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Outcomes of Patients With Metastatic Renal Cell Carcinoma and Bone Metastases in the Targeted Therapy Era
Accepted Manuscript Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted-therapy era S. Kalra, J. Verma, B.J. Atkinson, S.F. Matin, C.G. Wood, J.A. Karam, S.H. Lin, S.L. Satcher, P. Tamboli, K. Sircar, P. Rao, P.G. Corn, N.M. Tannir, E. Jonasch PII:
S1558-7673(17)30010-1
DOI:
10.1016/j.clgc.2017.01.010
Reference:
CLGC 777
To appear in:
Clinical Genitourinary Cancer
Received Date: 20 September 2016 Revised Date:
7 January 2017
Accepted Date: 10 January 2017
Please cite this article as: Kalra S, Verma J, Atkinson B, Matin S, Wood C, Karam J, Lin S, Satcher S, Tamboli P, Sircar K, Rao P, Corn P, Tannir N, Jonasch E, Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted-therapy era, Clinical Genitourinary Cancer (2017), doi: 10.1016/j.clgc.2017.01.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted-therapy era.
Tamboli P1, Sircar K1, Rao P1, Corn PG1, Tannir NM1, Jonasch E1
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Kalra S1,2, Verma J3, Atkinson BJ1, Matin SF1, Wood CG1, Karam JA1, Lin SH1, Satcher SL1,
The University of Texas MD Anderson Cancer Center, Houston, TX1; Baylor College of Medicine,
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Houston, TX2, Department of Radiation Oncology, Department of Radiation Oncology, University
Corresponding author: Prof. Eric Jonasch
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of Miami, FL3
Department of Genitourinary Medical Oncology U.T. MD Anderson Cancer Center
Houston, TX 77030 Phone: 1-713-563-7232
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Fax: 1-713-563-7215
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1515 Holcombe Blvd, Unit 1374
email: [email protected]
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Total words:
Abstract: 259 words
Manuscript: 2,634 words
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Abstract Background: Bone metastases (BM) occur commonly in patients with metastatic renal cell
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carcinoma (mRCC). Tyrosine kinase inhibitors (TKIs) have improved outcomes for patients with mRCC. Data on outcomes of mRCC patients with BM treated with TKIs are limited. Herein, we describe outcomes of patients with BM treated with TKI therapy, and compare to outcomes in
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pre-TKI group.
Methods: Using institutional tumor registry, a retrospective review of patients with mRCC in the
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intervals of 2002-2003 and 2006-2007 was performed. Baseline characteristics were analyzed and overall-survival (OS) was estimated using Kaplan-Meier methods. Predictors of OS were analyzed using Cox regression.
Results: 375 patients were reviewed; 188 patients (50%) started treatment with TKIs and 187
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patients (50%) started treatment in pre-TKI-era. Distribution of patient characteristics was similar. Organ metastases were equally distributed, including BM in 48% of patients in each cohort. Median OS of patient treated with TKI therapy was 22 mo (95% CI: 17-25) compared to
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14 mo (95% CI: 10-19; p<0.01) for historical controls. Subset analysis of patients with BM in TKI-era demonstrated median OS of 24 mo (95% CI: 17-28) compared to 18 mo (95% CI: 10-
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21; p<0.01) in pre-TKI-era. Predictors of shorter OS were higher MSKCC score; liver, lung, and brain metastases; and multiple sites of BM (HR=1.38; 95% CI: 1.02-1.91; p=0.04). Rate of new BM development was the same in the pre-versus-post-TKI-era. Conclusion: Rate of BM development was the same in the pre-versus post-TKI era. The management of bone metastases in mRCC remains a challenge. Keywords: renal cell carcinoma, bone metastasis, tki, outcome, zoledronic acid, kidney
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Micro-Abstract Bone metastases (BM) are frequently seen in patients of metastatic renal cell carcinoma
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(mRCC). Tyrosine kinase inhibitors (TKI) have improved the overall outcomes. However, data for their impact in patients with BM seems to be limited. In this study, we describe outcomes of patients with BM treated with TKI therapy, and compare to outcomes in pre-TKI group. Our
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study shows that incidence of bone metastases is the same in the pre versus post TKI era. INTRODUCTION
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The rate of kidney and renal pelvis cancer has been increasing by 1.7% per year for the past 10 years, with 65,000 newly diagnosed cases accounting for nearly 14,080 deaths in 2015. Kidney cancer comprises approximately 3.9% of new cancers with a median age of 64 years. Renal cell carcinoma (RCC) is the most common kidney cancer accounting for 80-90% of cases with an
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overall 5-year survival rate of 45%. 1,2 RCC is subdivided into several histopathological entities, with clear cell RCC the most frequent tumor, followed by papillary and chromophobe variants. Nearly a third of RCC patients present with metastatic disease. In the last 10 years, the standard
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of care for a patient with metastatic RCC (mRCC) has rapidly evolved, with seven new agents approved for the treatment of mRCC between 2005 and 2012. Whether these new agents are
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universally beneficial or have impact on specific patient subpopulations is a subject of ongoing research.
The most common sites of metastases in mRCC include lung, lymph node and bone. Nearly 35% of patients with mRCC will develop bone metastases at some point during their disease course. Bone lesions tend to be osteolytic, which compromises bone integrity. They often lead to skeletal morbidities such as bone pain, pathological fractures and cord compression. Most of these
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complications require orthopedic intervention and/or palliative radiotherapy. Nearly 85% of patients with RCC metastatic to the bone experience skeletal related events (SREs) at some point
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in the course of the disease with a mean number of more than 2 SREs per patient. 3,4 Bone metastases are difficult to treat, and optimal management for bone metastases has yet to be defined in mRCC. Bone modifying agents (BMA) are widely used for preventing skeletal
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complications from bone metastases. Various studies have shown the efficacy of BMA such as zoledronic acid and denosumab in decreasing the incidence and delaying of skeletal related
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events in patients with mRCC.
