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1.
Artigo em Inglês | MEDLINE | ID: mdl-34610388

RESUMO

PURPOSE: The clinical cell-cycle risk (CCR) score, which combines the University of California San Francisco Cancer of the Prostate Risk Assessment (CAPRA) and the cell cycle progression (CCP) molecular score, has been validated to be prognostic of disease progression for men with prostate cancer. This study evaluated the ability of the CCR score to prognosticate the risk of metastasis in men receiving dose-escalated radiation therapy (RT) with or without androgen deprivation therapy (ADT). METHODS: This retrospective, multi-institutional cohort study included men with localized National Comprehensive Cancer Network (NCCN) intermediate-, high-, and very high-risk prostate cancer (N=741). Patients were treated with dose-escalated RT ± ADT. The primary outcome was time to metastasis. RESULTS: CCR score prognosticated metastasis [hazard ratio per unit score (HR) 2.22, 95% confidence interval (CI) 1.71-2.89, p<0.001]. CCR score better prognosticated metastasis than NCCN risk group (CCR p <0.001; NCCN p = 0.46), CAPRA score (CCR p = 0.002; CAPRA p = 0.59), or CCP score (CCR p <0.001; CCP p = 0.59) alone. In bivariable analyses, CCR score remained highly prognostic when accounting for ADT vs. no ADT (HR 2.18, 95% CI 1.61-2.96, p<0.001), ADT duration as a continuous variable (HR 2.11, 95% CI 1.59-2.79, p<0.001), or ADT given at or below the recommended duration for each NCCN risk group (HR 2.19, 95% CI 1.69-2.86, p<0.001). Men with CCR scores below or above the multimodality threshold (CCR=2.112) had a 10-year risk of metastasis of 3.7% and 21.24%, respectively. Men with below-threshold scores receiving RT alone had a 3.7% 10-year risk of metastasis whereas for men receiving RT plus ADT, 10-year risk of metastasis was 3.7%. CONCLUSIONS: CCR score accurately and precisely prognosticates metastasis and adds clinically actionable information relative to guideline-recommended therapies based on NCCN risk in men undergoing dose-escalated RT ±ADT. Men with scores below the multimodality threshold may not significantly reduce their 10-year risk of metastasis by adding ADT.

2.
BMJ Open Respir Res ; 8(1)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34551962

RESUMO

IMPORTANCE: Use of non-invasive respiratory modalities in COVID-19 has the potential to reduce rates of intubation and mortality in severe disease however data regarding the use of high-flow nasal cannula (HFNC) in this population is limited. OBJECTIVE: To interrogate clinical and laboratory features of SARS-CoV-2 infection associated with high-flow failure. DESIGN: We conducted a retrospective cohort study to evaluate characteristics of high-flow therapy use early in the pandemic and interrogate factors associated with respiratory therapy failure. SETTING: Multisite single centre hospital system within the metropolitan Detroit region. PARTICIPANTS: Patients from within the Detroit Medical Center (n=104, 89% African American) who received HFNC therapy during a COVID-19 admission between March and May of 2020. PRIMARY OUTCOME: HFNC failure is defined as death or intubation while on therapy. RESULTS: Therapy failure occurred in 57% of the patient population, factors significantly associated with failure centred around markers of multiorgan failure including hepatic dysfunction/transaminitis (OR=6.1, 95% CI 1.9 to 19.4, p<0.01), kidney injury (OR=7.0, 95% CI 2.7 to 17.8, p<0.01) and coagulation dysfunction (OR=4.5, 95% CI 1.2 to 17.1, p=0.03). Conversely, comorbidities, admission characteristics, early oxygen requirements and evaluation just prior to HFNC therapy initiation were not significantly associated with success or failure of therapy. CONCLUSIONS: In a population disproportionately affected by COVID-19, we present key indicators of likely HFNC failure and highlight a patient population in which aggressive monitoring and intervention are warranted.

