular filtration rate (GFR) for carboplatin dose calculation in women with ovarian cancer (OC).

e17051 Background:Carboplatin based chemotherapy is widely used to treat women with Ovarian cancer (OC) in the adjuvant, neoadjuvant and palliative settings. Carboplatin is normally dosed by the Calvert formula: [GRF+25] x AUC, with a target AUC (area under the plasma concentration curve) of 5-6 mg/ml/min. GFR (glomerular filtration rate) can be precisely measured with radionuclide based ligands such as 51Cr-ethylenediamine tetraacetic acid (51Cr-EDTA), but in clinical practice is often estimated using formulae incorporating serum creatinine, weight and age, such as the Cockcroft–Gault (CG) or Wright (WR) formulae. It is unknown, however, if these formulae allow a sufficiently accurate dosing of carboplatin in OC patients. Methods:We retrospectively compared measured (EDTA-based) and estimated (CG and WR formulae) GFR and the resulting carboplatin doses, in women with stage 1c to IV OC treated with carboplatin AUC 6 at our centre between 2015 and 2016. All patients (pts) had concurrent 51Cr-EDTA GFR and serum creatinine measurement before starting carboplatin. Accuracy and bias of The WR and CG formulae were analysed using mean absolute percentage error (MAPE) and mean percentage error (MPE). Results:92 pts were included in the study (median age = 69 years (r. 25 -89), median serum creatinine 63.5 umol/L (r. 38 – 168)). MPE was -37.3 and -26.0 and MAPE was 38.0 and 32.2 for the WR and CG formulae, respectively. If the WR or CG formulae had been used instead of EDTA to calculate the dose of carboplatin, the discrepancy would have been at least 10% in 77.1% and 69.8% of pts, respectively; a discrepancy of 50% or more would have occurred in 10% and 13% of pts. Conclusions:Neither the WR nor CG formulae precisely predict renal function in ovarian cancer pts. They often overestimate GFR, meaning that if these formulae are used instead of isotope-based measurement of GFR, most pts will receive a higher dose of carboplatin. Our findings are relevant for clinical practice and for the design and interpretation of clinical trials, where the choice between EDTA- or formulae- based calculations of carboplatin dose are often left to investigators’ preference.

A phase 1 and pharmacodynamic study of decitabine in combination with carboplatin in patients with recurrent, platinum‐resistant, epithelial ovarian cancer

Aberrant DNA methylation is a hallmark of cancer, and DNA methyltransferase inhibitors have demonstrated clinical efficacy in hematologic malignancies. On the basis of preclinical studies indicating that hypomethylating agents can reverse platinum resistance in ovarian cancer cells, the authors conducted a phase 1 trial of low-dose decitabine combined with carboplatin in patients with recurrent, platinum-resistant ovarian cancer. Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28-day cycle. By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m(2) (7 patients) or 20 mg/m(2) (3 patients). Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pretreatment), 5, 8, and 15 were used to assess global (LINE-1 repetitive element) and gene-specific DNA methylation. Dose-limiting toxicity (DLT) at the 20-mg/m(2) dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m(2). The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1-2. One complete response was observed, and 3 additional patients had stable disease for >/=6 months. LINE-1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs. Of 5 ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15. Repetitive low-dose decitabine is tolerated when combined with carboplatin in ovarian cancer patients, and demonstrates biological (ie, DNA-hypomethylating) activity, justifying further testing for clinical efficacy. Cancer 2010. (c) 2010 American Cancer Society.

Efficacy of pegylated liposomal doxorubicin (PLD) plus carboplatin in ovarian cancer patients who recur within six to twelve months: A phase II study

Objectives Pegylated liposomal doxorubicin is one of the preferred alternatives for ovarian cancer patients with early relapse (< 6 months) and taxane/carboplatin for late relapse (> 12 months), but the optimal therapy for the partially platinum-sensitive (6–12 months) population has not been defined. This single-arm phase II trial was designed to assess the efficacy of pegylated liposomal doxorubicin (PLD)/carboplatin in ovarian cancer patients who relapse between 6 and 12 months after initial treatment with platinum-based chemotherapy. Methods Ovarian cancer patients who previously completed a course of therapy with paclitaxel/carboplatin were administered PLD 30 mg/m 2 followed by carboplatin AUC 5 mg/mL/minute every 4 weeks. Results Fifty-eight patients were enrolled in the study and 54 were eligible for the efficacy analysis, of whom most (75%) received at least 6 cycles of PLD/carboplatin. The objective response rate was 46% (4% CR and 42% PR), with an additional 33% experiencing disease stabilization > 6 months. For those patients with measurable CA-125, the response rate was 66% (28% CR and 38% PR), with an additional 18% experiencing disease stabilization > 6 months. Median time-to-progression was 10 months (1.5–25). Median overall survival was 19.1 months (2.2–38.9). The most frequent adverse effects were neutropenia, thrombocytopenia, and constipation. Conclusions The combination of PLD/carboplatin is efficacious and well tolerated in women with partially platinum-sensitive ovarian cancer and represents a valuable alternative for patients who relapse within 6–12 months of completing paclitaxel/carboplatin chemotherapy.

