Adverse effects in the treatment of renal cell carcinoma with pazopanib

In the process of the treatment of renal cell carcinoma, adverse effects of pazopanib appear and are similar to other antiangiogenic compounds. Similar adverse effects among sunitinib, sorafenib and pazopanib contain diarhoea, rash, and hand-foot syndrome, as well as fatigue and elevation of liver enzymes. As with other targeted angiogenic inhibitors, pazopanib has been related with hypertension, hypothyroidism, arerial thrombosis, haemorrhage and proteinuria as well as gastrointestinal perforation or fistula. Due to the antiangiogenic properties of pazopanib, it may adversely affect wound healing. In addition, Pazopanib and sunitinib may trigger hair and skin depigmentation which is less well reported with sorafenib. In some severe cases, pazopanib may lead to pigmentation alteration that simulate albinism. Pazopanib-caused skin hypopigmentation develops after 1-2 cycles of pazopanib and reduces with dose reduction or discontinuation of pazopanib. It is shown that hypopigmentation of hair and skin may occur as a result of prevention of the activities of c-kit and platelet-derived growth factor (PDGF). Besides, pazopanib and sunitinib may also give rise to QT prolongation, which is not reported with sorafenib. A toxicity unique to pazopanib is its rare properties to trigger severe and fatal hepatotoxicity. Pazopanib-caused hepatotoxicity is related with increase in transaminases and total bilirubin. The increase in ALT typically occur within the first eighteen weeks of treatment. Elevations of ALT higher than three and eight times the upper limits of normal happens in fourteen and four percent of all patients treated with pazopanib, respectively. In spite of pazopanib-caused increases in hepatic function assays may be a marker of hepatotoxicity, mild elevatios in total bilirubin may be related with Gilbert’s syndrome. Otherwise, pazopanib represss the enzyme UGT1A1 which was involved in the metabolism of bilirubin. Pazopanib-induced hyperbilirubinaemia has been related with a polymorphism of the gene which expressed UGT1A1 and was discovered in patients with Gilbert’s syndrome. Accordingly, in a patient with mild elevation of indirect bilirubin without other potential causes, it has been shown that this laboratory abnormality may be a benign exhibition of Gilbert’s syndrome. So the therapy may not need interruption.[1]

The drugs which are benefit to the first-line setting include pazopanib, sunitinib and bevacizumabplus IFN-alpha, as well as Tyrosine Kinase Inhibitors. The only compound to induce durable complete responses in this group is high-dose interleukin-2. On the other hand, due to prominent toxicity, IL-2 was constricted in a very select group of patients. And few patients receive full benefit. Compared with placebo in patients that have failed cytokine treatment, tree anti-angiogenic agents including sorafenib and pazopanibm, as well as bevacizumab monotherapy have superior progression-free survival (PFS). In addition, phase II clinical studies have exhibited temsirolimus and sunitinib to have benefit in cytokine-pretreated patients. Everoliumus is the only compound which has been assessed in a randomized study in patients who have failed therapy with tyrosine kinase inhibitors. However, Everoliums showed superior progression-free survival (PFS) in contrast with placebo in patients which had failed snitinib and sorafenib or both. The majority of patients in the treatment setting had also been treated by prior cytokine.

References:
[1] Int J Cardiol. 2009 Jan 24;131(3):e92-4.

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