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1.
Lancet Oncol ; 22(7): 991-1001, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34051880

RESUMEN

BACKGROUND: Understanding patients' experience of cancer treatment is important. We aimed to evaluate patient-reported outcomes (PROs) with atezolizumab plus bevacizumab versus sorafenib in patients with advanced hepatocellular carcinoma in the IMbrave150 trial, which has already shown significant overall survival and progression-free survival benefits with this combination therapy. METHODS: We did an open-label, randomised, phase 3 trial in 111 hospitals and cancer centres across 17 countries or regions. We included patients aged 18 years or older with systemic, treatment-naive, histologically, cytologically, or clinically confirmed unresectable hepatocellular carcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with disease that was not amenable to curative surgical or locoregional therapies, or progressive disease after surgical or locoregional therapies. Participants were randomly assigned (2:1; using permuted block randomisation [blocks of six], stratified by geographical region; macrovascular invasion, extrahepatic spread, or both; baseline alpha-fetoprotein concentration; and ECOG performance status) to receive 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks or 400 mg sorafenib orally twice a day, until loss of clinical benefit or unacceptable toxicity. The independent review facility for tumour assessment was masked to the treatment allocation. Previously reported coprimary endpoints were overall survival and independently assessed progression-free survival per Response Evaluation Criteria in Solid Tumors 1.1. Prespecified secondary and exploratory analyses descriptively evaluated treatment effects on patient-reported quality of life, functioning, and disease symptoms per the European Organisation for Research and Treatment of Cancer (EORTC) quality-of-life questionnaire for cancer (QLQ-C30) and quality-of-life questionnaire for hepatocellular carcinoma (QLQ-HCC18). Time to confirmed deterioration of PROs was analysed in the intention-to-treat population; all other analyses were done in the PRO-evaluable population (patients who had a baseline PRO assessment and at least one assessment after baseline). The trial is ongoing; enrolment is closed. This trial is registered with ClinicalTrials.gov, NCT03434379. FINDINGS: Between March 15, 2018, and Jan 30, 2019, 725 patients were screened and 501 patients were enrolled and randomly assigned to atezolizumab plus bevacizumab (n=336) or sorafenib (n=165). 309 patients in the atezolizumab plus bevacizumab group and 145 patients in the sorafenib group were included in the PRO-evaluable population. At data cutoff (Aug 29, 2019) the median follow-up was 8·6 months (IQR 6·2-10·8). EORTC QLQ-C30 completion rates were 90% or greater for 23 of 24 treatment cycles in both groups (range 88-100% in the atezolizumab plus bevacizumab group and 80-100% in the sorafenib group). EORTC QLQ-HCC18 completion rates were 90% or greater for 20 of 24 cycles in the atezolizumab plus bevacizumab group (range 88-100%) and 21 of 24 cycles in the sorafenib group (range 89-100%). Compared with sorafenib, atezolizumab plus bevacizumab reduced the risk of deterioration on all EORTC QLQ-C30 generic cancer symptom scales that were prespecified for analysis (appetite loss [hazard ratio (HR) 0·57, 95% CI 0·40-0·81], diarrhoea [0·23, 0·16-0·34], fatigue [0·61, 0·46-0·81], pain [0·46, 0·34-0·62]), and two of three EORTC QLQ-HCC18 disease-specific symptom scales that were prespecified for analysis (fatigue [0·60, 0·45-0·80] and pain [0·65, 0·46-0·92], but not jaundice [0·76, 0·55-1·07]). At day 1 of treatment cycle five (after which attrition in the sorafenib group was more than 50%), the mean EORTC QLQ-C30 score changes from baseline in the atezolizumab plus bevacizumab versus sorafenib groups were: -3·29 (SD 17·56) versus -5·83 (20·63) for quality of life, -4·02 (19·42) versus -9·76 (21·33) for role functioning, and -3·77 (12·82) versus -7·60 (15·54) for physical functioning. INTERPRETATION: Prespecified analyses of PRO data showed clinically meaningful benefits in terms of patient-reported quality of life, functioning, and disease symptoms with atezolizumab plus bevacizumab compared with sorafenib, strengthening the combination therapy's positive benefit-risk profile versus that of sorafenib in patients with unresectable hepatocellular carcinoma. FUNDING: F Hoffmann-La Roche and Genentech.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Inhibidores de Proteínas Quinasas/uso terapéutico , Sorafenib/uso terapéutico , Inhibidores de la Angiogénesis/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/mortalidad , Carcinoma Hepatocelular/patología , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/patología , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Calidad de Vida , Sorafenib/efectos adversos , Factores de Tiempo
2.
N Engl J Med ; 379(23): 2220-2229, 2018 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-30280641

RESUMEN

BACKGROUND: Enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy. METHODS: We conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. RESULTS: A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed. CONCLUSIONS: The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann-La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579 .).


Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Método Doble Ciego , Etopósido/administración & dosificación , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Carcinoma Pulmonar de Células Pequeñas/mortalidad
3.
BJU Int ; 126(1): 73-82, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32233107

RESUMEN

OBJECTIVE: To evaluate patient-reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death-ligand 1 (PD-L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2-point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. RESULTS: Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22-0.71); RCC symptoms, 0.22 (0.12-0.41); and symptom interference, 0.36 (0.22-0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. CONCLUSION: PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Sunitinib/uso terapéutico , Adulto , Anciano , Antineoplásicos/uso terapéutico , Antígeno B7-H1 , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/secundario , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Prospectivos
4.
Ophthalmology ; 125(6): 878-886, 2018 06.
Artículo en Inglés | MEDLINE | ID: mdl-29477692

RESUMEN

PURPOSE: To evaluate macular atrophy (MA) presence in the 24-month HARBOR study (NCT00891735) for neovascular age-related macular degeneration (AMD). DESIGN: Post hoc analysis of a phase 3 multicenter, prospective, randomized, double-masked, active treatment-controlled clinical trial. PARTICIPANTS: Evaluable subjects (N = 1095) with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD treated with ranibizumab 0.5 mg or 2.0 mg monthly or pro re nata (PRN). METHODS: Fluorescein angiograms (FAs) and color fundus photographs at baseline and months 3, 12, and 24 were retrospectively graded by masked graders for MA: well-defined areas of depigmentation with increased choroidal vessel visibility, diameter ≥250 µm, corresponding to flat areas of well-demarcated staining on FA, excluding atrophy associated with retinal pigment epithelium tears. Atrophy immediately within, adjacent, and nonadjacent to CNV lesions was included. MAIN OUTCOME MEASURES: Macular atrophy incidence, best-corrected visual acuity (BCVA). RESULTS: At baseline, MA was detected in 11.2% (123/1095) of study eyes. At month 24, 29.4% (229/778) of eyes without baseline atrophy had detectable MA. Eyes with and without baseline MA had significant mean BCVA gains from baseline at month 24 (letters [95% confidence interval]: +6.7 [4.1-9.3]; +9.1 [8.0-10.2], respectively). Among eyes with and without MA at month 24, mean month 24 BCVA was 62.0 [60.3-63.7] and 64.7 [63.2-66.3] letters, respectively. Baseline risk factors for month 24 MA presence included intraretinal cysts (hazard ratio [HR], 2.45 [1.76-3.42]) and fellow eye atrophy (HR, 2.02 [1.42-2.87]); subretinal fluid was associated with a lower MA risk (HR, 0.50 [0.33-0.74]). Ranibizumab dose was not associated with MA development. Monthly versus PRN treatment trended toward an association with MA (HR, 1.29 [0.99-1.68]), but was not statistically significant. CONCLUSIONS: New MA was detected in 29% of study eyes after 24 months of treatment. Clinically significant BCVA gains were achieved with MA present over 24 months. Baseline subretinal fluid absence, intraretinal cyst presence, and fellow eye atrophy presence were associated with month 24 MA presence. With existing data, the benefits of ranibizumab for neovascular AMD outweighed the risk of MA development over 24 months in HARBOR, although outcomes >2 years were not evaluated.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neovascularización Coroidal/tratamiento farmacológico , Atrofia Geográfica/diagnóstico , Ranibizumab/uso terapéutico , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Neovascularización Coroidal/diagnóstico , Neovascularización Coroidal/fisiopatología , Método Doble Ciego , Femenino , Angiografía con Fluoresceína , Atrofia Geográfica/fisiopatología , Humanos , Incidencia , Inyecciones Intravítreas , Masculino , Estudios Prospectivos , Estudios Retrospectivos , Líquido Subretiniano , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual/fisiología , Degeneración Macular Húmeda/diagnóstico , Degeneración Macular Húmeda/fisiopatología
5.
Ophthalmology ; 123(6): 1345-50, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-26992841

RESUMEN

PURPOSE: To explore the visual acuity and anatomic outcomes over 24 months of patients with diabetic macular edema (DME) who showed a delayed anatomic response after 3 ranibizumab injections in the RIDE and RISE trials. DESIGN: Analysis of data from RIDE and RISE, 2 phase III, parallel, randomized, multicenter, double-masked trials (ClinicalTrials.gov identifiers, NCT00473382 and NCT00473330). PARTICIPANTS: Patients with DME (n = 681) who received monthly intravitreal ranibizumab 0.3-mg injections, ranibizumab 0.5-mg injections, or sham injections. METHODS: Patients were separated into 3 groups: delayed responders (ranibizumab-treated patients with ≤10% central foveal thickness [CFT] reduction after 3 injections), immediate responders (ranibizumab-treated patients with >10% CFT reduction after 3 injections), and sham recipients. Central foveal thickness was measured by time-domain optical coherence tomography, best-corrected visual acuity (BCVA) was measured by Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores, and diabetic retinopathy (DR) was measured by the standardized ETDRS severity scale (using fundus photographs). MAIN OUTCOME MEASURES: Month-24 CFT, BCVA, and DR severity levels. RESULTS: In RIDE and RISE, 9% to 10% of ranibizumab-treated eyes were delayed responders. At month 24, delayed responders had less CFT reduction (median, -102 µm) from baseline compared with immediate responders (median, -274 µm; P < 0.0001). Delayed responders gained a median of 10 letters at 24 months, similar to immediate responders (14 letters; P = 0.15). At month 24, DR improvement among the delayed responders (31% and 22% of patients with ≥2- or ≥3-step DR improvement, respectively) was comparable with that among immediate responders (42% and 17%, respectively; P = 0.21 and P = 0.48, respectively). CONCLUSIONS: With continued treatment, at month 24, patients with DME with delayed anatomic response (≤10% CFT reduction) after 3 ranibizumab injections had visual acuity gains and DR improvement similar to those of patients with DME who had immediate anatomic response.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Ranibizumab/uso terapéutico , Retina/patología , Agudeza Visual/fisiología , Anciano , Inhibidores de la Angiogénesis/administración & dosificación , Retinopatía Diabética/diagnóstico , Retinopatía Diabética/fisiopatología , Método Doble Ciego , Femenino , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/fisiopatología , Masculino , Persona de Mediana Edad , Ranibizumab/administración & dosificación , Tomografía de Coherencia Óptica , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores
6.
Ophthalmology ; 123(8): 1716-1721, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27208982

