Phase II and pharmacokinetic/pharmacodynamic trial of sequential topoisomerase I and II inhibition with topotecan and etoposide in advanced non-small-cell lung cancer

Purpose: In vitro and in vivo preclinical models have demonstrated synergis tic activity when topoisomerase I and II inhibitors are administered sequen tially. Topoisomerase I inhibitors increase topoisomerase II levels and inc rease cell kill induced by topoisomerase II poisons. We evaluated this hypo thesis in a cohort of patients with advanced non-small-cell lung cancer (NS CLC). Methods: A group of 19 patients with advanced NSCLC (70% adenocarcino ma) received topotecan at a dose of 0.85 mg/m(2) per day as a continuous 72 -h infusion from days 1 to 3. Etoposide was administered orally at a dose o f 100 mg twice daily for 3 days on days 7-9 (schedule and dose derived from prior phase I trials). Total and lactone topotecan concentrations were mea sured at the end of the 72-h infusion. Blood samples were obtained immediat ely after each 72-h topotecan infusion in order to measure the mutational f requency at the hypoxanthine phosphoribosyl transferase (HPRT) locus in per ipheral lymphocytes. Results: A total of 55 cycles were administered. Toxic ity was mainly hematologic with grade 4 neutropenia occurring in 7% of cour ses. Only one partial response and two stable diseases were observed. The 1 -year survival rate was 33%. There was a statistically Significant differen ce between steady-state lactone concentrations between cycle 1 and cycle 2 with decreasing concentrations with cycle 2 (P = 0.02). This was explained by a statistically significant increase in the clearance of topotecan lacto ne during cycle 2 (P = 0.03). Total but not lactone concentrations correlat ed with nadir WBC, ANC and platelet levels. Steady-state plasma lactone lev els correlated with the mutational frequency at the HPRT locus (P = 0.06). In the one patient with a partial response a sixfold increase in HPRT mutat ional frequency was observed, which was not seen in patients with progressi ve disease. Conclusion: The combination of topotecan and etoposide in this schedule of administration has minimal activity in adenocarcinoma of the lu ng. This lack of activity may be due to the delay in administration of etop oside after the topotecan as studies have shown that the compensatory incre ase in topoisomerase II levels after treatment with topoisomerase I inhibit ors is shortlived (<24 h). The HPRT mutational frequency results suggest th at the lack of clinical response may be associated with failure to achieve sufficient cytotoxic dose as indicated by a lack of increase in mutational frequency in those patients with progressive disease. HPRT mutational frequ ency may correlate with plasma steady-state topotecan lactone levels. Futur e studies should be directed toward earlier administration of topoisomerase II inhibitors after topoisomerase I inhibition.