A pharmacokinetic study of idarubicin hydrochloride, a new anthracycline anti-tumor drug, in patients with acute leukemia. Idarubicin Study Group]

In 21 patients with acute leukemia, idarubicin hydrochloride, a new anthracycline antitumor drug, was administered i.v. for 3 consecutive days to study the pharmacokinetics. The terminal half-lives (t1/2) of the drug in these patients were 6.40-15.10 hrs. in plasma, and 8.09-16.34 hrs. in blood cells. Its main metabolite idarubicinol remained longer in blood; t1/2 values were 43.46-51.01 hrs. in plasma and 36.61-54.70 hrs. in blood cells. After 2-4 hrs, the concentrations of idarubicinol in both plasma and blood cells exceeded those of idarubicin. The AUCs of idarubicinol in plasma were 5.16-8.36 times higher than those of idarubicin, and AUCs of idarubicinol in blood cells were 2.05-4.57 times higher than those of idarubicin. Among the doses ranged from 5 to 15 mg/m2/day, the AUCs of both idarubicin and idarubicinol increased dose-dependently. In 2-compartment multiple dose models, plasma t1/2 alpha and t1/2 beta of idarubicin were 0.25 +/- 0.13 hrs. and 9.4 +/- 3.4 hrs., respectively. The steady-state volume of distribution (Vdss) was 934.9 +/- 370.7 l/m2, and the plasma clearance was 82.3 +/- 29.7 l/hr/m2. The urinary excretion of the drug was comparatively low. Until 7 days after administration, the mean cumulative urinary recovery rates of idarubicin and idarubicinol were 2.04% and 11.53%, respectively, and 13.57% in total.     

High-dose idarubicin in combination with Ara-C in patients with relapsed or refractory acute lymphoblastic leukemia: a pharmacokinetic and clinical study

Objective High dose (HD) Ara-C combined with a single HD idarubicin dose (IDA) is an efficient and safe salvage regimen for patients with refractory or relapsed acute lymphoblastic leukemia as indicated by phase II studies. No data are available on the pharmacokinetics of IDA after a rapid HD intravenous infusion. An open phase II pharmacokinetic and clinical study was performed to evaluate antileukemic efficacy, IDA pharmacokinetics and to investigate the presence of IDA and its reduced metabolite idarubicinol (IDAol) in cerebrospinal fluid (CSF) of patients treated with HD-IDA. Patients and methods Twenty-five patients with refractory or relapsed acute lymphoblastic leukemia received Ara-C 3 g/m² from days 1–5, idarubicin (HD-IDA) 40 mg/m² as rapid intravenous (i.v.) infusion on day 3 and subcutaneous G-CSF 5 μg/kg from day 7 until PMN recovery. Pharmacokinetics of IDA was evaluated after HD idarubicin administration in nine of these patients. CSF samples were collected in 15 patients at different times. IDA and IDAol concentrations were quantified by a validated HPLC assay described in detail elsewhere. Results Eleven patients (44%, 95% CI: 23–65%) achieved complete remission with median disease free survival for 6 months. After administration of HD-IDA i.v. bolus of 40 mg/m², plasma level profiles of unchanged drug and IDAol were similar to those previously described after standard dose and measured with the same analytical method. The mean terminal half-life measured for IDA in this group of patients (14.9 h) was not significantly different from the mean value observed after standard dose (13.9 h, P = 0.72). IDAol t _1/2 was also similar after HD-IDA (46.2 h) and standard dose (39.4 h, P = 0.79). Pharmacokinetic data reveal that in our series of patients IDA and IDAol clearances are significantly higher than those observed in patients treated with 12 mg/m² of IDA but, although the administered dose (mg/m²) of the drug is 3.3 times higher, IDA exposure (measured in terms of AUC) is only 2.3 times and IDAol exposition 2.1 times greater. Furthermore, HD infusion resulted in a ratio between the AUC of parent drug and idarubicinol not different from the value observed with the standard-dose. IDA and IDAol were measurable only in 3 of the 15 cerebrospinal fluid samples collected. Conclusion Responses observed in our series are comparable to those reported with other salvage regimens. The IDA exposure lower than expected may explain the safety of the single i.v. administration of 40 mg/m² of IDA, combined with HD Ara-C, with a degree of myelosuppression equivalent to that reported with this agent administered in standard doses. Our data do not allow us to clearly attribute this behavior to a pharmacokinetic non-linearity since the baseline creatinine clearance, even within normal values, and patient age are significantly different in the two groups. Cerebrospinal fluid penetration was poor, reaching levels not considered as cytotoxic. The authors declare that they have no potential conflict of interest.     

