- Email: [email protected]
Management of bone complications in patients with genitourinary malignancies
ARTICLE IN PRESS
Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−11
Seminars Article
Management of bone complications in patients with genitourinary malignancies Eric Ballon-Landaa, Justine Panianb, Ithaar H. Derweesha, Rana R. McKayb,* a
b
Department of Urology, University of California San Diego, San Diego, CA Department of Medicine, Division of Hematology/Oncology, University of California San Diego, San Diego, CA Received 15 January 2019; received in revised form 28 July 2019; accepted 28 September 2019
Abstract Skeletal metastases are common in genitourinary malignancies—including prostate cancer, renal cell carcinoma, and urothelial cancer— and portend significant morbidity and poor prognosis. The presence of skeletal metastases can result in decreased quality of life and increased morbidity. Strategies can be employed to prevent bone-related complications including lifestyle modifications and dietary supplementation. Additionally, pharmacologic agents exist to prevent bone loss and may be appropriate for patients at high risk of fragility-related or skeletal complications, such as pathologic fracture related to bone metastases. Finally, advancement in effective systemic treatments, particularly novel hormone-targeted agents and immunotherapies, may limit the morbidity of advanced disease and delay the onset of skeletalrelated complications. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Genitourinary malignancy; Osteoporosis; Bone metastasis; Fracture Abbreviations: RCC, renal cell carcinoma; ADT, androgen deprivation therapy; SRE, skeletal related event; SSE, symptomatic skeletal event; OS, overall survival; BMD, bone mineral density; RANKL, receptor activator nuclear factor-kb ligand; RANK, receptor activator nuclear factor-kb; TGF-b, transforming growth factor-b; SD, standard deviation; ONJ, osteonecrosis of the jaw; RR, relative risk; mCRPC, metastatic castration-resistant prostate cancer; HR, hazard ratio; CKD, chronic kidney disease; TKI, tyrosine kinase inhibitor; CSPC, castration-sensitive prostate cancer; ORR, objective response rate
1. Introduction Skeletal metastases are common in genitourinary malignancies—including prostate cancer, renal cell carcinoma (RCC), and urothelial cancer—and portend significant morbidity and poor prognosis. The presence of skeletal metastases can result in decreased quality of life and survival [1]. Additionally, therapies used to treat genitourinary malignancies, specifically androgen deprivation therapy (ADT) for the treatment of men with prostate cancer, can have negative consequences on the skeleton. Two objective and distinguishable endpoints for clinical trials of patients with bone metastases are skeletal related events (SREs) and symptomatic skeletal events (SSEs). These outcomes were established in order to objectively *Corresponding author. Tel.: 8588226185. E-mail address: [email protected] (R.R. McKay). https://doi.org/10.1016/j.urolonc.2019.09.028 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
and reproducibly measure the impact of bone-targeting agents in patients with bone metastases. SREs include spinal cord compression, surgery or radiation to the bone, and pathological fracture detected by imaging or symptoms [2]. Several studies have demonstrated that the number of bone metastases and presence of a prior SRE are predictive of an increased risk of SRE [3,4]. SSEs are restricted to clinically apparent events and exclude incidental imaging findings [5]. The proportion of genitourinary cancer patients with bone metastases, rates of SREs/SSEs and overall survival (OS) data are delineated in Table 1. In addition to challenges related to bone metastases, bone-related complications, including treatment-related osteoporosis, may occur as a consequence of cancerdirected therapy. Loss of bone mineral density (BMD) can be observed after 6 months of ADT and longer ADT duration results in a higher risk of BMD loss and fragilityrelated fracture incidence [5,6].
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
2
Table 1 Epidemiology of bone metastatic genitourinary malignancy Disease
Metastatic cases per year
Percent patients with bone metastasis
Rates of SREs/SSEs
Overall survival (months)
Prostate cancer Renal cell carcinoma Urothelial cancer
8235 10454 3276
52% 30% 30%
44% 74% >50%
42 29.3 10.3
SRE = skeletal related event; SSE = symptomatic skeletal event.
Herein we describe the current knowledge of the biology of bone metastases and osteoporotic fractures related to the treatment of genitourinary malignancy, review the clinical data supporting the use of bone-targeting agents, and highlight management options for patients with genitourinary malignancies who develop bone metastases or receive therapy which can have a detrimental effect on the skeleton. 2. Pathophysiology of treatment-related osteoporosis and bone metastases 2.1. Bone physiology The skeleton is a metabolically active organ undergoing dynamic changes through the coupling of 2 processes: bone resorption by osteoclasts and bone formation by osteoblasts. Osteoclasts are generated by the differentiation of macrophage precursor cells, a process which requires colony stimulating factor-1 and receptor activator nuclear factorkb ligand (RANKL) to stimulate receptor activator of nuclear factor kb (RANK) on osteoclast precursor cell surfaces [7]. RANKL is released from osteoblasts, activating T-cells and stromal cells, and binds to the RANK transmembrane signaling receptor on osteoclast precursor cells promoting differentiation and activation [7]. Activated osteoclasts resorb bone via transcellular acid transport and generation of an acidic compartment on the bone surface to resorb bone [8]. Osteoblasts, which differentiate from mesenchymal progenitor cells via transforming growth factor-b (TGF-b), calcitonin, and platelet-derived growth factor, secrete and mineralize the bone matrix [9]. 2.2. Pathophysiology of treatment-related osteoporosis Estrogen is essential in regulating bone health in both men and women. In men, testosterone undergoes peripheral aromatization to form estradiol. Estradiol directly induces osteoblasts to maintain bone formation and inhibits osteoclast activity, resulting in decreased bone resorption [10,11]. In the castrate state, less peripheral testosterone is converted to estradiol; the sharp decrease in estradiol induces BMD loss and increases fracture risk [12]. Additionally, chemotherapy may result in BMD loss via indirect effects, such as loss of ovarian function in women, and direct effects on osteoblast and osteoclast function [13]. Additionally, corticosteroids, important in the treatment of men with
prostate cancer and administered concurrently with chemotherapy and newer targeted therapies, have direct effects on the bone and result in reduced osteoblast activity and increased osteoclastogenesis [14]. Limited studies have evaluated the direct impact of checkpoint inhibitors, such as nivolumab and ipilimumab, on the bone microenvironment. Immune-mediated side effects related to checkpoint inhibition, such as hypophysitis, can cause hormonal dysregulation and may have a potential negative impact on bone health via downstream effects. The diagnosis of osteoporosis is based on BMD, typically measured at the hip and spine on dual-energy X-ray absorptiometry. The World Health Organization has defined thresholds for osteopenia and osteoporosis based upon BMD measurements compared with a young adult reference population (T-score). Osteopenia is defined as BMD of 1.0 to 2.5 standard deviations (SD) below the mean (Tscore 1.0 to 2.5) and osteoporosis is defined as BMD of more than 2.5 SD below the mean (T-score < 2.5). The risk of fracture doubles for every SD decrease in BMD [15]. Additionally, the FRAX algorithm with or without the incorporation of BMD measurements can be utilized to estimate of fracture risk (https://www.sheffield.ac.uk/FRAX/). 2.3. Pathophysiology of bone metastasis Bone metastasis destabilizes the delicate balance of bone formation and resorption. Interactions between tumor and stromal cells in the bone microenvironment result in a vicious cycle of bone injury and tumor growth. Osteolytic lesions are characterized by stimulated osteoclast activity and bone resorption via TGF- b1 and RANKL-mediation activity [16]. Some cancers, including prostate cancer, stimulate osteoblast activity via various mechanisms including parathyroid hormone releasing protein, resulting in abnormal bone tissue production and down-regulation of tumorrelated bone resorption [17]. 2.4. Pharmacology of osteoclast-targeting agents Several pharmacotherapeutic agents are active against bone metastases and treatment-related bone loss (Table 2). Various adverse effects associated with these agents require close monitoring. Patients receiving denosumab, a monoclonal antibody against RANKL-ligand, and zoledronic acid, a bisphosphonate which inhibits bone resorption, can
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
3
Table 2 Pharmacology of osteoclast targeted therapies for SRE/SSE prevention Agent
FDA-approved indications
Mechanism of action
Mode of administration
Clearance
Side effects of interest
Zoledronic acid26
mCRPC or solid tumors with bone metastases 1. Increase bone mass in men receiving ADT for prostate cancer 2. Prevention of SREs in patient with bone metastases from solid tumors Treatment of mCRPC with symptomatic bone metastases and no visceral metastases
Osteoclast apoptosis and inhibition
Intravenous
Renal
Nephrotoxicity, hypocalcemia, ONJ
Monoclonal antibody against RANKL, inhibiting osteoclast activation
Subcutaneous
Reticulo-endothelial System
Hypocalcemia, ONJ
Calcium mimetic, delivers alpha particles to osteoblastic bone metastases
Intravenous
Gastro-intestinal
Thrombocytopenia, neutropenia, anemia, nausea, diarrhea, vomiting
Denosumab26
Radium-22336
ADT = androgen deprivation therapy; mCRPC = metastatic castration-resistant prostate cancer; ONJ = osteonecrosis of the jaw; RANKL = receptor activator nuclear factor-kb ligand; SRE = skeletal related event; SSE = symptomatic skeletal event.
experience hypocalcemia and thus calcium supplementation is recommended in this population; osteonecrosis of the jaw (ONJ) is a clinically significant but rare adverse effect. A phase III randomized trial of 1,904 metastatic prostate cancer patients randomized to receive zoledronic acid or denosumab found that both groups experienced hypocalcemia, although at higher rates in the denosumab group compared to zoledronic acid (13% vs. 6%, respectively) [18]. Thirtyfour patients (1.8%) experienced ONJ, of whom 17 (77%) were receiving denosumab. 2.5. Unique considerations in selected populations Due to the possible development of ONJ with antiresorptive agents, the use of osteoclast-targeted therapy in the setting of existing dental disease is challenging. The American Dental Association recommends that patients receiving antiresorptive therapy undergo regular dental examination and that providers review the risk of ONJ prior to initiation [19]. Oral and dental disease should be optimized prior to initiation of antiresorptive medications; a dental examination with radiographs should be completed prior to therapy to rule out occult disease, and procedures that can be performed prior to initiation of therapy are warranted. Unfortunately, high quality evidence is lacking regarding the optimal timing of use of antiresportive agents in the context of dental procedures in which the bone is manipulated (such as extractions or implant placement) [20,21]. Therefore, an individualized decision should be made on the part of patient, medical provider, and dental team caring for the patient. Use of osteoclast-targeting agents in patients with existing chronic kidney disease (CKD) poses another unique challenge secondary to medication side effects and the
propensity of CKD to lead to bone demineralization and calcium dysregulation [22]. Patients with CKD are at higher baseline risk for fragility-related fractures secondary to medical renal disease; in the setting of bone metastases, particular consideration should be given toward SRE prevention. Unfortunately, the nephrotoxicity of zoledronic acid limits its use in this population, with dosing modifications recommended to limit toxicity in patients with CKD [23,24]. Clinicians should also monitor for severe hypocalcemia in this high-risk population, and both denosumab and zoledronic acid should be used with caution in patients with stage 4 or greater CKD for this reason [25].