3.
Cancer Genet ; 258-259: 61-68, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34551377

RESUMO

BACKGROUND: High tumor mutation burden (TMB) and total mutation count (TMC) can be predictive of better response to immune checkpoint blockade (ICB). Nevertheless, TMB and TMC are limited by variation across cancers and inconsistent definitions due to different profiling methods (targeted vs whole genome sequencing). Our objective was to identify genomic alterations (GAs) associated with ICB response and builds a novel genomic signature predictive of ICB response, independent of TMB/TMC. METHODS: This was a pan-cancer next generation sequencing (NGS)-association study using January 2014-May 2016 data from AACR Project Genomics Evidence Neo-plasia Information Exchange (GENIE). Participants included 6619 patients with metastatic or un-resectable cancer across 9 cancer types (including 1572 ICB-treated patients). GA data was collected using next-generation sequencing (NGS) assays and downloaded from cbioportal.org. Predictive analyses for ICB response were performed to develop the signature (ImmGA). RESULTS: GAs in 16 genes were associated with improved OS in ICB-treated patients (p < 0.005). 13 GAs were associated with an OS benefit in ICB-treated patients (Pinteraction < 0.05); these genes composed the ImmGA signature. High ImmGA score (≥2 alterations out of 13 predictive GAs) was associated with better OS in ICB-treated patients (AHR:0.67, 95%CI [0.6-0.75], p = 1.4e-12), even after accounting for TMC (Pinteraction = 8e-16). High ImmGA was associated with better OS in ICB-treated patients across most cancers and across different ICB treatment modalities. CONCLUSION: A novel signature predictive of ICB response (ImmGA) was developed from 13 GAs. Further investigation of the utility of ImmGA for treatment and trial selection is warranted.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34530092

RESUMO

PURPOSE: Persistent immunosuppression in the tumor micro-environment is a major limitation to boosting the abscopal effect, whereby radiotherapy at one site can lead to regression of tumors at distant sites. Here, we investigate the use of radiation and immunogenic biomaterials (IBM) targeting only the gross tumor sub-volume for boosting the abscopal effect in immunologically cold tumors. METHODS: To evaluate the abscopal effect, two syngeneic contralateral tumors were implanted in each mouse, where only one tumor was treated. IBM was administered to the treated tumor with one fraction of radiation and results were compared, including as a function of different radiotherapy field sizes. The IBM was designed similar to fiducial markers using immunogenic polymer components loaded with anti-CD40 agonist. Tumor volumes of both treated and untreated tumors were measured over time, along with survival and corresponding immune cell responses. RESULTS: Results showed that radiation with IBM administered to the gross tumor sub-volume can effectively boost abscopal responses in both pancreatic and prostate cancers, significantly increasing survival (P<0.0001 and p<0.001, respectively). Results also showed equal or superior abscopal responses when using field sizes smaller than the gross tumor volume compared to irradiating the whole tumor volume. These results were buttressed by observation of higher infiltration of cytotoxic CD8+T-lymphocytes in the treated tumors (p<0.0001) and untreated tumors (p<0.0001) for prostate cancer. Significantly higher infiltration was also observed in treated tumors (p<0.0001) and untreated tumors p<0.01) for pancreatic cancer. Moreover, the immune responses were accompanied by a positive shift of pro-inflammatory cytokines in both prostate and pancreatic tumors. CONCLUSIONS: The approach targeting gross tumor sub-volumes with radiation and IBM offers opportunity for boosting the abscopal effect, while significantly minimizing healthy tissue toxicity. This approach proffers a radio-immunotherapy dose-painting strategy that can be developed for overcoming current barriers of immunosuppression especially for immunologically cold tumors.

5.
COPD ; : 1-9, 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530662

RESUMO

Literature regarding trends of incidence, mortality, and complications of acute exacerbation of chronic obstructive pulmonary disease (COPD) in the emergency departments (ED) is limited. What are trends of COPD exacerbation in ED? Data were obtained from the Nationwide Emergency Department Sample (NEDS) that constitutes a 20% sample of hospital-owned EDs and inpatient sample in the US. All ED encounters were included in the analysis. Complications of AECOPD were obtained by using ICD codes. Out of 1.082 billion ED encounters, 5,295,408 (mean age 63.31 ± 12.63 years, females 55%) presented with COPD exacerbation. Among these patients, 353,563(6.7%) had AECOPD-plus (features of pulmonary embolism, acute heart failure and/or pneumonia) while 4,941,845 (93.3%) had exacerbation without associated features or precipitating factors which we grouped as AECOPD. The AECOPD-plus group was associated with statistically significantly higher proportion of cardiovascular complications including AF (5.6% vs 3.5%; p < 0.001), VT/VF (0.14% vs 0.06%; p < 0.001), STEMI (0.22% vs 0.11%; p < 0.001) and NSTEMI (0.65% vs 0.2%; p < 0.001). The in-hospital mortality rates were greater in the AECOPD-plus population (0.7% vs 0.1%; p < 0.001). The incidence of both AECOPD and AECOPD-plus had worsened (p-trend 0.004 and 0.0003) and the trend of mortality had improved (p-trend 0.0055 and 0.003, respectively). The prevalence of smoking for among all COPD patients had increased (p-value 0.004), however, the prevalence trend of smoking among AECOPD groups was static over the years 2010-2018. There was an increasing trend of COPD exacerbation in conjunction with smoking; however, mortality trends improved significantly. Moreover, the rising burden of AECOPD would suggest improvement in diagnostics and policy making regarding management.

