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BACKGROUND AND PURPOSE: Treatment persistence is the continuation of therapy over time. It reflects a combination of treatment efficacy and tolerability. We aimed to describe real-world rates of persistence on disease-modifying therapies (DMTs) for people with multiple sclerosis (pwMS) and reasons for DMT discontinuation. METHODS: Treatment data on 4366 consecutive people with relapse-onset multiple sclerosis (MS) were pooled from 13 UK specialist centres during 2021. Inclusion criteria were exposure to at least one MS DMT and a complete history of DMT prescribing. PwMS in blinded clinical trials were excluded. Data collected included sex, age at MS onset, age at DMT initiation, DMT treatment dates, and reasons for stopping or switching DMT. For pwMS who had received immune reconstituting therapies (cladribine/alemtuzumab), discontinuation date was defined as starting an alternative DMT. Kaplan-Meier survival analyses were used to express DMT persistence. RESULTS: In 6997 treatment events (1.6 per person with MS), median time spent on any single maintenance DMT was 4.3 years (95% confidence interval = 4.1-4.5 years). The commonest overall reasons for DMT discontinuation were adverse events (35.0%) and lack of efficacy (30.3%). After 10 years, 20% of people treated with alemtuzumab had received another subsequent DMT, compared to 82% of people treated with interferon or glatiramer acetate. CONCLUSIONS: Immune reconstituting DMTs may have the highest potential to offer a single treatment for relapsing MS. Comparative data on DMT persistence and reasons for discontinuation are valuable to inform treatment decisions and in personalizing treatment in MS.
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Esclerose Múltipla Recidivante-Remitente , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Fatores Imunológicos/uso terapêuticoRESUMO
BACKGROUND: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2. METHODS: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974. FINDINGS: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037). INTERPRETATION: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality. FUNDING: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust.
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COVID-19 , Neoplasias , Humanos , Feminino , Masculino , SARS-CoV-2 , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/prevenção & controle , Teste para COVID-19 , Neoplasias/epidemiologia , Neoplasias/terapia , Progressão da DoençaAssuntos
COVID-19 , Vacinas , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Reino Unido/epidemiologia , VacinaçãoRESUMO
To ensure that patients receive timely access to care, it has become increasingly important to use existing care provider capacity as efficiently as possible and to make informed capacity planning decisions. To support this decision-making process at a regional cancer center in British Columbia (Canada), we undertook a simulation and optimization based study that investigated the simultaneous impact of the available number of new patient consultation slots, appointment scheduling policies and oncologist specialization configurations on the timeliness of patient access to care and physician workload. The key contribution of this paper is the methodological framework it provides to decision makers who manage specialty clinics to ensure that they are using their resources efficiently and making informed strategic short- and mid-term capacity planning decisions for new patient demand.
