Effects of cabozantinib on bone turnover markers in real-world metastatic renal cell carcinoma

2020 ◽  
pp. 030089162096981
Author(s):  
Raffaele Ratta ◽  
Elena Verzoni ◽  
Alessia Mennitto ◽  
Francesco Pantano ◽  
Antonia Martinetti ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Bone Resorption ◽  
Bone Turnover ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Bone Turnover Markers ◽  
The Mean ◽  
Turnover Markers ◽  
Paired Analysis

Background: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma. Methods: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves. Results: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population ( p = 0.013 and p < 0.0001, respectively), as well as at paired analysis ( p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months ( p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population ( p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively ( p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome. Conclusions: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.

Effects of cabozantinib on bone turnover markers in patients with metastatic renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 638-638 ◽  
Author(s):  
Raffaele Ratta ◽  
Elena Verzoni ◽  
Francesco Pantano ◽  
Paolo Grassi ◽  
Antonia Martinetti ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Vitamin D ◽  
Bone Resorption ◽  
Bone Turnover ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Bone Turnover Markers ◽  
Tracp 5B ◽  
Turnover Markers

638 Background: In-vitro studies have shown that cabozantinib has a strong inhibitory action on osteoclast differentiation and bone-resorption activity. The aim of this analysis was to investigate the effects of cabozantinib on bone turnover markers in patients (pts) with metastatic renal cell carcinoma (mRCC). Methods: We included mRCC pts treated with cabozantinib within the Italian Managed Access Program (MAP) at the Istituto Nazionale Tumori of Milan (Italy). Plasma samples from every patient were collected at baseline and after 3 and 6 months of treatment. The bone resorption markers C-terminal telopeptide of type I collagen (CTx) and tartrate-resistant acid phosphatase isoenzyme 5b (TRACP 5b), the osteoclastogenesis markers osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-B ligand (RANKL), vitamin D and parathormone (PTH) were measured by immunometric assay techniques. Data were analyzed using the RM One-Way ANOVA test with Greenhouse-Geisser correction followed by uncorrected Fisher’s LSD multiple comparison tests with individual variances computed for each comparison. Statistical tests were performed using the program GraphPad Prism (San Diego, CA). Results: Twenty-two pts have been treated with cabozantinib. Mature data were available for 11 pts. Analysis of TRACP 5b, OPG, RANKL and vitamin D did not show any significant variations during treatment with cabozantinib. CTx showed a significant reduction after 6 months of treatment (MV 171.5 pg/mL, STD 208.4) from baseline (mean value [MV] 352.2 pg/mL, standard deviation [STD] 210.1) (p = 0.0439) in the whole study population. PTH levels significantly increased after 3 months of treatment (MV 86.79 pg/mL, STD 34.99) from baseline (MV 30.77 pg/mL, STD 12.64) (p = 0.0003), while significantly decreased after 6 months (MV 75.01 pg/mL, STD 53.1) (p = 0.0174). Conclusions: Our data suggested that cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx; it was also associated with an asymptomatic transient secondary increase of parathormone. This is the first clinical evidence on effects of cabozantinib on bone metabolism in a small population of mRCC pts.

Diagnostic and Prognostic Validity of Serum Bone Turnover Markers in Metastatic Renal Cell Carcinoma

2006 ◽  
Vol 176 (4) ◽  
pp. 1326-1331 ◽  
Author(s):  
Klaus Jung ◽  
Michael Lein ◽  
Martin Ringsdorf ◽  
Jan Roigas ◽  
Dietmar Schnorr ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Bone Turnover ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Bone Turnover Markers ◽  
Turnover Markers