7.
Commun Biol ; 4(1): 670, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083737

RESUMO

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P < 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P < 0.001), and basal-like (P < 0.001) molecular subtypes. After adjusting for confounders, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6) (p < 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling. Based on cell lines data, AAM were predicted to have higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Genômica/métodos , Neoplasias da Próstata/genética , Afro-Americanos/estatística & dados numéricos , Idoso , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias da Próstata/etnologia , Neoplasias da Próstata/imunologia , Estudos Retrospectivos , Estados Unidos
8.
Radiother Oncol ; 161: 241-250, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34171451

RESUMO

BACKGROUND: Prostate radiotherapy has been associated with an increased risk of developing a second malignancy (SM). However, relative SM probabilities following treatment with contemporary radiation techniques such as stereotactic body radiotherapy (SBRT) or moderately hypofractionated intensity modulated radiotherapy (HF-IMRT) remain unknown. METHODS: A cohort analysis was performed of men from a nationally representative database with localized prostate cancer with at least 60 months of follow-up comparing SM probability amongst men receiving either radical prostatectomy (RP), conventionally fractionated intensity-modulated radiotherapy (CF-IMRT), HF-IMRT, brachytherapy (BT), or SBRT, using multivariable logistic models, which were used to generate predicted probabilities. Additionally, propensity score-adjusted pairwise assessments of modalities were performed. RESULTS: For 303,432 patients included in the study, median follow-up was 9.08 years (IQR 7.01-11.21). Predicted rates of SM by treatment modality and adjusted odds ratios (AOR) for development of SM (referent: RP) were: 6.0% for RP (AOR n/a), 7.1% for CF-IMRT (AOR 1.20, 95%CI 1.14-1.25, P < 0.001), 7.3% for HF-IMRT (AOR 1.25, 95%CI 1.01-1.55, P = 0.045), 6.6% for BT (AOR 1.11, 95%CI 1.07-1.16, P < 0.001), and 5.7% for SBRT (AOR 0.95, 95%CI 0.81-1.12, P = 0.567). On propensity score-adjusted analysis, SBRT was associated with lower odds of SM compared to CF-IMRT (AOR 0.78, 95%CI 0.66-0.93, P = 0.005); no significant difference was found when SBRT was compared to RP (AOR 0.86, 95%CI 0.73-1.03, P = 0.102). CONCLUSIONS: Conventionally fractionated intensity-modulated radiotherapy, moderately hypofractionated intensity-modulated radiotherapy, and brachytherapy but not stereotactic body radiotherapy were associated with increased probability of a second malignancy compared to radical prostatectomy. Patients treated with SBRT may be at lower risk of second malignancy due to improved conformality, radiobiological differences or patient selection. The possibility that SBRT in select patients may minimize the probability of SM underscores the need for assessment of second malignancy risk in prospective studies of SBRT.


Assuntos
Braquiterapia , Segunda Neoplasia Primária , Neoplasias da Próstata , Radiocirurgia , Radioterapia de Intensidade Modulada , Humanos , Masculino , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Pontuação de Propensão , Estudos Prospectivos , Neoplasias da Próstata/radioterapia , Radiocirurgia/efeitos adversos , Radioterapia de Intensidade Modulada/efeitos adversos
9.
J Clin Oncol ; 39(25): 2845-2846, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34086490
10.
Cancer Rep (Hoboken) ; : e1407, 2021 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-33934574

