title: Phase II study of sequential topotecan and etoposide in patients with intermediate grade non-Hodgkin's lymphoma: a National Cancer Institute of Canada Clinical Trials Group study.
abstract: Preliminary results indicate that inhibitors of the nuclear enzyme topoisomerase (topo) I, such as topotecan, may be active in non-Hodgkin's lymphoma (NHL). Pre-clinical studies have shown sequential administration of a topo I and II inhibitor has supra-additive anti-tumor effects in some model systems, and that greater cytotoxicity occurs if the topo I inhibitor is given first. We enrolled, 22 eligible patients with relapsed or refractory intermediate grade NHL in a phase II study ofsequential administration of topotecan 1.25 mg/m2 days 1-5 and etoposide 50 mg po b.i.d. days 6-12, every 28 days without G-CSF. Most patients had diffuse large B-cell lymphoma and all had received only one prior regimen (CHOP, 20 patients, or equivalent, 2 patients). Patients with stable or responding disease were allowed to proceed to high-dose therapy and autologous stem-cell transplant after 2 cycles of therapy. The 22 patients received a total of 62 cycles of topotecan + etoposide (median 2, range 1-6), and 4/22 completed all six planned cycles. Hematologic toxicity was significant and resulted in incomplete etoposide dosing in half of all cycles in 16/22 patients. Nineteen of twenty-two patients had grade 3/4 neutropenia, 12 had grade 3/4 thrombocytopenia, and 6 grade 3/4 anemia. Eleven patients had at least one episode of febrile neutropenia or had documented infection. Non-hematologic toxicity was mild. Four patients had a partial response (PR) (18.2%), nine had stable disease and seven progressed; three patients with stable disease went on to ABMT. The combination of topotecan and etoposide as given in this study has modest activity in relapsed/refractory aggressive histology NHL, and produces marked myelosuppression. Other doses and schedules combining topo I and II inhibitors, or topo I inhibitors with alkylating agents, should be explored with the addition of hematopoietic growth factors in this patient population.
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, Canada. michael.crump@uhn.on.ca
authors.forename: Michael
authors.initials: M
authors.lastname: Crump
authors.forename: Stephen
authors.initials: S
authors.lastname: Couban
authors.forename: Ralph
authors.initials: R
authors.lastname: Meyer
authors.forename: Leona
authors.initials: L
authors.lastname: Rudinskas
authors.forename: Brent
authors.initials: B
authors.lastname: Zanke
authors.forename: Stefan
authors.initials: S
authors.lastname: Gluck
authors.forename: Andrew
authors.initials: A
authors.lastname: Maksymiuk
authors.forename: Paul
authors.initials: P
authors.lastname: Hoskins
authors.forename: Sarah
authors.initials: S
authors.lastname: Matthews
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Eisenhauer
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D005047:Etoposide; D019772:Topotecan