Synopsis Etoposide is a podophyllotoxin derivative which delays progression of the cell cycle through the late S or early G2 phase. In vitro antitumour activity is dose and administration schedule— dependent and synergy, notably with cisplatin, has been demonstrated. The clinical profile of etoposide has been well characterised in small and non— small cell lung cancer and testicular cancer. The combination of etoposide and cisplatin has demonstrated substantial antineoplastic activity in the treatment of small cell lung cancer, testicular cancer, and promising activity in non— small cell lung cancer and acute myelogenous leukaemia. Etoposide and cisplatin provide a useful combination that is particularly beneficial as salvage chemotherapy in a variety of tumours resistant to other combination regimens. The therapeutic potential of the synergistic combination of etoposide with cisplatin or carboplatin continues to be explored and the optimum dosage schedule remains to be determined. Etoposide in combination with other cytotoxic drugs has shown substantial activity in the treatment of small cell lung cancer and testicular cancer, both seminomatous and nonseminomatous, as well as in the treatment of adult and childhood acute nonlymphoblastic leukaemia, Hodgkin’s and non- Hodgkin’s lymphoma, some childhood solid tumours and trophoblastic disease. The adverse effect profile of etoposide is well characterised with myelosuppression, predominantly leucopenia, as the only major dose-limiting toxicity. Thus, etoposide, administered as an intravenous infusion or orally, in conjunction with other cytotoxic drugs produces favourable remission rates as a first-line agent and as salvage chemotherapy in a variety of cancers, especially small cell lung and testicular cancer. Pharmacodynamic Properties The cytotoxicity of etoposide in vitro is both concentration-and time-dependent. Various animal and human carcinoma cell lines are sensitive to etoposide, and synergism has been demonstrated in tumours in mice with doxorubicin (adriamycin), cisplatin, 4-hydroxyperoxycyclophosphamide and vindesine. The sensitivity of cell lines to etoposide is also increased by verapamil. In vivo etoposide is particularly active against Lewis lung carcinoma and leukaemias in mice. The activity of etoposide is increased with multiple dosing and with certain frequencies of administration. Etoposide is thus dose schedule-dependent, with treatment every third or fourth day being optimal against murine leukaemias. Certain metabolites of etoposide may be cytotoxic, probably from oxidation-reduction with a dehydrogenase enzyme. The mechanism by which etoposide or its metabolites, or both, causes DNA damage is probably from stabilisation of a DNA topoisomerase II complex such that the strand-rejoining activity of the enzyme is impaired. The number of single- and double-strand breaks is proportional to the concentration and length of incubation with etoposide, with more double-strand breaks occurring at higher concentrations and longer incubation times. Crossresistance has been demonstrated between other cytotoxic drugs that share a similar action on DNA topoisomerase II. Etoposide delays progression of the cell cycle through late S or early G2 phases, and is without effect on tubulin assembly or accumulation of cells during metaphase. Inhibition of thymidine uptake as well as that of uridine, adenosine and guanosine, into isolated tumour cells is both concentration-and time-dependent. Recovery of granulocyte-macrophage colony-forming units (CFU-GM), an indicator of the haematopoietic reconstitution capacity of purged bone marrow in vitro, is also concentration-and time-dependent following addition of etoposide. Various leukaemia and lymphoma cell lines are sensitive to etoposide at concentrations which allow recovery of CFU-GM within 1 to 2 weeks. Other mechanisms, however, are involved in resistance and crossresistance such as reduced drug uptake, and deactivation of etoposide or its metabolites. Pharmacokinetic Properties The plasma decay of etoposide usually fits a 2-compartment model. The peak plasma concentration of etoposide and area under the concentration versus time curve (AUC) show an approximately linear relation to increasing intravenous dose. After intravenous infusion of etoposide 100 mg/m2 over a period of 30 to 60 minutes, a plasma concentration of 21 mg/L was observed within 5 minutes of completing administration. No evidence of drug accumulation is seen with daily infusions of etoposide 100 mg/m2. After