RESUMO

BACKGROUND: Currently, little is known about the effect of the Patient Protection and Affordable Care Act's Medicaid expansion on care delivery and outcomes in cervical cancer. AIM: We evaluated whether Medicaid expansion was associated with changes in insurance status, stage at diagnosis, timely treatment, and survival outcomes in cervical cancer. METHODS AND RESULTS: Using the National Cancer Database, we performed a difference-in-differences (DID) cross-sectional analysis to compare insurance status, stage at diagnosis, timely treatment, and survival outcomes among cervical cancer patients residing in Medicaid expansion and nonexpansion states before (2011-2013) and after (2014-2015) Medicaid expansion. January 1, 2014 was used as the timepoint for Medicaid expansion. The primary outcomes of interest were insurance status, stage at diagnosis, treatment within 30 and 90 days of diagnosis, and overall survival. Fifteen thousand two hundred sixty-five patients (median age 50) were included: 42% from Medicaid expansion and 58% from nonexpansion states. Medicaid expansion was significantly associated with increased Medicaid coverage (adjusted DID = 11.0%, 95%CI = 8.2, 13.8, p < .01) and decreased rates of uninsured (adjusted DID = -3.0%, 95%CI = -5.2, -0.8, p < .01) among patients in expansion states compared with non-expansion states. However, Medicaid expansion was not associated with any significant changes in cancer stage at diagnosis or timely treatment. There was no significant change in survival from the pre- to post-expansion period in either expansion or nonexpansion states, and no significant differences between the two (DID-HR = 0.95, 95%CI = 0.83, 1.09, p = .48). CONCLUSION: Although Medicaid expansion was associated with an increase in Medicaid coverage and decrease in uninsured among patients with cervical cancer, the effects of increased coverage on diagnosis and treatment outcomes may have yet to unfold. Future studies, including longer follow-up are necessary to understand the effects of Medicaid expansion.

11.
Cancer ; 127(13): 2213-2221, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33905530

RESUMO

BACKGROUND: For men with radiation-managed prostate cancer, there is conflicting evidence regarding the association between androgen deprivation therapy (ADT) and cardiovascular mortality (CVM), particularly among those who have with preexisting comorbidities. The objective of this study was to analyze the association between ADT and CVM across patient comorbidity status using prospectively collected data from a large clinical trial. METHODS: In total, 1463 men were identified who were diagnosed with clinically localized, intermediate-risk/high-risk prostate cancer (T2b-T4, Gleason 7-10, or prostate-specific antigen >10 ng/mL) from 1993 to 2001 and managed with either radiation therapy (RT) alone or RT plus ADT during the randomized Prostate, Lung, Colon, and Ovarian (PLCO) Cancer Screening Trial. Adjusted hazard ratios (aHRs) for cause-specific mortality (prostate cancer-specific mortality vs other-cause mortality-including the primary end point of CVM [death from ischemic heart disease, cerebrovascular accident, or other circulatory disease]) were determined using Fine and Gray competing-risk regression analysis and stratified by comorbidity history. RESULTS: There was no difference in the risk of 5-year CVM between ADT plus RT and RT alone (2.3% vs 3.3%, respectively; aHR, 0.69; 95% CI, 0.38-1.24; P = .21) overall or on subgroup analysis among men with a history of ≥1 preexisting comorbidities (3.2% vs 5.3%, respectively; aHR, 0.83; 95% CI, 0.43-1.60; P = .58), ≥2 preexisting comorbidities (6.9% vs 8.3%, respectively; aHR, 0.95; 95% CI, 0.40-2.25; P = .90), or cardiovascular disease/risk factors (3.6% vs 4.3%, respectively; aHR, 0.85; 95% CI, 0.44-1.65; P = .63). These results were all similar when each component of CVM was analyzed separately-either cardiac, stroke, or other vascular mortality (P > .05). CONCLUSIONS: This study provides prospectively collected evidence that the use of ADT plus RT, compared with RT alone, is not associated with an increased risk of CVM, even among subgroups of men who have preexisting comorbidities and cardiovascular disease.

12.
Urology ; 154: 208-214, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33857569

RESUMO

OBJECTIVE: To characterize the presentation, patterns of care, and outcomes of radiation-associated muscle-invasive bladder cancer (RA-MIBC) compared to primary (non-radiation associated) MIBC. RA-MIBC has been suggested to represent a more aggressive disease variant and be more difficult to treat compared to primary (non-radiation associated) MIBC. METHODS: We identified 60,090 patients diagnosed with MIBC between 1988-2015 using the Surveillance, Epidemiology, and End Results database and stratified patients based on whether radiation had been administered to a prior pelvic primary cancer. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC compared to primary MIBC. RESULTS: There were 1,093 patients with RA-MIBC and 58,997 patients with primary MIBC. RA-MIBCs were more likely to be T4 at diagnosis (21.0% vs 17.3%, P < .001), and less likely to be node-positive (10.3% vs 17.1%, P < .001). The rate of 5-year BCSM was significantly higher for patients with RA-MIBC vs primary MIBC (56.1% vs 35.3%, AHR 1.24, P < .001), even after stratification by other tumor, treatment and patient-specific factors. CONCLUSION: RA-MIBCs tended to present with higher grade and T stage disease and were less likely to receive curative treatment. Even when accounting for stage, grade, and receipt of treatment, patients with RA-MIBC had worse survival compared to those with primary MIBC. These findings suggest that RA-MIBC present unique clinical challenges and may also represent a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand the biology of RA-MIBC and develop improved treatment approaches.

