Dataset Information

Imatinib-induced liver cirrhosis in a patient with advanced gastrointestinal stroma tumor (GIST).

ABSTRACT: The use of imatinib mesylate is associated with a progression free survival of 41?months in first line treatment of metastatic or locally advanced gastrointestinal stromal tumors (GIST) and other studies approved that adjuvant imatinib treatment improves the recurrence-free survival in patients with GIST. Current recommendations include 1?year adjuvant treatment in GIST patients at risk but active studies explore different durations of treatment with an interval of up to 5?years. While the most frequent adverse events (AEs) are blood count alterations, abdominal discomfort and edema, the occurrence of grade 3 or 4 increase of AST or ALT is specified with 2.1% and 2.7% respectively.We report a 49-year old male with a gastrointestinal stromal tumor (GIST) of the small bowel who developed liver cirrhosis under adjuvant imatinib treatment.Our report supports the notion that imatinib-induced hepatotoxicity may lead to acute liver damage with subsequent cirrhotic remodelling. Patients developing grade 3 or 4 hepatotoxicity during imatinib treatment should therefore be carefully evaluated for chronic liver disease.

SUBMITTER: Seidel C

PROVIDER: S-EPMC3404905 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Imatinib-induced liver cirrhosis in a patient with advanced gastrointestinal stroma tumor (GIST).

Seidel Christoph C Fenner Martin M Länger Florian F Bantel Heike H Ganser Arnold A Grünwald Viktor V

BMC cancer 20120521

<h4>Background</h4>The use of imatinib mesylate is associated with a progression free survival of 41 months in first line treatment of metastatic or locally advanced gastrointestinal stromal tumors (GIST) and other studies approved that adjuvant imatinib treatment improves the recurrence-free survival in patients with GIST. Current recommendations include 1 year adjuvant treatment in GIST patients at risk but active studies explore different durations of treatment with an interval of up to 5 yea ...[more]

PMID: 22612794

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Project description:BackgroundMasitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance.Patients and methodsProspective, multicenter, randomized, open-label trial. Patients with inoperable, advanced imatinib-resistant GIST were randomized (1 : 1) to receive masitinib (12 mg/kg/day) or sunitinib (50 mg/day 4-weeks-on/2-weeks-off) until progression, intolerance, or refusal. Primary efficacy analysis was noncomparative, testing whether masitinib attained a median progression-free survival (PFS) (blind centrally reviewed RECIST) threshold of >3 months according to the lower bound of the 90% unilateral confidence interval (CI). Secondary analyses on overall survival (OS) and PFS were comparative with results presented according to a two-sided 95% CI.ResultsForty-four patients were randomized to receive masitinib (n = 23) or sunitinib (n = 21). Median follow-up was 14 months. Patients receiving masitinib experienced less toxicity than those receiving sunitinib, with significantly lower occurrence of severe adverse events (52% versus 91%, respectively, P = 0.008). Median PFS (central RECIST) for the noncomparative primary analysis in the masitinib treatment arm was 3.71 months (90% CI 3.65). Secondary analyses showed that median OS was significantly longer for patients receiving masitinib followed by post-progression addition of sunitinib when compared against patients treated directly with sunitinib in second-line [hazard ratio (HR) = 0.27, 95% CI 0.09-0.85, P = 0.016]. This improvement was sustainable as evidenced by 26-month follow-up OS data (HR = 0.40, 95% CI 0.16-0.96, P = 0.033); an additional 12.4 months survival advantage being reported for the masitinib treatment arm. Risk of progression while under treatment with masitinib was in the same range as for sunitinib (HR = 1.1, 95% CI 0.6-2.2, P = 0.833).ConclusionsPrimary efficacy analysis ensured the masitinib treatment arm could satisfy a prespecified PFS threshold. Secondary efficacy analysis showed that masitinib followed by the standard of care generated a statistically significant survival benefit over standard of care. Encouraging median OS and safety data from this well-controlled and appropriately designed randomized trial indicate a positive benefit-risk ratio. Further development of masitinib in imatinib-resistant/intolerant patients with advanced GIST is warranted.

Project description: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.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.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).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.

Dataset Information

Imatinib-induced liver cirrhosis in a patient with advanced gastrointestinal stroma tumor (GIST).

Publications

Imatinib-induced liver cirrhosis in a patient with advanced gastrointestinal stroma tumor (GIST).

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