oral administration peak plasma concentrations are achieved within 2 to 3 hours, but a linear relation of peak plasma concentration and AUC to increasing oral dose has not been clearly established although there is some evidence that such a dose-proportional relationship does exist up to 250 mg/m2 but not at higher dosages. The mean bioavailability of orally administered etoposide is approximately 50%. The median apparent volume of distribution after a single intravenous dose and at steady-state is 9.7 and 8.3 L/m2, respectively; slightly higher values are found after oral administration. Penetration of etoposide into cerebrospinal fluid has been variable but generally low, while distribution into other tissues is poorly documented. Etoposide is highly bound to plasma albumin (approximately 94%). Renal clearance accounts for up to 40% of the administered dose, and the principal metabolites recovered from urine are the hydroxy acid and the glucuronide. Biliary excretion plays a minor role in the elimination of etoposide. The median terminal phase elimination half-life of etoposide from studies in healthy adults evaluated using 2-compartment models is 5.6 hours after intravenous administration; similar half-lives are reported for the oral route. Renal impairment decreases the plasma clearance and increases volume of distribution and elimination half-life of etoposide; a good correlation of plasma clearance with creatinine clearance is observed. Hepatic impairment appears to have less influence on etoposide pharmacokinetics. Prior administration of cisplatin increased etoposide AUC. Apart from this, disposition of etoposide is not altered by concomitant administration of a number of other cytotoxic agents often used in chemotherapy regimens, although the Tween 80 component of the intravenous formulation of etoposide may alter the pharmacokinetics of doxorubicin. Therapeutic Trials Etoposide alone, administered intravenously, has demonstrated single agent cytotoxic activity with a response rate of at least 20% in the treatment of small cell lung cancer, nonseminomatous testicular cancer, non-Hodgkin’s lymphoma, acute nonlymphocytic leukaemia and neuroblastoma. Consequently, etoposide has been added to standard chemotherapy regimens shown to be active in these tumours in an attempt to improve response rates. The dose-schedule dependency of etoposide was shown in vitro against various human malignant cell lines and animal models of leukaemia, and the various schedules used in early studies were prompted by this awareness. Recent studies of etoposide as primary treatment of patients with previously untreated small cell lung cancer have clearly demonstrated that efficacy of etoposide is related to administration schedule, although the optimum schedule remains to be established. Etoposide has proved to be a very active cytotoxic agent in combination with cisplatin and the synergy of the 2 drugs is clinically relevant in small cell lung cancer, germ cell tumours and various other malignancies. Etoposide has been studied extensively in the initial treatment of small cell lung cancer. Nonrandomised studies of intravenous etoposide-containing regimens for primary treatment of limited disease small cell lung cancer showed the most active combinations to be etoposide with cyclosphosphamide, doxorubicin and vincristine (CAV) or etoposide/cisplatin alternating with CAV or ifosfamide. In limited disease, complete responses (CR) were achieved in up to 76% of patients and overall responses [CR + partial responses (PR)] in 88 to 93%. In extensive disease these combination regimens achieved complete responses in 27% and 34% of patients, and overall responses in 65% and 78%, respectively. Randomised studies in patients with small cell lung cancer also show intravenous etoposide and cisplatin is an effective combination either alone or alternating with CAV. Etoposide also effectively substitutes for doxorubicin in the CAV regimen, and to improve response and, in one study, survival, when added to this regimen (CAVE) in patients with extensive disease. Used in intensification or consolidation therapy, etoposide in combination with cisplatin has demonstrated activity in patients with limited small cell lung cancer. Generally, lower overall response rates (27 to 75%) are observed with etoposide and cisplatin as salvage chemotherapy in relapsed or resistant small cell lung cancer than when used in previously untreated patients. In non—small cell lung cancer, etoposide and cisplatin induced complete remission