Tyrosine kinase inhibitors (TKIs) have improved outcomes for patient with mRCC, paradoxically exposing patients with bone metastases to a longer time period where they are at risk of developing skeletal related events (SREs). Data on outcomes of mRCC patients with bone
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metastases treated with TKIs are limited but suggest a worse outcome compared to non-bone metastasis groups. Whether TKIs have altered the incidence of bone metastases in patients with mRCC compared with older systemic therapies (i.e. cytokines), and whether TKI treatment
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improved the survival of patients with mRCC with existing bone metastases is an open question. In this study, we sought to evaluate the effect of treatment with sunitinib and sorafenib on the
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development and progression of bone metastases in patients with mRCC. Patients were stratified into two groups: one that presented to The University of Texas MD Anderson Cancer Center in 2002 to 2003 and the other in 2006 to 2007, with the expectation that these time periods would segregate patients by TKI exposure status. We compared a large number of clinicopathological characteristics and used univariate and multivariable analyses to evaluate the potential treatment
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effects on the incidence of bone metastases, outcomes of patients with bone metastases and frequency of skeletal related events in the two cohorts.
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PATIENTS AND METHODS After Institutional Review Board approval, we conducted a single-center retrospective evaluation of patients with mRCC at the University of Texas MD Anderson Cancer Center (MDACC)
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during the periods of 1/1/2002 to 12/31/2003 and 1/1/2006 to 31/12/2007. Patients 18yrs of age or older with clear cell features on histological examination of their RCC were identified using
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the institutional tumor registry. Patients were stratified into TKI group and pre-TKI groups with the expectation that the two time periods would segregate them based on their exposure to TKI therapy. Patient characteristics including demographics, disease status, laboratory data,
Statistical analysis
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outcomes, incidence of skeletal related events and their interventions were analyzed.
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Patient characteristics were summarized using median and range for continuous variables and frequency and percentage for categorical variables. All statistical tests were two-sided and a p-
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value of less than 0.05 was considered statistically significant. Continuous variables in the two groups were compared using the Wilcoxon-rank sum tests and categorical variables were compared using Fisher’s exact test. Overall survival (OS) was estimated using Kaplan-Meier method. The log rank test was used to assess the difference between the pre-TKI and TKI groups. Cox proportional hazards regression model was used to assess the association between patient characteristics and OS, with goodness-of-fit assessed by the Grambsch-Therneau test and
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Martingale residual plots. Secondary analysis comparing outcomes of patients with metastases exclusively to bone and other sites was conducted in the pre-TKI versus TKI group. Exploratory analyses comparing the outcomes for burden of bone metastases and the impact of zoledronic
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acid were carried out using similar methods. All computations were completed in STATA (version 12).
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RESULTS
We identified a total of 375 patients with mRCC. 188 patients were treated in the pre-TKI era
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and 187 patients were treated in the TKI era. Baseline characteristics were comparable in the two groups (Table 1). There was a fairly even distribution of metastases to lung, mediastinal nodes, bone, brain and liver between the two groups. Eighty-nine patients either had or developed bone metastases in the pre-TKI and the TKI group, respectively.
According to MSKCC risk
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stratification, 14 (7%) of the pre-TKI patients were low risk, 111 (59%) were intermediate risk, and 63 (34%) were in the poor risk group, whereas in the TKI-group the numbers were 10 (5%), 108 (58%) and 69 (37%) in the low, intermediate and poor risk group respectively.
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Of the 178 patients that had bone metastases, a slightly smaller percentage of patients in the preTKI group had 1 site of bone metastases (33%) when compared to the TKI group (45%),
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although this difference was not statistically significant 1 (Table 2). In the pre-TKI group, spine 59 (66%), pelvis 42 (47%), ribs and sternum 39 (44%) were the common sites of metastases to the bone, and in the TKI group, spine 57 (64%), pelvis 37 (42%), femur and humerus 31 (35%) were the common sites. In the pre-TKI group, pain and fracture were seen in 65 (73%) and 43 (48%) patients, respectively. In the TKI group, 55 (62%) patients had pain and 30 (34%) patients
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had fracture. A significantly larger percentage of patients in the TKI group received zoledronic acid when compared to the pre-TKI group (Table 2).
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With a median follow-up of 20 months, the median OS in the pre-TKI group was 14 months (95% CI: 10-19 months, n=188) and in the TKI group it was 22 months (95% CI: 17-25 months, n=187, p<0.01). Based on the fitted univariate Cox model, we included variables with a p-value
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<0.10 in the multivariable Cox model. In the final multivariable Cox model for OS, nephrectomy was associated with an increased OS, whereas intermediate and poor risk stratification by
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MSKCC criteria, liver metastases, lung metastases and presence of higher number of bone metastases were associated with decreased OS (Table 3).
We also conducted a subset analysis comparing patients with bone metastases in the pre-TKI group to the TKI group. The median OS was 18 months in the pre-TKI group (95% CI: 10-21
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months) and 24 months in the TKI group (95%CI: 17-28 months and p-value<0.01) (Figure 1). We conducted further exploratory analyses in the pre-TKI and TKI group comparing outcomes of patients with bone metastases to those without bone metastases. In the pre-TKI group, the
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median OS for patients with bone metastases was 16 months (95% CI: 10-21 months) and for patients without bone metastases, it was 14 months (95% CI: 8-21 months, p-value=0.71)
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(Figure 2 A). In the TKI group, the median OS for patients with bone metastases was 22 months (95% CI: 15-26 months) whereas for patients without bone metastases it was 21 months (95% CI: 16-24, p-value=0.66) (Figure 2 B). Burden of bone metastases (1 versus ≥2) was associated with poor outcomes in both pre-TKI and TKI groups (Pre-TKI: One bone metastasis: 19 mo (95% CI: 9-30): >2 bone metastases: 11 mo (95% CI: 6-13); p-value= 0.004 (Figure 3 A); TKI:
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bone metastasis: 25 mo (95% CI: 16-41): >2 bone metastases: 17 mo (95% CI: 7-24) B. p-value = 0.11) (Figure 3 B).