13.
Support Care Cancer ; 29(9): 5523-5535, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33725174

RESUMO

BACKGROUND: A growing proportion of cancer survivors experience financial toxicity. However, the psychological burden of cancer costs and associated mental health outcomes require further investigation. We assessed prevalence and predictors of self-reported financial worry and mental health outcomes among cancer survivors. PATIENTS AND METHODS: Data from the 2013-2018 National Health Interview Survey (NHIS) for adults reporting a cancer diagnosis were used. Multivariable ordinal logistic regressions defined adjusted odds ratios (AORs) of reporting financial worry by relevant sociodemographic variables, and sample weight-adjusted prevalence of financial worry was estimated. The association between financial worry and psychological distress, as defined by the six-item Kessler Psychological Distress Scale was also assessed. RESULTS: Among 13,361 survey participants (median age 67; 60.0% female), 9567 (71.6%) self-reported financial worry, including worries regarding costs of paying for children's college education (62.7%), maintaining one's standard of living (59.7%), and medical costs due to illness or accident (58.3%). Female sex, younger age, and Asian American race were associated with increased odds of financial worry (P < 0.05 for all). Of 13,218 participants with complete responses to K6 questions, 701 (5.3%) met the threshold for severe psychological distress. Participants endorsing financial worry were more likely to have psychological distress (6.6 vs. 1.2%, AOR 2.89, 95% CI 2.03-4.13, P< 0.001) with each additional worry conferring 23.9% increased likelihood of psychological distress. CONCLUSIONS: A majority of cancer survivors reported financial worry, which was associated with greater odds of reporting psychological distress. Policies and guidelines are needed to identify and mitigate financial worries and psychologic distress among patients with cancer, with the goal of improving psychological well-being and overall cancer survivorship care.

14.
Prostate Cancer Prostatic Dis ; 24(2): 575-577, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33750906

RESUMO

BACKGROUND: Multiple genomic tests are available following radical prostatectomy (RP), however, there is a lack of head-to-head evidence for these tests. We sought to compare the performance of two genomic tests in predicting post-RP oncological outcomes. METHODS: A cohort of 16 post-RP patients with adverse pathological features who had obtained both Decipher (D) and Prolaris (P) testing. The Pearson correlation was used to compare scores from D and cell cycle progression (CCP) from P. Then, we derived a microarray CCP (mCCP) from D and correlated with P-CCP. The associations of D and mCCP with biochemical recurrence (BCR) and metastasis (M) was evaluated in multivariable survival analysis (MVA) in a large cohort of RP patients treated at Johns Hopkins University (1992-2010). In addition, we characterized the expression of the 31 P-CCP genes and mCCP scores in a cohort of 17,967 RP samples from Decipher platform. RESULTS: There was significant correlation between the D score and P-CCP (r = 0.67, p = 0.004), and between the 10-year probability of BCR reported by P and 5-year probability of M reported by D (r = 0.69, p = 0.003). In this cohort, mCCP derived from the D platform was highly correlated to the reported P-CCP scores from the P platform (r = 0.88, p = 6.7e-6). In a comparative retrospective RP cohort, both mCCP and D were significantly associated with M outcome (p < 0.01 for both). On MVA, D was a predictor of M (HR 1.3, 95% CI [1.12-1.52], p = 0.0005), while mCCP was not a predictor of M (p = 0.62). In the D platform cohort, the 31 P-CCP genes were correlated to each other, and TOP2A was the most correlated to mCCP (r = 0.7). CONCLUSIONS: We found that P and D scores post-RP were correlated and help in identifying patients who at high risk of BCR in this cohort. In a larger cohort with longer follow-up, D was predictor of M, whereas mCCP was not.

