Treatment of advanced,high-grade soft-tissue sarcoma with ifosfamide and continuous-infusion etoposide

A total of 33 patients (median age, 44 years) with high-grade, adult soft-tissue sarcoma were treated with etoposide given at 600 mg/m² in a 72-h continuous infusion and ifosfamide given at 1500 mg/m² per day for 3 days every 3 weeks. Dose escalation/reduction was protocolled depending on the level of hematological toxicity observed in the preceding course. Overall, 90% of patients had metastatic disease, and the most common histologies were malignant fibrous histiocytoma and leiomyosarcoma. A median of 5 (range, 1–9) courses were given. Of 30 patients who were evaluable for response, 12 (40%) obtained a partial remission, and the median time to progression was 8 (range, 4–13) months. Grade 3–4 leukopenia and thrombocytopenia were seen after 89% and 8% of the courses, respectively; neutropenic fever was seen in half of the patients (15% of courses); and 32% of courses had to be postponed by 7 days or more due to myelosuppression. Dose reduction to below the standard had to be performed in 46% of courses, and dose escalation was achieved in only 13%. The reduced toxicity seen after the addition of granulocyte colony-stimulating factor (G-CSF) in five patients indicates that growth-factor support may enhance the dose intensity of the regimen. The results indicate significant activity for this regimen in adult softtissue sarcoma, which may in part be a result of the escalated dose and prolonged mode of administration of the phasespecific agent etoposide. As a result of this pilot series, a phase II study with ifosfamide, etoposide, and G-CSF in advanced adult soft-tissue sarcoma has been initiated by the Scandinavian Sarcoma Group.     

Clinical trial of high-dose etoposide

In eleven patients with recurrent or refractory malignant lymphomas or lung cancers, a phase I study of high-dose etoposide without autologous bone marrow transplantation was performed. As a starting dose of etoposide 200 mg/m2 was administered for five consecutive days and the daily dose was increased step by step to a dose of 50 mg/m2. The dose of etoposide was escalated in order to define dose-limiting extramedullary toxicity, which was oropharyngeal mucositis and arrhythmias (PVC) at a dose level of 350 mg/m2/day. Bone marrow toxicity was completely reversible, supported by thrombocyte transfusion and antibiotics. Of nine evaluable patients with malignant lymphomas, two complete remissions and one partial remission were obtained. However, some patients unresponsive to standard-dose etoposide did not exhibit any response to the augmented dose of etoposide. Etoposide is thus a suitable drug for high-dose chemotherapy.     

Clinical pharmacology of intracarotid etoposide

Summary Pharmacokinetics studies were performed in ten patients who received VP-16 by intracarotid infusion at 100–300 mg/m². VP-16 was analyzed by high-pressure liquid chromatography. ESTRIP and NONLIN were used to characterize VP-16 pharmacokinetics. VP-16 disappeared biphasically, with a t_1/2 of 6.1±1.4 h; the total clearance was 26.8±2.8 ml/min/m², and the V_ss was 8.8±1.6 l/m². The pharmacokinetics was not significantly different after administration by the IV route. However, at a lower dosage, <140 mg/m², the half-life appears to be shorter. This may or may not be significant, since VP-16 pharmacokinetics is quite variable and the number of patients studied is relatively small. Overall, the brain and brain tumor do not appear to have any first-pass effect on VP-16 pharmacokinetics.The study reported in this paper was supported by a grant from Bristol Laboratories, Syracuse, NY     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Phase-I trial of combination therapy with continuous-infusion MMPR and continuous-infusion 5-FU

Summary Fourty-four evaluable patients were treated with 6-methylmercaptopurine riboside (MMPR) at a dose of 20 mg/m²/day x 5 by continuous IV infusion (days 1–5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300–1519 mg/m²/day x 5 by continuous IV infusion (days 2–6). Dose-limiting oral mucositis occured at a 5-FU dose of 1,381 mg/m²/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and occasional myelosuppression. A partial and a complete response were observed in two previously untreated patients with metastatic colon carcinoma given the highest 5-FU doses (1,381 and 1,519 mg/m²/day). Bone marrow phosphoribosyl pyrophosphate (PRPP) levels monitored after 24 h of MMPR treatment indicated increases of 7.8- and 9.2-fold those found prior to therapy.     