3. Prostate cancer 3.1. Management of treatment-related osteoporosis Strategies to prevent bone loss and osteoporosis in patients with genitourinary malignancies include nonpharmacologic approaches and the use of bone-targeting agents in select individuals. Lifestyle and nutritional modifications include routine weight-bearing exercise, physical activity, limited tobacco and alcohol use, and adequate intake of calcium and vitamin D. Fracture risk reduction also includes fall prevention including vision, hearing, balance and home safety assessments [13]. Micronutrient supplementation in men with prostate cancer receiving ADT is supported by guideline recommendations [26]. Calcium intake up to 1,200 mg/day is recommended by multiple national medical societies in divided doses no larger than 600 mg [13,27]. Vitamin D allows for gastrointestinal calcium absorption and normal bone mineralization. Guideline societies recommend 400 to 1000 IU of vitamin D daily [13]. The optimal
ARTICLE IN PRESS 4
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
25-OH D level is 30 ng/mL; patients who are found to have lower levels can be more aggressively supplemented. Because vitamin D insufficiency is common in the general population and in patients with cancer, many patients may require more aggressive supplementation initially. A population-based meta-analysis of 7 randomized-controlled trials pooling 9,820 elderly patients (men and women) randomized to receive vitamin D supplementation with or without calcium vs. calcium or placebo demonstrated a 26% and 23% relative risk (RR) reduction of hip and nonvertebral fractures, respectively; this reduction was limited to patients taking higher doses (700-800 IU/day) [28]. Pharmacologic therapeutic strategies for bone health include bisphosphonates and RANKL inhibition. Although a number of agents (pamidronate, alendronate, neridronate) demonstrated improvement of BMD loss in small studies, none has been individually demonstrated to prevent fragility-related fractures. A meta-analysis pooling 15 studies of 2,634 men with prostate cancer receiving ADT randomized to receive a bisphosphonate vs. placebo found that men receiving bisphosphonates had a significantly reduced risk of osteoporosis-related fractures (RR = 0.80) and osteoporosis (RR = 0.39), with the greatest risk reduction seen with zoledronic acid [29]. Denosumab increases BMD in prostate cancer patients and reduces fracture risk [30]. In a study of 1,438 men receiving ADT for prostate cancer, patients were randomized to denosumab or placebo. After 36 months, men receiving the denosumab had significantly increased BMD at all measured sites (lumbar spine, total hip, femoral neck, distal radius) and a decreased likelihood of vertebral fracture (RR = 0.38). Despite this evidence, the optimal selection of pharmacologic agent and dosing regimen has not been established. Clinicians should discuss these data with patients as optional management strategies. 3.2. Management of bone metastasis 3.2.1. Osteoclast inhibition in castration-resistant prostate cancer Osteoclast-targeting agents have been tested in men with metastatic castration-resistant prostate cancer (mCRPC) (Table 3). In a phase III, double-blind, placebo-controlled trial, Saad et al. randomly assigned men with mCRPC to receive zoledronic acid at 4 mg, 8 mg or placebo every 3 weeks for 15 months; the primary endpoint was the proportion of men experiencing at least 1 SRE. Men receiving zoledronic acid had significantly lower rates of SREs (33% with 4 mg vs. 44% with placebo; P = 0.021) and longer time to first SRE (>410 days with 4 mg and 321 days with placebo; P = 0.011) [31]. The rate of pathologic fractures was lower compared to placebo (13.1% with 4 mg vs. 22.1% for placebo). Fizazi et al. performed a phase III trial randomizing 1,904 men with mCRPC with bone metastases to receive
denosumab or zoledronic acid with primary noninferiority outcome of time to SRE, and a secondary superiority outcome of denosumab over zoledronic acid [18]. In addition to demonstrating noninferior time to first SRE for denosumab compared to zoledronic acid (20.7 vs. 17.1 months, P = 0.0002), this trial demonstrated the superiority of denosumab over zoledronic acid in improving time to first SRE (P = 0.008). The CALGB 70604 phase III, open-label trial randomized 1,822 patients with metastatic breast or prostate cancer or multiple myeloma to receive zoledronic acid every 4 weeks or every 12 weeks for 2 years (689 mCRPC patients) [32]. The trial demonstrated non-inferiority of a 12-week dosing interval for prevention of SREs. No differences were demonstrated for pain scores, performance status, ONJ, or kidney dysfunction. 3.2.2. Radiopharmaceuticals in castration-resistant prostate cancer While strontium-89 and samarium-153, b-emitting radiopharmaceuticals, demonstrated efficacy in palliation of bone pain, utilization of these agents has been limited given toxicity and administration challenges [33]. Radium223 dichloride is a bone-seeking a-emitter that targets calcium hydroxyapatite in osteoblastic bone lesions, promoting DNA strand breaks and tumor cell death [34]. The ALSYMPCA phase III, double-blind, placebo-controlled trial randomized men with symptomatic bony metastases without known visceral metastases to receive radium223 or placebo [35]. The primary outcome of OS was met by interim analysis, which demonstrated a 3.6 month increase in median survival and a 5.8 month increase in time to first SSE [36]. This landmark trial established radium-223 as the only radiopharmaceutical to improve OS in mCRPC. The ERA-223 phase III, double-blind, placebo-controlled trial randomized men with minimally symptomatic, bone-predominant mCRPC to receive radium-223 plus abiraterone, a CYP17 inhibitor, vs. placebo plus abiraterone [37]. The trial was stopped early after interim analyses demonstrated increased fracture risk among patients receiving radium-223 plus abiraterone (26% vs. 10%) and decreased time to SSE for the intervention group (22.3 vs. 26.0 months; Hazard ratio (HR) 1.12, P = 0.263). Sixty percent of SSEs occurred at sites without metastatic disease. Additionally, there was a nonstatistically significant decrease in OS in the radium223 plus abiraterone arm (30.7 vs. 33.3 months; HR = 1.195; P = 0.1280). Based on these data, radium223 should not be given with abiraterone. 3.2.3. Disease control in castration-resistant prostate cancer and bone metastases Building on earlier trials for bone-targeting agents in prostate cancer, modern trials evaluating disease-targeted
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
5
Table 3 Bone-specific outcomes in notable trial of genitourinary malignancy Trial
Number of patients
Patient population
Metastatic castration-resistant prostate cancer Saad et al., JNCI 2002 643 mCRPC with bone metastasis
Arms
SRE or SSE (% or months)
OS (months)
1: Zoledronic acid 4 mg 2: Zoledronic acid 8!4 mg 3: Placebo (1:1:1)
Fracture: 1: 33.2%, P = 0.015 2: 38.5%, P = 0.054 3: 44.2% Time to SRE (days): 1: 13.8, P = 0.011 2: 30.3, P = 0.491 3: 26.8 SRE: 1: 28.6% 2: 29.5% P < 0.001 for noninferiority Time to SRE: 1: 20.7 2: 17.2 P = 0.008 for superiority Time to SRE: 1: 15.6 2: 9.8 HR 0.66, P < 0.001 SSE: 1: 33% 2: 38% Time to SSE: 1: 15.6 2: 9.8 HR 0.66, P = 0.00037 SRE: 1: 22.6% 2: 24.6% Time to SRE: 1: 25.0 2: 20.3 HR 0.62, P = 0.0001 SRE: 1: 32% 2: 37% Time to SRE: 1: 31.1 2: 31.3 HR=0.72, P < 0.0001 SRE: 1: 36% 2: 40% Time to SRE: 1: 16.7 2: 13.3 HR 0.69, P = 0.0001
Not assessed
Himelstein et al., JAMA 2017 CALGB 70604
1,822
mCRPC (n = 689), Breast cancer (n = 855), Multiple myeloma (n = 278) with bone metastasis
1: Zoledronic acid q12 weeks 2: Zoledronic acid q4 weeks (1:1)
Fizazi et al., Lancet 2011
1,904
mCRPC with bone metastasis
1: Denosumab + IV placebo 2: Zoledronic acid + subcutaneous placebo (1:1)
Parker et al., NEJM 2013 ALSYMPCA
921
mCRPC with 2+ bone metastases, no known visceral metastasis
1: Radium-223 2: Placebo (2:1 randomization)
Sartor et al., Lancet Oncol 2014 ALSYMPCA
921
mCRPC, 2+ bone metastases, no known visceral metastasis
1: Radium-223 2: Placebo (2:1)
Logothetis et al., Lancet Oncol 2012 COU-AA-301
797
mCRPC, postchemotherapy
1: Abiraterone + prednisone 2: Placebo + prednisone (2:1)
Loriot et al., Lancet Oncol 2015 PREVAIL
1,717
mCRPC, prechemotherapy
1: Enzalutamide 2: Placebo (1:1)
Fizazi et al., Lancet Oncol 2014 AFFIRM
1,199
mCRPC, postchemotherapy
1: Enzalutamide 2: Placebo (2:1)
Not assessed
1: 19.4 2: 19.8 HR 1.03, P = 0.65
1: 14.9 2: 11.3 HR 0.7, P < 0.001 1: 14.9 2: 11.3 HR 0.7, P < 0.001
1: 15.8 2: 11.2 HR 0.74, P < 0.0001
1: 32.4 2: 30.2 HR 0.71, P < 0.001
1: 18.4 2: 13.6 HR 0.63, P < 0.0001
(continued)
ARTICLE IN PRESS 6
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
Table 3 (Continued) Trial
Number of patients
Castration-sensitive prostate cancer Smith et al., 645 JCO 2014 CALGB 90202
James et al., Lancet Oncol 2016 STAMPEDE
Renal cell carcinoma Lipton et al., Cancer 2003
2,962
74
Escudier et al., JCO 2018a
142
McKay et al., CCR 2018
30
Motzer et al., NEJM 2018 CheckMate 214
1,096b
Motzer et al., NEJM 2015 CheckMate 025
821c
Rosen et al., JCO 2003
773
Patient population
Arms
SRE or SSE (% or months)
OS (months)
CSPC with bone metastases
1: Zoledronic acid 2: Placebo (1:1)
HR 0.88, P = 0.29
High risk, locally advanced, metastatic or recurrent prostate cancer
1: Standard of care (SOC) + Zoledronic acid 2: SOC + docetaxel 3: SOC + both 4: SOC (1:1:1:2)
Time to SRE: 1: 31.9 2: 29.8 HR 0.97, P = 0.39 SRE: 1. 12.9%; HR 0.89, P = 0.221 2. 9.46%; HR 0.60, P < 0.001 3. 9.12%; HR 0.55, P < 0.001 4. 27.7% Time to SRE: 1. HR 0.94, P = 0.564 2. 68.0, P < 0.001 3. 68.3, P < 0.001 4. 61.4
RCC with bone metastasis
1: Zolendronic acid (4 mg or 8 gm) 2: Placebo
RCC, previously treated
1: Cabozantinib 2: Everolimus (1:1 randomization)
RCC with bone metastasis − cohort study
1: Pazopanib + radium-223 (treatment naı¨ve) 2: Sorafenib + radium-223 (previously treated)
RCC, treatment naı¨ve
1: Nivolumab + Ipilimumab 2: Sunitinib (1:1)
RCC, previously treated
1: Nivolumab 2: Everolimus (1:1)
Not evaluated
Bone metastasis secondary to lung cancer and other solid tumors not including breast and prostate cancer
1: Denosumab 2: Zoledronic acid
SRE 1: Not assessed 2: Not assessed Time to SRE 1: 20.6 2: 16.3 P = 0.06
SRE 1: 37% 2: 74% P = 0.015 Time to SRE: 1: Median not reached 2: 2.37, P = 0.006 SRE: 1: 23% 2: 29% Time to SRE 1: Not evaluated 2: Not evaluated SSE 1: 47% 2: 13% Time to SSE 1: 5.8 2: Not reached Not evaluated
1: Not reached; HR 0.94, P = 0.45 2: 81; HR 0.73, P = 0.006 3: 76; HR 0.82, P = 0.022 4. 71
1: 9.70 2: 7.11 P = 0.179
1: 20.1 2: 12.1 HR 0.54, 95%CI 0.34-0.84
1: 16.6 2: 14.2
1: Not reached 2: 26.0 HR 0.63, P < 0.001 1: 25.0 2: 19.6 HR 0.73, P = 0.002 Not assessed
(continued)
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
7
Table 3 (Continued) Trial
Urothelial cancer Henry et al., JCO 2011
Zaghloul et al., IJCO 2010
Number of patients
1,776
40
Patient population
Arms
SRE or SSE (% or months)
OS (months)
Solid tumors or multiple myeloma, bone metastasis
1: Zoledronic acid 2: Placebo
1: 6.68 2: 6.35 P = 0.623
Bladder cancer with bone metastasis
1: Zoledronic acid 2: Placebo
SRE 1: 38% 2: 47% Time to SRE 1: 7.57 2: 5.36 P = 0.023 SRE 1: 60% 2: 90% Time to SRE 1: 3.68 2: 1.84
Not assessed
CSPC = castration-sensitive prostate cancer; HR = hazard ratio; mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; ; RCC = renal cell carcinoma; SRE = skeletal related event; SSE = symptomatic skeletal event. a Subgroup analysis of METEOR trial including patients with bone metastases. b Checkmate 214: 192 bone-metastatic patients included in the study. c Checkmate 025: 146 bone-metastatic patients included in the study.