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Agendamento de Consultas , Institutos de Câncer/organização & administração , Simulação por Computador , Oncologistas/organização & administração , Colúmbia Britânica , Tomada de Decisões , Eficiência Organizacional , Humanos , Encaminhamento e Consulta/organização & administração , Fatores de Tempo , Listas de EsperaRESUMO
AIMS: Fluoropyrimidine chemotherapy is important for treatment of many solid tumours but is associated with cardiotoxicity. The relationship of fluoropyrimidine-associated cardiotoxicity (FAC) with conventional cardiovascular (CV) risk factors is poorly understood, and standard cardiovascular risk scores are not validated in this context. METHODS AND RESULTS: Single-centre retrospective study of patients treated with fluoropyrimidine chemotherapy using electronic health records for cardiovascular risk factors (and calculation of QRISK3 score), cancer treatment, and clinical outcomes. FAC was defined by cardiovascular events during or within 3 months of fluoropyrimidine treatment, and Cox regression was used to assess associations of CV risk and cancer treatment with FAC. One thousand eight hundred ninety-eight patients were included (45% male; median age 64 years), with median follow up 24.5 (11.5-48.3 months); 52.7% of patients were at moderate or high baseline CV risk (QRISK3 score >10%) Cardiovascular events occurred in 3.1% (59/1898)-most commonly angina (64.4%, 38/59) and atrial fibrillation (13.6%, 8/59), with 39% events during cycle one of treatment. In univariable analysis, QRISK3 score >20% was significantly associated with incident FAC (HR 2.25, 95% CI 1.11-4.93, P = 0.03). On multivariable analysis, beta-blocker use (HR 1.04, 95% CI 1.00-1.08, P = 0.04) and higher BMI (HR 2.33, 95% CI 1.04-5.19, P = 0.04) were independently associated with incident CV events. Thirty-two of the 59 patients with FAC were subsequently rechallenged with fluoropyrimidine chemotherapy, with repeat CV events in 6% (2/32). Incident FAC did not affect overall survival (P = 0.50). CONCLUSIONS: High BMI and use of beta-blockers are associated with risk of CV events during fluoropyrimidine chemotherapy. QRISK3 score may also play a role in identifying patients at high risk of CV events during fluoropyrimidine chemotherapy. Re-challenge with further fluoropyrimidine chemotherapy can be considered in patients following CV events during prior treatment.
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Multi-criteria decision analysis (MCDA) is a value assessment tool designed to help support complex decision-making by incorporating multiple factors and perspectives in a transparent, structured approach. We developed an MCDA rating tool, consisting of seven criteria evaluating the importance and feasibility of conducting potential real-world evidence (RWE) studies aimed at addressing uncertainties stemming from initial cancer drug funding recommendations. In collaboration with the Canadian Agency for Drugs and Technologies in Health's Provincial Advisory Group, a validation exercise was conducted to further evaluate the application of the rating tool using RWE proposals varying in complexity. Through this exercise, we aimed to gain insight into consensus building and deliberation processes and to identify efficiencies in the application of the rating tool. An experienced facilitator led a multidisciplinary committee, consisting of 11 Canadian experts, through consensus building, deliberation, and prioritization. A total of nine RWE proposals were evaluated and prioritized as low (n = 4), medium (n = 3), or high (n = 2) priority. Through an iterative process, efficiencies and recommendations to improve the rating tool and associated procedures were identified. The refined MCDA rating tool can help decision-makers prioritize important and feasible RWE studies for research and can enable the use of RWE for the life-cycle evaluation of cancer drugs.
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Antineoplásicos , Técnicas de Apoio para a Decisão , Humanos , Canadá , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Avaliação da Tecnologia Biomédica/métodos , ConsensoRESUMO
Background: To report on the implementation and outcomes of a virtual ward established for the management of mpox during the 2022 outbreak, we conducted a 2-center, observational, cross-sectional study over a 3-month period. Methods: All patients aged ≥17 years with laboratory polymerase chain reaction-confirmed monkeypox virus managed between 14 May and 15 August 2022, at the Hospital for Tropical Diseases at University College London Hospitals National Health Service (NHS) Foundation Trust and sexual health services at Central North and West London NHS Foundation Trust, were included. Main outcomes included the proportion of patients managed exclusively on the virtual ward, proportion of patients requiring inpatient admission, proportion of patients with human immunodeficiency virus, and duration of lesion reepithelialization. Results: Among confirmed cases (N = 221), 86% (191/221) were managed exclusively on the virtual ward, while 14% (30/221) required admission. Treatment for concomitant sexually transmitted infections was provided to 25% (55/221) of patients, antibiotics for other infective complications to 16% (35/221), and symptomatic relief to 27% (60/221). The median time from onset to complete lesion reepithelialization and de-isolation was 18 days (range, 8-56 days). Eleven percent (24/221) of individuals disengaged from services within 4 days of testing. Conclusions: The virtual ward model facilitated safe and holistic outpatient management of mpox, while minimizing admissions. This approach could serve as a model for future outbreak responses.
