Unresectable solid tumors

Sorafenib (l)11 is a multikinase inhibitor marketed by Bayer and Onyx. Sorafenib blocks tyrosine kinases as well as serine/threonine kinases. Its story began in 1994 when Bayer and Onyx entered a collaboration to discover novel Raf/MEK/ERK inhibitors. They first discovered a very mildly active compound 8 (/C50 17 pM) against Rafl kinase in 1995 from screening a collection of 200,000 compounds. The optimization of its potency and its ADMET profile using medicinal chemistry and combinatorial chemistry methods led to the identification of sorafenib (1) in 1999 as a preclinical development candidate. Multiple phase I studies started in 2000, when sorafenib tosylate (19) was evaluated in patents with advanced solid tumors of different types. In December 2005, Sorafenib tosylate (19) received U.S. FDA approval for the treatment of advanced renal cell carcinoma (RCC). Two years later, it was approved for the treatment of unresectable hepatocellular carcinoma (HCC). 

Unresectable and chemorefractory malignant tumors in the liver are a major cause of death in solid tumors. Potentially curative surgery is uncommon for these patients. A number of liver-directed therapies are now available and are making important contributions to quality of life, prolonged time to liver progression, and overall survival. Limited surgery involving laparoscopy and percutaneous access approaches enables local tumor resection, cryotherapy, laser-induced interstitial thermotherapy, and radiofrequency ablation. 

Highly targeted radiotherapy ( brachytherapy ) was the first clinical application of stain-etched silicon microparticles. We briefly review here the manufacture, testing, and clinical use of the P Si beta-emitting formulation for unresectable hepatocellular and pancreatic carcinoma. Clinical data Ifom a number of trials suggests that the technology offers patients with inoperable solid tumors an attractive alternative to external beam radiotherapy. 

Fig. 10.1. Axial, venous phase, gadolinium-enhanced MRI of a patient with unresectable HCC showing a peripherally enhanced lesion (arrows) in the medial segment of the left lobe. Solid, well demarcated lesions such as this one respond better to TACE than do diffuse or multifocal lesions. Additionally, hypervascular tumors appear to respond better to TACE showing a higher degree of necrosis on follow-up MRI...

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