RESUMO
Despite persistent inequities in access to care and treatments, advances in combined modality care have led to a steady improvement in outcomes for breast cancer patients across the globe. When estimating the magnitude of clinical benefit of therapies, providers and patients must contend with a multitude of factors that impact treatment decisions and can have long-term effects on quality of life and survival. These include commonly described early toxicities, like aromatase inhibitor-associated musculoskeletal syndrome and neuropathy. But longer-term comorbidities often observed among cancer survivors including weight gain, obesity, infertility, psychological distress, sexual dysfunction, second cancers, bone loss, and body image issues can have lasting effects on quality of life. Equally important, system-level factors such as access to care and resource allocation can have a systemic impact on survival and on the quality of survivorship. Financial toxicity including underemployment can have a lasting impact on patients and caregivers. The resulting disparities in access to treatment can help explain much of the observed variability in outcomes, even within high-income countries like the US. This article revisits some of secondary effects from therapies discussed in a prior 2015 review article, along with other impediments to the optimal delivery of breast cancer care that can affect patients anywhere.
Assuntos
Neoplasias da Mama/psicologia , Sobreviventes de Câncer/psicologia , Efeitos Adversos de Longa Duração/psicologia , Protocolos Antineoplásicos , Efeitos Psicossociais da Doença , Feminino , Humanos , Efeitos Adversos de Longa Duração/etiologia , Qualidade de Vida , Literatura de Revisão como AssuntoRESUMO
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer. METHODS: Women with HER2-positive, stage I through III breast cancer who initiated (neo)adjuvant HER2-targeted therapy (trastuzumab with or without pertuzumab) from January 2005 to March 2015 at the authors' institution were eligible. We analyzed differences in the incidence of cardiotoxicity (a decline in the left ventricular ejection fraction to <50% AND an absolute drop in the left ventricular ejection fraction of ≥10% from baseline) and incomplete therapy (<52 weeks of HER2-targeted therapy) between black and white women in univariate and multivariable analyses. RESULTS: The authors identified 59 black patients and 157 white patients who had a median follow-up 5.2 years. The median patient age was 53 years and was similar for black and white patients. The 1-year cardiotoxicity incidence was 12% overall (95% confidence interval [CI], 7%-16%), 24% in black women (95% CI, 12%-34%), and 7% in white women (95% CI, 3%-11%). Black patients had a significantly greater probability of incomplete therapy compared with white patients (odds ratio, 4.61; 95% CI, 1.70-13.07; P = .002). High correlation was observed between a cardiotoxicity event and incomplete therapy (96% concordance). CONCLUSIONS: Black patients have a higher rate of cardiotoxicity and resultant incomplete adjuvant HER2-targeted therapy than white patients. This patient population may benefit from enhanced cardiac surveillance, cardioprotective strategies, and early referral to cardiology when appropriate. Cancer 2018;124:1904-11. © 2018 American Cancer Society.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/terapia , Cardiotoxicidade/etnologia , Disparidades nos Níveis de Saúde , Receptor ErbB-2/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , População Negra/estatística & dados numéricos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Cardiotoxicidade/etiologia , Cardiotoxicidade/prevenção & controle , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Feminino , Seguimentos , Humanos , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Recidiva Local de Neoplasia/prevenção & controle , Estadiamento de Neoplasias , Receptor ErbB-2/imunologia , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , População Branca/estatística & dados numéricosRESUMO
BACKGROUND: Chemotherapy for early breast cancer is associated with a small risk of developing myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The aim of this study was to determine the risk of developing AML or MDS after modern adjuvant chemotherapy in older breast cancer patients and to further define the risk of individual chemotherapy regimens. METHODS: Patients diagnosed with stage I to III breast cancer from 2003 to 2009 were identified in the Surveillance, Epidemiology, and End Results-Medicare and Texas Cancer Registry-Medicare linked databases. The development of AML/MDS, chemotherapy use, and comorbidities were identified with International Classification of Diseases, Ninth Revision and Healthcare Common Procedure Coding System codes. Analyses included descriptive statistics, cumulative incidences, and Cox proportional hazards models to estimate the hazard of AML/MDS after adjustments for clinically relevant covariates. RESULTS: In all, 92,110 patients were included; after a median follow-up of 85 months, the overall rates per 1000 person-years were 0.65 for AML and 1.56 for MDS. Patients who received an anthracycline (A) or anthracycline and taxane (A+T) regimen were more likely to develop AML (hazard ratio [HR] for A, 1.70; 95% confidence