therapies have incorporated SREs/SSEs and bone-specific endpoints as secondary efficacy outcomes. Because the approval of current agents, such as abiraterone and enzalutamide, followed the trials demonstrating the efficacy of bisphosphonates and denosumab, the added utility of bonetargeting agents in combination with these agents has not been fully characterized. Abiraterone was studied in 2 randomized trials in patients pre- (COU-AA-302) and post- (COU-AA-301) chemotherapy. These studies established the use of abiraterone in patients with mCRPC given improvement of OS [38]. Secondary analyses from COU-AA-301 evaluated the impact of the intervention on pain control and SREs and found that abiraterone increased the time to SRE by 4.7 months [39]. The efficacy of enzalutamide, a next generation androgen receptor inhibitor, was evaluated in patients with mCRPC pre- (PREVAIL) and post- (AFFIRM) chemotherapy [40,41]. These studies demonstrated improvements of OS and also SREs with enzalutamide [42,43]. 3.2.4. Osteoclast inhibition in metastatic castrationsensitive prostate cancer Given the evidence to support the use of bisphosphonate therapy in mCRPC, several trials have evaluated zoledronic acid in castration-sensitive prostate cancer (CSPC). The CALGB 90202 phase III, double-blind, placebo-controlled trial randomized 645 men with metastatic CSPC on ADT to zoledronic acid or placebo [44]. No difference was seen in time to SRE, progression-free survival, or OS between the 2 arms. The STAMPEDE trial, a randomized controlled trial using a multi-arm, multi-stage platform in men with clinically localized, node-positive, or metastatic prostate cancer, evaluated the impact of zoledronic acid on 2,692
men with CSPC initiating ADT [45]. There was no improvement in time to SRE, failure-free survival, or OS. Thus, zoledronic acid is not recommended for men with CSPC to prevent SRE, but can be used in selected patients at high risk of fragility-related fracture. 3.2.5. Osteoclast inhibition in metastasis prevention The onset of bone metastasis in high-risk mCRPC portends worse survival and burdensome symptoms. Smith et al. performed a phase III, double-blind, placebo-controlled trial which randomized 1,432 men with nonmetastatic CRPC to denosumab or placebo [46]. The study met its primary endpoint of improvement in bone metastasisfree survival, however, OS was unchanged (HR = 1.01, P = 0.91). ONJ occurred in 4.6% of patients and hypocalcemia in 1.3%. Due to the limited degree of benefit balanced with the toxicity risk, the FDA did not extend approval of denosumab for metastasis prevention [47]. Bisphosphonate use is more limited in the setting of nonmetastatic CSPC. The Zeus trial randomized 1,433 men with nonmetastatic high-risk CSPC and found no difference in time to bone metastasis or OS after a median follow-up of 4.8 years [48]. Zoledronic acid was found to be ineffective in preventing bone metastases in high-risk nonmetastatic CSPC patients. 4. Renal cell carcinoma Bone health in patients with RCC is impacted by the prevalence of CKD in the population and the propensity of RCC to establish bone metastasis. While CKD in RCC is associated with surgical extirpation, patients with RCC also experience higher rates of medical renal disease [49,50].
ARTICLE IN PRESS 8
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
Retrospective data suggest that patients who undergo nephron sparing surgery rather than radical nephrectomy may be somewhat protected from the risk of fragility-related fractures [51]. Bone metastasis is observed in 30% of metastatic RCC patients and is associated with worse OS [52]. This has been demonstrated in several large analyses, including a review from the International Metastatic Renal Cell Carcinoma Database (IMDC) of 2027 patients with metastatic RCC. It demonstrated that patients with bone metastasis exhibited a shorter median OS (14.9 vs. 25.1 months; P < 0.0001) than patients without bone metastasis [53].
open-label, phase III trial of 658 patients with RCC who progressed after VEGF-targeted therapy and were randomized to receive cabozantinib vs. everolimus [60]. Treatment with cabozantinib resulted in improved objective response rate (ORR), progression-free survival, and OS compared to everolimus. A subset analysis was conducted in patients with bone metastases and demonstrated similar results [61]. Furthermore, SREs were less frequent with cabozantinib (23% vs.. 29%) and correlated with bone scan response (20% vs. 10%). Overall, cabozantinib exhibited greater efficacy in RCC patients with bone metastasis compared to everolimus.
4.1. Osteoclast inhibition in metastatic RCC with bone metastasis
4.3. Radium-223 in metastatic RCC with bone metastasis
Evidence supporting the use of osteoclast-targeted therapies in genitourinary malignancies other than prostate is limited. The efficacy of zoledronic acid was studied in 773 solid tumor patients with bone metastasis in a large phase III trial [54]. Subset analysis of RCC patients from this trial demonstrated that treatment with zoledronic acid significantly reduced the risk of SREs by 61% in the intervention arm (P = 0.008) and prolonged the time to first SRE without impacting OS [55]. The risk of ONJ may be increased when osteoclast-targeted therapies are combined with targeted therapies. Small, retrospective studies have investigated the side effects of tyrosine kinase inhibitors (TKIs) with respect to ONJ in RCC patients [56]. Combination therapy with TKIs and bisphosphonates is associated with a 10% to 30% frequency of ONJ [57]. The use of osteoclast-targeted therapies in combination with TKI warrants careful patient selection. Denosumab was approved for use in RCC based upon data from a double-blind phase III trial which randomized 1,776 patients with advanced cancer (excluding breast and prostate cancer) with bone metastasis or multiple myeloma to receive zoledronic acid or denosumab [58]. The proportion of RCC patients in the sample size was not available. Denosumab was noninferior compared to zoledronic acid in delaying time to SRE, the primary endpoint. OS and adverse effects were not significantly different between the 2 groups. Based upon these findings, clinicians can consider using denosumab or zoledronic acid for select patients with bone metastases and RCC. 4.2. Cabozantinib in metastatic RCC with bone metastasis Cabozantinib is an oral TKI that is FDA-approved for the treatment of RCC [59]. Because of its inhibitory effect on vascular endothelial growth factor (VEGF) and MET, cabozantinib is useful in patients with bone metastases, which tend to overexpress VEGF and MET in several solid tumors, including RCC [60]. The efficacy of cabozantinib was compared to everolimus in the METEOR trial, an
A pilot study in patients with RCC with bone metastases investigated the safety and efficacy radium-223 combined with VEGF targeted therapy in RCC [62]. Thirty patients with RCC were included in 2 cohorts: treatment naı¨ve— given pazopanib (n = 15)—and previously treated—given sorafenib (n = 15); both cohorts received radium-223. The primary endpoint was change in bone turnover markers and study demonstrated declines from baseline in all bone turnover markers at weeks 8 and 16. The authors concluded that the combination of radium-223 with VEGF-targeted therapy is feasible and safe. A phase II clinical trial of radium223 combined with cabozantinib is currently in development (RADICAL).
4.4. Immunotherapy in metastatic RCC with bone metastasis Despite several landmark immunotherapy trials for RCC, subset analyses in patients with bone metastases are limited. The Checkmate 025 phase III, open-label trial randomized 821 patients with previously treated RCC to nivolumab or everolimus [63]. Nivolumab demonstrated a 5.4 month improvement in OS and improved ORR (25% vs. 5%) compared to everolimus. Overall, 18% (n = 146) of patients enrolled had bone metastases. The Checkmate 214 phase III trial randomized treatment-naı¨ve clear cell RCC patients to nivolumab plus ipilimumab or sunitinib [64]. At a median follow-up of 25.2 months, there was a significant improvement in OS, ORR, and complete response rate with nivolumab plus ipilimumab vs. suntinib in patients with intermediate and poor-risk RCC. Overall, 21.1% (n = 231) of patients had bone metastases; subgroup analysis for OS in this group favored nivolumab plus ipilimumab. Immunotherapy may be particularly beneficial to patients with bone metastasis, though this has not been robustly investigated. Ongoing studies are evaluating immunotherapy and cabozantinib, which is particularly relevant to patients with bone metastasis.
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
9
Table 4 Ongoing trials in genitourinary malignancy with bone-specific outcomes Trial name (NCI number)
Expected Patient population patients
Arms
Primary endpoint
Expected completion date
Prevention of symptomatic skeletal events with Denosumab administered every 4 weeks vs. every 12 weeks − NCT02051218 Efficacy and safety of systemic treatments of bone metastases from kidney cancer in patients treated with targeted therapies (MOSCAR) − NCT03408652 Study Comparing Denosumab with Standard Treatment in Urothelial Cancer Patients With Bone Metastases − NCT03520231
1380
mCRPC; metastatic breast adenocarcinoma
Arm A: denosumab every 4 weeks Arm B: denosumab every 12 weeks
Time to first SSE noninferiority
December 2022
Metastatic RCC
Arm A: denosumab or zolendronic acid Arm B: control arm (no specific treatment)
Time to first SRE
June 2024
Metastatic urothelial carcinoma
Arm A: Denosumab plus chemotherapy Arm B: Placebo plus chemotherapy
Difference in mean percentage change in serum c-telopeptide
June 2020
216
50
mCRPC = metastatic castration-resistant prostate cancer; RCC = renal cell carcinoma; SRE = skeletal related event; SSE = symptomatic skeletal event.