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To assess the impact of zoledronic acid therapy, we performed a subset analysis including only those patients for whom we had a documented evidence of zoledronic acid administration. The distribution of baseline characteristics was comparable between the TKI and pre-TKI group for this subset analysis. The median overall survival for patients receiving zoledronic acid was 22 However, an assessment of baseline
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months and 11 months for those who did not.
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characteristics reveals that 18 percent of patients who received zolendronic acid were categorized as MSKCC poor risk versus 42 percent in the group who did not receive zolendronic acid. Univariate analysis did demonstrate a benefit to zolendronic acid treatment, but the uneven distribution of the patient population renders these findings suspect.
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DISCUSSION
We have performed an in-depth analysis of the development and progression of bone metastases in a large cohort of mRCC patients from the pre-versus post TKI era. Our access to longitudinal
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medical and pharmacy records allows us to carefully control for concomitant medication use. In our patient group we observed that patients with bone metastases had a statistically
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indistinguishable OS when compared to the overall group. We also found that multiple bone metastases were an independent predictor of poor outcome in a multivariable analysis and a solitary bone metastasis was prognostically favorable, regardless of how many other organs were involved with metastatic disease.
The latter is possibly due to organ specific immune
surveillance that prevents further organ specific lesion upon development of an index metastasis. A mechanistic understanding of why these patients developed only one lesion in bone, and why
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this was associated with a better outcome despite the presence metastases in other organs will undoubtedly assist us in developing our understanding of mRCC disease biology.
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Our analyses demonstrate that the rate of bone metastasis development was the same in the preTKI versus TKI treated patients. There was no proportionate advantage or disadvantage to patients with bone metastases treated in the pre-versus post TKI era. Thus, our data suggest that
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cytokines and antiangiogenic therapy are both equally ineffective at preventing the development of bone metastases. It is apparent that specific metastatic sites respond differently to systemic
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therapy. However, current and historical systemic therapy approaches are limited in their ability to impact patients with bone metastases. As seen with the studies published by Motzer et al and McKay et al, bone metastases remain a marker of poor prognosis in patients treated with antiangiogenic therapy.5,6
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This sobering observation leads to the question of what type of treatment would be effective against bone metastases in patients with mRCC. The bone microenvironment is fairly unique, and it stands to reason that therapies that predominantly impact the tumor microenvironment A xenograft bone model study comparing RCC to four other
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may provide particular benefit.
tumor types demonstrated the greatest degree of vasculogenesis in RCC tumors, and revealed
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high levels of vascular endothelial growth factor A (VEGFA) but very low levels of VEGF receptors in RCC xenografts relative to lung, prostate, breast and melanoma lines.7 The Ang-2 to Ang-1 ratio was high in RCC, suggesting a role for Ang-2-Tie-2 signaling axis in vessel maturation.7 These data suggest that non-VEGF driven angiogenic pathways may be responsible for vasculogenesis in RCC bone metastases. Satcher and colleagues showed that cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells compared to parental, liver, or lymph node-
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derived cells. Immunohistochemical analysis of cadherin-11 expression in a human RCC tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors.8 These data
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suggest that therapies targeting cadherin-11 may benefit mRCC patients harboring bone metastases. An overall schema summarizing currently known cytokines, chemokines and cells
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involved in the development of bone metastases is provided in Figure 4.
Recent studies testing MET inhibitors in prostate cancer and other cancers demonstrated
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dramatically decreased bone scan uptake in a number of patients after treatment.9 Emerging clinical data suggest that MET inhibition may have clinical benefit in patients with mRCC. Whether this benefit will be predominantly in patients with papillary RCC, who have amplification of or activating mutations in MET, or whether patients who have clear cell RCC with bone metastases will also benefit, remains to be seen. Cabozantinib is a small molecule
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inhibitor of MET, VEGFR2 and AXL receptors. In the METEOR trial, Choueiri et al have shown that in patients with refractory renal cell carcinoma, cabozantinib significantly increased
everolimus.10, 11
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overall survival, progression-free survival and improved the objective response compared to
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Our study did not address the potential benefit of mammalian target of rapamycin (mTOR) inhibitors in treating bone metastases. The large retrospective review of patients on various molecularly targeted therapies by McKay and colleagues did not differentiate between VEGF receptor targeted agents and mTOR inhibitors with regards to their ability to impact bone metastases.12 Further evaluation of this topic may shed some light on the potential benefit of this class of agents on the management of bone metastases.
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In our study, patients in the TKI group exhibited a lower incidence of skeletal-related events. However, a significantly higher percentage of the TKI cohort received zoledronic acid, a potential confounding factor. In a subset analysis, we do see an association between zoledronic
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acid use and superior clinical outcome, but our analysis is confounded by an imbalance in prognostic features between the patients who did and did not receive zoledronic acid. In a subanalysis of a prospective, randomized study assessing the benefit of zoledronic acid, patients
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with mRCC randomly assigned to zoledronic acid versus placebo demonstrated a significant decrease in skeletal related events (SREs) and time to first SRE.13 Retrospective reviews of the
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association between bisphosphonate use and a decrease in the incidence of SREs provide conflicting results.6,14,15 It is possible that TKI use impacted the SRE rate in our patient population, but in any case, it did not have a proportionate impact on OS. The median OS of patients in our TKI treated group was significantly longer than in the pre-TKI
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group, as has been inferred in phase III trials and in large cohort analyses.16 Since we did not a proportionate difference in bone-related outcomes between the TKI and the pre-TKI group, this
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survival benefit appears to be independent of bone related outcomes. Although our sample size is fairly large, our observations are based on a retrospective analysis,
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which is subject to inherent biases and limitations. Our data are also limited by accuracy and availability of documentation, the absence of randomization or blinding, and difficulty establishing cause and effect. In summary, we show that outcome of patients with bone metastases did not change between the pre-TKI and the TKI era. The rate of bone metastasis development was unaltered between the two groups. The incidence of skeletal related events was lower in patients on TKIs, but this
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patient group exhibited a far higher rate of bisphosphonate use. Patients with a solitary bone metastasis did significantly better than patients with multiple bone metastases regardless of systemic therapy received, hinting at a unique tumor or host biology that could be exploited
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therapeutically. As a field, we need to aggressively advance our understanding of the molecular biology underpinning bone metastases in RCC, so we can develop better therapies to combat this
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highly morbid disease manifestation. Clinical practice point
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From this study, we observe that the relative outcome of patients with bone metastases does not change between the pre-TKI and the TKI era and the rate of bone metastasis development is unaltered between the two groups. The incidence of skeletal related events is lower in patients on TKIs, which may be confounded by a far higher rate of bisphosphonate use. Patients with a
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solitary bone metastasis do significantly better than patients with multiple bone metastases regardless of systemic therapy received, hinting at a unique tumor or host biology that could be exploited therapeutically. As a field, we need to aggressively advance our understanding of the
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molecular biology underpinning bone metastases in RCC, so we can develop better therapies to combat this highly morbid disease manifestation.
