A pilot study of bevacizumab combined with etoposide and cisplatin in breast cancer patients with leptomeningeal carcinomatosis.

BACKGROUND: Elevated vascular endothelial growth factor (VEGF) was associated with poor prognosis in leptomeningeal carcinomatosis and anti-angiogenic therapy was found to prolong the survival of mice in preclinical studies. This prospective pilot study investigated the efficacy of anti-VEGF therapy plus chemotherapy in patients with leptomeningeal carcinomatosis originating from breast cancer. METHODS: Eligible patients were scheduled to receive bevacizumab combined with etoposide and cisplatin (BEEP) every 3 weeks for a maximum of 6 cycles or until unacceptable toxicity. The primary objective was the central nervous system (CNS)-specific response rate, which was defined as disappearance of cancer cells in the cerebrospinal fluid (CSF) and an improved or stabilized neurologic status. The impact of VEGF inhibition on etoposide penetration into the CSF was analyzed. RESULTS: Eight patients were enrolled. The CNS-specific response rate was 60% in 5 evaluable patients. According to intent-to-treat analysis, the median overall survival of the eight patients was 4.7 months (95% confidence interval, CI, 0.3-9.0) and the neurologic progression-free survival was 4.7 months (95% CI 0-10.5). The most common grade 3/4 adverse events were neutropenia (23.1%), leukopenia (23.1%), and hyponatremia (23.1%). The etoposide concentrations in the CSF were much lower than those in plasma, and bevacizumab did not increase etoposide delivery to the CSF. CONCLUSIONS: BEEP exhibited promising efficacy in breast cancer patients with leptomeningeal carcinomatosis. Additional studies are warranted to verify its efficacy and clarify the role of anti-angiogenic therapy in this disease. TRIAL REGISTRATION: ClinicalTrials.gov identifying number NCT01281696 .

Erlotinib in combination with pemetrexed/cisplatin for leptomeningeal metastases and cerebrospinal fluid drug concentrations in lung adenocarcinoma patients after gefitinib faliure.

Limited treatment options are available for lung cancer with brain metastases. Recent reports indicated that erlotinib and pemetrexed had synergistic effects in lung adenocarcinoma. Thus, we speculated that erlotinib plus pemetrexed/cisplatin may be more effective for the treatment of refractory central nervous system metastases in patients after gefitinib failure. Six lung adenocarcinoma patients with leptomeningeal metastasis (LM) who showed initial good response to gefitinib and subsequent gefitinib resistance were enrolled in this retrospective study. Five of the six patients had an epidermal growth factor receptor (EGFR) mutation in the primary tumor tissues or plasma. One patient showed complete remission, two patients showed a partial response, and two patients had stable disease. Performance and symptoms improved in the six patients. The survival time after the combination therapy was from 8 to 15 months (median, 9 months). There was no significant difference in cerebrospinal fluid (CSF) penetration rates of erlotinib between the erlotinib-only and the combination groups (P = 0.44). Erlotinib combined with pemetrexed/cisplatin may be effective in the treatment of LM in EGFR mutation patients after gefitinib failure. Small but measurable penetration of erlotinib and pemetrexed into the CSF was observed.

The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates.

BACKGROUND: Satraplatin is an orally bioavailable platinum analog with preclinical activity in cisplatin resistant models and clinical activity in adults with refractory cancers. The cerebrospinal fluid (CSF) penetration of cisplatin and carboplatin in non-human primates (NHP) is limited (3.7 and 2.6%, respectively). We evaluated the plasma and CSF pharmacokinetics (PK) of satraplatin after an intravenous (IV) dose in NHP. METHODS: Satraplatin (120 mg/m(2)) was administered as 1 h IV infusion in DMSO (5%) and normal saline to 5 NHP. Serial blood and CSF samples were obtained over 48 h. Plasma ultrafiltrate (UF) was immediately prepared by centrifugation. Platinum was quantified in plasma UF and CSF using a validated atomic absorption spectroscopy assay with lower limit of quantification (LLQ) of 0.025 µM in UF and 0.006 µM after concentration in CSF. Pharmacokinetic parameters were estimated using non-compartmental analyses. CSF penetration was calculated from the CSF AUC(0-48h) : plasma UF AUC(0-48h). RESULTS: Satraplatin was well tolerated. Median (range) PK parameters in plasma UF were: maximum concentration (C (max)) 8.3 µM (5.7-10.6), area under the curve (AUC(0-48h)) 29.2 µM h (22.6-33.2), clearance 0.36 l/h/kg (0.31-0.37), and t (1/2) 18.8 h (13.4-25). Satraplatin was detected in the CSF of all NHP. Median (range) PK parameters in CSF were: C (max) 0.07 µM (0.02-0.12), AUC(0-48h) 1.2 µM h (0.49-2.43). The median (range) CSF penetration of satraplatin was 4.3% (2.2-7.4). CONCLUSIONS: Satraplatin penetration into CSF is similar to that of carboplatin and cisplatin, despite its greater lipophilicity. The development of a phase I trial of satraplatin for refractory childhood solid tumors including brain tumors is in progress.

Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates.

PURPOSE: Cisplatin, carboplatin, and oxaliplatin are chemically reactive anticancer drugs with modest activity in brain tumors. Previously, we have demonstrated that drug exposure in cerebrospinal fluid (CSF) for these platinum analogs is <5% of the plasma ultrafiltrate (UF) drug exposure in nonhuman primates. Microdialysis is a minimally invasive in vivo method for sampling small molecules in the blood and tissue extracellular fluid (ECF). The purpose of this study was to estimate the penetration of platinum analogs into the brain ECF. METHODS: We measured free concentrations of cisplatin, carboplatin, and oxaliplatin in ECF of brain, muscle, and blood of nonhuman primates using microdialysis and compared ECF platinum concentrations in blood and brain to plasma UF and CSF concentrations obtained using conventional sampling methods. RESULTS: For all three platinum analogs, AUC(0-4h) for microdialysis sampling from the vein was similar to standard plasma UF sampling. The median AUC(0-4h) ratio for vein to plasma UF was 1.1 (range, 0.9-1.4). The platinum analogs had limited distribution (<5%) to the CSF and brain ECF. CSF penetration predicts for the limited penetration of the platinum analogs into brain ECF, but concordance between CSF and brain ECF measurements was poor. CSF oxaliplatin concentrations (AUC(0-4h), 0.4-0.9 microM h) were substantially lower than brain ECF concentrations (AUC(0-4h), 2.0-8.6 microM h). CONCLUSIONS: The penetration of platinum analogs into CSF and brain is limited. The differences in the CNS penetrations among the three platinum analogs are not clinically significant. For cisplatin and carboplatin, CSF penetration appears to be a surrogate for brain extracellular free drug exposure.

Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates.

PURPOSE: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species. EXPERIMENTAL DESIGN: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0-24)/plasma ultrafiltrate AUC(0-24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites. RESULTS: The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 +/- 22, 18 +/- 6, and 211 +/- 64 micromol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 micromol/L hour for oxaliplatin, 0.56 +/- 0.08 micromol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0%, 3.6%, and 3.8%, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29%, 79%, and 81% of platinum in plasma ultrafiltrate, respectively, and 25%, 89%, and 56% of platinum in CSF, respectively. The CSF penetration of active drug was 1.6% for oxaliplatin, 3.7% for cisplatin, and 2.6% for carboplatin. CONCLUSIONS: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.

Distribution of cisplatin in perilymph and cerebrospinal fluid after intravenous administration in the guinea pig.

The concentration of free cisplatin was followed in plasma, scala tympani perilymph and cerebrospinal fluid (CSF) after an intravenous injection (12.5 mg/kg) in guinea pigs. Liquid chromatography with postcolumn derivatization was used for quantitative determination of the drug. The distribution of cisplatin to CSF was fast; at 10 min after drug administration the concentration was 7 micrograms/ml and the CSF:plasma ratio was 0.37. Cisplatin seems to distribute more slowly to the perilymphatic compartment. The highest concentration measured was 4 micrograms/ml at 20 min after the injection, and the perilymph:plasma ratio was 0.40 at that time. The concentration-time curves generated for cisplatin in perilymph and CSF were similar. No accumulation in the perilymphatic compartment or CSF was observed.

[Pharmacokinetics of plasma and cerebrospinal fluid cisplatin in patients with malignant glioma and metastatic brain tumor after selective intraarterial or intravenous and intracarotid administration of etoposide and cisplatin].

CSF and plasma platinum levels were examined in patients with malignant glioma after administration of etoposide and cisplatin each at doses of 60 mg/m2 by 60-minute selective intraarterial infusion. These same factors were also examined in patients with metastatic brain tumors after administration of cisplatin at a dose of 60 or 100mg/m2 by 60-minute intracarotid or intravenous infusion. Plasma and CSF samples taken through an Ommaya reservoir placed in the lateral ventricle or postoperative cavity were analyzed for platinum content by atomic absorption spectroscopy. Plasma and CSF platinum levels were dose dependent. The overall plasma platinum curves were biphasic, with mean half-lives of 35 minutes and 56 hrs. The mean peak total CSF concentration was 10.0% of the peak total plasma platinum and 20.2% of the peak free plasma platinum in patients with malignant glioma. In patients with a solid metastatic brain tumor, the mean peak total CSF concentration was 1.9% of the peak total plasma platinum and 4.0% of the peak free plasma platinum after i.v. infusion. After intracarotid infusion, the mean peak total CSF concentration was 3.4% of the peak total plasma platinum and 7.0% for the peak free plasma platinum. In patients with meningeal carcinomatosis, the mean peak CSF concentrations were 7.7% of the peak total plasma platinum and 13.7% of the peak free plasma platinum. The free to total platinum ratio in plasma decreased quickly and that in CSF increased and was maintained at the high levels of 80% for two hours or more.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrospinal fluid pharmacokinetics of carboplatin in children with brain tumors.