Idarubicin and Idarubicinol Effects on Breast Cancer Multicellular Spheroids

Abstract

Despite extensive preclinical evaluation in several experimental models, no studies have determined the effect of idarubicin and its metabolite idarubicinol on multicellular spheroids, a model which mimics the microregions of solid tumors. The principal aim of the present study was to investigate the in vitro cytotoxicity of idarubicin and its metabolite idarubicinol on MCF-7 breast cancer cells growing as monolayers or multicellular spheroids and to evaluate the influence of the length of exposure on the cytotoxic effect of both drugs. Cytoxicity was evaluated on monolayer and spheroid cultures exposed to idarubicin and idarubicinol 0.01-1000 ng/ml for 24 h or treated for 6, 12, 24 and 48 h to 100 ng/ml of both drugs. The IC₅₀ of idarubicin and idarubicinol were 3.3±0.4 and 3.6±0.7 ng/ml, respectively, on MCF-7 monolayers and 7.9±1.1 and 5.3±0.7 ng/ml in multicellular spheroids, respectively. The antiproliferative effects of 100 ng/ml idarubicin and idarubicinol on MCF-7 spheroids was characterized by a marked time-dependence, which was less evident on MCF-7 growing as monolayer. In conclusion, the present experimental data demonstrate, for the first time, that idarubicin and idarubicinol have significant cytotoxic activity against multicellular spheroids, comparable to the antiproliferative effects on monolayer cells. In contrast, spheroids displayed substantial resistance after short exposure times that was not present in the two dimensional cultures.     

Comparison of idarubicin and daunorubicin and their main metabolites regarding intracellular uptake and effect on sensitive and multidrug-resistant HL60 cells

 To study the effect of the main metabolites on the cytotoxic effect of daunorubicin and idarubicin in human HL-60 cells, drug-sensitive and multidrug-resistant HL60 cells were incubated with idarubicin and daunorubicin and their metabolites idarubicinol and daunorubicinol over a wide range of concentrations. The intracellular uptake of the drugs was determined by photofluorometry, and the cytotoxic effect in vitro was determined by a bioluminescence assay of intracellular adenosine triphosphate (ATP) after 4 days of culture in liquid medium. The effect of intracellular drugs was calculated from the incubation-concentration versus intracellular-uptake and cytotoxic-effect curves. The intracellular uptake of idarubicin was 6 times that of daunorubicin in drug-sensitive cells and 25 times higher in resistant cells. For idarubicinol as compared with daunorubicinol the corresponding factors were 25 and 7, respectively. As compared with the parent substances, the uptake of idarubicinol and daunorubicinol was 16% and 4%, respectively, in sensitive cells and 40% and >100%, respectively, in resistant cells. An intracellular concentration of 0.5 nmol/mg protein of both parent substances caused a 50% growth inhibition in drug-sensitive cells as compared with 10 nmol/mg protein for drug-resistant cells. For the metabolites an intracellular concentration of 0.4 nmol/mg protein of idarubicinol and 2.0 nmol/mg protein of daunorubicinol was required to inhibit cells’ growth by 50% in drug-sensitive HL60 cells. In the resistant HL60 cells the corresponding values were 30 nmol/mg protein for idarubicinol and 40 nmol/mg protein for daunorubicinol. These results confirm that idarubicinol may significantly contribute to the clinical effect of idarubicin. However, in combination with previous results that have shown low intracellular concentrations of the metabolites in vivo, it appears that the pharmacokinetic properties of the mother substances provide the major explanation for the clinical effect of idarubicin. Received: 26 July 1996/Accepted: 17 January 1996     