Phase II pilot study with cisplatin, etoposide, and continuous-infusion 5-fluorouracil in metastatic non-small cell lung cancer

A pilot study was conducted using a combination of cisplatin (70 mg/m2 i.v., day 1), etoposide (60 mg/m2 i.v., days 1 through 5), continuous-infusion 5-fluorouracil (800 mg/m2 i.v., days 1 through 5), and allopurinol (600 mg p.o., days 1 through 7). Treatment was repeated every 3-4 weeks. Ten patients with metastatic non-small cell lung cancer were treated. Significant toxicities were observed, including electrocardiographic changes simulating acute myocardial infarction in three patients. There was no objective response, therefore the study was closed early according to its design.     

Pharmacokinetics and pharmacodynamics of oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia.

PURPOSE: To study the pharmacokinetics and pharmacodynamics of once- versus twice-daily oral etoposide in children with relapsed or refractory acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Fifty-eight patients were randomly assigned to etoposide at 50 mg/m(2)/d with once- versus twice-daily doses for 22 days. On day 8, vincristine, asparaginase, and dexamethasone were started. Etoposide pharmacokinetics and pharmacodynamics were studied for 47, 28, and 26 patients on day 1, 8, and 22, respectively, of remission reinduction therapy. RESULTS: Of 48 patients with pharmacokinetic data, 42 (87.5%) achieved complete remission, three (6.3%) failed to achieve remission, and three (6.3%) died during induction. Median etoposide day 8 area under concentration-time curve (AUC) and cumulative AUC tended to be greater (P =.06 and P =.07, respectively) in patients (n = 23) who achieved complete remission (24 and 522 micro mol/L x h, respectively) than in patients (n = 3) who did not (14 and 303 micro mol/L x h, respectively). Three of eight patients with plasma concentrations exceeding 1.7 micro M (1 micro g/mL) for more than 8 hours daily, compared with one of 20 patients with concentrations exceeding 1.7 micro M for 相似文献   

A phase I trial of combination therapy with continuous-infusion PALA and continuous-infusion 5-FU

Summary Thirty-four patients were treated with N-(phosphonacetyl)-l-aspartate (PALA) at a dose of 850 mg/m²/dayx5 by continuous intravenous infusion (days 1–5) and 5-fluorouracil (5-FU) on an escalating dose schedule of 300–630 mg/m²/dayx5 by continuous intravenous infusion (days 2–6). Dose-limiting oral mucositis occurred at a 5-FU dose of 560 mg/m²/day; other toxicities included nausea, vomiting, diarrhea, skin rash, and superficial venous phlebitis. Myelosuppression was rare. One partial response was observed in a patient with metastatic colorectal carcinoma. Plasma PALA levels were monitored in seven patients. Steady-state levels were achieved by the 2nd day of drug infusion and ranged between 10 and 20 g/ml.     

A phase I-II trial of continuous-infusion cisplatin, continuous-infusion 5-fluorouracil, and VP-16 in colorectal carcinoma

Twenty-nine evaluable patients with colorectal adenocarcinoma were treated in a phase I-II trial of combination chemotherapy with a 72-h continuous infusion of cisplatin (CDDP) and 5-fluorouracil (5-FU) with an infusion of VP-16 given at 24 and 48 h after the start of therapy. There were five (17 +/- 14%) partial responses lasting 2-6 months (median, 3). Three of these responses occurred among the 10 previously untreated patients. The toxicity of this regimen was pronounced. Four of eight patients with severe neutropenia required hospitalization for infections, two of which were life-threatening; one of six patients with severe thrombocytopenia had a life-threatening hemorrhagic complication; and four patients experienced severe, dose-limiting fatigue. These complications occurred principally with CDDP and VP-16 at doses above 27.5 mg/m2/day and 110 mg/m2/dose, respectively. Mucositis occurred in six patients and limited the dose of 5-FU to 1,300 mg/m2/day. Although the response rate appeared to be high in previously untreated patients, the minimal palliative benefit of treatment and the brief duration of the responses do not compensate for the toxicity observed.     

