title: A systematic review on topoisomerase 1 inhibition in the treatment of metastatic breast cancer.
abstract: Following treatment with anthracyclines and taxanes, few established options exist for the treatment of metastatic breast cancer (MBC). Although the topoisomerase 1 inhibitors irinotecan, etirinotecan, and topotecan have been used in clinical trials on MBC, the drugs have never been introduced as standard treatment for the disease. We performed a systematic review on topoisomerase 1 inhibitors in MBC and found 22 prospective trials and three retrospective ones. No phase III trials were identified. Only one study was randomized, and generally studies were small. Response rates (RR) for irinotecan monotherapy varied from 5 to 23 %, whereas RRs for etirinotecan were 26-32 %. Only four trials on topotecan monotherapy were reported with RRs of 6-31 %. Combination therapy with irinotecan and various chemotherapeutics resulted in RRs ranging from 14 to 64 %, whereas irinotecan combined with biologic agents showed very limited effect. Topotecan was studied in combination with either another chemotherapeutic or a biologic agent in two trials, both studies failing to show any effect of topotecan. The most common grade 3 and 4 adverse events (AE) for irinotecan were neutropenia, diarrhea, and nausea/vomiting. The dosing schedule appears to affect the toxicity profile of the drug. Hematologic AEs are most frequently reported for topotecan. Conclusively, topotecan does not seem to be efficient in the treatment of MBC. Irinotecan seem to be effective in some patients previously treated with anthracyclines and taxanes. RRs of 23 % for irinotecan and 32 % for etirinotecan are comparable to some of the more commonly used treatments for MBC. However, a large proportion of patients do not respond, thus emphasizing the need for a biomarker predictive of response to irinotecan in order to introduce this drug as the standard treatment for MBC.
authors.affiliation: Department of Oncology, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, 2730, Herlev, Denmark. iben.kumler@regionh.dk
authors.forename: Iben
authors.initials: I
authors.lastname: Kümler
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Jan
authors.initials: J
authors.lastname: Stenvang
authors.forename: Eva
authors.initials: E
authors.lastname: Balslev
authors.forename: Dorte L
authors.initials: DL
authors.lastname: Nielsen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002986:Clinical Trials as Topic; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D009362:Neoplasm Metastasis; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D059004:Topoisomerase I Inhibitors; D000077146:Irinotecan; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human; D002166:Camptothecin