Treatment of cancer-related anemia

Anemia with consequent tissue hypoxia is common problem in cancer patients. Developed via various patophysiological mechanisms, it has deleterious effect on quality of life and survival of patients with cancer. Recognition of symptoms and timely initiation of treatment improve patients' quality of life, as well as efficacy of oncological treatment. Red blood cells transfusions are well known and efficient way of anemia correction. They are "golden standard" in treatment of cancer-related anemia today, and are unavoidable in almost all patients with hemoglobin concentration below 80 g/L. Newest therapy guidelines in developed countries, supported by recent literature, encourage use of recombinant human erythropoietin (rHu-EPO), although detailed meta-analyses and prospective randomized clinical trials have shown that rHu-EPO decreases the need for transfusions in only 9-45% patients with cancer, only if they have mild anemia, rHu-EPO increases incidence of thromboembolic events, and suspicion arises that it supports tumor cells growth and multiplication. Therefore, it is necessary to define subgroups of patients which are best candidates for rHu-EPO therapy, to accomplish lower intensity of transfusion therapy.     

Do we protect or discriminate? Representation of senior adults in clinical trials

Aim

The analysis of barriers responsible for low recruitment of older patients in clinical trials and presentation of possible solutions are the subject of this review.

Background

Europe''s population is ageing, and the group of people who more frequently develop neoplasms increases. Oncologists are confronted with a new challenge – how to treat cancer in this group of patients, especially considering the lack of Evidence Based Medicine (EBM) guidelines for treatment of cancer in the elderly population.

Materials and methods

Medline search and analysis of studies published between 1999 and 2012, containing key words: senior adults, cancer, elderly in clinical trials.

Results

Detailed analysis of relevant studies demonstrated that senior adults are underrepresented in clinical trials. Moreover, there is a lack of trials exclusively designed for this heterogeneous group of patients. The analysis of reasons for low recruitment of older patients in clinical trials revealed barriers dependent on patient''s and physician''s attitudes as well as institutional and logistic problems.

Conclusions

It is necessary to widen the scale of trials of all phases in the group of seniors with appropriate assessment of toxicity. This will allow a proper stratification and obtaining representative groups for statistical analysis and credible trial results. Another priority is the design of trials dedicated exclusively to the elderly.     

Comorbid Diseases Interact with Breast Cancer to Affect Mortality in the First Year after Diagnosis—A Danish Nationwide Matched Cohort Study

Background

Survival of breast cancer patients with comorbidity, compared to those without comorbidity, has been well characterized. The interaction between comorbid diseases and breast cancer, however, has not been well-studied.

Methods

From Danish nationwide medical registries, we identified all breast cancer patients between 45 and 85 years of age diagnosed from 1994 to 2008. Women without breast cancer were matched to the breast cancer patients on specific comorbid diseases included in the Charlson comorbidity Index (CCI). Interaction contrasts were calculated as a measure of synergistic effect on mortality between comorbidity and breast cancer.

Results

The study included 47,904 breast cancer patients and 237,938 matched comparison women. In the first year, the strongest interaction between comorbidity and breast cancer was observed in breast cancer patients with a CCI score of ≥4, which accounted for 29 deaths per 1000 person-years. Among individual comorbidities, dementia interacted strongly with breast cancer and accounted for 148 deaths per 1000 person-years within one year of follow-up. There was little interaction between comorbidity and breast cancer during one to five years of follow-up.

Conclusions

There was substantial interaction between comorbid diseases and breast cancer, affecting mortality. Successful treatment of the comorbid diseases or the breast cancer can delay mortality caused by this interaction in breast cancer patients.     

On the Validity of Using Increases in 5-Year Survival Rates to Measure Success in the Fight against Cancer

Background

The 5-year survival rate of cancer patients is the most commonly used statistic to reflect improvements in the war against cancer. This idea, however, was refuted based on an analysis showing that changes in 5-year survival over time bear no relationship with changes in cancer mortality.

Methods

Here we show that progress in the fight against cancer can be evaluated by analyzing the association between 5-year survival rates and mortality rates normalized by the incidence (mortality over incidence, MOI). Changes in mortality rates are caused by improved clinical management as well as changing incidence rates, and since the latter can mask the effects of the former, it can also mask the correlation between survival and mortality rates. However, MOI is a more robust quantity and reflects improvements in cancer outcomes by overcoming the masking effect of changing incidence rates. Using population-based statistics for the US and the European Nordic countries, we determined the association of changes in 5-year survival rates and MOI.