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DISCLOSURES
Authors SK, JV, BJA, SFM, CGW, PT, SL, RLS, KS, PR, PGC have no financial disclosures. JAK reports personal fees from Pfizer. NMT received grants from UT MD Anderson Cancer Center; has Research Support and is on Advisory Board for Pfizer, Novartis, GlaxoSmithKline, and is on Advisory Board for Aveo. EJ reports grants from Pfizer, GSK, Novartis, Onyx and Exelixis and Personal fees from Pfizer, GSK and Novartis.
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Motzer RJ, Jonasch E, Agarwal N, et al. Kidney Cancer, Version 2.2014. J Natl Compr
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Canc Netw. 2014;12(2):175–182. Woodward E, Jagdev S, McParland L, et al. Skeletal complications and survival in renal cancer patients with bone metastases. Bone. 2011;48(1):160–166. doi:10.1016/j.bone.2010.09.008.
Zekri J, Ahmed N, Coleman RE, Hancock BW. The skeletal metastatic complications of renal cell carcinoma. 2001.
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Wood SL, Brown JE. Skeletal metastasis in renal cell carcinoma: current and future
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management options. Cancer Treat Rev. 2012;38(4):284–291. doi:10.1016/j.ctrv.2011.06.011.
Motzer RJ, Escudier B, Bukowski R, et al. Prognostic factors for survival in 1059 patients treated with sunitinib for metastatic renal cell carcinoma. Br J Cancer. 2013;108(12):2470–2477. doi:10.1038/bjc.2013.236.
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McKay RR, Kroeger N, Xie W, et al. Impact of bone and liver metastases on patients with
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renal cell carcinoma treated with targeted therapy. European Urology. 2014;65(3):577– 584. doi:10.1016/j.eururo.2013.08.012. Xie C, Schwarz EM, Sampson ER, et al. Unique angiogenic and vasculogenic properties of renal cell carcinoma in a xenograft model of bone metastasis are associated with high
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Satcher RL, Pan T, Cheng C-J, et al. Cadherin-11 in renal cell carcinoma bone metastasis. PLoS ONE. 2014;9(2):e89880. doi:10.1371/journal.pone.0089880.
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levels of vegf-a and decreased ang-1 expression. J Orthop Res. 2012;30(2):325–333. doi:10.1002/jor.21500.
Brown MS, Chu GH, Kim HJ, et al. Computer-aided quantitative bone scan assessment of
prostate cancer treatment response. Nucl Med Commun. 2012;33(4):384–394. doi:10.1097/MNM.0b013e3283503ebf.
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Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ. Cabozantinib versus everolimus in advanced renal-cell carcinoma. New England Journal of Medicine. 2015 Nov 5;373(19):1814-23. doi:10.1056/NEJMoa1510016.
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Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, Hammers HJ,
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Donskov F, Roth BJ, Peltola K, Lee JL. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. The Lancet Oncology. 2016 Jun 5. doi:10.1016/S1470-2045(16)30107-3. McKay RR, Lin X, Perkins JJ, Heng DYC, Simantov R, Choueiri TK. Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma. European Urology. 2014. Mar;65(3):577-84. doi:10.1016/j.eururo.2014.02.040.
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Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma.
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Cancer. 2003;98(5):962–969. doi:10.1002/cncr.11571.
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Beuselinck B, Wolter P, Karadimou A, et al. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer.
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2012;107(10):1665–1671. doi:10.1038/bjc.2012.385. 15.
Santini D, Procopio G, Porta C, et al. Natural history of malignant bone disease in renal cancer: final results of an Italian bone metastasis survey. PLoS ONE. 2013;8(12):e83026. doi:10.1371/journal.pone.0083026.
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Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma.
