Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes

Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, has demonstrated survival benefit in patients with metastatic renal cell carcinoma (mRCC) and is generally well tolerated with most adverse events, manifesting as mild to moderate in severity. The most frequent related adverse events include hand-foot syndrome (HFS), hypertension, proteinuria, cardiac toxicities, myelosuppression, fatigue/asthenia, hypothyroidism, diarrhea and hepatotoxicity. The study aims to determine incidence of adverse events among patients with metastatic renal cell carcinoma (mRCC) treated Sunitinib within five years from 2010 to 2015 and comparing the results with data from literature. The study included a total of 56 patients treated with Sunitinib, with a dose of 50 mg (Schedule 4/2). Due to adverse events and individual safety and tolerability, at the indication of the personal clinician, 11 patients needed dose reduction, with a continuous dose of 37.5 mg, daily and 28 patients continued the dose of 50 mg taken daily, on a different schedule (2/1 schedule). The most important toxicities were anemia, leukopenia, thrombocytopenia, gastrointestinal effects (diarrhea), fatigue and hypertension. After dose reduction or modified schedule the incidence of the most frequent toxicities (HFS, leukopenia, thrombocytopenia and fatigue) decreased, but hypertension was still observed in 30% of patients. The results are similar with data from literature. Early identification of individuals at risk and monitoring patients during Sunitinib treatment is very important and it can facilitate early intervention with prophylactic measures or supportive treatment, thus increasing quality of life and adherence to treatment. Further studies need to establish which targeted population can benefit the most from adjusted regimens and to correlate them with prognostic factors for survival.

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2001 NODAL DISEASE IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA CAN A LYMPH NODE DISSECTION POTENTIALLY ALTER PATIENT OUTCOMES?

The Journal of Urology ◽

10.1016/j.juro.2012.02.2163 ◽

2012 ◽

Vol 187 (4S) ◽

Author(s):

Brian F. Chapin ◽

Scott E. Delacroix ◽

Patrick A. Kemney ◽

Graciela M. Nogueras-Gonzalez ◽

Pheroze Tamboli ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Lymph Node ◽

Cell Carcinoma ◽

Patient Outcomes ◽

Lymph Node Dissection ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Node Dissection ◽

Nodal Disease ◽

Alter Patient

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Interstitial lung diseases during treatment with sunitinib or mTOR inhibitors in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.420 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 420-420

Author(s):

Philipp Ivanyi ◽

Thomas Fuehner ◽

Meike Adam ◽

Christian Eichelberg ◽

Edwin Herrmann ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Dose Reduction ◽

Metastatic Renal Cell Carcinoma ◽

Targeted Therapies ◽

Renal Cell ◽

Pulmonary Function Tests ◽

Mtor Inhibitors ◽

Treatment Withdrawal ◽

Steroid Pulse

420 Background: Targeted therapies are the mainstay for metastatic renal cell carcinoma (mRCC) treatment. Interstitial lung disease (ILD) represents an adverse event (AE) of such therapies while its incidence and management is poorly defined. Here, the experience on ILD with targeted agents in mRCC is reported. Methods: Retrospective analysis of mRCC patients receiving sunitinib, everolimus, or temsirolimus at three German tertiary centers between January 2006 and August 2009 was performed, accessing ILD incidence, management, and outcomes. Results: In total 26 ILD patients were identified out of 306 mRCC patients (8.5%) treated with targeted therapies. Median treatment duration to ILD diagnosis was 3.8 (range 0.98-21.5) months. ILD occurred in 6 of 204 sunitinib treated patients (2.9%), and in 20 of 102 mTOR inhibitor (mTORi) treated patients (19.6%). Cough represents the predominant symptom (69.2%, n=18). Chest CTs revealed 4 patterns: interstitial (n=13), nodular (n=3), ground glass opacities (n=8), or complex patterns (n=2). Pulmonary function tests (PFT) illustrates frequently a restrictive disorder (n=9), often accompanied by a diminished diffusion capacity (n=8). In 53.8% (n=14) a bronchoscopy with broncho-alveolar-lavage (BAL) was performed (lymphocytic cellularity n=6, eosinophilic cellularity n=4). Dose reduction (42.3%, n=11), temporary interruption (46.2%, n=12), or treatment withdrawal (53.8%, n=14) occurred frequently. Nine patients (34.6%) received steroids. Continuation of targeted therapies was maintained in 65.4% (n=17). No patient died from ILD. Conclusions: ILD represents a frequent AE with targeted therapies and also occurs in sunitinib treated patients. For diagnosis of ILD chest CTs are mandatory, whereas PFT and BALs are important subsidiary tools. Clinical relevance of ILD may vary and management of ILD ranges from watch and wait to termination of treatment and steroid pulse therapy. Severe complaints were more frequently associated with eosinophilic BAL, often required an aggressive treatment. However, in most patients, temporary interruption and/or dose reduction with subsequent continuation of targeted therapy remain sufficient to manage ILD.

