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1.
Oncologist ; 27(6): 487-492, 2022 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-35278074

RESUMO

BACKGROUND: Many randomized control trials (RCTs) evaluating programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) targeting monoclonal antibodies (mAbs) have been completed or are in progress. We examined hypothesized hazard ratios (HHRs) and observed hazard ratios (OHRs) from published RCTs evaluating these mAbs. METHODS: Publications of RCTs evaluating at least one PD-1/PD-L1 targeting mAbs approved by the US Food and Drug Administration were identified through PubMed searches. The primary reports of RCTs were retrieved. Two investigators extracted HHR, OHR for the primary endpoint among other data elements independently. The differences (∆HR) in HHR and OHR were analyzed statistically. A separate search was conducted for secondary reports after longer follow-ups, the updated OHR was extracted. RESULTS: Forty-nine RCTs enrolling 36 867 patients were included. The mean HHR and OHR were 0.672 and 0.738 respectively. The mean ∆HR was 0.067 (range: -0.300 to 0.895; 95% confidence interval (CI), 0.003-0.130). HHR was met or exceeded in 22 (45%) RCTs. OHR was ≥ 1.0 in 6 RCTs (12%). PD-L1 expression was not associated with the magnitude of effect. Of 18 RCTs with follow-up reports, the magnitude of benefit decreased in 8 RCTs with extended follow-ups. CONCLUSION: The majority of published RCTs evaluating PD-1/PD-L1 targeting mAbs did not achieve their hypothesized magnitude of benefit. The optimism bias requires attention from the cancer clinical research community given the number of these agents in development and the intense interest in evaluating these agents in a variety of disease settings.


Assuntos
Antineoplásicos Imunológicos , Neoplasias , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1 , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1 , Ensaios Clínicos Controlados Aleatórios como Assunto
3.
J Cancer ; 15(4): 1021-1029, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38230223

RESUMO

Background: There remains a scarcity of published data on the clinical significance of paraneoplastic cutaneous manifestations in hepatocellular carcinoma (HCC). Method: A systematic search of MEDLINE was performed in December 2022. Inclusion criteria comprised studies reporting on patients with HCC, who had paraneoplastic cutaneous manifestations. Outcomes of interests comprise survival and response to cancer-directed and/or skin directed therapy. Results: A total of 48 studies comprising 60 HCC patients were included in the analysis. The most frequent reported skin abnormalities were dermatomyositis, pityriasis rotunda, and porphyria. Most patients presented with dermatomyositis had underlying viral hepatitis, while all reported porphyria and acanthosis cases were associated with metabolic causes of HCC, such as steatosis. Paraneoplastic skin changes were more common in patients with metastatic disease. Pityriasis Rotunda was associated with the lowest risk of death, (OR: 0.05, 95% CI: 0.003 to 0.89; p = 0.04), while dermatomyositis had a statistically significant higher risk of death (OR: 3.37, 95% CI: 1.01-12.1; p = 0.03). Most patients showed an improvement in their cutaneous abnormalities, following cancer-directed therapy. Conclusion: Paraneoplastic cutaneous manifestations are reported more frequently in patients with a higher burden of disease, especially presence of metastases. Certain cutaneous manifestations have prognostic implication.

4.
Crit Rev Oncol Hematol ; 181: 103880, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36435297

RESUMO

BACKGROUND: Outcomes for breast cancer patients with residual disease (RD) after neoadjuvant chemotherapy (NACT) and HER2-targeted therapy may be better than anticipated leading to a smaller absolute benefit of adjuvant trastuzumab emtansine (T-DM1). Therefore, accurate estimates of 3-year disease-free survival (DFS) can aid in treatment planning. METHODS: We reviewed randomized trials of NACT and HER2-targeted therapy in breast cancer (excluding T-DM1) and calculated mean 3-year DFS weighted by study sample size. Meta-regression comprising linear regression weighted by sample size (mixed-effects) was performed to explore associations between 3-year DFS and year of accrual and trial-level patient, disease, and treatment factors. Data were reported quantitatively irrespective of statistical significance. RESULTS: Eleven studies (N = 3581) were included in the primary analysis. The mean 3-year DFS for patients with RD was 79.7% (95% CI 77.4-80.9). This was higher for trials completing accrual after 2010 [83% (95% CI 79.3-86.3)] and for those receiving dual HER2 targeted therapy [83.4% (95% CI 79.2-87.7]. Better outcomes for ER positivity, later accrual and dual Her-2 targeted therapy were confirmed in meta-regression. Negative quantitative significance was observed for larger clinical tumor size and nodal involvement. CONCLUSIONS: The 3-year DFS for patients with RD has improved over time possibly due to dual HER2 targeted therapy. This will reduce the absolute benefit of adjuvant T-DM1 in this group of patients.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Trastuzumab/uso terapêutico , Terapia Neoadjuvante , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2 , Ado-Trastuzumab Emtansina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante
5.
J Immunother Cancer ; 11(2)2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36792122

