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BMC Cancer. 2012; 12: 107.
Published online Mar 22, 2012. doi:  10.1186/1471-2407-12-107
PMCID: PMC3361487
The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST) after imatinib failure - one institution study
Piotr Rutkowski,corresponding author1 Elżbieta Bylina,1 Anna Klimczak,1 Tomasz Świtaj,1 Sławomir Falkowski,1 Jacek Kroc,2 Iwona Ługowska,1 Magdalena Brzeskwiniewicz,3 Wojciech Melerowicz,4 Czesław Osuch,5 Ewa Mierzejewska,6 Kacper Wasielewski,3 Agnieszka Woźniak,7 Urszula Grzesiakowska,8 Zbigniew I Nowecki,9 Janusz A Siedlecki,10 and Janusz Limon3
1Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
2Pfizer Poland, Warsaw, Poland
3Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland
4GreaterPoland Oncological Center, Poznan, Poland
5Department of General Surgery, Jagiellonian University, Medical Faculty, Cracow, Poland
6Department of Biostatistics, Institute of Mother and Child, Warsaw, Poland
7Laboratory of Experimental Oncology and Department of General Medical Oncology, KU Leuven and University Hospital, Leuven, Belgium
8Department of Radiology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
9Department of Gastrointestinal Tumors, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
10Department of Molecular Biology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland
corresponding authorCorresponding author.
Piotr Rutkowski: rutkowskip/at/coi.waw.pl; Elżbieta Bylina: elab/at/coi.waw.pl; Anna Klimczak: aniaklimczak/at/poczta.onet.pl; Tomasz Świtaj: tomek89/at/yahoo.co.uk; Sławomir Falkowski: sfalcon/at/neostrada.pl; Jacek Kroc: jacek.kroc/at/pfizer.com; Iwona Ługowska: iwonalugowska/at/coi.waw.pl; Magdalena Brzeskwiniewicz: magda_brzeskwiniewicz/at/interia.pl; Wojciech Melerowicz: wojmel5/at/wp.pl; Czesław Osuch: msosuch/at/cyf-kr.edu.pl; Ewa Mierzejewska: emierzejewska/at/imid.med.pl; Kacper Wasielewski: k.wasielewski/at/gumed.edu.pl; Agnieszka Woźniak: agnieszka.wozniak/at/med.kuleuven.be; Urszula Grzesiakowska: ugrzesiakowska/at/yahoo.com; Zbigniew I Nowecki: nowecki/at/coi.waw.pl; Janusz A Siedlecki: jas/at/coi.waw.pl; Janusz Limon: jlimon/at/gumed.edu.pl
Received November 27, 2011; Accepted March 22, 2012.
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 (2nd 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.
Keywords: Sunitinib, Genotype, GIST, Prognosis, Predictive factors, Arterial hypertension
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