Frequency Of Skeletal-related Events Research Articles

Newly Diagnosed Multiple Myeloma Patients with Skeletal-Related Events and Abnormal MRI Pattern Have Poor Survival Outcomes: A Prospective Study on 370 Patients.

Contemporary information is sparse on the frequency of skeletal-related events (SREs) in multiple myeloma (MM) patients at a population-based level in the era of novel agents. In this context, we conducted this single-center, prospective, observational study to determine the incidence of SREs among newly diagnosed MMs (NDMM) and to explore the possible correlations with disease characteristics, imaging finding, and patient prognosis. A total of 370 patients with available baseline MRIs were included. Among them, 208 (56%) presented with at least one SRE at diagnosis. Fractures were the most common reported SREs (48%). The incidence of SREs at diagnosis was higher in patients with osteolytic lesions, abnormal MRI pattern, hypercalcemia, and at least 60% bone marrow infiltration by plasma cells. Importantly, the patients with normal MRI pattern, who did not present with SREs at diagnosis, had statistically significant improved median OS in comparison with the patients who had abnormal MRI patterns and/or the presence of SREs at diagnosis (9.3 vs. 6.6 years, p = 0.048). Our data, which represent one of a few systematic reports on the incidence and characteristics of SREs in the era of novel agents, was indicative of a high incidence of SREs at the time of MM diagnosis. Early detection of myeloma bone disease and tailored patient management are essential to optimize patient outcomes.

Association of radical cystectomy and increased risk of skeletal-related events in bone-metastatic urothelial carcinoma.

477 Background: Bone metastases are common in patients with advanced cancer of the bladder or upper urinary tract; however, few studies have assessed the morbidity of bone metastases in these patients. We sought to characterize bone-associated morbidity by measuring the frequency of skeletal-related events (SREs) and identify predictors of SREs in this population. Methods: We retrospectively identified 328 patients with bone-metastatic bladder or upper urinary tract cancer managed at Memorial Sloan Kettering between 2000 and 2018. SREs were defined as presence of spinal cord compression from bone metastasis, pathologic fracture, treatment of bone metastasis with radiotherapy or surgery, or hypercalcemia of malignancy. SRE-free survival was estimated using Kaplan-Meier analysis; competing-risks regression analysis was used to identify predictors of SREs. Results: In total, 198 patients (60%) developed ≥1 SRE, including 84 (26%) with multiple SREs. The most common SREs were bone radiotherapy (n=165 [83%]), pathologic fracture (n=73 [37%]), and orthopedic surgery (n=39 [20%]). Median SRE-free survival was 7.4 months. On competing-risks regression analysis, history of radical cystectomy (hazard ratio [HR], 1.40; 95% CI, 1.05-1.86; P=0.02) and hip involvement at the time of bone metastasis diagnosis (HR, 1.65; 95% CI, 1.12-2.42; P=0.01) were independently associated with risk of SRE. Conclusions: SREs are common among patients with bone-metastatic cancer of the bladder or upper urinary tract and typically occur soon after the development of bone metastasis. Patients with a history of radical cystectomy or with hip involvement at the time of bone metastasis diagnosis have a higher risk of SRE.

Bone Metastases in Medullary Thyroid Carcinoma: High Morbidity and Poor Prognosis Associated With Osteolytic Morphology.

The clinical relevance of bone metastases (BM) in advanced medullary thyroid carcinoma (MTC) is poorly described. The objectives of this work are to describe the prevalence of BM, frequency of skeletal related events (SREs), and impact of BM morphology and SREs on prognosis, and to assess the role of antiresorptive treatment (ART). A retrospective cohort study was conducted. This study was conducted at 4 German referral centers. A total of 1060 MTC patients were included. Main outcome measures include descriptive statistics, overall survival (OS) by the Kaplan-Meier method, and risk factors by Cox proportional hazards modeling. A total of 120 of 416 patients (29%) with metastatic MTC had BM, of which 97% had concurrent nonosseous metastases. BM occurred 2.1 years (median, range -0.1 to 20.6 years) after initial diagnosis, were multifocal in 79%, and were located preferentially in the spine (86%) and pelvis (60%). BM morphology was osteolytic in 32%, osteoblastic in 25%, and mixed in 22% of cases (unknown: 21%). Within a median observation period of 26.6 months (range, 0-188 months) after BM diagnosis, 47% of patients experienced one or more SREs (bone radiation 50%, pathological fractures 32%), of which 42% occurred in osteolytic and 17% in osteoblastic BM (P = .047). Presence of osteolytic metastases (hazard ratio 3.85, 95% CI 1.52-9.77, P = .005) but not occurrence of SREs was associated with impaired OS. Among the 36 patients who received ART (no ART: n = 71), SREs were significantly less frequent than in untreated patients (P = .04). BM are common in metastatic MTC and most often with an osteolytic morphology and an unfavorable prognosis. The majority of SREs occur in osteolytic metastases and may be prevented by ART.