Anthracyclines and their C-13 alcohol metabolites: growth inhibition and DNA damage following incubation with human tumor cells in culture

Summary Anthracyclines are important antitumor agents used in the treatment of solid tumors, lymphomas, and acute lymphoblastic as well as myelocytic leukemias. The clinical utility of agents such as doxorubicin and daunorubicin and their well-characterized cardiotoxicity have prompted many efforts to develop analogs that retain the desired spectrum of activity but are less cardiotoxic. One such analog is idarubicin (4-demethoxydaunorubicin), which is currently under study in the treatment of adult and pediatric leukemias. The major circulating metabolite of idarubicin is the alcohol product of ketoreductase biotransformation, idarubicinol. Following the administration of idarubicin to adult or pediatric patients, systemic exposure to idarubicinol is greater than that to idarubicin. Moreover, we have also documented the presence of idarubicinol in the cerebrospinal fluid of pediatric patients who have received idarubicin. Idarubicinol has been reported to have greater cytotoxic activity than other anthracycline alcohol metabolites, which are regarded as much less active products of metabolism. We therefore evaluated the growth-inhibitory and DNA-damaging activities of idarubicin, daunorubicin, doxorubicin, epirubicin, and their alcohol metabolites against three relevant (CCRF-CEM lymphoblastic leukemia, K562 myelogenous leukemia, and U87-MG glioblastoma) human tumor cell lines. We found that whereas idarubicin was 2–5 times more potent than the other three anthracycline analogs against these tumor cell lines, idarubicinol was 16–122 times more active than the other alcohol metabolites against the same three cell lines. In addition, idarubicinol and the parent drug idarubicin were equipotent, unlike the other anthracycline alcohol metabolites, which were much less cytotoxic than the corresponding parent drugs. We also assessed the ability of the four parent drugs and their alcohol metabolites to induce DNA single-strand breaks. Idarubicin was more potent than the other three anthracycline analogs and idarubicinol was much more effective than the other alcohol metabolites in inducing DNA damage. These studies in human leukemia and human glioblastoma cell lines support the hypothesis that idarubicinol plays an important role in the antitumor activity of idarubicin and that the activities of idarubicin and idarubicinol are related to their ability to damage DNA.This research was partially supported by funds from Adria Laboratories and by NCI grant CA 15083, DHHS     

Pharmacokinetic Comparison of 120-Hour Infusion Versus Hyperfractionated Oral Administration of Idarubicin

Abstract

The aim of this study was to compare the pharmacokinetics of idarubicin (IDA) and its active metabolite idarubicinol (IDOL) after chronic oral and continuous intravenous (i.v.) IDA administration in order to establish the oral doses needed to reach the i.v. equiactive plasma drug exposure. The pharmacokinetic profile of IDA and IDOL was investigated in 23 patients receiving 12 mg/m² IDA by 120-h i.v. infusion (2.4 mg/m²/day) combined with cyclophosphamide, etoposide and pred-nisone in comparison to 28 patients receiving oral IDA doses ranging from 2 to 10 mg/day for 21 days in a phase I study. We found that IDA AUC_24h/dose/m² was 4.7-fold greater during i.v. than oral administration, whereas IDOL AUC_24h/dose/m² was only about 2-fold higher after i.v. administration. The metabolic ratio between IDOL AUC_24h and IDA AUC_24h in plasma was about 3-fold higher after oral adminis-tration. Based on these results we were able to estimate that equiactive plasma drug exposure was reached with an ～2.5-fold greater oral dose/m² of IDA than the corresponding i.v. dose.     

A phase 2 study of a fixed combination of uracil and ftorafur (UFT) and leucovorin given orally in a 3‐times‐daily regimen to treat patients with recurrent metastatic breast cancer

BACKGROUND:

A combination of uracil and ftorafur (UFT) was developed to combine the cytotoxic effects of 5‐fluorouracil (5‐FU) with convenient oral dosing. Leucovorin was combined with UFT to further potentiate the effect of 5‐FU on tumor cells. Orally administered UFT and leucovorin provided higher peak plasma concentrations of 5‐FU and prolonged therapeutic 5‐FU concentrations compared with continuous infusion of 5‐FU.