Results

We observed a strong correlation between changes in 5-year survival rates of cancer patients and changes in the MOI for all the countries tested. This finding demonstrates that there is no reason to assume that the improvements in 5-year survival rates are artificial. We obtained consistent results when examining the subset of cancer types whose incidence did not increase, suggesting that over-diagnosis does not obscure the results.

Conclusions

We have demonstrated, via the negative correlation between changes in 5-year survival rates and changes in MOI, that increases in 5-year survival rates reflect real improvements over time made in the clinical management of cancer. Furthermore, we found that increases in 5-year survival rates are not predominantly artificial byproducts of lead-time bias, as implied in the literature. The survival measure alone can therefore be used for a rough approximation of the amount of progress in the clinical management of cancer, but should ideally be used with other measures.     

A structural analysis of glycosaminoglycans from lethal and nonlethal breast cancer tissues: toward a novel class of theragnostics for personalized medicine in oncology?

Cancer is one of the leading noncommunicable diseases that vastly impacts both developed and developing countries. Truly innovative diagnostics that inform disease susceptibility, prognosis, and/or response to treatment (theragnostics) are seriously needed for global public health and personalized medicine for patients with cancer. This study examined the structure and content of glycosaminoglycans (GAGs) in lethal and nonlethal breast cancer tissues from six patients. The glycosaminoglycan content isolated from tissue containing lethal cancer tumors was approximately twice that of other tissues. Molecular weight analysis showed that glycosaminoglycans from cancerous tissue had a longer weight average chain length by an average of five disaccharide units, an increase of approximately 15%. Dissacharide analysis found differences in sulfation patterns between cancerous and normal tissues, as well as sulfation differences in GAG chains isolated from patients with lethal and nonlethal cancer. Specifically, cancerous tissue showed an increase in sulfation at the "6S" position of CS chains and an increase in the levels of the HS disaccharide NSCS. Patients with lethal cancer showed a decrease in HS sulfation, with lower levels of "6S" and higher levels of the unsulfated "0S" disaccharide. Although these findings come from a limited sample size, they indicate that structural changes in GAGs exist between cancerous and noncancerous tissues and between tissues from patients with highly metastatic cancer and cancer that was successfully treated by chemotherapy. Based on these findings, we hypothesize that (1) there are putative changes in the body's construction of GAGs as tissue becomes cancerous; (2) there may be innate structural person-to-person variations in GAG composition that facilitate the metastasis of tumors in some patients when they develop cancer.     

The DNA-instability test as a specific marker of malignancy and its application to detect cancer clones in borderline malignancy

Recent progress in cytogenetic and biochemical mutation assay technologies has enabled us to detect single gene alterations and gross chromosomal rearrangements, and it became clear that all cancer cells are genetically unstable. In order to detect the genome-wide instability of cancer cells, a new simple method, the DNA-instability test, was developed. The methods to detect genomic instability so far reported have only demonstrated the presence of qualitative and quantitative alterations in certain specific genomic loci. In contrast to these commonly used methods to reveal the genomic instability at certain specific DNA regions, the newly introduced DNA-instability test revealed the presence of physical DNA-instability in the entire DNA molecule of a cancer cell nucleus as revealed by increased liability to denature upon HCl hydrolysis or formamide exposure. When this test was applied to borderline malignancies, cancer clones were detected in all cases at an early-stage of cancer progression. We proposed a new concept of "procancer" clones to define those cancer clones with "functional atypia" showing positivities for various cancer markers, as well as DNA-instability testing, but showing no remarkable ordinary "morphological atypia" which is commonly used as the basis of histopathological diagnosis of malignancy.     

Accurate cancer classification using expressions of very few genes

We aim at finding the smallest set of genes that can ensure highly accurate classification of cancers from microarray data by using supervised machine learning algorithms. The significance of finding the minimum gene subsets is three-fold: 1) it greatly reduces the computational burden and "noise" arising from irrelevant genes. In the examples studied in this paper, finding the minimum gene subsets even allows for extraction of simple diagnostic rules which lead to accurate diagnosis without the need for any classifiers, 2) it simplifies gene expression tests to include only a very small number of genes rather than thousands of genes, which can bring down the cost for cancer testing significantly, 3) it calls for further investigation into the possible biological relationship between these small numbers of genes and cancer development and treatment. Our simple yet very effective method involves two steps. In the first step, we choose some important genes using a feature importance ranking scheme. In the second step, we test the classification capability of all simple combinations of those important genes by using a good classifier. For three "small" and "simple" data sets with two, three, and four cancer (sub)types, our approach obtained very high accuracy with only two or three genes. For a "large" and "complex" data set with 14 cancer types, we divided the whole problem into a group of binary classification problems and applied the 2-step approach to each of these binary classification problems. Through this "divide-and-conquer" approach, we obtained accuracy comparable to previously reported results but with only 28 genes rather than 16,063 genes. In general, our method can significantly reduce the number of genes required for highly reliable diagnosis     