RESUMEN

PURPOSE: To investigate the role of baseline demographics, disease characteristics, and treatment responses to ranibizumab during RIDE/RISE in predicting long-term treatment frequency with a criteria-based pro re nata (PRN) regimen during the open-label extension (OLE). DESIGN: Pooled, retrospective, post hoc analysis from the phase III, randomized RIDE/RISE studies and subsequent OLE. PARTICIPANTS: Five hundred patients enrolled in the OLE after completion of the 36-month RIDE/RISE studies. METHODS: Summary statistics of RIDE/RISE baseline characteristics and treatment responses were generated by PRN ranibizumab 0.5 mg annualized injection frequency in the OLE (0 and >7 annualized injections). Univariable regression and analysis of variance, and multivariable analysis of covariance were performed on the annualized number of ranibizumab injections administered during the OLE versus baseline characteristics and response to treatment during the RIDE/RISE studies. MAIN OUTCOME MEASURES: Association of patient characteristics and responses to treatment during RIDE/RISE with the observed ranibizumab treatment burden during the OLE. RESULTS: During the OLE, 121 patients required no treatment, 132 required >0 to ≤3 annualized injections, 159 required >3 to ≤7 annualized injections, and 88 required >7 annualized injections. Parameters identified in the multivariable analysis as related to the annualized number of injections included the total number of rescue focal macular lasers received during the core studies (P = 0.0203), central foveal thickness at baseline (P = 0.0002) and month 36 (P < 0.0001), fluorescein leakage area at month 36 (P = 0.0137), and glycated hemoglobin (HbA1c) levels at month 36 (P = 0.0054). Patients receiving 0 versus >7 annualized injections during the OLE had, on average, a shorter duration of diabetes and diabetic macular edema (DME) at baseline, were less likely to have proliferative diabetic retinopathy at baseline, received fewer rescue focal macular laser treatments, and were more likely to experience diabetic retinopathy severity scale improvement of ≥2 steps. CONCLUSIONS: Patients who received less frequent injections during the RIDE/RISE OLE tended to have less advanced disease at baseline and responded better to initial ranibizumab treatment, suggesting that earlier anti-vascular endothelial growth factor treatment of center-involving DME with visual acuity loss may decrease long-term treatment burden.


Asunto(s)
Inhibidores de la Angiogénesis/administración & dosificación , Retinopatía Diabética/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Ranibizumab/administración & dosificación , Anciano , Glucemia/metabolismo , Retinopatía Diabética/diagnóstico , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Agudeza Visual/fisiología
7.
J Biopharm Stat ; 25(3): 508-24, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25723915

RESUMEN

Clinical trials generally allow various efficacy and safety outcomes to be collected for health interventions. Benefit-risk assessment is an important issue when evaluating a new drug. Currently, there is a lack of standardized and validated benefit-risk assessment approaches in drug development due to various challenges. To quantify benefits and risks, we propose a counterfactual p-value (CP) approach. Our approach considers a spectrum of weights for weighting benefit-risk values and computes the extreme probabilities of observing the weighted benefit-risk value in one treatment group as if patients were treated in the other treatment group. The proposed approach is applicable to single benefit and single risk outcome as well as multiple benefit and risk outcomes assessment. In addition, the prior information in the weight schemes relevant to the importance of outcomes can be incorporated in the approach. The proposed CPs plot is intuitive with a visualized weight pattern. The average area under CP and preferred probability over time are used for overall treatment comparison and a bootstrap approach is applied for statistical inference. We assess the proposed approach using simulated data with multiple efficacy and safety endpoints and compare its performance with a stochastic multi-criteria acceptability analysis approach.


Asunto(s)
Ensayos Clínicos como Asunto/estadística & datos numéricos , Descubrimiento de Drogas/estadística & datos numéricos , Medición de Riesgo/estadística & datos numéricos , Simulación por Computador , Técnicas de Apoyo para la Decisión , Determinación de Punto Final , Análisis de Supervivencia
8.
J Thorac Cardiovasc Surg ; 166(3): 655-666.e7, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-36841745