5. Urothelial cancer Bone metastasis is found in approximately 30% of metastatic urothelial cancer patients [52]. Specific data on this patient population is limited by the poor survival of bonemetastatic urothelial cancer patients. Within these limitations, the management recommendations for urothelial cancer patients with bone metastasis are based upon larger studies of solid tumor patients. 5.1. Osteoclast inhibition in metastatic urothelial cancer Bisphosphonate therapy in metastatic urothelial cancer is supported by data from evaluation of solid tumors with bone metastases. Urothelial cancer was included in the phase III trial of zoledronic acid vs. placebo that led to its FDAapproval [54]. In this study, zoledronic acid significantly reduced the proportion of patients experiencing SREs (38% for 4 mg and 35% for 8/4 mg zoledronic acid vs. 44% for placebo). No subset analysis of urothelial cancer was performed. A small trial of 40 patients with metastatic urothelial cancer randomized participants to zoledronic acid or placebo group, with the intervention group experiencing a lower incidence of SREs compared to placebo [65]. One-year OS was increased (36% vs. 0%, respectively). 6. Clinical considerations Bone metastases in genitourinary malignancy portend worse outcomes and confer significant morbidity, and as such clinicians should attend closely to the overall disease and bone-specific needs of these patients. In select patients at risk of treatment-related bone loss, an evaluation for osteoporosis should be considered, including recommendations for lifestyle changes including weight bearing activity and
consideration of calcium and vitamin D supplementation. Bone-targeting agents including zoledronic acid and denosumab can be considered to prevent bone loss and decrease the risk of osteoporotic fractures. Clinicians should consider dental assessment prior to initiating antiresorptive therapies due to the infrequent but serious risk of ONJ. Several trial are ongoing that are evaluating osteoclast targeting agents in patients with genitourinary malignancies (Table 4). While the evidence regarding SRE prevention in mCRPC largely supports denosumab or zoledronic acid, the different routes, schedules, and toxicity should be considering with tailoring therapy for a specific individual. Additionally, several prostate cancer directed therapies including abiraterone, enzalutamide, and radium-223 have demonstrated a positive impact on bone-related outcomes. In RCC and urothelial malignancies, there is evidence to support the use of osteoclast-targeted therapy for SRE prevention and improvement of bone health. With the proliferation of targeted therapies and immunotherapies extending the survival of patients with genitourinary malignancy, supporting patients’ bone health is increasingly important to limit the morbidity of advanced disease. Conflicts of interest RRM receives research funding from Bayer and Pfizer. RRM serves as a consultant for Janssen, Novartis, Tempus, Bristol-Myers Squibb, and Exelixis. References [1] Froehner M, H€olscher T, Hakenberg OW, Wirth MP. Treatment of bone metastases in urologic malignancies. Urol Int 2014;93(3):249–56. [2] Saylor PJ, Armstrong AJ, Fizazi K, Freedland S, Saad F, Smith MR, et al. New and emerging therapies for bone metastases in genitourinary cancers. Eur Urol 2013;63(2):309–20.
ARTICLE IN PRESS 10
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
[3] Tchekmedyian NS, Chen YM, Saad F. Disease progression increases the risk of skeletal-related events in patients with bone metastases from castration-resistant prostate cancer, lung cancer, or other solid tumors. Cancer Invest 2010;28(8):849–55. [4] Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormonerefractory prostate cancer. J Natl Cancer Inst 2004;96(11):879–82. [5] Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163(1):181–6. [6] Malcolm JB, Derweesh IH, Kincade MC, DiBlasio CJ, Lamar KD, Wake RW, et al. Osteoporosis and fractures after androgen deprivation initiation for prostate cancer. Can J Urol 2007;14(3):3551–9. [7] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423(6937):337–42. [8] Feng X, Teitelbaum SL. Osteoclasts: New Insights. Bone Res 2013;1 (1):11–26. [9] Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol 2008;3(Suppl 3):S131–9. [10] Tuck SP, Hanusch B, Walker J, Datta HK. Prostate cancer and osteoporosis. Curr Osteoporos Rep 2013;11(1):11–20. [11] Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab 2012;23(11):576–81. [12] Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345 (13):948–55. [13] Gralow JR, Biermann JS, Farooki A, Fornier MN, Gagel RF, Kumar R, et al. NCCN task force report: bone health in cancer care. J Natl Compr Canc Netw 2013;11(Suppl 3):S1–50:quiz S1. [14] Wissing MD. Chemotherapy- and irradiation-induced bone loss in adults with solid tumors. Curr Osteoporos Rep 2015;13(3):140–5. [15] Bilezikian JP. Osteoporosis in men. J Clin Endocrinol Metab 1999;84 (10):3431–4. [16] Umer M, Mohib Y, Atif M, Nazim M. Skeletal metastasis in renal cell carcinoma: a review. Ann Med Surg (Lond) 2018;27:9–16. [17] Cramer SD, Chen Z, Peehl DM. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J Urol 1996;156(2 Pt 1):526–31. [18] Fizazi K, Carducci M, Smith M, Dami~ao R, Brown J, Karsh L, et al. Denosumab versus Zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377(9768):813–22. [19] Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2011;142(11):1243–51. [20] Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw −2014 update. J Oral Maxillofac Surg 2014;72(10):1938–56. [21] Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015;30(1):3–23. [22] Torres PAU, Cohen-Solal M. Evaluation of fracture risk in chronic kidney disease. J Nephrol 2017;30(5):653–61. [23] Toussaint ND, Elder GJ, Kerr PG. Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue. Clin J Am Soc Nephrol 2009;4(1):221–33. [24] Miller PD, Jamal SA, Evenepoel P, Eastell R, Boonen S. Renal safety in patients treated with bisphosphonates for osteoporosis: a review. J Bone Miner Res 2013;28(10):2049–59.
[25] Nitta K, Yajima A, Tsuchiya K. Management of osteoporosis in chronic kidney disease. Intern Med 2017;56(24):3271–6. [26] Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, Davidson KW, et al. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: US preventive services task force recommendation statement. JAMA 2018;319(15):1592–9. [27] National Osteoporosis Foundation 2019 [Available from: http://nof. org/patients. [28] Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293(18):2257–64. [29] Serpa Neto A, Tobias-Machado M, Esteves MA, Senra MD, Wroclawski ML, Fonseca FL, et al. Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2012;15 (1):36–44. [30] Smith MR, Egerdie B, Hernandez Toriz N, Feldman R, Tammela TL, Saad F, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361(8):745–55. [31] Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94(19):1458–68. [32] Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, et al. Effect of longer-interval vs standard dosing of Zoledronic Acid on skeletal events in patients with bone metastases: a randomized clinical trial. JAMA 2017;317(1):48–58. [33] Goyal J, Antonarakis ES. Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases. Cancer Lett 2012;323(2):135–46. [34] Bruland Ø, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res 2006;12(20 Pt 2):6250s−7s. [35] Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213–23. [36] Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014;15(7):738–46. [37] Smith MR, Parker CC, Saad F, Miller K, Tombal B, et al. ERA 223— A phase 3 trial of Ra-223 in combination with abiraterone acetate & prednisone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naı¨ve patients with mCRPC. ESMO 2018 Congress; 2018; Munich, Germany2018. [38] de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364(21):1995–2005. [39] Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012;13(12):1210–7. [40] Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368(2):138–48. [41] Fizazi K, Scher HI, Miller K, Basch E, Sternberg CN, Cella D, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 2014;15(10):1147–56.
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11 [42] Beer TM, Tombal B. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(18):1755–6. [43] Loriot Y, Miller K, Sternberg CN, Fizazi K, De Bono JS, Chowdhury S, et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol 2015;16(5):509–21. [44] Smith MR, Halabi S, Ryan CJ, Hussain A, Vogelzang N, Stadler W, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol 2014;32(11):1143–50. [45] James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387(10024):1163–77. [46] Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379(9810):39–46. [47] Paller CJ, Carducci MA, Philips GK. Management of bone metastases in refractory prostate cancer—role of denosumab. Clin Interv Aging 2012;7:363–72. [48] Wirth M, Tammela T, Cicalese V, Gomez Veiga F, Delaere K, Miller K, et al. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol 2015;67(3):482–91. [49] Chang A, Finelli A, Berns JS, Rosner M. Chronic kidney disease in patients with renal cell carcinoma. Adv Chronic Kidney Dis 2014;21 (1):91–5. [50] Lowrance WT, Ordo~nez J, Udaltsova N, Russo P, Go AS. CKD and the risk of incident cancer. J Am Soc Nephrol 2014;25(10):2327–34. [51] Bagrodia A, Mehrazin R, Bazzi WM, Silberstein J, Malcolm JB, Stroup SP, et al. Comparison of rates and risk factors for development of osteoporosis and fractures after radical or partial nephrectomy. Urology 2011;78(3):614–9. [52] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7–30. [53] McKay RR, Kroeger N, Xie W, Lee JL, Knox JJ, Bjarnason GA, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014;65(3):577–84. [54] Rosen LS, Gordon D, Tchekmedyian S, Yanagihara R, Hirsh V, Krzakowski M, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial−the Zoledronic
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
11
Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21(16):3150–7. 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. Cancer 2003;98 (5):962–9. Smidt-Hansen T, Folkmar TB, Fode K, Agerbaek M, Donskov F. Combination of zoledronic Acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg 2013;71(9):1532–40. Beuselinck B, Wolter P, Karadimou A, Elaidi R, Dumez H, Rogiers A, et al. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer 2012;107(10):1665–71. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29(9):1125–32. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011;10(12):2298–308. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1814–23. Escudier B, Powles T, Motzer RJ, Olencki T, Aren Frontera O, Oudard S, et al. Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial. J Clin Oncol 2018;36 (8):765–72. McKay RR, Bosse D, Gray KP, Michaelson MD, Krajewski K, Jacene HA, et al. Radium-223 Dichloride in combination with vascular endothelial growth factor-targeting therapy in advanced renal cell carcinoma with bone metastases. Clin Cancer Res 2018;24(17): 4081–8. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1803–13. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378(14):1277– 90. Zaghloul MS, Boutrus R, El-Hossieny H, Kader YA, El-Attar I, Nazmy M. A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol 2010;15(4):382–9.
Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−11
Seminars Article
Management of bone complications in patients with genitourinary malignancies Eric Ballon-Landaa, Justine Panianb, Ithaar H. Derweesha, Rana R. McKayb,* a
b
Department of Urology, University of California San Diego, San Diego, CA Department of Medicine, Division of Hematology/Oncology, University of California San Diego, San Diego, CA Received 15 January 2019; received in revised form 28 July 2019; accepted 28 September 2019
Abstract Skeletal metastases are common in genitourinary malignancies—including prostate cancer, renal cell carcinoma, and urothelial cancer— and portend significant morbidity and poor prognosis. The presence of skeletal metastases can result in decreased quality of life and increased morbidity. Strategies can be employed to prevent bone-related complications including lifestyle modifications and dietary supplementation. Additionally, pharmacologic agents exist to prevent bone loss and may be appropriate for patients at high risk of fragility-related or skeletal complications, such as pathologic fracture related to bone metastases. Finally, advancement in effective systemic treatments, particularly novel hormone-targeted agents and immunotherapies, may limit the morbidity of advanced disease and delay the onset of skeletalrelated complications. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Genitourinary malignancy; Osteoporosis; Bone metastasis; Fracture Abbreviations: RCC, renal cell carcinoma; ADT, androgen deprivation therapy; SRE, skeletal related event; SSE, symptomatic skeletal event; OS, overall survival; BMD, bone mineral density; RANKL, receptor activator nuclear factor-kb ligand; RANK, receptor activator nuclear factor-kb; TGF-b, transforming growth factor-b; SD, standard deviation; ONJ, osteonecrosis of the jaw; RR, relative risk; mCRPC, metastatic castration-resistant prostate cancer; HR, hazard ratio; CKD, chronic kidney disease; TKI, tyrosine kinase inhibitor; CSPC, castration-sensitive prostate cancer; ORR, objective response rate
1. Introduction Skeletal metastases are common in genitourinary malignancies—including prostate cancer, renal cell carcinoma (RCC), and urothelial cancer—and portend significant morbidity and poor prognosis. The presence of skeletal metastases can result in decreased quality of life and survival [1]. Additionally, therapies used to treat genitourinary malignancies, specifically androgen deprivation therapy (ADT) for the treatment of men with prostate cancer, can have negative consequences on the skeleton. Two objective and distinguishable endpoints for clinical trials of patients with bone metastases are skeletal related events (SREs) and symptomatic skeletal events (SSEs). These outcomes were established in order to objectively *Corresponding author. Tel.: 8588226185. E-mail address: [email protected] (R.R. McKay). https://doi.org/10.1016/j.urolonc.2019.09.028 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
and reproducibly measure the impact of bone-targeting agents in patients with bone metastases. SREs include spinal cord compression, surgery or radiation to the bone, and pathological fracture detected by imaging or symptoms [2]. Several studies have demonstrated that the number of bone metastases and presence of a prior SRE are predictive of an increased risk of SRE [3,4]. SSEs are restricted to clinically apparent events and exclude incidental imaging findings [5]. The proportion of genitourinary cancer patients with bone metastases, rates of SREs/SSEs and overall survival (OS) data are delineated in Table 1. In addition to challenges related to bone metastases, bone-related complications, including treatment-related osteoporosis, may occur as a consequence of cancerdirected therapy. Loss of bone mineral density (BMD) can be observed after 6 months of ADT and longer ADT duration results in a higher risk of BMD loss and fragilityrelated fracture incidence [5,6].
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
2
Table 1 Epidemiology of bone metastatic genitourinary malignancy Disease
Metastatic cases per year
Percent patients with bone metastasis
Rates of SREs/SSEs
Overall survival (months)
Prostate cancer Renal cell carcinoma Urothelial cancer
8235 10454 3276
52% 30% 30%
44% 74% >50%
42 29.3 10.3
SRE = skeletal related event; SSE = symptomatic skeletal event.
Herein we describe the current knowledge of the biology of bone metastases and osteoporotic fractures related to the treatment of genitourinary malignancy, review the clinical data supporting the use of bone-targeting agents, and highlight management options for patients with genitourinary malignancies who develop bone metastases or receive therapy which can have a detrimental effect on the skeleton. 2. Pathophysiology of treatment-related osteoporosis and bone metastases 2.1. Bone physiology The skeleton is a metabolically active organ undergoing dynamic changes through the coupling of 2 processes: bone resorption by osteoclasts and bone formation by osteoblasts. Osteoclasts are generated by the differentiation of macrophage precursor cells, a process which requires colony stimulating factor-1 and receptor activator nuclear factorkb ligand (RANKL) to stimulate receptor activator of nuclear factor kb (RANK) on osteoclast precursor cell surfaces [7]. RANKL is released from osteoblasts, activating T-cells and stromal cells, and binds to the RANK transmembrane signaling receptor on osteoclast precursor cells promoting differentiation and activation [7]. Activated osteoclasts resorb bone via transcellular acid transport and generation of an acidic compartment on the bone surface to resorb bone [8]. Osteoblasts, which differentiate from mesenchymal progenitor cells via transforming growth factor-b (TGF-b), calcitonin, and platelet-derived growth factor, secrete and mineralize the bone matrix [9]. 2.2. Pathophysiology of treatment-related osteoporosis Estrogen is essential in regulating bone health in both men and women. In men, testosterone undergoes peripheral aromatization to form estradiol. Estradiol directly induces osteoblasts to maintain bone formation and inhibits osteoclast activity, resulting in decreased bone resorption [10,11]. In the castrate state, less peripheral testosterone is converted to estradiol; the sharp decrease in estradiol induces BMD loss and increases fracture risk [12]. Additionally, chemotherapy may result in BMD loss via indirect effects, such as loss of ovarian function in women, and direct effects on osteoblast and osteoclast function [13]. Additionally, corticosteroids, important in the treatment of men with
prostate cancer and administered concurrently with chemotherapy and newer targeted therapies, have direct effects on the bone and result in reduced osteoblast activity and increased osteoclastogenesis [14]. Limited studies have evaluated the direct impact of checkpoint inhibitors, such as nivolumab and ipilimumab, on the bone microenvironment. Immune-mediated side effects related to checkpoint inhibition, such as hypophysitis, can cause hormonal dysregulation and may have a potential negative impact on bone health via downstream effects. The diagnosis of osteoporosis is based on BMD, typically measured at the hip and spine on dual-energy X-ray absorptiometry. The World Health Organization has defined thresholds for osteopenia and osteoporosis based upon BMD measurements compared with a young adult reference population (T-score). Osteopenia is defined as BMD of 1.0 to 2.5 standard deviations (SD) below the mean (Tscore 1.0 to 2.5) and osteoporosis is defined as BMD of more than 2.5 SD below the mean (T-score < 2.5). The risk of fracture doubles for every SD decrease in BMD [15]. Additionally, the FRAX algorithm with or without the incorporation of BMD measurements can be utilized to estimate of fracture risk (https://www.sheffield.ac.uk/FRAX/). 2.3. Pathophysiology of bone metastasis Bone metastasis destabilizes the delicate balance of bone formation and resorption. Interactions between tumor and stromal cells in the bone microenvironment result in a vicious cycle of bone injury and tumor growth. Osteolytic lesions are characterized by stimulated osteoclast activity and bone resorption via TGF- b1 and RANKL-mediation activity [16]. Some cancers, including prostate cancer, stimulate osteoblast activity via various mechanisms including parathyroid hormone releasing protein, resulting in abnormal bone tissue production and down-regulation of tumorrelated bone resorption [17]. 2.4. Pharmacology of osteoclast-targeting agents Several pharmacotherapeutic agents are active against bone metastases and treatment-related bone loss (Table 2). Various adverse effects associated with these agents require close monitoring. Patients receiving denosumab, a monoclonal antibody against RANKL-ligand, and zoledronic acid, a bisphosphonate which inhibits bone resorption, can
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
3
Table 2 Pharmacology of osteoclast targeted therapies for SRE/SSE prevention Agent
FDA-approved indications
Mechanism of action
Mode of administration
Clearance
Side effects of interest
Zoledronic acid26
mCRPC or solid tumors with bone metastases 1. Increase bone mass in men receiving ADT for prostate cancer 2. Prevention of SREs in patient with bone metastases from solid tumors Treatment of mCRPC with symptomatic bone metastases and no visceral metastases
Osteoclast apoptosis and inhibition
Intravenous
Renal
Nephrotoxicity, hypocalcemia, ONJ
Monoclonal antibody against RANKL, inhibiting osteoclast activation
Subcutaneous
Reticulo-endothelial System
Hypocalcemia, ONJ
Calcium mimetic, delivers alpha particles to osteoblastic bone metastases
Intravenous
Gastro-intestinal
Thrombocytopenia, neutropenia, anemia, nausea, diarrhea, vomiting
Denosumab26
Radium-22336
ADT = androgen deprivation therapy; mCRPC = metastatic castration-resistant prostate cancer; ONJ = osteonecrosis of the jaw; RANKL = receptor activator nuclear factor-kb ligand; SRE = skeletal related event; SSE = symptomatic skeletal event.
experience hypocalcemia and thus calcium supplementation is recommended in this population; osteonecrosis of the jaw (ONJ) is a clinically significant but rare adverse effect. A phase III randomized trial of 1,904 metastatic prostate cancer patients randomized to receive zoledronic acid or denosumab found that both groups experienced hypocalcemia, although at higher rates in the denosumab group compared to zoledronic acid (13% vs. 6%, respectively) [18]. Thirtyfour patients (1.8%) experienced ONJ, of whom 17 (77%) were receiving denosumab. 2.5. Unique considerations in selected populations Due to the possible development of ONJ with antiresorptive agents, the use of osteoclast-targeted therapy in the setting of existing dental disease is challenging. The American Dental Association recommends that patients receiving antiresorptive therapy undergo regular dental examination and that providers review the risk of ONJ prior to initiation [19]. Oral and dental disease should be optimized prior to initiation of antiresorptive medications; a dental examination with radiographs should be completed prior to therapy to rule out occult disease, and procedures that can be performed prior to initiation of therapy are warranted. Unfortunately, high quality evidence is lacking regarding the optimal timing of use of antiresportive agents in the context of dental procedures in which the bone is manipulated (such as extractions or implant placement) [20,21]. Therefore, an individualized decision should be made on the part of patient, medical provider, and dental team caring for the patient. Use of osteoclast-targeting agents in patients with existing chronic kidney disease (CKD) poses another unique challenge secondary to medication side effects and the
propensity of CKD to lead to bone demineralization and calcium dysregulation [22]. Patients with CKD are at higher baseline risk for fragility-related fractures secondary to medical renal disease; in the setting of bone metastases, particular consideration should be given toward SRE prevention. Unfortunately, the nephrotoxicity of zoledronic acid limits its use in this population, with dosing modifications recommended to limit toxicity in patients with CKD [23,24]. Clinicians should also monitor for severe hypocalcemia in this high-risk population, and both denosumab and zoledronic acid should be used with caution in patients with stage 4 or greater CKD for this reason [25].
