Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Abou‐Alfa, Ghassan K.; Schwartz, Lawrence H.; Ricci, Sergio; Amadori, Dino; Santoro, Armando; Figer, Arié; Grève, Jacques De; Douillard, Jean Yves; Lathia, Chetan; Schwartz, Brian; Taylor, Ian; Moscovici, M.; Saltz, Leonard B.

doi:10.1200/jco.2005.01.3441

Cited by 1,089 publications

(882 citation statements)

References 21 publications

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“…Especially in HCC patients an impaired liver function is common, but only very limited data on pharmacokinetics for Child-Pugh A or B patients exist from a phase I trial in 14 Japanese patients and 22 patients in a phase II trial [20,21], but none for Child-Pugh C and effect on liver function including cytochrome p450 activity can be extremely heterogeneous in patients with the same stage of liver cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

High-performance liquid chromatographic method for the determination of sorafenib in human serum and peritoneal fluid

Heinz

Kahle

Helle-Beyersdorf

et al. 2010

Cancer Chemother Pharmacol

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In clinical trials adverse events improve after dose reduction suggesting a dose-dependent toxicity. Given dose has a direct impact on the drug serum concentration, but the latter also can be influenced by multiple factors including interaction and metabolization. To enable the investigation of concentration related effects, an easy and sensitive assay for sorafenib drug monitoring is essential. Methods:A high performance liquid chromatography (HPLC) analysis involving an extraction with diethyl ether followed by separation on a Pinnacle™ DB C18 column and quantitation by UV absorbance at 260 nm was established. Sorafenib concentrations in samples of serum and peritoneal fluid have been determined. Results:The assay was validated for serum samples and is linear over the concentration range of 100 to 5000 ng/mL with a determination coefficient of >0.999. The limit of detection is 0.25 ng/mL. The intra-and inter-day coefficients of variation were below 3.03%. Sorafenib recovery in spiked probes of peritoneal fluid was above 85 %. Sorafenib concentrations in 44 serum samples and 14 probes of peritoneal fluid have been determined with a mean of 3328 and 1380 ng/mL respectively (standard deviation 2267 and 659 ng/ml). Conclusions:A sensitive and selective HPLC method for the determination of sorafenib in human serum was developed and also verified for peritoneal fluid. This method provides a useful tool for pharmacokinetic investigations as well as for therapeutic drug monitoring of sorafenib.

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Section: Discussionmentioning

confidence: 99%

High-performance liquid chromatographic method for the determination of sorafenib in human serum and peritoneal fluid

Heinz

Kahle

Helle-Beyersdorf

et al. 2010

Cancer Chemother Pharmacol

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“…In computed tomography this is seen as a reduced tumor density that is indirectly related to perfusion and cell density (measured in Hounsfield units). This can be accompanied by swelling of the cells and thus by a radiological increase in size [10]. Different forms of tumor cell death occur in the case of direct and indirect cell damage: In necrosis the cells swell due to an inflow of water.…”

Section: Key Pointsmentioning

confidence: 99%

“…There is no pronounced inflammatory reaction as in necrosis. However, solid malignant tumors have often lost the ability to undergo apoptosis so that many triggers of programmed cell death are ineffective [10]. Chemotherapy or radiation therapy based on such apoptosis triggers is not successful -a possible reason why a reduction in size as a result of treatment doesn't occur until a relatively late stage [10 -12].…”

Section: Key Pointsmentioning

confidence: 99%

Radiological Monitoring of the Treatment of Solid Tumors in Practice

Ganten

2014

Fortschr Röntgenstr

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!Purpose: Thanks to advances in cancer therapy, the diagnosis of "incurable cancer" is increasingly able to be changed to a chronic disease that is manageable over long periods, resulting in a change in the clinical management of cancer patients with solid tumors. New parameters are needed to measure the success of targeted therapy in clinical trials. Materials and Methods: Review article on the basis of selective literature research. Results: In order to assess how well solid tumors respond to treatment, size-based criteria called RECIST (Response Evaluation Criteria in Solid tumors) have been defined. These criteria have been validated in large oncology trials and are currently used most frequently. New molecular therapies often do not -or at least do not immediately -reduce the size of a tumor. Therefore, RECIST evaluation should be critically assessed especially in the case of modern therapies. Any additional available tumor biology information should be considered. In radiology new methods and developments of RECIST have been introduced to better assess the success of targeted therapy. Conclusion: Assessment according to RECIST has been proven for the follow-up of classic tumor therapy. For the monitoring of targeted therapies, new parameters are often required. Therefore, some specific tumor-and therapy-adapted criteria have already been defined to better evaluate treatment success in clinical trials. Key points:▶ Follow-up evaluation of treatment is becoming increasingly important in modern oncology.▶ Conventional cytostatic/cytotoxic treatments can be evaluated on the basis of size according to RECIST. ▶ However, approx. 80 % of newly approved oncological agents are based on molecular mechanisms of action.

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“…In addition, vascular changes have been described with sorafenib which also are evidence of treatment effect. 29 More recently, changes in enhancement have been incorporated into assessing response to molecular therapeutics in the management of HCC. 7 If sorafenib does not cause tumor shrinkage, outside of unmanageable toxicity, the question of when to stop the drug becomes important.…”

Section: Monitoring Of Therapymentioning

confidence: 99%

“…Efficacy is hard to assess as these are single-arm studies without a control arm. 29,30 One could rationalize that because sorafenib has proven anticancer activity in Child-Pugh A patients it would have the same activity in patients with less compensated liver disease so in the absence of a clinical trial, patients in stable condition and adequate performance status could be offered treatment with close monitoring. The unknown variable being, that even if their cancer was controlled with sorafenib, will it impact their overall survival given the extent of liver dysfunction.…”

Section: Areas Of Uncertaintymentioning

confidence: 99%

Drug Therapy: Sorafenib

Finn

2010

Hepatology

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A 72-year-old active male patient with cirrhosis secondary to nonalcoholic steatohepatitis is evaluated for liver masses. He has no stigmata of end-stage liver disease such as ascites, icterus, or hepatic encephalopathy on physical examination. Laboratory values include a hemoglobin of 12 g/dL with a mean corpuscular volume of 98, white cell count of 3.9 thousand, platelet count of 76,000, total bilirubin of 1.2 mg/dL, albumin of 3.5 g/dL, international normalized ratio of 1.2, and serum creatinine of 1.3 mg/dL. The alpha-fetoprotein is 620 ng/mL. The computed tomographic scan of the abdomen shows two masses in the right lobe of the liver and three in the left lobe, all with arterial enhancement. The largest mass is 4 cm in diameter and appears to invade the portal vein; the liver appears cirrhotic but there is no ascites.

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Phase II Study of Sorafenib in Patients With Advanced Hepatocellular Carcinoma

Abstract: Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.

Cited by 1,089 publications

References 21 publications

High-performance liquid chromatographic method for the determination of sorafenib in human serum and peritoneal fluid

High-performance liquid chromatographic method for the determination of sorafenib in human serum and peritoneal fluid

Radiological Monitoring of the Treatment of Solid Tumors in Practice

Drug Therapy: Sorafenib

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