Anti-osteolytic use to prevent skeletal related events in solid tumour bone metastases

Abstract Background Bone metastases from solid tumours remain a serious burden on patient morbidity leading to decreased quality of life, increased narcotic use, and higher healthcare cost. We examined the current use of anti-osteolytics including RANK-L inhibitors and Bisphosphonates with the frequency of Skeletal Related Events (SRE) in coordination with current ESMO treatment guidelines. Methods Patients with bone metastases from solid tumours in the University of Pennsylvania Hospital system (UPHS) between August 2014 and August 2019 were identified. Data regarding treatment of metastases and frequency of SREs were obtained from patient charts in EPIC EMR. This included: type of therapy, documented SRE, and documented reasoning for lack of treatment. SREs were defined as pathological fractures, spinal cord compression, radiotherapy/surgery for fracture risk, and chronic metastatic bone pain. Descriptive statistical analyses and a single two variable relative risk analysis were performed to evaluate data. Results 400 patients were identified in the UPHS to have bone metastases from solid tumours. 240 (65%) received anti-osteolytic treatment while 140 (35%) did not. The total number of SREs numbered 173 (43%). Of those receiving treatment 173 (63%) were treated with denosumab while 87 (33%) were treated with a bisphosphonate. Lack of anti-osteolytic therapy reasoning was documented in 41 cases (29%) while 99 cases (71%) had no documented reasoning. In patients who did receive treatment there was an absolute 16% reduction in SREs from 54% without treatment to 38% with (Relative risk: .540, 95% Confidence Interval: .438 to .666, P-Value: Conclusions The use of anti-osteolytic treatment after diagnosis of bone metastasis was associated with a decrease in the risk of subsequent SREs. However, at 65% use, it would appear that these drugs are being underutilized and could better be employed in accordance with current ESMO guidelines so as to optimize patient care. We suggest further study to better understand reasoning behind lack of use, timing of SREs, and associated metastatic risk in regards to primary tumor type. Legal entity responsible for the study University of Pennsylvania Hospital System - Pennsylvania Hospital. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Multicenter study of zoledronic acid administration in non-small-cell lung cancer patients with bone metastasis: Thoracic Oncology Research Group (TORG) 1017.

Skeletal-related events (SREs) may occur at the time of first diagnosis in 20–30% of lung cancer patients with bone metastases. Several clinical trials have shown that zoledronic acid (ZA) is effective for decreasing SREs. The main objective of the present study was to discuss clinical data of ZA and compare the frequency of SREs with previous reports. All patients with non-small-cell lung cancer (NSCLC) with metastatic bone disease who were administered ZA at least twice between January 2008 and December 2009 were eligible for inclusion in the study. In total, 198 consecutive patients were identified. The median duration of ZA administration was 106 days [95% confidence interval (CI), 92–133 days], and the median number of ZA administrations was 4 (range, 2–41). The median time to first SRE in patients who experienced SRE following ZA treatment was 202 days (95% CI, 156–264 days). Among the 78 patients who had already experienced SRE prior to ZA treatment, 35 (45%) experienced SRE subsequently after starting ZA treatment. On the other hand, among the 120 patients without a history of SRE before starting ZA treatment, 42 (35%) experienced SRE after the start of ZA administration (P=0.16). No osteonecrosis of the jaw (ONJ) was reported in any of the patients. The present study revealed that ZA had a certain level of efficacy regardless of the presence or absence of prior SREs. However, the duration of ZA therapy was short in this study; further accumulation of data on the long-term prognosis and incidence rates of ONJ and other late complications of ZA therapy seems to be particularly important.

Bone metastases from head and neck malignancies: Prognostic factors and skeletal-related events.

BackgroundWe conducted a multicenter retrospective analysis to describe the characteristics, frequency of skeletal-related events (SREs), and prognosis of head and neck cancer (HNC) in patients with bone metastases (BM).Patients and methodsThe data of 192 HNC patients with BMs were collected. Analyses were conducted separately in 64 nasopharyngeal cancer (NPC) patients and in 128 non-NPC patients.ResultsSREs occurred in 34 (27%) non-NPC and in 6 (9%) NPC patients, respectively. Median overall survival (OS) was 25 and 6 months in NPC and non-NPC patients, respectively. Locoregional recurrence (hazard ratio [HR] 2.33, 95% confidence interval (CI) 1.1–4.93), synchronous BM (HR 0.25, 95% CI 0.59–0.71) and bone-directed therapies (BDT) (HR 0.26, 95% CI 0.10–0.68) were independent prognostic factors for OS in NPC patients. Combined bone radiotherapy (RT) and BDT in NPC patients obtained longer survival (38 months) than either therapy alone (25 months) or neither of these therapies (8 months).ConclusionsPatients with BMs from non-NPC have a poor prognosis and are at high risk of SREs. NPC patients with BMs are at relatively low risk of SREs. BDT may potentially improve survival, particularly when combined with bone RT. This last finding deserves prospective confirmation.

Frequency, Morbidity, and Mortality of Bone Metastases in Advanced Hepatocellular Carcinoma.

