Pharmacokinetics and toxicity of the epipodophyllotoxin derivative etoposide (VP 16-213) in patients with gestational choriocarcinoma and malignant teratoma

Summary Serum levels of etoposide obtained 5 min after administration of 100 mg/m² were between 11 and 30 g/ml. By 24 h after drug administration, serum levels had fallen to between 0.19 and 1.11 g/ml. Interpatient variation of etoposide serum concentrations obtained 5 min after drug administration was low, whereas interpatient variation 24 h later was noticeably higher. A significant correlation was observed (r=-0.698) between the WBC nadir and the mean etoposide serum concentrations, measured 24 h after drug administration, in patients receiving etoposide in combination with cyclophosphamide and actinomycin D. However, a relationship was not observed in those patients receiving etoposide alone.There was no observed difference in the efficacy or toxicity of 500 mg/m² etoposide when the dose was administered either as 100 mg/m² on each of 5 consecutive days or as 250 mg/m² on days 1 and 3. There was no significant difference between AUC values calculated from etoposide concentration versus time profiles in patients receiving the drug on days 1 and 3 and those values obtained with the 5-day schedule.Patients resistant to a conventional dose of etoposide were given a higher dose of 1 g/m²/24 h, but this schedule did not cause an increase in efficacy despite an increase in serum levels of the drug. CSF levels in two of these patients receiving high-dose etoposide were 1.28% and 2.09% of the serum concentrations.     

Penetration of etoposide into human malignant brain tumors after intravenous and oral administration

Summary Penetration of etoposide into the cerebrospinal fluid, brain tumor, and brain tissue after intravenous administration was investigated in patients presenting with malignant brain tumors. A relatively low dose (55–65 mg/m²) was used to compare intravenous with oral administration. High-performance liquid chromatography with fluorescence detection was used to evaluate drug levels. Plasma and cerebrospinal fluid levels of etoposide after oral administration (50–150 mg/day) were also studied so as to determine the adequate oral dose for the treatment of malignant brain tumors. The peak plasma concentration after intravenous administration ranged from 7.01 to 10.47 g/ml, varying in proportion to the injected dose, whereas that after oral administration was lower, namely, 1.44–4.99 g/ml, and was unstable when the oral dose was 150 mg daily. The peak cerebrospinal fluid level following either intravenous or oral administration was much lower than the plasma concentration and was influenced by the peak plasma level and the sampling site. The etoposide concentration in cerebrospinal fluid taken from the subarachnoid space and ventricle of patients displaying no tumor invasion and of those presenting with meningeal carcinomatosis and in cerebrospinal fluid taken from the dead space after tumor resection was 0.7%±0.5%, 3.4%±1.0%, and 7.2% ± 8.5%, respectively, of the plasma concentration. Serial oral administration did not result in the accumulation of etoposide in cerebrospinal fluid. The tumor concentration (1.04–4.80 g/g) was 14.0%±2.9% of the plasma level after intravenous administration, was related to the injected dose, and was approximately twice the concentration detected in the brain tissue. Therefore, a relatively low dose of etoposide injected intravenously penetrates the brain tumor at an efficacious concentration. Our results indicate than an oral dose of 100 mg etoposide be given for malignant brain tumors, as limited penetration of the drug into the intracranial region was observed.     

Unaltered pharmacokinetics after the administration of high-dose etoposide without prior dilution

Summary The pharmacokinetics of etoposide following a new method of administration was determined. Undiluted etoposide was given at a dose of 30 mg/kg as part an intensified conditioning regimen prior to bone marrow transplantation. A terminal half-life of 3.4±0.7 h and a volume of distribution of 15.4±9.61 were found (n=8); the AUC was 764±302 g h ml^–1. As compared with those obtained in other pharmacokinetic studies using etoposide diluted in normal saline, our data reflect full systemic bioavailability and unaltered pharmacokinetics. The application of undiluted etoposide makes the therapy easier and less time-consuming and avoids a high fluid volume and a high saline load.     

