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]

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.

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.

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.

Cardiotoxicity of tyrosine kinase inhibitors among veterans diagnosed with renal cell carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18248-e18248
Author(s):  
Kristine E. Lynch ◽  
Julie Ann Lynch ◽  
Olga Efimova ◽  
Jiwon Chang ◽  
Brygida Berse ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renal Cell Carcinoma ◽  
Congestive Heart Failure ◽  
Tyrosine Kinase ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cardiac Event ◽  
Kinase Inhibitors ◽  
Cardiac Events ◽  
Increased Risk

e18248 Background: Renal cell carcinoma (RCC) accounts for 3% of cancers diagnosed in the Department of Veterans Affairs (VA). Each year, 15% of the 1,600 veterans diagnosed with RCC have advanced disease. Until a decade ago, there were few non-surgical treatments for advanced RCC. Approval of multi-targeted tyrosine kinase inhibitors (TKIs), sorafenib, sunitinib, and pazopanib significantly improved outcomes for patients. However, several studies demonstrated increased risk of congestive heart failure, stroke, and thromboembolic events in patients treated with TKIs. We sought to understand whether veterans, who have a high prevalence of comorbidities, have increased risk of cardiac events following TKI treatment. Methods: This was a retrospective study of patients diagnosed with advanced RCC from 2006 to 2015. The outcome variable was whether the patient had congestive heart failure, cardiomyopathy, acute myocardial infarction, stroke, or cardiovascular related death after initiation of at least one TKI. Clinical, demographic, and pharmacy data came from the VA Central Cancer Registry and Corporate Data Warehouse. Patient characteristics across treatments were evaluated using chi square tests, t-tests and ANOVAs, as appropriate. We used multivariate logistic regression to determine the likelihood of cardiac event in patients treated with TKIs. Results: We identified 3,510 patients eligible for treatment who did not have a prior cardiac event. Overall, 1,840 patients were treated with at least one TKI prior to any cardiac event: 953 (27.1%) were treated with only sunitinib, 179 (5.1%) with sorafinib, 289 (8.2%) with pazopanib, and 419 (11.9%) treated with a combination. There were 909 who had a cardiac event (25.9% of all patients). Only 259 (28.49%) were treated with a TKI. On multivariate analysis, statistically significant predictors of a cardiac event were having diagnoses of dyslipidemia (Odds ratio [OR] 2.1, 95% confidence interval [CI] 1.7-2.5) or diabetes (OR 1.5, 95% CI 1.3-1.8). Patients treated with TKIs had a lower likelihood of a cardiac event (OR 0.3, CI 0.2-0.3). Conclusions: Among veterans, treatment with TKIs do not pose as great a risk for cardiac events as underlying comorbid diagnoses.

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

Comparing the Responses of Osseous Versus Soft-Tissue Metastases of Renal Cell Carcinoma to Receptor Tyrosine Kinase Inhibitors and Immunotherapy

Kidney Cancer ◽  
2020 ◽  
Vol 4 (3) ◽  
pp. 151-158
Author(s):  
Katherine Yuxi Tai ◽  
Jad M. El Abiad ◽  
Carol D. Morris ◽  
Mark Christopher Markowski ◽  
Adam S. Levin
Keyword(s):  
Renal Cell Carcinoma ◽  
Soft Tissue ◽  
Cell Carcinoma ◽  
Receptor Tyrosine Kinase ◽  
Renal Cell ◽  
Kinase Inhibitors ◽  
Tissue Response ◽  
Bone Response ◽  
Soft Tissue Response ◽  
Receptor Tyrosine Kinase Inhibitors

BACKGROUND: Checkpoint inhibitors and receptor tyrosine kinase inhibitors (RTKIs) have changed the standard of care for metastatic renal cell carcinoma (mRCC). Anecdotal evidence suggests these therapies may be less effective for treating bone than soft-tissue metastases. PURPOSE: We performed a retrospective review evaluating the relative clinical responses in soft-tissue and bone metastases in patients undergoing therapy using RTKIs and anti-programmed death-1 (PD-1) agents for mRCC. METHODS: Of the 2,212 patients in our institutional cancer registry with renal cell carcinoma (1997–2017), 68 (82 disease courses) were identified with measurable bone and soft-tissue metastases treated with RTKIs and/or PD-1s. Extent of metastasis was quantified at the time of therapy initiation (baseline) and at 3 months, 6 months, and 1 year. Changes in disease status were categorized as complete response, partial response, stable, mixed, or progression of disease according to RECIST v1.1 and MD Anderson criteria. These categories were further organized into “response to treatment” or “evidence of progression” to generate a generalized linear effects model with soft-tissue response as the independent variable and bone response as the dependent variable. Alpha = 0.05. RESULTS: Soft-tissue response correlated with bone response at 3 months (76 disease courses, p = 0.005) and 6 months (48 disease courses, p = 0.017). Of the patients with controlled soft-tissue disease, only 14 (19%) and 15 (32%) had progression in bone at 3 and 6 months, respectively. CONCLUSION: Contrary to anecdotal reports, osseous metastases do not appear to respond worse than soft-tissue metastases to treatment with these agents.

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