Lookup NU author(s): Professor Ruth Plummer
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Introduction: Because a dose-response relationship is characteristic of conventional chemotherapy, this concept is widely used for the development of novel cytotoxic (CTX) drugs. However, the need to reach the MTD to obtain optimal benefit with molecularly targeted agents (MTA) is controversial. In this study, we evaluated the relationship between dose and efficacy in a large cohort of phase I patients with solid tumors.Experimental Design: We collected data on 1,182 consecutive patients treated in phase I trials in 14 European institutions in 2005-2007. Inclusion criteria were: (i) patients treated within completed single-agent studies in which a maximum-administered dose was defined and (ii) RECIST/survival data available.Results: Seventy-two percent of patients were included in trials with MTA (N = 854) and 28% in trials with CTX (N = 328). The objective response (OR) rate was 3% and disease control at 6 months was 11%. OR for CTX was associated with higher doses (median 92% of MTD); this was not the case for MTA, where patients achieving OR received a median of 50% of MTD. For trials with MTA, patients treated at intermediate doses (40%-80%) had better survival compared with those receiving low or high doses (P = 0.038). On the contrary, there was a direct association between higher dose and better OS for CTX agents (P = 0.003).Conclusion: Although these results support the development of novel CTX based on MTD, we found no direct relationship between higher doses and response with MTA in unselected patients. However, the longest OS was seen in patients treated with MTA at intermediate doses (40%-80% of MTD). (C) 2014 AACR.
Author(s): Garcia VM, Olmos D, Gomez-Roca C, Cassier PA, Morales-Barrera R, Del Conte G, Gallerani E, Brunetto AT, Schoffski P, Marsoni S, Schellens JHM, Penel N, Voest E, Evans J, Plummer R, Wilson RH, Soria JC, Tabernero J, Verweij J, Kaye SB
Publication type: Article
Publication status: Published
Journal: Clinical Cancer Research
Print publication date: 15/11/2014
Online publication date: 24/09/2014
ISSN (print): 1078-0432
ISSN (electronic): 1557-3265
Publisher: American Association for Cancer Research
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