Background: Bone metastases are common in hepatocellular carcinoma (HCC), but their incidence, morbidity, and mortality are not well defined. Methods: The Memorial Sloan Kettering Cancer Center database was queried for all patients with HCC and metastases seen from 2002 to 2014. The prevalence of bone metastasis was determined and cumulative incidence function was used to estimate the probability of developing a bone metastasis. Regression models were created to identify risk factors for osseous metastasis. The frequency of skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, need for radiation therapy to bone, and/or surgical resection of bone, was determined and cumulative incidence function was used to estimate the probability of SRE development. Regression models were created to identify SRE risk factors. Correlation of clinicopathologic parameters, including bone metastases and SREs, with overall survival was analyzed using Kaplan-Meier methodology. Results: A total of 459 patients with HCC and extrahepatic metastases were identified; 151 patients (32.9%) had or developed bone metastases: 128 (27.9%) as a primary site and 23 (4.6%) as a secondary site of extrahepatic disease. Among the 331 patients without bone metastasis at presentation, the yearly incidence of bone metastasis was 6.4% (95% CI, 3.6%-9.2%). Hepatitis B virus (HBV) infection increased the chance of developing a bone metastasis (P=.02). The cumulative incidence of SREs was 50% at 6 months. Univariate analysis showed that patients with HBV-related HCC had a significantly higher incidence of SREs (P=.02). Sorafenib and bisphosphonates each protected against SREs. The presence of SREs was independently associated with a worse overall survival (hazard ratio, 2.13; 95% CI, 1.52-2.97; P<.01) in the multivariable model. Conclusions: Patients with AJCC stage IV HCC and bone metastases that are clinically evident on routine radiography or on clinical examination at presentation are apt to develop frequent, morbid, and mortal SREs, whereas those without evident bone metastasis at presentation are unlikely to develop these complications.

Protocolo de manejo clínico de las metástasis óseas

RationalBone metastases are a common manifestation of distant relapse from many types of solid cancers, especially those arising in the lung, breast, and prostate. Bone metastases represent a prominent source of morbidity. Skeletal-related events (SREs) due to bone metastases can include pain, pathologic fracture, hypercalcemia, and spinal cord compression. TreatmentAcross a wide variety of tumors involving bone, the frequency of SREs can be reduced through the use of osteoclast inhibitors, such as denosumab, or bisphosphonates. For most patients with a pathologic fracture of a long bone, this will necessitate surgical fixation. A significant proportion of patients with symptomatic skeletal metastases with inadequate pain relief can benefit from external beam radiation therapy (RT). Also minimally invasive methods for local ablation of skeletal metastases have been developed (image-guided radiofrequency ablation, cryoablation, focused ultrasound, and other percutaneous methods such as laser and microwave ablation and irreversible electroporation).

Frequency of skeletal-related events and associated healthcare resource use and costs in US patients with multiple myeloma

Objective:A potential complication for all new multiple myeloma (MM) patients is the clinical presentation of osteolytic lesions which increase the risk for skeletal-related events (SREs). However, the contribution of SREs to the overall economic impact of MM is unclear. The impact of SREs on healthcare resource utilization (HCRU) and costs for US patients with MM was analyzed in Truven Health Marketscan Commercial Claims and Medicare Supplemental Databases.Methods:Adults diagnosed with MM between January 1, 2005 and December 31, 2010 with ≥2 claims ≥30 days apart (first claim = index date) were included. SREs included: hypercalcemia, pathologic fracture, surgery for the prevention and treatment of pathologic fractures or spinal cord compression, and radiation for bone pain. Rates of HCRU (outpatient [OP], inpatient [IP], emergency room [ER], orthopedic consultation [OC], and ancillary) and healthcare costs were compared between MM patients with and without SREs. Inverse propensity weighting was applied to adjust for potential bias.Results:Of 1028 MM patients (mean age = 67, standard deviation = 13.2), 596 patients with ≥1 SRE and 432 without SREs were assessed. HCRU rates in IP, ER, and ancillary (p < 0.01) and mean total costs of OP, IP, and ER were significantly higher (p < 0.05) for patients with vs without SREs during follow-up. HCRU rates also increased with SRE frequency (p < 0.05 in OP, IP, ER, OC, and ancillary), as did mean total healthcare costs, except for OC (p < 0.001).Limitations:A broad assessment of pharmacotherapy for the treatment of MM was not an objective of the current study. Bisphosphonate use was evaluated; however, results were descriptively focused on frequency of utilization only and were not included in the broader cost and HCRU analysis.Conclusions:Among US patients with MM, higher SRE frequency was associated with a significant trend of higher HCRU and total healthcare costs in several settings.

Risk factors for skeletal-related events (SREs) and factors affecting SRE-free survival for nonsmall cell lung cancer patients with bone metastases.