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Fecal microbiota transplantation for TKI-induced diarrhea in patients with metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.615 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 615-615 ◽

Cited By ~ 2

Author(s):

Ernesto Rossi ◽

Gianluca Ianiro ◽

Brigida Anna Maiorano ◽

Roberto Iacovelli ◽

Loris Lopetuso ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Dose Reduction ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Fecal Microbiota Transplantation ◽

Controlled Trial ◽

Fecal Microbiota ◽

Control Group ◽

Serious Adverse Events

615 Background: Diarrhea is a common adverse event of tyrosine kinase inhibitors (TKI). No standard treatment for TKI-induced diarrhea has been established, although probiotics are commonly used. In several patients TKI dose reduction is necessary. Data showing the interplay between microbiota and TKI-induced diarrhea are reported. The therapeutic modulation of gut microbiota could be useful to ameliorate TKI-related diarrhea. Our study aims to explore the efficacy and safety of fecal microbiota transplantation (FMT), compared with current clinical practice approach, for the treatment of TKI-associated diarrhea in patients with metastatic renal cell carcinoma. Methods: Patients on treatment with Pazopanib/Sunitinib as first line therapy for metastatic renal cell carcinoma and TKI-associated diarrhea (³ 4 stools per day over baseline) were randomize to receive FMT from healthy donor by colonoscopy (fresh faeces) or probiotics (L. casei DG). The primary endpoint was the resolution of TKI-related diarrhea. Baseline fecal samples were collected from all patients and donors. All patients were followed up 7, 15, 30 and 60 days after the treatment for diarrhea. Results: 21 subjects, 10 in FMT arm and 11 in control arm, have been enrolled. At 7 day-follow-up, TKI-related diarrhea disappeared in 10 patients of the FMT group and in 6 patients of the control group (100% vs 54.5%, p = 0.02). At 15-day and 30-day, 9 patients in the FMT group and 0 patients in the control group experienced resolution of diarrhea (90% vs 0%, p = 0.0001). At 60-days 8/10 patients in FMT arm did not have diarrhea. Dose reduction was necessary in 4 patients of the control group. No serious adverse events associated with any of the two treatment protocols were observed. Metagenomic analyses on collected stool samples are ongoing. Conclusions: This open-label randomised controlled trial showed the effectiveness and safety of FMT compared with probiotics in curing TKI-related diarrhea in patients with metastatic renal cell carcinoma, avoiding the necessity of dose reduction. Considering the increasing evidence, the modulation of microbiota trough FMT could also affect the efficacy of immunotherapy for metastatic renal cell carcinoma.

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Vascular endothelial growth factor (VEGF) therapy in metastatic renal cell carcinoma (mRCC): Differences between Asian and non-Asian patients.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.451 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 451-451 ◽

Cited By ~ 1

Author(s):

Ying Wang ◽

Toni K. Choueiri ◽

Jae-Lyun Lee ◽

Min-Han Tan ◽

Sun Young Rha ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Targeted Therapy ◽

Cell Carcinoma ◽

Dose Reduction ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Progression Free Survival ◽

Risk Groups ◽

Asian Patients

451 Background: Several reports have indicated that VEGF targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in the Asian versus Caucasian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterized. Methods: Eight centers participating in the International mRCC Database Consortium with available dose reduction data on patients with mRCC treated with VEGF targeted therapy were included in this analysis. Asian patients were derived from centers in Korea and Singapore. Results: 1024 patients with a median follow-up of 29.4 months were included in this analysis. Baseline characteristics are below. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% p=0.1197) but more patients completely discontinued treatment due to toxicity in the non-Asian vs the Asian group (28% vs 21% p=0.0197). When adjusted for the Heng et al poor prognostic criteria, there was no difference in overall survival (HR 0.887, 95%CI 0.729-1.08, p=0.2322) or progression-free survival (HR 1.069, 95%CI 0.910-1.256, p=0.4184) between non-Asians and Asians. Interestingly, when patients were dose reduced due to toxicity, they had a longer treatment duration and overall survival than those that did not require a dose reduction in both the non-Asian (10.6 vs 5.0 months p<0.0001 and 22.6 vs 16.1 months p=0.0016, respectively) and in the Asian populations (8.9 vs 5.4 months p=0.0028 and 28.0 vs 18.7 months p=0.0069). Conclusions: After adjusting for risk groups, there appears to be no difference in outcome between Asians vs. non-Asian patients with mRCC treated withVEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations possibly due to longer treatment durations, but direct comparisons are needed. [Table: see text]

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Prospective exploratory analysis of the association between genetic polymorphisms and sunitinib toxicity and efficacy in metastatic renal-cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4620 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4620-4620 ◽

Cited By ~ 1

Author(s):