RESUMEN

OBJECTIVE: Adjuvant atezolizumab is a standard of care after chemotherapy in completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or greater non-small cell lung cancer based on results from the phase III IMpower010 study. We explored the safety and tolerability of adjuvant atezolizumab by surgery type in IMpower010. METHODS: Patients had completely resected stage IB-IIIA non-small cell lung cancer (Union Internationale Contre le Cancer/American Joint Committee on Cancer, 7th Ed), received up to four 21-day cycles of cisplatin-based chemotherapy, and were randomized 1:1 to receive atezolizumab 1200 mg every 3 weeks (≤16 cycles or 1 year) or best supportive care. Adverse events and clinical characteristics were investigated by surgery type (pneumonectomy/bilobectomy or lobectomy/sleeve lobectomy) in the randomized stage II-IIIA population who received 1 or more atezolizumab dose or with 1 or more postbaseline assessment (safety evaluable) for best supportive care. RESULTS: Overall, 871 patients comprised the safety-evaluable randomized stage II-IIIA population. In the atezolizumab arm, 23% (100/433) received pneumonectomy/bilobectomy and 77% (332/433) received lobectomy/sleeve lobectomy. Atezolizumab discontinuation occurred in 32% (n = 32) and 35% (n = 115) of the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. Grade 3/4 adverse events were reported in 21% (n = 21) and 23% (n = 76) of patients in the atezolizumab arms in the pneumonectomy/bilobectomy and lobectomy/sleeve lobectomy groups, respectively. In the atezolizumab arms of the surgery groups, 13% (n = 13) and 17% (n = 55) had an adverse event leading to hospitalization. Atezolizumab-related adverse events leading to hospitalization occurred in 5% (n = 5) and 7% (n = 23) of the surgery groups. CONCLUSIONS: These exploratory findings support use of adjuvant atezolizumab after platinum-based chemotherapy in patients with completely resected stage II-IIIA programmed death ligand-1 tumor cell 1% or more non-small cell lung cancer, regardless of surgery type.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/cirugía , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/cirugía , Neoplasias Pulmonares/patología , Neumonectomía/efectos adversos , Neumonectomía/métodos , Quimioterapia Adyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estadificación de Neoplasias
9.
Clin Trials ; 9(6): 730-5, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22879575

RESUMEN

BACKGROUND: In a clinical study to evaluate noninferiority (NI) of an experimental drug relative to an established therapy, it is common to further test superiority of the experimental drug after NI is established. It has been shown that no multiplicity issue exists between NI and superiority tests of the primary endpoint. However, when there is an additional, or secondary, endpoint that will be tested for superiority in a hierarchical fashion to the NI testing of the primary endpoint, it is not clear whether the overall type I error rate is strictly controlled among all the tests. PURPOSE: In this article, our goal is to evaluate if the family-wise type I error rate is strictly controlled in this setting. We also evaluate a multiplicity adjustment procedure based on the Hochberg procedure. METHODS: We use the closed testing principle to evaluate the family-wise type I error rate. Some simulations are performed to appreciate the magnitude of the potential inflation of the type I error rate. RESULTS: It is demonstrated that the family-wise type I error rate is not controlled and an appropriate multiplicity adjustment procedure must take into account the NI and superiority tests of the two endpoints. When the test statistic used for superiority testing of the primary endpoint is the same as that for the NI testing, a multiplicity adjustment method using the popular Hochberg procedure is shown to be potentially conservative. LIMITATION: The assessment is based on a simplified set-up where there is only one secondary endpoint tested for superiority in addition to the primary endpoint. CONCLUSION: It is necessary to evaluate the issue of multiplicity in non-inferiority studies to assure strict control of the family-wise type I error rate.


Asunto(s)
Sesgo , Ensayos Clínicos como Asunto/métodos , Investigación sobre la Eficacia Comparativa/métodos , Interpretación Estadística de Datos , Proyectos de Investigación , Simulación por Computador , Modelos Estadísticos
10.
Cancer Med ; 10(16): 5437-5447, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34189869

RESUMEN

BACKGROUND: IMbrave150 is a phase III trial that assessed atezolizumab + bevacizumab (ATEZO/BEV) versus sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (HCC) and demonstrated a significant improvement in clinical outcomes. Exploratory analyses characterized objective response rate (ORR), depth (DpR), and duration of response (DoR), and patients with a complete response (CR). METHODS: Patients were randomized 2:1 to intravenous ATEZO (1200 mg) + BEV (15 mg/kg) every 3 weeks or oral SOR (400 mg) twice daily. Tumors were evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) and HCC-modified RECIST (mRECIST). ORR by prior treatment and largest baseline liver lesion size, DoR, time to response (TTR), and complete response (TTCR) were analyzed. RESULTS: For both criteria, responses favored ATEZO/BEV versus SOR regardless of prior treatment and in patients with lesions ≥3 cm. Median TTR was 2.8 months per RECIST 1.1 (range: 1.2-12.3 months) and 2.8 months per mRECIST (range: 1.1-12.3 months) with ATEZO/BEV. Patients receiving ATEZO/BEV had a greater DpR, per both criteria, across baseline liver lesion sizes. Characteristics of complete responders were similar to those of the intent-to-treat population. In complete responders receiving ATEZO/BEV per mRECIST versus RECIST 1.1, respectively, median TTCR was shorter (5.5 vs. 7.0 months), mean baseline sum of lesion diameter was longer (5.0 [SD, 5.1] vs. 2.6 [SD, 1.4] cm), and mean largest liver lesion size was larger (4.8 [SD, 4.2] vs. 2.3 [SD, 1.0] cm). CONCLUSIONS: These data highlight the improved ORR, DpR, and CR rates with ATEZO/BEV in unresectable HCC.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/administración & dosificación , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/mortalidad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Sorafenib/efectos adversos , Tomografía Computarizada por Rayos X
11.
Eur Urol ; 79(5): 665-673, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33678522