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Table 1. Baseline patient characteristics (categorical variables as N (%) and continuous variables as median values) P=
Pre-TKI
TKI
Number in each group
188
187
Age
59.3
58.5
Male
135(72%)
114(61%)
Caucasian
143(76%)
Prior nephrectomy
100(54%)
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Variable
Bone
0.73
100(53%)
0.61
Brain Lungs
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Mediastinal Nodes
89(29%)
89(33%)
0.96
34(18%)
33(18%)
0.87
17(9%)
20(11%)
0.61
129(69%)
121(64%)
0.34
49(26%)
62(33%)
0.15
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Liver
0.46
Fuhrman Nuclear Grade
21(11%)
24(13%)
3
67(36%)
52(28%)
4
38(20%)
44(24%)
NA
62(33%)
67(36%)
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2
MSKCC group6
0.02
148(79%)
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Metastases
0.35
0.55
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14(7%)
10(5%)
Intermediate
111(59%)
108(58%)
Poor
63(34%)
69(37%)
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Good
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Table 2. Distribution of bone metastases in patients Pre-TKI
Variable
TKI
P= 0.08
29(33%)
40(45%)
2
40(45%)
29(33%)
>3
20(23%)
20(23%)
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Sites
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1
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Number
Pelvis
42(47%)
37(42%)
0.45
59(66%)
57(64%)
0.75
39(45%)
27(30%)
0.06
33(37%)
31(35%)
0.75
2(2%)
2(2%)
1.0
4(5%)
13(15%)
0.03
65(73%)
55(62%)
0.11
43(48%)
30(34%)
0.05
Radiation therapy
47(53%)
34(38%)
0.05
Surgery
42(47%)
38(43%)
0.54
Spine Ribs and Sternum
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Femur and Humerus Scapula
Pain
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Fracture
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Other
Zoledronic acid Yes
0.001 43(48%)
85(96%)
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20(22%)
4(5%)
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NA
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Table 3. Multivariable Cox proportional hazards model for OS HR
95% CI
P=
Nephrectomy
0.36
0.25-0.51
0.001
>2 vs 1
1.38
1.02-1.91
0.04
MSKCC Inter vs good
1.34
1.23-1.99
0.01
MSKCC Poor vs good
2.42
0.38-0.87
0.01
Pre-TKI vs TKI
1.03
Liver
2.17
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0.98-1.11
0.06
1.33-3.5
0.002
1.11-2.27
0.001
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Bone metastasis
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Variable
1.59
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Lung
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S1558-7673(17)30010-1
DOI:
10.1016/j.clgc.2017.01.010
Reference:
CLGC 777
To appear in:
Clinical Genitourinary Cancer
Received Date: 20 September 2016 Revised Date:
7 January 2017
Accepted Date: 10 January 2017
Please cite this article as: Kalra S, Verma J, Atkinson B, Matin S, Wood C, Karam J, Lin S, Satcher S, Tamboli P, Sircar K, Rao P, Corn P, Tannir N, Jonasch E, Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted-therapy era, Clinical Genitourinary Cancer (2017), doi: 10.1016/j.clgc.2017.01.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Outcomes of patients with metastatic renal cell carcinoma and bone metastases in the targeted-therapy era.
Tamboli P1, Sircar K1, Rao P1, Corn PG1, Tannir NM1, Jonasch E1
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Kalra S1,2, Verma J3, Atkinson BJ1, Matin SF1, Wood CG1, Karam JA1, Lin SH1, Satcher SL1,
The University of Texas MD Anderson Cancer Center, Houston, TX1; Baylor College of Medicine,
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Houston, TX2, Department of Radiation Oncology, Department of Radiation Oncology, University
Corresponding author: Prof. Eric Jonasch
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of Miami, FL3
Department of Genitourinary Medical Oncology U.T. MD Anderson Cancer Center
Houston, TX 77030 Phone: 1-713-563-7232
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Fax: 1-713-563-7215
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1515 Holcombe Blvd, Unit 1374
email: [email protected]
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Total words:
Abstract: 259 words
Manuscript: 2,634 words
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Abstract Background: Bone metastases (BM) occur commonly in patients with metastatic renal cell
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carcinoma (mRCC). Tyrosine kinase inhibitors (TKIs) have improved outcomes for patients with mRCC. Data on outcomes of mRCC patients with BM treated with TKIs are limited. Herein, we describe outcomes of patients with BM treated with TKI therapy, and compare to outcomes in
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pre-TKI group.
Methods: Using institutional tumor registry, a retrospective review of patients with mRCC in the
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intervals of 2002-2003 and 2006-2007 was performed. Baseline characteristics were analyzed and overall-survival (OS) was estimated using Kaplan-Meier methods. Predictors of OS were analyzed using Cox regression.
Results: 375 patients were reviewed; 188 patients (50%) started treatment with TKIs and 187
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patients (50%) started treatment in pre-TKI-era. Distribution of patient characteristics was similar. Organ metastases were equally distributed, including BM in 48% of patients in each cohort. Median OS of patient treated with TKI therapy was 22 mo (95% CI: 17-25) compared to
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14 mo (95% CI: 10-19; p<0.01) for historical controls. Subset analysis of patients with BM in TKI-era demonstrated median OS of 24 mo (95% CI: 17-28) compared to 18 mo (95% CI: 10-
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21; p<0.01) in pre-TKI-era. Predictors of shorter OS were higher MSKCC score; liver, lung, and brain metastases; and multiple sites of BM (HR=1.38; 95% CI: 1.02-1.91; p=0.04). Rate of new BM development was the same in the pre-versus-post-TKI-era. Conclusion: Rate of BM development was the same in the pre-versus post-TKI era. The management of bone metastases in mRCC remains a challenge. Keywords: renal cell carcinoma, bone metastasis, tki, outcome, zoledronic acid, kidney
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Micro-Abstract Bone metastases (BM) are frequently seen in patients of metastatic renal cell carcinoma
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(mRCC). Tyrosine kinase inhibitors (TKI) have improved the overall outcomes. However, data for their impact in patients with BM seems to be limited. In this study, we describe outcomes of patients with BM treated with TKI therapy, and compare to outcomes in pre-TKI group. Our
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study shows that incidence of bone metastases is the same in the pre versus post TKI era. INTRODUCTION
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The rate of kidney and renal pelvis cancer has been increasing by 1.7% per year for the past 10 years, with 65,000 newly diagnosed cases accounting for nearly 14,080 deaths in 2015. Kidney cancer comprises approximately 3.9% of new cancers with a median age of 64 years. Renal cell carcinoma (RCC) is the most common kidney cancer accounting for 80-90% of cases with an
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overall 5-year survival rate of 45%. 1,2 RCC is subdivided into several histopathological entities, with clear cell RCC the most frequent tumor, followed by papillary and chromophobe variants. Nearly a third of RCC patients present with metastatic disease. In the last 10 years, the standard
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of care for a patient with metastatic RCC (mRCC) has rapidly evolved, with seven new agents approved for the treatment of mRCC between 2005 and 2012. Whether these new agents are
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universally beneficial or have impact on specific patient subpopulations is a subject of ongoing research.