Developmental pharmacokinetics of etoposide in 67 children: lack of dexamethasone effect

Purpose

A randomized clinical trial examined whether dexamethasone administration prior to ondansetron followed by etoposide and carboplatin infusions, and single-nucleotide polymorphisms (SNPs) of CYP3A4, CYP3A5 and MDR1 genes could modify etoposide pharmacokinetics in pediatric patients.

Methods

Patients, 67 children, aged 14?weeks to 16.7?years, were treated for various malignancies and received either 3- or 5-day courses of etoposide and carboplatin: these two drugs were always administered after ondansetron infusion but combined or not with dexamethasone 5?mg/m2/day 30?min prior to etoposide infusion. Population pharmacokinetics was modeled using a non-linear mixed effect model program (Monolix version 31?s).

Results

Etoposide pharmacokinetics was ascribed to a 2-compartment model. The most significant covariate effect was bodyweight (BW), so the parameters were standardized to a 70-kg BW using the allometric ? or 1 power model for clearance (CL, Q) or volume terms (V), respectively. The population means for clearance and central volume of distribution were 2.05?l/h/70?kg and 9.21?l/70?kg with the corresponding between-subject variabilities, 0.26 and 0.28. Dexamethasone treatment had no effect on CL, either at the first or at the last administration occasion. CYP3A and MDR1 examined SNPs had no significant effect.

Conclusion

Pharmacokinetics of etoposide was influenced by BW on an allometric basis in this pediatric population. Dexamethasone did not influence etoposide pharmacokinetics during these 3?C5?days courses. These results should allow a better individualization of etoposide dosing in children.     

Pharmacological attempts to improve the bioavailability of oral etoposide

Etoposide demonstrates incomplete and variable bioavailability after oral dosing, which may be due to its concentration and pH-dependent stability in artificial gastric and intestinal fluids. The use of agents that may influence etoposide stability and, thereby, bioavailability, was investigated in a number of clinical studies. Drugs that influence the rate of gastric emptying, while modulating the time of drug absorption, did not significantly alter the etoposide area under the concentration-time curve (AUC) or bioavailability. Specifically, metoclopramide had little effect on the etoposide absorption profile and did not significantly alter the AUC (AUC with etoposide alone, 68.4±20.3 g ml^–1 h, versus 74.3±25.9 g ml^–1 h with metoclopramide), suggesting that in most patients the drug is already emptied rapidly from the stomach. In contrast, propantheline produced a dramatic effect on etoposide absorption, delaying the time of maximal concentrationt _max from 1.1 to 3.5 h (P<0.01), but again without a significant improvement in drug AUC or bioavailability across the 24-h study period (AUC with etoposide alone 78.3±19.1 g ml^–1 h, versus 88.1±23.6 g ml^–1 h with propantheline). The effect of these drugs on the absorption of oral paracetamol, a drug included in the study as a marker of gastric emptying, was exactly the same as that found for etoposide, with no change in AUC being observed after metoclopramide or propantheline administration but a significant delay int _max being seen on co-administration with etoposide and propantheline. The co-administration of ethanol or bile salts (agents that significantly improved the stability of etoposide in artificial intestinal fluid) with oral etoposide similarly had no effect on improving the etoposide AUC or reducing the variability in AUC, suggesting that drug stability in vivo was not affected by these agents. In the third study the co-administration of cimetidine had no effect on the pharmacokinetics of oral or i.v. etoposide, despite the previous observation that etoposide stability was markedly improved at pH 3–5 as compared with pH 1 in artificial gastric fluid. This series of studies, designed to investigate factors that improved etoposide stability in laboratory studies, failed to demonstrate any potentially useful improvement in AUC or bioavailability in the clinical setting.     

Intravenous versus oral etoposide: efficacy and correlation to clinical outcome in patients with high-grade metastatic gastroenteropancreatic neuroendocrine neoplasms (WHO G3)

High-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs, G3) are aggressive cancers of the digestive system with poor prognosis and survival. Platinum-based chemotherapy (cisplatin/carboplatin?+?etoposide) is considered the first-line palliative treatment. Etoposide is frequently administered intravenously; however, oral etoposide may be used as an alternative. Concerns for oral etoposide include decreased bioavailability, inter- and intra-patient variability and patient compliance. We aimed to evaluate possible differences in progression-free survival (PFS) and overall survival (OS) in patients treated with oral etoposide compared to etoposide given as infusion. Patients (n?=?236) from the Nordic NEC study were divided into three groups receiving etoposide as a long infusion (24 h, n?=?170), short infusion (≤?5 h, n?=?33) or oral etoposide (n?=?33) according to hospital tradition. PFS and OS were analyzed with Kaplan–Meier (log-rank), cox proportional hazard ratios and confidence intervals. No statistical differences were observed in PFS or OS when comparing patients receiving long infusion (median PFS 3.8 months, median OS 14.5 months), short infusion (PFS 5.6 months, OS 11.0 months) or oral etoposide (PFS 5.4 months, OS 11.3 months). We observed equal efficacy for the three administration routes suggesting oral etoposide may be safe and efficient in treating high-grade GEP-NEN, G3 patients scheduled for cisplatin/carboplatin?+?etoposide therapy.     

Combined oral administration of etoposide and arabinofuranosylcytosine-5′-stearylphosphate enhances the antitumor effect against P388 ascites tumors

We investigated the antitumor effect of oral administration of etoposide and arabinofuranosylcytosine-5-stearylphosphate (C18PCA) against P388 ascites tumors in B6D2F1 mice. Etoposide (25 mg/kg) and C18PCA (5 mg/kg) were given orally on days 1–5 after tumor inoculation. The median life span of the mice treated with etoposide or C18PCA alone was 19.5 and 18 days, respectively. The combination of both drugs significantly extended the median life span to 33 days. To clarify this enhancement of the increase in median life span, we examined intracellular deoxyribonucleoside triphosphate (dNTP) pools, cell-cycle distribution, DNA fragmentation, and the time course of the plasma drug concentration. Etoposide had no effect on intracellular dNTP pools in this experimental system, whereas treatment of cells with C18PCA or with the combination of both drugs resulted in a significant increase in dTTP pools to values ranging from 1.8-to 2.0-fold higher than the control levels. There was a significant increase in cells in the S+G2/M phase when cells had been treated with both etoposide and C18PCA. Agarose-gel electrophoresis of the extracted DNA revealed that C18PCA enhanced the fragmentation of DNA, with a length of about 180 bp being induced by etoposide. The plasma peak levels of etoposide (100 nM) and ara-C (50 nM) were observed at 20 and 30 min after the simultaneous administration of both drugs, respectively. The plasma etoposide level gradually decreased to 10% of the peak level at 240 min after administration. On the other hand, the plasma concentration of ara-C was maintained at above 20 nM at 240 min. These observations suggest that C18PCA and etoposide act on P388 murine leukemic cells by accumulating cells in the S+G2/M phase. Even if the plasma concentration of ara-C is low, the repair of DNA damage by etoposide may be hindered in the presence of ara-C following an increase in DNA fragmentation.     

