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At least 19 recordsLinked to original sources
PubMed2000

Treatment of brain metastases of small-cell lung cancer: comparing teniposide and teniposide with whole-brain radiotherapy--a phase III study of the European Organization for the Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: Approximately 60% of patients with small-cell lung cancer (SCLC) develop brain metastases. Whole-brain radiotherapy (WBRT) gives symptomatic improvement in more than 50% of these patients. Because brain metastases are a sign of systemic progression, and chemotherapy was found to be effective as well, it becomes questionable whether WBRT is the only appropriate therapy in this situation. PATIENTS AND METHODS: In a phase III study, SCLC patients with brain metastases were randomized to receive teniposide with or without WBRT. Teniposide 120 mg/m(2) was given intravenously three times a week, every 3 weeks. WBRT (10 fractions of 3 Gy) had to start within 3 weeks from the start of chemotherapy. Response was measured clinically and by computed tomography of the brain. RESULTS: One hundred twenty eligible patients were randomized. A 57% response rate was seen in the combined-modality arm (95% confidence interval [CI], 43% to 69%), and a 22% response rate was seen in the teniposide-alone arm (95% CI, 12% to 34%) (P<.001). Time to progression in the brain was longer in the combined-modality group (P=.005). Clinical response and response outside the brain were not different. The median survival time was 3.5 months in the combined-modality arm and 3.2 months in the teniposide-alone arm. Overall survival in both groups was not different (P=.087). CONCLUSION: Adding WBRT to teniposide results in a much higher response rate of brain metastases and in a longer time to progression of brain metastases than teniposide alone. Survival was poor in both groups and not significantly different.

Adult↗
PubMed1993

Feasibility study of intraarterial vs intravenous cisplatin, BCNU, and teniposide combined with systemic cisplatin, teniposide, cytosine arabinoside, glycerol and mannitol in the treatment of primary and metastatic brain tumors.

Sixteen patients with intracerebral tumors received intraarterial cisplatin, teniposide, and BCNU combined with intravenous cisplatin, teniposide, and cytosine arabinoside. Oral glycerol and intravenous mannitol were given along with the intravenous chemotherapy in an attempt to increase drug delivery to tumor by augmenting tumor blood flow. Thirteen additional patients were treated with the same regimen, but received all the chemotherapy intravenously. Of the 16 patients receiving intraarterial chemotherapy (median survival, 14 weeks), none responded, 5 (31%) were stable for > 8 weeks, 8 (50%) failed, and 3 (19%) were unevaluable due to early death. Of the 13 patients receiving all their treatment intravenously (median survival, 13 weeks), 3 (23%) responded, 1 (8%) was stable, 7 (54%) failed, and 2 (15%) were unevaluable due to early death. In the patients receiving intraarterial chemotherapy, toxicity included ipsilateral retinal toxicity (2 patients), ocular pain or headache (10), periorbital swelling and flushing (6), increased brain edema with focal neurological deficits and drowsiness (5), and catheter-related carotid artery thrombosis followed by fatal herniation (1). Myelosuppression was worse in patients who received all their treatment intravenously than in those receiving intraarterial chemotherapy (p < 0.05). Neutropenic sepsis developed in 4 patients on the intraarterial arm (1 fatal) and in 5 patients on the intravenous arm (2 fatal). Other toxic effects were similar whether or not patients received intraarterial treatment or only intravenous treatment. Overall, toxicity of this regimen was excessive, and response rates were lower than would have been expected with single agent therapy.

Adult↗
PubMed1984

Flux of teniposide (VM-26) across the plasma membrane of teniposide-resistant sublines of L1210 cells.

