Bone-directed Therapy Research Articles

Metastatic Prostate Cancer: The Optimal Sequencing and Bone Health Management Strategies

Summary Remarkable progress has been made in the treatment of metastatic prostate cancer in the last decade. Prior to initiation of therapy, risk stratification is of paramount importance. Androgen deprivation therapy along with newer systemic therapies are the mainstay of treatment in the metastatic setting. Local therapy and bone directed therapy are important considerations. In this review we discuss the appropriate sequencing strategies in metastatic prostate cancer.

Breast Cancer in Elderly Females

Breast cancer develops when the breast’s cells multiply uncontrollably. Breast cancer ranks as the second leading cause of cancer-related mortality among women. Breast cancer risk increases with age. Almost 1 in 7 women will experience the onset of breast cancer during their lifetime. Breast cancer is a malignant or cancerous tumour that develops from cells in breast tissue. Although they are non-life-threatening and confined to the breast, some women develop benevolent or non-cancerous breast lumps. Many people are unaware they have breast cancer since the early stages of the disease are frequently benign. Early discovery provides more time for evaluation and treatment, which can help prevent negative effects. Self-examination and several diagnostic tools as mammography, ultrasound, and nuclear medicine, are used to evaluate invasive and non-invasive breast cancer. Several therapies associated with breast cancer treatments include chemotherapy, radiation therapy, hormone therapy, and bone-directed therapy. Surgeries can also effectively treat breast cancer, such as lumpectomy and mastectomy. This suggests that effective therapies are progressing. This review aims to determine breast cancer’s causes, prevalence, and treatments in elderly women. The authors have discussed the disease’s treatment criteria and protocols, such as pharmacological therapies, herbal treatment, lifestyle modifications, and physical activities

Abstract #1400018: Genetic Alterations in NRAS, TERT, PIK3CA and SPEN Genes Leading to an Aggressive Metastatic RAI Refractory Follicular Thyroid Cancer

Follicular thyroid cancer (FTC) is a well-differentiated thyroid tumor and the second most common type after papillary thyroid cancer (PTC) with higher incidence of distant metastases, more aggressive behavior, and poorer outcome than PTC Patient is 43-year-old female with 6.2 cm TR4 left thyroid nodule on Neck US. On Exam, Cricoid is deviated to the right with left thyroid firm nodule. FNA showed Follicular neoplasm. TSH level was 1.59 (0.45-4.70 mIU/L) and Free T4 level: 1.19 (0.78-2.20 ng/dl) CT scan of neck with contrast and MRI thoracic spine: Large, solid heterogenous mass in left thyroid lobe causing lateral displacement and mild narrowing of the trachea with retrosternal extension, Osteolytic lesion of T4 vertebral body and right sided pleura-based mass at the level of T7-T8 with No enlarged cervical lymph nodes. IR biopsy of vertebra: thyroid Origin Metastatic Carcinoma, Patient underwent total thyroidectomy with central neck dissection. Follicular thyroid cancer (STAGE II pT3A,pN1B,pM1) Mutational Testing: Negative BRAF and KRAS with Positive NRAS, PIK3CA, SPEN and TERT. Patient started on TSH suppression therapy. 1 month Later: Thyroglobulin: 2443.4 ng/ml (1.3-31.8), Thyroglobulin Ab< 0.9 (0.0-4.0 IU/ml), TSH 0.02 with Free T4 2.53 FDG PET: Multifocal osseous metastatic disease, predominantly in the axial skeleton Thyrogen stimulated WBS I-123 showed No evidence of residual or metastatic disease. Patient recieved 214 mCi of iodine-131. Post treatment MN scan showed accumulation of iodine in the metastatic bone lesions with small focal activity in the thyroidectomy bed. Post RAI treatment: TG trended to 1102.7 then 1307 Patient Completed 10 fractions of external beam radiation on T4 spine Ultrasound thyroid: No residual thyroid tissue or suspicious lymph nodes Oncology started Bone directed therapy with zoledronate with consideration of PIK3CA mutation targeted therapy with Everolimus or Temsirolimus FTC is more aggressive with poorer prognosis than PTC that is more likely to hematogenously disseminate, with mortality rate of 50%. The neoplastic proliferation of thyroid follicular cells develops by altering multiple molecular pathways such as the PI3K/AKT pathway involving the RAS, RAF, RET, and NTRK1 genes. RAS is a dual activator of the mitogen activated protein kinase and PI3K/AKT pathways TERT is a catalytic subunit of the telomerase complex. Reported in 11–17% of FTC. TERT promoter mutations associated with tumor aggressiveness and mortality PIK3CA encodes p110-alpha, is a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) involves in thyroid cancer tumorigenesis and progression, reported in 7.7% of FTC with sensitivity to therapies targeting PI3K49-56, AKT57-58, or mTOR59-66. In our patient, pretreatment MN scan failed to show RAI avid lesions but PET showed increase FDG uptake and since receiving RAI treatment helped in lowering TG that indicate a possibility of mixture of RAI avid and non-RAI avid lesions existing at same time so RAI treatment is still recommended despite negative Diagnostic Scan for persistent elevated TG.

