Currently, the only approved second-line drug is sunitinib malate - a multitargeted agent, an inhibitor of tyrosine kinase, of KIT and PDGFRA/B and of the vascular endothelial growth factor receptors (VEGFRs)-1, -2 and 3, FMS-like tyrosine kinase-3 (FLT3), colony stimulating factor 1 receptor (CSF-1R), and glial cell-line derived neurotrophic factor receptor (REarranged during Transfection; RET) [6-11]. Sunitinib possesses both antiangiogenic and cytostatic properties and by competing with ATP binding prevents multiple receptor tyrosine kinases phosphorylation in vitro and in vivo. Two phase II, one phase III and one "treatment-use" trials have investigated the activity of sunitinib in GIST patients after the failure of prior imatinib treatment, and all these trials have shown the significant activity of sunitinib in this population of patients [11-14]. The objective clinical benefit was achieved in approximately 60% of GIST patients who received sunitinib after failure of prior imatinib treatment [11-14]. Median progression -free survival time on sunitinib is 6-8 months. The adverse events reported during this therapy are frequent. The most common treatment-related adverse events were fatigue, diarrhea, skin discoloration, nausea, mucositis, arterial hypertension, hand and foot syndrome (palmar-plantar erythrodysesthesia), impairment of left ventricular ejection fraction and hypothyroidism [12,14].

Moreover, arterial hypertension was not only the common adverse event during sunitinib therapy, but it was reported as predictive factor for results of renal-cell carcinoma (RCC) patients [15,16]. This phenomenon has not been yet analyzed in GIST patients.

We have also attempted to prove tumor genotype implications and to find new predictive factors in this group of patients. We have confirmed that many advanced GIST patients benefit from sunitinib therapy (mainly due to stabilization of disease according to RECIST, not Choi criteria [21]) with OS exceeding 1.5 years. The median PFS longer than seven months is almost equal to the results of the Korean one-institution study [22]. We have also confirmed in more detailed way and on the larger group of patients, than ever published, data regarding the correlation between primary tumor mutational status and sunitinib treatment outcomes [22-24]. As for imatinib, KIT mutation status appears to serve as a predictor of tumor response to sunitinib. We have proven that, contrary to imatinib, tumors initially (pre-imatinib treatment) bearing KIT exon 9 mutation or with wild-type genotype have a higher chance to respond to sunitinib. Moreover, GISTs harboring KIT exon 9 mutations appear to be more sensitive to sunitinib than those with primary KIT exon 11 mutations (however we have observed some objective responses also in this group of patients). The clinical benefit of sunitinib in wild-type cases is also clear. We have not observed any response to sunitinib in group of patients with PDGFRA mutations (mainly D842V), which has been also shown in preclinical data. We did not analyze the impact of secondary mutations, although patients from clinical trials with tumors harboring a secondary mutation in exon 13 or exon 14 KIT have a longer PFS than patients with exon 17 or 18 mutations [23,25-27]. On the other hand, utility of analysis of secondary mutations is very challenging because imatinib-resistant GISTs are very heterogeneous with multiple clones having different secondary mutations within the same or different nodules [28-30].

Sunitinib therapy is associated with several adverse events, which were generally mild to moderate and could be managed by dose modulation (including continuous administration of lower dose) [20,22,24]. The toxicity profile reported in our study is similar to that observed in clinical trials, with exception of hypothyroidism, which occurred in more than 30% of patients (it has been reported outside clinical trials [31,32]). However, up to one third of cases were classified as more severe toxicity (and two deaths due to tumor hemorrhage were classified as related to sunitinib therapy). Our own experience with patients with unresectable or metastatic GISTs, treated with tyrosine kinase inhibitors, suggested the higher incidence of emergency operations for gastrointestinal bleeding, bowel obstruction, or abscess, occur during second-line therapy with sunitinib than during first-line therapy with imatinib [33,34]. This increased incidence of complications leading to surgical interventions with sunitinib could be associated with the presence of more advanced and drug-resistant disease, or to the direct mechanism of action of sunitinib, i.e., the combination of cytotoxic and antiangiogenic activity, leading to dramatic tumor response.

Arterial hypertension is one of the most common complications of sunitinib therapy, occurring usually early after treatment initiation. Serial monitoring of blood pressure is recommended during therapy with sunitinib. Sunitinib-induced arterial hypertension may also serve as biomarker of antitumor efficacy (probably by antiangiogenic mechanism), because it was an independent factor influencing patient both progression-free and overall survival. Antiagiogenic activity may play an important role in therapy of sarcomas, what has been recently confirmed by positive results of phase III trial with pazopanib in pre-treated soft tissue sarcoma patients [35]. Similar relationships between arterial hypertension induced by VEGF inhibitors (including sunitinib) and oncological outcomes have been reported in renal cell carcinoma patients [15,16,36-39]. Treatment-induced persistent hypertension was associated with frequent tumor response, a long time to disease progression and longer overall survival [39]. Clinical outcomes are not compromised by treatment with anti-hypertension medications, moreover, patients who required at least three antihypertensive drugs had the longest PFS and OS [38]. There are proposed some hypothetical mechanisms leading to hypertension related to sunitinib, e.g. presence of less-perfused microvessels and/or diminished number of microvessels, decreasing nitric oxide production and activation of the endothelin-1 pathway leading to vasoconstriction [40,41].