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Do children tend to trust same-sex adults when learning new information? A sample of 325 4- to 7-year-olds completed two tasks. The testimony task pitted previous reliability against the sex of the informant. Children first viewed clips of a man and a woman naming familiar objects (neutral, feminine, or masculine) to establish prior accuracy. They then decided (a) whom to ask for help in naming novel objects, (b) whose label to choose, and (c) who was better at answering questions. Children also completed measures of personal sex typing and stereotyped attitudes toward others. For all testimony measures, children responded based on prior accuracy when only one adult (same sex or other sex) was reliable. They were above chance in favoring the same-sex informant when both adults were equally reliable/unreliable for ask and choice questions. The more sex-typed girls were, the more likely they were to favor the female informant's testimony even when she was unreliable or equally reliable. There were no correlations for boys. Object type in the learning context had no effect. Overall, children have a subtle but significant preference to learn new information from a same-sex adult when both adults are equally reliable/unreliable. Findings are discussed in terms of in-group favoritism.
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Confiança/psicologia , Adulto , Atitude , Criança , Pré-Escolar , Feminino , Humanos , Individualidade , Julgamento , Masculino , Fatores Sexuais , Sexismo/psicologiaRESUMO
The availability of low-cost biometric hardware sensors and software makes it possible to rapidly, affordably and securely sample and store a unique and invariant biological signature (or biometric "template") for the purposes of identification. This has applications in research and trials, particularly for purposes of consent, linkage of case reporting forms collected at different times, and in the confirmation of participant identity for purposes of safety monitoring and adherence to international data laws. More broadly, these methods are applicable to the needs of the billion people who live in resource-restricted settings without identification credentials. The use of mobile electronic data collection software has recently become commonplace in clinical trials, research and actions for public good. A raft of tools based on the open-source ODK project now provide diverse options for data management that work consistently in resource-restricted settings, but none have built-in functionality for capturing biometric templates. In this study, we report the development and validation of a novel open-source app and associated method for capturing and matching biometric fingerprint templates during data collection with the popular data platforms ODK, KoBoToolbox, SurveyCTO, Ona and CommCare. Using data from more than 1,000 fingers, we show that fingerprint templates can be used to link data records with high accuracy. The accuracy of this process increases through the linkage of multiple fingerprints to each data record. By focussing on publishing open-source code and documentation, and by using an affordable (<£50) and mass-produced model of fingerprint sensor, we are able to make this platform freely available to the large global user community that utilises ODK and related data collection systems.
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The Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration developed an MCDA rating tool to assess and prioritize potential post-market real-world evidence (RWE) questions/uncertainties emerging from public drug funding decisions in Canada. In collaboration with a group of multidisciplinary stakeholders from across Canada, the rating tool was developed following a three-step process: (1) selection of criteria to assess the importance and feasibility of an RWE question; (2) development of rating scales, application of weights and calculating aggregate scores; and (3) validation testing. An initial MCDA rating tool was developed, composed of seven criteria, divided into two groups. Group A criteria assess the importance of an RWE question by examining the (1) drug's perceived clinical benefit, (2) magnitude of uncertainty identified, and (3) relevance of the uncertainty to decision-makers. Group B criteria assess the feasibility of conducting an RWE analysis including the (1) feasibility of identifying a comparator, (2) ability to identify cases, (3) availability of comprehensive data, and (4) availability of necessary expertise and methodology. Future directions include partnering with the Canadian Agency for Drugs and Technology in Health's Provincial Advisory Group for further tool refinement and to gain insight into incorporating the tool into drug funding deliberations.