15.
Lancet Oncol ; 22(3): 402-410, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33662287

RESUMO

BACKGROUND: The international Intermediate Clinical Endpoints in Cancer of the Prostate working group has established metastasis-free survival as a surrogate for overall survival in localised prostate cancer based on the findings of 19 predominantly radiotherapy-based trials. We sought to comprehensively assess aggregate trial-level performance of commonly reported intermediate clinical endpoints across all randomised trials in localised prostate cancer. METHODS: For this meta-analysis, we searched PubMed for all trials in localised or biochemically recurrent prostate cancer published between Jan 1, 1970, and Jan 15, 2020. Eligible trials had to be randomised, therapeutic, reporting overall survival and at least one intermediate clinical endpoint, and with a sample size of at least 70 participants. Trials of metastatic disease were excluded. Intermediate clinical endpoints included biochemical failure, local failure, distant metastases, biochemical failure-free survival, progression-free survival, and metastasis-free survival. Candidacy for surrogacy was assessed using the second condition of the meta-analytical approach (ie, correlation of the treatment effect of the intermediate clinical endpoint and overall survival), using R2 weighted by the inverse variance of the log intermediate clinical endpoint hazard ratio. The intermediate clinical endpoint was deemed to be a surrogate for overall survival if R2 was 0·7 or greater. FINDINGS: 75 trials (53 631 patients) were included in our analysis. Median follow-up was 9·1 years (IQR 5·7-10·6). Biochemical failure (R2 0·38 [95% CI 0·11-0·64]), biochemical failure-free survival (R2 0·12 [0·0030-0·33]), biochemical failure and clinical failure (R2 0·28 [0·0045-0·65]), and local failure (R2 0·085 [0·00-0·37]) correlated poorly with overall survival. Progression-free survival (R2 0·46 [95% CI 0·22-0·67]) showed moderate correlation with overall survival, and metastasis-free survival (R2 0·78 [0·59-0·89]) correlated strongly. INTERPRETATION: Intermediate clinical endpoints based on biochemical and local failure did not meet the second condition of the meta-analytical approach and are not surrogate endpoints for overall survival in localised prostate cancer. Our findings validate metastasis-free survival as the only identified surrogate endpoint for overall survival to date. FUNDING: Prostate Cancer Foundation and National Institutes of Health.


Assuntos
Biomarcadores/análise , Recidiva Local de Neoplasia/mortalidade , Neoplasias da Próstata/mortalidade , Idoso , Terapia Combinada , Seguimentos , Humanos , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Prognóstico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Taxa de Sobrevida
16.
JAMA Netw Open ; 4(3): e213304, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33779742

RESUMO

Importance: During the COVID-19 pandemic, cancer therapy may put patients at risk of SARS-CoV-2 infection and mortality. The impacts of proposed alternatives on reducing infection risk are unknown. Objective: To investigate how the COVID-19 pandemic is associated with the risks and benefits of standard radiation therapy (RT). Design, Setting, and Participants: This comparative effectiveness study used estimated individual patient-level data extracted from published Kaplan-Meier survival figures from 8 randomized clinical trials across oncology from 1993 to 2014 that evaluated the inclusion of RT or compared different RT fractionation regimens. Included trials were Dutch TME and TROG 01.04 examining rectal cancer; CALGB 9343, OCOG hypofractionation trial, FAST-Forward, and NSABP B-39 examining early stage breast cancer, and CHHiP and HYPO-RT-PC examining prostate cancer. Risk of SARS-CoV-2 infection and mortality associated with receipt of RT in the treatment arms were simulated and trials were reanalyzed. Data were analyzed between April 1, 2020, and June 30, 2020. Exposures: COVID-19 risk associated with treatment was simulated across different pandemic scenarios, varying infection risk per fractions (IRFs) and case fatality rates (CFRs). Main Outcomes and Measures: Overall survival was evaluated using Cox proportional hazards modeling under different pandemic scenarios. Results: Estimated IPLD from a total of 14 170 patients were included in the simulations. In scenarios with low COVID-19-associated risks (IRF, 0.5%; CFR, 5%), fractionation was not significantly associated with outcomes. In locally advanced rectal cancer, short-course RT was associated with better outcomes than long-course chemoradiation (TROG 01.04) and was associated with similar outcomes as RT omission (Dutch TME) in most settings (eg, TROG 01.04 median HR, 0.66 [95% CI, 0.46-0.96]; Dutch TME median HR, 0.91 [95% CI, 0.80-1.03] in a scenario with IRF 5% and CFR 20%). Moderate hypofractionation in early stage breast cancer (OCOG hypofractionation trial) and prostate cancer (CHHiP) was not associated with survival benefits in the setting of COVID-19 (eg, OCOG hypofractionation trial median HR, 0.89 [95% CI, 0.74-1.06]; CHHiP median HR, 0.87 [95% CI, 0.75-1.01] under high-risk scenario with IRF 10% and CFR 30%). More aggressive hypofractionation (FAST-Forward, HYPO-RT-PC) and accelerated partial breast irradiation (NSABP B-39) were associated with improved survival in higher risk scenarios (eg, FAST-Forward median HR, 0.58 [95% CI, 0.49-0.68]; HYPO-RT-PC median HR, 0.60 [95% CI, 0.48-0.75] under scenario with IRF 10% and CFR 30%). Conclusions and Relevance: In this comparative effectiveness study of data from 8 clinical trials of patients receiving radiation therapy to simulate COVID-19 risk and mortality rates, treatment modification was not associated with altered risk from COVID-19 in lower-risk scenarios and was only associated with decreased mortality in very high COVID-19-risk scenarios. This model, which can be adapted to dynamic changes in COVID-19 risk, provides a flexible, quantitative approach to assess the potential impact of treatment modifications and supports the continued delivery of standard evidence-based care with appropriate precautions against COVID-19.


Assuntos
Neoplasias da Mama/radioterapia , COVID-19 , Fracionamento da Dose de Radiação , Pandemias , Assistência ao Paciente/métodos , Neoplasias da Próstata/radioterapia , Neoplasias Retais/radioterapia , Algoritmos , COVID-19/mortalidade , COVID-19/prevenção & controle , Pesquisa Comparativa da Efetividade , Conjuntos de Dados como Assunto , Feminino , Humanos , Controle de Infecções , Masculino , Modelos de Riscos Proporcionais , Hipofracionamento da Dose de Radiação , Radiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco , Medição de Risco , Padrão de Cuidado
17.
JAMA Oncol ; 7(4): 544-552, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33570548

RESUMO

Importance: Decipher (Decipher Biosciences Inc) is a genomic classifier (GC) developed to estimate the risk of distant metastasis (DM) after radical prostatectomy (RP) in patients with prostate cancer. Objective: To validate the GC in the context of a randomized phase 3 trial. Design, Setting, and Participants: This ancillary study used RP specimens from the phase 3 placebo-controlled NRG/RTOG 9601 randomized clinical trial conducted from March 1998 to March 2003. The specimens were centrally reviewed, and RNA was extracted from the highest-grade tumor available in 2019 with a median follow-up of 13 years. Clinical-grade whole transcriptomes from samples passing quality control were assigned GC scores (scale, 0-1). A National Clinical Trials Network-approved prespecified statistical plan included the primary objective of validating the independent prognostic ability of GC for DM, with secondary end points of prostate cancer-specific mortality (PCSM) and overall survival (OS). Data were analyzed from September 2019 to December 2019. Intervention: Salvage radiotherapy (sRT) with or without 2 years of bicalutamide. Main Outcomes and Measures: The preplanned primary end point of this study was the independent association of the GC with the development of DM. Results: In this ancillary study of specimens from a phase 3 randomized clinical trial, GC scores were generated from 486 of 760 randomized patients with a median follow-up of 13 years; samples from a total of 352 men (median [interquartile range] age, 64.5 (60-70) years; 314 White [89.2%] participants) passed microarray quality control and comprised the final cohort for analysis. On multivariable analysis, the GC (continuous variable, per 0.1 unit) was independently associated with DM (hazard ratio [HR], 1.17; 95% CI, 1.05-1.32; P = .006), PCSM (HR, 1.39; 95% CI, 1.20-1.63; P < .001), and OS (HR, 1.17; 95% CI, 1.06-1.29; P = .002) after adjusting for age, race/ethnicity, Gleason score, T stage, margin status, entry prostate-specific antigen, and treatment arm. Although the original planned analysis was not powered to detect a treatment effect interaction by GC score, the estimated absolute effect of bicalutamide on 12-year OS was less when comparing patients with lower vs higher GC scores (2.4% vs 8.9%), which was further demonstrated in men receiving early sRT at a prostate-specific antigen level lower than 0.7 ng/mL (-7.8% vs 4.6%). Conclusions and Relevance: This ancillary validation study of the Decipher GC in a randomized trial cohort demonstrated association of the GC with DM, PCSM, and OS independent of standard clinicopathologic variables. These results suggest that not all men with biochemically recurrent prostate cancer after surgery benefit equally from the addition of hormone therapy to sRT. Trial Registration: ClinicalTrials.gov identifier: NCT00002874.