RESUMEN

BACKGROUND: The use of immune checkpoint inhibitors combined with vascular endothelial growth factor (VEGF)-targeted therapy as second-line treatment for metastatic clear cell renal cancer (mRCC) has not been evaluated prospectively. OBJECTIVE: To evaluate the efficacy and safety of atezolizumab + bevacizumab following disease progression on atezolizumab or sunitinib monotherapy in patients with mRCC. DESIGN, SETTING, AND PARTICIPANTS: IMmotion150 was a multicenter, randomized, open-label, phase 2 study of patients with untreated mRCC. Patients randomized to the atezolizumab or sunitinib arm who had investigator-assessed progression as per RECIST 1.1 could be treated with second-line atezolizumab + bevacizumab. INTERVENTION: Patients received atezolizumab 1200 mg intravenously (IV) plus bevacizumab 15 mg/kg IV every 3 wk following disease progression on either atezolizumab or sunitinib monotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The secondary endpoints analyzed during the second-line part of IMmotion150 included objective response rate (ORR), progression-free survival (PFS), and safety. PFS was examined using Kaplan-Meier methods. RESULTS AND LIMITATIONS: Fifty-nine patients in the atezolizumab arm and 78 in the sunitinib arm were eligible, and 103 initiated second-line atezolizumab + bevacizumab (atezolizumab arm, n = 44; sunitinib arm, n = 59). ORR (95% confidence interval [CI]) was 27% (19-37%). The median PFS (95% CI) from the start of second line was 8.7 (5.6-13.7) mo. The median event follow-up duration was 19.4 (12.9-21.9) mo among the 25 patients without a PFS event. Eighty-six (83%) patients had treatment-related adverse events; 31 of 103 (30%) had grade 3/4 events. Limitations were the small sample size and selection for progressors. CONCLUSIONS: The atezolizumab + bevacizumab combination had activity and was tolerable in patients with progression on atezolizumab or sunitinib. Further studies are needed to investigate sequencing strategies in mRCC. PATIENT SUMMARY: Patients with advanced kidney cancer whose disease had worsened during treatment with atezolizumab or sunitinib began second-line treatment with atezolizumab + bevacizumab. Tumors shrank in more than one-quarter of patients treated with this combination, and side effects were manageable.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bevacizumab/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Progresión de la Enfermedad , Humanos , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéutico , Factor A de Crecimiento Endotelial Vascular
12.
J Immunother Cancer ; 8(2)2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32641319

RESUMEN

BACKGROUND: Atezolizumab is a treatment for locally advanced/metastatic urothelial carcinoma (mUC). However, its use in patients with renal insufficiency or UC with mixed variant histology (MVH) is not well characterized. OBJECTIVE: To report efficacy and safety of atezolizumab in these special subpopulations from an expanded access program (EAP). DESIGN, SETTING, AND PARTICIPANTS: A total of 218 patients were enrolled at 36 US study sites (November 2015-August 2016), and the trial ended following the approval of atezolizumab by the US Food and Drug Administration. This post hoc analysis investigated outcomes in specific study subgroups. INTERVENTION: Atezolizumab 1200 mg was administered intravenously every 3 weeks until loss of clinical benefit, unacceptable toxicity, death, consent withdrawal, decision to discontinue, commercial availability, or study closure. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Response Evaluation Criteria in Solid Tumors V.1.1 responses and safety were evaluated by baseline renal function and histology. RESULTS AND LIMITATIONS: Objective responses occurred in 0/6 (0%), 4/19 (21%), 1/27 (3.7%), and 12/62 (19%) of evaluable patients with creatinine clearance (CrCl) <30, 30-45, 45-60, and ≥60 mL/min, respectively, and stable disease was seen in three patients with CrCl <30 mL/min. Objective responses were seen in 13/102 patients (13%) with urothelial carcinoma (UC) histology only and in 4/12 patients (33%) with UC with MVH. Treatment-related adverse event frequencies ranged from 35% to 54% across the earlier indicated CrCl subgroups and they were also similar in patients with pure UC or UC with MVH (46%). CONCLUSIONS: In this EAP mUC subgroup analysis, clinical benefit of atezolizumab occurred in patients with compromised renal function or MVH UC tumors. Safety was comparable across subgroups. PATIENT SUMMARY: We examined the efficacy and safety of atezolizumab for UC in certain patients participating in an EAP. We found that responses to atezolizumab occurred, and safety was similar, in most patient subgroups with varying levels of kidney functioning or less common types of tumor tissue histology.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Platino (Metal)/uso terapéutico , Insuficiencia Renal/tratamiento farmacológico , Neoplasias Urológicas/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Femenino , Humanos , Masculino , Platino (Metal)/farmacología
13.
Clin Cancer Res ; 26(11): 2506-2514, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32127394

RESUMEN

PURPOSE: Patient-reported outcomes (PRO) were evaluated in the phase III IMmotion151 trial (NCT02420821) to inform overall treatment/disease burden of atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients were randomized 1:1 to receive atezolizumab 1,200 mg intravenous (i.v.) infusions every 3 weeks (q3w) plus bevacizumab 15 mg/kg i.v. q3w or sunitinib 50 mg per day orally 4 weeks on/2 weeks off. Patients completed the MD Anderson Symptom Inventory (MDASI), National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Kidney Symptom Index (FKSI-19), and Brief Fatigue Inventory (BFI) at baseline, q3w during treatment, at end of treatment, and during survival follow-up. Longitudinal and time to deterioration (TTD) analyses for core and RCC symptoms and their interference with daily life, treatment side-effect bother, and health-related quality of life (HRQOL) were evaluated. RESULTS: The intent-to-treat population included 454 and 461 patients in the atezolizumab plus bevacizumab and sunitinib arms, respectively. Completion rates for each instrument were 83% to 86% at baseline and ≥ 70% through week 54. Milder symptoms, less symptom interference and treatment side-effect bother, and better HRQOL at most visits were reported with atezolizumab plus bevacizumab versus sunitinib. The TTD HR (95% CI) favored atezolizumab plus bevacizumab for core (HR, 0.50; 0.40-0.62) and RCC symptoms (HR, 0.45; 0.37-0.55), symptom interference (HR, 0.56; 0.46-0.68), and HRQOL (HR, 0.68; 0.58-0.81). CONCLUSIONS: PROs in IMmotion151 suggest lower overall treatment burden with atezolizumab plus bevacizumab compared with sunitinib in patients with treatment-naïve mRCC and provide further evidence for clinical benefit of this regimen.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Calidad de Vida , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bevacizumab/administración & dosificación , Carcinoma de Células Renales/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/patología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Sunitinib/administración & dosificación , Tasa de Supervivencia
14.
Bone ; 43(2): 222-229, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18539106

RESUMEN

INTRODUCTION: Denosumab is a fully human monoclonal antibody that inhibits receptor activator of nuclear factor-kappa B ligand (RANKL), an essential mediator of osteoclast formation, function, and survival that has been shown to decrease bone turnover and increase bone mineral density (BMD) in treated patients. We assessed the long-term efficacy and safety of denosumab, and the effects of discontinuing and restarting denosumab treatment in postmenopausal women with low bone mass. METHODS: Postmenopausal women with a lumbar spine T-score of -1.8 to -4.0 or proximal femur T-score of -1.8 to -3.5 were randomized to denosumab every 3 months (Q3M; 6, 14, or 30 mg) or every 6 months (Q6M; 14, 60, 100, or 210 mg); placebo; or open-label oral alendronate weekly. After 24 months, patients receiving denosumab either continued treatment at 60 mg Q6M for an additional 24 months, discontinued therapy, or discontinued treatment for 12 months then re-initiated denosumab (60 mg Q6M) for 12 months. The placebo cohort was maintained. Alendronate-treated patients discontinued alendronate and were followed. Changes in BMD and bone turnover markers (BTM) as well as safety outcomes were evaluated. RESULTS: Overall, 262/412 (64%) patients completed 48 months of study. Continuous, long-term denosumab treatment increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). BTM were consistently suppressed over 48 months. Discontinuation of denosumab was associated with a BMD decrease of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months of treatment discontinuation. Retreatment with denosumab increased lumbar spine BMD by 9.0% from original baseline values. Levels of BTM increased upon discontinuation and decreased with retreatment. Adverse event rates were similar among treatment groups. CONCLUSIONS: In postmenopausal women with low BMD, long-term denosumab treatment led to gains in BMD and reduction of BTM throughout the course of the study. The effects on bone turnover were fully reversible with discontinuation and restored with subsequent retreatment.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Conservadores de la Densidad Ósea/farmacología , Densidad Ósea/efectos de los fármacos , Huesos/efectos de los fármacos , Huesos/patología , Posmenopausia/efectos de los fármacos , Ligando RANK/farmacología , Alendronato/farmacología , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Biomarcadores/metabolismo , Demografía , Denosumab , Femenino , Humanos , Persona de Mediana Edad , Tamaño de los Órganos/efectos de los fármacos , Ligando RANK/efectos adversos , Método Simple Ciego , Factores de Tiempo , Resultado del Tratamiento
15.
J Clin Densitom ; 11(3): 351-9, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18495508

RESUMEN

Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, an essential mediator of osteoclast activity and survival. In postmenopausal women with low bone mineral density (BMD), subcutaneous denosumab decreases bone resorption and increases BMD. This post hoc analysis reports on subjects treated for up to 24 months with denosumab 60mg 6 monthly (N=39), placebo (N=39), or open-label alendronate 70mg once weekly (N=38) in a phase 2 study. Hip scans were done by dual-energy X-ray absorptiometry at baseline, 12, and 24 months; these were analyzed with hip structural analysis software to evaluate BMD and cross-sectional geometry parameters at the narrowest segment of the femoral neck, the intertrochanter, and the proximal shaft. Geometric parameters and derived strength indices included bone cross-sectional area, section modulus, and buckling ratio. At 12 and 24 months denosumab and alendronate improved these parameters compared with placebo. Denosumab effects were greater than alendronate at the intertrochanteric and shaft sites. The magnitude and direction of the changes in structural geometry parameters observed in this study suggest that denosumab treatment may lead to improved bone mechanical properties. Ongoing phase 3 studies will determine whether denosumab reduces fracture risk.