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Técnicas de Apoio para a Decisão , Neoplasias , Humanos , Canadá , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Although SARS-CoV-2 vaccines immunogenicity in patients with cancer has been investigated, whether they can significantly improve the severity of COVID-19 in this specific population is undefined. METHODS: Capitalizing on OnCovid (NCT04393974) registry data we reported COVID-19 mortality and proxies of COVID-19 morbidity, including post-COVID-19 outcomes, according to the vaccination status of the included patients. RESULTS: 2090 eligible patients diagnosed with COVID-19 between 02/2020 and 11/2021 were included, of whom 1930 (92.3%) unvaccinated, 91 (4.4%) fully vaccinated and 69 (3.3%) partially vaccinated. With the exception of a higher prevalence of patients from the UK (p = 0.0003) and receiving systemic anticancer therapy at COVID-19 diagnosis (p = 0.0082) among fully vaccinated patients, no demographics/oncological features were associated with vaccination status. The 14-days case fatality rate (CFR) (5.5% vs 20.7%, p = 0.0004) and the 28-days CFR (13.2% vs 27.4%, p = 0.0028) demonstrated a significant improvement for fully vaccinated patients in comparison with unvaccinated patients. The receipt of prior full vaccination was also associated with reduced symptomatic COVID-19 (79.1% vs 88.5%, p = 0.0070), need of COVID-19 oriented therapy (34.9% vs 63.2%, p < 0.0001), complications from COVID-19 (28.6% vs 39.4%, p = 0.0379), hospitalizations due to COVID-19 (42.2% vs 52.5%, p = 0.0007) and oxygen therapy requirement (35.7% vs 52%, p = 0.0036). Following Inverse Probability Treatment Weighting (IPTW) procedure no statistically significant difference according to the vaccination status was confirmed; however, all COVID-19 related outcomes were concordantly in favour of full vaccination. Among the 1228 (58.8%) patients who underwent a formal reassessment at participating centres after COVID-19 resolution, fully vaccinated patients experienced less sequelae than unvaccinated patients (6.7% vs 17.2%, p = 0.0320). CONCLUSIONS: This analysis provides initial evidence in support of the beneficial effect of SARS-CoV-2 vaccines against morbidity and mortality from COVID-19 in patients with cancer.
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COVID-19 , Neoplasias , COVID-19/epidemiologia , COVID-19/prevenção & controle , Teste para COVID-19 , Vacinas contra COVID-19 , Humanos , Morbidade , Neoplasias/complicações , Neoplasias/terapia , SARS-CoV-2 , VacinaçãoRESUMO
The CanREValue Collaboration established the Reassessment & Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework.
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Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Canadá , Exercício Físico , Humanos , Neoplasias/tratamento farmacológico , Avaliação da Tecnologia BiomédicaRESUMO
OBJECTIVE: Our objective was to describe the characteristics of patients admitted, discharged and readmitted, due to COVID-19, to a central London acute-care hospital during the second peak, in particular in relation to corticosteroids use. METHODS: We reviewed patients admitted from the community to University College Hospital (UCH) with COVID-19 as their primary diagnosis between 1st-31st December 2020. Re-attendance and readmission data were collected for patients who re-presented within 10 days following discharge. Data were retrospectively collected. RESULTS: 196 patients were admitted from the community with a diagnosis of COVID-19 and discharged alive in December 2020. Corticosteroids were prescribed in hospital for a median of 5 days (IQR 3-8). 20 patients (10.2%) were readmitted within 10 days. 11/20 received corticosteroids in the first admission of which 10 had received 1-3 days of corticosteroids. Readmission rate in those receiving 1-3 days of corticosteroids was 25%. CONCLUSIONS: Most international guidelines have recommended providing up to 10 days of corticosteroids for severe COVID-19 but stopping on discharge. Our findings show shorter courses of corticosteroids during admission are associated with an increased risk of being readmitted and support continuing the course of corticosteroids after hospital discharge monitored in the virtual ward setting.
