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PubMed1988

Identification of etoposide glucuronide as a major metabolite of etoposide in the rat and rabbit.

Isolated livers from male Sprague-Dawley rats were perfused at 20 ml/min for 3 h at 37 degrees C with 100 ml of an oxygenated, recirculating solution of 20% rat blood in Krebs bicarbonate buffer containing 20 micrograms/ml [3H]etoposide. Ninety % of administered radioactivity was eliminated in bile over a 3-h collection period. The clearance of etoposide was 3.56 ml/min indicating that, in the rat, it is not highly extracted. Its clearance is, therefore, independent of hepatic blood flow. Etoposide was both excreted into the bile and metabolized by the liver. Perfusate and bile samples analyzed by reverse-phase high-performance liquid chromatography techniques were found to contain three peaks of radioactivity. Positive and negative ion fast atom bombardment mass spectrometry identified the first two peaks as etoposide glucuronides and the third peak as parent drug. Following the i.v. administration of etoposide to rabbits, etoposide glucuronide was also identified in rabbit urine. The recovery of etoposide both from rabbit urine and rat bile was increased by preincubation with glucuronidase. However, the glucuronides were relatively resistant to the action of glucuronidase and showed varying sensitivity to the type of glucuronidase and the reaction conditions used. These studies document the presence of etoposide glucuronide as an etoposide metabolite in two mammalian species and suggest that previous clinical studies using beta-glucuronidase to quantitate glucuronide formation may have underestimated this metabolite due to its relative resistance to some glucuronidase preparations.

Animals↗
PubMed1990

Etoposide versus etoposide plus high-dose cisplatin in the management of advanced non-small cell lung cancer. Results of a prospective randomized FONICAP trial. Italian Lung Cancer Task Force.

Two hundred sixteen patients with unresectable non-small cell lung carcinoma were randomly allocated to receive etoposide (120 mg/m2, days 1-3) either alone or in combination with high-dose cisplatin (60 mg/m2, days 1-2). The patients' distribution and characteristics were similar in the two treatment arms. The objective response rate for etoposide was 7% versus 25.8% for etoposide plus cisplatin (P less than 0.005). Median progression-free survival in etoposide arm was 3.5 months versus 5 months in the combination arm (P = 0.43). The median survival time for etoposide was 6 months compared with 8 months for etoposide combined with cisplatin (P = 0.87). Significantly more nausea/vomiting (P less than 0.005), serum creatinine elevation (P less than 0.005), hearing loss and/or tinnitus (P less than 0.005), peripheral neuropathy (P less than 0.005), leukopenia (P less than 0.025), and anemia (P less than 0.005) occurred in the etoposide plus cisplatin arm. No statistically significant difference was recorded between the two arms in terms of performance status changes. In conclusion the addition of high-dose cisplatin to single-agent etoposide significantly increases the chance of obtaining tumor response in advanced non-small cell lung cancer at the cost of an increased toxicity without any significant long-term impact on survival and progression-free survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein.

The breast cancer resistance protein [BCRP (BCRP/ABCG2)] has not previously been directly identified as a source of resistance to epipodophyllotoxins.However, when P-glycoprotein (P-gp)- and Mrp1-deficient mouse fibroblast and kidney cell lines were selected for resistance to etoposide, amplification and overexpression of Bcrp1 emerged as the dominant resistance mechanism in five of five cases. Resistance was accompanied by reduced intracellular etoposide accumulation. Bcrp1 sequence in all of the resistant lines was wild-type in the region spanning the R482 mutation hot spot known to alter the substrate specificity of mouse Bcrp1 (mouse cognate of BCRP) and human BCRP. Transduced wild-type Bcrp1 cDNA mediated resistance to etoposide and teniposide in fibroblast lines and trans-epithelial etoposide transport in polarized Madin-Darby canine kidney II cells. Bcrp1-mediated etoposide resistance was reversed by two structurally different BCRP/Bcrp1 inhibitors, GF120918 and Ko143. BCRP/Bcrp1 (inhibition) might thus impact on the antitumor activity and pharmacokinetics of epipodophyllotoxins. However, treatment of P-gp-deficient mice with GF120918 did not improve etoposide oral uptake, suggesting that Bcrp1 activity is not a major limiting factor in this process. In contrast, use of GF120918 to inhibit P-gp in wild-type mice increased the plasma levels of etoposide after oral administration 4-5-fold. It may thus be worthwhile to test inhibition of P-gp in humans to improve the oral availability of etoposide.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Are 3 cycles of bleomycin, etoposide and cisplatin or 4 cycles of etoposide and cisplatin equivalent optimal regimens for patients with good risk metastatic germ cell tumors of the testis? The need for a randomized trial.