interval [CI], 1.16-2.50; HR for A+T, 1.68; 95% CI, 1.22-2.30) or MDS (HR for A, 2.18; 95% CI, 1.70-2.80; HR for A+T, 1.62; 95% CI, 1.29-2.03) than patients who did not receive chemotherapy. Patients using docetaxel and cyclophosphamide (TC) were not at increased risk for AML or MDS. CONCLUSIONS: Adjuvant chemotherapy is associated with a small but significant increase in the risk of AML and MDS, especially with regimens that include A. Longer follow-up is needed to confirm that risk is not increased with the recently adopted TC regimen. Cancer 2018;124:899-906. © 2017 American Cancer Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Leucemia Mieloide/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Doença Aguda , Idoso , Antraciclinas/administração & dosagem , Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Ciclofosfamida/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Humanos , Leucemia Mieloide/induzido quimicamente , Medicare/estatística & dados numéricos , Síndromes Mielodisplásicas/induzido quimicamente , Estadiamento de Neoplasias , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Programa de SEER/estatística & dados numéricos , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Texas , Estados UnidosRESUMO
PURPOSE: To estimate the association between cancer survivors' comorbid condition care quality and costs; to determine whether the association differs between cancer survivors and other patients. METHODS: Using the SEER-Medicare-linked database, we identified survivors of breast, prostate, and colorectal cancers who were diagnosed in 2004, enrolled in Medicare fee-for-service for at least 12 months before diagnosis, and survived ≥ 3 years. Quality of care was assessed using nine process indicators for chronic conditions, and a composite indicator representing seven avoidable outcomes. Total costs on the basis of Medicare amount paid were grouped as inpatient and outpatient. We examined the association between care quality and costs for cancer survivors, and compared this association among 2:1 frequency-matched noncancer controls, using comparisons of means and generalized linear regressions. RESULTS: Our sample included 8,661 cancer survivors and 17,332 matched noncancer controls. Receipt of recommended care was associated with higher outpatient costs for eight indicators, and higher inpatient and total costs for five indicators. For three measures (visit every 6 months for patients with chronic obstructive pulmonary disease or diabetes, and glycosylated hemoglobin or fructosamine every 6 months for patients with diabetes), costs for cancer survivors who received recommended care increased less than for noncancer controls. The absence of avoidable events was associated with lower costs of each type. An annual eye examination for patients with diabetes was associated with lower inpatient costs. CONCLUSION: Higher-quality processes of care may not reduce short-term costs, but the prevention of avoidable outcomes reduces costs. The association between quality and cost was similar for cancer survivors and noncancer controls.
Assuntos
Neoplasias da Mama/economia , Neoplasias Colorretais/economia , Neoplasias da Próstata/economia , Qualidade da Assistência à Saúde/economia , Sobreviventes , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias Colorretais/epidemiologia , Comorbidade , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino , Medicare , Neoplasias da Próstata/epidemiologia , Programa de SEER , Estados UnidosRESUMO
Breast cancer is the second leading cause of cancer death among US women, and the chance of a woman developing breast cancer sometime during her lifetime is one in eight. Early detection and diagnosis to allow appropriate locoregional and systemic treatment are key to improve the odds of surviving its diagnosis. Emerging data also suggest that different breast cancer subtypes (phenotypes) may respond differently to available adjuvant therapies. There is a growing understanding that not all patients benefit equally from systemic therapies, and therapeutic approaches are being increasingly personalized based on predictive biomarkers of clinical benefit. Optimal use of established and novel radiological imaging methods, such as magnetic resonance imaging and positron emission tomography, which have different biophysical mechanisms can simultaneously identify key functional parameters. These methods provide unique multiparametric radiological signatures of breast cancer, that will improve the accuracy of early diagnosis, help select appropriate therapies for early stage disease, and allow early assessment of therapeutic benefit.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Detecção Precoce de Câncer/métodos , Imagem Multimodal/métodos , Avaliação de Resultados em Cuidados de Saúde/métodos , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Tomografia por Emissão de Pósitrons/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores de Tempo , Tomografia Computadorizada por Raios X/métodosRESUMO
