Drugs and natural products for the treatment of COVID-19 during 2020, the first year of the pandemic / Fármacos y productos naturales para el tratamiento de la COVID-19 durante 2020, el primer año de la pandemia

Abstract This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients.

Resumen El objetivo del presente trabajo fue conocer qué tratamientos mostraron efectividad contra COVID-19, para lo cual se revisan y discuten los resultados de 37 estudios clínicos iniciados durante 2020 y concluidos en 2021. Estos fueron seleccionados de bases de datos, excluyendo vacunas, estudios computacionales, in silico, in vitro y con sueros hiperinmunes de pacientes recuperados. Se documentaron 34 fármacos, una vitamina y un remedio herbolario, con actividad farmacológica ante COVID-19 sintomático. Estos redujeron la mortalidad, el progreso de la enfermedad, o el tiempo de recuperación. Para cada tratamiento se presenta identificador y tipo de estudio, la gravedad de la enfermedad, patrocinador, país donde se realizó, así como sus resultados. Los fármacos se clasificaron de acuerdo con su mecanismo de acción. Varios fármacos que redujeron la mortalidad también disminuyeron la inflamación en los casos más graves. Esto incluyendo algunos no considerados antiinflamatorios, como el aviptadil, el bromuro de piridostigmina, el anakinra, el imatinib, el baricitinib y el bevacizumab, así como la combinación de ivermectina, aspirina, dexametasona y enoxaparina. También se reportaron con actividad terapéutica las semillas de Nigella sativa con miel. Además, resultaron efectivos el tofacitinib, el novaferón con ritonavir y lopinavir, así como los antivirales en terapias combinadas como el danoprevir con ritonavir. Los productos naturales colchicina y vitamina D3, solo tuvieron actividad en los pacientes en estado leve a moderado de la COVID-19, así como la hidroxicloroquina. El reposicionamiento de fármacos fue la principal herramienta para buscar terapias efectivas ampliando las opciones farmacológicas accesibles a los pacientes.

The Polypharmacological Effects of Cannabidiol.

Cannabidiol (CBD) is a major phytocannabinoid present in Cannabis sativa (Linneo, 1753). This naturally occurring secondary metabolite does not induce intoxication or exhibit the characteristic profile of drugs of abuse from cannabis like Δ9-tetrahydrocannabinol (∆9-THC) does. In contrast to ∆9-THC, our knowledge of the neuro-molecular mechanisms of CBD is limited, and its pharmacology, which appears to be complex, has not yet been fully elucidated. The study of the pharmacological effects of CBD has grown exponentially in recent years, making it necessary to generate frequently updated reports on this important metabolite. In this article, a rationalized integration of the mechanisms of action of CBD on molecular targets and pharmacological implications in animal models and human diseases, such as epilepsy, pain, neuropsychiatric disorders, Alzheimer's disease, and inflammatory diseases, are presented. We identify around 56 different molecular targets for CBD, including enzymes and ion channels/metabotropic receptors involved in neurologic conditions. Herein, we compiled the knowledge found in the scientific literature on the multiple mechanisms of actions of CBD. The in vitro and in vivo findings are essential for fully understanding the polypharmacological nature of this natural product.

Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein.

BACKGROUND: COVID-19, the disease caused by SARS-CoV-2 virus infection, has been a major public health problem worldwide in the last 2 years. SARS-CoV-2-dependent activation of innate immune receptors contributes to the strong local and systemic inflammatory reaction associated with rapid disease evolution. The receptor-binding domain (RBD) of Spike (S) viral protein (S-RBD) is essential for virus infection and its interacting molecules in target cells are still under identification. On the other hand, the search for accessible natural molecules with potential therapeutic use has been intense and remains an active field of investigation. METHODS: C57BL6/J (control) and Toll-like receptor (TLR) 4-deficient (Lps del) mice were nebulized with recombinant S-RBD. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin (IL)-6 production in bronchoalveolar lavages (BALs) was determined by enzyme-linked immunosorbent assay (ELISA). Lung-infiltrating cells recovered in BALs were quantified by hematoxylin-eosin (H&E) stain. In selected groups of animals, the natural compound Jacareubin or dexamethasone were intraperitoneally (ip) administered 2 hours before nebulization. RESULTS: A rapid lung production of TNF-α and IL-6 and cell infiltration was induced by S-RBD nebulization in control but not in Lps del mice. Pre-treatment with Jacareubin or dexamethasone prevented S-RBD-induced TNF-α and IL-6 secretion in BALs from control animals. CONCLUSIONS: S-RBD domain promotes lung TNF-α and IL-6 production in a TLR4-dependent fashion in C57BL6/J mice. Xanthone Jacareubin possesses potential anti-COVID-19 properties that, together with the previously tested anti-inflammatory activity, safety, and tolerance, make it a valuable drug to be further investigated for the treatment of cytokine production caused by SARS-CoV-2 infection.

ECMO venovenoso durante procedimiento endoscópico de permeabilización de la vía aérea central en pacientes con riesgo vital: reporte de 2 casos / Use of venovenous extracorporeal membrane oxygenation (ECMO) during endoscopic treatment of central airway obstruction and vital risk: report of 2 cases

Resumen: La oxigenación por membrana extracorpórea (ECMO) es de gran utilidad al proveer soporte ventilatorio a pacientes con hipoxia, pero su utilidad en el manejo de pacientes con obstrucción central de la vía aérea y riesgo vital no ha sido frecuentemente usada. La broncoscopía intervencional como terapia bajo ventilación convencional es de alto riesgo en este tipo de pacientes, pero es posible lograr excelentes resultados al ser asociada a ECMO. Comunicamos el caso clínico de 2 pacientes que presentaban disnea en reposo y falla ven1ila1oria aguda ca1as1rófica debido a una obstrucción casi total del lumen traqueal, de causa tumoral. En ambos pacientes en forma urgente se inició soporte circulatorio mediante ECMO VV, mientras se efectuaba la resección tumoral broncoscópica. Luego de terminada la cirugía traqueal, en ambos pacientes se retiró el soporte, siendo decanulados sin eventos y con una buena evolución clínica posterior. Se discute el beneficio del soporte ECMO en este tipo de pacientes.

Abstract: In patients with severe central airway stenosis bronchoscopy-guided intervention therapy under conventional ventilation conveys a high risk. Extracorporeal membrane oxygenation (ECMO) provides very good cardiopulmonary support, but is rarely used in bronchoscopy-guided interventional therapy. We report 2 patients with resting dyspnea due to severe tumor tracheal obstruction and acute pulmonary failure with imminent vital risk. Both patients were cannulated and the ECMO circuit installed on a nearly emergency basis. Tumors were excised, and the patients weaned from cardiopulmonary bypass uneventfully. Subsequent clinical course was satisfactory in both cases. A brief discussion of this condition is included.

Mast Cells Localize in Hypoxic Zones of Tumors and Secrete CCL-2 under Hypoxia through Activation of L-Type Calcium Channels.

Hypoxia is a condition that together with low pH, high amounts of reactive oxygen species (ROS), and increased adenosine levels characterize tumor microenvironment. Mast cells (MCs) are part of tumor microenvironment, but the effect of hypoxia on the production of MC-derived cytokines has not been fully described. Using the hypoxia marker pimonidazole in vivo, we found that MCs were largely located in the low-oxygen areas within B16-F1 mice melanoma tumors. In vitro, hypoxia promoted ROS production, a ROS-dependent increase of intracellular calcium, and the production of MCP 1 (CCL-2) in murine bone marrow-derived MCs. Hypoxia-induced CCL-2 production was sensitive to the antioxidant trolox and to nifedipine, a blocker of L-type voltage-dependent Ca2+ channels (LVDCCs). Simultaneously with CCL-2 production, hypoxia caused the ROS-dependent glutathionylation and membrane translocation of the α1c subunit of Cav1.2 LVDCCs. Relationship between ROS production, calcium rise, and CCL-2 synthesis was also observed when cells were treated with H2O2 In vivo, high CCL-2 production was detected on hypoxic zones of melanoma tumors (where tryptase-positive MCs were also found). Pimonidazole and CCL-2 positive staining diminished when B16-F1 cell-inoculated animals were treated with trolox, nifedipine, or the adenosine receptor 2A antagonist KW6002. Our results show that MCs are located preferentially in hypoxic zones of melanoma tumors, hypoxia-induced CCL-2 production in MCs requires calcium rise mediated by glutathionylation and membrane translocation of LVDCCs, and this mechanism of CCL-2 synthesis seems to operate in other cells inside melanoma tumors, with the participation of the adenosine receptor 2A.

Physicians' preferences for bone metastases treatments in France, Germany and the United Kingdom.

BACKGROUND: Several bone-targeted agents (BTAs) are available for preventing skeletal-related events (SREs), but they vary in terms of efficacy, safety and mode of administration. This study assessed data on European physicians' treatment preferences for preventing SREs in patients with bone metastases from solid tumours. METHODS: Physicians completed a web-based discrete-choice experiment survey of 10 choices between pairs of profiles of hypothetical BTAs for a putative patient. Each profile included five attributes within a pre-defined range (primarily based on existing BTAs' prescribing information): time (months) until the first SRE; time (months) until worsening of pain; annual risk of osteonecrosis of the jaw (ONJ); annual risk of renal impairment; and mode of administration. Choice questions were developed using an experimental design with known statistical properties. A separate main-effects random parameters logit model was estimated for each country and provided the relative preference for the treatment attributes in the study. RESULTS: A total of 191 physicians in France, 192 physicians in Germany, and 197 physicians in the United Kingdom completed the survey. In France and the United Kingdom, time until the first SRE and risk of renal impairment were the most important attributes; in Germany, time until the first SRE and delay in worsening of pain were the most important. In all countries, a 120-min infusion every 4 weeks was the least preferred mode of administration (p < 0.05) and the annual risk of ONJ was judged to be the least important attribute. CONCLUSIONS: When making treatment decisions regarding the choice of BTA, delaying the onset of SREs/worsening of pain and reducing the risk of renal impairment are the primary objectives for physicians.

Prevalence and risk of skeletal complications and use of radiation therapy in elderly women diagnosed with metastatic breast cancer.

OBJECTIVE: Real-world data regarding patient factors associated with the occurrence of spinal cord compression (SCC) or pathological fracture (PF), or need for bone surgery (BS), or use of radiation therapy (RAD) (i.e. skeletal complications and radiation therapy; SCRT) are limited for women with metastatic breast cancer (BCa). Given the substantial clinical and economic burden of these events in advanced BCa, we conducted the present study to understand the prevalence and identify the risk factors associated with these events among elderly women presenting with de novo metastatic BCa. METHODS: Using linked Surveillance, Epidemiology, and End Results and Medicare data, we identified women with incident metastatic BCa diagnosed during 2005-2009. Associations between patient demographics and select clinically relevant factors, and SCRT were examined using the Cox proportional hazards model, accounting for death as a competing risk. RESULTS: Of 3,731 Medicare beneficiaries with incident metastatic BCa, 1,808 (48.5%) experienced at least one SCRT event during a median follow-up of 13.2 months; a majority (69%) experienced a subsequent SCRT event. The proportions of women who had RAD, PF, BS, and SCC were: 32%, 28%, 8%, and 4%. Older women (80+ years), or those with more comorbid conditions (CCI≥2) had a statistically significant lower risk of SCRT (HR 0.78 [CI: 0.67-0.92, p<0.01]; HR 0.77 [CI: 0.67-0.89, p<0.01], respectively), primarily due to lower frequency of radiotherapy (p<0.01). Compared to Caucasians, African Americans had lower risk of SCRT (HR 0.70 [CI: 0.60-0.82, p<0.01]), as well as all SCRT subtypes defining this group except for SCC, which was the same for both race groups. CONCLUSION: This study highlights that certain patient characteristics and clinical factors are associated with the risk of spinal cord compression or pathologic fractures, or need for bone surgery or radiation among women with metastatic BCa. In future studies, it will also be important to consider the clinical and economic burden based on these components of skeletal complications and radiation therapy use in order to guide and improve the management of women with advanced BCa.

Small-Group Randomized Controlled Trial to Increase Condom Use and HIV Testing Among Hispanic/Latino Gay, Bisexual, and Other Men Who Have Sex With Men.

OBJECTIVES: To evaluate the HOLA en Grupos intervention, a Spanish-language small-group behavioral HIV prevention intervention designed to increase condom use and HIV testing among Hispanic/Latino gay, bisexual, and other men who have sex with men. METHODS: In 2012 to 2015, we recruited and randomized 304 Hispanic/Latino men who have sex with men, aged 18 to 55 years in North Carolina, to the 4-session HOLA en Grupos intervention or an attention-equivalent general health education comparison intervention. Participants completed structured assessments at baseline and 6-month follow-up. Follow-up retention was 100%. RESULTS: At follow-up, relative to comparison participants, HOLA en Grupos participants reported increased consistent condom use during the past 3 months (adjusted odds ratio [AOR] = 4.1; 95% confidence interval [CI] = 2.2, 7.9; P < .001) and HIV testing during the past 6 months (AOR = 13.8; 95% CI = 7.6, 25.3; P < .001). HOLA en Grupos participants also reported increased knowledge of HIV (P < .001) and sexually transmitted infections (P < .001); condom use skills (P < .001), self-efficacy (P < .001), expectancies (P < .001), and intentions (P < .001); sexual communication skills (P < .01); and decreased fatalism (P < .001). CONCLUSIONS: The HOLA en Grupos intervention is efficacious for reducing HIV risk behaviors among Hispanic/Latino men who have sex with men.

Healthcare resource use and costs associated with renal impairment in US patients with bone metastases from solid tumors.

Introduction During cancer progression, more than half of patients develop renal insufficiency, including chronic kidney disease. The primary and secondary objectives of this study were to estimate healthcare resource use and costs, respectively, associated with renal impairment in patients with bone metastases from solid tumors in the United States. Methods and materials This was a retrospective, observational cohort study conducted using administrative claims data for individuals with solid tumors and bone metastases. Control patients were matched to renal impairment patients using propensity scores (ratio up to 3:1) based on demographics, clinical characteristics, and baseline costs. Average per-patient per-year healthcare resource utilization and costs (total costs and cost components; 2013 dollars) were reported. Results In total, 2616 renal impairment patients were matched to 7211 control patients. Renal impairment patients had greater healthcare resource use compared with controls, including a greater mean number of hospital admissions (4.4 versus 2.1), longer average stay per hospital admission (7.4 versus 6.5 days), as well as greater mean number of physician office visits (22.9 versus 18.8), emergency department visits (3.1 versus 2.0), and hospital-based outpatient visits (18.8 versus 16.0) compared with control patients. Total costs were > $50,000 higher among renal impairment patients ($142,267 versus $88,839; P < 0.001), with hospital costs accounting for $72,557 for renal impairment patients, and $27,858 for control patients ( P < 0.001). Conclusion The healthcare resource use and costs associated with renal impairment in patients with bone metastases from solid tumors is high; efforts to reduce renal impairment in this population, including the potential avoidance of nephrotoxic agents, are warranted.

International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries.

BACKGROUND: Continuous androgen deprivation therapy (CADT) is commonly used for patients with non-metastatic prostate cancer as primary therapy for high-risk disease, adjuvant therapy together with radiation or for recurrence after initial local therapy. Intermittent ADT (IADT), a recently developed alternative strategy for providing ADT, is thought to potentially reduce adverse effects, but little is known about practice patterns relating to it. We aimed to describe factors related to physicians' ADT use and modality for patients with non-metastatic prostate cancer. METHODS: A 45 min online survey was completed by urologists and oncologists responsible for treatment decisions for non-metastatic prostate cancer from 19 countries with high or increasing prevalence of non-metastatic prostate cancer. RESULTS: There were 441 treating physicians who completed the survey which represented 99 177 patients with prostate cancer under their care, of which 76 386 (77%) had non-metastatic prostate cancer. Of patients with non-metastatic prostate cancer, 38% received ADT (37% gonadotropin-releasing hormone (GnRH), 2% orchiectomy); among patients on GnRH, 54% received CADT (≥6 without >3 months interruption), 23% IADT and 23% <6 months. Highest rates of ADT were reported among oncologists (62%) and in Eastern Europe (Czech Republic, Hungary and Poland). Prostate-specific antigen (PSA) levels (65%), Gleason score (52%) and treatment guidelines (48%) were the most common reasons for CADT whereas PSA levels (54%), patient request (48%), desire to maintain sexual function (40%), patient age and comorbidities (38%) were cited most frequently as reasons for IADT. CONCLUSIONS: This international survey with 441 treating physicians from 19 countries showed that ADT is commonly used in treating patients with non-metastatic prostate cancer, and type of ADT is influenced by high-risk criteria (PSA and Gleason), treatment guidelines and patient preferences. IADT use was primarily driven by PSA levels, patient request and patient age/comorbidities, likely reflecting an attempt to minimise adverse effects of ADT in patients with lower risk tumours.

Risk of skeletal related events among elderly prostate cancer patients by site of metastasis at diagnosis.

The purpose of this study was to estimate the risk of developing skeletal-related events (SREs) based on site of metastasis at diagnosis and identify other predictors of developing SREs among metastatic prostate cancer patients. We conducted a retrospective cohort study using linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data and identified men over the age of 65 with incident metastatic prostate cancer diagnosed during 2005-2009. SREs included radiation (RAD), pathological fractures (PF), bone surgery (BS), and spinal cord compression (SCC). The association between site of metastasis at diagnosis and SRE was examined using a Cox proportional hazards model that accounts for death as a competing risk. Among 4404 men (median age: 79 years) with incident metastatic prostate cancer, 44% experienced SREs at a median of 9.6 months post diagnosis. Compared to bone metastasis only, our model showed that patients were significantly less likely to develop SREs if they had LN-only metastasis at diagnosis (Sub-Hazard Ratio [SHR] 0.56; 95% Confidence Interval [CI]: 0.43-0.72) or unknown site of metastasis (SHR: 0.79; CI: 0.64-0.97). Other predictors of reduced SRE risk were age 80+ years (SHR: 0.83; CI: 0.75-0.91), non-Hispanic Black (SHR: 0.77; CI: 0.65-0.90), or being diagnosed in year 2009 (SHR: 0.85; CI: 0.72-0.99). Patients were significantly more likely to develop SREs if they received androgen deprivation therapy (SHR: 1.73; CI: 1.48-2.02) or had Gleason score 8-10 disease (SHR: 0.79; CI: 0.64-0.97). Compared to patients who present with bone metastasis only at diagnosis, patients presenting with other metastatic sites have similar risk of developing SREs, with the exception of those presenting with lymph node only metastasis who have a significantly reduced risk of SREs.

Protein Tyrosine Kinase Fyn Regulates TLR4-Elicited Responses on Mast Cells Controlling the Function of a PP2A-PKCα/ß Signaling Node Leading to TNF Secretion.

Mast cells produce proinflammatory cytokines in response to TLR4 ligands, but the signaling pathways involved are not fully described. In this study, the participation of the Src family kinase Fyn in the production of TNF after stimulation with LPS was evaluated using bone marrow-derived mast cells from wild-type and Fyn-deficient mice. Fyn(-/-) cells showed higher LPS-induced secretion of preformed and de novo-synthesized TNF. In both cell types, TNF colocalized with vesicle-associated membrane protein (VAMP)3-positive compartments. Addition of LPS provoked coalescence of VAMP3 and its interaction with synaptosomal-associated protein 23; those events were increased in the absence of Fyn. Higher TNF mRNA levels were also observed in Fyn-deficient cells as a result of increased transcription and greater mRNA stability after LPS treatment. Fyn(-/-) cells also showed higher LPS-induced activation of TAK-1 and ERK1/2, whereas IκB kinase and IκB were phosphorylated, even in basal conditions. Increased responsiveness in Fyn(-/-) cells was associated with a lower activity of protein phosphatase 2A (PP2A) and augmented activity of protein kinase C (PKC)α/ß, which was dissociated from PP2A and increased its association with the adapter protein neuroblast differentiation-associated protein (AHNAK, desmoyokin). LPS-induced PKCα/ß activity was associated with VAMP3 coalescence in WT and Fyn-deficient cells. Reconstitution of MC-deficient Wsh mice with Fyn(-/-) MCs produced greater LPS-dependent production of TNF in the peritoneal cavity. Our data show that Fyn kinase is activated after TLR4 triggering and exerts an important negative control on LPS-dependent TNF production in MCs controlling the inactivation of PP2Ac and activation of PKCα/ß necessary for the secretion of TNF by VAMP3(+) carriers.

Burden of symptoms associated with development of metastatic bone disease in patients with breast cancer.

PURPOSE: Women with breast cancer frequently develop painful bone metastases. This retrospective study was designed to longitudinally characterize patterns of patient-reported symptoms among patients with breast cancer relative to the diagnosis of bone metastases. METHODS: Patient records were identified from the Oncology Services Comprehensive Electronic Records (OSCER) database which includes outpatient oncology practices across the USA. Symptom burden was assessed by Patient Care Monitor (PCM) assessments, which are administered as part of routine care in a subset of these practices. Eligible patients were women diagnosed with breast cancer (ICD-9-CM 174.xx) who developed bone metastases (ICD-9-CM 198.5) and had ≥1 PCM assessment between January 2007 and December 2012. The pre-specified endpoint was the occurrence of moderate to severe symptom burden, defined as PCM score ≥4 (0-10 scale). RESULTS: One thousand one hundred five women (median age, 61) met the eligibility criteria. Worsening of symptoms, particularly fatigue and pain, occurred in the months leading up to the diagnosis of bone metastases. After bone metastases diagnosis, the rate of increase in the proportion of patients experiencing moderate/severe symptoms slowed, but continued to climb during follow-up. Median time to moderate/severe symptoms was 0.9 month for fatigue, 1 month for pain, 2.9 months for trouble sleeping, and 7.7 months for numbness/tingling. Half of the patients received bone-targeted agents after diagnosis of bone metastases. CONCLUSIONS: Symptom burden, especially pain and fatigue, increased both before and after the diagnosis of bone metastases, highlighting the need for proactive monitoring and management of symptoms in breast cancer patients.

Patient, Caregiver, and Nurse Preferences for Treatments for Bone Metastases from Solid Tumors.