Disposition of total and unbound etoposide following high-dose therapy

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18–61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35–60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0±0.4 g/dl and 0.5±0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (% unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. Te mean (±SD) parameters for total etoposide included: clearance (CL), 31.8±17.7 ml min^–1 m^–2; volume of distribution (V_ss), 11.5±5.9 l/m², and terminal half-life (t _1/2 ), 7.2±3.7 h. Mean unbound CL was 209.6±62.7 ml min^–1 m^–2 and %unbound was 16%±5%. The mean etoposide %unbound was inversely related to serum albumin (r ²=0.45,P=0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively;P=0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of 3.0 g/dl than in those with levels of >3.0 g/dl (34.6 vs 23.5 ml min^–1 m^–2,P=0.05). Total CL was directly related to %unbound (r ²=0.61,P=0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.This study was supported in part by Bristol-Myers. Oncology Division     

Pharmacokinetics of etoposide in cancer patients treated with high-dose etoposide and with dexrazoxane (ICRF-187) as a rescue agent

Purpose The pharmacokinetics of etoposide were studied in cancer patients with brain metastases treated with high-dose etoposide in order to determine if the pharmacokinetics were altered by the use of dexrazoxane as a rescue agent to reduce the extracerebral toxicity of etoposide.Methods Etoposide plasma levels were determined by HPLC.Results The etoposide pharmacokinetics described by a monophasic first-order elimination model were found to be similar to other reported data in other settings and at similar doses.Conclusions The pharmacokinetics of etoposide were unaffected by dexrazoxane rescue.Abbreviations AUC_0– Area under the curve from time zero to infinity - C_max Maximum plasma concentration of drug - Cl_tot Total plasma clearance - HPLC High-pressure liquid chromatography - P_oct Octanol-water partition coefficient - t_1/2 Beta phase plasma elimination half-time - t_r Retention time Patricia Schroeder and Kenneth Hofland contributed equally to this work.     

A limited sampling model for the pharmacokinetics of etoposide given orally

A limited sampling model of etoposide after oral administration to estimate the area under the plasma concentration-time curve from 0 to 24 h (AUC) by determination of the drug plasma levels at only two time points was developed by a multiple regression analysis on a training data set of 15 patients receiving oral doses ranging from 54 to 90 mg/m². The equation describing the model is AUC (g ml^–1 h)=5.183 (g ml^–1 h)+1.193 (h)×C_1h (g/ml)+8.439 (h)×C_4h (g/ml) (R ²=0.93,P=0.0001), whereC _1h andC _4h represent the plasma etoposide concentrations at 1 and 4 h, respectively. The model was validated prospectively on a test data set of 13 patients receiving oral doses ranging from 52 to 87 mg/m² and, additionally, on a data set of 7 patients receiving oral doses ranging between 176 and 200 mg/m², investigated in a previous study. Validation on both test data sets gave a relative mean predictive error of 0.1% and a relative root mean square error of 15.8% and 16.7%, respectively. The present study shows that it is possible to obtain a good estimate of the plasma AUC after oral administration of etoposide using a two-time-point sampling model. The model can be used to monitor the etoposide AUC in patients receiving chronic oral treatment.     

Activity and distribution studies of etoposide and mitozolomide in vivo and in vitro against human choriocarcinoma cell lines

Summary The in vivo antitumor activity of etoposide and mitozolomide was assessed in nude mice bearing a xenograft (CC3) of human gestational choriocarcinoma. Both agents demonstrated, at best, marginal activity observed as a delay in tumour growth. This lack of sensitivity suggests that the CC3 xenograft is not a good model for selection of agents for clinical evaluation in gestational choriocarcinoma.Plasma and tissue concentrations of etoposide and mitozolomide were measured in nude mice. Drug concentrations found in tumour tissue were 60% and 30% of plasma levels for mitozolomide and etoposide respectively.Etoposide and mitozolomide activity was also evaluated in vitro with another choriocarcinoma cell line (JAR). Maximum cell-kill was achieved after exposure to etoposide 0.05–1 g/ml for 3–24 h. In vitro response to etoposide demonstrates the importance of exposure time in determining cytotoxicity. In contrast, mitozolomide at concentrations from 1–100 g/ml did not have a marked effect against JAR after exposure for 3–24 h.This work was supported by the Cancer Research Campaign     

Double-platinum chemotherapy combined with etoposide in metastatic brain tumor from small cell lung carcinoma