RAD001 and zoledronic acid in renal cell carcinoma patients with bone metastases (RAZOR): A randomized phase II trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15054-e15054
Author(s):  
Reuben James Broom ◽  
Vicky Hinder ◽  
Katrina Sharples ◽  
Janie Proctor ◽  
Steven Duffey ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Zoledronic Acid ◽  
Bone Turnover ◽  
Bone Metastases ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Bone Turnover Markers ◽  
Treatment Naïve ◽  
Prognostic Feature ◽  
Turnover Markers

e15054 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause major morbidity and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (ZOL) reduces skeletal-related-events (SRE’s) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving ZOL. We sought to evaluate the effect on BM of RAD001 (everolimus) alone compared to RAD001 plus ZOL in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to RAD001 10mg daily (Arm A) vs. RAD001 + ZOL 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl], Arm B). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates or radiotherapy within 4 weeks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, weeks 1,4,8 and12. Treatment was continued on the allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12-weeks. The primary endpoint was urine N-telopeptide (uNTX) levels with plasma C-telopeptide (CTX) being secondary. Secondary objectives include comparison of quality of life (QoL) and pain (FACT-BP, BPI scores), SREs, safety and efficacy (PFS, RR). Results: Heng prognostic group was poor, intermediate and favorable-risk in; 40.0%, 46.7%, 13.3% respectively in Arm A and 20.0%, 46.7%, 33.3% (Arm B). 53.3% (Arm A) and 60.0% (Arm B) of pts had prior nephrectomy. Over the first 12 weeks, the reduction in mean CTX on Arm B relative to Arm A was 77% (95% CI (68%, 83%); p<0.0001). Median PFS was 7.5mo (95% CI 3.5, 14.7) in Arm B and 5.5mo (95% CI 3.2, 7.2) in Arm A (p=0.11). Data on uNTX, QoL and SREs will be presented. At data cut off, 8 pts in Arm B had stopped ZOL before progression with either a drop in CrCl or hypocalcaemia. No cases of osteonecrosis of the jaw were seen. Conclusions: The addition of ZOL to RAD001 significantly reduced the bone resorption marker CTX in this treatment-naïve RCC population of pts with the adverse prognostic feature of BM.

RAD001 and zoledronic acid in patients with renal cell carcinoma with bone metastases (RAZOR): A randomized phase II trial.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 402-402
Author(s):  
Reuben James Broom ◽  
Vicky Hinder ◽  
Katrina Sharples ◽  
Janie Proctor ◽  
Steven Duffey ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Zoledronic Acid ◽  
Bone Turnover ◽  
Bone Metastases ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Bone Turnover Markers ◽  
Weekly Dose ◽  
Prognostic Feature ◽  
Turnover Markers

402 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common, cause morbidity, and have been identified as an adverse prognostic feature. Previous trials have not assessed the effects of modern therapies on BM from RCC. Randomized data has demonstrated that zoledronic acid (Z) reduces skeletal-related-events (SREs) in RCC patients (pts). Bone turnover markers can identify pts at risk of SREs among those receiving Z. We sought to evaluate the effect on BM of RAD001 (R) (everolimus) alone compared to R+Z in the first-line setting. Methods: 30 treatment naïve pts with RCC and ≥ 1 BM were randomized 1:1 to R 10mg daily vs. R+Z 4mg IV 4-weekly (dose adjusted for creatinine clearance [CrCl]). Key eligibility criteria were ECOG PS ≤ 2, no bisphosphonates, or radiotherapy within 4 wks and CrCl >35ml/min. Bone-specific assessments were performed at baseline, wks-1, 4, 8, and 12. Treatment was continued on allocated arm until progression (RECIST 1.1). The primary objective was to assess the difference in bone turnover markers over the first 12 wks. The primary endpoint was urine N-telopeptide (uNTX) level with secondary endpoints being plasma C-telopeptide (CTX), quality of life (FACT-BP, BPI), progression free survival (PFS), SREs, and safety. Results: Heng prognostic group poor, intermediate, and good risk was 20.0%, 46.7%, 33.3% in R+Z and 40.0%, 46.7%, 13.3% in R. Over first 12 wks, the reduction in mean: uNTX on R+Z relative to R was 68.4% (95% CI (60.1%, 74.9%); p<0.0001); CTX on R+Z relative to R was 77% (95% CI (68%, 83%); p<0.0001). For FACT-BP there was no evidence of a difference (p = 0.5) but addition of Z was favourable for BPI Severity -1.1 (-2.2, 0.23; p = 0.05) and BPI Interference -1.3 (-2.5, 0.03; p = 0.06). Median PFS was 7.5 mo (95% CI 3.4, 14.7) on R+Z and 4.6 mo (95% CI 3.2, 6.3) on R (p = 0.03). Median time to 1st SRE was 9.6 mo (95% CI 4.3, 15.5) on R+Z and 5.2 mo (95% CI 1.6-8.2) on R (p = 0.03). Conclusions: Addition of Z to R significantly reduced bone resorption markers in this RCC population of pts with the adverse prognostic feature of BM. Pts receiving R+Z had prolonged time to 1st SRE and PFS; larger studies are required to further evaluate the addition of bone-specific to targeted therapies in this disease. Clinical trial information: ACTRN12609000980235.