Skeletal-related events (SREs) for nonsmall cell lung cancer (NSCLC) patients with bone metastasis lead to serious morbidity. The aim of this study was to determine risk factors for SREs in NSCLC patients with bone metastasis and the factors influencing SRE-free survival and overall survival (OS). From 2000 to 2012, we evaluated retrospectively 835 NSCLC patients. Three hundred and thirty-five of them with bone metastasis were included in the study. SREs and the other prognostic factors were evaluated by univariate and multivariate analysis for SRE-free survival and OS. SREs were detected in 244 patients (72.8%). The most common SREs were the need for radiotherapy (43.2%) and malignant hypercalcemia (17.6%). The median time to first SRE was 3.5months at the median follow-up of 17months. A multivariate analysis showed that the presence of bone metastasis at diagnosis (p < 0.001), the number of bone metastasis (p = 0.001), baseline hypercalcemia (p = 0.004), and the presence of palliative radiotherapy (p = 0.04) were independent prognostic factors for SRE-free survival. A logistic regression analysis identified that the presence of bone metastasis at diagnosis [odds ratio (OR), 12.6], number of bone metastasis (OR, 3.05), and baseline hypercalcemia (OR, 0.33) were found to be predictive factors in the developing of SRE. The median OS time for patients with SRE was worse than that for patients without SRE (7 vs 12months, respectively). For OS, male gender, ECOG performance status (PS), high lactate dehydrogenase (LDH) level, hypoalbuminemia, the presence of bone metastasis at diagnosis, the number of bone metastasis, the presence of SREs, the presence of bisphosphonate therapy, and palliative radiotherapy were independent prognostic indicators for OS by the multivariate analysis. Our results indicated that the frequency of SREs was high and the presence of bone metastasis at the time of diagnosis, baseline hypercalcemia, and multiple bone metastases were significant factors predicting the occurrence of SREs. If bone metastases diagnose earlier, treatments for the prevention of SREs may be initiated earlier; thus, the deterioration of quality of life may be preserved.

137P - Risk Factors for Skeletal-Related Events in Patients with Non-Small Cell Lung Cancer Patients with Bone Metastases

Aim: We purposed to determine the risk factors for SREs (skeletal related events) SRE free survival and overall survival in NSCLC patients with bone metastasis. Methods: We retrospectively reviewed the data of 335 NSCLC patients with bone metastasis. The association between clinicopathological features of the patients with respect to the presence of SRE was compared with the chi-squared test and Fisher's exact test. The survival analyses and curves were established with the Kaplan-Meier method. To identify predictive factors related to SRE, logistic regression analysis was used. Results: Of the 335 patients, 244 (72.8%) patients developed SREs at the diagnosis or during treatment of disease. Of these, 145 required radiotherapy to the bone or pathological fracture, 59 developed malignant hypercalcemia, 21 developed compression fracture of the vertebrae and 5 required surgical treatment of the bone. The mean time-to first SRE was 6.9 months at the median follow-up of 17months. A multivariate analysis demonstrated that the presence of bone metastasis at diagnosis (p < 0.001, HR:1.96), number of bone metastasis (p < 0.001, HR:1.70) and the presence of palliative radiotherapy (p = 0.011, HR:1.68) were independent prognostic indicators for SRE-free survival. The results of univariate analysis revealed that PS, the presence of bone metastasis at diagnosis, number of bone metastasis, SRE, the presence of palliative radiotherapy and bisphosphonate therapy were significant prognostic factors for OS. The median OS interval for patients with SRE were worse than for patients without SRE (7 vs. 12 months, p < 0.001). All of significant factors were found to be independent prognostic indicators for OS in the multivariate analysis. Logistic regression analysis showed that the presence of bone metastasis at diagnosis and number of bone metastasis were found to be an independent factors for predicting the occurrence of SRE (p < 0.001, OR:12 and p < 0.001, OR:2.59). Conclusions: The frequency of SREs was found to be higher in our study. The presence of bone metastasis at diagnosis and multiple bone metastases might be predictive factors of SREs. Further studies would focus on developing novel strategies for reducing and preventing the occurrence of SREs. Disclosure: All authors have declared no conflicts of interest.

Frequency, Health Care Resource Use (HCRU), and Costs Associated With Skeletal Related Events (SREs) In US Patients With Multiple Myeloma (MM)

