Evaluation of topotecan and etoposide for non-Hodgkin lymphoma - Correlation of topoisomerase-DNA complex formation with clinical response

BACKGROUND. Topotecan, a topoisomerase I inhibitor, acts by stabilizing the topoisomerase DNA cleavage complex. Etoposide, a topoisomerase II inhibito r, mediates antitumor activity by stabilizing cleavage complex formed betwe en topoisomerase II and DNA. These two agents have therapeutic activity in non-Hodgkin lymphoma. The authors report Phase I data of topotecan and etop oside combination for patients with recurrent or refractory non-Hodgkin lym phoma and correlation of topoisomerase-DNA complex formation to clinical re sponse. METHODS. Twenty-two patients with recurrent or refractory aggressive non-Ho dgkin lymphoma were treated at four dose levels of topotecan (1 mg/m(2)/day to 2.5 mg/m(2)/day). Topotecan was given at a 30-minute infusion daily wit h etoposide 150 mg/m(2)/day, both for 5 days. Topoisomerase-DNA covalent co mplex formation was measured using in vivo link assay, whereas topoisomeras e I, II alpha, and II beta in RNA expression levels were determined by reve rse transcription-polymerase chain reaction in blood samples. The relation of these levels to clinical response was studied. RESULTS. The maximum tolerated dose of topotecan was 2.0 mg/m(2)/day for 5 days. Oropharyngeal mucositis was dose-limiting. Of 21 examinable patients, 3 patients achieved complete remission, and 5 patients achieved partial re mission. Of six untreated patients who experienced a recurrence, three had complete remission, and the other three had partial remission. Drug-induced topoisomerase-DNA complex formation was observed throughout the treatment in blood samples of all the patients who responded. However, only 4 of 13 p atients, who did not respond, formed covalent complex at all time points. T his was statistically significant (P = 0.024). In all patients, expression levels of topoisomerase I and II beta mRNA remained similar to pretreatment levels, whereas topoisomerase II alpha mRNA levels decreased dramatically by the third day. CONCLUSION. The recommended Phase II dose of topotecan with etoposide of 15 0 mg/m(2)/day for 5 days was 2.0 mg/m(2)/day for 5 days. Topoisomerase-DNA complex formation correlated with response to treatment. (C) 2001 American Cancer Society.