This case report has 2 new learning messages: we present a patient with an ESS with a remarkable response on pazopanib and we describe clinical management of pazopanib induced recurrent liver toxicity.
Liver function test abnormalities, mainly elevations in ASAT and ALAT, are a common side effect of pazopanib and more in general of TKIs [
14]. The exact pathophysiologic mechanism is unknown. A distinctive class effect seems to be unlikely, because pharmacologically different TKIs are known to be hepatotoxic and the substances are also very different chemical compounds. In a case series of two patients with liver toxicity of pazopanib liver histology showed mild active cholestatic hepatitis with inflammation that predominantly involved portal tracts [
15]. Recently, it was reported that treatment with pazopanib in combination with prednisolone in case of liver function abnormalities prevented recurrence of liver function abnormalities in two patients [
16]. UDP-glucuronosyltransferase isoform 1A1 has been related to bilirubin elevations during pazopanib treatment. These are probably patients with latent Gilbert syndrome becoming evident due to the inhibitory effect of pazopanib [
14]. More recently, an association between HLA-B*57:01 and pazopanib induced liver toxicity was found [
17]. Whether other germline genetic causes of pazopanib induced liver toxicity exist is unclear. The summary of product characteristics (SmPC) of pazopanib contains guidelines on handling liver toxicity [
6]. If the elevation of ASAT and ALAT between 3 and 8× ULN it is safe to continue pazopanib with strict control of ASAT and ALAT until grade 1 toxicity. If ASAT and/or ALAT is more than 8× ULN then pazopanib should be stopped until recovery till grade I or less and if reinitiated restart with pazopanib once daily 400 mg. It should be stopped permanently if ASAT and/or ALAT rise again to > 3× ULN. Pazopanib should also be stopped if ASAT and/or ALAT are elevated > 3× ULN concurrently with a bilirubin elevated > 2× ULN. In our case, despite these recommendations, pazopanib was reintroduced at further reduced dose and no progressive liver insufficiency developed. Ultimately this strategy seemed to be effective until a dose reduction to 200 mg once every second day. Another possible solution for toxicity management would be therapeutic drug monitoring, which is possible for pazopanib with a dried blood spot assay [
18]. However, because the intrapatient variability of pazopanib levels is high, a recent study could not show an effect of therapeutic drug monitoring on the interpatient variation [
19]. A SNP analysis of genes for enzymes known to be involved in the metabolism of pazopanib did not provide an explanation for elevated pazopanib levels or liver toxicity in our patient. In case of further dose reductions after reduction to once daily 400 mg, we suggest that patients should be monitored closely with once weekly liver function testing.
The second message of this case report regards the pazopanib response related to the tumour type. When feasible ESS is treated with radical surgery. Treatment of metastatic or locally progressive ESS consists of endocrine therapy as first line and when progressive on endocrine therapy chemotherapy. No specific data on the use of pazopanib in ESS is available, but this case report shows that pazopanib induced a partial response and prolonged PFS of 9 months which is more than the median PFS in the PALETTE study. Although in general ESS does not overexpress KIT, it was recently shown that ESS harbouring the YWHAE-FAM22 fusion gene frequently overexpress KIT (without a mutation in the KIT oncogene) in the high grade component of the tumour, as was the case in our patient [
11,
20]. This could explain the good response, in this rare histologic subtype, to pazopanib, which is an inhibitor of VEGFRs, PDGFRs and KIT. Based on these findings there may also be a potential role for imatinib, which was already reported in two cases [
21,
22]. Most probably the evidence for treatments in ESS will be not better than small case series due to the rarity of this disease.