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

Rutkowski P, Bylina E, Klimczak A, Switaj T, Falkowski S, Kroc J, Lugowska I, Brzeskwiniewicz M, Melerowicz W, Osuch C, Mierzejewska E, Wasielewski K, Woźniak A, Grzesiakowska U, Nowecki ZI, Siedlecki JA, Limon J - BMC Cancer (2012)

Bottom Line: The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea.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).Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. rutkowskip@coi.waw.pl

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.

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Related in: MedlinePlus

Progression-free survival during sunitinib therapy according to presence of arterial hypertension.
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Figure 2: Progression-free survival during sunitinib therapy according to presence of arterial hypertension.

Mentions: In univariate analysis two factors significantly correlated with shorter PFS and OS that were: tumor genotype: exon 11 KIT or PDGFRA mutation (p = 0.04 and p = 0.04, respectively) (Figure 1), and absence of arterial hypertension during sunitinib therapy (p = 0.0001 and p = 0.001) (Figure 2). We did not find any significant correlation between PFS/OS and patients gender and age at diagnosis, GIST primary tumor location, WHO performance status 0 vs. 1, or time on previous imatinib treatment. Estimated 1-year PFS and 2-year OS according to primary tumor genotype were as follows: KIT exon 9 mutations - 68%/73% (median 65.5/151.5 weeks), wild type - 57%/70% (median 50.5/121 weeks), KIT exon 11 mutations - 34%/34% (median 36.8/65.5 weeks) and PDGFRA mutations - 15%/25% (median 9/40 weeks). Patients with presence of arterial hypertension during first three months of sunitinib therapy had substantially better 1-year PFS and 2-year OS than patients without this adverse event (65% vs. 22%, and 63% vs. 18%; median 77 vs. 25.5 weeks, and 128.5 vs. 43 weeks, respectively).


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

Rutkowski P, Bylina E, Klimczak A, Switaj T, Falkowski S, Kroc J, Lugowska I, Brzeskwiniewicz M, Melerowicz W, Osuch C, Mierzejewska E, Wasielewski K, Woźniak A, Grzesiakowska U, Nowecki ZI, Siedlecki JA, Limon J - BMC Cancer (2012)

Progression-free survival during sunitinib therapy according to presence of arterial hypertension.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3361487&req=5

Figure 2: Progression-free survival during sunitinib therapy according to presence of arterial hypertension.
Mentions: In univariate analysis two factors significantly correlated with shorter PFS and OS that were: tumor genotype: exon 11 KIT or PDGFRA mutation (p = 0.04 and p = 0.04, respectively) (Figure 1), and absence of arterial hypertension during sunitinib therapy (p = 0.0001 and p = 0.001) (Figure 2). We did not find any significant correlation between PFS/OS and patients gender and age at diagnosis, GIST primary tumor location, WHO performance status 0 vs. 1, or time on previous imatinib treatment. Estimated 1-year PFS and 2-year OS according to primary tumor genotype were as follows: KIT exon 9 mutations - 68%/73% (median 65.5/151.5 weeks), wild type - 57%/70% (median 50.5/121 weeks), KIT exon 11 mutations - 34%/34% (median 36.8/65.5 weeks) and PDGFRA mutations - 15%/25% (median 9/40 weeks). Patients with presence of arterial hypertension during first three months of sunitinib therapy had substantially better 1-year PFS and 2-year OS than patients without this adverse event (65% vs. 22%, and 63% vs. 18%; median 77 vs. 25.5 weeks, and 128.5 vs. 43 weeks, respectively).

Bottom Line: The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea.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).Primary tumor KIT/PDGFRA genotype and SU-induced AH, as surrogate of its antiangiogenic activity are two independent factors influencing both PFS and OS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland. rutkowskip@coi.waw.pl

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.

Show MeSH
Related in: MedlinePlus