BackgroundExisting data demonstrate that SREs can impose a significant economic burden. Much of the cost data for MM patients are combined with other tumor types and do not make comparisons between MM patients with SRE and MM patients without SRE. This research provides updated, comprehensive cost data in MM patients to address these gaps. MethodsPatients 18 years of age or older were required to have ≥2 claims in any position with a diagnosis of MM (ICD-9-CM codes 203.00, 203.01, 203.02), at least 30 days apart, between 01 January 2005 and 31 December 2010; the date of the first MM diagnosis was the index date. Marketscan(r) data were used to select patients continuously enrolled in a non-capitated commercial health plan with a medical and pharmacy benefit for 12 months before the index date (i.e., baseline period) and at least 3 months after the index date (post-index period). Patients were followed until the earliest of death or disenrollment from the health plan or end of the study period on 31 December 2011. MM patients with ≥ 1 SRE were compared to those without SRE to characterize the associated incremental cost of SRE. Frequency of SREs, HCRU (events/person-mth), and costs (USD/person-mth) were determined. Cost is defined as total gross payment to providers for a specific service, which includes amount paid by the patient and payer. Due to skewed distributions, bootstrapping (replication=1000) methodology was used to estimate standard error of rates of HCRU and costs and to compare cohorts. P-values were generated utilizing 2-sample t-tests. ResultsMM patients with SRE (n=596, mean age=67.8, 45.6 % male, mean Charlson/Deyo [CD] =1.1) were compared to MM patients without SRE (n=432, mean age=65.7, 47.5 % male, mean CD=0.8). Patients are categorized by number of SREs experienced during the study period in Table 1. MM patients with SRE experienced significantly greater HCRU during both the baseline and post-index periods (Tables 2&3). The HCRU increases translated into mean total costs for patients with SRE that were significantly greater during both the baseline (w/o SRE: USD 953; w/SRE: USD 1328; p=0.005) and post-index (w/o SRE: USD 3307; w/SRE: USD 4763; p<0.0001) periods. Increasing frequency of SRE was significantly associated with increasing trend of HCRU and cost throughout the study (all p values <0.0001). [Display omitted] [Display omitted] [Display omitted] ConclusionIn addition to the clinical burden, SREs significantly add to the economic burden associated with MM in US patients by increasing the rate of HCRU and cost. Disclosures:Smyth:Eli Lilly and Company: Employment, Equity Ownership. Off Label Use: The frequency of bisphosphonate use (both oral and IV) will be described in the poster. Conti:Eli Lilly and Company: Employment, Equity Ownership. Wooldridge:Eli Lilly and Company: Employment, Equity Ownership. Bowman:Eli Lilly and Company: Employment, Equity Ownership. Li:Eli Lilly and Company: Employment, Equity Ownership. Nelson:Eli Lilly and Company: Employment. Xie:Eli Lilly and Company: Employment, Equity Ownership. Ball:Eli Lilly and Company: Employment, Equity Ownership.

Bone metastases in soft tissue sarcoma patients: A survey of natural, prognostic value, and treatment.

10063 Background: Given the limited data currently available, we surveyed the natural history of bone metastases in patients affected by soft tissue sarcoma (STS). Methods: This retrospective, multicenter, observational study evaluated data from 135 patients with STS metastatic to the bone who presented between 2001 and 2011. For all patients, we recorded the primary tumor histological subtype, bone metastases characteristics (onset, site), type of treatment received (surgery, radiotherapy, zoledronic acid), type and frequency of skeletal related events (SRE) and disease outcome. Results: The most represented histological subtypes among the enrolled patients were leiomyosarcoma (27%), angiosarcoma (13%) and spindle cell sarcoma (8%). The spine was the most common site for bone involvement (51%), followed by hip/pelvis (20%), long bones (15%) and other sites (14%). In 27% of cases, bone metastases were present at the time of diagnosis. Fiftyfour patients (40%) developed SREs and the median time to first SRE (if developed) was 4 months. The most common SRE was the need for radiotherapy occurring in 28% of patients followed by pathologic fracture (22%). Patients survived for a median of 6 months after bone metastases diagnosis. The occurrence of a SRE was associated with a decreased overall survival (P=0.04). A subgroup analysis revealed that zoledronic acid significantly prolonged median time to first SRE (5 versus 2 months; P = 0.002). Conversely, It did not determine an improvement in terms of overall survival, even if favorable trend was identified (median, 7 versus 5 months, respectively; P = 0.105). Conclusions: This study illustrates the burden of bone disease from STS and supports the use of zoledronic acid in this setting.

Abstract 849: Cabozantinib (XL184) inhibits growth of prostate cancer in the bone and results in an altered bone environment