scholarly journals OSSMAR: An Observational Study to Describe the Use of Sunitinib in Real-Life Practice for the Treatment of Metastatic Renal Cell Carcinoma

2019 ◽  
pp. 1-10 ◽  
Author(s):  
Marwan Ghosn ◽  
Roland Eid ◽  
Emad Hamada ◽  
Hamdy Abdel Azim ◽  
Jamal Zekri ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Clinical Practice ◽  
Middle East ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Real Life ◽  
Routine Clinical Practice ◽  
The Mean

PURPOSE Sunitinib offers improved efficacy for patients with metastatic renal cell carcinoma (mRCC). To provide better disease management in the Middle East, we studied its use in mRCC in real-life practice in this region. MATERIAL AND METHODS Patients diagnosed with mRCC and started on sunitinib between 2006 and 2016 from 10 centers in Africa and the Middle East region were studied in this regional, multicenter, observational, retrospective trial to obtain routine clinical practice data on the usage patterns and outcomes of sunitinib in mRCC in real-life practice. RESULTS A total of 289 patients were enrolled. Median age at diagnosis was 58.7 years. The patient characteristics were as follows: 73.6% of patients were males; 85.8% had clear-cell renal cell carcinoma (RCC); 97.5% had unilateral RCC; 66.3% had metastatic disease at initial diagnosis; 56.3% received previous treatment for RCC, among which 98.7% had undergone surgery; and 15.2% and 31.4% were classified in the favorable and poor-risk groups (expanded Memorial Sloan Kettering Cancer Center criteria), respectively. On treatment initiation, the mean total sunitinib dose was 48.1 mg, and 87.6% of patients were started on a sunitinib dose of 50 mg. The mean duration of sunitinib treatment was 9.6 months. Overall response rate was 20.8%, with a median duration of 8.2 months. Median time to progression was 5.7 months. Median follow-up time was 7.8 months. By months 12 and 24, 34.3% and 11.4% of patients, respectively, were still alive. Seventy-six patients (60.9%) experienced 314 adverse events. Twenty-three patients (8.0%) experienced 28 serious adverse events. Overall, 83 patients (28.7%) discontinued their sunitinib treatment. CONCLUSION The results are indicative of the general treatment outcomes of patients with mRCC in the Middle East using sunitinib in routine clinical practice. Reported adverse events are similar to those described in the literature but at lower frequencies.

The value of PET-CT (positron emission tomography) in the treatment of metastatic renal cell carcinoma with sorafenib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15621-15621 ◽  
Author(s):  
U. Stierner ◽  
M. Boijsen ◽  
M. Suurküla ◽  
S. Lundstam
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Glucose Uptake ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Initial Value ◽  
Pet Ct ◽  
The Mean ◽  
Mean Glucose ◽  
Skeletal Lesions