PURPOSE: Standard chemotherapy for good prognosis metastatic nonseminomatous germ cell tumors of the testis currently includes etoposide and cisplatin. The optimal number of cycles and the need for bleomycin remain matters of debate. Three cycles of bleomycin, etoposide and cisplatin (BEP) or 4 cycles of etoposide and cisplatin are supposed to represent equivalent optimal regimens. MATERIALS AND METHODS: We analyzed the therapeutic outcome of 75 patients with good risk metastatic nonseminomatous germ cell tumor of the testis who were routinely treated at our institute. The chemotherapy regimens consisted of 4 cycles of BEP in 17 patients, 3 cycles of BEP in 23 patients, and 4 cycles of etoposide and cisplatin in 35 patients. RESULTS: All 75 patients achieved a complete or partial response with normal serum tumor markers. After a median followup of 3.5 years (range 2 to 7.5) the overall no evidence of disease rate was 91% (100, 96 and 83% in patients treated with 4 cycles of BEP, 3 cycles of BEP, and 4 cycles of etoposide and cisplatin, respectively). When considering the number of adverse events in each treatment group, that is the number of surgical complete responses or relapses after complete remission, results appeared similar with 3 or 4 cycles of BEP (2 and 3, respectively) but lower in patients who received 4 cycles of etoposide and cisplatin (11 adverse events). Of the 35 patients treated with etoposide and cisplatin 4 (11%) died of disease while only 1 of the 40 (3%) treated with BEP died of disease. CONCLUSIONS: Four cycles of etoposide and cisplatin could yield inferior results compared to 3 cycles of BEP in patients with good risk nonseminomatous germ cell tumor of the testis. Our results highlight the need for a randomized trial addressing the question of therapeutic equivalence between these 2 chemotherapy regimens.

Adolescent↗
PubMed1996

Etoposide phosphate, the water soluble prodrug of etoposide.

Etoposide (Vepesid) is a widely used drug in a variety of neoplasms. To improve the pharmaceutical characteristics of etoposide, etoposide phosphate (Etopophos, Bristol-Myers Squibb) has been developed as a prodrug. Etoposide phosphate is the phosphate ester derivative of etoposide. In comparison to the parent compound, etoposide phosphate is highly soluble in water and can be readily formulated for intravenous use, resulting in higher clinical application. This paper presents information on the pharmaceutical properties and the current status of etoposide phosphate in clinical trials.

Antineoplastic Agents, Phytogenic↗
PubMed1990

Cytotoxic synergism between trimetrexate and etoposide. Evidence that trimetrexate potentiates etoposide-induced protein-associated DNA strand breaks in L1210 leukemia cells through alterations in intracellular ATP concentrations.

Using an outgrowth method, combinations of trimetrexate and etoposide were synergistic against L1210 leukemia as assessed by the median-effect method. Trimetrexate was also found to stimulate etoposide-mediated protein-associated DNA strand breaks by nearly 2-fold when L1210 cells were exposed to 0.5 microM drug(s) for 2 hr. Trimetrexate had no effect on the transport of etoposide or the repair of etoposide-induced DNA strand breaks. Other drugs that interfere with de novo purine biosynthesis, including methotrexate and 5,10-dideazatetrahydrofolate, also potentiated etoposide-induced DNA strand breaks, whereas agents that specifically reduce intracellular concentrations of pyrimidines (pyrazofurin or CB-3717) had no effect. Only those protectants that restored ATP levels (adenosine or hypoxanthine) could abolish the stimulatory effect of trimetrexate. Finally, it was shown that by exposing cells to various concentrations of 2,4-dinitrophenol, there was an inverse relationship between the number of DNA strand breaks produced by etoposide and the intracellular concentrations of ATP down to about 600 microM. The results indicate that trimetrexate stimulates etoposide-induced DNA strand breaks possibly by modulating intracellular ATP levels which may contribute to the synergistic interaction between these drugs.

