Etoposide toxicity

Bisogno G, Cowie F, Boddy A, Thomas HD, Dick G, Pinkerton CR. High-dose cyclosporin with etoposide— toxicity and pharmacokinetic interaction in children with solid tumours. Br J Cancer 1998 77(12) 2304-9. 

Joel SP, Shah R, Clark PI, Slevin ML. Predicting etoposide toxicity relationship to organ function and protein binding. J Clin Oncol 1996 14(l) 257-67. 

Of particular interest is the utility of population modeling when sampling is limited, as is often the case in pediatric studies. For example, etoposide toxicity and efficacy have been related to exposure. It was not reasonable to execute an intense sampling PK study in the pediatric population, therefore a limited sampling strategy was proposed and done. In each subject only two samples were collected—one at about 3 hours postdose and another 5.5 hours postdose. The approach was shown to be able to estimate PK parameters that had little bias (18). 

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

Podophyllotoxin (3) is a precursor to the three cUnically used anticancer drugs, etoposide (4), teniposide (5), and etoposide phosphate (6). Its mechanism of action involves inhibition of tubuUn polymerization and disruption of mitosis during metaphase of the cell cycle. Both etoposide and teniposide are modifications of podophyllotoxin specifically designed to increase the water solubility, reduce gastric toxicity in addition to inhibiting topoisomerase II, and disrupting the cell cycle. 

The RT consisted of 45 Gy in 3 wk using 1.5 Gy bid concurrent with either cisplatin/etoposide or carboplatin/vindesine after the same drugs had been given alone at higher dosage. Acute toxicity was acceptable and treatment-related deaths were 9% or... 

It is interesting to note that the results from our studies at Vanderbilt using lower doses of radiation have led to similar survival rates, local control, and less toxicity when compared to centers using higher doses of radiation. This dose of radiation was based on earlier studies that utilized two cycles of cisplatin, 5-FU, etoposide, and leucovorin with 3000 cGy of radiation followed by resection. The median survival of 24 mo and 2-yr survival of 51% was better than historical controls treated with surgery alone (63,64). 

Etoposide is eliminated mainly by urinary excretion with an elimination half-life of 6-12 hours. In contrast teniposide is for some 80% metabolized before excretion in the urine. Both drugs are highly protein bound and display increased toxicity in patients with low plasma albumin. 

The dose-limiting toxicity of etoposide is leukopenia. Alopecia is frequent. Secondary leukemia has been reported after combination regimens with etoposide. Myelosuppression, nausea, and vomiting are the primary toxic effects of teniposide. 

Etoposide is most useful against testicular and ovarian germ cell cancers, lymphomas, small cell lung cancers, and acute myelogenous and lymphoblastic leukemia. Toxicities include mild nausea, alopecia, allergic reaction, phlebitis at the injection site, and bone marrow toxicity. 

Extensive structure modulations were performed to obtain more potent and less toxic anti-cancer agents, such as etoposide used in the therapy of numerous cancers (Fig. 41) [113], In contrast to podophyllotoxin, etoposide derivatives act as DNA topoisomerase II inhibitors. Tafluposide (F 11782) is an etoposide where both hydroxyl functions of the glycoside moiety are acylated with the pen-tafluorophenoxyacetic acid (Fig. 41). It has been demonstrated that tafiuposide does not act as a pro-drug of etoposide, but through a specific mechanism of interaction with both topoisomerases I and lla [114]. 

With regard to long-term toxicity, some reports in the literature have suggested a relationship of secondary malignancies after treatment of childhood ALL with TPMT /TPMT and TPMTVTPMT phenotypes. In a study at St. Jude Children s Research Hospital, SJCRH Total XlllHR, patients with lower TPMT activity showed a trend towards a higher incidence of AML associated with application of the topoiso-merase II inhibitor etoposide (203). 

Williams, P.C., et al. 1995. Toxicity and efficacy of carboplatin and etoposide in conjunction with disruption of the blood-brain tumor barrier in the treatment of intracranial neoplasms. Neurosurgery 37 17. 

Moreover, Fiorillo et al. [393] studied the effect of a combination of liposomal daunorubicin, etoposide, and carboplatin administered to seven children with recurrent malignant supratentorial brain tumors as a second-line therapy. Chemotherapy consisted of infusion of liposomal daunorubicin on days 1 and 2 and infusion of etoposide and carboplatin on day 1 whereas courses were repeated every 3M weeks. After a total of eight courses, five of seven children evaluated were alive 12-64 months after diagnosis and 8-29 months from the start of the second-line chemotherapy. Of the seven children, three showed complete response, two partial responses, one stable disease, and one progressive disease. The time to the best response was 3-10 months, while the median time to progression was 23 months. The toxicity observed was minimum. 

CALCIUM CHANNEL BLOCKERS ETOPOSIDE T serum concentrations and risk of toxicity when verapamil is given to patients on etoposide Verapamil inhibits CYP3A4-mediated metabolism of etoposide Watch for symptoms/signs of toxicity (nausea, vomiting and bone marrow suppression) in patients taking calcium channel blockers... 

CARMUSTINE ANTICANCER AND IMMUNOMODULATING DRUGS-ETOPOSIDE (HIGH DOSE) t risk of liver toxicity, which usually occurs after 1 -2 months after initiating treatment without an improvement in tumour response Possible additive hepatotoxic effects Avoid co-administration... 

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