RESUMO

BACKGROUND: Quantification of circulating tumor DNA (ctDNA) levels is a reliable prognostic tool in several malignancies. Dynamic changes in ctDNA levels in response to treatment may also provide prognostic information. Here, we explore the value of changes in ctDNA levels in response to immune checkpoint inhibitors (ICIs). METHODS: We searched MEDLINE (host: PubMed) for trials of ICIs in advanced solid tumors in which outcomes were reported based on change in ctDNA levels. ctDNA reduction was defined as reported in individual trials. Typically, this was either >50% reduction or a reduction to undetectable levels. We extracted HRs and related 95% CIs and/or p values comparing ctDNA reduction versus no reduction for progression-free survival (PFS) and/or overall survival (OS). Data were then pooled in a meta-analysis. Variation in effect size was examined using subgroup analyses. RESULTS: Eighteen trials were included in the meta-analysis. ctDNA levels were detectable in all participants in all studies prior to initiation of ICIs. A reduction in ctDNA measured 6-16 weeks after starting treatment was associated with significantly better PFS (HR 0.20; 95% CI, 0.14 to 0.28; p<0.001). Similarly, OS was superior in patients with reduced ctDNA levels (HR 0.18; 95% CI, 0.12 to 0.26; p<0.001). The results were consistent across all disease sites, lines of treatment, magnitude of change (to undetectable vs >50% reduction) and whether treatment exposure comprised single or combination ICIs. CONCLUSIONS: In advanced solid tumors, a reduction in ctDNA levels in response to ICIs is associated with substantial improvements in outcome. ctDNA change is an early response biomarker which may allow for de-escalation of cross-sectional imaging in patients receiving ICIs or support treatment de-escalation strategies.


Assuntos
DNA Tumoral Circulante , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamento farmacológico , DNA Tumoral Circulante/genética , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Prognóstico , Biomarcadores
6.
JNCI Cancer Spectr ; 7(4)2023 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-37243731

RESUMO

BACKGROUND: Presence of circulating tumor DNA (ctDNA) is prognostic in solid tumors treated with curative intent. Studies have evaluated ctDNA at specific "landmark" or multiple "surveillance" time points. However, variable results have led to uncertainty about its clinical validity. METHODS: A PubMed search identified relevant studies evaluating ctDNA monitoring in solid tumors after curative intent therapy. Odds ratios for recurrence at both landmark and surveillance time points for each study were calculated and pooled in a meta-analysis using the Peto method. Pooled sensitivity and specificity weighted by individual study inverse variance were estimated and meta-regression using linear regression weighted by inverse variance was performed to explore associations between patient and tumor characteristics and the odds ratio for disease recurrence. RESULTS: Of 39 studies identified, 30 (1924 patients) and 24 studies (1516 patients) reported on landmark and surveillance time points, respectively. The pooled odds ratio for recurrence at landmark was 15.47 (95% confidence interval = 11.84 to 20.22) and at surveillance was 31.0 (95% confidence interval = 23.9 to 40.2). The pooled sensitivity for ctDNA at landmark and surveillance analyses was 58.3% and 82.2%, respectively. The corresponding specificities were 92% and 94.1%, respectively. Prognostic accuracy was lower with tumor agnostic panels and higher with longer time to landmark analysis, number of surveillance draws, and smoking history. Adjuvant chemotherapy negatively affected landmark specificity. CONCLUSIONS: Although prognostic accuracy of ctDNA is high, it has low sensitivity, borderline high specificity, and therefore modest discriminatory accuracy, especially for landmark analyses. Adequately designed clinical trials with appropriate testing strategies and assay parameters are required to demonstrate clinical utility.


Assuntos
DNA Tumoral Circulante , Neoplasias , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Recidiva , DNA Tumoral Circulante/genética , Prognóstico
7.
J Geriatr Oncol ; 13(3): 318-324, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34924306

RESUMO

BACKGROUND: Grip strength (GS) and the Short Physical Performance Battery (SPPB) are brief objective tests used during a comprehensive geriatric assessment (CGA) to assess physical performance. Abnormal GS and SPPB scores are associated with greater morbidity and mortality in older adults with cancer but their relationship with chemotherapy tolerability is unclear. We explored the performance of GS and SPPB in predicting therapy delay, dose reduction, and treatment completion in older adults undergoing chemotherapy or chemoradiation. Additionally, we examined associations between GS, SPPB, and instrumental activities of daily living (IADLs). METHODS: Retrospective review of patients ≥65 years old who had undergone a pre-treatment CGA in a geriatric oncology clinic were retrieved from electronic charts and institutional databases. Abnormal GS was defined as <26 kg and < 16 kg for men and women, respectively. Abnormal SPPB was defined as ≤9 points. Logistic regression was used to examine the associations between abnormal GS or SPPB alone or combined with chemotherapy-related outcomes (e.g., delay, dose reduction, completion). Chi-squared tests were used to determine associations between physical performance measures (GS and SPPB) and IADLs. RESULTS: A total of 85 participants (mean age 79.1 years old) with mixed cancer diagnoses were included. Approximately 67% of participants exhibited abnormal GS or SPPB prior to treatment. Abnormal GS or SPPB (combined) was associated with treatment delay (odds ratio (OR) = 7.58, 95% confidence interval (CI) = 1.77, 32.43, P = 0.006). When physical performance measures were examined separately, only SPPB predicted treatment delay (OR = 3.26, 95%CI = 1.04, 10.21, P = 0.043). Abnormal GS or SPPB were not associated with dose reduction or treatment completion. Abnormal GS and SPPB alone or combined demonstrated only modest sensitivity (41.9-76.7%) and negative predictive value (57.9-64.2%) in identifying IADLs dependence. CONCLUSION: GS and SPPB may be used to predict treatment delay in older adults prior to chemotherapy and chemoradiation. Additional studies are warranted to examine whether GS and/or SPPB can predict dose reduction and treatment completion in older adults prior to receiving chemotherapy or chemoradiation.


Assuntos
Atividades Cotidianas , Neoplasias , Idoso , Feminino , Avaliação Geriátrica , Força da Mão , Humanos , Masculino , Neoplasias/tratamento farmacológico , Desempenho Físico Funcional
8.
Sci Rep ; 12(1): 6352, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35428842

RESUMO

Disease-free survival (DFS) comprises both breast cancer and non-breast cancer events. DFS has not been validated as a surrogate endpoint for overall survival (OS) in most breast cancer subtypes. We assessed changes to the type of events contributing to DFS over time. We identified adjuvant studies in breast cancer (BC) from 2000 to 2020 where the endpoint was DFS. We examined change in distant DFS events and the BC-related DFS using univariable and multivariable linear regression. Data were reported quantitatively using the Burnand criteria irrespective of statistical significance. We included 84 studies (88 cohorts), comprising 212,191 participants, 41,604 DFS events and 23,205 distant DFS events. The DFS event rate/100 participants/year has declined modestly over time (ß - 0.34, p = 0.001). Start year was negatively associated with distant DFS events (ß - 0.58, p < 0.0001); however, the effect was lost after adjusting for follow-up time (ß - 0.18, p = 0.096). The average number of BC-related events/100 participants/year also declined over time (ß - 0.28, p = 0.009). In multivariable analysis, start year and ER expression were quantitatively associated with distant DFS events and BC-related DFS events. DFS events have declined over time driven by a reduction in BC related events. As DFS events are increasingly defined by non-BC events, there will be limited surrogacy between DFS and OS.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Intervalo Livre de Progressão , Estudos Retrospectivos
9.
J Cancer ; 12(14): 4372-4378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093837

RESUMO

Background: Multiple anti-PD-1/PD-L1 antibodies have been approved, and in some diseases, there is a choice of more than one. Comparative efficacy, safety and tolerability are unknown. Methods: Randomized trials (RCTs) supporting the registration of single agent anti-PD1 or anti-PDL1 inhibitors between 2015-2019 were identified. We extracted the hazard ratio (HR) for overall survival (OS) and calculated the odds ratio (OR) for commonly reported safety and tolerability outcomes. We then performed a network meta-analysis, reporting multiple pair-wise comparisons between different anti-PD-1/PD-L1 antibodies. Results: Sixteen RCTs comprising 10673 patients were included; 10 in non-small-cell lung cancer, 2 in melanoma, 2 in head and neck squamous cell carcinoma and 2 in urothelial cancer. Compared to pembrolizumab, efficacy was similar for nivolumab (HR: 1.02 95% CI: 0.91-1.14) and for atezolizumab (HR: 0.97 95% CI: 0.85-1.10), however, avelumab appeared inferior (HR: 1.30, 95% CI: 1.06-1.56). Pembrolizumab showed similar odds of serious adverse events (SAEs) as nivolumab (OR: 1.12, 95% CI: 0.56-2.27) and atezolizumab (OR: 1.05, 95% CI: 0.55-2.04). Compared to nivolumab, atezolizumab was associated with more SAEs (OR: 2.14, 95% CI: 1.47-3.12). Avelumab had the lowest odds of grade 3-4 adverse events compared to pembrolizumab (OR: 0.42, 95% CI: 0.24-0.74), nivolumab (OR: 0.38, 95% CI: 0.24-0.62) and atezolizumab (OR: 0.21, 95% CI: 0.14-0.33). The odds of treatment discontinuation without progression were similar between nivolumab and atezolizumab (OR: 1.20, 95% CI: 0.73-2.00), and between pembrolizumab and nivolumab (OR: 1.35, 95% CI: 0.83-2.17), but was higher with atezolizumab compared to nivolumab (OR: 2.56, 95% CI: 1.29-5.00). Pembrolizumab was associated with higher OR of immune-related adverse events (IRAEs) compared to nivolumab (OR: 2.12, 95% CI: 1.49-3.03) and atezolizumab (OR: 1.63, 95% CI: 1.09-2.43). Conclusions: Pembrolizumab, nivolumab, and atezolizumab have similar efficacy. Avelumab appears less efficacious. Safety and tolerability seem better with avelumab, but worse with atezolizumab and pembrolizumab.

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