3. Prostate cancer 3.1. Management of treatment-related osteoporosis Strategies to prevent bone loss and osteoporosis in patients with genitourinary malignancies include nonpharmacologic approaches and the use of bone-targeting agents in select individuals. Lifestyle and nutritional modifications include routine weight-bearing exercise, physical activity, limited tobacco and alcohol use, and adequate intake of calcium and vitamin D. Fracture risk reduction also includes fall prevention including vision, hearing, balance and home safety assessments [13]. Micronutrient supplementation in men with prostate cancer receiving ADT is supported by guideline recommendations [26]. Calcium intake up to 1,200 mg/day is recommended by multiple national medical societies in divided doses no larger than 600 mg [13,27]. Vitamin D allows for gastrointestinal calcium absorption and normal bone mineralization. Guideline societies recommend 400 to 1000 IU of vitamin D daily [13]. The optimal
ARTICLE IN PRESS 4
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
25-OH D level is 30 ng/mL; patients who are found to have lower levels can be more aggressively supplemented. Because vitamin D insufficiency is common in the general population and in patients with cancer, many patients may require more aggressive supplementation initially. A population-based meta-analysis of 7 randomized-controlled trials pooling 9,820 elderly patients (men and women) randomized to receive vitamin D supplementation with or without calcium vs. calcium or placebo demonstrated a 26% and 23% relative risk (RR) reduction of hip and nonvertebral fractures, respectively; this reduction was limited to patients taking higher doses (700-800 IU/day) [28]. Pharmacologic therapeutic strategies for bone health include bisphosphonates and RANKL inhibition. Although a number of agents (pamidronate, alendronate, neridronate) demonstrated improvement of BMD loss in small studies, none has been individually demonstrated to prevent fragility-related fractures. A meta-analysis pooling 15 studies of 2,634 men with prostate cancer receiving ADT randomized to receive a bisphosphonate vs. placebo found that men receiving bisphosphonates had a significantly reduced risk of osteoporosis-related fractures (RR = 0.80) and osteoporosis (RR = 0.39), with the greatest risk reduction seen with zoledronic acid [29]. Denosumab increases BMD in prostate cancer patients and reduces fracture risk [30]. In a study of 1,438 men receiving ADT for prostate cancer, patients were randomized to denosumab or placebo. After 36 months, men receiving the denosumab had significantly increased BMD at all measured sites (lumbar spine, total hip, femoral neck, distal radius) and a decreased likelihood of vertebral fracture (RR = 0.38). Despite this evidence, the optimal selection of pharmacologic agent and dosing regimen has not been established. Clinicians should discuss these data with patients as optional management strategies. 3.2. Management of bone metastasis 3.2.1. Osteoclast inhibition in castration-resistant prostate cancer Osteoclast-targeting agents have been tested in men with metastatic castration-resistant prostate cancer (mCRPC) (Table 3). In a phase III, double-blind, placebo-controlled trial, Saad et al. randomly assigned men with mCRPC to receive zoledronic acid at 4 mg, 8 mg or placebo every 3 weeks for 15 months; the primary endpoint was the proportion of men experiencing at least 1 SRE. Men receiving zoledronic acid had significantly lower rates of SREs (33% with 4 mg vs. 44% with placebo; P = 0.021) and longer time to first SRE (>410 days with 4 mg and 321 days with placebo; P = 0.011) [31]. The rate of pathologic fractures was lower compared to placebo (13.1% with 4 mg vs. 22.1% for placebo). Fizazi et al. performed a phase III trial randomizing 1,904 men with mCRPC with bone metastases to receive
denosumab or zoledronic acid with primary noninferiority outcome of time to SRE, and a secondary superiority outcome of denosumab over zoledronic acid [18]. In addition to demonstrating noninferior time to first SRE for denosumab compared to zoledronic acid (20.7 vs. 17.1 months, P = 0.0002), this trial demonstrated the superiority of denosumab over zoledronic acid in improving time to first SRE (P = 0.008). The CALGB 70604 phase III, open-label trial randomized 1,822 patients with metastatic breast or prostate cancer or multiple myeloma to receive zoledronic acid every 4 weeks or every 12 weeks for 2 years (689 mCRPC patients) [32]. The trial demonstrated non-inferiority of a 12-week dosing interval for prevention of SREs. No differences were demonstrated for pain scores, performance status, ONJ, or kidney dysfunction. 3.2.2. Radiopharmaceuticals in castration-resistant prostate cancer While strontium-89 and samarium-153, b-emitting radiopharmaceuticals, demonstrated efficacy in palliation of bone pain, utilization of these agents has been limited given toxicity and administration challenges [33]. Radium223 dichloride is a bone-seeking a-emitter that targets calcium hydroxyapatite in osteoblastic bone lesions, promoting DNA strand breaks and tumor cell death [34]. The ALSYMPCA phase III, double-blind, placebo-controlled trial randomized men with symptomatic bony metastases without known visceral metastases to receive radium223 or placebo [35]. The primary outcome of OS was met by interim analysis, which demonstrated a 3.6 month increase in median survival and a 5.8 month increase in time to first SSE [36]. This landmark trial established radium-223 as the only radiopharmaceutical to improve OS in mCRPC. The ERA-223 phase III, double-blind, placebo-controlled trial randomized men with minimally symptomatic, bone-predominant mCRPC to receive radium-223 plus abiraterone, a CYP17 inhibitor, vs. placebo plus abiraterone [37]. The trial was stopped early after interim analyses demonstrated increased fracture risk among patients receiving radium-223 plus abiraterone (26% vs. 10%) and decreased time to SSE for the intervention group (22.3 vs. 26.0 months; Hazard ratio (HR) 1.12, P = 0.263). Sixty percent of SSEs occurred at sites without metastatic disease. Additionally, there was a nonstatistically significant decrease in OS in the radium223 plus abiraterone arm (30.7 vs. 33.3 months; HR = 1.195; P = 0.1280). Based on these data, radium223 should not be given with abiraterone. 3.2.3. Disease control in castration-resistant prostate cancer and bone metastases Building on earlier trials for bone-targeting agents in prostate cancer, modern trials evaluating disease-targeted
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
5
Table 3 Bone-specific outcomes in notable trial of genitourinary malignancy Trial
Number of patients
Patient population
Metastatic castration-resistant prostate cancer Saad et al., JNCI 2002 643 mCRPC with bone metastasis
Arms
SRE or SSE (% or months)
OS (months)
1: Zoledronic acid 4 mg 2: Zoledronic acid 8!4 mg 3: Placebo (1:1:1)
Fracture: 1: 33.2%, P = 0.015 2: 38.5%, P = 0.054 3: 44.2% Time to SRE (days): 1: 13.8, P = 0.011 2: 30.3, P = 0.491 3: 26.8 SRE: 1: 28.6% 2: 29.5% P < 0.001 for noninferiority Time to SRE: 1: 20.7 2: 17.2 P = 0.008 for superiority Time to SRE: 1: 15.6 2: 9.8 HR 0.66, P < 0.001 SSE: 1: 33% 2: 38% Time to SSE: 1: 15.6 2: 9.8 HR 0.66, P = 0.00037 SRE: 1: 22.6% 2: 24.6% Time to SRE: 1: 25.0 2: 20.3 HR 0.62, P = 0.0001 SRE: 1: 32% 2: 37% Time to SRE: 1: 31.1 2: 31.3 HR=0.72, P < 0.0001 SRE: 1: 36% 2: 40% Time to SRE: 1: 16.7 2: 13.3 HR 0.69, P = 0.0001
Not assessed
Himelstein et al., JAMA 2017 CALGB 70604
1,822
mCRPC (n = 689), Breast cancer (n = 855), Multiple myeloma (n = 278) with bone metastasis
1: Zoledronic acid q12 weeks 2: Zoledronic acid q4 weeks (1:1)
Fizazi et al., Lancet 2011
1,904
mCRPC with bone metastasis
1: Denosumab + IV placebo 2: Zoledronic acid + subcutaneous placebo (1:1)
Parker et al., NEJM 2013 ALSYMPCA
921
mCRPC with 2+ bone metastases, no known visceral metastasis
1: Radium-223 2: Placebo (2:1 randomization)
Sartor et al., Lancet Oncol 2014 ALSYMPCA
921
mCRPC, 2+ bone metastases, no known visceral metastasis
1: Radium-223 2: Placebo (2:1)
Logothetis et al., Lancet Oncol 2012 COU-AA-301
797
mCRPC, postchemotherapy
1: Abiraterone + prednisone 2: Placebo + prednisone (2:1)
Loriot et al., Lancet Oncol 2015 PREVAIL
1,717
mCRPC, prechemotherapy
1: Enzalutamide 2: Placebo (1:1)
Fizazi et al., Lancet Oncol 2014 AFFIRM
1,199
mCRPC, postchemotherapy
1: Enzalutamide 2: Placebo (2:1)
Not assessed
1: 19.4 2: 19.8 HR 1.03, P = 0.65
1: 14.9 2: 11.3 HR 0.7, P < 0.001 1: 14.9 2: 11.3 HR 0.7, P < 0.001
1: 15.8 2: 11.2 HR 0.74, P < 0.0001
1: 32.4 2: 30.2 HR 0.71, P < 0.001
1: 18.4 2: 13.6 HR 0.63, P < 0.0001
(continued)
ARTICLE IN PRESS 6
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
Table 3 (Continued) Trial
Number of patients
Castration-sensitive prostate cancer Smith et al., 645 JCO 2014 CALGB 90202
James et al., Lancet Oncol 2016 STAMPEDE
Renal cell carcinoma Lipton et al., Cancer 2003
2,962
74
Escudier et al., JCO 2018a
142
McKay et al., CCR 2018
30
Motzer et al., NEJM 2018 CheckMate 214
1,096b
Motzer et al., NEJM 2015 CheckMate 025
821c
Rosen et al., JCO 2003
773
Patient population
Arms
SRE or SSE (% or months)
OS (months)
CSPC with bone metastases
1: Zoledronic acid 2: Placebo (1:1)
HR 0.88, P = 0.29
High risk, locally advanced, metastatic or recurrent prostate cancer
1: Standard of care (SOC) + Zoledronic acid 2: SOC + docetaxel 3: SOC + both 4: SOC (1:1:1:2)
Time to SRE: 1: 31.9 2: 29.8 HR 0.97, P = 0.39 SRE: 1. 12.9%; HR 0.89, P = 0.221 2. 9.46%; HR 0.60, P < 0.001 3. 9.12%; HR 0.55, P < 0.001 4. 27.7% Time to SRE: 1. HR 0.94, P = 0.564 2. 68.0, P < 0.001 3. 68.3, P < 0.001 4. 61.4
RCC with bone metastasis
1: Zolendronic acid (4 mg or 8 gm) 2: Placebo
RCC, previously treated
1: Cabozantinib 2: Everolimus (1:1 randomization)
RCC with bone metastasis − cohort study
1: Pazopanib + radium-223 (treatment naı¨ve) 2: Sorafenib + radium-223 (previously treated)
RCC, treatment naı¨ve
1: Nivolumab + Ipilimumab 2: Sunitinib (1:1)
RCC, previously treated
1: Nivolumab 2: Everolimus (1:1)
Not evaluated
Bone metastasis secondary to lung cancer and other solid tumors not including breast and prostate cancer
1: Denosumab 2: Zoledronic acid
SRE 1: Not assessed 2: Not assessed Time to SRE 1: 20.6 2: 16.3 P = 0.06
SRE 1: 37% 2: 74% P = 0.015 Time to SRE: 1: Median not reached 2: 2.37, P = 0.006 SRE: 1: 23% 2: 29% Time to SRE 1: Not evaluated 2: Not evaluated SSE 1: 47% 2: 13% Time to SSE 1: 5.8 2: Not reached Not evaluated
1: Not reached; HR 0.94, P = 0.45 2: 81; HR 0.73, P = 0.006 3: 76; HR 0.82, P = 0.022 4. 71
1: 9.70 2: 7.11 P = 0.179
1: 20.1 2: 12.1 HR 0.54, 95%CI 0.34-0.84
1: 16.6 2: 14.2
1: Not reached 2: 26.0 HR 0.63, P < 0.001 1: 25.0 2: 19.6 HR 0.73, P = 0.002 Not assessed
(continued)
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
7
Table 3 (Continued) Trial
Urothelial cancer Henry et al., JCO 2011
Zaghloul et al., IJCO 2010
Number of patients
1,776
40
Patient population
Arms
SRE or SSE (% or months)
OS (months)
Solid tumors or multiple myeloma, bone metastasis
1: Zoledronic acid 2: Placebo
1: 6.68 2: 6.35 P = 0.623
Bladder cancer with bone metastasis
1: Zoledronic acid 2: Placebo
SRE 1: 38% 2: 47% Time to SRE 1: 7.57 2: 5.36 P = 0.023 SRE 1: 60% 2: 90% Time to SRE 1: 3.68 2: 1.84
Not assessed
CSPC = castration-sensitive prostate cancer; HR = hazard ratio; mCRPC = metastatic castration-resistant prostate cancer; OS = overall survival; ; RCC = renal cell carcinoma; SRE = skeletal related event; SSE = symptomatic skeletal event. a Subgroup analysis of METEOR trial including patients with bone metastases. b Checkmate 214: 192 bone-metastatic patients included in the study. c Checkmate 025: 146 bone-metastatic patients included in the study.