The platinum-based chemotherapeutic agents, such as cisplatin (CDDP) and carboplatin (CBDCA), are effective for small cell lung carcinoma (SCLC). However, high dose treatment of these agents required for advanced-stage SCLC is often associated with severe toxicity. The authors used combination of lower doses of both cisplatin and carboplatin combined with etoposide (VP-16) to minimize side effects of these agents. This goal was accomplished by utilizing the facts that each agent has its own toxicity that can be controlled individually. Two patients (60- and 71-year old men) with multiple metastatic brain tumors from SCLC were treated by our chemotherapeutic regimen. After fourth chemotherapy, remarkable shrinking of brain masses was associated with significant decrease the size of original lung lesions in both cases. The two patients were discharged without any side effects of the treatment, and neurological deficits subsided in both cases. Each course provided the following schedules: carboplatin 200 mg/m² × 1 day, cisplatin 25 mg/m² × 2 days (intravenous administration), and etoposide 25 mg oral × 14 days. After second chemotherapy, the patient of Case 1 was irradiated to both brain and chest lesions, and only to brain in Case 2. The authors concluded from our two cases that the combination of these agents extremely effective to treat this malignancy with less toxicity. We named this double platinum chemotherapy as PEC, abbreviated from cisplatin, etoposide, and carboplatin.     

Etoposide With or Without Mannitol for the Treatment of Recurrent or Primarily Unresponsive Brain Tumors: A Children's Cancer Group Study, CCG-9881

Purpose. This study was undertaken to evaluate the response of recurrent brain tumors to intravenous etoposide and to evaluate the efficacy of mannitol in augmenting etoposide's tumoricidal effect. Patients and methods. Ninety-nine children between one and 21 years of age with recurrent brain tumors were randomly assigned to treatment with intravenous etoposide 150mg/M², with or without mannitol 15gm/M², daily for five days every three weeks for one year or until disease progression or death. Computerized tomographic (CT) or magnetic resonance image (MRI) scans, obtained after three cycles of therapy, were compared with pre-therapy scans. Scans were centrally reviewed. Results. Of 87 evaluable patients, 12 (13.8%) were determined to have had an objective response by the institutional radiologist. On central review, 7/66 (10.6%) responses were documented. Responses in centrally reviewed patients were observed in 2/12 (16.7%) low grade astrocytomas, 4/26 (15.4%) medulloblastoma or primitive neuroectodermal tumors (PNET), 1/13 (7.7%) high grade astrocytomas and 0/15 (0%) brain stem gliomas. Survival at one year was 53% (SE 12%) for low grade astrocytomas, 38% (SE 7%) for medulloblastoma or PNET, 28% (SE 10%) for high grade astrocytomas and 9% (SE 5%) for brain stem gliomas. An effect of mannitol was not observed. Conclusion. Intravenous etoposide has a low level of activity in the treatment of recurrent low grade astrocytomas and medulloblastoma or PNET. The efficacy of this agent was not enhanced by the coincident intravenous administration of mannitol.     

Protection of acute myeloblastic leukemia cells against apoptotic cell death by high glutathione and gamma-glutamylcysteine synthetase levels during etoposide-induced oxidative stress