Studies have suggested a decreased breast cancer risk in women with systemic lupus erythematosus. However, these studies enrolled younger patients identified primarily from lupus clinics. We compared the 5-year incidence of breast cancer among women with and without a diagnosis of SLE in a large population-based study of Medicare beneficiaries. We used a 20 % sample to create a cohort of 3,670,138 women from 2006 Medicare claims data with and without SLE at baseline. The study had 80 % power to detect whether the 5-year breast cancer incidence in the SLE cohort was 13 % higher or lower than the non-SLE cohort. Of the 18,423 women with SLE, 21 % were African American and 53 % were ≥65 years. The absolute age-adjusted risk for breast cancer in women with SLE was 2.23 (95 % CI 1.94-2.55) and 2.14 (95 % CI 1.96-2.34) in controls per 100 women. The overall absolute age and race adjusted incidence rate was 1.04 (95 % CI 0.90-1.21). Among women with SLE from "Others" (Hispanic, Native American, and/or Asian), the age-adjusted risk for breast cancer was 2.44 per 100 women (95 % CI 1.07-2.18), and age-adjusted incidence rate was 1.52 (95 % CI 1.07-2.18). In contrast to prior clinic-based studies, this population-based cohort study showed that the risk of breast cancer in women with SLE was not lower than in women without SLE. Women with SLE should follow routine breast cancer screening recommendations for their age group to avoid delay in diagnosis, because the presence of SLE may affect selection of early breast cancer therapies.
Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Lúpus Eritematoso Sistêmico/complicações , Medicare , Vigilância em Saúde Pública , Feminino , Humanos , Incidência , Razão de Chances , Risco , Estados Unidos/epidemiologia , Estados Unidos/etnologiaRESUMO
PURPOSE: Cancer survivors frequently receive care from a large number of physicians, creating challenges for coordination. We sought to explore whether cancer survivors whose providers have more patients in common (e.g., shared patients) tend to have higher quality and lower cost care. METHODS: We performed a retrospective cohort study of 8,661 patients diagnosed with loco-regional breast, prostate, or colorectal cancer. We examined survivorship care from days 366 to 1,095 following their cancer diagnosis. Our primary independent variable was "care density," a novel metric of the extent to which a patient's providers share patients with one another. Our outcome measures were health care utilization, quality metrics, and costs. RESULTS: In adjusted analyses, we found that patients with high care density--indicating high levels of patient-sharing among their providers--had significantly lower rates of hospitalization (OR 0.87, 95% CI 0.75-1.00) and higher odds of an eye examination for diabetes (OR 1.31, 95% CI 1.03-1.66) compared to patients with low care density. High care density was not associated with emergency department visits, avoidable outcomes, lipid profile following an angina diagnosis, or odds of glycosylated hemoglobin testing for diabetes. Patients with high care density had significantly lower total costs of care over 24 months (beta coefficient -$2,116, 95% CI -$3,107 to -$1,125) along with lower inpatient and outpatient costs. CONCLUSION: Cancer survivors treated by physicians who share more patients with one another tend to have some higher aspects of quality and lower cost care. IMPLICATIONS OF CANCER SURVIVORS: If validated, care density may be a useful indicator for monitoring care coordination among cancer survivors and potentially targeting interventions that seek to improve care delivery.
Assuntos
Custos de Cuidados de Saúde , Neoplasias/terapia , Qualidade da Assistência à Saúde , Sobreviventes , Estudos de Coortes , Humanos , Neoplasias/mortalidade , Estudos RetrospectivosRESUMO
BACKGROUND: The PatientViewpoint website collects patient-reported outcomes and links them with the electronic health record to aid patient management. This pilot test evaluated PatientViewpoint's use, usefulness, and acceptability to patients and clinicians. METHODS: This was a single-arm prospective study that enrolled breast and prostate cancer patients undergoing treatment and the clinicians who managed them. Patients completed patient-reported outcomes every 2 weeks, and clinicians could access the results for patient visits. Scores that were poor relative to norms or substantially worse than the previous assessment were highlighted. After three on-study visits, we assessed patient and clinician perspectives on PatientViewpoint using close-ended and open-ended questions. RESULTS: Eleven out of 12 eligible clinicians (92%) and 52/76 eligible patients (68%) enrolled. Patients completed a median of 71% of assigned questionnaires; clinicians reported using the information for 79% of patients, most commonly as a source of additional information (51%). At the median, score reports identified three potential issues, of which 1 was discussed during the visit. Patients reported the system was easy to use (92%), useful (70%), aided recall of symptoms/side effects (72%), helped them feel more in control of their care (60%), improved discussions with their provider (49%), and improved care quality (39%). Patients and clinicians desired more information on score interpretation and minor adjustments to site navigation. CONCLUSIONS: These results support the feasibility and value of PatientViewpoint. An ongoing study is using a continuous quality improvement approach to further refine PatientViewpoint. Future studies will evaluate its impact on patient care and outcomes.
Assuntos
Neoplasias da Mama/terapia , Internet , Avaliação de Resultados em Cuidados de Saúde/métodos , Participação do Paciente , Satisfação do Paciente , Neoplasias da Próstata/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude do Pessoal de Saúde , Neoplasias da Mama/psicologia , Estudos de Viabilidade , Feminino , Humanos , Masculino , Registro Médico Coordenado , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Assistência Centrada no Paciente , Relações Médico-Paciente , Médicos , Estudos Prospectivos , Neoplasias da Próstata/psicologia , Inquéritos e QuestionáriosRESUMO
PURPOSE: A barrier to using HRQOL questionnaires for individual patient management is knowing what score represents a problem deserving attention. We explored using needs assessments to identify HRQOL scores associated with patient-reported unmet needs. METHODS: This cross-sectional study included 117 cancer patients (mean age 61 years; 51% men; 77% white) who completed the Supportive Care Needs Survey (SCNS) and EORTC QLQ-C30. SCNS scores were dichotomized as "no unmet need" versus "some unmet need" and served as an external criterion for identifying problem scores. We evaluated the discriminative ability of QLQ-C30 scores using receiver operating characteristic (ROC) analysis. Domains with an area under the ROC curve (AUC) >or= .70 were examined further to determine how well QLQ-C30 scores predicted presence/absence of unmet need. RESULTS: We found AUCs >or= .70 for 6 of 14 EORTC domains: physical, emotional, role, global QOL, pain, fatigue. All 6 domains had sensitivity >or= .85 and specificity >or= .50. EORTC domains that closely matched the content of SCNS item(s) were more likely to have AUCs >or= .70. The appropriate cut-off depends on the relative importance of false positives and false negatives. CONCLUSIONS: Needs assessments can identify HRQOL scores requiring clinicians' attention. Future research should confirm these findings using other HRQOL questionnaires and needs assessments.
Assuntos
Necessidades e Demandas de Serviços de Saúde , Neoplasias/psicologia , Qualidade de Vida , Inquéritos e Questionários/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Apoio SocialRESUMO
PURPOSE: Although patients' function, symptoms, and supportive care needs are obviously related, a better understanding of these relationships could improve patient management. METHODS: In this cross-sectional, observational study, 117 cancer patients completed the Supportive Care Needs Survey-34 and EORTC-QLQ-C30. Each symptom and function domain from the EORTC-QLQ-C30 was dichotomized (high vs. low) using a cut-off of reference sample mean scores. Each need domain was dichotomized using a cut-off of an average score representing an unmet need. We explored within-patient patterns of function, symptom, and need domains using latent class analysis. Based on these patterns, patients were categorized as high versus low function; high versus low symptom; and high versus low need. We examined the concordance between categorizations of patients' function, symptoms, and needs. RESULTS: The categorizations of function, symptoms, and needs were concordant for 66 patients (56%). Among patients with deficits in at least one area (n = 68), categorizations for 51 patients (75%) were discordant. CONCLUSIONS: About 50% of patients have similar classifications of their level of function, symptoms, and needs, but discordance was common among patients with deficits in at least one area, emphasizing the importance of assessing all of these outcomes as part of patient evaluations.
Assuntos
Necessidades e Demandas de Serviços de Saúde , Neoplasias , Qualidade de Vida , Apoio Social , Adaptação Psicológica , Estudos Transversais , Feminino , Acessibilidade aos Serviços de Saúde , Indicadores Básicos de Saúde , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Estresse Psicológico , Inquéritos e QuestionáriosRESUMO
AIMS: To explore the associations among symptoms, supportive care needs, and function. METHODS: One hundred and seventeen cancer patients completed the Supportive Care Needs Survey and EORTC-QLQ-C30 in a cross-sectional study. Associations among function (physical, role, emotional, cognitive, social), symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea), and supportive care needs (physical and daily living, psychological, patient care and support, health system and information, sexual) were tested using multivariate item regression (MIR). We tested (1) function as the dependent variable with symptoms and supportive care needs as independent variables and (2) supportive care needs as the dependent variable with symptoms and function as independent variables. RESULTS: Worse fatigue, pain, and appetite loss were associated with worse function. Greater unmet physical and daily living needs were associated with worse physical, role, and cognitive function. Greater unmet psychological needs were associated with worse emotional and cognitive function. Worse sleep problems were associated with greater unmet needs. Better physical function was associated with fewer unmet physical and daily living needs, and better emotional function was associated with fewer unmet psychological, patient care and support, and health system and information needs. CONCLUSIONS: The results obtained with these models suggest several consistent relationships among symptoms, supportive care needs, and function.