大剂量异环磷酰胺持续静滴联合阿霉素治疗进展期软组织肉瘤的临床观察

目的：评价大剂量异环磷酰胺持续７２ｈ静滴联合阿霉素治疗进展期软组织肉瘤的临床疗效和毒副反应。方法：２００８年３月～２００８年１０月收治进展期软组织肉瘤患者１５例,应用大剂量异环磷酰胺联合阿霉素治疗,异环磷酰胺总量１２ｇ／ｍ^２,持续静滴７２ｈ;阿霉素６０ｍｇ／ｍ^２第１天静滴。２１天为１周期。完成２～６周期,中位周期数为４。结果：全组患者ＣＲ１例（６.６７％）,ＰＲ１例（６.６７％）,ＳＤ１２例（８０.０％）,ＰＤ１例（６.６７％）,有效率１３.３％（２／１５）,疾病控制率９３.３％（１４／１５）。中位无疾病进展生存期６个月（３～１０个月）,中位总生存期７个月（３～１０个月）。主要毒副反应为粒细胞减少、胃肠道反应和脱发,其他毒副反应少见。结论：大剂量异环磷酰胺持续７２ｈ静脉滴注联合阿霉素方案治疗进展期软组织肉瘤可行,能够有效控制疾病进展,毒副反应可以耐受,值得进一步深入研究。     

Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance.

PURPOSE: To determine the effects of high-dose cyclosporine (CsA) infusion on the pharmacokinetics of etoposide in patients with cancer. PATIENTS AND METHODS: Sixteen patients were administered 20 paired courses of etoposide and CsA/etoposide. Etoposide was administered daily for three days, alone or with CsA, which was delivered by a loading dose and 3-day infusion. Etoposide was measured by high-performance liquid chromatography (HPLC) and serum CsA by nonspecific immunoassay. Etoposide pharmacokinetics included area under the concentration-time curve (AUC), total and renal clearance (CL), half-life (T1/2), and volume of distribution at steady state (Vss). RESULTS: CsA concentrations more than 2,000 ng/mL produced an increase in etoposide AUC of 80% (P less than .001), a 38% decrease in total CL (P < .01), a > twofold increase in T1/2 (P < .01), and a 46% larger Vss (P = .01) compared with etoposide alone. CsA levels ranged from 297 to 5,073 ng/mL. Higher CsA levels (< 2,000 ng/mL v > 2,000 ng/mL) resulted in greater changes in etoposide kinetics: Vss (1.4% v 46%) and T1/2 (40% v 108%). CsA produced a 38% decrease in renal and a 52% decrease in nonrenal CL of etoposide. Etoposide with CsA levels > 2,000 ng/mL produced a lower WBC count nadir (900/mm3 v 1,600/mm3) compared with baseline etoposide cycles. CONCLUSIONS: High-dose CsA produces significant increases in etoposide systemic exposure and leukopenia. These pharmacokinetic changes are consistent with inhibition by CsA of the multidrug transporter P-glycoprotein in normal tissues. Etoposide doses should be reduced by 50% when used with high-dose CsA in patients with normal renal and liver function. Alterations in the disposition of other multidrug resistance (MDR)-related drugs should be expected to occur with modulation of P-glycoprotein function in clinical trials.     

A phase I trial of high-dose continuous-infusion hydroxyurea

Hydroxyurea inhibits ribonucleotide reductase, resulting in depletion of intracellular deoxynucleotide pools and inhibition of DNA repair. It has been used in a variety of malignancies and is usually given orally. Deoxynucleotide depletion is directly related to the concentration of and duration of exposure to hydroxyurea; thus, prolonged continuous infusion may result in increased therapeutic efficacy. A total of 30 patients were treated on this trial, designed to determine the maximum tolerated, doses (MTD) of intravenous hydroxyurea given as a 24-or 48-h continuous infusion. The MTD for the 24-h infusion was 13,520 mg/m² following a bolus of 1,690 mg/m², and the mean (±SD) plasma steady-state concentration was 1.93±0.52 mM. For the 48-h infusion, the MTD was 17,576 mg/m² following a bolus of 2,197 mg/m² and the mean steady-state level was 1.43±0.31 mM. The doselimiting toxicity on both schedules was marrow suppression manifesting as, neutropenia and thrombocytopenia. Pharmacokinetic analysis revealed decreasing clearance with increasing dose, implying that drug elimination is saturable. Pharmacodynamic analysis showed a slight correlation between steady-state plasma levels and the degree of marrow suppression.This work was supported in part by grants 5T32-CA-09307, P30-A-14236-18, and 5-R01-CA45529 from the National Institutes of Health and the National Cancer Institute and by the P.B. Cohen Memorial Fund     