The flux of teniposide (VM-26) across the cell membrane was compared for L1210 cells, nine VM-26-resistant L1210 sublines, and three partially revertant lines. The nine resistant sublines were maintained in medium with VM-26. A "zero-time," temperature-independent binding of VM-26 to cells, attributable to adsorption on the cell membrane or to solvation in the membrane, varied independently of the sensitivity of cell lines to the drug as measured by the extracellular concentration of drug required to inhibit growth of a subline by 50% at the end of 24 hr (IC50). The IC50 values varied from 22 nM VM-26 for parental cells to 45 microM VM-26 for the most resistant subline. After subtraction of the zero-time values, the initial rates of influx for VM-26 (extracellular concentration, 20.5 microM) and the apparent equilibrium constants for the flux of drug across the cell membrane correlated inversely with the logarithm of the IC50 values. Cellular steady-state levels of VM-26, initial rates of efflux of the drug, and cellular levels of nondiffusible drug varied independently of the IC50 values but in relation to each other. The efflux of VM-26 from the sublines was faster than from the parental cells at both 4 degrees and at 37 degrees. We conclude that resistance of L1210 cells to VM-26 is associated with changes in the flux of the drug across the cell membrane.

Animals↗
PubMedDate not supplied

Stabilization of teniposide in aqueous mixtures of detergent-phospholipid.

Teniposide-containing mixed micelles and liposomes consisting of detergent and phospholipid were investigated and compared for their teniposide latency as functions of the mixed micellar preparation method, stabilizers, type of detergent,lipid composition and serum proteins after storage at 10 degrees C, and 23 degrees C, and 45 degrees C or/and freezing and freeze-drying. There was no significant difference in teniposide loss from liposomes obtained using different micellar preparation methods. Sugars, dextrose or sorbitol, had no effect on teniposide loss from liposome but stabilized teniposide micelles. Glutamic acid had no effect on teniposide loss from micelles but increased the loss from liposomes. The presence of cholesterol in bile salt-egg PC micelles had little effect on teniposide loss at 10 degrees C but generally increased it at 23 degrees C, and 45 degrees C, while bile salt-egg PC-cholesterol (9:9:1) liposomes were more stable than bile salt-egg PC liposomes. In contrast, teniposide loss from bile salt-egg PC-egg PE (2:1:1) liposomes or bile salt-egg PC-egg PA (16:15:1) micelles and liposomes increased remarkably, probably due to the surface charge and/or the destabilization of PC bilayer. However, bile salt-egg PC-soy PC (2:1:1) micelles and liposomes lost less amounts of teniposide under the same storage conditions. Further, the stability of teniposide was greatly increased by neutral detergents (e.g., CHAPS or octylglucoside). The loss of teniposide from CHAPS- or octylglucoside-egg PC micelles and liposomes after six months' storage at the ambient temperature were approximately 16% and 10%, respectively. Teniposide-micelles and liposomes, prepared in the presence of serum or serum protein, were more stable than CHAPS- or octylglucoside-egg PC liposomes. Teniposide was physically stable for at least 12 months when micelles were stored as the frozen or freeze-dried state. This result suggested that long-term storage for teniposide in neutral detergent-egg PC-soy PC micelles may be feasible in the presence of serum proteins.

Carbohydrates↗
PubMed1987

The clinical pharmacology of etoposide and teniposide.

Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin and are increasingly used in cancer medicine. Teniposide is more highly protein-bound than etoposide, and its uptake and binding to cells is also greater. Etoposide and teniposide are phase-specific cytotoxic drugs acting in the late S and early G2 phases of the cell cycle. They appear to act by causing breaks in DNA via an interaction with DNA topoisomerase II or by the formation of free radicals. Teniposide is more potent as regards the production of DNA damage and cytotoxicity. Most studies show a biexponential decay following intravenous administration of etoposide and teniposide. The terminal elimination half-life of etoposide is less than that of teniposide, and the plasma and renal clearances of etoposide are greater. The peak plasma concentrations of drug and the area under the concentration versus time curve are linearly related to the intravenous dose of both drugs. Considerable interpatient variability of pharmacokinetic parameters exists following intravenous etoposide and teniposide. Various metabolites of etoposide and teniposide have been identified but their detection and quantitation are disputed. Approximately 30 to 70% of a dose of etoposide is accounted for by excretion, whereas the figure appears to be only 5 to 20% for teniposide. The bioavailability of oral etoposide is about 50% but its absorption is not linear with increasing dose within the range in clinical use. There is considerable inter- and intrapatient variability in the pharmacokinetics of oral etoposide. There is no evidence of accumulation of etoposide and teniposide after multiple consecutive doses by the intravenous or oral routes. The exact roles of the liver and kidney in metabolism and excretion of etoposide and teniposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This together with the phase-specific action of etoposide and teniposide and their increasingly widespread use in cancer medicine make the clinical pharmacology of these drugs of great clinical importance.

