Pazopanib induced liver toxicity: incidence, pathogenesis and value of liver enzymes increase as a predictor of outcome in metastatic soft tissues sarcoma patients. A retrospective multi-centric study

Pazopanib induced liver toxicity: incidence, pathogenesis and value of liver enzymes increase as a predictor of outcome in metastatic soft tissues sarcoma patients. A retrospective multi-centric study

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Pazopanib is a type of orally available drug called multi-tyrosine kinase inhibitor (TKI) acting by blocking (inhibiting) signals within the cancer cells that make them grow and divide. Pazopanib also stop the cancer cells from developing new blood vessels. Pazopanib has been recently licensed to treat people with certain types of soft tissue sarcoma (STS), a rare disease accounting for less than 1% of all cancer diagnoses in adults. A large study (PALETTE study) was designed to compare the outcome of STS patients who had previously received chemotherapy, treated with either pazopanib (800 mg/day) or with a substance containing no medication (placebo). The PALETTE study, including 369 STS patients, proved how pazopanib increased the length of time during which the disease being treated does not getting worse (4.6 compared with 1.6 months for placebo) as also the length of life-time (12.5 compared to 10.7 months with placebo). The most common side effects recorded were tiredness, feeling or being sick and high blood pressure. Pazopanib may also cause changes in the way the liver works (liver toxicity), leading to an increase in the liver protein (enzymes) commonly dosed in the peripheral blood: glutamyl transpeptidase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALKP) and total bilirubin level (TBL). An increase in liver enzymes occurs in 23-40% of all patients treated with TKIs, usually manageable and rarely (5%) severe. In the PALETTE study, 13% of the patients receiving pazopanib developed an increase in GGT, 10% in ALT, 8% in AST and 2% in TBL. Changes in liver function were also the main reason for dose reduction. To address these outstanding question, we will retrospectively review data of all patients treated within the PALETTE study will be performed with the aim of:

Defining how many STS patients treated with pazopanib develop changes in liver function (incidence of liver toxicity);

Understanding the mechanism through which liver toxicity occurs by using the R-value (R). R is the ratio of ALT to ALKP, both expresses as multiples of the upper limit of normal. An R>5 is used to define hepatocellular injury (i.e. liver injury characterised by cell damage and inflammation), R<2 cholestatic injury (i.e. liver injury characterised by interference with bile flow) ad R between 2.0 and 5.0 a mixed hepatocellular.cholestatic injury.

Enquiring if STS patients developing an increase in liver enzymes on pazopanib do better than those who do not.

The results of our study will help in clarifying the mechanism through which this common side effect occurs and better identifying those patients who are benefitting from pazopanib the most. The findings of the present retrospective analysis will be communicated to public through a publication in a peer reviewed, european, scientific journal (Annals of Oncology, European Journal of Cancer, British Medical Journal)

[{ "PostingID": 90, "Title": "GSK-VEG110727", "Description": "Medicine: pazopanib, Condition: Sarcoma, Soft tissue, Phase: 3, GSK Clinical Study ID: VEG110727, Sponsor: GSK." }]

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