Abstract There is a critical need for novel effective therapies for advanced prostate cancer (PCa) and associated bone metastases. A great deal of focus is being placed on investigations into the use of small molecule kinase inhibitors. Cabozantinib (XL184) is a small molecule kinase inhibitor which potently inhibits MET and VEGF receptor 2 (VEGFR2). In a phase 2 adaptive randomized discontinuation trial cabozantinib has demonstrated encouraging signs of clinical benefit in patients with metastatic castration-resistant PCa. Complete or partial resolution of lesions was evident in 82 of 110 (76%) patients with bone metastases as assessed by bone scan. The objectives of our preclinical studies were to investigate the efficacy of cabozantinib on growth of androgen-sensitive and castration-resistant PCa in the bone and on the bone itself. For our in vivo studies we used the androgen-sensitive LuCaP 23.1 PCa xenograft that elicits an osteoblastic reaction in the bone, and the castration-resistant C4-2B PCa xenograft that elicits mixed osteolytic/osteoblastic lesions. Cabozantinib inhibited growth of LuCaP 23.1 in the bone as demonstrated by serum PSA levels (control: 20.1± 0.8ng/ml vs. cabozantinib: 1.5 ±0.4ng/ml, P=0.020). Micro-CT analysis of trabecular bone showed that LuCaP 23.1 growth in the bone resulted in significant increases in bone volume (BV: 7.6 fold increase vs non-tumored tibiae; P=0.017). These increases were attenuated by cabozantinib (BV: 1.3 fold increase vs non-tumored tibiae, P=0.0021). Micro-CT analysis also showed that cabozantinib treatment affected normal bone. BV in non-tumored tibiae from mice treated with cabozantinib was 1.8 fold higher than BV of non-tumored tibiae from untreated mice (P=0.013). To evaluate the effects on osteoblasts in vitro we used MC3T3 cells. In concordance with the detected effects on normal bone, cabozantinib increased alkaline phosphatase activity in MC3T3 cells (1-3 μM, 1.5-2.2 fold increases, ANOVA P&amp;lt;0.0001) and their mineralization (3 μM: 2.2 fold increase, P=0.0023). In the castration-resistant model, C4-2B, cabozantinib treatment also significantly decreased tumor growth based on serum PSA (control: 24.93±6.80 ng/ml vs. cabozantinib: 5.77±1.29 ng/ml, P=0.0096). Micro-CT assessment of tibiae from the C4-2B study and further analyses of all generated tissues are ongoing to further investigate the mechanisms underlying cabozantinib efficacy.In summary, our preclinical results show that cabozantinib is an effective inhibitor of androgen-sensitive as well as castration-resistant PCa in the bone. Importantly our data also indicate that cabozantinib treatment results in increases in bone formation which might be particularly beneficial to patients with advanced PCa who are on androgen ablation therapy and experiencing decreases in bone mineral density and increased frequency of skeletal-related events. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 849. doi:1538-7445.AM2012-849

Abstract PR6: Cabozantinib (XL184) inhibits androgen-sensitive and castration-resistant prostate cancer in the bone and increases bone formation in non-tumored bones

Abstract Bone metastases are the major cause of morbidity and mortality in advanced PCa, and there is therefore a critical need for novel effective therapies for PCa associated bone metastases. The objective of our studies was to evaluate in detail efficacy and mechanisms of action of cabozantinib in androgen-sensitive and castration-resistant PCa in the bone. Cabozantinib (XL184) is a potent dual inhibitor of MET and VEGF receptor 2 (VEGFR2) as well as other receptor tyrosine kinases (e.g., AXL and KIT) that have been implicated in cancer progression. In the clinical setting, cabozantinib demonstrated encouraging signs of clinical benefit in patients with metastatic castration-resistant PCa. However a detailed investigation of the effects of cabozantinib on PCa and bone in the preclinical setting has not been reported. In our preclinical studies we directly injected PCa cells into mouse tibiae and evaluated effects of cabozantinib on an androgensensitive LuCaP 23.1 xenograft that elicits an osteoblastic reaction in the bone, and a castration-resistant C4-2B PCa xenograft that elicits mixed osteolytic/osteoblastic lesions. Serum PSA was measured to monitor tumor growth and response to the treatment. Effects of tumor and cabozantinib on bone were evaluated using micro-CT. Cabozantinib inhibited growth of both LuCaP 23.1 and C4-2B in the bone as demonstrated by serum PSA levels (LuCaP 23.1: control: 20.1 ± 0.8ng/ml vs. cabozantinib: 1.5 ±0.4ng/ml, P=0.020; C4-2B: control: 25.0 ± 6.8 ng/ml vs. cabozantinib: 5.8 ± 1.3ng/ml, P=0.0096). Micro-CT analysis showed that cabozantinib treatment resulted in decreased bone formation caused by LuCaP 23.1 (BV/TV: 49% of control, P=0.0056) while increases were detected in C4-2B tumored tibiae (BV/TV: 158% of control; P=0.077). Micro-CT analysis showed that cabozantinib treatment also affected normal bone. BV/TV in non-tumored tibiae of intact mice treated with cabozantinib was 186% of BV/TV of nontumored tibiae from untreated mice (P=0.030). Increases in BV/TV were also detected in castrated mice treated with cabozantinib (136% of control, P=0.0009.) In summary, our preclinical results show that cabozantinib exhibits inhibitory effects on androgen-sensitive as well as castration-resistant tumor cells in the bone environment and suggest that the overall effects of cabozantinib on bone depend on the underlying bone response to the tumor. Importantly our data also indicate that cabozantinib treatment results in increases in bone formation which might be particularly beneficial to patients with advanced PCa who are on androgen ablation therapy and experiencing decreases in bone mineral density and increased frequency of skeletalrelated events. This abstract is also presented as Poster A20. Citation Format: Holly M. Nguyen, Lisha G. Brown, Ted S. Gross, Douglas A. Laird, Robert L. Vessella, Eva Corey. Cabozantinib (XL184) inhibits androgen-sensitive and castrationresistant prostate cancer in the bone and increases bone formation in nontumored bones [abstract]. In: Proceedings of the AACR Special Conference on Advances in Prostate Cancer Research; 2012 Feb 6-9; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(4 Suppl):Abstract nr PR6.