Chemical Phenomena↗
PubMed1987

Mutagenicity and clastogenicity of teniposide (VM-26) in L5178Y/TK +/- -3.7.2C mouse lymphoma cells.

The antitumor drug teniposide (VM-26) is a potent inducer of DNA breaks (Long et al., Cancer Res., (1985) 45, 3106), but it is only weakly mutagenic at the hprt locus in CHO cells (Singh and Gupta, Cancer Res., (1983) 43, 577). In the present study, the mutagenic and clastogenic activities of teniposide were evaluated in L5178Y/TK +/- -3.7.2C mouse lymphoma cells. Although teniposide is a weak mutagen at the hprt locus, it is a potent mutagen at the tk locus, with as little as 0.5 ng/ml producing 220 TK mutants/10(6) survivors at 96% survival (background = 100/10(6) survivors). This same dose of teniposide induced 38 aberrations per 100 metaphases (background = 7/100 cells). At 7 ng/ml, teniposide induced approximately 2700 TK mutants/10(6) survivors at approximately 10% survival. At the highest dose sampled for aberration analysis (5 ng/ml), teniposide induced 44 aberrations/100 cells. Most of the aberrations were chromosomal rather than chromatid events. As expected for a compound acting primarily by a clastogenic mechanism, most of the TK mutants were small colonies. Thus, teniposide is a potent clastogen, and it is a potent mutagen at the tk locus but not at the hprt locus. These results support the hypothesis that the location of the target gene affects the ability of the assay to detect both intragenic events and events causing functional multilocus effects. Thus, a heterozygous locus (like tk) but not a functionally hemizygous locus (like hprt) may permit the detection of mutagens that act primarily by a clastogenic mechanism. Because teniposide induces topoisomerase II-associated DNA breaks, and because there is evidence that teniposide may not interact directly with DNA, we discuss the possibility that the potent clastogenic/mutagenic activity of teniposide may be mediated by topoisomerase II.

Animals↗
PubMed1991

Pharmacokinetics of continuous-infusion amsacrine and teniposide for the treatment of relapsed childhood acute nonlymphocytic leukemia.

The systemic disposition of both amsacrine and teniposide was determined in children receiving treatment for resistant acute nonlymphocytic leukemia. As part of a phase I-II study, amsacrine and teniposide were given as continuous 72-h i.v. infusions at doses of 75-150 and 150-250 mg m-2 day-1, respectively. Plasma samples obtained during steady state were analyzed for drug concentrations by high-performance liquid chromatography assays specific for each compound. Clearance and systemic exposure values for both amsacrine and teniposide were calculated for 14 patients, and data were available for teniposide alone in an additional 14 subjects. Interpatient variability in clearance was substantial for each drug, producing overlapping systemic exposure across dose levels. No evidence of dose-dependent drug clearance was evident. Clearance values for teniposide given in combination with amsacrine were similar to previous values obtained when teniposide was given in an identical manner but as a single agent. In all, 80% of patients experienced some degree of mucositis after chemotherapy administration. Severe mucositis (Pediatric Oncology Group grades 3-4) occurred in 18% of cases, all of whom showed teniposide steady-state plasma concentrations above the median population value (11.9 micrograms/ml; P less than 0.0001). A comparison of the results of the present study on teniposide combined with amsacrine with those previously obtained for single-agent teniposide suggest that amsacrine produced little additive gastrointestinal toxicity. The evaluation of anti-cancer drug pharmacokinetics in individual patients during combination chemotherapy regimens helps to determine the relative importance of each agent when toxicity patterns are similar.