Asunto(s)
Alendronato/farmacología , Anticuerpos Monoclonales/farmacología , Conservadores de la Densidad Ósea/farmacología , Densidad Ósea/efectos de los fármacos , Fémur/efectos de los fármacos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Ligando RANK/farmacología , Absorciometría de Fotón , Alendronato/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Conservadores de la Densidad Ósea/administración & dosificación , Denosumab , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Persona de Mediana Edad , Ligando RANK/administración & dosificación , Resultado del Tratamiento
16.
JAMA Oncol ; 4(4): 537-544, 2018 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-29423515

RESUMEN

IMPORTANCE: Atezolizumab (anti-programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown. OBJECTIVE: To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma. DESIGN, SETTING, AND PARTICIPANTS: Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay). INTERVENTIONS: Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit. MAIN OUTCOMES AND MEASURES: Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups. RESULTS: Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively. CONCLUSIONS AND RELEVANCE: Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01375842.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Carcinoma de Células Transicionales/mortalidad , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Análisis de Supervivencia , Factores de Tiempo , Neoplasias de la Vejiga Urinaria/mortalidad , Urotelio/patología
17.
Clin Lymphoma Myeloma ; 7(6): 413-20, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17621407

RESUMEN

BACKGROUND: Most alterations to chemotherapy dose and schedule are because of neutropenic events, which mainly occur in the first chemotherapy cycle. This prospective, community-based study evaluated the effectiveness of pegfilgrastim in patients with lymphoma who were also receiving chemotherapy. PATIENTS AND METHODS: Patients aged > or = 18 years with cancer other than leukemia or myelodysplastic syndromes were eligible, including patients with major comorbidities who were generally not eligible for most clinical trials. Key exclusions were weekly chemotherapy and concurrent radiation therapy. Patients received pegfilgrastim 6 mg approximately 24 hours after chemotherapy in each cycle (up to 8 cycles). Endpoints included neutropenic complications and serious adverse events. RESULTS: This open-label single-arm study enrolled 2249 patients at 319 sites. Of these 2249 patients, 325 patients with non-Hodgkin lymphoma (NHL) and 46 patients with Hodgkin disease were included in the primary analysis set. The median age was 65 years for patients with NHL and 41 years for patients with Hodgkin disease, and 31% and 26% had major comorbidities, respectively. Few patients experienced neutropenic complications, including grade 4 febrile neutropenia (patients with Hodgkin disease: 0 [95% confidence interval (CI), 0-8%]; patients with NHL: 13% [95% CI, 10%-17%]); febrile neutropenia-related hospitalization (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 10% [95% CI, 7%-14%]), neutropenia-related dose reduction (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]), and neutropenia-related dose delay (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]). Serious adverse events were consistent with those observed in patients receiving myelosuppressive chemotherapy. CONCLUSION: Patients with lymphoma receiving myelosuppressive chemotherapy supported by pegfilgrastim experienced few neutropenic complications or neutropenia-related alterations in chemotherapy dose and schedule.


Asunto(s)
Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Linfoma/complicaciones , Linfoma/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Neutropenia/etiología , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Determinación de Punto Final , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Humanos , Linfoma/sangre , Masculino , Persona de Mediana Edad , Neutropenia/sangre , Polietilenglicoles , Estudios Prospectivos , Proteínas Recombinantes
18.
J Manag Care Pharm ; 13(4): 337-48, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17506600

RESUMEN

BACKGROUND: Colony-stimulating factors (CSFs) significantly decrease the risk of febrile neutropenia (FN), a common complication of myelosuppressive chemotherapy. Pegfilgrastim (6 mg), introduced in 2002, has a sustained duration of action, with a single dose comparable in efficacy to daily injections of filgrastim (5 g per kg per day) for 10 to 11 days; both agents should be initiated 24 hours after completing chemotherapy. OBJECTIVES: To (1) describe the use of pegfilgrastim and filgrastim in oncology practices throughout the United States and (2) compare their effectiveness in actual practice as measured by the outcome of febrile neutropenia in patients who received chemotherapy regimens administered every 3 to 4 weeks for breast, lung, ovarian, colon cancer, or lymphoma and who received a CSF prior to developing FN. METHODS: Data were retrospectively obtained from the medical records of a cohort of adult patients aged 18 years or older treated in 99 community oncology practices in the United States in 2001 and 2003. Eligible patients were treated with chemotherapy every 3 to 4 weeks for breast, lung, ovarian, colon cancer, or lymphoma and were users of filgrastim in 2001 (prior to the U.S. Food and Drug Administration approval of pegfilgrastim in January 2002) or users of either filgrastim or pegfilgrastim or both CSF agents in 2003. RESULTS: Pegfilgrastim was initiated, on average, 2.4 days (SD +/-3.2) after chemotherapy in the first cycle of use and 1.9 (+/-3.0) days in subsequent cycles of use. In contrast, filgrastim was started on average 7.7 (+/-6.5) days and 4.9 (4.6) days after chemotherapy in the first and subsequent cycles of use in 2001, increasing to 9.6 (+/-6.2) and 6.4 (+/-6.4) days in 2003. In the first cycle of CSF use, filgrastim was administered for an average of 5.2 (+/-3.5) days to 583 patients in 2001 and 3.7 (+/-2.8) days to 868 patients in 2003 (P <0.001). Among patients who received more than 1 cycle of filgrastim (n = 457 in 2001 and n = 489 in 2003; 78.4% and 56.3% of filgrastim users, respectively), the mean days of filgrastim administered in subsequent cycles was 6.0 (+/-3.5) in 2001 and 4.6 (+/-3.2) in 2003. Pegfilgrastim was administered as a single dose per chemotherapy course to 1,412 patients in 2003. Patients who received pegfilgrastim were more likely to have at least 1 myelosuppressive drug (74.8%) in the regimen compared with patients who received filgrastim in 2003 (70.0%, P = 0.013), but a greater proportion of filgrastim patients in 2003 (19.4%) had advanced-stage disease compared with pegfilgrastim patients (14.8%, P = 0.005). More patients who received filgrastim in 2003 (36.2%) had a cancer other than breast cancer or non-Hodgkin's lymphoma compared with those who received pegfilgrastim (29.5%, P = 0.001). A total of 94 of 1,451 patients (6.5%) who received filgrastim experienced FN compared with 67 of 1,412 patients (4.7%) for pegfilgrastim. The odds ratio of developing FN among patients who received filgrastim versus pegfilgrastim was 1.41 (95% confidence interval, 1.02-1.96; P = 0.040) after adjusting for patient and chemotherapy regimen characteristics. CONCLUSION: In this retrospective study of patients treated in 99 community oncology practices, patients who received filgrastim often initiated treatment later than recommended and received fewer days per cycle than demonstrated to be effective in randomized controlled trials. Pegfilgrastim was generally initiated earlier within the course of chemotherapy compared with filgrastim, and because of its sustained duration of action, only a single injection was required. In these patients treated with a heterogeneous group of chemotherapy regimens with a broad range of risk of FN, overall, an absolute 1.8% increase in the incidence of developing FN was observed in patients who received filgrastim compared with patients who received pegfilgrastim, (absolute rates of 6.5% and 4.7%, respectively).