Background: Etoposide mediates its cytotoxicity by inducing apoptosis. Thus, mechanisms which regulate apoptosis should also affect drug resistance. Oxidants and antioxidants have been shown to participate in the regulation of apoptosis. We were interested in studying whether responsiveness of acute myeloblastic leukemia (AML) cells to etoposide is mediated by oxidative stress and glutathione levels.Patients and methods: Two subclones of the OCI/AML-2 cell line which are etoposide-sensitive (ES), and etoposide-resistant (ER), were established by the authors at the University of Oulu, and used as models. Assays for apoptosis included externalization of phosphatidylserine (as evidenced by annexin V binding), and caspase activation as indicated by cleavage of poly(ADP-ribose)polymerase (Western blotting). Peroxide formation was analyzed by flow cytometry. Glutathione and gamma-glutamylcysteine synthetase (-GCS) levels were determined spectrophotometrically and by Western blotting, respectively.Results: Etoposide-induced apoptosis was evident 12 hours after treatment in the ES subclone, but was apparent in the ER subclone only after 24 hours. The basal glutathione and -GCS levels were higher in the ER than the ES subclone. Etoposide increased peroxide formation in both subclones after 12-hour exposure. Significant depletion of glutathione was observed in the ES subclone during etoposide exposure, while glutathione levels were maintained in the ER subclone. In neither of the subclones was induction of -GCS observed during 24-hour exposure to etoposide. Furthermore, the catalytic subunit of -GCS was cleaved during apoptosis, concurrent with depletion of intracellular glutathione. When glutathione was depleted by treatment with buthionine sulfoximine, a direct inhibitor of -GCS, the sensitivity to etoposide was increased, particularly in the ER subclone.Conclusions: The results underline the significance of glutathione biosynthesis in the responsiveness of AML cells to etoposide. The molecular mechanisms mediating glutathione depletion during etoposide exposure might include the cleavage of the catalytic subunit of -GCS.     

Metastatic Medulloblastoma in 10-year-old Girl Treated Successfully with Chemotherapy without Radiotherapy

We report a case of high risk medulloblastoma with leptomeningeal intracranial and spinal metastasis in a 10-year-old girl treated successfully with conventional prolonged chemotherapy without radiotherapy.This is a particular case of medulloblastoma that at onset did not receive standard therapy for medulloblastoma i.e. neither surgery nor craniospinal irradiation. This 10-year-old Chinese girl affected with localized medulloblastoma was previously treated at a medical department in China only with radiotherapy on the posterior fossa. When the child arrived in Italy with progressed metastatic medulloblastoma, she was treated with carboplatin/etoposide association i.v. followed by oral etoposide and partial surgery of the primitive mass. The schedule of chemotherapy was etoposide 300mg/sqm followed by carboplatin 1000mg/sqm in one day every 21–28 days for the first six courses, then etoposide 200mg/sqm and carboplatin 600mg/sqm in one day every 28–35 days for further 11 courses and oral etoposide 50mg/sqm/day for ten consecutive days and one week interval between two cycles for one year. At present the girl is alive and disease-free, and has been off-therapy for 31 months.Interestingly, in this case a long-lasting complete remission was obtained without radiotherapy and without myeloablative chemotherapy. Oral etoposide played an important role in achieving a complete remission.     

Phase 1/2 Study of the CD56-Targeting Antibody-Drug Conjugate Lorvotuzumab Mertansine (IMGN901) in Combination With Carboplatin/Etoposide in Small-Cell Lung Cancer Patients With Extensive-Stage Disease

Introduction

This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC).

Pharmacokinetics of high-dose etoposide after short-term infusion

Summary The pharmacokinetics of high-dose etoposide (total dose, 2100 mg/m² divided into three doses given as 30-min infusions on 3 consecutive days) were studied in ten patients receiving high-dose combination chemotherapy followed by autologous bone marrow transplantation. In addition to etoposide, all subjects received 2×60 mg/kg cyclophosphamide and either 6×1,000 mg/m² cytosine arabinoside (ara-C), 300 mg/m² carmustine (BCNU), or 1,200 mg/m² carboplatin. Plasma etoposide concentrations were determined by²⁵²Cf plasma desorption mass spectrometry. In all, 27 measurements of kinetics in 10 patients were analyzed. According to graphic analysis, the plasma concentration versus time data for all postinfusion plasma ctoposide values were fitted to a biexponential equation. The mean values for the calculated pharmacokinetic parameters were:t1/2, 256±38 min; mean residence time (MRT), 346±47 min; AUC, 4,972±629g min ml^–1 (normalized to a dose of 100 mg/m²); volume of distribution at steady state (Vd_ss), 6.6±1.2l/m²; and clearance (CL), 20.4±2.4 ml min^–1 m^–2. A comparison of these values with standard-dose etoposide pharmacokinetics revealed that the distribution and elimination processes were not influenced by the dose over the range tested (70–700 mg/m²). Also, the coadministration of carboplatin did not lead to significant pharmacokinetic alterations. Although plasma etoposide concentrations at the time of bone marrow reinfusion (generally at 30 h after the last etoposide infusion) ranged between 0.57 and 2.39 g/ml, all patients exhibited undelayed hematopoietic reconstitution.     