The most common sites of metastases in mRCC include lung, lymph node and bone. Nearly 35% of patients with mRCC will develop bone metastases at some point during their disease course. Bone lesions tend to be osteolytic, which compromises bone integrity. They often lead to skeletal morbidities such as bone pain, pathological fractures and cord compression. Most of these
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complications require orthopedic intervention and/or palliative radiotherapy. Nearly 85% of patients with RCC metastatic to the bone experience skeletal related events (SREs) at some point
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in the course of the disease with a mean number of more than 2 SREs per patient. 3,4 Bone metastases are difficult to treat, and optimal management for bone metastases has yet to be defined in mRCC. Bone modifying agents (BMA) are widely used for preventing skeletal
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complications from bone metastases. Various studies have shown the efficacy of BMA such as zoledronic acid and denosumab in decreasing the incidence and delaying of skeletal related
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events in patients with mRCC.
Tyrosine kinase inhibitors (TKIs) have improved outcomes for patient with mRCC, paradoxically exposing patients with bone metastases to a longer time period where they are at risk of developing skeletal related events (SREs). Data on outcomes of mRCC patients with bone
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metastases treated with TKIs are limited but suggest a worse outcome compared to non-bone metastasis groups. Whether TKIs have altered the incidence of bone metastases in patients with mRCC compared with older systemic therapies (i.e. cytokines), and whether TKI treatment
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improved the survival of patients with mRCC with existing bone metastases is an open question. In this study, we sought to evaluate the effect of treatment with sunitinib and sorafenib on the
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development and progression of bone metastases in patients with mRCC. Patients were stratified into two groups: one that presented to The University of Texas MD Anderson Cancer Center in 2002 to 2003 and the other in 2006 to 2007, with the expectation that these time periods would segregate patients by TKI exposure status. We compared a large number of clinicopathological characteristics and used univariate and multivariable analyses to evaluate the potential treatment
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effects on the incidence of bone metastases, outcomes of patients with bone metastases and frequency of skeletal related events in the two cohorts.
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PATIENTS AND METHODS After Institutional Review Board approval, we conducted a single-center retrospective evaluation of patients with mRCC at the University of Texas MD Anderson Cancer Center (MDACC)
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during the periods of 1/1/2002 to 12/31/2003 and 1/1/2006 to 31/12/2007. Patients 18yrs of age or older with clear cell features on histological examination of their RCC were identified using
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the institutional tumor registry. Patients were stratified into TKI group and pre-TKI groups with the expectation that the two time periods would segregate them based on their exposure to TKI therapy. Patient characteristics including demographics, disease status, laboratory data,
Statistical analysis
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outcomes, incidence of skeletal related events and their interventions were analyzed.
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Patient characteristics were summarized using median and range for continuous variables and frequency and percentage for categorical variables. All statistical tests were two-sided and a p-
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value of less than 0.05 was considered statistically significant. Continuous variables in the two groups were compared using the Wilcoxon-rank sum tests and categorical variables were compared using Fisher’s exact test. Overall survival (OS) was estimated using Kaplan-Meier method. The log rank test was used to assess the difference between the pre-TKI and TKI groups. Cox proportional hazards regression model was used to assess the association between patient characteristics and OS, with goodness-of-fit assessed by the Grambsch-Therneau test and
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Martingale residual plots. Secondary analysis comparing outcomes of patients with metastases exclusively to bone and other sites was conducted in the pre-TKI versus TKI group. Exploratory analyses comparing the outcomes for burden of bone metastases and the impact of zoledronic
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acid were carried out using similar methods. All computations were completed in STATA (version 12).
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RESULTS
We identified a total of 375 patients with mRCC. 188 patients were treated in the pre-TKI era
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and 187 patients were treated in the TKI era. Baseline characteristics were comparable in the two groups (Table 1). There was a fairly even distribution of metastases to lung, mediastinal nodes, bone, brain and liver between the two groups. Eighty-nine patients either had or developed bone metastases in the pre-TKI and the TKI group, respectively.
According to MSKCC risk
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stratification, 14 (7%) of the pre-TKI patients were low risk, 111 (59%) were intermediate risk, and 63 (34%) were in the poor risk group, whereas in the TKI-group the numbers were 10 (5%), 108 (58%) and 69 (37%) in the low, intermediate and poor risk group respectively.
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Of the 178 patients that had bone metastases, a slightly smaller percentage of patients in the preTKI group had 1 site of bone metastases (33%) when compared to the TKI group (45%),
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although this difference was not statistically significant 1 (Table 2). In the pre-TKI group, spine 59 (66%), pelvis 42 (47%), ribs and sternum 39 (44%) were the common sites of metastases to the bone, and in the TKI group, spine 57 (64%), pelvis 37 (42%), femur and humerus 31 (35%) were the common sites. In the pre-TKI group, pain and fracture were seen in 65 (73%) and 43 (48%) patients, respectively. In the TKI group, 55 (62%) patients had pain and 30 (34%) patients
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had fracture. A significantly larger percentage of patients in the TKI group received zoledronic acid when compared to the pre-TKI group (Table 2).
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With a median follow-up of 20 months, the median OS in the pre-TKI group was 14 months (95% CI: 10-19 months, n=188) and in the TKI group it was 22 months (95% CI: 17-25 months, n=187, p<0.01). Based on the fitted univariate Cox model, we included variables with a p-value
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<0.10 in the multivariable Cox model. In the final multivariable Cox model for OS, nephrectomy was associated with an increased OS, whereas intermediate and poor risk stratification by
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MSKCC criteria, liver metastases, lung metastases and presence of higher number of bone metastases were associated with decreased OS (Table 3).
