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Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma.

ABSTRACT: In patients with metastatic renal cell carcinoma (mRCC), the timing of systemic targeted therapy in relation to cytoreductive nephrectomy (CN) is under investigation.To evaluate postoperative complications after the use of presurgical targeted therapy prior to CN.A retrospective review of all patients who underwent a CN at The University of Texas M.D. Anderson Cancer Center from 2004 to 2010 was performed. Inclusion in this study required documented evidence of mRCC, with treatment incorporating CN.Patients receiving presurgical systemic targeted therapy prior to CN were compared to those undergoing immediate CN.Complications were assessed using the modified Clavien system for a period of 12 mo postoperatively.Presurgical therapy was administered to 70 patients prior to CN (presurgical), while 103 patients had an immediate CN (immediate). A total of 232 complications occurred in 57% of patients (99 of 173). Use of presurgical systemic targeted therapy was predictive of having a complication>90 d postoperatively (p=0.002) and having multiple complications (p=0.013), and it was predictive of having a wound complication (p<0.001). Despite these specific complications, presurgical systemic targeted therapy was not associated with an increased overall complication risk on univariable or multivariate analysis (p=0.064 and p=0.237) and was not predictive for severe (Clavien ?3) complications (p=0.625). This study is limited by its retrospective nature. As is inherent to any retrospective study reporting on complications, we are limited by reporting bias and the potential for misclassification of specific complications.Despite an increased risk for specific wound-related complications, overall surgical complications and the risk of severe complications (Clavien ?3) are not greater after presurgical targeted therapy in comparison to upfront cytoreductive surgery.

SUBMITTER: Chapin BF

PROVIDER: S-EPMC4378825 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

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Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma.

Chapin Brian F BF Delacroix Scott E SE Culp Stephen H SH Nogueras Gonzalez Graciela M GM Tannir Nizar M NM Jonasch Eric E Tamboli Pheroz P Wood Christopher G CG

European urology 20110525 5

<h4>Background</h4>In patients with metastatic renal cell carcinoma (mRCC), the timing of systemic targeted therapy in relation to cytoreductive nephrectomy (CN) is under investigation.<h4>Objective</h4>To evaluate postoperative complications after the use of presurgical targeted therapy prior to CN.<h4>Design, setting, and participants</h4>A retrospective review of all patients who underwent a CN at The University of Texas M.D. Anderson Cancer Center from 2004 to 2010 was performed. Inclusion i ...[more]

PMID: 21621907

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Project description:BackgroundTargeted therapy (TT) in metastatic renal cell carcinoma (mRCC) may be associated with a high rate of toxicity that undermines treatment efficacy and patient quality of life. Polymorphisms in genes involved in the pharmacokinetic pathways of TTs may predict toxicity.ObjectiveTo investigate whether selected single-nucleotide polymorphisms (SNPs) in three core genes involved in the metabolism and transport of sunitinib and the mTOR inhibitors everolimus and temsirolimus are associated with adverse events (AEs).Design, setting, and participantsGermline DNA was extracted from blood or normal kidney tissue from mRCC patients of Caucasian ethnicity in two cohorts treated with either sunitinib (n=159) or mTOR inhibitors (n=62). Six SNPs in three candidate genes (CYP3A4: rs2242480, rs4646437, and rs2246709; CYP3A5: rs15524; and ABCB1: rs2032582 and rs1045642) were analyzed.Outcome measurements and statistical analysisPrimary endpoints were grade ≥3 AEs for all patients; grade ≥3 hypertension in the sunitinib cohort, and any grade pneumonitis in the mTOR inhibitors cohort. A logistic regression model was used to assess the association between SNPs and AEs, with adjustment for relevant clinical factors.Results and limitationsIn total, 221 samples were successfully genotyped for the selected SNPs. In the sunitinib cohort, the CYP3A4 rs464637 AG variant was associated with a lower risk of high-grade AEs (odds ratio 0.27, 95% confidence interval 0.08-0.88; p=0.03), but no SNPs were associated with hypertension. In the mTOR inhibitor cohort, none of the selected SNPs was associated with analyzed toxicities.ConclusionsWe observed an association between CYP3A4 polymorphisms and toxicity outcomes in mRCC patients treated with sunitinib, but not with everolimus or temsirolimus. Our findings are exploratory in nature, and further validation in independent and larger cohorts is needed.Patient summaryWe found that variants of CYP3A4, a gene involved in drug metabolism, are associated with sunitinib toxicity. This information may help in better selection of patients for targeted therapies in metastatic renal cell carcinoma.

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Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma.

Publications

Safety of presurgical targeted therapy in the setting of metastatic renal cell carcinoma.

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