On estimation in relative survival

Estimation of relative survival has become the first and the most basic step when reporting cancer survival statistics. Standard estimators are in routine use by all cancer registries. However, it has been recently noted that these estimators do not provide information on cancer mortality that is independent of the national general population mortality. Thus they are not suitable for comparison between countries. Furthermore, the commonly used interpretation of the relative survival curve is vague and misleading. The present article attempts to remedy these basic problems. The population quantities of the traditional estimators are carefully described and their interpretation discussed. We then propose a new estimator of net survival probability that enables the desired comparability between countries. The new estimator requires no modeling and is accompanied with a straightforward variance estimate. The methods are described on real as well as simulated data.     

How Outpatient Palliative Care Teleconsultation Facilitates Empathic Patient-Professional Relationships: A Qualitative Study

Objective

The problems and needs of advanced cancer patients and proxies normally increase as the disease progresses. Home-based advanced cancer patients and their proxies benefit from collaborations between primary care physicians and hospital-based palliative care specialists when confronted with complex problems in the last phase of life. Telemedicine might facilitate direct, patient-centered communication between patients and proxies, primary care physicians, and specialist palliative care teams (SPCTs). This study focuses on the impact of teleconsultation technologies on the relationships between home-based palliative care patients and hospital-based palliative care specialists.

Methods

This work consists of a qualitative study among patients, family members, and caregivers that utilizes long-term direct observations, semi-structured interviews, and open interviews following the observations.

Results

The analysis of the empirical data resulted in three key concepts that describe the impact of teleconsultation on the patient-professional relationship in palliative homecare: transcending the institutional walls of home and hospital; transparency of teleconsultation technology; and technologized, intimate patient-professional relationships. Teleconsultation offers (1) condensed encounters between home-based palliative care patients and distant professionals, (2) a unique insight into the patients’ daily lives for palliative care specialists, and (3) long-term interaction that results in trustful relationships and experiences of intimacy and relief.

Conclusions

Teleconsultation fits the practice of home-based palliative care. Teleconsultation can, if well applied, facilitate computer-mediated but empathic patient-palliative care specialist relationships, which enable professional care attuned to the patient’s context as well as patient involvement. This article proposes a teleconsultation implementation guide for optimal use of teleconsultation in daily palliative care practice.     

Cancer and aging: symposium of the 27th annual meeting of the Japanese society for biomedical gerontology, Tokyo

Although many hypotheses have been proposed to explain the strong link between aging and cancer, the exact mechanisms responsible for the increased frequency of occurrence of cancer with advancing age have not been fully defined. Recent evidence indicates that malregulation of the apoptotic process may be involved in some aging process as well as in the development of cancer. Although it is still under debate how apoptosis is expressed during aging in vivo, this phenomenon is an important factor in unwinding the complicated mechanisms that link cancer and aging. In this review, we report on the discussion at the symposium of the 27th annual meeting of the Japanese society for biomedical gerontology, regarding recent findings from aging and carcinogenesis studies using animal models, the characteristics of cancer in patients with Werners syndrome, the epigenetic changes in human cancers and aging, and the characteristics of human cancers in the elderly. It was concluded that apoptosis plays a role in the aging process and carcinogenesis in vivo, likely as an inherent protective mechanism against various kinds of damages to genes/chromosomes.     

Impact du délai diagnostique sur la survie du cancer du testicule

Objectives

Testicular cancer is the leading cancer of young adults and its incidence is increasing in almost all industrialized countries. The survival rate after testicular cancer is 95%, all stages combined, but a group of patients with poor prognosis still fails to respond to treatment. The time to diagnosis is defined as the time in months between perception of the first symptoms of testicular cancer by the patient and the diagnosis of the disease by the doctor. The objective of this study is to determine whether the time to diagnosis has a prognostic value, particularly whether it is correlated with the stage of the disease and survival.

Material and Methods

The time to diagnosis was studied in 542 patients with a diagnosis of testicular cancer between 1983 and 2002 in the Midi-Pyrenées region. Information concerning the disease and treatments contained in medical files was collected on a summary document. The time to diagnosis was correlated with prognostic parameters, including stage and survival.

Results

The mean time to diagnosis was 3.7±5.1 months and was longer for seminomas (4.9±6.1 months) than for non-seminomatous germ cell tumours (NSGCT) (2.8 ±4.0 months). The time to diagnosis was correlated with the stage of the disease and the 5-year survival on the overall population and in the NSGCT group, but not in the seminoma group.

Conclusions

Early diagnosis has a prognostic value (correlation with stage of the disease and 5-year survival rate). Testicular cancer information campaigns should therefore be envisaged.     

CANCER OF THE LUNG IN TUBERCULOUS PATIENTS

Of all tuberculous patients over 45 years of age admitted to Olive View Sanatorium in the five-year period ended July, 1958, 1.4 per cent had cancer of the lung. This is a much higher incidence than in a comparable segment of the general population.Careful examination of serial roentgenographic studies in all cases of suspected pulmonary lesions was found to increase diagnostic acuity. Scalene node biopsy, cytologic study and bronchoscopy were of less help. Diagnostic thoracotomy was the single most useful procedure for diagnosis.As to operability, the results in patients with both cancer and tuberculosis compared very well with those in patients who had only cancer. Patients who have inactive pulmonary tuberculosis and cancer have much poorer results than patients with active tuberculosis and cancer. There are difficulties in accurately diagnosing cancer in the presence of tuberculosis; and there are special problems in patients with inactive tuberculosis and cancer.     

Laparoscopic ovarian transposition before pelvic radiation in rectal cancer patient: safety and feasibility

Background

Infertility due to pelvic radiation for advanced rectal cancer treatment is a major concern particularly in young patients. Pre-radiation laparoscopic ovarian transposition may offer preservation of ovarian function during the treatment however its use is limited.

Aim

The study investigates the safety, feasibility and effectiveness of pre-radiation laparoscopic ovarian transposition and its effect on ovarian function in the treatment o locally advanced rectal cancer.

Methods

Charts review of all young female patients diagnosed with locally advanced rectal cancer, underwent laparoscopic ovarian transposition, then received preoperative radiotherapy at king Faisal Specialist Hospital and Research Centre between 2003?C2007.

Results

During the period studied three single patients age between 21?C27?years underwent pre-radiation laparoscopic ovarian transposition for advanced rectal cancer. All required pretreatment laparoscopic diversion stoma due to rectal stricture secondary to tumor that was performed at the same time. One patient died of metastatic disease during treatment. The ovarian hormonal levels (FSH and LH) were normal in two patients. One has had normal menstrual period and other had amenorrhoea after 4?months follow-up however her ovarian hormonal level were within normal limits.

Conclusions

Laparoscopic ovarian transposition before pelvic radiation in advanced rectal cancer treatment is an effective and feasible way of preservation of ovarian function in young patients at risk of radiotherapy induced ovarian failure. However, this procedure is still under used and it is advisable to discuss and propose it to suitable patients.     

Assessment of health status in elderly patients with cancer

Background

Health status assessment of senior adults is one of the most important aspects of a treatment decision making process. A group of elderly cancer patients is very heterogeneous according to the health status – some of them are fit enough for aggressive treatment, but others are frail and vulnerable. Treatment for the latter group has to be adapted and carefully monitored.

Aim

To review and analyze relevant literature on the usage and optimization of Comprehensive Geriatric Assessment (CGA).

Materials and methods

Medline search of studies published between 2000 and 2011, containing key words: Comprehensive Geriatric Assessment, aging, cancer in senior adults, frailty.

Results

To recognize and address individual needs of senior adults, a special holistic approach has been developed – comprehensive geriatric assessment (CGA). This tool is a gold standard in gerontooncology, recommended by International Society of Geriatric Oncology. CGA evaluates all important health domains, from physiology to social and economical problems, using sets of different tests. Assessment has to be performed by a trained team, including a physician, nurse and social worker. CGA has been clinically validated in many studies, but it is still not clear whether CGA improves the outcome of treatment of the elderly with cancer.

Conclusions

Complexity and multidimensionality of CGA pose a logistic challenge for everyday clinical practice. Special senior programs, which could be developed inside comprehensive cancer center, focusing attention on seniors’ problems and needs seem to be a way forward for geriatric oncology.     

A sequence-specific exopeptidase activity test (SSEAT) for "functional" biomarker discovery

One form of functional proteomics entails profiling of genuine activities, as opposed to surrogates of activity or active "states," in a complex biological matrix: for example, tracking enzyme-catalyzed changes, in real time, ranging from simple modifications to complex anabolic or catabolic reactions. Here we present a test to compare defined exoprotease activities within individual proteomes of two or more groups of biological samples. It tracks degradation of artificial substrates, under strictly controlled conditions, using semiautomated MALDI-TOF mass spectrometric analysis of the resulting patterns. Each fragment is quantitated by comparison with double labeled, non-degradable internal standards (all-d-amino acid peptides) spiked into the samples at the same time as the substrates to reflect adsorptive and processing-related losses. The full array of metabolites is then quantitated (coefficients of variation of 6.3-14.3% over five replicates) and subjected to multivariate statistical analysis. Using this approach, we tested serum samples of 48 metastatic thyroid cancer patients and 48 healthy controls, with selected peptide substrates taken from earlier standard peptidomics screens (i.e. the "discovery" phase), and obtained class predictions with 94% sensitivity and 90% specificity without prior feature selection (24 features). The test all but eliminates reproducibility problems related to sample collection, storage, and handling as well as to possible variability in endogenous peptide precursor levels because of hemostatic alterations in cancer patients.     

Involvement of IL17A,IL17F and IL23R Polymorphisms in Colorectal Cancer Therapy

IL23/IL17 pathway plays an important role in the development of inflammatory bowel diseases (IBD). In general, the genes encoding the cytokines are genetically polymorphic and polymorphisms in genes IL23R and IL17 have been proved to be associated with its susceptibility to inflammatory diseases as well as cancer including colorectal cancer. Moreover, it has been shown that these interleukins are involved in anti-tumor or pro-tumor effects of various cancers. Previously, we showed that there is a significant association between IL17A, IL17F and IL23R polymorphisms as well as the occurrence of colorectal cancer and the clinical features of the disease. The purpose of the present work is to investigate an association between IL17A, IL17F and IL23R polymorphisms in 102 Tunisian patients with colorectal cancer treatment. The association was analyzed by statistical tools. We found that patients with mutated genotypes of IL17A G197A SNP could be a risk factor for the inefficiency of chemotherapy and radiotherapy. Unlike IL17F variant, patients with wild type genotypes require surgery and adjuvant chemotherapy. On the one hand, we found no evidence that supports a significant association between IL23R polymorphism and the combined genotypes of these three genes and the colorectal cancer treatment. On the other hand, we showed that there is an important interaction between IL17A/IL17F polymorphisms and the stage of the disease as well as its treatment. Finally, patients with IL17F wild type genotype highlighted that there is a valid longer OS without all treatments and with radiotherapy and a neoadjuvant chemotherapy. In contrast, we observed that there are no relationships between IL17A, IL23R and the survival of these patients neither with nor without the treatment. Our results suggest that polymorphisms in IL17A and IL17F genes may be a predictive source of colorectal cancer therapy type. Therefore, IL17F may serve as an independent prognostic factor for overall survival in patients with colorectal cancer.     

Potentialities of ultrasound study in diagnosis of endophytic carcinoma of stomach

The data of studies of 45 patients with gastric cancer are used to consider the potentialities of ultrasonography (USG) in the diagnosis of its endophytic forms. Its use in the diagnosis of "small" gastric carcinomas is evaluated. The USG semiotics of endophytic tumors of the stomach, including its "small" and early forms, is presented. The place of USG in the diagnostic algorithmic of gastric cancer is specified. In the authors' opinion, gastric USG along with traditional X-ray and endoscopic studies should take an appropriate place as it is beneficial in solving a great deal of differential diagnostic problems associated with the intramural spread of tumors.     

Inhibition of miR-191 contributes to radiation-resistance of two lung cancer cell lines by altering autophagy activity

Background

Lung cancer is the leading cause of cancer-related morbidity and mortality all over the world. Surgery resection, radiotherapy, chemotherapy, immunotherapy and combined treatments have been discovered and well established for treatments. However, low survival rate of five years after clinical treatments mainly due to recurrence of stress-resistant cancer cells calls for better understanding and new ideas. Our project aimed to understand the forming process of stress resistant lung cancer cells after radiotherapy.