We also conducted a subset analysis comparing patients with bone metastases in the pre-TKI group to the TKI group. The median OS was 18 months in the pre-TKI group (95% CI: 10-21
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months) and 24 months in the TKI group (95%CI: 17-28 months and p-value<0.01) (Figure 1). We conducted further exploratory analyses in the pre-TKI and TKI group comparing outcomes of patients with bone metastases to those without bone metastases. In the pre-TKI group, the
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median OS for patients with bone metastases was 16 months (95% CI: 10-21 months) and for patients without bone metastases, it was 14 months (95% CI: 8-21 months, p-value=0.71)
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(Figure 2 A). In the TKI group, the median OS for patients with bone metastases was 22 months (95% CI: 15-26 months) whereas for patients without bone metastases it was 21 months (95% CI: 16-24, p-value=0.66) (Figure 2 B). Burden of bone metastases (1 versus ≥2) was associated with poor outcomes in both pre-TKI and TKI groups (Pre-TKI: One bone metastasis: 19 mo (95% CI: 9-30): >2 bone metastases: 11 mo (95% CI: 6-13); p-value= 0.004 (Figure 3 A); TKI:
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bone metastasis: 25 mo (95% CI: 16-41): >2 bone metastases: 17 mo (95% CI: 7-24) B. p-value = 0.11) (Figure 3 B).
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To assess the impact of zoledronic acid therapy, we performed a subset analysis including only those patients for whom we had a documented evidence of zoledronic acid administration. The distribution of baseline characteristics was comparable between the TKI and pre-TKI group for this subset analysis. The median overall survival for patients receiving zoledronic acid was 22 However, an assessment of baseline
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months and 11 months for those who did not.
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characteristics reveals that 18 percent of patients who received zolendronic acid were categorized as MSKCC poor risk versus 42 percent in the group who did not receive zolendronic acid. Univariate analysis did demonstrate a benefit to zolendronic acid treatment, but the uneven distribution of the patient population renders these findings suspect.
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DISCUSSION
We have performed an in-depth analysis of the development and progression of bone metastases in a large cohort of mRCC patients from the pre-versus post TKI era. Our access to longitudinal
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medical and pharmacy records allows us to carefully control for concomitant medication use. In our patient group we observed that patients with bone metastases had a statistically
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indistinguishable OS when compared to the overall group. We also found that multiple bone metastases were an independent predictor of poor outcome in a multivariable analysis and a solitary bone metastasis was prognostically favorable, regardless of how many other organs were involved with metastatic disease.
The latter is possibly due to organ specific immune
surveillance that prevents further organ specific lesion upon development of an index metastasis. A mechanistic understanding of why these patients developed only one lesion in bone, and why
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this was associated with a better outcome despite the presence metastases in other organs will undoubtedly assist us in developing our understanding of mRCC disease biology.
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Our analyses demonstrate that the rate of bone metastasis development was the same in the preTKI versus TKI treated patients. There was no proportionate advantage or disadvantage to patients with bone metastases treated in the pre-versus post TKI era. Thus, our data suggest that
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cytokines and antiangiogenic therapy are both equally ineffective at preventing the development of bone metastases. It is apparent that specific metastatic sites respond differently to systemic
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therapy. However, current and historical systemic therapy approaches are limited in their ability to impact patients with bone metastases. As seen with the studies published by Motzer et al and McKay et al, bone metastases remain a marker of poor prognosis in patients treated with antiangiogenic therapy.5,6
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This sobering observation leads to the question of what type of treatment would be effective against bone metastases in patients with mRCC. The bone microenvironment is fairly unique, and it stands to reason that therapies that predominantly impact the tumor microenvironment A xenograft bone model study comparing RCC to four other
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may provide particular benefit.
tumor types demonstrated the greatest degree of vasculogenesis in RCC tumors, and revealed
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high levels of vascular endothelial growth factor A (VEGFA) but very low levels of VEGF receptors in RCC xenografts relative to lung, prostate, breast and melanoma lines.7 The Ang-2 to Ang-1 ratio was high in RCC, suggesting a role for Ang-2-Tie-2 signaling axis in vessel maturation.7 These data suggest that non-VEGF driven angiogenic pathways may be responsible for vasculogenesis in RCC bone metastases. Satcher and colleagues showed that cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells compared to parental, liver, or lymph node-
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derived cells. Immunohistochemical analysis of cadherin-11 expression in a human RCC tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors.8 These data
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suggest that therapies targeting cadherin-11 may benefit mRCC patients harboring bone metastases. An overall schema summarizing currently known cytokines, chemokines and cells
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involved in the development of bone metastases is provided in Figure 4.
Recent studies testing MET inhibitors in prostate cancer and other cancers demonstrated
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dramatically decreased bone scan uptake in a number of patients after treatment.9 Emerging clinical data suggest that MET inhibition may have clinical benefit in patients with mRCC. Whether this benefit will be predominantly in patients with papillary RCC, who have amplification of or activating mutations in MET, or whether patients who have clear cell RCC with bone metastases will also benefit, remains to be seen. Cabozantinib is a small molecule
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inhibitor of MET, VEGFR2 and AXL receptors. In the METEOR trial, Choueiri et al have shown that in patients with refractory renal cell carcinoma, cabozantinib significantly increased
everolimus.10, 11
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overall survival, progression-free survival and improved the objective response compared to
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Our study did not address the potential benefit of mammalian target of rapamycin (mTOR) inhibitors in treating bone metastases. The large retrospective review of patients on various molecularly targeted therapies by McKay and colleagues did not differentiate between VEGF receptor targeted agents and mTOR inhibitors with regards to their ability to impact bone metastases.12 Further evaluation of this topic may shed some light on the potential benefit of this class of agents on the management of bone metastases.
