Topotecan Sample Clauses

Topotecan. Topo’s mechanism of action is different from that of Pac, as it does not directly block cell division, but instead induces irreversible DNA damage. Topo inhibits topoisomerase 1, leading to both single and double stranded DNA breaks that eventually promote apoptosis. Topo (administered QD the first 5 days of 21-day cycles) was approved for treatment of EOC after failure of initial or subsequent chemotherapy. This approval was based on a Phase 3 trial that showed it to be at least as effective as Pac, with XXX of 21% vs. 13%, and median PFS of 23 weeks vs. 14 weeks, respectively (ten Xxxxxx Xxxxxxx 1997). Unfortunately, Topo treatment led to severe bone marrow suppression with 80% Grade 4 neutropenia, 25% Grade 4 thrombocytopenia, and 41% Grade 3 or 4 anemia (ten Xxxxxx Xxxxxxx 1997). As such toxicities are often dose limiting, multiple clinical trials have studied alternative dosing schedules to improve the tolerability of Topo treatment (Xxxxxxxxx 2019, Xxxxxxxxx 2004, Xxxxxxx 1998, Xxxxxxx 2000). For example, one Phase 2 trial tested the effect of the “standard” dosing of Topo (1.5 mg/m2, daily the first 5 days of 21-day cycles) compared with an alternative dosing regimen (1.75 mg/m2, QW for 4 weeks, repeated every six weeks) in patients with recurrent EOC. The alternative dosing regimen led to a lower XXX (9.6% compared with 22.6% in the standard dosing arm), but also decreased myelotoxicity (52% of patients had Grade 3 or 4 granulocytopenia in comparison with 94% in the standard dosing arm) (Xxxxxxx 1998). A subsequent Phase 2 trial tested the effect of yet another dosing schedule (1.5 mg/m2, daily the first three days of 21-day cycles) (Xxxxxxx 2000). Compared to historical controls, this alternative dosing regimen seemed to decrease the toxicity of Xxxx (Xxxxxxxxx 2004). In a meta- analysis of various clinical trials, it was concluded that modification of the Topo dose, and potentially the dosing schedule, can indeed reduce hematologic toxicity without decreasing the efficacy of the drug (Xxxxxxxxx 2019). The approved Topo dosing for relapsed EOC is 1.5 mg/ m2/d, administered on days 1 to 5 of a 3- week schedule. However, reduced doses (ie, 1.25 mg/m2/d) are associated with decreased toxicity and similar outcome, thereby being widely used in routine clinical practice (Sehouli 2009). Results from several studies suggest that women with relapsed EOC may benefit from similar effectiveness but significantly lower hematologic toxicity if Topo is administe...
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