Oral treatment with etoposide in small cell lung cancer – dilemmas and solutions

Background

Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity.

Conclusions

The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient.Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice.     

Intra-arterial Carboplatin and Intravenous Etoposide for the Treatment of Recurrent and Progressive Non-GBM Gliomas

Recurrent and progressive non-GBM gliomas are a diverse group of brain tumors that often respond poorly to adjuvant chemotherapy treatment. Regional intra-arterial (IA) administration of chemotherapy may result in increased tumor uptake of drug, with improvement in response rates and time to progression (TTP). Twenty-five patients with recurrent or progressive non-GBM gliomas were treated with IA carboplatin (200mg/m²/d) and intravenous (IV) etoposide (100mg/m²/d) for 2 days every 4 weeks. Patients ranged in age from 22 to 68 years (mean 37.8). All but one patient had received standard irradiation, and eight patients had attempted prior chemotherapy. Five of 25 patients had objective responses (20%), while another 15 patients had stable disease (60%), receiving a total of 318 IA treatment procedures. There was one complete response (4.0%), three partial responses (12.0%), one minor response (4.0%), 15 stable diseases (60.0%), and five progressive diseases (20.0%). The median TTP was 24.2 weeks overall and 32 weeks in responders. Overall median survival was 34.2 weeks. Therapy was well tolerated, with mainly hematologic toxicity. Two patients had embolic complications. Although these are preliminary results, IA carboplatin and IV etoposide have modest activity against recurrent and progressive non-GBM gliomas and warrants further study.     

Combination of three cytotoxic agents in small-cell lung cancer

Purpose

The established treatment for small-cell lung cancer has been a cisplatin–etoposide combination, as the most effective chemotherapy regimen. Paclitaxel has also been used in combination with cisplatin and etoposide but this has been unacceptable due to the toxicity. This toxicity could be attributed to the three consequent days of treatment with etoposide plus the doses of each of the three drugs. Our objectives were to determine an equal or longer survival and lower toxicity by administering all 3 drugs with low dosage on day one, compared to the established guideline of 3-day administration.

Methods

We tested the aforementioned three-drug combination and avoided the toxicity in the majority of patients by administering all 3 drugs on day one. Fifty-one patients (50 evaluable) were recruited from 4 oncology clinics. All patients had histologically or cytologically confirmed small-cell lung cancer with limited and extensive disease in 40 and 60 % of the patients, respectively. The treatment was: cisplatin 75 mg/m², etoposide 120 mg/m² (maximum 200 mg), and paclitaxel 135 mg/m². The agents were administered on day one and repeated every 3 weeks for 6 cycles.

Results

The median survival was 15 months (95 % CI 13.6–16.4) (mean 16 months). Forty-five (90 %) patients achieved a response: 20 (40 %) patients, a complete response and 25 (50 %), a partial response. Adverse reactions included grade 3 and 4 neutropenia in 12 and 2 % of the patients, respectively. Other side effects were of very low toxicity.

Conclusion

The 1-day, three-agent (cisplatin–etoposide–paclitaxel) treatment of small-cell lung cancer is beneficial with respect to response rate and survival, and the toxicity is low and well-tolerated.