Open Access Research article

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

Piotr Rutkowski1*, Elżbieta Bylina1, Anna Klimczak1, Tomasz Świtaj1, Sławomir Falkowski1, Jacek Kroc2, Iwona Ługowska1, Magdalena Brzeskwiniewicz3, Wojciech Melerowicz4, Czesław Osuch5, Ewa Mierzejewska6, Kacper Wasielewski3, Agnieszka Woźniak7, Urszula Grzesiakowska8, Zbigniew I Nowecki9, Janusz A Siedlecki10 and Janusz Limon3

Author Affiliations

1 Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

2 Pfizer Poland, Warsaw, Poland

3 Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland

4 GreaterPoland Oncological Center, Poznan, Poland

5 Department of General Surgery, Jagiellonian University, Medical Faculty, Cracow, Poland

6 Department of Biostatistics, Institute of Mother and Child, Warsaw, Poland

7 Laboratory of Experimental Oncology and Department of General Medical Oncology, KU Leuven and University Hospital, Leuven, Belgium

8 Department of Radiology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

9 Department of Gastrointestinal Tumors, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

10 Department of Molecular Biology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland

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BMC Cancer 2012, 12:107  doi:10.1186/1471-2407-12-107

Published: 22 March 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