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The University of Florida Health conducted a pragmatic implementation of a pharmacogenetics (PGx) panel-based test to guide medications used for supportive care prescribed to patients undergoing chemotherapy. The implementation was in the context of a pragmatic clinical trial for patients with non-hematologic cancers being treated with chemotherapy. Patients were randomized to either the intervention arm or control arm and received PGx testing immediately or at the end of the study, respectively. Patients completed the MD Anderson Symptom Inventory (MDASI) to assess quality of life (QoL). A total of 150 patients received PGx testing and enrolled in the study. Clinical decision support and implementation infrastructure were developed. While the study was originally planned for 500 patients, we were underpowered in our sample of 150 patients to test differences in the patient-reported MDASI scores. We did observed a high completion rate (92%) of the questionnaires; however, there were few medication changes (n = 6 in the intervention arm) based on PGx test results. Despite this, we learned several lessons through this pragmatic implementation of a PGx panel-based test in an outpatient oncology setting. Most notably, patients were less willing to undergo PGx testing if the cost of the test exceeded $100. In addition, to enhance PGx implementation success, reoccurring provider education is necessary, clinical decision support needs to appear in a more conducive way to fit in with oncologists' workflow, and PGx test results need to be available earlier in treatment planning.
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Antineoplásicos , Neoplasias , Pruebas de Farmacogenómica , Calidad de Vida , Humanos , Femenino , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Pruebas de Farmacogenómica/economía , Pruebas de Farmacogenómica/estadística & datos numéricos , Adulto , Anciano , Antineoplásicos/uso terapéutico , Oncología Médica/métodos , Sistemas de Apoyo a Decisiones Clínicas , FarmacogenéticaRESUMEN
OBJECTIVE: To review the pharmacology, efficacy, and safety of capivasertib for the treatment of adults with hormone receptor-positive, HER2-negative (HR+/HER2-) locally advanced or metastatic breast cancer with 1 or more PIK3CA/AKT1/PTEN alterations. DATA SOURCES: A literature search was conducted using PubMed and MEDLINE databases, published abstracts, and studies from ClinicalTrials.gov between 2003 and February 2024. Keywords included capivasertib, AZD5363, PI3K/AKT/mTOR pathway, and breast cancer. DATA EXTRACTION: All applicable publications, package inserts, meeting abstracts, and clinical trials with capivasertib were reviewed. DATA SYNTHESIS: Capivasertib is a first-in-class inhibitor of 3 isoforms of AKT (AKT-1, AKT-2, and AKT-3) which is an essential component in the PI3K/AKT/mTOR signaling pathway involved in oncogenesis. In the phase III CAPItello-291 trial, capivasertib in combination with fulvestrant (C+F) demonstrated improved progression-free survival (PFS) (7.3 vs 3.1 months) compared with placebo-fulvestrant (P+F) cohort in AKT-altered pathway patients who had progressed through prior aromatase inhibitor. The most common adverse reactions of any grade reported in the C+F group were diarrhea, cutaneous skin reactions, nausea, fatigue, and vomiting. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: HR+/HER2- advanced breast cancer patients experience progression following endocrine therapies and cyclin-dependent kinase (CDK) 4/6 inhibitors. Capivasertib is a viable treatment option for patients with PIK3CA/AKT1/PTEN activating mutations following progression on endocrine-based regimens in the metastatic setting or recurrence within 12 months of completing adjuvant therapy. CONCLUSION: Integration of capivasertib into clinical practice is ongoing; intermittent dosing and favorable toxicity are attractive for future novel combination prospective trials.