Treatment outcomes of patients with metastatic prostate cancer and co-morbid diabetes mellitus.

113 Background: In metastatic castrate resistant prostate cancer (mCRPC) there is a lack of studies that explore the interaction of comorbidities on treatment outcomes, which presents a challenge in choosing the right drug. In patients with diabetes mellitus, two common therapies, enzalutamide (ENZ) and abiraterone (ABI) have different effectiveness due to different mechanisms of action and because ABI requires co-administration of prednisone. Thus, in this study, we aim to assess the survival of patients with comorbid diabetes treated with ENZ and ABI. Methods: Patients treated with AA or ENZ for mCRPC from September 10, 2014, to June 2, 2017 were identified within the Veterans Health Administration. For these patients, presence of diabetes or complicated diabetes was determined using the Charlson method from the International Classification of Diseases (ICD) 9/10 codes. A Kaplan–Meier time to event analysis and the cox proportional hazards modeling was used to analyze the data with the latter including covariates such as age, Charlson Comorbidity Index, body-mass index, treatment with bone-directed therapy, black race, and baseline PSA at start of treatment with ENZ or ABI. Results: We identified 5822 patients treated for mCRPC, of which 2202 had diabetes and were treated using either ENZ (n = 1041) or ABI (n = 1161). Median survival of patients with diabetes treated with ENZ was 3 months longer than in patients treated with ABI (23.8 vs. 20.8, p = 0.002 by log-rank). In 3620 patients without diabetes, no significant difference in median survival (24.7 vs. 22.7 months, p = 0.065) was seen between ENZ (n = 1463) and ABI (n = 2157). In a multivariable model, ENZ was associated with improved survival in patients with diabetes (adjusted HR 0.87, 95% CI 0.79-0.97) and in patients without diabetes (adjusted HR 0.90, 95% CI 0.83-0.98). Conclusions: ENZ was associated with improved 3-month median survival in patients with diabetes compared to ABI in unadjusted analyses. Additionally, in adjusted analyses the cox proportional model also showed significantly better survival in mCRPC patients treated with ENZ both with and without diabetes, although the findings are more robust for patients with diabetes. The cause of these differences is unknown, so there may be differences in efficacy and adverse events between the two agents in real-world use. Further assessment of patient outcomes with comorbid disease is appropriate to improve care of patients with advanced prostate cancer.

Survival of patients with metastatic prostate cancer and comorbid obesity.