METHODS:

Ninety‐one patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35‐day cycle. The total daily dose of UFT was 300 mg/m², administered in 3 doses of 100 mg/m² each every 8 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (overall response equals complete response plus partial response) and overall survival.

RESULTS:

Of the 91 patients enrolled, 70 were evaluable for efficacy. Although no complete responses were observed, 7 patients had partial responses, for an overall response rate of 10% in the evaluable population. The median TTP for the evaluable population was 10 weeks, and the proportion of patients who were free of disease progression at 6 months was 23%. The median overall survival was 59.4 weeks for all patients enrolled. Common, drug‐related ≥ grade 3 adverse events (graded according to National Cancer Institute Common Toxicity Criteria, version 2) included diarrhea, vomiting, abdominal pain, and nausea.

CONCLUSIONS:

The combination of UFT and leucovorin administered orally in a 3‐times‐daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010. © 2010 American Cancer Society.     

Bioavailability and pharmacology of oral idarubicin

Summary A total of 9 patients entered in a phase I trial who received oral idarubicin daily for 3 days took part in pharmacokinetic studies, and bioavailability studies were performed on 13 additional patients receiving single doses of oral idarubicin alternating with i.v. treatment. The data were best fit by a two-compartment model (distribution and elimination compartments for i.v. drug and absorption and single-phase elimination for oral drug). For different idarubicin doses in the phase I and bioavailability studies, the median values for the terminal half-life of idarubicin varied from 5.6 to 11.6 h. High concentrations of the active metabolite idarubicinol were formed. Idarubicinol was climinated more slowly than was the parent compound, with median half-lives for different dose levels varying from 8 to 32.7 h. Although most pharmacokinetic parameters were similar in plasma and whole blood, peak concentrations and AUCs in whole blood were about 3–4 times those calculated in plasma for idarubicin and about 1.5–2 times those determined in plasma for idarubicinol, indicating fairly extensive uptake into erythrocytes. Oral bioavailability was determined by comparing oral idarubicin to i.v. drug with respect to the combined idarubicin and idarubicinol plasma AUCs, and it varied from 12%–49% (median, 29%). Bioavailability was essentially the same (30%) when whole-blood values were used. Urinary excretion of the drug was <5% of the delivered dose by 96 h. Granulocytopenia correlated with plasma idarubicinol estimated clearance and steady-state volume of distribution, with whole-blood idarubicinol AUC, area under the moment curve (AuMC), and estimated clearance and volume of distribution, and with whole-blood combined idarubicin and idarubicinol AUCs. This suggests that drug contained in erythrocytes plays a major role in toxicity and that idarubicinol may play a larger role in toxicity than does the parent compound.Supported by a grant from Adria Laboratories     

The combination of gemcitabine and vinorelbine is an active regimen as second-line therapy in patients with metastatic breast cancer pretreated with taxanes and/or anthracyclines: a phase I-II study

