Therapeutic monitoring of continuous infusion etoposide in small-cell lung cancer.
OBJECTIVE
To investigate the feasibility of therapeutic monitoring of etoposide at different plasma concentrations of the drug, and the resulting pharmacodynamic effects of such an approach.


METHODS
Forty-nine previously untreated small-cell lung cancer (SCLC) patients received single-agent etoposide every 3 weeks by continuous infusion over 5 days. Plasma etoposide concentrations were monitored 18 and 66 hours into the infusion to permit dose modification. The first cohort of 15 patients began treatment with etoposide 2 micrograms/mL, with dose escalation to 3 micrograms/mL for cycles 3 and 4 and 4 micrograms/mL for cycles 5 and 6, toxicity permitting. The second cohort of 34 patients commenced at 3 micrograms/mL, with dose escalation to 4 and 5 micrograms/mL on cycles 3 and 5, respectively.


RESULTS
Mean plasma etoposide concentration during the first treatment cycle was 93.4% +/- 26.6% of the target level at 18 hours (57% of patients within +/- 20% of the target) and 98.9% +/- 14.5% of the target level at 66 hours (82% of patients within +/- 20%). Hematologic toxicity was more pronounced in those treated with 3 micrograms/mL versus 2 micrograms/mL (median nadir neutrophil count, 1.3 v 2.6 x 10(9)/L, P = .032). Tumor responses, typically documented by the third cycle, were similar in each cohort (71% in patients commenced at 2 micrograms/mL and 70% at 3 micrograms/mL). Treatment cohort was not independently predictive of survival.


CONCLUSIONS
Therapeutic monitoring of infusional etoposide is feasible and dramatically reduces interpatient pharmacokinetic variability. Although this was a small nonrandomized trial, the observation of different hematologic toxicity at the two starting concentrations but similar antitumor activity further suggests that these effects may be associated with different plasma etoposide concentrations.
Joel
S P
SP
Department of Medical Oncology, St Bartholomew's Hospital, West Smithfield, London. joel@icrf.icnet.uk
Ellis
P
P
O'Byrne
K
K
Papamichael
D
D
Hall
M
M
Penson
R
R
Nicholls
S
S
O'Donnell
C
C
Constantinou
A
A
Woodhull
J
J
Nicholson
M
M
Smith
I
I
Talbot
D
D
Slevin
M
M
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D018288:Carcinoma, Small Cell / Q000097:blood / Q000188:drug therapy*; D016903:Drug Monitoring; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy*; D008297:Male; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide