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Background: Leptomeningeal disease (LMD) is a devastating complication for patients with advanced cancer. Diagnosis and monitoring the response to therapy remains challenging due to limited sensitivity and specificity of standard-of-care (SOC) diagnostic modalities, including cerebrospinal fluid (CSF) cytology, MRI, and clinical evaluation. These hindrances contribute to the poor survival of LMD patients. CNSide is a CLIA-validated test that detects and characterizes CSF-derived tumor cells and cell-free (cf) DNA. We performed a retrospective analysis on the utility of CNSide to analyze CSF obtained from advanced non-small cell lung cancer (aNSCLC) patients with suspected LMD treated at the Huntsman Cancer Institute in Salt Lake City, UT. Methods: CNSide was used to evaluate CSF from 15 patients with aNSCLC. CSF tumor cell quantification was performed throughout treatment for 5 patients. CSF tumor cells and cfDNA were characterized for actionable mutations. Results: In LMD-positive patients, CNSide detected CSF tumor cells in 88% (22/25) samples versus 40% (10/25) for cytology (matched samples). CSF tumor cell numbers tracked response to therapy in 5 patients where CNSide was used to quantify tumor cells throughout treatment. In 75% (9/12) of the patients, genetic alterations were detected in CSF, with the majority representing gene mutations and amplifications with therapeutic potential. The median survival for LMD patients was 16.1 m (5.2-NR). Conclusions: We show that CNSide can supplement the management of LMD in conjunction with SOC methods for the diagnosis, monitoring response to therapy, and identifying actionable mutations unique to the CSF in patients with LMD.
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OBJECTIVE: The objective of this research was to assess physical and sexual violence experienced by sexual and gender minorities in nine African countries, and to examine factors associated with violence. METHODS: We conducted an exploratory multi-country cross-sectional study among self-identifying sexual and gender minorities, using a survey tool available in paper and online. Participants were sampled through venue-based and web-based convenience sampling. We analysed data using descriptive statistics and logistic regression, with Stata15. FINDINGS: Of 3798 participants, 23% were gender minorities, 20% were living with HIV, and 18% had been coerced into marriage. Fifty-six per cent of all participants had experienced physical or sexual violence in their lifetime, and 29% in the past year. Gender minorities had experienced significantly higher levels of violence compared to cisgender (sexual minority) participants. The variable most strongly associated with having experienced violence was being coerced into marriage (AOR, 3.02), followed by people living nearby knowing about one's sexual orientation and/or gender identity (AOR, 1.90) and living with HIV (AOR, 1.47). CONCLUSION: Sexual and gender minorities in Eastern and Southern Africa experience high levels of violence. Sexual orientation and gender identity need to be recognised as risk factors for violence in national and regional law and policy frameworks. States should follow the African Commission Resolution 275 and provide protection against violence based on real or perceived sexual orientation or gender identity.
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Identidad de Género , Minorías Sexuales y de Género , África Austral , Estudios Transversales , Femenino , Humanos , Masculino , Conducta Sexual , ViolenciaRESUMEN
PURPOSE: Performance status (PS), an established prognostic surrogate of cancer survival, is a physician-synthesized metric of patient symptoms and mobility that is prone to bias and subjectivity. The National Cancer Institute (NCI) Patient-Reported Outcomes Measurement Information System-Cancer (PROMIS-Ca) Bank, a patient-centric patient-reported outcome (PRO) evaluation of physical function (PF), fatigue, depression, anxiety, and pain, shares subject matter with PS and, therefore, may also be prognostic while eliminating physician interpretation. METHODS: Patients at Huntsman Cancer Institute were assessed using the NCI PROMIS-Ca Bank. Using tablets at routine office visits, PF, fatigue, depression, anxiety, and pain scores were collected from patients with advanced melanoma, non-small-cell lung cancer, colorectal cancer, and breast cancer. A PRO score collected at a single time point within 6 months of metastatic diagnosis for each patient was merged with curated clinical outcome data. The association of PROs, overall survival (OS), and hospitalization-free survival (HFS) were assessed in multivariable analysis that included sex and cancer type. RESULTS: Two hundred eighty-two complete sets of patient data were available for analysis. All 5 PRO domains were strongly prognostic of OS and HFS. While the PRO domains were interrelated with moderate to strong correlations (0.40-0.79), multivariable regression suggested that PF was most strongly associated with the clinical outcomes of OS (P < .001) and HFS (P < .001). CONCLUSION: NCI PROMIS-Ca PROs may be prognostic of both cancer survival and likelihood of hospitalization. Future prospective studies are needed for all major prognostic factors to fully understand the independent prognostic value of PROs.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Medición de Resultados Informados por el Paciente , Humanos , Pronóstico , Estudios ProspectivosRESUMEN
BACKGROUND: The natural histories of, and treatment options for, epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancers (NSCLCs) are distinctly different from those of lung cancer that lacks actionable mutations. Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor that has been approved in other malignancies. OBJECTIVE: A phase I trial of ipilimumab plus targeted therapy with either erlotinib or crizotinib was performed to assess the safety of the combination in patients with EGFR-mutated or ALK-rearranged advanced NSCLC. METHODS: Patients with EGFR-mutated or ALK-rearranged NSCLC on a stable dose of erlotinib or crizotinib for > 28 days were eligible for the study. Patients were treated with ipilimumab 3 mg/kg for four cycles plus erlotinib or crizotinib. RESULTS: Treatment of the EGFR cohort resulted in dose-limiting toxicity in three of eight patients, with grade 3 diarrhea. The protocol was amended to reduce the ipilimumab dose to 1 mg/kg. Excessive toxicity resulted in the study being closed after 14 patients. Four of 11 EGFR-mutated patients ultimately developed grade 3 colitis. Of three ALK-rearranged patients, one developed hypophysitis and another grade 2 pneumonitis. For 11 EGFR-mutated patients, progression-free survival (PFS) from the start of ipilimumab was 17.9 months. Erlotinib treatment began a median 7.7 months before ipilimumab; therefore, erlotinib PFS was 27.8 months. Median overall survival (OS) has not been reached but will be > 42.3 months from erlotinib initiation. For three ALK-rearranged patients, ipilimumab PFS was 24.1 months. Median OS has not been reached but will be at least 47.2 months from the initiation of crizotinib. CONCLUSION: Erlotinib plus ipilimumab caused excessive short-term gastrointestinal toxicity leading to early study closure. However, PFS and OS were notable; therefore, targeted therapies with immunotherapy in NSCLC merit further study. Clinicaltrials.gov registration number: NCT01998126.
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Quinasa de Linfoma Anaplásico/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Ipilimumab/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos Inmunológicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Estudios de Seguimiento , Humanos , Ipilimumab/farmacología , Neoplasias Pulmonares/patología , Masculino , Metástasis de la Neoplasia , Estudios ProspectivosRESUMEN
Therapies for advanced non-small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600-mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression-free survival of 10-11 months. BRAF mutations are a high-frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical-trial and real-world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. IMPLICATIONS FOR PRACTICE: The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E-mutant non-small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.
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Adenocarcinoma del Pulmón/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Corticoesteroides/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Estudios de Cohortes , Manejo de la Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Estudios de Seguimiento , Humanos , Imidazoles/administración & dosificación , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Oximas/administración & dosificación , Pronóstico , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Tasa de SupervivenciaRESUMEN
In patients with non-small cell lung cancer (NSCLC) progression with leptomeningeal (LM) metastases is a catastrophic event with limited treatment options. We report a patient who developed leptomeningeal disease while on front-line erlotinib. High-dose tyrosine kinase inhibitor was started but ineffective. She was transitioned to third-generation TKI osimertinib, despite lacking a T790M mutation, and responded with complete resolution of symptoms and malignant cytology in the cerebrospinal fluid (CSF). Recent phase one data and our case indicate osimertinib should be viewed as a best practice for treatment of LM disease in epidermal growth factor receptor (EGFR) mutated NSCLC regardless of T790M status.
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Carcinoma de Pulmón de Células no Pequeñas/secundario , Líquido Cefalorraquídeo/citología , Receptores ErbB/efectos de los fármacos , Neoplasias Pulmonares/secundario , Neoplasias Meníngeas/tratamiento farmacológico , Neoplasias Meníngeas/secundario , Piperazinas/farmacología , Acrilamidas , Anciano , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Líquido Cefalorraquídeo/efectos de los fármacos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Imagen por Resonancia Magnética/métodos , Neoplasias Meníngeas/patología , Mutación/efectos de los fármacos , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: The conventional frontline therapy for fit patients with chronic lymphocytic leukaemia (CLL) is fludarabine, cyclophosphamide and rituximab (FCR). Rituximab (Mabthera®, Roche Products Ltd) targets the CD20 antigen, which is expressed at low levels in CLL. The standard dose of rituximab in CLL (375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2-6) was selected based on toxicity data only. Small doses of rituximab (as low as 20 mg) have biological activity in CLL, with an immediate reduction in circulating CLL cells and down-regulation of CD20. Phase II trials had suggested improved efficacy with the addition of mitoxantrone to FCR. The key assumption for the Attenuated dose Rituximab with ChemoTherapy In CLL (ARCTIC) trial was that the addition of mitoxantrone to fludarabine, cyclophosphamide and low-dose rituximab would be more effective than conventional FCR. OBJECTIVES: To assess whether fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab (FCM-miniR) (100 mg of rituximab per cycle) was non-inferior to FCR in frontline CLL. Complete response (CR) rate was the primary end point, with the secondary end points being progression-free survival (PFS), overall survival (OS), overall response rate, eradication of minimal residual disease (MRD), safety and cost-effectiveness. DESIGN: ARCTIC was a UK multicentre, randomised, controlled, open, Phase IIB non-inferiority trial in previously untreated CLL. A total of 206 patients with previously untreated CLL who required treatment, according to the International Workshop on Chronic Lymphocytic Leukaemia criteria, were to be randomised to FCR or FCM-miniR. There was an independent Data Monitoring and Ethics Committee (DMEC) with a pre-planned interim efficacy assessment on 103 participants. RESULTS: The DMEC's interim analysis led to early trial closure. Although the response rates in both arms were higher than anticipated, FCM-miniR had a lower CR rate than FCR. This was partly attributable to the higher toxicity associated with mitoxantrone. A total of 100 participants completed FCR, 79 completed FCM-miniR and 21 commenced FCM-miniR but switched to FCR following DMEC recommendations. The CR rate for participants receiving FCR was 76%, compared with 55% for FCM-miniR (adjusted odds ratio 0.37; 95% confidence interval 0.19 to 0.73). Key secondary end points also showed that FCR was superior, with more participants achieving MRD negativity (57% for FCR vs. 46% for FCM-miniR). More participants experienced a serious adverse reaction with FCM-miniR compared with FCR (50% vs. 41%). At a median of 37.3 months' follow-up, the PFS and OS rates are good compared with previous studies, with no significant difference between the treatment arms. The economic analysis indicates that because FCM-miniR is less effective than FCR, FCM-miniR is not expected to be cost-effective over a lifetime horizon, producing a mean cost-saving of -£7723, a quality-adjusted life-year loss of -0.73 and a resulting incremental net monetary loss of -£6780. CONCLUSIONS: FCM-miniR is less well tolerated, with poorer response rates, than FCR, partly owing to the additional toxicity associated with mitoxantrone. In view of this, FCM-miniR will not be taken forward into a larger definitive Phase III trial. The trial demonstrated that oral FCR yields extremely high response rates compared with historical series with intravenous chemotherapy. FUTURE WORK: We shall compare the results of ARCTIC with those of the ADMIRE (Does the ADdition of Mitoxantrone Improve Response to FCR chemotherapy in patients with CLL?) trial, which compared FCR with FCM-R to assess the efficacy of low- versus standard-dose rituximab, allowing for the toxicity associated with mitoxantrone. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16544962. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 28. See the NIHR Journals Library website for further project information.
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Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Médula Ósea , Análisis Costo-Beneficio , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Mitoxantrona/uso terapéutico , Años de Vida Ajustados por Calidad de Vida , Rituximab/uso terapéutico , Medicina Estatal , Reino Unido , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Transfusion-dependent anemia is a common feature in a wide array of hematological disorders, including thalassemia, sickle cell disease, aplastic anemia, myelofibrosis, and myelo-dysplastic syndromes. In the absence of a physiological mechanism to excrete excess iron, chronic transfusions ultimately cause iron overload. Without correction, iron overload can lead to end-organ damage, resulting in cardiac, hepatic, and endocrine dysfunction/failure. Iron chelating agents are utilized to reduce iron overload, as they form a complex with iron, leading to its clearance. Iron chelation has been proven to decrease organ dysfunction and improve survival in certain transfusion-dependent anemias, such as ß-thalassemia. Several chelating agents have been approved by the United States Food and Drug Administration for the treatment of iron overload, including deferoxamine, deferiprone, and deferasirox. A variety of factors have to be considered when choosing an iron chelator, including dosing schedule, route of administration, tolerability, and side effect profile. Deferasirox is an orally administered iron chelator with proven efficacy and safety in multiple hematological disorders. There are two formulations of deferasirox, a tablet for suspension, and a new tablet form. This paper is intended to provide an overview of iron overload, with a focus on deferasirox, and its recently approved formulation Jadenu(®) for the reduction of transfusional iron overload in hematological disorders.
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The phase III British Society of Blood and Marrow Transplantation/United Kingdom Myeloma Forum Myeloma X trial (MMX) demonstrated prospectively, for the first time, superiority of salvage autologous stem cell transplantation over chemotherapy maintenance for multiple myeloma (MM) in first relapse after previous ASCT. However, many patients have stored insufficient stem cells (PBSC) for second ASCT and robust evidence for remobilization after first ASCT is lacking. We report the feasibility, safety, and efficacy of remobilization after bortezomib-doxorubicin-dexamethasone reinduction in MMX and outcomes of second ASCT with these cells. One hundred ten patients underwent ≥1 remobilization with 32 and 4, undergoing second and third attempts, respectively. Toxicities of remobilization were similar to those seen in first-line mobilization. After all attempts, 52% of those with insufficient previously stored PBSC had harvested a sufficient quantity to proceed to second ASCT. Median PBSC doses infused, neutrophil engraftment, and time to discharge after second ASCT were similar regardless of stem cell source, as were the toxicities of second ASCT. No significant differences between PBSC sources were noted in depth of response to ASCT or time to progression. Harvesting after bortezomib-doxorubicin-dexamethasone reinduction for MM at first relapse is safe and feasible and yields a reliable cell product for second ASCT. The study is registered with ClinicalTrials.gov (NCT00747877) and EudraCT (2006-005890-24).
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Bortezomib/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucaféresis/normas , Mieloma Múltiple/terapia , Terapia Recuperativa/métodos , Dexametasona/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Movilización de Célula Madre Hematopoyética/normas , Humanos , Quimioterapia de Mantención/métodos , Quimioterapia de Mantención/normas , Masculino , Persona de Mediana Edad , Inducción de Remisión/métodos , Trasplante Autólogo , Resultado del Tratamiento , Reino UnidoRESUMEN
BACKGROUND: Relapsed multiple myeloma has no standard treatment, and the role of autologous stem-cell transplantation (ASCT) has not been fully defined. We aimed to compare high-dose melphalan plus salvage ASCT with cyclophosphamide in patients with relapsed multiple myeloma who had previously undergone ASCT. METHODS: This multicentre, randomised, open-label, phase 3 study recruited patients aged at least 18 years with multiple myeloma who needed treatment for first progressive or relapsed disease at least 18 months after a previous ASCT from 51 centres across the UK. Before randomisation, eligible patients received bortezomib, doxorubicin, and dexamethasone (PAD) induction therapy and then underwent peripheral blood stem-cell mobilisation and harvesting if applicable. Eligible patients (with adequate stem-cell harvest) were randomly assigned (1:1), using an automated telephone randomisation line, to either high-dose melphalan 200 mg/m(2) plus salvage ASCT or oral cyclophosphamide (400mg/m(2) per week for 12 weeks). Randomisation was stratified by length of first remission or plateau and response to PAD re-induction therapy. The primary endpoint was time to disease progression, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00747877, and EudraCT, number 2006-005890-24. FINDINGS: Between April 16, 2008, and Nov 19, 2012, 297 patients were registered, of whom 293 received PAD re-induction therapy. Between Aug 26, 2008, and Nov 16, 2012, 174 patients with sufficient PBSCs were randomised to salvage ASCT (n=89) or cyclophosphamide (n=85). After a median follow-up of 31 months (IQR 19-42), median time to progression was significantly longer in the salvage ASCT than in the cyclophosphamide group (19 months [95% CI 16-25] vs 11 months [9-12]; hazard ratio 0·36 [95% CI 0·25-0·53]; p<0·0001). Frequently reported (in >10% of patients) grade 3-4 adverse events with PAD induction, salvage ASCT, and cyclophosphamide were: neutropenia (125 [43%] of 293 patients after PAD, and 63 [76%] of 83 patients in the salvage ASCT group vs 11 [13%] of 84 patients in the cyclophosphamide group), thrombocytopenia (150 [51%] after PAD, and 60 [72%] vs four [5%], respectively), and peripheral neuropathy (35 [12%] after PAD, and none vs none, respectively). INTERPRETATION: This study provides evidence for the improved efficacy of high-dose melphalan plus salvage ASCT when compared with cyclophosphamide in patients with relapsed multiple myeloma eligible for intensive therapy, which might help to guide clinical decisions regarding the management of such patients. FUNDING: Cancer Research UK.