Purpose. To evaluate the activity and toxicity of gemcitabine and vinorelbine (GemVin), in patients with advanced breast cancer, previously treated with anthracyclines alone or with taxanes. Patients and methods. Nine patients were entered into the phase I and 50 patients were entered into the phase II study. Gemcitabine was administered beginning with the dose of 800 mg/m² and vinorelbine was given at the fixed dose of 25 mg/m², both on days 1 and 8, every 21 days. Escalated dose levels of gemcitabine were planned by increments of 200 mg/m² per level. The median age of the 50 assessable patients for the phase II study was 56.5 years (range 30–70) and median performance status (PS, ECOG score), 1 (range 0–2). The dominant sites of metastases were viscera in 40, bone in five and soft tissue in five patients. First-line chemotherapy for metastatic disease with taxanes and anthracyclines or with anthracyclines alone was administered in 36 and 14 patients, respectively. Results. The optimal schedule for the combination was gemcitabine 800 mg/m² and vinorelbine 25 mg/m². The maximum tolerated dose of gemcitabine was 1000 mg/m², with grade 4 neutropenia occurring in two cases at this dose level. Overall, 267 cycles were given to the 50 patients enrolled into the phase II (mean 5.3; range 3–9). The schedule was well tolerated: three patients experienced grade 4 neutropenia and another four patients experienced grade 3 anemia. Non-hematological toxicities were moderate. A major objective response was observed in 42% of patients (95% confidence interval (CI), 28–57%), with complete remission in four (8%) and partial response in 17 (34%) patients. The median time to progression was 6 months. Activity as well as toxicity were similar in the subgroups of the patients pretreated either with combinations of taxanes and anthracyclines or anthracyclines alone. Conclusions. The optimal GemVin schedule is an effective and well tolerated second-line therapy in patients with metastatic breast cancer pre-treated with anthracycline – based schedules or with combinations of anthracyclines and taxanes.     

Idarubicin and idarubicinol effects on breast cancer multicellular spheroids

Despite extensive preclinical evaluation in several experimental models, no studies have determined the effect of idarubicin and its metabolite idarubicinol on multicellular spheroids, a model which mimics the microregions of solid tumors. The principal aim of the present study was to investigate the in vitro cytotoxicity of idarubicin and its metabolite idarubicinol on MCF-7 breast cancer cells growing as monolayers or multicellular spheroids and to evaluate the influence of the length of exposure on the cytotoxic effect of both drugs. Cytoxicity was evaluated on monolayer and spheroid cultures exposed to idarubicin and idarubicinol 0.01-1000 ng/ml for 24 h or treated for 6, 12, 24 and 48 h to 100 ng/ml of both drugs. The IC50 of idarubicin and idarubicinol were 3.3+/-0.4 and 3.6+/-0.7 ng/ml, respectively, on MCF-7 monolayers and 7.9+/-1.1 and 5.3+/-0.7 ng/ml in multicellular spheroids, respectively. The antiproliferative effects of 100 ng/ml idarubicin and idarubicinol on MCF-7 spheroids was characterized by a marked time-dependence, which was less evident on MCF-7 growing as monolayer. In conclusion, the present experimental data demonstrate, for the first time, that idarubicin and idarubicinol have significant cytotoxic activity against multicellular spheroids, comparable to the antiproliferative effects on monolayer cells. In contrast, spheroids displayed substantial resistance after short exposure times that was not present in the two dimensional cultures.     

Phase I study of bendamustine with concurrent whole brain radiation therapy in patients with brain metastases from solid tumors

A phase I study was conducted to evaluate the dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD)/recommended phase II dose of bendamustine with concurrent whole brain radiation (WBR) in patients with brain metastases (BM) from solid tumors. Four doses of intravenous weekly bendamustine were administered with 3 weeks of WBR at three dose levels (60, 80, and 100 mg/m²) according to a standard 3 + 3 phase I design. A total of 12 patients with solid tumor BM were enrolled in the study (six with non-small cell lung cancer, four with melanoma, one with breast cancer, and one with neuroendocrine carcinoma). The first two dose levels had three patients each, and the third dose level had six total patients. Plasma pharmacokinetic studies of bendamustine demonstrated no significant differences from pharmacokinetic characteristics of bendamustine in other studies. No DLTs were noted at any dose levels, and no grade 4 toxicities occurred. The MTD of weekly bendamustine with concurrent WBR was 100 mg/m². The majority of trial patients died from progressive systemic disease rather than their brain disease. The combination of weekly bendamustine with concurrent WBR was acceptably tolerated. The efficacy of this combination may be evaluated in a phase II trial with stratification by histologies.     