Five-day continuous-infusion vinblastine in the treatment of breast cancer

One hundred six evaluable patients with metastatic breast cancer refractory to prior chemotherapy were treated with 5-day intravenous infusions of vinblastine at 1.4 to 2.0 mg/m2/day, through silastic elastomer permanent central venous catheters. Thirty-nine patients achieved objective responses; 5 were considered complete. The overall response rate of 37% was independent of prior exposure to intermittent intravenous vinca alkaloids or prior response to front-line doxorubicin combination chemotherapy. Objective responses were documented in 48% of the patients who received daily doses above 1.7 mg/m2 and in 32% and 29% of those treated with 1.7 mg/m2 or less, respectively (P = 0.10). Myelosuppression was more severe in responders, who received higher average doses, (median average nadir, 850 granulocytes/mm3) than in nonresponders (median, 1300 granulocytes/mm3), but was always rapidly reversible. Infections related to neutropenia were uncommon. Catheter-related toxicities occurred in 13 of 106 patients. Other toxicities were limited. These results confirm that vinblastine given as a continuous 5-day infusion is one of the most effective agents in the treatment of metastatic breast cancer and suggest that its activity is dose-dependent.     

Randomized comparison of etoposide pharmacokinetics after oral etoposide phosphate and oral etoposide.

Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m(-2) on days 1-5 every 3 weeks, with escalation to 175 mg m(-2) from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2. Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUC(inf) (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg l(-1) h after etoposide phosphate (95% CI 61.3-100.5) and 62.0 mg l(-1) h after oral etoposide (95% CI 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg l(-1) h (95% CI 0.1-32.8 mg l(-1) h; P = 0.05). However, the inter-patient variability of etoposide AUC(inf) was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.     

Effect of high-dose cyclosporine on etoposide pharmacodynamics in a trial to reverse P-glycoprotein (MDR1 gene) mediated drug resistance

Purpose: The consequences of using cyclosporine (CsA) therapy to modulate P-glycoprotein-mediated multidrug resistance include increased myelosuppression, hyperbilirubinemia, and altered disposition of the cytotoxin. The purpose of this study was to analyze further the relationship between the degree of leukopenia, and etoposide pharmacokinetic factors. Methods: Each patient initially received intravenously-administered etoposide alone (150–200 mg/m²/d × 3). Later it was given in combination with CsA administered at escalating loading doses (range 2–7 mg/kg) as a 2 hour intravenous (IV) infusion followed by a 3 day continuous infusion, at doses ranging from 5 to 21 mg/kg/day. Serial plasma etoposide concentration-time samples were assayed by high-performance liquid chromatography (HPLC). The area under the curve (AUC) of unbound etoposide was calculated from the total plasma etoposide AUC using a previous published equation [22] where % unbound etoposide = (1.4 × total bilirubin) – (6.8 × serum albumin) + 34.4. The percent decrease in white blood cell (WBC) count and the total or unbound etoposide AUC relationship was fitted to a sigmoid Emax model adapted for paired observations, where: In this equation, Z was the variable describing the two treatment groups (0=no CsA and 1=CsA). The fitted parameters were PDRV₅₀, the pharmacodynamic response variable (PDRV) producing 50% of the maximal response; parameter β, which describes the effect of the treatment group on the PDRV₅₀; parameter H (Hill constant), which defines the slope of the response curve and parameter δ, which describes the effect of the treatment group on parameter H. Results: CsA at a median concentration of 1,938 μg/ml resulted in a median increase in the total plasma etoposide AUC by 103% and the calculated unbound plasma etoposide AUC by 104%. This paralleled a 12% greater median percent decrease in WBC count during etoposide + CsA treatment (72% vs. 84%, P=0.03). The percent decrease in WBC count and total or unbound etoposide AUC relationship was fitted to the sigmoid Emax model. The model using the unbound etoposide AUC described the data adequately (r=0.790) and was precise, with a mean absolute error of 6.4% (95% confidence interval: −4.9, 7.8). The fitted parameter-estimates suggested that at equivalent unbound etoposide AUC values above 10 μg × h/ml, the sigmoid Emax model predicted a 5% greater WBC count suppression when CsA was added to the treatment regimen. Conclusion: These findings suggest that a small degree of the enhanced myelosuppression observed with CsA combined with etoposide might be attributable to inhibition of P-glycoprotein in bone marrow precursor cells. However, the majority of the effect observed appears to be due to pharmacokinetic interactions, which result in increases in unbound etoposide. Received: 14 December 1998 / Accepted: 15 September 1999     