Adolescent↗
PubMed1998

Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression.

Teniposide (VM26) enhanced the anti-glioma activity of the cytotoxic cytokine, CD95 ligand. Synergy was observed at concentrations of teniposide that were insufficient for cleavable DNA topoisomerase II complex formation. CD95 ligand did not modulate the formation or removal of such complexes after teniposide treatment. These processes were also unaffected by ectopic expression of bcl-2. Teniposide enhanced CD95 expression in a glioma cell line with wild-type p53 (LN-229) but not in two p53 mutant cell lines (T98G, LN-308). Forced expression of a transdominant negative p53 mutant prevented the teniposide induced augmentation of CD95 expression in LN-229 cells but did not prevent the synergy of CD95 ligand and teniposide. Teniposide did not alter CD95 ligand expression, and forced expression of CD95 did not modulate sensitivity to VM26. Thus, teniposide-induced DNA lesions and alterations in CD95 or CD95 ligand are not necessary for teniposide-induced sensitization of human malignant glioma cells to CD95-mediated apoptosis.

Antineoplastic Agents, Phytogenic↗
PubMed1995

Targeting of teniposide to the mononuclear phagocytic system (MPS) by incorporation in liposomes and submicron lipid particles; an autoradiographic study in mice.

Liposomes are concentrated in the mononuclear phagocytic system in vivo and may therefore be of value as carriers of drugs when treating diseases involving phagocytic cells. Teniposide (VM-26) is a potent and lipophilic cytotoxic drug. Teniposide was incorporated in large unilamellar liposomes (LUVs) consisting of egg phosphatidylcholine and dioleoyl phosphatidic acid and into the novel submicron lipid particles containing cholesteryl oleate, cholesteryl palmitate and soybean lecithin, in order to evaluate the drug targeting effect. Radiolabelled teniposide and lipids were used and the organ distribution in mice was studied with whole-body autoradiography 20 and 90 min post i.v. injection. When the commercial formulation of teniposide (Vumon) was administered, teniposide accumulated in the liver where the drug is metabolized. Biliary excretion was rapid and considerable already after 20 min. The liposomal formulation enhanced liver uptake of teniposide slightly. The distribution of radiolabelled phosphatidyl choline differed from that of teniposide indicating instability of the liposomes in circulation. Despite this, the splenic uptake of the drug was significantly enhanced by administration in liposomes. In the red pulp of the spleen the teniposide level was 23 times higher 90 min post injection, using the liposomal formulation as compared to free drug. The submicron lipid particles were mainly accumulated in the liver and to a lesser extent in the spleen. The study shows that liposomes and lipid particles enhance splenic and liver uptake and can be used to target teniposide to the MPS.

Animals↗
PubMed1999

[A pharmacokinetic study of teniposide in intraperitoneal chemotherapy of ovarian cancer].

The objectives of this study were to determine the characteristics of pharmacokinetics of teniposide (VM-26) instilled intraperitoneally with three dosages (100 mg, 150 mg and 200 mg) and to evaluate its toxicity. Twelve patients with ovarian cancer were divided into three groups: teniposide 100 mg i.p., 5 patients; teniposide 150 mg i.p., 5 patients; and teniposide 200 mg i.p., 2 patients. Samples of ascitic fluid, blood and urine were collected after administration of these drugs in 24 hours. Concentrations of teniposide were determined with high-performance liquid chromatographic procedure. The results showed that the data collected from peritoneum and plasma were found to conform to a two-compartment open model. The peak concentration (Cmax) and the area under the curves (AUC) in peritoneal cavity and plasma were dose-dependent. The ratios of Cmax and AUC between peritoneal fluid and plasma varied within 13.46 +/- 1.89 and 7.65 +/- 2.03 respectively. The elimination half-lives (T1/2 beta) in the peritoneum and plasma of teniposide were 5.28 +/- 0.95 and 6.64 +/- 2.73 hours respectively. The volume of peritoneal distribution and its clearance were lower than those of plasma (P < 0.001). The side effects were mild and were not dependent on drug dosage. The results suggest that teniposide as an intraperitoneal therapeutic agent offers some advantages in the treatment of ovarian cancer. The tumor tissues and peritoneal growths could be bathed in a high concentration of teniposide. Teniposide is safe, reasonable in intraperitoneal chemotherapy and shows prospects in the treatment of ovarian cancer.