therapies have incorporated SREs/SSEs and bone-specific endpoints as secondary efficacy outcomes. Because the approval of current agents, such as abiraterone and enzalutamide, followed the trials demonstrating the efficacy of bisphosphonates and denosumab, the added utility of bonetargeting agents in combination with these agents has not been fully characterized. Abiraterone was studied in 2 randomized trials in patients pre- (COU-AA-302) and post- (COU-AA-301) chemotherapy. These studies established the use of abiraterone in patients with mCRPC given improvement of OS [38]. Secondary analyses from COU-AA-301 evaluated the impact of the intervention on pain control and SREs and found that abiraterone increased the time to SRE by 4.7 months [39]. The efficacy of enzalutamide, a next generation androgen receptor inhibitor, was evaluated in patients with mCRPC pre- (PREVAIL) and post- (AFFIRM) chemotherapy [40,41]. These studies demonstrated improvements of OS and also SREs with enzalutamide [42,43]. 3.2.4. Osteoclast inhibition in metastatic castrationsensitive prostate cancer Given the evidence to support the use of bisphosphonate therapy in mCRPC, several trials have evaluated zoledronic acid in castration-sensitive prostate cancer (CSPC). The CALGB 90202 phase III, double-blind, placebo-controlled trial randomized 645 men with metastatic CSPC on ADT to zoledronic acid or placebo [44]. No difference was seen in time to SRE, progression-free survival, or OS between the 2 arms. The STAMPEDE trial, a randomized controlled trial using a multi-arm, multi-stage platform in men with clinically localized, node-positive, or metastatic prostate cancer, evaluated the impact of zoledronic acid on 2,692
men with CSPC initiating ADT [45]. There was no improvement in time to SRE, failure-free survival, or OS. Thus, zoledronic acid is not recommended for men with CSPC to prevent SRE, but can be used in selected patients at high risk of fragility-related fracture. 3.2.5. Osteoclast inhibition in metastasis prevention The onset of bone metastasis in high-risk mCRPC portends worse survival and burdensome symptoms. Smith et al. performed a phase III, double-blind, placebo-controlled trial which randomized 1,432 men with nonmetastatic CRPC to denosumab or placebo [46]. The study met its primary endpoint of improvement in bone metastasisfree survival, however, OS was unchanged (HR = 1.01, P = 0.91). ONJ occurred in 4.6% of patients and hypocalcemia in 1.3%. Due to the limited degree of benefit balanced with the toxicity risk, the FDA did not extend approval of denosumab for metastasis prevention [47]. Bisphosphonate use is more limited in the setting of nonmetastatic CSPC. The Zeus trial randomized 1,433 men with nonmetastatic high-risk CSPC and found no difference in time to bone metastasis or OS after a median follow-up of 4.8 years [48]. Zoledronic acid was found to be ineffective in preventing bone metastases in high-risk nonmetastatic CSPC patients. 4. Renal cell carcinoma Bone health in patients with RCC is impacted by the prevalence of CKD in the population and the propensity of RCC to establish bone metastasis. While CKD in RCC is associated with surgical extirpation, patients with RCC also experience higher rates of medical renal disease [49,50].
ARTICLE IN PRESS 8
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
Retrospective data suggest that patients who undergo nephron sparing surgery rather than radical nephrectomy may be somewhat protected from the risk of fragility-related fractures [51]. Bone metastasis is observed in 30% of metastatic RCC patients and is associated with worse OS [52]. This has been demonstrated in several large analyses, including a review from the International Metastatic Renal Cell Carcinoma Database (IMDC) of 2027 patients with metastatic RCC. It demonstrated that patients with bone metastasis exhibited a shorter median OS (14.9 vs. 25.1 months; P < 0.0001) than patients without bone metastasis [53].
open-label, phase III trial of 658 patients with RCC who progressed after VEGF-targeted therapy and were randomized to receive cabozantinib vs. everolimus [60]. Treatment with cabozantinib resulted in improved objective response rate (ORR), progression-free survival, and OS compared to everolimus. A subset analysis was conducted in patients with bone metastases and demonstrated similar results [61]. Furthermore, SREs were less frequent with cabozantinib (23% vs.. 29%) and correlated with bone scan response (20% vs. 10%). Overall, cabozantinib exhibited greater efficacy in RCC patients with bone metastasis compared to everolimus.
4.1. Osteoclast inhibition in metastatic RCC with bone metastasis
4.3. Radium-223 in metastatic RCC with bone metastasis
Evidence supporting the use of osteoclast-targeted therapies in genitourinary malignancies other than prostate is limited. The efficacy of zoledronic acid was studied in 773 solid tumor patients with bone metastasis in a large phase III trial [54]. Subset analysis of RCC patients from this trial demonstrated that treatment with zoledronic acid significantly reduced the risk of SREs by 61% in the intervention arm (P = 0.008) and prolonged the time to first SRE without impacting OS [55]. The risk of ONJ may be increased when osteoclast-targeted therapies are combined with targeted therapies. Small, retrospective studies have investigated the side effects of tyrosine kinase inhibitors (TKIs) with respect to ONJ in RCC patients [56]. Combination therapy with TKIs and bisphosphonates is associated with a 10% to 30% frequency of ONJ [57]. The use of osteoclast-targeted therapies in combination with TKI warrants careful patient selection. Denosumab was approved for use in RCC based upon data from a double-blind phase III trial which randomized 1,776 patients with advanced cancer (excluding breast and prostate cancer) with bone metastasis or multiple myeloma to receive zoledronic acid or denosumab [58]. The proportion of RCC patients in the sample size was not available. Denosumab was noninferior compared to zoledronic acid in delaying time to SRE, the primary endpoint. OS and adverse effects were not significantly different between the 2 groups. Based upon these findings, clinicians can consider using denosumab or zoledronic acid for select patients with bone metastases and RCC. 4.2. Cabozantinib in metastatic RCC with bone metastasis Cabozantinib is an oral TKI that is FDA-approved for the treatment of RCC [59]. Because of its inhibitory effect on vascular endothelial growth factor (VEGF) and MET, cabozantinib is useful in patients with bone metastases, which tend to overexpress VEGF and MET in several solid tumors, including RCC [60]. The efficacy of cabozantinib was compared to everolimus in the METEOR trial, an
A pilot study in patients with RCC with bone metastases investigated the safety and efficacy radium-223 combined with VEGF targeted therapy in RCC [62]. Thirty patients with RCC were included in 2 cohorts: treatment naı¨ve— given pazopanib (n = 15)—and previously treated—given sorafenib (n = 15); both cohorts received radium-223. The primary endpoint was change in bone turnover markers and study demonstrated declines from baseline in all bone turnover markers at weeks 8 and 16. The authors concluded that the combination of radium-223 with VEGF-targeted therapy is feasible and safe. A phase II clinical trial of radium223 combined with cabozantinib is currently in development (RADICAL).
4.4. Immunotherapy in metastatic RCC with bone metastasis Despite several landmark immunotherapy trials for RCC, subset analyses in patients with bone metastases are limited. The Checkmate 025 phase III, open-label trial randomized 821 patients with previously treated RCC to nivolumab or everolimus [63]. Nivolumab demonstrated a 5.4 month improvement in OS and improved ORR (25% vs. 5%) compared to everolimus. Overall, 18% (n = 146) of patients enrolled had bone metastases. The Checkmate 214 phase III trial randomized treatment-naı¨ve clear cell RCC patients to nivolumab plus ipilimumab or sunitinib [64]. At a median follow-up of 25.2 months, there was a significant improvement in OS, ORR, and complete response rate with nivolumab plus ipilimumab vs. suntinib in patients with intermediate and poor-risk RCC. Overall, 21.1% (n = 231) of patients had bone metastases; subgroup analysis for OS in this group favored nivolumab plus ipilimumab. Immunotherapy may be particularly beneficial to patients with bone metastasis, though this has not been robustly investigated. Ongoing studies are evaluating immunotherapy and cabozantinib, which is particularly relevant to patients with bone metastasis.
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
9
Table 4 Ongoing trials in genitourinary malignancy with bone-specific outcomes Trial name (NCI number)
Expected Patient population patients
Arms
Primary endpoint
Expected completion date
Prevention of symptomatic skeletal events with Denosumab administered every 4 weeks vs. every 12 weeks − NCT02051218 Efficacy and safety of systemic treatments of bone metastases from kidney cancer in patients treated with targeted therapies (MOSCAR) − NCT03408652 Study Comparing Denosumab with Standard Treatment in Urothelial Cancer Patients With Bone Metastases − NCT03520231
1380
mCRPC; metastatic breast adenocarcinoma
Arm A: denosumab every 4 weeks Arm B: denosumab every 12 weeks
Time to first SSE noninferiority
December 2022
Metastatic RCC
Arm A: denosumab or zolendronic acid Arm B: control arm (no specific treatment)
Time to first SRE
June 2024
Metastatic urothelial carcinoma
Arm A: Denosumab plus chemotherapy Arm B: Placebo plus chemotherapy
Difference in mean percentage change in serum c-telopeptide
June 2020
216
50
mCRPC = metastatic castration-resistant prostate cancer; RCC = renal cell carcinoma; SRE = skeletal related event; SSE = symptomatic skeletal event.