Idarubicinol myelotoxicity: a comparison of in vitro data with clinical outcome in patients treated with high-dose idarubicin

We evaluated in vitro the toxicity of idarubicin and its active metabolite idarubicinol on haematopoietic progenitors, using human umbilical cord blood and peripheral blood progenitors to obtain dose-response curves. We treated 16 patients with poor prognosis lymphoma in a phase I-II trial of high-dose idarubicin and melphalan and investigated if idarubicinol persisting in patients' plasma at the time of transplantation (day 0), on day +1 and +2 could result in an inhibition of infused progenitors. Colony inhibition was correlated with pharmacokinetic data and with the time of patients' engraftment. Plasma samples obtained before idarubicin treatment demonstrated a colony-stimulating effect, increasing the cloning efficiency by 72%. The inhibitory activity on colony forming unit granulocyte-macrophage (CFU-GM) of patients' plasma collected on the day of transplantation was lower than expected from dose-response curves (21% measured vs 70% expected). The time to patients' WBC and PLT recovery correlated with the amount of CD34+ cells reinfused and, to a lesser extent, with the colony-inhibiting effect of patients' plasma. The correlation between idarubicinol concentration and CFU-GM inhibition was not significant. These data suggest that plasma drug concentration on the day of stem cell reinfusion may overestimate the toxicity of residual anthracyclines to the transplanted cells.     

Plasma pharmacokinetics and cerebrospinal fluid concentrations of idarubicin and idarubicinol in pediatric leukemia patients: a Childrens Cancer Study Group report

Idarubicin (4-demethoxydaunomycin) is an anthracycline analogue with striking in vitro and in vivo activity against murine leukemias. Based on activity in adults with acute lymphoblastic leukemia, the Childrens Cancer Study Group initiated studies to evaluate idarubicin in children with leukemia in second or subsequent relapses. As part of those studies, we have characterized the plasma pharmacokinetics of idarubicin and the major circulating metabolite idarubicinol in 21 patients. Idarubicin plasma elimination was described by a three-compartment open model following i.v. infusion (10-15 mg/m2) on a schedule of weekly for 3 weeks and on a schedule of daily for 3 days every 3 weeks (total dose, 30-45 mg/m2). There was substantial variability in idarubicin elimination among patients, but no indication of dose-dependent or of schedule-dependent changes in pharmacokinetic parameters. The mean terminal half-life, total body clearance, and steady state volume of distribution were 17.6 h, 679 ml/min/m2, and 562 l/m2, respectively. Idarubicinol elimination was prolonged compared to that of the parent drug with a terminal half-life of 56.8 h. This metabolite clearly accumulated in plasma during the 3 days of treatment on the schedule of daily for 3 days. Urinary recoveries (48 h) of idarubicin and idarubicinol after a single dose of idarubicin were 2.4 and 10.1%, respectively. Idarubicin was detected in 2 of 21 cerebrospinal fluid samples obtained 18-30 h after administration. In marked contrast, idarubicinol was detected in 20 of those 21 samples. Concentrations in the 20 samples varied from 0.22-1.05 ng/ml with a mean value of 0.51 ng/ml.     

Pharmacokinetics of idarubicin after oral administration in elderly leukemic patients

We have studied the plasma pharmacokinetics of idarubicin (4-demethoxy daunorubicin) in 11 elderly patients suffering from acute myeloblastic leukemia receiving orally 30 mg/m2 per day for 3 consecutive days. Idarubicin culminated in plasma 4 hr after administration and followed three similar time courses after the three administrations. Idarubicinol (13-dihydro-4-demethoxy daunorubicin) was the only fluorescent metabolite in plasma and no aglycone could be detected; idarubicinol concentration was always higher than that of unchanged idarubicin. Due to its protracted half-life (64 hr in this study), this metabolite progressively accumulated and the ratio of the areas under the curve (0-24) idarubicinol/idarubicin increased from day to day. By comparison to results obtained after i.v. administration of the drug in another study, the bioavailability of idarubicin alone can be estimated to about 21%, whereas the bioavailability of the sum idarubicin + idarubicinol is about 41%.     