Adult↗
PubMed1992

Teniposide in lymphomas and leukemias.

The epipodophyllotoxins, etoposide and teniposide, have been used in leukemias and malignant lymphomas for the past 15 years. Although etoposide has acquired a place in many first-line protocols for lymphomas and, more recently, for leukemias, the role of teniposide has remained limited. Teniposide is a more potent inhibitor of topoisomerase II than etoposide, and has a less toxic effect on hematopoietic progenitor cells. Both drugs have been regarded as equitoxic and cross-resistant. The role of teniposide in front-line treatment of leukemias has only been established in childhood acute lymphoblastic leukemia (ALL). Some promising results have been obtained in small numbers of patients with refractory adult ALL and acute monoblastic leukemia. However, the remission rates and remission duration were not significantly different from those of other combination regimens. Data on teniposide in untreated acute nonlymphoblastic leukemia are very scarce. In non-Hodgkin's lymphoma, the antineoplastic activity of teniposide has been demonstrated in studies by the European Organization for Research and Treatment of Cancer and in two large studies conducted by the Australian and New Zealand Lymphoma Co-operative Chemotherapy Study Group. In these studies, teniposide had comparable but not significantly better activity than vincristine. The dose-dependent antineoplastic activity of teniposide has led to its use in several conditioning regimens in bone marrow transplantation for leukemias and lymphomas. The limited clinical data currently available on teniposide seem to warrant further clinical trials with this agent in leukemias and lymphomas.

Adult↗
PubMedDate not supplied

Physical stability of teniposide in bile salt-egg phosphatidylcholine mixed micelles and liposomes.

Teniposide-containing bile salt-egg PC mixed micelles and their liposomes formed from dilution were investigated and compared for (i) their teniposide contents as a function of bile salt species, drug dose, the egg PC/BS molar ratio, total lipid concentration, ionic strength and storage states (freeze-thawed and freeze-dried state, and the presence of light and oxygen) and (ii) their mean particle size, stored under different conditions. The physical stability of teniposide in micelles and their liposomes increased with increasing hydrophobicity of bile salt the order being deoxycholate > cholate > conjugated cholate at all temperatures (10 degrees C, 23 degrees C, and 45 degrees C) studied. Teniposide-micelles were more stable at lower egg PC/BS molar ratios, while teniposide-liposomes were more stable at higher ratios. Teniposide stability slightly increased at higher total lipid concentration, indicating that bile salt-egg PC mixed micellar systems were in dynamic states. The presence of neither light nor oxygen significantly affected the stability of teniposide over the time and temperature range studied. However, the presence of salt in micellar and liposomal solutions greatly reduced teniposide loss by precipitation. Freezing or freeze-drying of teniposide-micelles induced neither micellar aggregation nor drug leakage. The stabilization may be due to the presence of detergent-like bile salts in the system.

Antineoplastic Agents, Phytogenic↗
PubMed1991

Somnolence, hypotension, and metabolic acidosis following high-dose teniposide treatment in children with leukemia.