OT1-01-02: A Multicentre Study Assessing 12-Weekly Intravenous Bisphosphonate Therapy in Women with Low Risk Bone Metastases from Breast Cancer – The TRIUMPH Trial.

Abstract Background: Metastatic bone disease is a major cause of morbidity and mortality for breast cancer patients. Bisphosphonates (BP) have been shown to significantly delay the onset and frequency of skeletal related events (SREs), improve pain control and overall quality of life. Most patients receive intravenous BP every 3–4 weeks regardless of their individual risk for a SRE. This “one size fits all” strategy could expose those patients at a relatively low risk of SREs to an increased chance of adverse drug effects, as well as to the financial and quality of life burden of multiple visits to the cancer centre for treatments. This study aimed to assess whether IV BP can be safely given at reduced frequency. Methods: The primary objective of this study is to demonstrate in women with biochemically defined low-risk bone metastases that the administration of IV BP every 12 weeks is sufficient to maintain biochemical stability for one year. Eligibility criteria include; bone metastases from breast cancer, have received at least three months of regular 3–4 weekly IV BP, satisfactory renal function, adequate dental health, no systemic treatment change or recent SRE within 4 weeks of study entry. Low risk disease will be defined as serum CTx levels &amp;lt;600 ng/L Biochemical failure is defined as CTx levels &amp;gt;600 ng/L measured at predefined time points (6, 12, 24, 36 and 48th). Secondary objectives are to evaluate the palliative benefit of 12-weekly IV BP therapy as reflected by occurrence of SREs, analgesic use, self-reported pain using the validated BP and FACT-BP questionnaires. Sample size was calculated at 68 patients. Given the small sample size, nonparametric Bootstrapping will be employed to calculate point estimates, standard deviations and 95% confidence intervals (CIs). An exploratory multivariable analysis will also be undertaken to determine baseline factors that were associated with patient's maintaining their telopeptide levels in the low risk range. Conclusion: TRIUMPH opened in October 2010 and as of June 2011, has quickly accrued 54/68 patients (79%). This trial has the potential to allow lower risk women to receive less frequent dosing of bisphosphonates, thus improving their quality of life with less cancer center visits and reducing their chance of drug induced adverse events. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT1-01-02.

A multicenter study assessing 12-weekly intravenous bisphosphonate therapy in women with low-risk bone metastases from breast cancer: The TRIUMPH trial.

TPS242 Background: Metastatic bone disease is a major cause of morbidity and mortality for breast cancer patients (pts). Bisphosphonates (BP) have been shown to significantly delay the onset and frequency of skeletal related events (SREs), improve pain control and overall quality of life. Most pts receive intravenous BP every 3-4 weeks regardless of their individual risk for a SRE. This “one size fits all” strategy exposes those pts at a relatively low risk of SREs to the financial and quality of life burden of multiple visits to the cancer centre for treatments as well as an increased risk of drug toxicity. This study aimed to assess whether IV BP can be safely given at reduced frequency. Methods: The primary objective of this study is to demonstrate in women with biochemically defined low-risk bone metastases that the administration of IV BP every 12 weeks is sufficient to maintain biochemical stability for one year. Eligibility criteria include; bone metastases from breast cancer, have received at least three months of regular 3-4 weekly IV BP, satisfactory renal function, adequate dental health, no systemic treatment change or SRE within 4 weeks of study entry. Low risk disease will be defined as serum CTx levels <600 ng/L Biochemical failure defined as CTx levels >600 ng/L measured at predefined time points. Secondary objectives are to evaluate the palliative benefit of 12-weekly IV BP therapy as reflected by occurrence of SREs, analgesic use, self-reported pain using the validated BPI and FACT-BP questionnaires. Sample size was calculated at 68 pts. Given the small sample size, nonparametric Bootstrapping will be employed to calculate point estimates, standard deviations and 95% confidence intervals. An exploratory multivariable analysis will also be undertaken to determine baseline factors that were associated with pt’s maintaining their telopeptide levels in the low risk range. Conclusion: TRIUMPH opened Oct. 2010 has quickly accrued 20/68 pts. This trial has the potential to allow lower risk women to receive less frequent dosing of BP, thus improving their quality of life with less cancer center visits and reducing their chance of drug induced adverse events.

Cost-Effectiveness of Zoledronic Acid in the Management of Skeletal Metastases in Patients With Lung Cancer in France, Germany, Portugal, The Netherlands, and the United Kingdom