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COVID-19 , Readmissão do Paciente , Corticosteroides/uso terapêutico , Humanos , Londres/epidemiologia , Alta do Paciente , Estudos Retrospectivos , SARS-CoV-2 , Estados UnidosRESUMO
Two studies (N = 456) compared the development of concepts of animal species and human gender, using a switched-at-birth reasoning task. Younger children (5- and 6-year-olds) treated animal species and human gender as equivalent; they made similar levels of category-based inferences and endorsed similar explanations for development in these 2 domains. In contrast, 10-year-olds and adults treated gender and species concepts as distinct from one another. They viewed gender-linked behavioral properties as open to environmental influence and endorsed environment-based mechanisms to explain gender development. At all ages, children demonstrated differentiated reasoning about physical and behavioral properties, although this differentiation became more stable with age. The role of psychological essentialism in guiding conceptual development is discussed.
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Desenvolvimento Infantil , Cognição , Formação de Conceito , Identidade de Gênero , Adulto , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Terminologia como AssuntoRESUMO
Glucagon-like peptide (GLP)-2 stimulates intestinal epithelial proliferation by acting, in part, via IGF release from sub-epithelial myofibroblasts. The response of myofibroblasts to GLP-2 remains incompletely understood. We studied the action of GLP-2 on myofibroblasts from colon cancer and adjacent tissue, and the effects of conditioned medium from these cells on epithelial cell proliferation, migration and invasion. GLP-2 stimulated proliferation, migration and invasion of myofibroblasts and the proliferative and invasive responses of cancer-associated myofibroblasts were greater than those of myofibroblasts from adjacent tissue. The responses were inhibited by an IGF receptor inhibitor, AG1024. Conditioned medium from GLP-2 treated myofibroblasts increased proliferation, migration and invasion of SW480, HT29, LoVo epithelial cells and these responses were inhibited by AG1024; GLP-2 alone had no effect on these cells. In addition, when myofibroblasts and epithelial cells were co-cultured in Ibidi chambers there was mutual stimulation of migration in response to GLP-2. The latter increased both IGF-1 and IGF-2 transcript abundance in myofibroblasts. Moreover, a number of IGF binding proteins (IGFBP-4, -5, -7) were identified in myofibroblast medium; in the presence of GLP-2 there was increased abundance of the cleavage products of IGBBP-4 and IGFBP-5 suggesting activation of a degradation mechanism that might increase IGF bioavailability. The data suggest that GLP-2 stimulates cancer myofibroblast proliferation, migration and invasion; GLP-2 acts indirectly on epithelial cells partly via increased IGF expression in myofibroblasts and partly, perhaps, by increased bioavailability through degradation of IGFBPs.
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Movimento Celular , Neoplasias do Colo/patologia , Peptídeo 2 Semelhante ao Glucagon/fisiologia , Mucosa Intestinal/patologia , Miofibroblastos/patologia , Idoso de 80 Anos ou mais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Neoplasias do Colo/metabolismo , Meios de Cultivo Condicionados/farmacologia , Células Epiteliais/efeitos dos fármacos , Feminino , Peptídeo 2 Semelhante ao Glucagon/farmacologia , Células HT29 , Humanos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Miofibroblastos/efeitos dos fármacos , Invasividade Neoplásica , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/metabolismo , Receptor IGF Tipo 2/antagonistas & inibidores , Receptor IGF Tipo 2/metabolismo , Células Tumorais Cultivadas , Tirfostinas/farmacologiaRESUMO
Background: Small bowel adenocarcinoma (SBA) is associated with a poor prognosis. It is an uncommon malignancy and therefore difficult to study. Randomized phase III trials are not available to guide best approaches. The Provincial Cancer Registry of the British Columbia Cancer Agency contains long-term data on patients with SBA. The authors analyzed characteristics and treatment outcomes for SBA patients diagnosed between 1990 and 2008. Material and methods: Charts of 150 patients with a histological diagnosis of SBA were retrospectively analyzed. Epidemiological and treatment data were collected. Disease-free survival (DFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Baseline characteristics, such as median age at diagnosis (64.5 years), tumor stage (I-II 33%, III-IV 58%, unknown 9%), and location (duodenum 48%, jejunum 31%, ileum 21%) were consistent with published data. 55% of patients had a positive family history of cancer. DFS and OS of 29 patients treated with adjuvant chemotherapy were not significantly different to that of 47 patients without (p = 1 and p = 0.211, respectively). In the palliative setting patients treated with polychemotherapy (21 patients) had statistically better OS than patients treated with monochemotherapy (12 patients) (p = 0.0228). Conclusions: Our study suggests a survival benefit for advanced-stage SBA patients treated with poly- versus monochemotherapy. This, however, was a retrospective analysis with several potential confounders. Nevertheless, our study adds to the evidence suggesting that chemotherapy may be beneficial for patients with SBA, at least in the palliative setting.