Adenosine Triphosphate↗
PubMed1995

Phase I and pharmacokinetic study of a water-soluble etoposide prodrug, etoposide phosphate (BMY-40481).

Etoposide phosphate is a water-soluble prodrug of etoposide. A phase I and pharmacokinetic study has been performed over the dose range 25-110 mg/m2/day for 5 days (etoposide equivalent doses). The maximum tolerated dose (MTD) was 110 mg/m2/day for 5 days every 3 weeks and the dose-limiting toxicity was neutropenia. Other toxicities were mild, with the exception of 2 patients who displayed significant hypersensitivity reactions. The etoposide phosphate:etoposide area under the plasma concentration versus time curve (AUC) ratio was < 1% and the pharmacokinetic parameters for etoposide were within previously reported ranges. Pharmacodynamic analyses demonstrated that etoposide AUC and baseline white blood cell count were significant determinants of leucopenia (model r2 = 0.51).

Adult↗
PubMed2002

Maintenance daily oral etoposide versus no further therapy following induction chemotherapy with etoposide plus ifosfamide plus cisplatin in extensive small-cell lung cancer: a Hoosier Oncology Group randomized study.

BACKGROUND: We performed this phase III study to determine whether the addition of 3 months of oral etoposide in non-progressing patients with extensive small-cell lung cancer (SCLC) treated with four cycles of etoposide plus ifosfamide plus cisplatin (VIP) improves progression-free survival (PFS) or overall survival. PATIENTS AND METHODS: Patients with extensive SCLC with a Karnofsky performance score (KPS) > or =50, adequate renal function and bone marrow reserve were eligible. Patients with CNS metastasis were eligible and received concurrent whole-brain radiotherapy. All patients received etoposide 75 mg/m2, ifosfamide 1.2 g/m2 and cisplatin 20 mg/m2 intravenously on days 1-4 every 3 weeks for four cycles. Non-progressing patients were randomized to oral etoposide 50 mg/m2 for 21 consecutive days every 4 weeks for three courses versus no further therapy until progression. RESULTS: From September 1993 to June 1998, 233 patients were entered and treated with VIP with 144 non-progressing patients subsequently randomized to oral etoposide (n = 72) or observation (n = 72). Minimum follow up for all patients is 2 years. Toxicity with oral etoposide was mild. There was an improvement in median PFS favoring the maintenance arm of 8.23 versus 6.5 months (P = 0.0018). There was a trend towards an improvement in median (12.2 versus 11.2 months), 1-year (51.4% versus 40.3%), 2-year (16.7% versus 6.9%) and 3-year (9.1% versus 1.9%) survival (P = 0.0704) favoring the maintenance arm. CONCLUSIONS: Three months of oral etoposide in non-progressing patients with extensive SCLC was associated with a significant improvement in PFS and a trend towards improved overall survival.

Administration, Oral↗
PubMed2006

UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes: structural characterization of phenolic and alcoholic glucuronides of etoposide and estimation of enzyme kinetics.

Etoposide, an important anticancer agent, undergoes glucuronidation both in vitro and in vivo. In this study, three isomeric glucuronides of etoposide, including one phenolic (EPG) and two alcoholic glucuronides (EAG1 and EAG2), were biosynthesized in vitro with human liver microsomes (HLMs), and identified by liquid chromatography-electrospray ionization-mass spectrometry and confirmed by beta-glucuronidase cleavage. In vitro UDP-glucuronosyltransferase (UGT) reaction screening with 12 recombinant human UGTs demonstrated that etoposide glucuronidation is mainly catalyzed by UGT1A1. Although UGT1A8 and 1A3 also catalyzed the glucuronidation of etoposide, their activities were approximately 10 and 1% of UGT1A1. Enzyme kinetic study indicated that the predominant form of etoposide glucuronide in HLMs and human intestinal microsomes (HIMs) was EPG, whereas EAG1 and EAG2 were the minor metabolites, with approximately an 8 to 10% glucuronidation rate of EPG. For the formation of EPG, the V(max) of HLMs (110 pmol/min/mg protein) was very similar to that of recombinant UGT1A1 (124 pmol/min/mg protein), whereas the V(max) of HIMs (54.4 pmol/min/mg protein) was 2-fold lower than those of HIMs and UGT1A1. The K(m) values of HLMs (530 microM) and HIMs (608 microM) were 2-fold higher than that of UGT1A1 (285 microM). The V(max)/K(m) values for the formation of EPG were 0.21 and 0.09 microl/min/mg protein for HLMs and HIMs, respectively. The data indicated that UGT1A1 is principally responsible for the formation of etoposide glucuronides, mainly in the form of phenolic glucuronide, suggesting that etoposide can be used as a highly selective probe substrate for human UGT1A1 in vitro.