116 Background: In metastatic castrate resistant prostate cancer (mCRPC), the oral treatments of enzalutamide (ENZ) and abiraterone (AA) are used interchangeably because there are few large-scale comparative studies of the therapies. However, both drugs have different mechanisms of action, AA being an androgen biosynthesis inhibitor and ENZ being an androgen receptor inhibitor, so there may be therapeutic variance between the two drugs based on their interactions with comorbid conditions like obesity. Obesity not only increases the risk of other comorbidities, like heart disease, diabetes, and stroke, but has also been implicated in the development of CRPC. Methods: Patients treated with abiraterone or enzalutamide from September 10, 2014 to June 2, 2017 in the Veterans Health Administration were identified via pharmacy records. Among this population, patients were separated into body mass index (BMI) categories for underweight ( &lt; 18.5), normal (18.5 to &lt; 25), overweight (25 to &lt; 30), and obese ( &gt; 30). Age, Charlson Comorbidity Index and mCRPC treatments were collected and analyzed for the primary outcome of survival via the Kaplan-Meier method. A multivariate Cox proportional hazard model was performed with the following variables: BMI, Charlson Comorbidity Index, age, Black race, treatment with bone-directed therapy, and baseline PSA. Results: In patients with BMI &gt; 25, there was a significantly improved overall survival for treatment with ENZ (n = 1623) over AA (n = 2159), with medians of 30.0 and 27.0 months respectively (p = 0.002). There was no significant difference in survival for patients with BMI &lt; 25 (p = 0.48), with median survival of 17.7 months for ENZ (n = 589) and 16.1 months for AA (n = 860). The overall survival difference between underweight (n = 113), normal (n = 1336), overweight (n = 1879), and obese (n = 1903) groups shows significant increase in survival with increasing BMI, with the median survival durations of 9.2, 15.9, 23.9, and 29.8 months respectively (p &lt; 0.001). This finding was corroborated by the Cox proportional hazard model, with the data indicating an increased risk of death (aHR = 1.58; 95% CI: 1.29, 1.94; p &lt; 0.001) with the underweight group and decreased risk with the overweight (aHR = 0.75; 95% CI: 0.69, 0.81; p &lt; 0.001) and obese (aHR = 0.64; 95% CI: 0.59, 0.70; p &lt; 0.001) groups. Conclusions: Treatment with ENZ was associated with longer survival for mCRPC patients with overweight and obesity (BMI &gt; 25) over AA. Otherwise, for normal and underweight patients (BMI &lt; 25), there was no significant difference in overall survival between the two drugs. Higher BMI is associated with improved survival, suggesting a protective effect of obesity in mCRPC patients. While the reason for this finding warrants further investigation, similar findings have been seen in obese patients in some hormone driven cancers, like breast cancer and myeloma.

Secular Trends in the Pharmacologic Treatment of Osteoporosis and Malignancy-Related Bone Disease from 2009 to 2020.

New bone-directed therapies, including denosumab, abaloparatide, and romosozumab, emerged during the past decade, and recent trends in use of these therapies are unknown. To examine temporal trends in bone-directed therapies. An open cohort study in a US commercial insurance database, January 2009 to March 2020. All-users of bone-directed therapies age >50 years, users with osteoporosis, users with malignancies, and patients with recent (within 180 days) fractures at key osteoporotic sites. The percentage of each cohort with prescription dispensing or medication administration claims for each bone-directed therapy during each quarter of the study period. We analyzed 15.48 million prescription dispensings or medication administration claims from 1.46 million unique individuals (89% women, mean age 69 years). Among all users of bone-directed therapies, alendronate, and zoledronic acid use increased modestly (49 to 63% and 2 to 4%, respectively, during the study period). In contrast, denosumab use increased rapidly after approval in 2010, overtaking use of all other medications except alendronate by 2017 and reaching 16% of users by March 2020. Similar trends were seen in cohorts of osteoporosis, malignancy, and recent fractures. Importantly, use of any bone-directed therapy after fractures was low and declined from 15 to 8%. Rates of denosumab use outpaced growth of all other bone-directed therapies over the past decade. Treatment rates after osteoporotic fractures were low and declined over time, highlighting major failings in osteoporosis treatment in the US.

Effect of cytotoxic chemotherapy on bone health among breast cancer patients. Does it require intervention?