Population Pharmacokinetics and Pharmacodynamics of Paclitaxel and Carboplatin in Ovarian Cancer Patients: A Study by the European Organization for Research and Treatment of Cancer-Pharmacology and Molecular Mechanisms Group and New Drug Development Group

Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokinetic-pharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 micromol/L (t(C > 0.05-0.2)) predicts neutropenia. The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m(2)) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t(C > 0.05) was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively). Patients with paclitaxel t(C > 0.05) > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t(C > 0.05) < 61.4 h (89.0 versus 61.9 weeks; P = 0.05). Paclitaxel t(C > 0.05) was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C(max) and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10(-4)). In this group of patients, paclitaxel t(C > 0.05) is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

Phase I trial of the proteasome inhibitor bortezomib in combination with carboplatin in patients with platinum- and taxane-resistant ovarian cancer

Objective. This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the proteasome inhibitor bortezomib when combined with carboplatin in ovarian cancer patients with recurrent and platinum- and taxane-resistant disease. Methods. Patients with platinum- and taxane-resistant recurrent ovarian cancer, measurable disease, and a performance status of 0 to 2 were eligible. Bortezomib (0.8, 1.0, 1.3, or 1.5 mg/m 2) was administered on days 1, 4, 8, and 11 by intravenous push with carboplatin (area under curve = 5) on day 1; therapy was repeated every 28 days. Results. Twenty-one women (median age, 63 years; range, 43 to 83 years) were treated with carboplatin and bortezomib at 0.8 mg/m 2 ( n = 6), 1.0 mg/m 2 ( n = 3), 1.3 mg/m 2 ( n = 6), or 1.5 mg/m 2 ( n = 6). At these levels, there were 1, 0, 1, and 3 DLTs, respectively, attributable to bortezomib; all were grade 3. The DLTs were fatigue ( n = 3); nausea, vomiting, and dehydration ( n = 1); and anorexia, dehydration, and syncope ( n = 1). Common grade 2 toxicities included fatigue ( n = 12), nausea ( n = 10), and anorexia, anemia, and dyspnea ( n = 7 each). The 18 patients evaluable for response all had stable disease (SD; n = 8) or progressive disease ( n = 10). The median duration of SD was 4 months (range, 3 to 7 months). At the MTD of 1.3 mg/m 2, 3 of 6 patients had SD. Conclusions. The recommended dose of bortezomib in combination with carboplatin is 1.3 mg/m 2. Treatment was reasonably well tolerated at the MTD.

A phase I trial of the proteosome inhibitor PS-341 in combination with carboplatin in platinum and taxane resistant ovarian cancer patinets

5558 Background. PS-341 (Millenium Pharmaceuticals, Inc.), a proteosome inhibitor, affects p53, NFκB, cell adhesion molecules, and sensitivity to cytotoxic agents to promote apoptosis and inhibit metastasis in cancer cells. PS-341 alone rarely causes myelosupression or renal toxicity, and therefore is an attractive agent to use in combination with cytotoxic chemotherapy. This phase I study evaluates the safety, dose-limiting toxicities (DLTs), and optimal dose of PS-341 when combined with carboplatin in ovarian cancer patients with recurrent, platinum- and taxane-resistant disease. Methods: After IRB approval, patients with recurrent ovarian cancer, platinum and taxane resistant (progression on platinum and/or taxane therapy or recurrence within 6 months of completing platinum and/or taxane therapy), measurable disease, and performance status 0–2 were eligible and enrolled after giving informed consent. As guided by toxicity and pharmacokinetic data from single-agent phase I trials, PS-341 was administered on days 1, 4, 8, and 11 by IV push every 28 days with carboplatin (AUC 5) on day 1. Four dose levels were evaluated: 0.8, 1.0, 1.3, and 1.5 mg/m2. Dose was escalated if 0 of 3 or 1 of 6 patients had a DLT. The MTD was defined as 2 or more patients out of 6 with a DLT. Results: 21 women (median age 63, range 43–83), were treated with carboplatin and PS-341 at 0.8mg/ m2 (n=6), 1.0 mg/m2 (n=3), 1.3 mg/m2 (n=6), or 1.5 mg/m2. (n=6). At each level, respectively, there were 1, 0, 1, and 3 DLT’s attributable to PS- 341; all were grade 3, consisting of fatigue (n=3), nausea/vomiting/dehydration (n=1), and anorexia/dehydration/syncope (n=1). There were no Grade 4 toxicities. Common grade 2 toxicities included fatigue (n=12), nausea (n=10), anorexia, anemia, and dyspnea (n=7 each). 18 patients evaluable for response had stable disease (SD) or progression of disease (PD): at 0.8 mg/m2, SD=2, PD=3; at 1.0 mg/m2, PD=3; at 1.3 mg/m2, SD=3, PD=3; at 1.5 mg/m2, SD=3, PD=1. Median duration of stable disease was 4 months (range 3–10). Conclusions: The recommended dose of PS-341 in combination is 1.3 mg/m2. Treatment was well-tolerated with reversible side effects and no grade 4 toxicities, and at the optimal dose, there was a 50% rate of stable disease. No significant financial relationships to disclose.