A phase 2 study of a fixed combination of uracil and ftorafur and leucovorin given orally in a twice‐daily regimen to treat patients with recurrent metastatic breast cancer

BACKGROUND:

UFT, a combination of uracil and ftorafur, was developed to combine the cytotoxic effects of 5‐fluorouracil (5‐FU) with convenient oral dosing. Leucovorin is combined with UFT to further potentiate the effect of 5‐FU on tumor cells. Orally administered UFT and leucovorin provide higher peak plasma concentrations of 5‐FU and prolonged therapeutic 5‐FU concentrations compared with continuous infusion of 5‐FU.

METHODS:

Ninety‐four patients with metastatic breast cancer who had been previously treated with anthracyclines and/or taxanes were treated with UFT and leucovorin, given orally, for the first 28 days of a 35‐day cycle. The total daily dose of UFT was 300 mg/m², which was given in 2 divided doses every 12 hours. The primary endpoint was time to disease progression (TTP). Secondary objectives included overall tumor response rate (OR = complete response [CR] + partial response [PR]) and overall survival (OS).

RESULTS:

Of the 94 patients enrolled, 68 were evaluable for efficacy. Although no CRs were observed, 9 patients achieved PRs, for an OR of 13.2% in the evaluable population. The median TTP for the evaluable population was 10.3 weeks, and the proportion of patients free of disease progression at 6 months was 17%. The median OS was 61.6 weeks for all patients enrolled. The most common drug‐related ≥ grade 3 adverse events (graded using the National Cancer Institute Common Toxicity Criteria version 2) were diarrhea, asthenia, nausea, and dehydration.

CONCLUSIONS:

The combination of UFT and leucovorin administered orally in a twice‐daily regimen was found to have modest activity. Grade 3 toxicities were manageable with appropriate dose adjustments in patients with metastatic breast cancer previously treated with anthracyclines and/or taxanes. Cancer 2010. © 2010 American Cancer Society.     

Pharmacokinetics and tissue distribution of idarubicin and its active metabolite idarubicinol in the rabbit

 A three-compartment model was fitted to idarubicin data in a NONMEM pooled-data approach. Clearance (CL) of 221.7 ml/min was relatively high, and drug distribution was rapid (CL_D=248.3 ml/min) and extensive [steady-state volume of distribution (V_ss) 24 l]. The area under the concentration-time curve (AUC) of idarubicinol was 8 times that of idarubicin. Concentrations of idarubicin (idarubicinol) measured in the myocardium at 24 h after i.v. administration of idarubicin were 20 (5) times those determined in plasma. Tissue concentrations of idarubicinol were up to 400 times those of idarubicin, indicating that the active metabolite contributes significantly to the overall drug action. Received: 16 June 1996 / Accepted: 4 November 1996     

The vascular compartment hampers accurate determination of teniposide penetration into brain tumor tissue

After a pre-operative 1-h i.v infusion of 150 mg/m² of teniposide (Vumon; VM26), the drug levels were determined in resected brain tumor specimens from three patients with malignant glioma and from three patients with brain metastases. Tissue dissections were performed within 0–2.5 h after drug administration in three patients and after 24 h in the other three patients. Teniposide was quantified by high-performance liquid chromatography and the levels of albumin in the resected tissue samples were quantified by radial immunodiffusion. In addition, albumin levels were quantified in normal brain tissue, in malignant glioma and in metastatic brain tumor tissue obtained post mortem from deceased patients. The albumin levels indicated that a substantial fraction (range: 0.16–0.50) of the resected brain tumor specimens consisted of blood. As the plasma concentration of teniposide during the first hours after infusion is high, the major part of the drug measured in the tumor specimens collected within 2.5 h after drug administration originated from the blood compartment. At 24 h after drug administration, when the plasma level of teniposide had declined to approximately 0.20 μg/ml, we could discern a real tissue uptake of teniposide ranging from 0.15–0.27 μg/g wet tissue weight in the resected tumor. Although the number of patients in this study is small, this work clearly illustrates that an accurate determination of the tissue concentration of teniposide is hindered by the high concurrent plasma levels. It is therefore essential that future tissue distribution studies also include a suitable procedure that establishes the contribution of drug originating from the blood compartment. Received: 4 November 1996 / Accepted: 15 February 1997     

A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer

BACKGROUND

A study was conducted to determine the efficacy, tolerability, and safety of concurrent cisplatin and vinorelbine chemotherapy and radiotherapy in patients with previously untreated brain metastases from breast cancer.