Breast cancer (BC) is one of the most common malignancies worldwide. Although the burden and mechanisms of endocrine therapy-related bone loss are known, the evidence is scanty regarding the impact of cytotoxic chemotherapy on bone health. We have attempted to summarize the effect of cytotoxic chemotherapy on bone health in BC patients. A comprehensive literature search was performed via MEDLINE and Cochrane library databases to evaluate the effect of chemotherapy on bone health among women with BC. We included articles related to skeletal-related events, bone mineral density, bone turnover markers, osteoporosis-specific quality of life, bisphosphonate, and other bone-directed therapy. We excluded articles that included patients with metastatic breast cancer and patients receiving hormonal therapy. Bone microenvironment in cancer is directly or indirectly influenced by clinical, hormonal, nutritional, and treatment factors. Calcitonin, parathyroid hormone, calcitriol, and estrogen are the major hormonal regulators. Bone turnover markers, namely bone formation and resorption markers, have been used to predict bone loss, fracture risk, and monitoring treatment response. Chemotherapeutic drugs such as anthracyclines and taxanes synergistically affect BMD and quality of life. Calcium, vitamin D, bisphosphonates, and denosumab are supplemented to prevent excess bone resorption. Bone-targeted anti-resorptive agents have been studied as potential anticancer agents in the adjuvant treatment of breast cancer. This review summarizes the negative effect of chemotherapy on bone health of BC patients and the importance of preventing or treating bone loss.

Special emphasis on bone health management in prostate cancer patients: a prospective longitudinal study.

ABSTRACTIntroduction:Use of androgen deprivation therapy (ADT) in carcinoma prostate (CaP) has deleterious effect on bone mineral density (BMD) leading to increase incidence of osteoporosis and skeletal-related events. We evaluated bone health status and impact of bone-directed therapy (BDT) and ADT on BMD in these patients from Jan 2015-Dec 2018.Materials and Method:Baseline bone health was assessed using Tc-99 MDP Bone scan/ DEXA scan for patients on ADT. Monthly zoledronic acid (ZA) was given to high-risk candidates (T-score ≤2.5 or previous hip/vertebral fracture) or Skel et al. metastatic patients who were receiving ADT. Baseline and follow-up (at 12-months) BMD using DEXA scan at various sites (spine, femur total, femur neck and radius) and subjective improvement in bony pain using Numeric Pain Rating Score after administration of ZA were compared.Results:A total of 96-patients of locally advanced and metastatic prostate cancer receiving ADT with or without BDT were included in the study cohort. Mean age of presentation was 68.4±15.61 years. Median serum PSA was 32.2±13.1ng/mL. There was significant improvement in mean BMD (T-score) in 64-patients post ZA therapy at 12-months (at femoral total, femoral neck and spine; 0.95, 0.79 and 0.68, respectively) (p <0.05) while there was significant deterioration in mean BMD at 12-months (at spine, femoral neck and femoral total; −0.77, −0.55 and −0.66, respectively) in 32 patients who did not receive ZA and were on ADT (p <0.05). Pain scores significantly decreased in patients after 12-months of ZA use (−2.92±2.16, p <0.01).Conclusion:Bone-directed therapy (Zoledronic acid) leads to both subjective and objective improvement in bone health of prostate cancer patients on ADT.

A phase II, single-arm study of denosumab in multiple myeloma patients with renal insufficiency.