Population PKPD of paclitaxel and carboplatin in ovarian cancer patients: A study by the EORTC‐PAMM‐NDDG

Introduction: The paclitaxel/carboplatin doublet is standard treatment in advanced ovarian cancer and usually applied following cytoreductive surgery. Paclitaxel displays nonlinear PK, and the exposure‐toxicity relationship has been described by threshold‐models, whereas the time above a paclitaxel plasma concentration of 0.05–0.2 μmol/L (T&gt;C0.05‐T&gt;C0.2) was correlated with hematological toxicity. A semimechanistic PKPD model has recently been described for paclitaxel‐induced myelosuppression. The aim of this study was to investigate the population PKPD of paclitaxel and carboplatin in ovarian cancer patients.Methods: 139 ovarian cancer patients received paclitaxel 175 mg/m2 over three hours, followed by carboplatin AUC 5 mg*min/mL over 30 min, after cytoreductive surgery. Plasma concentration‐time data of paclitaxel and carboplatin were measured, and the relationship between PK, hematological toxicity and drug response was evaluated using nonlinear mixed‐effect modelling. Data were analysed according to a semiphysiological model, including proliferation –, transit – and circulation compartments for neutrophils and thrombocytes. Linear and sigmoidal maximum response models were tested for the influence of paclitaxel and carboplatin on the proliferation rate of neutrophils or thrombocytes. Toxicity and clinical outcome data were analysed by previously established threshold models.Results: 105 patients had complete PK and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Hematological toxicity was adequately described by an inhibitory linear drug effect model. Mean paclitaxel T&gt;C0.1 was 16.4 hrs, mean T&gt;C0.05 61.4 hrs. Patients with a complete response to paclitaxel/carboplatin had a higher T&gt;C0.05 as compared to patients with progressive disease (91.9 vs 31.5 hrs, p=0.02). Similarly, T&gt;C0.05 was higher in patients with at least stable as compared to progressive disease (78.3 vs 31.5 hrs, p=0.05). Patients with T&gt;C0.05 &gt; 61.4 hrs (mean value) had a longer time‐to‐disease‐progression compared to patients with T&gt;C0.05 &lt; 61.4 hours (89.0 vs 61.9 weeks, p=0.05). T&gt;C0.05 was also a good predictor for neutropenia, in that patients with absent or mild (WHO grade 1 or 2) neutropenia had a lower T&gt;C0.05 as compared to patients with severe (WHO grade 3 or 4) neutropenia (50.3 vs 74.1 hrs, p=0.01). Carboplatin drug exposure was the best predictor for thrombocytopenia, in that patients with absent thrombopenia had lower values for Cmax and AUC as compared to patients experiencing mild or severe thrombopenia (82.6 vs 132 μmol/L for Cmax, 1.24 vs 1.79 mg*min/mL for AUC, p &lt; 10−4 for both comparisons).Conclusions: Paclitaxel T&gt;C0.05 was useful to predict neutropenia and clinical outcome in ovarian cancer patients receiving paclitaxel/carboplatin, while carboplatin exposure was useful to predict thrombocytopenia. Prospective studies should assess the value of therapeutic drug monitoring in this patient group.

The disposition of carboplatin in ovarian cancer patients.

Carboplatin was given as a 30-min infusion to 11 ovarian cancer patients at doses of 170-500 mg/m2. The ages, weights, and creatinine clearances (Clcr) ranged from 44 to 75 years, from 44 to 74 kg, and from 32 to 101 ml/min, respectively. Plasma, plasma ultrafiltrate (PU), and urine samples were obtained at appropriate times for 96 h and were analyzed for platinum. The PU and urine were also analyzed for the parent compound by HPLC. In patients with a Clcr of about 60 ml/min or greater, carboplatin decayed biexponentially with a mean t1/2 alpha of 1.6 h and a t1/2 beta of 3.0 h. The mean (+/- SD) residence time, total body clearance, and apparent volume of distribution were 3.5 +/- 0.4 h, 4.4 +/- 0.85 l/h, and 16 +/- 3 l, respectively. Cmax and AUCinf values increased linearly with dose, and the latter values correlated better with the dose in mg than in mg/m2. No significant quantities of free, ultrafilterable, platinum-containing species other than the parent compound were found in plasma, but platinum from carboplatin became protein-bound and was slowly eliminated with a minimal t1/2 of 5 days. The major route of elimination was excretion via the kidneys. Patients with a Clcr of 60 ml/min or greater excreted 70% of the dose as the parent compound in the urine, with most of this occurring within 12-16 h. All of the platinum in 24-h urine was carboplatin, and only 2%-3% of the dosed platinum was excreted from 48 to 96 h. Patients with a Clcr of less than about 60 ml/min exhibited dose-disproportional increases in AUCinf and MRT values. The latter were inversely related to Clcr (r = -0.98). Over a dose range of 300-500 mg/m2, carboplatin exhibited linear, dose-independent pharmacokinetics in patients with a Clcr of about 60 ml/min or greater, but dose reductions are necessary for patients with mild renal failure.