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BACKGROUND: Supportive care medication use differences may contribute to racial disparities observed in health-related quality of life in patients with pancreatic cancer. METHODS: In this observation study using the Surveillance, Epidemiology, and End Results-Medicare linked database, we sought to examine supportive care medication use disparities in patients with pancreatic cancer from 2005 to 2017 by race and ethnicity. RESULTS: Among 74,309 patients included in the final analysis, racial and ethnic disparities in the use of supportive care medications were identified. After adjustment for confounding factors and compared with non-Hispanic Whites, minorities had significantly less use of opioids [Black: adjusted OR (aOR), 0.84; 95% confidence interval (CI), 0.79-0.88; Asian: aOR, 0.84; 95% CI, 0.79-0.90), and skeletomuscular relaxants (Black: aOR, 0.90; 95% CI, 0.82-0.99; Hispanic: aOR, 0.82; 95% CI, 0.74-0.91; Asian: aOR, 0.59; 95% CI, 0.51-0.68), and increased use of non-opioid analgesics (Hispanic: aOR, 1.16; 95% CI, 1.01-1.14; Asian: aOR, 1.37; 95% CI, 1.26-1.49). Racial and ethnic minorities had less use of antidepressants (Black: aOR, 0.56; 95% CI, 0.53-0.59; Hispanic: aOR, 0.77; 95% CI, 0.73-0.82; Asian: aOR, 0.47; 95% CI, 0.44-0.51), anxiolytics (Black: aOR, 0.78; 95% CI, 0.74-0.82; Hispanic: aOR, 0.66; 95% CI, 0.62-0.71; Asian: aOR, 0.52; 95% CI, 0.48-0.57), and antipsychotics (Hispanic: aOR, 0.90; 95% CI, 0.82-0.99; Asian: aOR, 0.84; 95% CI, 0.74-0.95). CONCLUSIONS: Racial and ethnic disparities in the use of supportive care medications among patients with pancreatic cancer were observed, with the differences unexplained by sociodemographic factors. IMPACT: Future studies should identify strategies to promote equitable use of supportive care medications among racial minorities and explore factors that may influence their use in these populations.
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Manejo del Dolor , Neoplasias Pancreáticas , Humanos , Anciano , Estados Unidos/epidemiología , Calidad de Vida , Disparidades en Atención de Salud , Medicare , Muerte , Neoplasias Pancreáticas/tratamiento farmacológicoRESUMEN
For patients with localized pancreatic cancer with minimal vascular involvement, optimal survivability requires a multidisciplinary approach of surgical resection and systemic chemotherapy. FOLFIRINOX is a combination chemotherapy regimen that offers promising results in the perioperative and metastatic settings; however, it can cause significant adverse effects. Such toxicity can negatively impact some patients, resulting in chemotherapy discontinuation or surgical unsuitability. In an effort to reduce toxicities and optimize outcomes, this investigation explores the safety and feasibility of substituting liposomal irinotecan (nal-IRI) for nonliposomal irinotecan to improve tumor drug delivery and potentially reduce toxicity. This regimen, NALIRIFOX, has the potential to be both safer and more effective when administered in the preoperative setting.
For patients with pancreatic cancer with little to no cancer near the blood vessels, the best life expectancy usually requires surgery and chemotherapy. FOLFIRINOX is a chemotherapy medicine that offers promising results for both patients getting surgery and for patients with widespread disease. However, it can cause harmful side effects. The side effects can be so bad that the chemotherapy has to be stopped or that surgery is no longer possible. In order to reduce the harmful side effects and improve outcomes, this investigation looks into the safety and practicality of using a different version of one of the medicines. The different version hopes to improve drug delivery and reduce harmful side effects. This regimen, NALIRIFOX, can be safer and more effective in patients awaiting surgery. Clinical Trial Registration: UF-STO-PANC-004 (NCT03483038) (ClinicalTrials.gov).