Alcohols↗
PubMed1994

Etoposide (VP-16) is a potent inducer of micronuclei in male rat meiosis: spermatid micronucleus test and DNA flow cytometry after etoposide treatment.

The genotoxic and cytotoxic effects of etoposide (VP-16), a topoisomerase II inhibitor, on male rat spermatogenic cells were studied by analysing induction of micronuclei during meiosis. Micronuclei (MN) were scored in early spermatids after different time intervals corresponding to exposure of different stages of meiotic prophase. Etoposide had a strong effect on diplotene-diakinesis I cells harvested 1 day after exposure, and a significant effect also on late pachytene cells harvested 3 days after exposure. The effect at 18 days corresponding to exposure of preleptotene stage of meiosis (S-phase) was weaker but also statistically significant. Adriamycin was used as a positive control in this study. The results indicate a different mechanism of action of etoposide compared with adriamycin and other chemicals studied previously with the spermatid micronucleus test. DNA flow cytometry was carried out to assess cytotoxic damage at the same time intervals (1, 3, and 18 days after treatment) at stages I and VII of the seminiferous epithelial cycle allowing a study of cytotoxicity to different spermatogenic cell stages. Damage of differentiating spermatogonia was observed by a decrease in the cell numbers of the 2C peak 1 and 3 days after treatment and by a reduction of the number of 4C cells (primary spermatocytes) 18 d after etoposide treatment. Adriamycin also killed differentiating spermatogonia. Since the cell population which showed a high induction of MN by etoposide was not reduced in number, the genotoxic effect is remarkable. We conclude that etoposide is a potent inducer of genotoxicity and patients treated with this agent during cancer chemotherapy are at a risk of genetic damage.

Animals↗
PubMed2003

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.

Adult↗
PubMed2006

A phase I/II study of docetaxel, etoposide, and carboplatin before concurrent chemoradiotherapy with cisplatin and etoposide in limited-stage small cell lung cancer.

Limited stage small cell lung cancer (LS-SCLC) is an infrequent but aggressive tumor. No major advances in the treatment of this disease have been achieved in recent years. This study was conducted to determine the maximum-tolerated dose (MTD) and efficacy of docetaxel, etoposide, and carboplatin (DEC) given before definitive chest radiotherapy with concurrent cisplatin and etoposide. Seventeen untreated LS-SCLC patients received docetaxel 50 mg/m2, etoposide 50-80 mg/m2, and carboplatin AUC = 5-6, intravenously on day 1 followed by etoposide 100-160 mg/m2 orally on days 2 and 3 every 21 days for two cycles followed by once daily radiotherapy to a total dose of 50 Gy given concurrently with cisplatin (60 mg/m2, d1) and etoposide (120 mg/m2, d1 and 240 mg/m2 day 2-3) for 2 cycles. All patients were assessable for toxicity and 15 for response. The most frequent toxicity was grade 3 and 4 neutropenia in 41% of patients during DEC and in 57% with chemoradiation. The MTD for DEC was docetaxel 50 mg/m2 plus carboplatin AUC = 5 and etoposide 50/100 mg/m2 with growth factor support. Significant nonhematologic toxicities were primarily radiation-related esophagitis (43%). One patient (6%) died from toxicity. The overall response rate was 82% with 10 patients (59%) achieving a complete response. The median survival was 12.1 months (95% CI, 6.4-17.8 months) and the 1-year survival rate was 47%. This novel approach produced similar efficacy results to current two drug regimens but was associated with significant neutropenia. Alternative strategies to increase complete response rates and survival are needed.

Adult↗
PubMed1989

Preformulation study of etoposide: identification of physicochemical characteristics responsible for the low and erratic oral bioavailability of etoposide.