BACKGROUND: Bone-targeted agents (BTAs) used for the prevention of skeletal-related events (SREs) associated with metastatic bone disease possess different attributes that factor into treatment decisions. OBJECTIVE: The aim of this study was to evaluate preferences of patients, caregivers, and nurses for features of BTAs used to prevent SREs in patients with a self-reported physician diagnosis of bone metastasis from solid tumors. METHODS: Patients (n = 187), primary caregivers (n = 197), or nurses (n = 196) completed a web-enabled discrete-choice experiment (10-question survey) in which they chose between pairs of hypothetical profiles of BTAs. Each profile was defined by six key treatment attributes, including efficacy and safety (two each) and route/frequency of administration and cost (one each). The relative importance of treatment attributes and levels was estimated. RESULTS: The most important treatment attribute for patients and nurses was out-of-pocket cost, and for caregivers, treatment-related risk of renal impairment. Risk of renal impairment was the second most important attribute for patients and nurses, while time until first SRE was the third most important attribute for all respondents. For nurses, risk of osteonecrosis of the jaw was least important, and for patients and caregivers, mode of administration was least important. LIMITATIONS: Respondents considered hypothetical medications; therefore, their decisions may not have the same consequences as actual decisions. CONCLUSIONS: The perspectives of patients, caregivers, and nurses are integral when making treatment decisions about BTAs to prevent SREs associated with solid tumors. Identifying the relative importance of attributes of BTAs will aid in the proper selection of therapy in this setting, which may improve patient outcomes.

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer.

PURPOSE: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. METHODS: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. RESULTS: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9%) and 31 (1.2%) in the denosumab and ZA groups, respectively. In total, 32 (6.9%) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1%, in patients continuing and switching to denosumab, respectively. CONCLUSION: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports.

Measurement of skeletal related events in SEER-Medicare: a comparison of claims-based methods.

BACKGROUND: Skeletal related events (SREs) are common in men with metastatic prostate cancer (mPC). Various methods have been used to identify SREs from claims data. The objective of this study was to provide a framework for measuring SREs from claims and compare SRE prevalence and cumulative incidence estimates based on alternative approaches in men with mPC. METHODS: Several claims-based approaches for identifying SREs were developed and applied to data for men aged [greater than or equal to] 66 years newly diagnosed with mPC between 2000 and 2009 in the SEER-Medicare datasets and followed through 2010 or until censoring. Post-diagnosis SREs were identified using claims that indicated spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (BS), or radiation (suggestive of bone palliative radiation, RAD). To measure SRE prevalence, two SRE definitions were created: 'base case' (most commonly used in the literature) and 'alternative' in which different claims were used to identify each type of SRE. To measure cumulative incidence, we used the 'base case' definition and applied three periods in which claims were clustered to episodes: 14-, 21-, and 28-day windows. RESULTS: Among 8997 mPC patients, 46 % experienced an SRE according to the 'base case' definition and 43 % patients experienced an SRE according to the 'alternative' definition. Varying the code definition from 'base case' to 'alternative' resulted in an 8 % increase in the overall SRE prevalence. Using the 21-day window, a total of 12,930 SRE episodes were observed during follow up. Varying the window length from 21 to 28 days resulted in an 8 % decrease in SRE cumulative incidence (RAD: 10 %, PF: 8 %, SCC: 6 %, BS: 0.2 %). CONCLUSIONS: SRE prevalence was affected by the codes used, with PF being most impacted. The overall SRE cumulative incidence was affected by the window length used, with RAD being most affected. These results underscore the importance of the baseline definitions used to study claims data when attempting to understand relevant clinical events such as SREs in the real world setting.

Prevalence of bone metastases and bone-targeting agent use among solid tumor patients in the United States.