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Adenocarcinoma , Neoplasias Pancreáticas , Fármacos Sensibilizantes a Radiaciones , Humanos , Irinotecán/uso terapéutico , Neoplasias Pancreáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Oxaliplatino/uso terapéutico , Adenocarcinoma/patología , Terapia Neoadyuvante/métodos , Fluorouracilo/efectos adversos , Leucovorina/efectos adversos , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Ensayos Clínicos Fase II como AsuntoRESUMEN
Background Cyclin-dependent kinase (CDK) 4 and 6 inhibitors have significantly improved survival in patients with hormone receptor-positive metastatic breast cancer. There are few data regarding the epidemiology of cardiovascular adverse events (CVAEs) with these therapies. Methods and Results Using the OneFlorida Data Trust, adult patients without prior cardiovascular disease who received at least 1 CDK4/6 inhibitor were included in the analysis. CVAEs identified from International Classification of Diseases, Ninth and Tenth Revisions (ICD-9/10) codes included hypertension, atrial fibrillation(AF)/atrial flutter (AFL), heart failure/cardiomyopathy, ischemic heart disease, and pericardial disease. Competing risk analysis (Fine-Gray model) was used to determine the association between CDK4/6 inhibitor therapy and incident CVAEs. The effect of CVAEs on all-cause death was studied using Cox proportional hazard models. Propensity-weight analyses were performed to compare these patients to a cohort of patients treated with anthracyclines. A total of 1376 patients treated with CDK4/6 inhibitors were included in the analysis. CVAEs occurred in 24% (35.9 per 100 person-years). CVAEs were slightly higher in patients who received CKD4/6 inhibitors compared with anthracyclines (P=0.063), with higher death rate associated with the development of AF/AFL or cardiomyopathy/heart failure in the CDK4/6 group. The development of cardiomyopathy/heart failure and AF/AFL was associated with increased all-cause death (adjusted hazard ratio [HR], 4.89 [95% CI, 2.98-8.05]; and 5.88 [95% CI, 3.56-9.73], respectively). Conclusions CVAEs may be more common with CDK4/6 inhibitors than previously recognized, with increased death rates in these patients who develop AF/AFL or heart failure. Further research is needed to definitively determine cardiovascular risk associated with these novel anticancer treatments.
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Fibrilación Atrial , Neoplasias de la Mama , Sistema Cardiovascular , Insuficiencia Cardíaca , Adulto , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/complicaciones , Quinasa 4 Dependiente de la Ciclina , Fibrilación Atrial/epidemiologíaRESUMEN
Background Anthracyclines remain a key treatment for many malignancies but can increase the risk of heart failure or cardiomyopathy. Specific guidelines recommend echocardiography and serum cardiac biomarkers such as BNP (B-type natriuretic peptide) or NT-proBNP (N-terminal proBNP) evaluation before and 6 to 12 months after treatment. Our objective was to evaluate associations between racial and ethnic groups in cardiac surveillance of survivors of cancer after exposure to anthracyclines. Methods and Results Adult patients in the OneFlorida Consortium without prior cardiovascular disease who received at least 2 cycles of anthracyclines were included in the analysis. Multivariable logistic regression was performed to estimate the odds ratios (ORs) and 95% CIs for receiving cardiac surveillance at baseline before anthracycline therapy, 6 months after, and 12 months after anthracycline exposure among different racial and ethnic groups. Among the entire cohort of 5430 patients, 63.4% had a baseline echocardiogram, with 22.3% receiving an echocardiogram at 6 months and 25% at 12 months. Non-Hispanic Black (NHB) patients had a lower likelihood of receiving a baseline echocardiogram than Non-Hispanic White (NHW) patients (OR, 0.75 [95% CI, 0.63-0.88]; P=0.0006) or any baseline cardiac surveillance (OR, 0.76 [95% CI, 0.64-0.89]; P=0.001). Compared with NHW patients, Hispanic patients received significantly less cardiac surveillance at the 6-month (OR, 0.84 [95% CI, 0.72-0.98]; P=0.03) and 12-month (OR, 0.85 [95% CI, 0.74-0.98]; P=0.03) time points, respectively. Conclusions There were significant racial and ethnic differences in cardiac surveillance among survivors of cancer at baseline and following anthracycline-based treatment in NHB and Hispanic cohorts. Health care providers need to be cognizant of these social inequities and initiate efforts to ensure recommended cardiac surveillance occurs following anthracyclines.
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Cardiomiopatías , Neoplasias , Adulto , Humanos , Antraciclinas/efectos adversos , Corazón , Antibióticos Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/inducido químicamente , BiomarcadoresRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality and the incidence is projected to increase by 2030. Despite recent advances in its treatment, African Americans have a 50-60% higher incidence and 30% higher mortality rate when compared to European Americans possibly resulting from differences in socioeconomic status, access to healthcare, and genetics. Genetics plays a role in cancer predisposition, response to cancer therapeutics (pharmacogenetics), and in tumor behavior, making some genes targets for oncologic therapeutics. We hypothesize that the germline genetic differences in predisposition, drug response, and targeted therapies also impact PDAC disparities. To demonstrate the impact of genetics and pharmacogenetics on PDAC disparities, a review of the literature was performed using PubMed with variations of the following keywords: pharmacogenetics, pancreatic cancer, race, ethnicity, African, Black, toxicity, and the FDA-approved drug names: Fluoropyrimidines, Topoisomerase inhibitors, Gemcitabine, Nab-Paclitaxel, Platinum agents, Pembrolizumab, PARP-inhibitors, and NTRK fusion inhibitors. Our findings suggest that the genetic profiles of African Americans may contribute to disparities related to FDA approved chemotherapeutic response for patients with PDAC. We recommend a strong focus on improving genetic testing and participation in biobank sample donations for African Americans. In this way, we can improve our current understanding of genes that influence drug response for patients with PDAC.
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Antineoplásicos , Negro o Afroamericano , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Negro o Afroamericano/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/etnología , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/etnología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Farmacogenética , Terapia Molecular Dirigida/métodosRESUMEN
Immune checkpoint inhibitor therapy represents a significant advance in cancer care. The interaction between PD-1 and PD-L1 induces immune tolerance and the inhibition of this interaction is an effective treatment strategy for numerous malignancies. Despite its demonstrated potential, immunotherapy is not clinically effective in immunogenically 'cold' tumors such as pancreatic cancer, prostate cancer and neuroendocrine tumors. Through the inhibition of VEGF, it may be possible to potentiate the effect of immune checkpoint blockade in tumors that have traditionally shown a lack of clinical response to immunotherapy. This signal-seeking, single-arm, prospective clinical trial aims to determine the objective response of tivozanib and atezolizumab in advanced immunogenically cold solid tumors. Clinical Trial Registration: NCT05000294 (ClinicalTrials.gov).
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Along with the fast pace of oncology drug approvals is the heightened opportunity for drug-drug, drug-food, and drug-herbal interactions. Attendees at the JADPRO Live Virtual 2021 conference learned about the pharmacodynamic and pharmacokinetic mechanisms of drug interactions and how to integrate appropriate therapeutic management strategies to optimize patient care and minimize the potential outcomes of severe drug interactions.
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PURPOSE: Drug shortages are a clear and growing challenge. Prominent shortages included oncology medications and supportive care products essential for the care of patients with cancer. Oncology drug shortages often result in disruptions in the timing of chemotherapy treatments, alterations in the dose or regimen administered, or even missed doses when alternative agents are unavailable. The purpose of this survey was to characterize the impact of oncology drug shortages across the United States, including the experiences of health care organizations, resource implications, and the impact on patient safety, patient care, and clinical trials. METHODS: A 36-item online survey was distributed to membership of the Hematology/Oncology Pharmacy Association to gather information on shortages of oncology drugs (ie, all drugs essential in the care of patients with cancer, including supportive care agents). RESULTS: Sixty-eight US organizations participated in the survey between December 2019 and July 2020. Sixty-three percent of institutions reported one or more drug shortages per month, with a 34% increase in 2019 from 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents. The most difficult agents to obtain were vincristine, vinblastine, intravenous immunoglobulin, leucovorin, and Bacillus Calmette-Guerin. CONCLUSION: A survey of US oncology pharmacists indicated that oncology drug shortages occurred frequently in 2020. Shortages led to delays in chemotherapy and changes in treatment or omission, complicated clinical research, and increased risk of medication errors and adverse outcomes.
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Hematología , Neoplasias , Farmacia , Humanos , Oncología Médica , Neoplasias/tratamiento farmacológico , Encuestas y Cuestionarios , Estados UnidosRESUMEN
As cancer treatment evolves in the era of precision oncology, molecularly targeted agents (MTAs) have become frontline therapy for many cancers. MTAs are biologically targeted and thought to have less off-target toxicity; however, the eye is particularly susceptible to off-target toxicities given its unique microenvironment. In this review, we present commonly used FDA-approved MTAs, any associated ocular toxicities and review the mechanisms, frequency, severity, and management. Increased awareness and communication between clinicians caring for cancer patients is needed for individualized risk assessment, earlier diagnosis, and mitigation of ocular toxicities.
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Antineoplásicos , Neoplasias , Oncólogos , Antineoplásicos/uso terapéutico , Humanos , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Medicina de Precisión , Microambiente TumoralRESUMEN
There is surmounting levels of evidence on the health disparities within cancer treatment in the United States (US). Most of the research focused on cancer specific factors including anticancer incidence, screening, treatment and follow-up, and clinical outcomes such as overall survival (OS). Less is known about the disparities present with supportive care medication use in cancer patients. Supportive care utilization during cancer treatment has been linked to improved quality of life (QoL) and OS among patients. The goal of this scoping review is to summarize findings of current literature on the relationship between race and ethnicity and the receipt of supportive care medications during cancer treatment for pain and chemotherapy-induced nausea and vomiting (CINV). This scoping review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA-ScR) guidelines. Our literature search included quantitative studies, qualitative studies, and grey literature written in the English language with clinically relevant outcomes pertaining to pain and CINV management in cancer treatment published from 2001-2021. Articles that met the predefined inclusion criteria were considered for inclusion in the analysis. The initial search yielded 308 studies. Following de-duplication and screening, 14 studies met the predefined inclusion criteria, with majority of the studies being quantitative studies (n=13). Collectively, results were mixed results regarding the presence of racial disparities for supportive care medication use. Half of the studies (n=7) supported this finding whereas, the other half (n=7) did not identify any racial disparities. In our review, multiple studies illustrate the existence of disparities in the use of supportive care medications in some cancer types. Clinical pharmacists should strive to eliminate supportive medication use disparities as part of a multidisciplinary team. In order to develop strategies to prevent supportive care medication use disparities in this population, further research and analysis of external factors that influence them are needed.
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INTRODUCTION: The coronavirus of 2019 pandemic has necessitated vast and rapid changes in the way oncology pharmacy services are delivered around the world. METHODS/AIMS: An international survey of oncology pharmacists and technicians was conducted via the International Society of Oncology Pharmacy Practitioners and collaborating global pharmacy organisations to determine the impact that the coronavirus of 2019 has had on pharmacy service delivery, pharmacy practitioners and oncology practice. RESULTS: The survey received 862 responses from 40 different countries from September to October 2020. The majority of respondents were pharmacists (n = 841, 97.6%), with 24% involved in the direct care of patients with the coronavirus of 2019. Of the survey participants, 55% increased their time working remotely, with remote activities including dispensing, patient assessment/follow-up and attending multi-disciplinary rounds. Respondents reported a 72% increase in the use of technology to perform remote patient interaction activities and that participation in educational meetings and quality improvement projects was reduced by 68% and 44%, respectively. Workforce impacts included altered working hours (50%), cancelled leave (48%) and forced leave/furloughing (30%). During the pandemic, respondents reported reduced access to intensive care (19%) and anti-cancer (15%) medications. In addition, 39% of respondents reported reduced access to personal protective equipment, including N95 masks for chemotherapy compounding. Almost half of respondents (49%) reported that cancer treatments were delayed or intervals were altered for patients being treated with curative intent. A third of practitioners (30%) believed that patient outcomes would be adversely impacted by changes to pharmacy services. Sixty-five percent of respondents reported impacts on their mental health, with 12% utilising support services. CONCLUSION: The coronavirus of 2019 pandemic has altered the way oncology pharmacy services are delivered. These results demonstrate the adaptability of the oncology pharmacy profession and highlight the importance of formal evaluation of the varied practice models to determine the evidence-based practices that enhance pharmacy services and, thus, should be reinstated as soon as practical and reasonable.
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Infecciones por Coronavirus , Coronavirus , Neoplasias , Servicios Farmacéuticos , Farmacia , Humanos , Oncología Médica , Farmacéuticos , Neoplasias/tratamiento farmacológico , Encuestas y CuestionariosRESUMEN
ABSTRACT: Cardiometabolic disease (CMD) is the most common preventable cause of death in the world. A number of components are included in the spectrum of CMD, such as metabolic syndrome/obesity, hyperglycemia/diabetes, dyslipidemia, and hypertension, which are independently associated with cardiovascular disease risk. These conditions often occur together, and patients with cancer frequently undergo treatments that can generate or worsen CMD. This review highlights and presents mechanistic and epidemiological evidence regarding CMD in 4 categories of anticancer medications, namely, mTOR/PI3K-Akt inhibitors, multitargeted tyrosine kinase inhibitor, immune checkpoint inhibitor therapy, and endocrine therapy. Patients taking these medications need careful monitoring during therapy. There is a role for cardio-oncology and onco-primary care specialists in optimally managing patients at risk to mitigate CMD during treatment with these and other investigational anticancer medications.
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Hipertensión , Fosfatidilinositol 3-Quinasas , Humanos , Inhibidores de Puntos de Control Inmunológico , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Proto-Oncogénicas c-akt , Serina-Treonina Quinasas TORRESUMEN
LESSONS LEARNED: Preclinical studies have demonstrated that Src inhibition through dasatinib synergistically enhances the antitumor effects of oxaliplatin. In this phase II, single-arm study, FOLFOX with dasatinib in previously untreated patients with mPC only showed only modest clinical activity, with a progressive-free survival of 4 months and overall survival of 10.6 months. Continued investigation is ongoing to better understand the role of Src inhibition with concurrent 5-fluorouracil and oxaliplatin in a subset of exceptional responders. BACKGROUND: Src tyrosine kinase activity is overexpressed in many human cancers, including metastatic pancreatic cancer (mPC). Dasatinib is a potent inhibitor of Src family of tyrosine kinases. This study was designed to investigate whether dasatinib can synergistically enhance antitumor effects of FOLFOX regimen (FOLFOX-D). METHODS: In this single-arm, phase II study, previously untreated patients received dasatinib 150 mg oral daily on days 1-14, oxaliplatin 85 mg/m2 intravenous (IV) on day 1 every 14 days, leucovorin (LV) 400 mg/m2 IV on day 1 every 14 days, 5-fluorouracil (5-FU) bolus 400 mg/m2 on day 1 every 14 days, and 5-FU continuous infusion 2,400 mg/m2 on day 1 every 14 days. Primary endpoint was progression-free survival (PFS) with preplanned comparison to historical controls. RESULTS: Forty-four patients enrolled with an estimated median PFS of 4.0 (95% confidence interval [CI], 2.3-8.5) months and overall survival (OS) of 10.6 (95% CI, 6.9-12.7) months. Overall response rate (ORR) was 22.7% (n = 10): one patient (2.3%) with complete response (CR) and nine patients (20.5%) with partial response (PR). Fifteen patients (34.1%) had stable disease (SD). Nausea was the most common adverse event (AE) seen in 35 patients (79.5%). CONCLUSION: The addition of dasatinib did not appear to add incremental clinical benefit to FOLFOX in untreated patients with mPC.