8520 Background: Bone destruction is a devastating consequence of multiple myeloma (MM). An unmet medical need exists for the management of skeletal complications in MM patients with renal insufficiency. Despite the effectiveness of intravenous bisphosphonates, their use is limited in situations where renal dysfunction is present. Denosumab is a fully human monoclonal IgG2 antibody to RANKL that has been shown to be non-inferior to zoledronic acid for SRE rates in MM (Raje, et al. Lancet Oncol). More importantly, it does not have the same renal toxicity as the bisphosphonates. We hypothesize that denosumab can be safely and effectively administered in MM patients with renal insufficiency to improve bone health. This may fill a gap in clinical care for bone-directed therapy in this patient population. Methods: This multi-center study will include forty adult patients with newly diagnosed or relapsed MM with a creatinine clearance of less than 30 mL/min (NCT02833610). All patients will receive a subcutaneous injection of denosumab 120 mg Q4W for a total of 12 cycles. In addition, it is required that all subjects receive daily vitamin D and calcium supplementation at standard doses (at least 2000 mg calcium citrate and1000 IU of vitamin D), unless documented hypercalcemia develops on study. The primary objective is to assess the effect of denosumab 120 mg Q4W on serum c-terminal telopeptide (sCTX). Secondary objectives include evaluation of safety and tolerability of denosumab in patients with renal insufficiency, incidence of hypocalcemia, effect on bone mineral density, effect on urinary n-terminal telopeptide, and proportion of patients who have a documented skeletal-related event. Results: At the time of this analysis, a total of 20 out of a planned 40 patients have been enrolled, including 9 women, 11 men. Of those treated, 8 patients have completed the planned 12 cycles of therapy. Hypocalcemia was observed in 7 (35%) patients. Four patients (20%) experienced grade 3 hypocalcemia, 3 (15%) grade 2 or less. Two patients developed osteonecrosis of the jaw, one (5%) grade 1 and one (5%) grade 4 event. Data for the analysis of the primary endpoint of sCTX levels will be presented. Conclusions: Investigation of denosumab in MM patients with renal insufficiency defined as a creatinine clearance less than 30 mL/min is ongoing. Early data support that denosumab can be safely administered in this population. However, incidence of hypocalcemia despite aggressive prophylactic calcium dosing underscores the importance of the trial to inform safe practice in this more fragile population. Clinical trial information: NCT02833610 .

Implications of the Fracture Risk Assessment Algorithm for the assessment and improvement of bone health in patients with prostate cancer: A comprehensive review.

Maintaining the optimum bone health is one of the important concerns in patients with prostate cancer, but it usually remains neglected. Failure to screen these patients is detrimental to both the length and the quality of life. The estimation of bone mineral density (BMD) and more recently the World Health Organization's fracture risk assessment (FRAX) algorithm in appropriate patients is recommended by several specialty organizations/associations at the time of instituting androgen deprivation therapy (ADT) for metastatic and high-risk individuals. It provides a 10-year risk evaluation of hip and major osteoporotic fractures (MOF). Using this web-based new investigating tool, candidates at high risk of fractures can be predicted more accurately according to clinical risk factors (CRF) alone or in combination with the femoral neck BMD. The FRAX application for senile osteoporosis has been studied and reviewed extensively, but no systematic review has ever been conducted for assessing the implication of FRAX in prostate cancer. This review article will give insight about the validity, role, and utility of this investigating tool in clinical practice for fracture risk assessment in these individuals. This systematic review was carried out as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and Cochrane review principles. We searched the PubMed, Cochrane database of systematic reviews, and the EMBASE electronic database until December 2018 using the medical subject heading terms prostate cancer and FRAX. A total of nine studies meet the inclusion criteria and were included in the review. These studies enrolled a total of 3704 patients (sample size range, 78-1220) of localized, metastatic, castration resistant prostate cancer with or without ADT and/or on photon or radiotherapy. The factors that influenced FRAX included age, ethnicity, baseline BMD, duration of ADT, presence of CRF, and measurement methods (CRF, with/without BMD, computed tomography based). An advanced age and duration of ADT were the most robust risk factors. A 10-year MOF and hip fracture risk estimation was higher when the femoral neck BMD was not incorporated in the FRAX measurement. Despite several well-known strengths of using FRAX in the fracture risk assessment of suitable candidates with prostate cancer, several risk factors such as the mode/duration of ADT, mode of radiotherapy, Vitamin D levels, bone remodeling markers, and recent/recurrent fractures need to be incorporated in the FRAX calculator for improving the predictive ability. In contrast to senile osteoporosis with a longer life expectancy, the fracture risk in patients with prostate cancer need to be measured more frequently and for a shorter time. Therefore, models like Garvan calculator with both 5- and 10-year risk estimates have to be developed for these patients. Additionally, its utilization is of limited value in the presence of recurrent fractures or falls. The FRAX algorithm is beneficial in identifying patients who require early intervention or bone-directed therapy as an early step to decrease skeletal-related events and other morbidity. Several risk factors need to be added for improving the FRAX predictive value. This model is still underutilized in the clinical practice and increasing the awareness among treating physicians will help in optimizing the bone health and the quality of life of this important population subgroup.

Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial

PurposeRadium 223 dichloride (radium-223) is an alpha particle–emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective. Patients and methodsPhase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m2 every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers. ResultsTwenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m2 q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers. ConclusionsRadium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.

Comparative effectiveness of early-line nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer: a US community-based real-world analysis.

BackgroundReal-world analyses of treatments for patients with metastatic breast cancer are limited. We evaluated the comparative effectiveness of nab-paclitaxel vs. paclitaxel in patients with metastatic breast cancer using data from an electronic medical record database from community practices across the USA.MethodsWe performed a retrospective cohort study using fully de-identified data from an independent US electronic medical record platform of patients with metastatic breast cancer initiating single-agent nab-paclitaxel or paclitaxel as a first- or second-line treatment from December 1, 2010 to October 6, 2014. The clinical efficacy objectives were time to treatment discontinuation (TTD) and time to next treatment (TTNT). Subgroup analyses were performed in patients with 2 types of metastatic breast cancer as follows: 1) hormone receptor-positive and human epidermal growth factor receptor 2 negative, and 2) triple-negative disease.ResultsThis analysis included 925 patients. Patients receiving nab-paclitaxel vs. paclitaxel had significantly longer TTD (median 4.2 vs. 2.8 months, P<0.0001) and TTNT (median 6.0 vs. 4.2 months, P<0.0001); similar outcomes were observed for patients with hormone receptor-positive/human epidermal growth factor receptor 2 negative disease. Compared with paclitaxel, nab-paclitaxel was associated with significantly longer TTD in patients with triple-negative disease. nab-Paclitaxel was associated with significantly less all-grade neuropathy, anemia, pain, and diarrhea than paclitaxel. Antiemetic and antihistamine use were significantly less frequent with nab-paclitaxel vs. paclitaxel, whereas use of granulocyte colony-stimulating factor, hydrating agents, and bone-directed therapy to decrease skeletal-related events were more frequent.Conclusionnab-Paclitaxel demonstrated improved clinical effectiveness compared with paclitaxel when examining TTD and TTNT in patients with metastatic breast cancer in a real-world setting.

Management of castrate-resistant prostate cancer in older men.

Prostate cancer is the most common cancer diagnosed in men with the highest incidence in older men. Older men are more likely to present with metastatic disease compared with younger patients and eventually all will develop castrate resistant disease. In recent years, a number of new treatment options have demonstrated survival benefits for metastatic castrate resistant prostate cancer. However, the lack of randomized trials directly comparing the different available options results in some uncertainty on how best to choose and sequence therapy. In this paper, we outline the therapeutic options available to men with metastatic castrate-resistant prostate cancer, including cytotoxic therapy, hormonal agents and bone-directed therapy. We focus particularly on the evidence for specific treatment options and the challenges faced in choosing the appropriate therapy for the older patient.

The impact of response on bone-directed therapy in patients with multiple myeloma

AbstractSignificant benefits for zoledronic acid (ZOL) over clodronate acid (CLO) were seen in the Medical Research Council Myeloma IX randomized trial. ZOL significantly reduced skeletal-related events (SREs), and improved progression-free survival and overall survival (OS), making it the bisphosphonate of choice for newly diagnosed myeloma patients. In this analysis of Myeloma IX data, we have investigated the impact of response on bone disease in 1111 transplant-eligible patients. At posttransplant day 100, complete response (CR) was seen in 48% of patients, very good partial response (VGPR) in 20%, and partial response (PR) in 23%. For patients in VGPR or less, ZOL was superior to CLO in reducing SREs (P = .048), whereas for patients in CR, both agents were equivalent (P = .83). For OS, ZOL was associated with a significant benefit in patients in PR (P = .0091). No difference in OS was seen with patients in CR (P = .91) or VGPR (P = .74). These findings indicate that response category posttransplant may influence the impact of bisphosphonate therapy. This trial was registered as #ISRCTN68454111 at www.isrctn.org.