PURPOSE: Patients with bone metastases are at an increased risk of experiencing morbidity due to bone complications, and bone-targeting agents (BTA) are indicated for the prevention of these complications. Population-based estimates of the prevalence of bone metastases associated with solid tumors, and current treatment patterns for these patients, are limited. This study was undertaken to estimate the prevalence of bone metastases from solid tumors and to describe recent trends in the use of BTA in the US. METHODS: We estimated the prevalence of bone metastases in the US in 2012 using data from Medicare fee-for-service and PharMetrics Plus, a large commercial claims database. We evaluated the proportion of patients with bone metastases who were treated with BTA in 2012, timing of initiation of BTA relative to bone metastasis diagnosis, and persistence on BTA, overall and by primary tumor type and treatment. RESULTS: There were ~330,000 (168,063 Medicare fee-for-service; 162,239 other) patients aged ≥18 years living with solid tumors and bone metastases in 2012. BTA were used by 43% (Commercial) to 47% (Medicare) of patients in 2012, with the greatest use among breast cancer patients. Over half (Medicare: 57%; Commercial: 53%) of BTA-treated patients initiated BTA after experiencing a bone complication. CONCLUSION: Of the estimated 330,000 solid tumor patients living with bone metastases in the US in 2012, many may have received less than optimal care to prevent bone complications during the calendar year.

Cost of palliative external beam radiotherapy (EBRT) use for bone metastases secondary to prostate cancer.

BACKGROUND: Evaluations of the costs of palliative external beam radiation therapy (EBRT) for treatment of bone metastases are limited. OBJECTIVE: To summarize EBRT lifetime care patterns in deceased men with metastatic prostate cancer treated in a cancer hospital in the United States. METHODS: A retrospective review of electronic health records identified deceased adult prostate cancer (ICD-9 185.xx) patients with bone metastases (ICD-9 198.5) and who were treated for bone pain and metastasis management with EBRT between January 1, 1995 and December 17, 2012. Common Procedural Terminology codes were used to identify all EBRT episodes (total billed EBRT services; initial and final evaluation) to calculate length of EBRT treatments and per episode costs (2011 US$). Bootstrapping approximated the 95% confidence interval for final cost estimates. RESULTS: 176 men were identified; 19 (10.8%) had bone metastases in >1 site. Eighty-nine men (50.6%) received >1 EBRT episode (range, 1-6; median, 2), with first episode length ranging from 1-44 calendar days (mean, 13.4; SD, 8.4) at a mean cost of $7,084 (SD, $4,028). About 70% of costs were attributable to hospital charges and 30% to physician charges. LIMITATIONS: Small sample size limits broad applicability to large populations of men with prostate cancer. CONCLUSION: Care costs for EBRT constitute one of many costs that should be taken into account when planning for palliative care of prostate cancer and bone metastasis.

Prevalence of renal impairment and use of nephrotoxic agents among patients with bone metastases from solid tumors in the United States.

The renal status of patients with bone metastases secondary to solid tumors and their treatment with nephrotoxic agents is not well characterized. This retrospective study analyzed electronic medical records data from US-based oncology clinics to identify adult (age ≥18) solid tumor patients with first bone metastasis diagnosis and ≥1 serum creatinine recorded between January 1, 2009 and December 31, 2013. Patients with multiple myeloma, multiple primary tumor types, acute renal failure, and/or end-stage renal disease were excluded. Using the Chronic Kidney Disease Epidemiology Collaboration formula, we determined the prevalence of renal impairment (RI: single estimated glomerular filtration rate [eGFR] value <60 mL/min per 1.73 m(2) ) and chronic kidney disease (CKD: ≥2 eGFR values <60, at least 90 days apart). We also examined the use of intravenous bisphosphonates (IV BP) and other nephrotoxic agents. Approximately half of the 11,809 patients were female. Breast (34%) and lung (28%) tumors were the most common. At bone metastasis diagnosis, mean age was 67 years and 24% of patients exhibited RI. The 5-year prevalence was 43% for RI and 71% for CKD among RI patients. Nearly half (46%) of CKD patients received IV BP in the 12 months following their confirming eGFR and 13% of these patients received at least one other nephrotoxic agent during that period. This is the first US-based study to examine the prevalence of RI among patients with bone metastases from solid tumors. RI is common at bone metastases diagnosis, and a substantial proportion of patients develop RI or CKD as their disease progresses. Whenever possible, treatments that are potentially less damaging for the kidney should be considered for patients with or predisposed to RI.