Background Zoledronic acid (ZOL) significantly reduces the risk of new skeletal-related events (SREs) in patients with non–small cell lung cancer (NSCLC) who have bone metastases. Objective The purpose of this study was to assess the cost and cost-effectiveness of ZOL in the management of skeletal metastases in this population across 5 European countries (France, Germany, United Kingdom, Portugal, and the Netherlands) from the perspective of national health care. Methods This cost-effectiveness analysis was based on a subset of patients with NSCLC who were enrolled in a Phase III trial of patients with bone metastases secondary to a variety of solid tumors. In this trial, patients were randomized to receive ZOL or placebo every 3 weeks for up to 21 months. Survival, SRE incidence, and number of infusions administered were derived from the clinical trial. Costs of SREs were estimated using hospital Diagnosis Related Group tariffs and published data. Drug, drug administration, and supply costs were obtained from published and internet sources. Quality-adjusted life-years (QALYs) were estimated based on the published utilities and modeled survival and frequency of SREs. Uncertainty surrounding outcomes was addressed via univariate and probabilistic sensitivity analyses. Results Compared with patients receiving placebo (n = 120), patients receiving ZOL (n = 124) experienced an estimated 0.79 fewer SREs and gained an estimated 0.02 QALYs. ZOL use in patients with NSCLC and bone metastases was associated with a reduction in SRE costs (ranging from €1547 to €1893 [2007–2008 €], depending on the country). After adding drug and drug administration costs, ZOL use resulted in a net savings of €288 per patient in Germany, €209 in the United Kingdom, and €113 in Portugal. In France and the Netherlands, costs increased (€17 and €178, respectively), but the costs per QALY gained were low (€786 and €8278, respectively). In univariate sensitivity analyses, the cost per QALY for ZOL versus placebo was ≤€50,000 for all scenarios tested. The results were most sensitive to assumptions regarding survival, number of ZOL infusions, and the costs of SREs. The probabilistic sensitivity analysis indicated that ZOL cost ≤€50,000 per QALY in 65% to 83% of model simulations (depending on country). However, some degree of uncertainty remained as the 95th percentile of cost per QALY was high. Conclusions This analysis is subject to the usual limitations of cost-effectiveness models, which combine assumptions and data from multiple sources. Nevertheless, based on the assumptions used herein, the present model suggests that ZOL increases QALYs and is cost saving and/or cost effective compared with placebo in patients with NSCLC in France, Germany, the United Kingdom, Portugal, and the Netherlands.

Improving management of patients with advanced cancer

Development of bone metastases in patients with advanced cancer is associated with skeletal-related events (SREs) such as pathologic fractures, spinal cord compression, the requirement for surgery or palliative radiotherapy to bone, and hypercalcemia of malignancy. Skeletal morbidity may reduce patient mobility, limit functional independence, and impair quality of life (QOL). Proactive management of new or worsening bone pain or motor impairment is crucial because of the potential for rapid progression of symptoms. Administration of bisphosphonate therapy as a monthly infusion to patients with bone metastases prevents or delays the onset and reduces the frequency of SREs and provides clinically meaningful improvements in bone pain and QOL. In addition to administration of therapy, the monthly infusion visit allows a dedicated team of healthcare professionals to regularly assess SREs, response to therapy, adverse events (AEs), QOL, and adherence to oral medications and supplements. The continuity of care that occurs during the monthly infusion visit provides oncology nurses with an opportunity to educate patients about effective strategies to manage SREs and AEs. In addition, regular interaction provides oncology nurses with an opportunity to recognize and proactively address subtle changes in the patients’ medical condition. Using a multidisciplinary medical team also eliminates barriers between the various healthcare professionals involved in patient management. Consequently, the monthly infusion visit can result in effective patient management and improved clinical outcomes in patients with malignant bone disease.

Skeletal-related events (SREs) in breast cancer patients with bone metastases treated in the nontrial setting

Clinical trials exploring bisphosphonate (BP) use in patients with bone metastases from breast cancer (BC) consistently state skeletal-related event (SRE) rates >50%. These trials predominantly include patients with bone only disease, and also frequently use screening radiology to detect asymptomatic fractures. Both these variables are likely to increase the incidence of SREs and thereby overestimate BP benefit. Little data exists regarding the natural history of SREs among patients treated with i.v. BPs in the nontrial setting. Charts from two institutions (PMH and CVH) were reviewed to determine predictive risk factors for SRE development post i.v. pamidronate therapy in BC patients with bone metastases. Eighty-seven charts from 1999 to 2005 with complete outcome data were identified and reviewed. Pain was the most common presentation for bone metastases occurring in 49 women (56%). At diagnosis, 31 patients (35%) had bone only disease, and 57 (65%) had concomitant visceral metastases. Twenty-nine patients (33%) experienced an SRE prior to commencing BP treatment. Thirty-three women (38%) subsequently developed an SRE after a median of 5 BP treatments. SREs included radiation (79%), pathologic fractures (12%), and hypercalcemia (9%). On Cox regression, baseline history of osteoporosis (HR = 2.8; p = 0.045) and the presence of bone only disease (HR 3.0; p = 0.003) were predictive of SRE development. In patients with and without osteoporosis, median time to SRE was 305 and 866 days, respectively (p < 0.001). The frequency of SREs in this study was significantly lower than that reported in clinical trials of i.v. BP use. The lower incidence of SREs in this setting could affect sample size calculations for future event-driven BP trials. While the greatest risk of SREs despite BP therapy appears to be in patients with osteoporosis and with metastatic disease confined to the skeleton, further prospective study is merited to confirm and characterize the impact of these risk factors on SRE development.