Bisphosphonates and vascular endothelial growth factor-targeted drugs in the treatment of patients with renal cell carcinoma metastatic to bone

Skeletal involvement is common in patients with renal cell carcinoma (RCC): ∼30% of patients with metastatic RCC (mRCC) will develop bone metastases. Inhibition of vascular endothelial growth factor (VEGF) has been pursued as a therapeutic target in the treatment of metastatic clear-cell RCC (m-ccRCC). Tyrosine kinase inhibitors (TKIs), such as sunitinib, pazopanib, sorafenib, and the monoclonal antibody bevacizumab, became the therapy of choice for patients with m-ccRCC. Besides the undisputed efficacy of TKI in the treatment of m-ccRCC, the problem of metastatic bone disease still remains. There is evidence that the presence of bone metastases in m-ccRCC patients has a significant and clinically relevant negative impact on survival and potentially on the outcome of VEGF-targeted therapy. Also, a relatively common practice in the treatment of such patients is bone-directed therapy with bisphosphonates (BPs). Recent evidence shows a potentially synergistic effect on efficacy but also the potential for increased toxicity of combining TKIs and BPs. This review article highlights the importance of this subject and aims to facilitate further research and optimize the treatment of this important and common group of RCC patients.

Radium-223 for the treatment of prostate cancer

Introduction: Bone metastases cause significant morbidity and mortality in castration-resistant prostate cancer (CRPC). Until recently, treatment options have been limited, but now six drugs are known to extend life expectancy, with docetaxel the current standard first-line cytotoxic therapy. Phase III studies have also shown a survival advantage for sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and radium-223. Radium-223 is unique among these agents, as the only bone-directed therapy shown to prolong survival in CRPC.Areas covered: This review covers the current standard of care for CRPC and recent drug developments that have demonstrated a survival benefit. It focuses on bone-directed therapies, in particular radium-223, the first-in-class alpha-emitting radionuclide and discusses the pivotal studies to date. A PubMed search using the keywords below was performed.Expert opinion: Radium-223 is set to become a new standard of care for the treatment of bony metastatic CRPC. It improves both survival and quality of life, delays skeletal events and is well tolerated. Its optimal use in the evolving treatment strategies for men with CRPC and bone metastases is yet to be determined.

Treatment patterns of castration-resistant prostate cancer: A retrospective claims database analysis.

198 Background: Prostate cancer is the most commonly diagnosed malignancy among men in the US; mortality rates are highest among those with castration-resistant prostate cancer (CRPC). Observational data on CRPC are limited. This study examined CRPC treatment patterns relative to NCCN guidelines in a large US health plan. Methods: This was a retrospective claims database analysis of commercial and Medicare Advantage enrollees with evidence of prostate cancer (ICD-9: 185.xx) between 07/01/06 – 03/31/11. CRPC patients were then identified based on prostate-specific antigen (PSA) progression (≥2 PSA increases based on ≥3 PSA values) and/or use of chemotherapy: docetaxel (DOC), mitoxantrone (MIT), estramustine (EST), or cabazitaxel (CAB). The CRPC index date was the first date of PSA progression or chemotherapy. Patients were continuously enrolled for 6 months before (baseline) and ≥6 months after the index date until 09/30/2011 or until death, if sooner (follow-up). Results: A total of 1651 patients met the CRPC selection criteria. Mean (SD) age was 70 ± 9 years, 1085 (66%) received DOC on the index date, and 467 (28%) died during follow-up. A third of patients with DOC received additional CRPC therapy during follow-up: 160 (15%) received MIT, EST, or CAB, and 239 (22%) received a secondary hormonal therapy (SHT: antiandrogens, aminoglutethimide, GnRH/LHRH antagonists, estrogen, or abiraterone acetate). Among 566 patients without DOC, 99 (17%) received a different chemotherapy (MIT = 45; EST = 52; CAB = 2), and 178 (31%) received a SHT. More than half 311 (55%) without DOC did not receive any other CRPC therapy during follow-up, of which 40 (13%) received bone-directed therapy (BDT: denosumab = 0; bisphosphonates = 27; radiation = 13). Conclusions: Consistent with NCCN guidelines, DOC was the most commonly used therapy. However, two-thirds of patients with DOC and over half of patients without DOC did not receive additional CRPC therapy after the index date. In addition, only 13% of patients with no CRPC therapy received any follow-up BDT. Additional research is warranted to understand whether clinical rationale, patient preference, or access to care may have resulted in patients not receiving additional therapy.

Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Therapie des kastrationsrefraktären Prostatakarzinoms

Within the last two years the therapy of castration resistant prostate cancer (CRPC) has made major advances. Both the COU-AA-301 phase III trial and the TROPIC trial showed a survival benefit for patients after docetaxel failure treated with abiraterone or cabazitaxel, respectively. With rising interest for chemotherapeutic options and novel drugs, our goal was to review within the context of a multidisciplinary team the available evidence and explore the standards for medical treatment of prostate cancer outside of clinical trials. From this background, we are carefully evaluating the current treatment recommendations, based on the available evidence, and highlight potential future treatment options but also discuss important clinical topics like treatment until progression versus the advantage of chemo holidays and definition of particular patient subgroups. Additionally, we focus on novel molecular entities, which will most likely be available in the near future, such as MDV3100 and Sipuleucel T. The role and importance of palliation with radiotherapy and proactive medical management of pain is also discussed, as well as new options for bone directed therapy. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists.

Prostate-Specific Antigen Kinetics and Outcomes in Patients with Bone Metastases from Castration-Resistant Prostate Cancer Treated with or Without Zoledronic Acid

BackgroundZoledronic acid (ZOL) is a standard therapy for the prevention of skeletal-related events (SREs) in patients with castration-resistant prostate cancer (CRPC). Although prostate-specific antigen (PSA) is an established marker for monitoring prostate cancer patients, correlations between PSA and disease outcomes during ZOL therapy are unclear. ObjectiveTo evaluate the relationships among PSA kinetics, bone-directed therapy with ZOL, and clinical outcomes in men with bone metastases from CRPC using a ZOL phase 3 trial database. Design, setting, and participantsExploratory analyses from a phase 3 trial in men with bone metastases from CRPC (n=643) randomized to ZOL or placebo every 3 wk. Outcome measurements and statistical analysisPSA levels during the first 3 mo of the study were evaluated in linear and logarithmic (log) models stratified using prognostic factors established in a ZOL phase 3 trial and a CRPC nomogram. Relative risks of SREs, bone disease progression (BDP), and death were calculated per 1 log (nanograms per milliliter) PSA increase. Baseline PSA models used the study median (PSA: 77.3 ng/ml) as the high/low cut-off point. Results and limitationsA total of 202 placebo- and 434 ZOL-treated patients were assessable. In both groups, PSA increases correlated with significantly increased risks of death, BDP, and first SRE. In the placebo and ZOL groups, associated increases in risk per 1 log (nanograms per milliliter) PSA increase were 29% (p<0.0001) and 10% (p<0.0074), respectively, for BDP, and 24% (p=0.0010) and 13% (p=0.0079), respectively, for first SRE. Limitations include the retrospective nature of these analyses and the potential confounding effects of concurrent antineoplastic therapies. ConclusionsPSA is an important prognostic tool for survival in patients with bone metastases from CRPC, and these analyses show that PSA is also prognostic for BDP and SREs regardless of bone-targeted therapy.