Assuntos
Necessidades e Demandas de Serviços de Saúde , Neoplasias/fisiopatologia , Apoio Social , Atividades Cotidianas , Idoso , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
GOALS OF WORK: Questionnaires used in oncology practice for individual patient management need to address issues patients find important and want help with and issues cancer center health professionals can address. We investigated the item content from two health-related quality-of-life (HRQOL) questionnaires and two needs assessments for this purpose. PATIENTS AND METHODS: In this preliminary study, 61 cancer patients and 19 cancer center health professionals rated the item content from the EORTC-QLQ-C30, FACT-G, Supportive Care Needs Survey-34 (SCNS), and Kingston Needs Assessment--Cancer. Patients rated each item's importance and whether they wanted help with it; health professionals rated each item's importance and whether they felt able to help patients address it. Patients and health professionals also reported their overall questionnaire preference. MAIN RESULTS: Patients rated information about treatments (options, benefits, side effects) and care coordination as the most important issues and those for which they most wanted help from their health professionals. Health professionals rated pain and other symptom/side effect items as most important to patients and those for which they were most able to help. Findings were consistent across tumor type and treatment status. Patients had an overall preference for the SCNS. Health professionals had no clear questionnaire preference. CONCLUSIONS: This preliminary study suggests that the issues patients most want help with may not be the issues that health professionals feel most able to address. If these findings are confirmed in more representative samples, interventions may be needed to assist health professionals in managing cancer patients' HRQOL issues and needs.
Assuntos
Avaliação das Necessidades , Neoplasias , Qualidade de Vida , Inquéritos e Questionários , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude do Pessoal de Saúde , Atitude Frente a Saúde , Estudos Transversais , Feminino , Necessidades e Demandas de Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Projetos PilotoRESUMO
PURPOSE: To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. RECOMMENDATIONS: Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. CONCLUSION: The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.
Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia , Pós-Menopausa , Idoso , Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Fatores de RiscoRESUMO
Dimethyl benzoylphenyl urea (BPU), a poorly water-soluble benzoylphenyl urea derivative, inhibits tubulin polymerization and causes microtubule depolymerization in vitro with activity against solid tumors. BPU is currently being tested in Phase I clinical trials. A rapid, sensitive and specific method using LC/MS/MS has been developed for the quantitation of BPU in human plasma to perform pharmacokinetic (PK) and pharmacodynamic (PD) studies of BPU administered orally once a week. BPU is extracted from plasma into acetonitrile-n-butylchloride and separated on a Waters X-Terra MS C18 (50 x 2.1 mm, 3.5 microm) column with acetonitrile/water mobile phase (80:20, v/v) containing 0.1% formic acid using isocratic flow at 0.15 ml/min for 5 min. The analyte of interest was monitored by tandem-mass spectrometry with electrospray positive ionization with a cone voltage 15 V for BPU and 30 V for the internal standard, paclitaxel. The detector settings allowed the monitoring of the [MH](+) ion of BPU (m/z 470.3) and the [MH](+) of internal standard paclitaxel (m/z 854.5), with subsequent monitoring of the product ions of BPU (m/z 148.0) and paclitaxel (m/z 286.1). Calibration curves were generated over the range of 0.05-10 ng/ml with values for coefficient of determination of >0.99. The values for precision and accuracy were <20 and < or =15%, respectively. Following administration of BPU 5 mg as a weekly oral dose to a patient with advanced solid tumor malignancies, the maximum plasma concentration was 6.5 ng/ml and concentrations were quantifiable up to 173 h after administration. The lower limit of quantitation (LLOQ) of 0.05 ng/ml allows for successful measurement of plasma concentrations in patients receiving therapy with BPU as a once weekly oral dose.