METHODS

Twenty‐five patients with untreated brain metastases from breast cancer were treated with cisplatin (at a dose of 20 mg/m²/day, Days 1‐5) and vinorelbine (6‐mg/m² bolus on Day 1 and 6 mg/m²/day continuous infusion on Days 1‐5) chemotherapy combined with concurrent 30‐gray fractionated external‐beam radiotherapy. Chemotherapy was given at 3‐week intervals for a total of 4 cycles. Primary endpoint was the rate of radiologic response of brain metastases.

RESULTS

Complete response in the brain was observed in 3 patients, and partial response was noted in 16 patients, yielding a 76% response rate in the brain. The overall systemic response rate was 44%. Progression‐free and overall survival were 3.7 months and 6.5 months, respectively. Overall toxicity was acceptable; nonhematologic grade 3‐4 events were noted in 5 (20%) patients, and there were no toxic deaths.

CONCLUSIONS

Concurrent chemoradiation with cisplatin and vinorelbine for brain metastases from breast cancer appears to be active and well tolerated. Cancer 2008. © 2008 American Cancer Society.     

Phase I study of concurrent vinorelbine and radiation therapy in high-risk postmastectomy breast cancer patients

Background

Postmastectomy chest wall irradiation is recommended for high-risk breast cancer patients, such as those with ≥4 positive nodes. Irradiation is performed sequentially rather than concurrently with chemotherapy. However, the 5-year locoregional recurrence-free survival was statistically better in the concurrent method in node-positive patients in a prior study. The benefit of concurrent chemoradiotherapy for postmastectomy breast cancer patients is uncertain. Vinorelbine is often used as concurrent chemoradiotherapy for non-small cell lung cancer in Japan and has antitumor activity in breast cancer as well. Thus, we planned this dose-finding study of concurrent vinorelbine and radiation therapy in high-risk postmastectomy breast cancer patients.

Methods

High-risk postmastectomy breast cancer patients were recruited. Patients received weekly vinorelbine administered concurrently with radiation therapy. The radiation dose was 50 Gy in 25 fractions over 5 weeks. Vinorelbine was administered weekly without a break, so the maximum number of vinorelbine cycles was five. A 3 + 3 dose-escalation design was used for determining maximal tolerable dose, recommended dose and safety.

Results

A total of 10 patients were enrolled in cohorts of 10 and 15 mg/m². Dose-limiting toxicity was observed in one case in 10 mg/m² and two cases in 15 mg/m². Therefore, the maximal tolerable dose was defined at 15 mg/m² and the recommended dose was determined at 10 mg/m². The main adverse events included radiation dermatitis and neutropenia. Recurrence was observed in one patient with a median follow-up of 40 months.

Conclusions

Concurrent vinorelbine and radiation therapy has a manageable safety profile at 10 mg/m² in high-risk postmastectomy breast cancer patients.

     

Paclitaxel (TAXOL(R)) concentrations in brain tumor tissue

BACKGROUND: Paclitaxel (Taxol^®) is a novel chemotherapeutic agent, activeagainst a variety of tumors. It is not known whether the drugpenetrates brain tumor tissue. PATIENTS AND METHODS: Three patients with a recurrent glioma received paclitaxel (175mg/m²) in a 3-hour i.v. infusion prior to surgery. Paclitaxelconcentrations were measured in the tumor tissue, cerebrospinalfluid, cyst fluid, plasma and, in one patient, normal braintissue. RESULTS: Tumor tissue concentrations were in the thera- peutic rangein all three patients. Brain tissue concentration, however,was below the detection limit of the trial. CONCLUSIONS: These findings suggest that paclitaxel may have a place in braintumor therapy. The low concentration in normal brain tissue,as observed in one patient, may suggest, however, that the drugdoes not cross the intact blood-brain barrier. brain tumor, chemotherapy, glioma, paclitaxel, tissue concentrations