5. Urothelial cancer Bone metastasis is found in approximately 30% of metastatic urothelial cancer patients [52]. Specific data on this patient population is limited by the poor survival of bonemetastatic urothelial cancer patients. Within these limitations, the management recommendations for urothelial cancer patients with bone metastasis are based upon larger studies of solid tumor patients. 5.1. Osteoclast inhibition in metastatic urothelial cancer Bisphosphonate therapy in metastatic urothelial cancer is supported by data from evaluation of solid tumors with bone metastases. Urothelial cancer was included in the phase III trial of zoledronic acid vs. placebo that led to its FDAapproval [54]. In this study, zoledronic acid significantly reduced the proportion of patients experiencing SREs (38% for 4 mg and 35% for 8/4 mg zoledronic acid vs. 44% for placebo). No subset analysis of urothelial cancer was performed. A small trial of 40 patients with metastatic urothelial cancer randomized participants to zoledronic acid or placebo group, with the intervention group experiencing a lower incidence of SREs compared to placebo [65]. One-year OS was increased (36% vs. 0%, respectively). 6. Clinical considerations Bone metastases in genitourinary malignancy portend worse outcomes and confer significant morbidity, and as such clinicians should attend closely to the overall disease and bone-specific needs of these patients. In select patients at risk of treatment-related bone loss, an evaluation for osteoporosis should be considered, including recommendations for lifestyle changes including weight bearing activity and
consideration of calcium and vitamin D supplementation. Bone-targeting agents including zoledronic acid and denosumab can be considered to prevent bone loss and decrease the risk of osteoporotic fractures. Clinicians should consider dental assessment prior to initiating antiresorptive therapies due to the infrequent but serious risk of ONJ. Several trial are ongoing that are evaluating osteoclast targeting agents in patients with genitourinary malignancies (Table 4). While the evidence regarding SRE prevention in mCRPC largely supports denosumab or zoledronic acid, the different routes, schedules, and toxicity should be considering with tailoring therapy for a specific individual. Additionally, several prostate cancer directed therapies including abiraterone, enzalutamide, and radium-223 have demonstrated a positive impact on bone-related outcomes. In RCC and urothelial malignancies, there is evidence to support the use of osteoclast-targeted therapy for SRE prevention and improvement of bone health. With the proliferation of targeted therapies and immunotherapies extending the survival of patients with genitourinary malignancy, supporting patients’ bone health is increasingly important to limit the morbidity of advanced disease. Conflicts of interest RRM receives research funding from Bayer and Pfizer. RRM serves as a consultant for Janssen, Novartis, Tempus, Bristol-Myers Squibb, and Exelixis. References [1] Froehner M, H€olscher T, Hakenberg OW, Wirth MP. Treatment of bone metastases in urologic malignancies. Urol Int 2014;93(3):249–56. [2] Saylor PJ, Armstrong AJ, Fizazi K, Freedland S, Saad F, Smith MR, et al. New and emerging therapies for bone metastases in genitourinary cancers. Eur Urol 2013;63(2):309–20.
ARTICLE IN PRESS 10
E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11
[3] Tchekmedyian NS, Chen YM, Saad F. Disease progression increases the risk of skeletal-related events in patients with bone metastases from castration-resistant prostate cancer, lung cancer, or other solid tumors. Cancer Invest 2010;28(8):849–55. [4] Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormonerefractory prostate cancer. J Natl Cancer Inst 2004;96(11):879–82. [5] Daniell HW, Dunn SR, Ferguson DW, Lomas G, Niazi Z, Stratte PT. Progressive osteoporosis during androgen deprivation therapy for prostate cancer. J Urol 2000;163(1):181–6. [6] Malcolm JB, Derweesh IH, Kincade MC, DiBlasio CJ, Lamar KD, Wake RW, et al. Osteoporosis and fractures after androgen deprivation initiation for prostate cancer. Can J Urol 2007;14(3):3551–9. [7] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423(6937):337–42. [8] Feng X, Teitelbaum SL. Osteoclasts: New Insights. Bone Res 2013;1 (1):11–26. [9] Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol 2008;3(Suppl 3):S131–9. [10] Tuck SP, Hanusch B, Walker J, Datta HK. Prostate cancer and osteoporosis. Curr Osteoporos Rep 2013;11(1):11–20. [11] Khosla S, Oursler MJ, Monroe DG. Estrogen and the skeleton. Trends Endocrinol Metab 2012;23(11):576–81. [12] Smith MR, McGovern FJ, Zietman AL, Fallon MA, Hayden DL, Schoenfeld DA, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345 (13):948–55. [13] Gralow JR, Biermann JS, Farooki A, Fornier MN, Gagel RF, Kumar R, et al. NCCN task force report: bone health in cancer care. J Natl Compr Canc Netw 2013;11(Suppl 3):S1–50:quiz S1. [14] Wissing MD. Chemotherapy- and irradiation-induced bone loss in adults with solid tumors. Curr Osteoporos Rep 2015;13(3):140–5. [15] Bilezikian JP. Osteoporosis in men. J Clin Endocrinol Metab 1999;84 (10):3431–4. [16] Umer M, Mohib Y, Atif M, Nazim M. Skeletal metastasis in renal cell carcinoma: a review. Ann Med Surg (Lond) 2018;27:9–16. [17] Cramer SD, Chen Z, Peehl DM. Prostate specific antigen cleaves parathyroid hormone-related protein in the PTH-like domain: inactivation of PTHrP-stimulated cAMP accumulation in mouse osteoblasts. J Urol 1996;156(2 Pt 1):526–31. [18] Fizazi K, Carducci M, Smith M, Dami~ao R, Brown J, Karsh L, et al. Denosumab versus Zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 2011;377(9768):813–22. [19] Hellstein JW, Adler RA, Edwards B, Jacobsen PL, Kalmar JR, Koka S, et al. Managing the care of patients receiving antiresorptive therapy for prevention and treatment of osteoporosis: executive summary of recommendations from the American Dental Association Council on Scientific Affairs. J Am Dent Assoc 2011;142(11):1243–51. [20] Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw −2014 update. J Oral Maxillofac Surg 2014;72(10):1938–56. [21] Khan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O’Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res 2015;30(1):3–23. [22] Torres PAU, Cohen-Solal M. Evaluation of fracture risk in chronic kidney disease. J Nephrol 2017;30(5):653–61. [23] Toussaint ND, Elder GJ, Kerr PG. Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue. Clin J Am Soc Nephrol 2009;4(1):221–33. [24] Miller PD, Jamal SA, Evenepoel P, Eastell R, Boonen S. Renal safety in patients treated with bisphosphonates for osteoporosis: a review. J Bone Miner Res 2013;28(10):2049–59.
[25] Nitta K, Yajima A, Tsuchiya K. Management of osteoporosis in chronic kidney disease. Intern Med 2017;56(24):3271–6. [26] Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, Davidson KW, et al. Vitamin D, calcium, or combined supplementation for the primary prevention of fractures in community-dwelling adults: US preventive services task force recommendation statement. JAMA 2018;319(15):1592–9. [27] National Osteoporosis Foundation 2019 [Available from: http://nof. org/patients. [28] Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA 2005;293(18):2257–64. [29] Serpa Neto A, Tobias-Machado M, Esteves MA, Senra MD, Wroclawski ML, Fonseca FL, et al. Bisphosphonate therapy in patients under androgen deprivation therapy for prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2012;15 (1):36–44. [30] Smith MR, Egerdie B, Hernandez Toriz N, Feldman R, Tammela TL, Saad F, et al. Denosumab in men receiving androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361(8):745–55. [31] Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94(19):1458–68. [32] Himelstein AL, Foster JC, Khatcheressian JL, Roberts JD, Seisler DK, Novotny PJ, et al. Effect of longer-interval vs standard dosing of Zoledronic Acid on skeletal events in patients with bone metastases: a randomized clinical trial. JAMA 2017;317(1):48–58. [33] Goyal J, Antonarakis ES. Bone-targeting radiopharmaceuticals for the treatment of prostate cancer with bone metastases. Cancer Lett 2012;323(2):135–46. [34] Bruland Ø, Nilsson S, Fisher DR, Larsen RH. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res 2006;12(20 Pt 2):6250s−7s. [35] Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fossa SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213–23. [36] Sartor O, Coleman R, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014;15(7):738–46. [37] Smith MR, Parker CC, Saad F, Miller K, Tombal B, et al. ERA 223— A phase 3 trial of Ra-223 in combination with abiraterone acetate & prednisone for the treatment of asymptomatic or mildly symptomatic chemotherapy-naı¨ve patients with mCRPC. ESMO 2018 Congress; 2018; Munich, Germany2018. [38] de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364(21):1995–2005. [39] Logothetis CJ, Basch E, Molina A, Fizazi K, North SA, Chi KN, et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol 2012;13(12):1210–7. [40] Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368(2):138–48. [41] Fizazi K, Scher HI, Miller K, Basch E, Sternberg CN, Cella D, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 2014;15(10):1147–56.
ARTICLE IN PRESS E. Ballon-Landa et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−11 [42] Beer TM, Tombal B. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371(18):1755–6. [43] Loriot Y, Miller K, Sternberg CN, Fizazi K, De Bono JS, Chowdhury S, et al. Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial. Lancet Oncol 2015;16(5):509–21. [44] Smith MR, Halabi S, Ryan CJ, Hussain A, Vogelzang N, Stadler W, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol 2014;32(11):1143–50. [45] James ND, Sydes MR, Clarke NW, Mason MD, Dearnaley DP, Spears MR, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387(10024):1163–77. [46] Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 2012;379(9810):39–46. [47] Paller CJ, Carducci MA, Philips GK. Management of bone metastases in refractory prostate cancer—role of denosumab. Clin Interv Aging 2012;7:363–72. [48] Wirth M, Tammela T, Cicalese V, Gomez Veiga F, Delaere K, Miller K, et al. Prevention of bone metastases in patients with high-risk nonmetastatic prostate cancer treated with zoledronic acid: efficacy and safety results of the Zometa European Study (ZEUS). Eur Urol 2015;67(3):482–91. [49] Chang A, Finelli A, Berns JS, Rosner M. Chronic kidney disease in patients with renal cell carcinoma. Adv Chronic Kidney Dis 2014;21 (1):91–5. [50] Lowrance WT, Ordo~nez J, Udaltsova N, Russo P, Go AS. CKD and the risk of incident cancer. J Am Soc Nephrol 2014;25(10):2327–34. [51] Bagrodia A, Mehrazin R, Bazzi WM, Silberstein J, Malcolm JB, Stroup SP, et al. Comparison of rates and risk factors for development of osteoporosis and fractures after radical or partial nephrectomy. Urology 2011;78(3):614–9. [52] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68(1):7–30. [53] McKay RR, Kroeger N, Xie W, Lee JL, Knox JJ, Bjarnason GA, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014;65(3):577–84. [54] Rosen LS, Gordon D, Tchekmedyian S, Yanagihara R, Hirsh V, Krzakowski M, et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: a phase III, double-blind, randomized trial−the Zoledronic
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
11
Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21(16):3150–7. 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. Cancer 2003;98 (5):962–9. Smidt-Hansen T, Folkmar TB, Fode K, Agerbaek M, Donskov F. Combination of zoledronic Acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg 2013;71(9):1532–40. Beuselinck B, Wolter P, Karadimou A, Elaidi R, Dumez H, Rogiers A, et al. Concomitant oral tyrosine kinase inhibitors and bisphosphonates in advanced renal cell carcinoma with bone metastases. Br J Cancer 2012;107(10):1665–71. Henry DH, Costa L, Goldwasser F, Hirsh V, Hungria V, Prausova J, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011;29(9):1125–32. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther 2011;10(12):2298–308. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1814–23. Escudier B, Powles T, Motzer RJ, Olencki T, Aren Frontera O, Oudard S, et al. Cabozantinib, a new standard of care for patients with advanced renal cell carcinoma and bone metastases? Subgroup analysis of the METEOR trial. J Clin Oncol 2018;36 (8):765–72. McKay RR, Bosse D, Gray KP, Michaelson MD, Krajewski K, Jacene HA, et al. Radium-223 Dichloride in combination with vascular endothelial growth factor-targeting therapy in advanced renal cell carcinoma with bone metastases. Clin Cancer Res 2018;24(17): 4081–8. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373(19):1803–13. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378(14):1277– 90. Zaghloul MS, Boutrus R, El-Hossieny H, Kader YA, El-Attar I, Nazmy M. A prospective, randomized, placebo-controlled trial of zoledronic acid in bony metastatic bladder cancer. Int J Clin Oncol 2010;15(4):382–9.