in 2 to 16% and partial remission in a further 24 to 53% of patients, with a median survival of 11 to 15 months. Addition of other drugs to this combination did not improve the response and survival rates. These results have been confirmed in randomised studies where complete remission in 1 to 11% and an overall response rate of 10 to 38% has been achieved with etoposide/cisplatin, or with etoposide combined with cyclophosphamide and/or doxorubicin (ACE). Etoposide in combination with other cytotoxic drugs has also shown considerable activity in the treatment of testicular cancer. Complete remission rates achieved with cisplatin, bleomycin and vincristine were similar to those with cisplatin, bleomycin and etoposide in patients with seminoma (74 vs 68%), embryonal carcinoma (88 vs 93%) and teratocarcinoma (70 vs 78%), with a 2-year survival rate of approximately 80% in both treatment groups. Etoposide and cisplatin produced a 93% CR rate in seminomatous testicular cancer, and addition of bleomycin to this combination achieved 83 to 100% complete remission rate in nonseminomatous patients. As salvage chemotherapy, etoposide as monotherapy or in combination is of variable activity inducing CR in 11 to 71% of patients. In acute nonlymphoblastic leukaemia (ANLL), etoposide in combination with standard therapy of daunorubicin and cytarabine (cytosine arabinoside) improved remission duration and disease-free survival compared with doxorubicin and cytarabine. As salvage chemotherapy, etoposide has shown promising activity in combination with doxorubicin and cytarabine, and with amsacrine or azacitidine, or both, in children or adults with ANLL. In Hodgkin’s disease, etoposide as first-line chemotherapy in combination with standard chemotherapy consisting of vincristine, chlorambucil and prednisolone, and etoposide alternated with these drugs plus procarbazine, was active as induction (77% CR). As salvage therapy, when combined with cyclophosphamide and carmustine, or combined with vinblastine, doxorubicin and prednisone and alternated with chlorambucil, vincristine, procarbazine and prednisolone, etoposide was effective (CR) in 23 to 67% of patients. In non-Hodgkin’s lymphoma, induction with etoposide as monotherapy or in combination with CAV as first line therapy achieved response rates of 56 to 100%, while as salvage chemotherapy etoposide-containing regimens induced complete response in up to 29% of patients with refractory or relapsed lymphomas. Etoposide in combination with doxorubicin as salvage therapy, induced complete remission in about 10% and overall response in less than 40% of patients with advanced breast cancer. In patients with advanced refractory ovarian adenocarcinoma, etoposide exhibited minimal activity when used intravenously, although better results were achieved when given intraperitoneally. In trophoblastic disease, etoposide as monotherapy or in combination produced complete remission in all of the small number of patients studied. The combination of etoposide and cisplatin has also demonstrated promising activity in small numbers of children with solid tumours including advanced neuroblastoma, advanced germ cell tumours and soft tissue sarcomas, both as induction or salvage therapy. Adverse Effects The dose-limiting toxicity of etoposide alone is myelosuppression, predominantly leucopenia. The leucocyte nadir occurs 8 to 10 days after treatment, with recovery usually by day 21. Thrombocytopenia is less common and recovery is evident by 21 to 28 days. Stomatitis is generally reported only occasionally at usual therapeutic dosages, although it is dose-limiting with high-dose regimens, diarrhoea is infrequent, and bronchospasm has occurred rarely. Alopecia, however, is frequent and even universal with some etoposide regimens. Neurotoxicity has seldom been reported, but the possible potentiation of vincristine-induced neurotoxicity by etoposide needs further investigation. Bolus intravenous injection has been associated with hypotension; thus it is recommended that etoposide be administered over a period of 30 to 60 minutes. Dosage and Administration The recommended intravenous dose of etoposide is an infusion of 50 to 100 mg/m2 over 30 to 60 minutes on 5 consecutive days, or 100 mg/m2 on days 1, 3 and 5. For oral administration, twice the relevant intravenous dose should be given. The dosage should be repeated every 21 or 28 days, but should be adjusted on the basis of both nadir and pretreatment blood counts. © 1990, ADIS Press Limited. All rights reserved.