The pharmacokinetics of carboplatin in cerebrospinal fluid (CSF) and plasma was studied in five children with brain tumors (four medulloblastomas and one ependimoblastoma) who underwent preirradiation treatment with carboplatin. Carboplatin pharmacokinetics was studied following the administration of 600 mg/m2 as a 1-h infusion. Four children were treated a few weeks after surgery, whereas one child with an unresectable tumor was treated prior to surgery. All patients had a ventricular-peritoneal CSF shunt connected to a subcutaneous reservoir. Total platinum and free carboplatin were measured. The mean AUC values for free carboplatin in CSF and plasma were 2.29 +/- 1.20 and 8.18 +/- 1.27 mg ml-1 min, respectively. The mean ratio of CSF AUC to plasma AUC was 0.28 (range, 0.17-0.46). Both plasma peak levels and AUC values showed limited interpatient variability. On the other hand, carboplatin levels in CSF showed substantial interpatient variability, with a greater than 5-fold difference in peak levels and a 3-fold difference in AUC values being recorded. The interpatient difference in CSF pharmacokinetics may have been related at least in part to the different anatomical alterations induced by the surgical procedures or by the presence of a large tumor mass. In the four evaluable patients exhibiting macroscopic residual tumor, we observed one complete remission (CR) and two partial remissions (PR) following two cycles that consisted of two doses of 600 mg/m2 carboplatin given on 2 consecutive days (total dose, 1200 mg/m2) and were separated by a 1-month interval. These results may give some indication as to the optimal dose and schedule for carboplatin administration in the treatment of primitive neuroectodermic tumors (PNET).

Transport of cisplatin in rat brain following microinfusion: an analysis.

The post-microinfusion transport of cis-diamminedichloroplatinum(II) (cisplatin) in rat brain has been modeled as a linear diffusion-reaction-permeation process. The model has been used to analyze the experimental data of Kroin and Penn to obtain the macromolecular binding constant of cisplatin in the brain, k = 0.0050 +/- 0.0023 min-1, and the capillary permeability, p = (9.0 +/- 4.4) X 10(-7) cm/s. Inclusion of saturation effects led to the same p value and a higher k value of 0.007 min-1. The corresponding diffusion length is 0.8 mm. The reaction constant is similar to those reported for plasma (0.008 min-1) and muscle (0.004 min-1), and the permeability value is within the range predicted by correlation with the permeability-octanol/water partition coefficient. Fits to data were accomplished with mathematical expressions giving the average total platinum concentration in saggital cerebellar sections which were not subdivided. Both time-dependent and steady-state solutions were obtained for the transport model, the former predicting a half-time to steady state of 3 h. Boundary effects were also investigated. Concentration profiles, calculated for a point source and for a 23-gauge cannula, were shown to differ by 7%. Similar comparisons between two profiles, one computed for an infinite diffusion range and another computed for drug diffusion into a flowing cerebrospinal fluid (CSF) at a finite range of 3 mm, showed differences of less than 3%. Free and bound drug forms, protein turnover, and CSF uptake have been accounted for as well as the percent infusate recoveries at 100 and 160 h reported by Kroin and Penn.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic study of cerebrospinal fluid penetration of cis-diamminedichloroplatinum (II).

The ability of cis-DDP and several analogs to enter the CSF was investigated in rhesus monkeys that had subcutaneously implanted Ommaya reservoirs connected to catheters in each monkey's fourth ventricle. Plasma and CSF samples were analyzed for platinum content by atomic absorption spectroscopy. Plasma platinum curves were biphasic with a very slowly declining terminal phase. CSF platinum curves rose to maximum concentrations 30-40 min after an IV bolus injection and declined mono-exponentially (T 1/2 = 60 min) without displaying a detectable slow terminal phase. cis-DDP given as an IV bolus of 1.5 mg/kg or 3.0 mg/kg produced peak CSF concentrations of 0.35 and 0.78 microM platinum. The ratio of CSF platinum:plasma platinum never exceeded 0.04. When cis-DDP at 3.0 mg/kg was given as a 2- or 7-h infusion, the peak CSF concentrations were 0.28 and 0.17 microM platinum, respectively. The total CSF exposure, measured as concentration X time, was the same for bolus and for 2- and 7-h infusions. Studies with analogs showed that neither malonato 1,2-diaminocyclohexane platinum (II) nor 4-carboxyphthalato 1,2-diaminocyclohexane platinum (II) had better CSF penetrance than cis-DDP. Sulfato 1,2-diaminocyclohexane platinum (II) could not be detected in the CSF. The ratio of CSF platinum:plasma platinum was never greater tha 0.02-0.03 for any of the analogs.