Year: 2012
Type: letter
Abstract: in the ATTRACT-1 trial achieved near-maximal tumor vascular disruption, as measured by pharmacodynamic changes in plasma 5-hydroxyl-indole acetic acid and in tumor blood flow measured by dynamic-contrast enhanced magnetic resonance imaging, in the early clinical studies.[2][3][4] In ATTRACT-1 and other combination trials, [5][6][7] ASA404 at this dose significantly increased the incidence of grade 4 neutropenia and other toxicities when added to carboplatin and paclitaxel.In early preclinical studies, 8 the therapeutic synergy of ASA404 combined with carboplatin and paclitaxel occurred without any major dependence on sequencing or scheduling or significant changes in plasma or tumor-drug concentrations.In fact, optimal preclinical activity was achieved by administering chemotherapy at any time within a few hours either before or after the use of ASA404.8 Therefore, it is highly unlikely that the clear lack of efficacy of ASA404 in this large, well-conducted phase III study could have been attributed simply to a suboptimal dose, sequence, or schedule of drug delivery.Wang et al 1 also suggest that the optimal way of giving a vascular disrupting agent (VDA) is before chemotherapy rather than the other way around, as was done in the ATTRACT-1 trial.Their suggestion appears to be reasonable on theoretical grounds but, to our knowledge, is unsupported by any conclusive data that showed improved antitumor activity with this approach.For example, in early preclinical work on ASA404 combined with carboplatin and paclitaxel, 8 no advantage was apparent with the particular sequence suggested by Wang et al 1 over that used in the ATTRACT-1 trial.Our view is that the disappointing efficacy results of the ATTRACT-1 trial would not have been dramatically altered by subtle changes in the sequencing or scheduling of the study treatments.However, as we previously acknowledged in the Discussion of the ATTRACT-1 article, 5 the success of additional VDA drug development relies on a better understanding of the molecular determinants of tumor sensitivity to vascular disruption and the identification of a putative biomarker that will enrich the patient pool to those likely to benefit from VDA therapy.
Source: Journal of Clinical Oncology
Institution: Wayne State University
Language: French
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2125646555