15621 Background: Sorafenib is a new potent multikinase inhibitor directed against both tumour proliferation and angiogenesis. Clinical benefit has been shown in 75% of patients with metastatic renal cell carcinoma. The aim of this study was to evaluate this new treatment with PET-CT with fluorodeoxyglucose (FDG), since the use of only CT measurements has been questioned. Methods: 10 patients (8 male, 2 female, 49–72 years) with metastatic renal cell carcinoma (9 clear cell, 1 chromophobe). All had progressive disease (8 after interferon). Sorafenib 400 mg b.i.d was given orally. FDG-PET-CT scan was performed from head-proximal thigh before treatment and after one month. Up to 6 target lesions in each patient were studied. The sum of the largest diameters was calculated from CT images for each patient. To evaluate the glucose uptake, a region of interest (roi) was designed for each leasion on the initial PET on the transverse section where the lesion appeared to be largest and/or most intense. Using the same roi for subsequent examinations the mean glucose uptake/mean cerebellar uptake was calculated. For each patient the mean change from baseline was calculated. Results: After one month of treatment the sum of tumour diameters measured by CT was mean 85% (53–110%) of the initial value. Measured by PET the mean glucose uptake at one month was mean 73% (29–100%) of the initial value. Seven patients had skeletal lesions. These were often difficult to measure on CT and only small changes were detected. Using PET the mean uptake in skeletal lesions was 77% (62–104%) at one month. Conclusions: Early effects of sorafenib treatment in metastatic renal cell carcinoma can be detected and quantified by PET-CT. Especially in skeletal lesions PET-CT exhibits considerable benefits over CT by visualizing responses otherwise missed. Future studies will reveal if a decrease in tumour glucose uptake at one month correlates with the more clinically relevant endpoints PFS and OS. [Table: see text]

The effects of sorafenib and sunitinib on bone turnover markers in patients with bone metastases from renal cell carcinoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e16145-e16145
Author(s):  
C. Sahi ◽  
J. J. Knox ◽  
V. Hinder ◽  
S. Deva ◽  
D. Cole ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Bone Turnover ◽  
Bone Metastases ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Serum Samples ◽  
Baseline Serum ◽  
Increased Risk ◽  
Turnover Markers

e16145 Background: Bone metastases (BM) from renal cell carcinoma (RCC) are common and associated with poor outcomes. While the multi-tyrosine kinase inhibitors (TKI's) sunitinib and sorafenib have advanced the treatment of metastatic RCC, their efficacy on BM is unknown. Urinary N-telopeptide (uNTX) is a marker of bone turnover measured in nmol/mmol creatinine. Elevated uNTX levels correlate with an increased risk of skeletal related events and mortality in patients receiving bisphosphonates for BM from a range of primaries. In this pilot biomarker study we sought to prospectively evaluate the effects on BM of these multi-TKI's in RCC patients. Methods: Eligible patients had advanced RCC, at least one BM evident on imaging and no bisphosphonate exposure within 4 weeks. UNTX levels (OsteoMark) were measured at; baseline and weeks-1, 4, 8 and 12 after commencing either sunitinib or sorafenib. The primary endpoint was the percentage change (Ch) in uNTX levels from baseline. Serum samples were also collected for KIT and VEGFR-2 (Quantikine). Patients also completed pain (including bone pain) and quality of life questionnaires. Results: The uNTX results on the first 9 patients are presented in the table below (7 received sunitinib and 2 sorafenib). In this group, sVEGFR-2 and sKIT levels fell by week-1 and 4 respectively and at week-12 the mean % changes (95% CI) were -34% (-0.53,-0.14) and -38% (-0.58,-0.18). Conclusions: In patients with BM from RCC and at least moderately elevated uNTX levels at baseline, these multi-TKI's show a significant trend to decrease uNTX levels, but perhaps not as effectively as bone-specific therapies (e.g. bisphosphonates) do in other malignancies. SVEGFR-2 and sKIT levels also fell across the patient group over the same period. This pilot data raises questions about the activity of the multi-TKI's in BM from RCC and further research is needed. [Table: see text] [Table: see text]

scholarly journals Prognostic factors for overall survival with targeted therapy in Chinese patients with metastatic renal cell carcinoma

2014 ◽  
Vol 8 (11-12) ◽  
pp. 821 ◽  
Author(s):  
Juping Zhao ◽  
Xin Huang ◽  
Fukang Sun ◽  
Renyi Ma ◽  
Haofei Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Targeted Therapy ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Chinese Patients ◽  
Patient Specific ◽  
The Mean