Preformulation studies of etoposide, including pH-solubility profile, partition coefficient, pH-stability profile, and in vitro dissolution kinetics, were conducted to identify the responsible factor(s) for the low and erratic oral bioavailability of etoposide. A stability-indicating high-performance liquid chromatographic (HPLC) assay was used for drug monitoring. The equilibrium aqueous solubility of etoposide at 37 degrees C was low, 148.5-167.25 micrograms/ml, and did not vary over the pH range of 2 to 6. The pH-stability profile indicated rapid degradation of etoposide at pH 1.3 and 10, with degradation half-lives of 2.88 and 3.83 hr, respectively, at 25 degrees C. The half-life at pH 7.30 was 27.72 days. Maximum stability at 25 degrees C was reached at pH 5 to 6.15, with half-lives of 63 and 49.5 days, respectively. The intrinsic dissolution rate, determined on a Wood's apparatus, was slow, 0.0094 mg/min/cm2, while the etoposide partition coefficient between n-octanol and water was 9.94. Therefore, etoposide absorption appears to be dissolution rate limited rather than permeation rate limited. The low equilibrium aqueous solubility, slow intrinsic dissolution rate, and chemical instability at pH 1.3 could account for the low oral bioavailability.

Biological Availability↗
PubMed1993

Cisplatin-etoposide and carboplatin-etoposide induction chemotherapy for good-risk patients with germ cell tumors.

BACKGROUND: In an attempt to reduce the toxicity of chemotherapy in good-risk testicular cancer patients the two drug combinations, cisplatin plus etoposide (EP) and carboplatin plus etoposide (EC), have been compared. METHODS: Good risk was defined according to the MSKCC and IU criteria. 39 Patients have been treated with EP (cisplatin 20 mg/m2 i.v. and etoposide 100 mg/m2 i.v. on days 1 to 5), and 23 patients received EC (carboplatin 350 mg/m2 on day 1 and etoposide 100 mg/m2 on days 1 to 5). Four cycles of chemotherapy were given at 21- and 28-day intervals, respectively, with delays of up to 7 days in instances of leukocyte counts less than 3.0 x 10(9)/l or platelet counts less than 100 x 10(9)/l. RESULTS: In the EP group 34 (87%) of 39 patients achieved CR (26 with chemotherapy alone, 8 with additional surgery). After a median follow-up of 26 (12-58) months 3 (9%) patients relapsed from CR. Currently 38 patients are alive, and 37 (94%) are NED. In the EC group 20 (87%) of 23 patients achieved CR (15 with chemotherapy alone and 5 with additional surgery). After a median follow-up of 45 (26-57) months 6 (30%) patients relapsed from CR. Currently 19 patients are alive and 17 (74%) are NED. There was no difference in survival between the two groups (p = 0.13), but in the EC group the relapse rate was higher (p = 0.052) and the proportion of patients with NED was lower (p = 0.03) in comparison with EP. Toxicity in both groups was mild and similar, but 3 EP-treated patients presented hair loss. CONCLUSIONS: The study suggests that carboplatin-etoposide combination therapy is inferior to cisplatin-etoposide in patients with good-risk germ cell tumors.

Adult↗
PubMed1993

Selective delivery of etoposide to intraperitoneal tissues using a new dosage format: etoposide microcrystals suspended in oil.

Rats received an intraperitoneal bolus injection of etoposide at 5 mg/kg of body weight in the form of an etoposide microcrystal suspension in oil (ETOP-OIL) or an aqueous etoposide solution. The tissue distribution was subsequently analyzed using high performance liquid chromatography. ETOP-OIL delivered significantly greater amounts of etoposide and for a longer duration to the intraperitoneal tissues such as the omentum and the spleen, whereas it delivered significantly less etoposide to the rest of the body such as the lung, the heart and the bone marrow, than the aqueous etoposide solution.

Animals↗
PubMed1992

What is the optimal dose and duration of treatment with etoposide? I. Maximum tolerated duration of daily treatment with 50, 75, and 100 mg of oral etoposide.