Carlos Alberto Farfan ◽

Juan Sepulveda ◽

Julio Benitez ◽

Guillermo de Velasco ◽

Felipe Villacampa ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Dose Reduction ◽

Median Time ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Preliminary Analysis ◽

Complete Analysis ◽

Increased Risk ◽

Dose Reductions

4620 Background: Sunitinib (SU) is a multi-targeted receptor tyrosine kinase inhibitor treatment that is approved for metastatic renal cell carcinoma (mRCC). However, several patients either do not respond to treatment or they experience significant toxicity.Our study aims to find genetic markers of toxicity and efficacy using a commercially available DNA microarray genotyping system. Methods: 30 patients with newly diagnosed mRCC, from January 2010 to May 2011, were evaluated prospectively at Hospital 12 de Octubre (Madrid, Spain). Pts received SU 50 mg/day, 4 wks on / 2 wks off treatment schedule. A total of 92 of single nucleotide polymorphisms (SNPs) in 34 genes in the pharmacokinetic and pharmacodynamic pathways of drugs were analyzed using Drug inCode pharmacogenetic service. SNPs in candidate genes, together with clinical characteristics were tested univariately for association with the number of days of SU treatment until the first reduction of dose, PFS and OS. Results: Complete analysis was possible in 25 pts. Pts with CYP1A2*1/*1.a low metabolizing genotype, had an increased risk of dose reductions due to toxicity compare to allele *1F (Median time to dose reduction : 2.33 months vs NR; p<0.006). Pts with CYP2C19*1/*1 , wild type genotype, had an increased risk of dose reductions due to toxicity vs. other genotypes (Median time to dose reduction: 2.8 vs 9.73 months; p<0.021). Catechol-O-methyltransferase (COMT) V158M polymorphisms, was associated with PFS and OS (Met/Met carriers median PFS and OS NR; Met/Val pts PFS= 15 months; OS=17.2 months and Val/Val pts PFS=3.3 months; OS= 4.4 months ; p=0.005 for PFS and p=0.003 for OS). Conclusions: This preliminary analysis suggests that CYP1A2 and CYP2C19 SNPs may be associated with toxicity in patients with RCC treated with SU. As CYP1A2 and CYP2C19 activity could be affected by a variety of non-genetic factors, if these is confirmed, it could lead to the necessity of controlling toxic and dietary habits of pts treated with SU. SNPs associated with toxicity and survival in this preliminary analysis are being validated in an independent cohort of RCC treated with SU (García-Donas J, et al. Lancet Oncol 2011).

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U.K. experience of sunitinib malate in the treatment of metastatic renal cell carcinoma: Predictors of response from clinical practice.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.455 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 455-455 ◽

Cited By ~ 1

Author(s):

Rebecca Allison Goranova ◽

Bojidar Bojidarov Goranov ◽

Ian David Pedley ◽

Ashraf Azzabi ◽

Alison Humphreys ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Dose Reduction ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Treatment Initiation ◽

Performance Status ◽

Median Number ◽

Predictors Of Response ◽

Cancer Network

455 Background: Sunitinib gained NICE approval in March 2009 as first line treatment for metastatic renal cell carcinoma (mRCC) and UK experience of use of Sunitinib is growing. The North of England Cancer Network (NECN) was the first cancer network in the UK to approve the use of Sunitinib in July 2007 and has the longest UK experience with this drug. The clinical outcomes of the NECN patients are presented. Methods: Data was collected and analysed regarding all patients started on Sunitinib from 01/07/2007 to 30/09/2010. Follow up extended to 28/02/2011. Previously published predictors of response were compared to the NECN data to check applicability in this population. Results: 129 patients were identified with a median age of 63 years (range 21-87), 67% were male and WHO performance status was 0, 1 or 2 (33%, 51%, 16%). 80% of patients had nephrectomy (60% radical) and 22% had prior systemic treatment. Median PFS was 10 months (range 0.25-27). Median OS (from Sunitinib initiation) was 17 months (range 0.25 - 47). Performance status was significantly associated with PFS and OS. The median number of treatment cycles was 5 (range 0.25-27). 64% of patients were dose reduced and 9% had a schedule modification to minimise toxicity. 21% of patients had a delay of 4 weeks or more which was not detrimental to median PFS. Dose reduction at treatment initiation was associated with a significant decrease in OS. 11.6% of patients required treatment for hypothyroidism which was associated with a significant improvement in PFS and OS. 15.5% of patients required treatment for hypertension, which was associated with an improvement in OS, but not PFS. Conclusions: PFS in the NECN population is similar to trial data. Strategies to deal with side effects, including dose reduction (after treatment initiation), treatment delay and schedule changes, did not adversely affect PFS. Performance status 0, the development of new hypertension or new hypothyroidism can be regarded as markers of good prognosis in this population. Initial dose reduction should be avoided as this adversely affects prognosis.

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