Introduction: We wanted to identify the prognostic factors for overall survival (OS) in Chinese patients with metastatic renal cell carcinoma (mRCC) treated with first-line targeted therapy (sorafenib or sunitinib).Methods: We retrospectively reviewed clinical data from 119 mRCC patients administered sorafenib or sunitinib at the Ruijin Hospital since 2007. OS rates were calculated by the Kaplan-Meier method. Each variable was investigated univariately and then multivariately using a stepwise algorithm. A multivariate Cox regression model analyzed baseline variables for prognostic significance.Results: The mean patient age was 57 ± 12 years; 37 patients (31%) received sorafenib and 82 (69%) received sunitinib. The mean OS was 22.7 ± 15.6 months (range: 2.8–68.7). OS rates at year 1, 3 and 5 were 74%, 57%, and 36%, respectively. Univariate analysis identified significant negative prognostic factors (p < 0.05) as Eastern Cooperative Oncology Group (ECOG) performance status ≥2, symptoms, no prior nephrectomy, microscopic necrosis, ≥2 metastatic sites, presence of liver, bone, or pancreas metastasis, hemoglobin less than the lower limit of normal (female <115 g/L, male <130 g/L), and serum alkaline phosphatase greater than the upper limit of normal (126 IU/L) at baseline, as well as a relative dose intensity of targeting agents in the first month (1M-RDI) of <50%. Multivariate analysis of OS identified 4 independent predictors: no symptoms, no bone or pancreas metastasis, and 1M-RDI of targeting agents (≥50%).Conclusions: With targeted therapy, there is some change in the prognostic factors for mRCC and target drug therapies (1M-RDI ≥50%) play an important role in the prognosis of mRCC. Continued progress in the identification of patient-specific prognostic factors for mRCC will require further advances in the understanding of tumour biology.

The impact of UGT1A1 and SLCO1B1 genetic polymorphisms and pharmacokinetics of axitinib on clinical safety and efficacy in patients with metastatic renal cell carcinoma.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 448-448
Author(s):  
Shintaro Narita ◽  
Ryoma Igarashi ◽  
Norihiko Tsuchiya ◽  
Takamitsu Inoue ◽  
Nobuhiro Fujiyama ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Genetic Polymorphisms ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Clinical Safety ◽  
The Mean ◽  
The Impact

448 Background: We investigated the impact of genetic polymorphisms and pharmacokinetics of axitinib on adverse events, objective responses, and survival in patients with metastatic renal cell carcinoma (mRCC). Methods: In total, 53 patients with mRCC treated with axitinib were analyzed. Patient was classified as favorable (n = 5), intermediate (n = 36), and poor (n = 12) using the MSKCC risk classification system. High-performance liquid chromatography was used to measure serum axitinib levels. AUC0–12 (ng∙h/mL) was calculated using various serum levels at 0 to 12 h (C0–C12) following administration on day 7 of treatment. The genetic polymorphisms related to the drug pharmacokinetics, including SLCO1B1, SLCO1B3, SLCO2B1, ABCB1, ABCG2, CYP2C19, CYP3A5, and UGT1A1, were analyzed using PCR-RFLP analysis. Results: The most frequently reported ≥ G3 adverse events were hypertension (43.3%), proteinuria (30.2%), and anorexia (20.1%). The axitinib trough levels (C0) were significantly correlated with AUC0–12 of axitinib. Patients with axitinib C0 ≥ 10 ng/mL had a significantly higher rate of hand-foot syndrome ≥ G2 and hypothyroidism ≥ G2 than those with axitinib C0 < 10 ng/mL (p = 0.013, p = 0.005). The overall survival in patients with axitinib C0 ≥ 5 ng/mL was significantly better than that in those with axitinib C0 < 5 ng/mL (p = 0.022). The mean C0 and AUC0–12 values in patients with a poor metabolizer (*6/*6, *6/*28, and *28/*28) of UGT1A1 polymorphism were significantly higher than those in patients with an extensive metabolizer (p = 0.045, p = 0.035, respectively). The mean AUC0–12 value in patients with the SLCO1B1 *15 was significantly higher than that in those without the SLCO1B1 *15 (p = 0.038). Conclusions: Serum axitinib levels were associated with adverse events and overall survival of patients with mRCC. The genetic polymorphisms in UGT1A1 and SLCO1B1 may affect serum axitinib levels in patients with mRCC. Pharmacokinetics and genetic polymorphisms play important roles in the outcomes of patients with mRCC treated with axitinib.

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