부산대학교 도서관

2513 Background: For decades, the phase-2-recommended dose (P2RD) depends on toxicity (especially 'the maximal tolerated dose', MTD) experienced by patients enrolled in dose-escalating phase 1 trials. Recent studies suggest that this policy is not suitable for modern anti-cancer agents.Methods: We retrospectively studied288 recently (1997-2008) published phase-I-trials using the maximal tolerated dose (MTD) to define the P2RD. We analysed how the P2RD was actually defined and then identified the risk factors for failure to establish the P2RD.Results: Seventeen percent (37/288) of the trials failed to identify the P2RD: 13% of studies investigating cytotoxic agents, 23% of studies investigating molecular targeted therapies and 33% of studies investigating immunostimulant agents. The risk factors for this failure were: trials investigating immunostimulant agents (Relative risk (RR)=2.9 [1.1-8.0]) or molecular targeted therapy (RR=3.1 [1.6-6.0]), single-agent regimen (RR=2.5 [1.3-4.9]), dose increments using of Fibonacci-modified series (RR=3.0 [1.5-5.8]), other method of escalation than 'classical 3+3' (RR=4.9 [1.6-14.2]) and almost the absence of clear definition of the MTD (RR=10.7 [3.6-32.2]). Indeed, in 9% of these studies (26/288), the definition of the MTD was not clearly established. Moreover, in 17% of all studies (38/288), the authors had proposed alternative but not standardised definitions of the P2RD (13 different definitions). These alternative definitions of P2DR were used in 18% of studies investigating cytotoxic agents, in 19% of studies investigating immunostimulant agents and in 24% of studies investigating molecular targeted therapies.Conclusions: In studies investigating cytotoxic agents, the definition of the MTD needs to be clarified in its 3 dimensions: severity of toxicity, duration of toxicity and proportion of patients experiencing this toxicity. Nevertheless, this appears less relevant for studies investigating immunostimulant agents and molecular targeted therapies. We have to explore and standardise alternative definitions of the P2DR in the era of modern agents. [Table: see text].