Evaluation of continuous-infusion alpha-difluoromethylornithine therapy for colorectal carcinoma

Summary A total of 32 evaluable patients with measurable advanced colorectal carcinoma were treated with continuous-infusion alpha-difluoromethylomithine (DFMO) at a median daily dose of 8 g/m² (range, 6–14 g/m²). DFMO was infused over 24 h daily for 28 days, followed by a rest period of 7 days. Of the 32 patients, 14 had received no prior chemotherapy. A total of 65 courses was given, with the median being 2 (range, 1–9 courses). None of the patients achieved a partial or complete response; however, 3 patients achieved a minor response and 14 had stable disease. The frequent toxic effects of DFMO included thrombocytopenia (which was dose-limiting), malaise, nausea, vomiting, reversible hearing loss, and diarrhea. Our data suggest that continuous-infusion DFMO therapy is feasible and results in only mild gastrointestinal toxicity. Although DFMO proved to be ineffective as a single agent in this trial, it could probably best be used in combination with cytotoxic agents known to enhance its antitumor activity in a preclinical setting. This study was supported by grant RO1 CA34465 from the National Cancer Institute, Bethesda, Maryland, and by a grant from Baxter-Travenol Corporation, Deerfield, Illinois     

Chronic oral etoposide in small-cell lung cancer: Clinical and pharmacokinetic results

AIMS:: To evaluate antitumour activity, toxicity, pharmacokinetics,and the pharmacodynamic relationship with neutropenia of chronicoral etoposide (E) in patients (pts) with small-cell lung cancer(SCLC) previously untreated with chemotherapy. PATIENTS AND METHODS:: Twenty-seven (14 extensive-, 13 limited-stage) pts receiving100 mg daily of oral E for 21 days every 4 weeks. CBC with differentialrepeated every week. E plasma levels determined by HPLC method(sensitivity limit: 0.1 µg/ml) with evaluation duringthe first cycle of weekly 24-hour drug concentrations. RESULTS:: Among 25 evaluable pts, 60% (95% CI: 39%–79%) overallresponse, 144 and 217 days of median PFS and survival. Dose-limitingnon-cumulative neutropenia of high interpatient variability.Linear reduction (30% per week) of absolute neutrophil counts(ANC) up to the 3rd week, recovering the following week. Riskfactors for neutropenia(age, PS, serum creatinine and albumin)not identified. High inter-patient variability of 24-hour Eplasma levels. A weak correlation between mean 24-hour E plasmalevels and ANC nadir or relative decrease of ANC, but higherrelative decrease of ANC in pts with 24-hour E plasma levelsof >0.32 µg/ml. CONCLUSIONS:: Chronic oral E is effective in SCLC pts previously untreatedwith chemotherapy. Careful hematological monitoring is essentialto avoid severe myelosuppression. The degree of neutropeniamight be related to the maintenance of a critical drug concentrationlevel for a critical period of time. oral etoposide, small-cell lung cancer, pharmacodynamics     

Phase I trial of a 72-h continuous-infusion schedule of fazarabine

Summary Fazarabine (Ara-AC), a structural analog derived from the antitumor nucleoside cytosine arabanoside (Ara-C) and 5-azacytidine (5-AC), was studied in a phase I clinical trial. Doses ranging from 0.2 to 2.0 mg m^–2 h^–1 were given intravenously over 72 h every 28 days. The maximum tolerated dose (MDT) was 2.00 mg m^–2 h^–1. The dose-limiting toxicity was myelosuppression, with granulocytopenia being quantitatively more important than thrombocytopenia or anemia. Nonhematologic toxicity was minimal. Associated with the solvent dimethylsulfoxide (DMSO) was a bitter taste and a garlic-like odor.Supported in part by contract NOICM57739, National Cancer Institute, National Institutes of Health, Bethesda, Maryland