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In our study, patients in the TKI group exhibited a lower incidence of skeletal-related events. However, a significantly higher percentage of the TKI cohort received zoledronic acid, a potential confounding factor. In a subset analysis, we do see an association between zoledronic
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acid use and superior clinical outcome, but our analysis is confounded by an imbalance in prognostic features between the patients who did and did not receive zoledronic acid. In a subanalysis of a prospective, randomized study assessing the benefit of zoledronic acid, patients
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with mRCC randomly assigned to zoledronic acid versus placebo demonstrated a significant decrease in skeletal related events (SREs) and time to first SRE.13 Retrospective reviews of the
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association between bisphosphonate use and a decrease in the incidence of SREs provide conflicting results.6,14,15 It is possible that TKI use impacted the SRE rate in our patient population, but in any case, it did not have a proportionate impact on OS. The median OS of patients in our TKI treated group was significantly longer than in the pre-TKI
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group, as has been inferred in phase III trials and in large cohort analyses.16 Since we did not a proportionate difference in bone-related outcomes between the TKI and the pre-TKI group, this
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survival benefit appears to be independent of bone related outcomes. Although our sample size is fairly large, our observations are based on a retrospective analysis,
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which is subject to inherent biases and limitations. Our data are also limited by accuracy and availability of documentation, the absence of randomization or blinding, and difficulty establishing cause and effect. In summary, we show that outcome of patients with bone metastases did not change between the pre-TKI and the TKI era. The rate of bone metastasis development was unaltered between the two groups. The incidence of skeletal related events was lower in patients on TKIs, but this
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patient group exhibited a far higher rate of bisphosphonate use. Patients with a solitary bone metastasis did significantly better than patients with multiple bone metastases regardless of systemic therapy received, hinting at a unique tumor or host biology that could be exploited
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therapeutically. As a field, we need to aggressively advance our understanding of the molecular biology underpinning bone metastases in RCC, so we can develop better therapies to combat this
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highly morbid disease manifestation. Clinical practice point
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From this study, we observe that the relative outcome of patients with bone metastases does not change between the pre-TKI and the TKI era and the rate of bone metastasis development is unaltered between the two groups. The incidence of skeletal related events is lower in patients on TKIs, which may be confounded by a far higher rate of bisphosphonate use. Patients with a
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solitary bone metastasis do significantly better than patients with multiple bone metastases regardless of systemic therapy received, hinting at a unique tumor or host biology that could be exploited therapeutically. As a field, we need to aggressively advance our understanding of the
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molecular biology underpinning bone metastases in RCC, so we can develop better therapies to combat this highly morbid disease manifestation.
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DISCLOSURES
Authors SK, JV, BJA, SFM, CGW, PT, SL, RLS, KS, PR, PGC have no financial disclosures. JAK reports personal fees from Pfizer. NMT received grants from UT MD Anderson Cancer Center; has Research Support and is on Advisory Board for Pfizer, Novartis, GlaxoSmithKline, and is on Advisory Board for Aveo. EJ reports grants from Pfizer, GSK, Novartis, Onyx and Exelixis and Personal fees from Pfizer, GSK and Novartis.
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Donskov F, Roth BJ, Peltola K, Lee JL. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. The Lancet Oncology. 2016 Jun 5. doi:10.1016/S1470-2045(16)30107-3. McKay RR, Lin X, Perkins JJ, Heng DYC, Simantov R, Choueiri TK. Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma. European Urology. 2014. Mar;65(3):577-84. doi:10.1016/j.eururo.2014.02.040.
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Lipton A, Zheng M, Seaman J. Zoledronic acid delays the onset of skeletal-related events and progression of skeletal disease in patients with advanced renal cell carcinoma.
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Table 1. Baseline patient characteristics (categorical variables as N (%) and continuous variables as median values) P=
Pre-TKI
TKI
Number in each group
188
187
Age
59.3
58.5
Male
135(72%)
114(61%)
Caucasian
143(76%)
Prior nephrectomy
100(54%)
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Variable
Bone
0.73
100(53%)
0.61
Brain Lungs
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Mediastinal Nodes
89(29%)
89(33%)
0.96
34(18%)
33(18%)
0.87
17(9%)
20(11%)
0.61
129(69%)
121(64%)
0.34
49(26%)
62(33%)
0.15
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Liver
0.46
Fuhrman Nuclear Grade
21(11%)
24(13%)
3
67(36%)
52(28%)
4
38(20%)
44(24%)
NA
62(33%)
67(36%)
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2
MSKCC group6
0.02
148(79%)
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Metastases
0.35
0.55
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14(7%)
10(5%)
Intermediate
111(59%)
108(58%)
Poor
63(34%)
69(37%)
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Good
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Table 2. Distribution of bone metastases in patients Pre-TKI
Variable
TKI
P= 0.08
29(33%)
40(45%)
2
40(45%)
29(33%)
>3
20(23%)
20(23%)
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Sites
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1
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Number
Pelvis
42(47%)
37(42%)
0.45
59(66%)
57(64%)
0.75
39(45%)
27(30%)
0.06
33(37%)
31(35%)
0.75
2(2%)
2(2%)
1.0
4(5%)
13(15%)
0.03
65(73%)
55(62%)
0.11
43(48%)
30(34%)
0.05
Radiation therapy
47(53%)
34(38%)
0.05
Surgery
42(47%)
38(43%)
0.54
Spine Ribs and Sternum
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Femur and Humerus Scapula
Pain
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Fracture
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Other
Zoledronic acid Yes
0.001 43(48%)
85(96%)
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20(22%)
4(5%)
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NA
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Table 3. Multivariable Cox proportional hazards model for OS HR
95% CI
P=
Nephrectomy
0.36
0.25-0.51
0.001
>2 vs 1
1.38
1.02-1.91
0.04
MSKCC Inter vs good
1.34
1.23-1.99
0.01
MSKCC Poor vs good
2.42
0.38-0.87
0.01
Pre-TKI vs TKI
1.03
Liver
2.17
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0.98-1.11
0.06
1.33-3.5
0.002
1.11-2.27
0.001
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Bone metastasis
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Variable
1.59
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Lung
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