The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study

Abstract

Background Gastrointestinal stromal tumors (GIST) mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM) or sunitinib (SU). Arterial hypertension (AH) is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+) GIST patients after IM failure. Methods We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2 nd line treatment). Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs) of VEGFA and VEGFR2 genes. Results One year progression-free survival (PFS; calculated from the start of SU) rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM) was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks) in 55 patients with AH vs . 22% (median 17 weeks) in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively) than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively). We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism (OR: 10.0 p = 0.041 and OR: 10.5; p = 0.015, respectively). Conclusions We confirmed that many advanced GIST patients benefit from SU therapy with OS > 1.5 year. Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS. Note The preliminary data of this study were presented during Annual Meeting of American Society of Clinical Oncology, 4-8 June 2011 and Connective Tissue Oncology Society Meeting, 26-28 October 2011 in Chicago, IL.

Thyroid Dysfunction as an Unintended Side Effect of Anticancer Drugs

“…Whether prolonged treatment with a TKI, or previous treatments with cytokines (i.e., IFN/IL-2) or another TKI might influence the incidence or the course of thyroid dysfunction remains to be clarified. Among TKI approved for clinical use, sunitinib, a TKI mainly targeting angiogenic kinase-receptors, exposes patients to a higher risk of developing TKI hypothyroidism (14-71% of patients in prospective studies) (146)(147)(148)(149)(150)(151)(152)(153). Thyroid dysfunction has also been described with other antiangiogenic TKI, such as sorafenib, motesanib, pazopanib, cediranib, and linifarib, but at lower rates (Table 2).…”

“…In renal cell carcinoma patients receiving sorafenib/sunitinib, better clinical outcomes were seen when hypothyroidism developed (158,159,168,230). Interestingly, higher risk of hypothyroidism during sunitinib therapy has been significantly associated with VEGF-A/VEGFR-2 gene single-nucleotide polymorphisms (152), suggesting that TKIinduced thyroid dysfunction may depend on a specific genetic predisposition. However, in this study better survival did not correlate with TKI-induced hypothyroidism.…”

Phase IV Study of Sunitinib in Chinese Patients with Imatinib-Resistant or Imatinib-Intolerant Gastrointestinal Stromal Tumors

“…Patients with exon 9 mutations require an escalated dose of imatinib [25], whereas certain patients, especially those with exon 11 mutations, show no benefit from imatinib dose escalation [26]. More recent studies [27,28] showed improved efficacy in sunitinib-treated patients with primary mutations in KIT exon 9 compared with exon 11. A limitation of the current study is that correlation between mutational status and sunitinib efficacy and safety were not examined.…”

Optimal use of lenvatinib in the treatment of advanced thyroid cancer

“…Hypothyroidism has been reported in sorafenib-treated patients with renal cancer and in sunitinib-treated patients with gastrointestinal stromal cancer [21,22]. Additionally, thyroid hormone replacement therapy improved fatigue in axitinib-treated patients with cancer [23].…”