Methods

Two classic non-small cell lung cancer (NSCLC) cell lines A549 and H1299 initially were radiated with a ¹³⁷Cs gamma-ray source with doses ranging from 0 to 12 Gy to generate radiation-resistant cancer cells. 8 Gy of radiation was regard as a standard dosage since it provides effective killing as well as good amount of survivals. The expression levels of autophagy-related proteins including Beclin-1, LC3-II and p62 were studied and measured by both western blot and quantitative real-time polymerase chain reaction (real-time RT-PCR).

Results

Increased Beclin-1, LC3-II and decreased p62 have been observed in radiation-resistant cells indicating elevated autophagy level. Decreased miR-191 in radiation-resistant cells performed by Taqman qRT-PCR also has been seen. Two binding sites between Beclin-1 and miR-191 suggest potential association between.

Conclusions

It is reasonable to speculate that inhibition of miR-191 expression in lung cancer cells would contribute to the establishment of radiation-resistant cells via mediating cellular autophagy. Therefore, miR-191 is a potential target for therapy in treating radiation-resistant lung cancer.     

Mitochondrial Haplogroups and Control Region Polymorphisms Are Not Associated with Prostate Cancer in Middle European Caucasians

Background

Besides being responsible for energy production in the cell, mitochondria are central players in apoptosis as well as the main source of harmful reactive oxygen species. Therefore, it can be hypothesised that sequence variation in the mitochondrial genome is a contributing factor to the etiology of diseases related to these different cellular events, including cancer. The aim of the present study was to assess the frequency of haplogroups and polymorphisms in the control region (CR) of mitochondrial DNA of peripheral blood mononuclear cells from patients with prostate carcinoma (n = 304) versus patients screened for prostate disease but found to be negative for cancer on biopsy (n = 278) in a Middle European population.

Methodology/Principal Findings

The nine major European haplogroups and the CR polymorphisms were identified by means of primer extension analysis and DNA sequencing, respectively. We found that mitochondrial haplogroup frequencies and CR polymorphisms do not differ significantly between patients with or without prostate cancer, implying no impact of inherited mitochondrial DNA variation on predisposition to prostate carcinoma in a Middle European population.

Conclusions/Significance

Our results contrast with a recent report claiming an association between mtDNA haplogroup U and prostate cancer in a North American population of caucasian descent.     

Emerging Therapeutic for the Treatment of Skeletal-related Events Associated With Metastatic Castrate-resistant Prostate Cancer

Prostate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who succumb to the disease will ultimately develop bone metastasis. Morbidity from bone metastasis-referred to as skeletal-related events, which include fractures, cord compression, radiation to bone, and surgery to bone—leads to significant costs and impaired quality of life. This article reviews three agents and the roles they play in the ever-changing armamentarium of treatments for metastatic castrate-resistant prostate cancer (mCRPC). The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis.Key words: Metastatic castrate-resistant prostate cancer, Skeletal-related events, Bone metastasis, Zoledronic acid, Denosumab, Radium Ra 223 dichlorideProstate cancer is the most prevalent cancer in US and European men and the second leading cause of cancer death in those populations. It is somewhat unique in that nearly all patients who have the disease will ultimately develop bone metastasis.¹ Morbidity from bone metastasis—referred to as skeletal—related events (SREs), which include fractures, cord compression, radiation to bone, and surgery to bone-leads to significant costs and impaired quality of life. An estimated 241,740 men are diagnosed with prostate cancer each year in the United States¹; between 9.5% and 17.8% of these patients have M0 + M1 castrate-resistant prostate cancer (CRPC).^2,3Skeletal tumor burden and fracture are both independent predictors of death in men with metastatic CRPC (mCRPC).^2,3 In addition, pain is an independent prognosticator for death⁴; thus, agents that reduce pain may improve quality as well as quantity of life. In the past decade, three new agents have been approved in the United States for the treatment and/or prevention of SREs in men with mCRPC. However, urologists continue to under-treat this condition.⁵ A recent clinical trial that screened a large population of men thought to have CRPC without metastasis found nearly one third of patients to have metastatic prostate cancer.⁶ And a recent large clinical trial in men with mCRPC, most of whom had bone metastases, showed fewer than 50% of patients were receiving a bisphosphonate.⁷This article reviews these three agents and the new roles they play in the ever-changing armamentarium of treatments for mCRPC. The potential benefits of these agents are discussed, as well as the continuing use of these agents and their earlier introduction in the patient with progressive mCRPC with bone metastasis.