Asunto(s)
Servicios de Salud Comunitaria , Quimioterapia , Fiebre/epidemiología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Oncología Médica , Neutropenia/epidemiología , Anciano , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Masculino , Auditoría Médica , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Polietilenglicoles , Proteínas Recombinantes , Estudios Retrospectivos , Estados Unidos/epidemiología
19.
Pulm Ther ; 3(2): 317-325, 2017 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32026347

RESUMEN

INTRODUCTION: In phase 3 clinical trials, pirfenidone significantly slowed disease progression with a well-defined and medically manageable safety profile in patients with idiopathic pulmonary fibrosis (IPF). This study examined safety events related to pirfenidone in patients with IPF in an expanded access program in the US. METHODS: The Expanded Access Program allowed patients with IPF access to pirfenidone prior to US Food and Drug Administration approval. Patients had an IPF diagnosis including a definite or possible usual interstitial pneumonia (UIP) pattern, predicted forced vital capacity ≥50%, and predicted diffusing capacity for carbon monoxide ≥30%. Clinical laboratory data and adverse drug reactions (ADRs) deemed causally related to pirfenidone were analyzed using descriptive summary statistics. RESULTS: Of the 1620 patients treated, 1221 (75.4%) completed the program: 66.5% had definite UIP, and 33.2% had possible UIP. Mean (SD) pirfenidone exposure was 22.8 (9.6) weeks, and mean (SD) daily dose during the course of treatment was 2058.7 (399.2) mg. ADRs occurred in 64.9% of patients: 3.3% were severe and 0.2% life threatening. The most common ADRs were nausea (22.6%) and fatigue (19.6%); 13.0% of patients discontinued due to ADRs. Serious ADRs occurred in 24 patients (1.5%), which were primarily related to elevated liver function enzymes (ten patients, 0.6%). No ADRs led to death. CONCLUSIONS: In this open-label study of 1620 patients with IPF, including those with possible UIP, the safety profile of pirfenidone was consistent with that of earlier clinical trials, and no new safety signals were identified. NCT02141087. FUNDING: Genentech, Inc., a member of the Roche group.

20.
Am J Ophthalmol ; 160(5): 1014-1023.e2, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26231305

RESUMEN

PURPOSE: To identify baseline characteristics predictive of visual acuity (VA) outcomes at month 12 (M12) and treatment frequency in the first 12 months of the phase III HARBOR study. DESIGN: Retrospective, exploratory analysis of multicenter randomized controlled trial data. METHODS: setting: Randomized, multicenter. STUDY POPULATION: Patients aged ≥50 years with subfoveal wet age-related macular degeneration (AMD) who had best-corrected VA (BCVA) values measured at baseline and M12. INTERVENTION: Intravitreal ranibizumab 0.5 mg administered monthly (n = 249) or as needed (PRN) after 3 monthly loading doses (n = 251). MAIN OUTCOME MEASURES: BCVA change from baseline at M12, percentage of patients who gained ≥15 letters (3 lines) in BCVA from baseline at M12, and percentage of patients who achieved ≥20/40 vision (Snellen) at M12 served as the basis for analyzing baseline predictors of observed VA outcomes in the monthly and PRN groups. Total number of ranibizumab PRN injections in the first 12 months was also evaluated. Only variables that were statistically significant (P < .05) remained in the final statistical models. RESULTS: Baseline predictors of BCVA change from baseline at M12 and/or percentage of 3-line gainers included lower BCVA, younger age, smaller total choroidal neovascularization (CNV) leakage area, smaller area of occult CNV, and presence of subretinal fluid (SRF). Baseline predictors of ≥20/40 vision at M12 included higher BCVA, smaller total CNV leakage area, and presence of SRF. SRF thickness >118.25 µm at baseline predicted requiring more ranibizumab injections in the first 12 months of treatment. CONCLUSIONS: Select baseline characteristics have predictive value for visual prognosis and treatment frequency in ranibizumab-treated patients with wet AMD.


Asunto(s)
Ranibizumab/administración & dosificación , Agudeza Visual , Degeneración Macular Húmeda/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/administración & dosificación , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Intravítreas , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Degeneración Macular Húmeda/patología , Degeneración Macular Húmeda/fisiopatología
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