Survival and Cost-Effectiveness of Trabectedin Compared to Ifosfamide Monotherapy in Advanced Soft Tissue Sarcoma Patients

Contains fulltext : 208922.pdf (publisher's version ) (Open Access)Trabectedin and ifosfamide are among the few cytostatic agents active in advanced soft tissue sarcomas (STSs). Trabectedin is most potent against so-called L-sarcomas (leiomyosarcoma and liposarcoma). The survival gain and cost-effectiveness of these agents in a second-line setting were analysed in the setting of advanced STS after failure of anthracyclines. A prospective observational trial had previously been performed to assess the use of trabectedin in a Dutch real-world setting. Data on ifosfamide monotherapy were acquired from previous studies, and an indirect comparison of survival was made. A state-transition economic model was constructed, in which patients could be in mutually exclusive states of being preprogression, postprogression, or deceased. The costs and quality-adjusted life years (QALYs) for both treatments were assessed from a Dutch health-care perspective. Separate analyses for the group of L-sarcomas and non-L-sarcomas were performed. Trabectedin treatment resulted in a median progression-free survival of 5.2 months for L-sarcoma patients, 2.0 months for non-L-sarcoma patients, and a median overall survival of 11.8 and 6.0 months, respectively. For L-sarcoma patients, trabectedin offered an increase of 0.368 life years and 0.251 QALYs compared to ifosfamide and euro20,082 in additional costs, for an incremental cost-effectiveness ratio (ICER) of euro80,000 per QALY gained. In the non-L-sarcoma patients, trabectedin resulted in 0.413 less life years and 0.266 less QALYs, at the increased cost of euro4,698. The difference in survival between drugs and the acquisition costs of trabectedin were the main influences in these models. Trabectedin was shown to have antitumour efficacy in advanced L-sarcoma. From a health economics perspective, the costs per QALY gained compared to ifosfamide monotherapy that may be acceptable, considering what is currently regarded as acceptable in the Netherlands

In the Pursuit for Better Actinide Ligands: An Efficient Strategy for their Discovery\ud

A novel method for the efficient discovery of new types of minor actinide (MA) ligands is based on the unique combination of “tea bag” split pool combinatorial chemistry and screening based on the inherent radioactivity of the complexed cations. Four multicoordinating Am3+ chelating groups, such as CMPO (diphenylcarbamoylmethyl)phosphine oxide), PICO (picolinamide), DGA (N,N′-dimethyldiglycoldiamide), and MPMA (N-methyl-N-phenylmalonamide), on a trityl platform immobilized on TentaGelS served as a model library for the development of the screening method. This model library was screened under various conditions (i.e., 0.001 M ≤ [HNO3] ≤ 3 M, NaNO3 ≤ 4 M, and [Eu] ≤ 10 × [ligand]) showing competitive extraction of the four ligands. Other libraries of 9 and 72 members were synthesized by functionalization of the trityl platform with ligating groups that are composed of four building blocks (including at least one amide and one (phosphoric) hydrazone moiety). The screening of these two libraries resulted in the discovery of two multicoordinate ligands that contain ligating groups previously not known to complex Am3+. Both are N-isopropyl amides terminated with a p-methoxyphenyl hydrazide (A2B1C1D10 KD(Am) = 2197) or a p-nitrophenyl hydrazide (A2B1C1D11 KD(Am) =1989) moiety, respectively. They are more efficient than the immobilized tritylCMPO ligand (KD(Am) = 1280) at 3 M HNO3. This method has the advantages of a high analytical sensitivity and the direct comparison of the extraction results. The method also allows the competitive screening of multiple nuclides which can be quantified by their radioactive emission spectru

The effect of crown ethers on enzyme-catalysed reactions in organic solvents

Crown ethers considerably enhance the rate of the α-chymotrypsin- catalysed transesterification of N-acetyl-L-phenylalanine ethyl ester (N-Ac-L-Phe-OEt) with propan-1-ol in n-octane; with subtilisin the effect is somewhat less pronounced

Thiacalix(4)arene derivatives as radium ionophores: a study on the requirements for Ra2+ extraction

The synthesis and NOE-based structural characterization is described of thiacalix[4]arene tricarboxylic acid ( 7), thiacalix[4]crown-5 and -6 monocarboxylic acids ( 2 and 5), and the bis(N-methylsulfonyl)thiacalix[4]crowns-5 and -6 ( 4a,b). The 226Ra2+ selectivity coefficients, log(KRaex/KMex), of the new thiacalix[4]arene derivatives are compared directly with those of thiacalix[4]crown-5 and -6 ( 1a,b), thiacalix[4]crown-5 and -6 dicarboxylic acids ( 3a,b), and thiacalix[4]arene di- and tetracarboxylic acids ( 6 and 8). Thiacalix[4]arene dicarboxylic acid ( 6) already exhibits a high 226Ra2+ selectivity, but this is significantly improved in the case of 3b, having an additional crown-(6-)ether bridge. The covalent combination of a crown ether and carboxylic acid substituents as in the thiacalix[4]arenes 2, 3a,b, 4a,b, and 5 gives a better 226Ra2+ selectivity in the presence of Sr2+ or Ba2+ than mixtures of dibenzo-21-crown-7 and thiacalix[4]arene dicarboxylic acid ( 6) or of pentadecanoic acid and thiacalix[4]crown-6 ( 1b)

Cation control on the synthesis of p-t-butylthiacalix[4]-(bis)crown ethers

Bridging of p-t-butylthiacalix[4]arene with ethylene glycol ditosylates gave diametrically bridged thiacalix[4]monocrowns-4 and -5, 1,2-alternate thiacalix[4]biscrowns-4 and -5 and 1,3-alternate thiacalix[4]biscrown-5, dependent on the metal carbonate used. They show excellent extraction ability towards Ag+ cations.\ud The synthesis of novel diametrically and proximally substituted p-t-butylthiacalix[4](bis)crown ethers and their extraction behavior towards monovalent metal ions are presented

Synthesis and Conformational Evaluation of p-tert-Butylthiacalix[4]arene-crowns

Bridging of p-tert-butylthiacalix[4]arene afforded 1,3-dihydroxythiacalix[4]arene-monocrown-5 (3b), 1,2-alternate thiacalix[4]arene-biscrown-4 and -5 (4a,b), and 1,3-alternate thiacalix[4]arene-biscrown-5 and -6 (5a,b), depending on the metal carbonates and oligoethylene glycol ditosylates used. Starting from 1,3-dialkylated thiacalix[4]arenes, the corresponding bridging reaction gave 1,3-alternate, partial-cone, and cone conformers 10-19, depending on the substituents present. Temperature-dependent studies revealed that the conformationally flexible 1,3-dimethoxythiacalix[4]arene-crowns 10a-c exclusively occupy the 1,3-alternate conformation. Demethylation exclusively gave the cone 1,3-dihydroxythiacalix[4]arene-crowns (3a,c), which could not be obtained by direct bridging of thiacalix[4]arene. The different structures were assigned on the basis of several X-ray crystal structures and extensive 2-D 1H NMR studies

Water-soluble neutral calix[4]arene-lanthanide complexes: synthesis and luminescence properties

Water-soluble calix[4]arenes 10a,b with chromophores ("antenna") attached to the lower rim via a short spacer are described. In the neutral lanthanide complexes of 10a,b photoexcitation of the antenna induces lanthanide emission via intramolecular energy transfer. Calix[4]arene 10b with a chrysene moiety as sensitizer shows strong lanthanide emission for Eu3+ with an excitation maximum at ^ = 363 nm