This report describes an unexpected adverse effect in three children receiving teniposide at 3-5 times the conventional dosage (i.e. 200 mg/m2) plus cytarabine as part of continuation therapy for acute lymphocytic leukemia. Pharmacokinetic studies in each patient had demonstrated high teniposide clearances, and thus the increased dosage requirements were necessary to attain plasma concentrations similar to those expected for patients with average drug clearance. At 3-4 h after the beginning of the 4-h simultaneous infusions of teniposide and cytarabine, these patients experienced somnolence, hypotension, and metabolic acidosis. The adverse events were associated with elevated teniposide plasma concentrations during the infusions compared with those in patients receiving similar doses without toxicity, and clinically significant ethanol concentrations, presumably from the teniposide formulation. Blood concentrations of cremophor and histamine, which are also constituents of the teniposide formulation, were not measured. In addition, concomitant therapy with antiemetic agents in patients who may have been mildly volume-depleted due to emesis may also play a contributory role. Prolonging the infusion time for patients receiving teniposide doses above 500 mg/m2 will avoid excessive teniposide and ethanol plasma concentrations and minimize the risk of this potentially serious side effect.

Acidosis↗
PubMed1988

Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases.

Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

Studies of the organ distribution in mice of teniposide liposomes designed for treatment of diseases in the mononuclear phagocytic system.

Liposomes can be used for the delivery of drugs in cancer chemotherapy. After i.v. injection liposomes are to a large extent taken up by the mononuclear phagocytic system (MPS). When treating diseases in the MPS, such as the histiocytic syndromes, this property is of potential value for drug targeting and may lead to a more efficient therapy with less systemic toxicity. Teniposide (VM-26) is a potent anti-tumor drug. Its lipophilicity makes it suitable for liposomal formulation. Teniposide liposomes were prepared by dissolving egg phosphatidylcholine and dioleoyl phosphatidic acid (19:1 molar ratio) in methylene chloride together with teniposide. After solvent evaporation, the dry lipid film was dispersed in a glucose solution (50 mg/mL), and size calibration was obtained by filtration through polycarbonate filters. The amount of teniposide incorporated was 2.5 mol%. To investigate the organ distribution, teniposide liposomes containing radiolabeled teniposide or phospholipid were given i.v. to mice. By increasing the size of the vesicles, the MPS uptake could be modulated. When vesicles of 200 nm and 1 and 3 microns were injected, the drug levels in the spleen were increased 2.6-, 6.8-, and 21-fold 40 min after injection, compared with levels after injection of the commercial teniposide formulation. It was concluded that organ distribution of teniposide in mice could be modified by administering the drug in liposomal form with the potential of improved treatment of diseases engaging the MPS.

Animals↗
PubMed1992

Teniposide in the treatment of small cell lung cancer: a review.

The epipodophyllotoxin derivatives teniposide and etoposide have been under clinical investigation for over 15 years. Although etoposide has been established as one of the most active compounds in the treatment of small cell lung cancer (SCLC), teniposide has received little attention. The results of seven phase II studies evaluating response rate and duration of response to teniposide in 10 previously treated and 102 untreated patients showed response rates of 21% and 58%, respectively. The most frequently used dosage schedule was 60 mg/m2 intravenously daily for 5 days every 3 weeks. The following are factors influencing the response rate and duration of response to teniposide: performance status; prior weight loss; prior chemotherapy exposure, including prior treatment with etoposide; stage; and effectiveness of prior chemotherapy, including time from last administration. Preliminary analyses from a study comparing the efficacy of teniposide with that of etoposide suggest that teniposide may be more effective in previously untreated patients with SCLC who are 70 years of age or older. The preliminary data, however, indicate that equivalent doses of teniposide cause more cases of leukopenia than etoposide. Before a final conclusion can be drawn, the results from an ongoing study using teniposide and etoposide at equitoxic doses must be evaluated.

Carcinoma, Small Cell↗
PubMed2002

Study of either ifosfamide or teniposide compared to a standard chemotherapy for extensive disease small cell lung cancer: an Eastern Cooperative Oncology Group randomized study (E1588).

This randomized study of previously untreated patients with extensive disease small cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anti-cancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. One hundred and thirty-five patients were randomly assigned to receive as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m(2)), doxorubicin (50 mg/m(2)) and vincristine (1.4 mg/m(2)) every 3 weeks--or the phase II drugs ifosfamide (1.5 gm/m(2)/days 1-5) with mesna (300 mg/m(2)) dose at 0, 4 and 8 h after IV daily ifosfamide every 3 weeks or teniposide (60 mg/m(2)/days 1-5) every 3 weeks. Nonresponders received salvage chemotherapy-etoposide (120 mg/m(2) on days 1, 2 and 3) and cisplatin (60 mg/m(2) on day 1), repeated every 3 weeks. Among the 46 patients on CAV, there were two complete and 24 partial responses (56%). Among the 43 patients on ifosfamide, there were three complete and 18 partial responses (49%), while among the 46 patients on teniposide, there were two complete and 18 partial responses (43%). Eighty-three of the patients proceeded onto salvage regimen, of which 81 were analyzable for response and toxicity. Among the 81 patients who continued on salvage therapy and were evaluable for response, the overall best response rate was 61% for CAV+salvage, 54% for ifosfamide+salvage, and 53% for teniposide+salvage. These rates were not significantly different (P=0.962). Of the 135 analyzable patients, 130 (96%) have died. The estimated median survival time was 42 weeks for CAV patients, 43 weeks for ifosfamide, and 38 weeks for teniposide. Seven patients survived longer than 2 years (four on CAV, one on ifosfamide and two on teniposide). There were 29 life-threatening complications to the induction regimen (22 (48%) on CAV, four (9%) on ifosfamide and three (7%) on teniposide) and seven lethal complications (two on CAV, four on ifosfamide and one on teniposide). The treatments were significantly different with respect to the overall degree of toxicity (P < 0.0001) with CAV being more toxic. The data of this study, like the previous ECOG study suggests that the administration of a new agent followed by effective salvage chemotherapy in the treatment of extensive disease small cell lung cancer may have no adverse effect on survival.

Adult↗
PubMed1993

Escalating teniposide systemic exposure to increase dose intensity for pediatric cancer patients.

PURPOSE: The primary objective for this study was to determine whether controlling pharmacokinetic variability, by designing patient-specific dosage regimens for teniposide using a Bayesian estimation control strategy, would permit an increase in dose intensity without increased toxicity. PATIENTS AND METHODS: Twenty patients with relapsed acute lymphocytic leukemia were given teniposide as part of their induction and maintenance therapy. Before beginning reinduction therapy, an intensive pharmacokinetic study was performed based on 12 measured teniposide plasma concentrations. Doses were determined to achieve a targeted systemic exposure defined by an area under the plasma concentration time curve (AUC) beginning at an AUC consistent with that predicted for a patient with average pharmacokinetic parameters receiving the currently accepted maximal-tolerated dose. The targeted systemic exposure was then escalated in increments of 25% in cohorts of at least three patients until unacceptable toxicity occurred. In 36 follow-up studies, when teniposide was administered during maintenance therapy, a Bayesian strategy based on only three or five measured drug concentrations was evaluated for precision and bias for achieving the targeted systemic exposure against the full pharmacokinetic study. RESULTS: Teniposide clearance varied over a fivefold range (3.7 to 21.6 mL/min/m2). With the use of the patient-specific dosage regimens, the intensity of systemic exposure was increased 50% (1,656 mumol.h v 1,060 mumol/L.h) over that previously possible with standard fixed doses, with no increase in acute, nonhematologic toxicity. Teniposide concentrations (n = 265) were well predicted (R2 = .82) with as few as three measured values from the initial study. CONCLUSION: Targeting systemic exposure is clinically feasible, precise, and allows increased dose intensity for teniposide without increased risk of acute, nonhematologic toxicity, when compared with fixed-dose regimens.

Adolescent↗