18.
JCO Oncol Pract ; 17(10): e1489-e1501, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33630666

RESUMO

PURPOSE: We assessed sociodemographic factors associated with and survival implications of refusal of potentially survival-prolonging locoregional treatment (LT, including radiotherapy and surgery) despite provider recommendation among men with localized prostate adenocarcinoma. METHODS: The National Cancer Database (2004-2015) identified men with TxN0M0 prostate cancer who either received or refused LT despite provider recommendation. Multivariable logistic regression defined adjusted odds ratios (AORs) with 95% CI of refusing LT, with sociodemographic and clinical covariates. Models were stratified by low-risk and intermediate- or high-risk (IR or HR) disease, with a separate interaction analysis between race and risk group. Multivariable Cox proportional hazard ratios compared overall survival (OS) among men who received versus refused LT. RESULTS: Of 887,839 men (median age 64 years, median follow-up 6.14 years), 2,487 (0.28%) refused LT. Among men with IR or HR disease (n = 651,345), Black and Asian patients were more likely to refuse LT than White patients (0.35% v 0.29% v 0.17%; Black v White AOR, 1.75; 95% CI, 1.52 to 2.01; P < .001; Asian v White AOR, 1.47; 95% CI, 1.05 to 2.06; P = .027, race * risk group interaction P < .001). Later year of diagnosis, community facility type, noninsurance or Medicaid, and older age were also associated with increased odds of LT refusal, overall and when stratifying by risk group. For men with IR or HR disease, LT refusal was associated with worse OS (5-year OS 80.1% v 91.5%, HR, 1.65, P < .001). CONCLUSION: LT refusal has increased over time; racial disparities were greater in higher-risk disease. Refusal despite provider recommendation highlights populations that may benefit from efforts to assess and reduce barriers to care.

19.
J Clin Oncol ; 39(11): 1274-1305, 2021 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-33497248

RESUMO

PURPOSE: Update all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer. METHODS: The Expert Panel based recommendations on a systematic literature review. Recommendations were approved by the Expert Panel and the ASCO Clinical Practice Guidelines Committee. RESULTS: Four clinical practice guidelines, one clinical practice guidelines endorsement, 19 systematic reviews with or without meta-analyses, 47 phase III randomized controlled trials, nine cohort studies, and two review papers informed the guideline update. RECOMMENDATIONS: Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with androgen deprivation therapy (ADT), represent four separate standards of care for noncastrate metastatic prostate cancer. Currently, the use of any of these agents in any particular combination or series cannot be recommended. ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide should be offered to men with metastatic noncastrate prostate cancer, including those who received prior therapies, but have not yet progressed. The combination of ADT plus abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer who have undergone radiotherapy, rather than castration monotherapy. Immediate ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiotherapy. Intermittent ADT may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer. The panel does not support use of either micronized abiraterone acetate or the 250 mg dose of abiraterone with a low-fat breakfast in the noncastrate setting at this time.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.


Assuntos
Neoplasias de Próstata Resistentes à Castração/terapia , Humanos , Masculino , Recidiva Local de Neoplasia
20.
Adv Radiat Oncol ; 6(1): 100566, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32984656

RESUMO

Purpose: In response to the coronavirus disease 2019 pandemic, current Association of American Medical Colleges guidelines discourage away rotations, posing significant challenges for attracting students to radiation oncology (RO). This is particularly concerning for medical students underrepresented in medicine (UIM) due to the potential of widening existing disparities in applicant and workforce composition. To proactively address this, we created a Radiation Oncology Intensive Shadowing Experience (RISE) to expose UIM students to the field of RO. Methods and Materials: Key stakeholders within the residency program, including both UIM faculty and residents with experience in health disparities and medical education, designed a 1-week virtual RISE intended for fourth year UIM students recruited through established national organizations serving UIM medical students. A 1-week disease-specific curriculum was developed using 4 components: (1) foundational exposure to RO, (2) didactic teaching, (3) mentorship opportunities, and (4) a capstone experience. Mentorship was continuously weaved through the experience by attendings, peer resident mentors, and a UIM resident panel to optimize exposure. Results: RISE was successfully initiated at 2 academic medical centers with 12 UIM students enrolled through August. Anonymized pre- and postclerkship surveys were developed for students, residents, and faculty involved in RISE to evaluate participants' satisfaction, resident and attending time burden, and perceptions of program effectiveness. Conclusions: We created a unique virtual RO shadowing experience for UIM students to address a critical gap in exposure to RO, heightened by the corona virus disease 2019 pandemic, with the goal of improving diversity, equity, and inclusion in our field.

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