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Adenocarcinoma , Neoplasias Colorrectales , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Dasatinib/farmacología , Dasatinib/uso terapéutico , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/uso terapéutico , Oxaliplatino/farmacología , Oxaliplatino/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Multiple myeloma (MM) is the second most frequent hematologic cancer in the United States. Carfilzomib (CFZ), an irreversible proteasome inhibitor being used to treat relapsed and refractory MM, has been associated with cardiotoxicity, including heart failure. We hypothesized that a multi-omics approach integrating data from different omics would provide insights into the mechanisms of CFZ-related cardiovascular adverse events (CVAEs). Plasma samples were collected from 13 MM patients treated with CFZ (including 7 with CVAEs and 6 with no CVAEs) at the University of Florida Health Cancer Center. These samples were evaluated in global metabolomic profiling, global proteomic profiling, and microRNA (miRNA) profiling. Integrative pathway analysis was performed to identify genes and pathways differentially expressed between patients with and without CVAEs. The proteomics analysis identified the up-regulation of lactate dehydrogenase B (LDHB) [fold change (FC) = 8.2, p = 0.01] in patients who experienced CVAEs. The metabolomics analysis identified lower plasma abundance of pyruvate (FC = 0.16, p = 0.0004) and higher abundance of lactate (FC = 2.4, p = 0.0001) in patients with CVAEs. Differential expression analysis of miRNAs profiling identified mir-146b to be up-regulatein (FC = 14, p = 0.046) in patients with CVAE. Pathway analysis suggested that the pyruvate fermentation to lactate pathway is associated with CFZ-CVAEs. In this pilot multi-omics integrative analysis, we observed the down-regulation of pyruvate and up-regulation of LDHB among patients who experienced CVAEs, suggesting the importance of the pyruvate oxidation pathway associated with mitochondrial dysfunction. Validation and further investigation in a larger independent cohort are warranted to better understand the mechanisms of CFZ-CVAEs.
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Introduction: Novel immunotherapeutic agents (e.g. monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engagers) as treatment options for hematologic malignancies continue to emerge. These agents have been used as the standard of care in specific disease states and are associated with high costs. Value assessment of these therapies is of critical importance for coverage and reimbursement decision-making.Areas covered: We identified 15 immunotherapeutic agents through the U.S. FDA approvals for hematologic malignancies until 2018 and systematically reviewed related cost-effectiveness studies. Additionally, we examined whether drug wastage was accounted for in these studies.Expert opinion: We reviewed 51 studies for 14 identified immunotherapeutic agents that met the inclusion criteria for this systematic review. Three studies were observational-based, one study was model-based and incorporated observational data. The remaining studies were model-based with the majority of the model parameters extracted from randomized control trials (RCTs). Among 43 model-based economic evaluations, 13 studies accounted for drug wastage. Most of the studies showed favorable incremental cost-effectiveness ratios of immunotherapeutic agents-containing regimens when compared with no immunotherapeutic agents-containing regimens. Alemtuzumab, brentuximab vedotin, and daratumumab were not considered cost-effective across all the studies. Further investigations are warranted to establish the value of recent immunotherapeutic agents for hematologic malignancies.
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Antineoplásicos Inmunológicos/administración & dosificación , Neoplasias Hematológicas/tratamiento farmacológico , Inmunoterapia/métodos , Antineoplásicos Inmunológicos/economía , Análisis Costo-Beneficio , Neoplasias Hematológicas/economía , Neoplasias Hematológicas/inmunología , Humanos , Inmunoterapia/economía , Modelos Económicos , Ensayos Clínicos Controlados Aleatorios como Asunto , Eliminación de Residuos/economíaRESUMEN
Patients with autoimmune disorders, multiple comorbidities, poor performance status, advanced age, and infection with SARS-CoV-2 (COVID-19) each represent unique subgroups of patients with cancer to whom little is known of the effects, benefits, and complications of checkpoint inhibitor (CPI) therapy. Although prospective trials are lacking in these populations, retrospective data and cohort series suggest that these patients can safely receive and benefit from CPI therapy. Here, we review the relevant data available and offer clinical recommendations in managing these complex patients with CPI therapy, where otherwise indicated.