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Non-Hodgkin's lymphoma (NHL) remains an important complication of associated HIV infection despite advances in antiretroviral therapy (ART), and the optimum chemotherapy regimen for this disease remains to be defined. A dose-escalation trial was performed to determine the maximum tolerated doses of etoposide and doxorubicin as part of the 12-week VACOP-B regimen, supported by filgrastim (r-metHuG-CSF). Patients with aggressive histology HIV-related NHL who were previously untreated with chemotherapy, and who had no active opportunistic infection were eligible for the study. Chemotherapy consisted of cyclophosphamide 350 mg/m2, vincristine 2 mg, bleomycin 10 U/m2; and prednisone 100 mg q2 days x 12 weeks, with increasing doses of doxorubicin 25-50 mg/m2 and etoposide 25-50 mg/m2 intravenously and 50-100 mg/m2 orally. Central nervous system prophylaxis (intrathecal cytarabine 50 mg x 4 doses), antifungal, and Pneumocystis carinii prophylaxis were used, and filgrastim was administered to prevent neutropenic complications. One dose level was expanded to permit the concomitant use of ART. Endpoints were determination of maximum tolerated dose of doxorubicin and etoposide, treatment tolerability, and survival. Forty-seven patients were enrolled, most with diffuse large-cell or immunoblastic NHL. Protocol-defined maximum tolerated dose was not reached and the limits of dose-limiting toxicity were not exceeded, even in patients receiving ART. Thirty-two cycles (4.9%) were delayed >6 days because of toxicity; 30 patients (64%) completed all 12 weeks of treatment. After completion of therapy, 14 patients had a complete response (30%), and 4 had a partial response (8%). Median time to progression was 9 months. At 42 months, progression-free survival was 25% and overall survival was 28%.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Relacionado a AIDS/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Administração Oral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/efeitos adversos , Bleomicina/uso terapêutico , Contagem de Linfócito CD4 , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Injeções Intravenosas , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Prospectivos , Proteínas Recombinantes , Análise de Sobrevida , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Because treatment of metastatic colon cancer is noncurative, new treatments are needed. This trial evaluated the antitumor effects of two targeted anticancer agents: (a) ISIS 3521, an antisense inhibitor of the protein kinase C alpha; and (b) ISIS 5132, an antisense inhibitor of c-raf kinase in patients untreated previously with recurrent or metastatic colorectal carcinoma. PATIENTS AND METHODS: All patients had colorectal adenocarcinoma with measurable disease and no prior chemotherapy for metastatic disease. Patients were randomized to receive either ISIS 3521 or ISIS 5132 at a dose of 2 mg/kg/day as a continuous i.v. infusion 21 of 28 days. Cycles were repeated as long as progression was not seen, and doses of both agents were modified according to toxic effects. A two-arm study design was used with each study arm considered independently. Steady-state blood levels of both antisense molecules were measured on days 8, 15, and 22 of the first cycle of therapy. RESULTS: Thirty-seven eligible patients were enrolled, and 32 were evaluable for response (17 receiving ISIS 3521 and 15 receiving ISIS 5132). No responses were noted. Four of the patients receiving ISIS 3521 had stable disease, and 5 patients receiving ISIS 5132 were stable. CONCLUSION: Neither ISIS 5132 nor ISIS 3521given in the dose and schedule studied induced objective responses in untreated colorectal cancer patients.