Because etoposide is a cell-cycle phase-specific drug, its degree of cytotoxicity likely relies on duration of cell exposure to a specific concentration. We investigated the maximum tolerated duration of oral etoposide treatment at doses of 100, 75, and 50 mg/d in previously treated patients with biopsy-proven, advanced cancer. "Maximum tolerated" was defined as tumor progression or hematologic toxicity (World Health Organization [WHO] grade > or = 2). The maximum tolerated duration in 19 patients given 100 mg/d was > or = 21 days, since this was the predetermined cutoff point; 3 patients discontinued etoposide because of early tumor progression, and 6 others had developed leukopenia or thrombocytopenia (WHO grade > 2) by day 21. The maximum tolerated duration in 13 patients given 75 mg/d was a median of 11 weeks (range, 2 to 19); 6 patients developed tumor progression and 6 others leukopenia (WHO grade > or = 2) requiring discontinuation of treatment. Ten patients given 50 mg/d tolerated therapy for a median of 13 weeks (range, 3 to 26 weeks); treatment was halted in seven patients because of tumor progression, two because of leukopenia (WHO grade > or = 2), and one because of stomatitis. The data from this study and others suggest that above a certain minimal plasma level, etoposide induces concentration-dependent cumulative toxicity. What remains to be determined is the minimal plasma level per tumor type. It will also be interesting to see whether myelopoiesis, thrombocytopoiesis, and erythropoiesis have differential sensitivity to etoposide, since thrombocytopenia did not occur using daily etoposide doses of 50 and 75 mg, whereas at the same doses 10 of 23 patients required erythrocyte transfusion.

Administration, Oral↗
PubMed1987

Drug monitoring of etoposide (VP16-213). Correlation of pharmacokinetic parameters to clinical and biochemical data from patients receiving etoposide.

Pharmacokinetic parameters established in 15 patients receiving parenterally administered etoposide (80-120 mg . m-2) are reported. The etoposide assay by means of mass spectrometry after sample separation by thin-layer chromatography or high-pressure liquid chromatography used in this study has been described elsewhere. Peak plasma levels (9.5-63.3 micrograms . ml-1), the area under the curve (AUC) (2707-10192 micrograms . ml-1 . min-1), the mean transit time MTT (2.7-10.6 h), etoposide half-lives t1/2 alpha (0.10-0.52 h) and t1/2 beta (2.18-8.17 h), the volume of distribution at steady state (Vdss) (2.5-15.1 . l/m-2) and the systemic clearance (Cls) (10.1-35.1 ml min-1 . m-2) with the resulting mean values and standard deviations were determined. Our findings are compared with those of other authors, especially with regard to the method of detection used. This comparison indicates similar individual deviations and shorter half-lives with increasing specificity of the employed assay. Four patients studied on 3 consecutive days and, in one instance, during two different cycles of chemotherapy showed no sign of accumulation or of accelerated excretion of etoposide. There was little intrapatient variability. The pharmacokinetic parameters were correlated to clinical and laboratory findings. Statistical analysis indicated that the AUC was increased by prior cisplatin therapy and in patients with elevated levels of alkaline phosphatase. The Cls was decreased by prior cisplatin therapy, in obese patients, and by elevated alkaline phosphatase. The t1/2 beta of etoposide was increased in older patients. Linear regression analysis yielded a greater Vdss in patients with lower serum albumin levels, but this correlation has not yet been found to be statistically significant.

Adult↗
PubMed1995

Prolonged daily administration of oral etoposide in lymphoma following prior therapy with adriamycin, an ifosfamide-containing salvage combination, and intravenous etoposide.

Prolonged daily administration of oral etoposide has been reported to be active in refractory lymphoma. The purpose of this phase II trial was to confirm the activity of this schedule of etoposide in a selected group of heavily pretreated patients with non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). A total of 26 patients (20 with NHL and 6 with HD) were entered in the trial; all had previously been treated with an Adriamycin-based chemotherapy, an ifosfamide-containing salvage combination, and i.v. etoposide. Etoposide was given in a fixed oral daily dose of 100 mg over 3 weeks; the weekly dose (500-700 mg) was selected such that the average daily dose was approximately 50 mg/m2. Cycles were repeated on day 29. An objective response was seen in 16 patients (62%; 95% confidence interval, 42%-80%), with a complete response (CR) being observed in 3 cases (12%) and a partial response (PR), in 13 (50%). The median duration of PRs was 3 months. CRs lasted for 15 months in one patient and continue at 12+ and 20+ months in the remaining two patients. The overall actuarial survival for the entire group was 40% at 2 years; the median survival time was 12 months. The main toxicity was myelosuppression; WHO grade 3 or 4 leukopenia and thrombocytopenia developed in 31% and 12% of the patients, respectively. There was no drug-related death. We conclude that oral etoposide is an effective and tolerable palliative treatment for heavily pretreated lymphoma patients.

Administration, Oral↗