Prospective evaluation of hypogonadism in male metastatic renal cell carcinoma patients treated with targeted therapies.

OBJECTIVES: To study the prevalence of hypogonadism in male patients with metastatic renal cell carcinoma (mRCC) starting with targeted therapies and the impact of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) sunitinib and pazopanib on the luteinizing hormone (LH)/testosterone (TT)-axis. METHODS: Male mRCC patients starting with targeted therapies were prospectively included in this study. TT- and LH-levels were sampled at start as well as during systemic therapy. Endpoints of the study were gonadal status (TT- and LH-levels) at start of targeted therapy and TT- and LH-evolution during targeted therapy. RESULTS: Sixty-three patients were included in this study. At start of targeted therapy, 30% of patients were eugonadal and 48% had secondary hypogonadism. Decreased TT- and increased LH-levels were associated with inflammatory state and poor prognosis. During sunitinib therapy, TT-levels decreased with 32% (p = 0.004) and LH-levels with 14% (p = 0.03). TT-levels were 13% lower (p = 0.007) and LH-levels 15% lower (p = 0.004) on day 28 compared to day 1. In four patients, a dramatic TT decrease was observed shortly after starting sunitinib. In patients treated with pazopanib, no impact on TT- or LH-levels was observed. CONCLUSION: Hypogonadism is a frequent finding in male mRCC-patients at start of targeted therapies. In contrast to pazopanib, during sunitinib therapy, TT- and LH-levels tend to decrease, leading to an increased incidence of secondary hypogonadism.

ABCG2 Polymorphism rs2231142 and hypothyroidism in metastatic renal cell carcinoma patients treated with sunitinib.

BACKGROUND AND AIM: Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) cause significant adverse events including thyroid dysfunction, mainly hypothyroidism, in a considerable proportion of patients. In a series of metastatic renal cell carcinoma (mRCC) patients treated with sunitinib, we aimed to study the correlation between hypothyroidism and single nucleotide polymorphisms (SNPs) in genes involved in sunitinib pharmacokinetics and pharmacodynamics. PATIENTS AND METHODS: We included 79 mRCC patients who started sunitinib between November 2005 and March 2016. Serum thyroid function markers were collected at start and during sunitinib therapy. Germ-line DNA genotyping for 16 SNPs in 8 candidate genes was performed. Endpoints were time to increase in thyroid stimulating hormone (TSH) and time to decrease in T4 or free T4 (FT4) on day 1 and day 28 of each sunitinib cycle. RESULTS: Patients with the ABCG2 rs2231142 CC-genotype had a significantly longer time-to-TSH-increase on day 1 (11 vs. 5 cycles; p = 0.0011), and time-to-T4/FT4-decrease on day 1 (not reached vs. 10 cycles; p = 0.013) and day 28 (28 vs. 7 cycles; p = 0.03) compared to CA-carriers. Patients with the CYP3A5 rs776746 GG-genotype had a significantly longer time-to-TSH-increase at day 1 compared to GA-patients: 11 vs. 5 cycles (p = 0.0071). Significant associations were also found between PDGFRA rs35597368 and rs1800812 and time-to-TSH-increase at day 28. CONCLUSION: Polymorphism rs2231142 in the efflux pump ABCG2 is associated with hypothyroidism in mRCC patients treated with sunitinib.

Functional decline in older patients with cancer receiving chemotherapy: A multicenter prospective study.

OBJECTIVES: This study aims to evaluate the evolution of functional status (FS) 2 to 3months after initiation of chemotherapy, to identify factors associated with functional decline during chemotherapy treatment and to investigate the prognostic value of functional decline for overall survival (OS). PATIENTS AND METHODS: Patients ≥70years with a malignant tumor were included when chemotherapy was initiated. All patients underwent a geriatric assessment (GA) including FS measured by Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL). FS of patients was followed by repeating ADL and IADL to identify functional decline. RESULTS: From 10/2009 until 07/2011, 439 patients were included. At follow-up, ADL and IADL data were available for 387 patients. Functional decline in ADL and IADL was observed in 19.9% and 41.3% of the patients respectively. In multivariable logistic regression analysis, baseline factors associated with decline in ADL are abnormal nutritional status (OR:2.02) and IADL dependency (OR:1.76). Oncological setting (disease progression/relapse vs new diagnosis) (OR:0.59) is the only determinant of decline in IADL. Functional decline in ADL is strongly prognostic for OS (logrank p-value<.0001; Wilcoxon p-value<.0001) with HR 2.34 and functional decline in IADL is also prognostic for OS but less prominent with HR 1.25. CONCLUSIONS: Functional decline occurs in about a third of older patients with cancer receiving chemotherapy and is associated with GA components. It strongly predicts survival, the most prominent for ADL. This knowledge can be used to identify older persons with cancer receiving chemotherapy eligible for interventions to prevent functional decline.