scholarly journals Effects of Corticosteroid Treatment and Antigen Avoidance in a Large Hypersensitivity Pneumonitis Cohort: A Single-Centre Cohort Study

2018 ◽  
Vol 8 (1) ◽  
pp. 14 ◽  
Author(s):  
Laurens De Sadeleer ◽  
Frederik Hermans ◽  
Els De Dycker ◽  
Jonas Yserbyt ◽  
Johny Verschakelen ◽  
...  
Keyword(s):  
Therapeutic Effect ◽  
Median Survival ◽  
Hypersensitivity Pneumonitis ◽  
Proportional Hazards Model ◽  
Pulmonary Function Tests ◽  
Corticosteroid Treatment ◽  
Cox Proportional Hazards Model ◽  
Therapeutic Interventions ◽  
Mixed Effect ◽  
Dismal Prognosis

Background: Although the third most frequent interstitial lung disease, hypersensitivity pneumonitis (HP) remains an enigmatic disease without clear diagnostic and therapeutic guidelines. We assessed the effect of the commonly used therapeutic interventions (i.e. exposure avoidance and corticosteroid treatment) in an HP cohort. Methods: We collected clinical data of all HP patients followed at our centre between January 1, 2005, and December 31, 2016. HP patients were stratified according to the presence of fibrosis on chest CT. Survival was analysed using the multivariate Cox proportional hazards model. Forced vital capacity (percent predicted, FVC%) and diffusing capacity of the lung for carbon monoxide (percent predicted, DLCO%) evolution were analysed using linear mixed-effect models. Results: Two hundred and two HP patients were identified: 93 non-fibrotic HP (nfHP) and 109 fibrotic HP (fHP), experiencing a monthly FVC% decline before treatment of 0.93% and 0.56%, respectively. While nfHP had an excellent survival, fHP patients experienced a median survival of 9.2 years. Corticosteroid treatment and exposure avoidance did not result in survival differences. Although nfHP patients showed FVC% and DLCO% increase after corticosteroid initiation, no therapeutic effect was seen in fHP patients. FVC% and DLCO% increased in nfHP patients after exposure avoidance, while a positive numerical trend was seen for FVC% after exposure avoidance in fHP patients (p = 0.15). Conclusions: nfHP patients experienced an excellent survival with good therapeutic effect on pulmonary function tests with both corticosteroid initiation as well as antigen avoidance. In contrast, fHP patients experienced a dismal prognosis (median survival of 9.2 years) without any therapeutic effect of corticosteroid treatment. Whether antigen avoidance is useful in fHP patients is still unclear.

scholarly journals The Efficacy of Corticosteroid Therapy in Fibrotic Hypersensitivity Pneumonitis: A Propensity Score-matched Cohort Analysis

2020 ◽  
Author(s):  
Masaru Ejima ◽  
Tsukasa Okamoto ◽  
Takafumi Suzuki ◽  
Tatsuhiko Anzai ◽  
Kunihiko Takahashi ◽  
...  
Keyword(s):  
Survival Rate ◽  
Propensity Score ◽  
Pulmonary Function ◽  
Hypersensitivity Pneumonitis ◽  
Proportional Hazards Model ◽  
Cohort Analysis ◽  
Corticosteroid Treatment ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Propensity Score Method

Abstract Background: Fibrotic hypersensitivity pneumonitis (HP) is a chronic interstitial lung disease caused by allergic responses to repeated exposures to a causative antigen. Therapeutic evidence of corticosteroid for fibrotic HP remains lacking, although corticosteroid is recognized as a major treatment option. The purpose of this study was to evaluate the efficacy of corticosteroid for patients with fibrotic HP in a propensity score-matched cohort.Methods: Retrospective medical record review from 2005 to 2019 in a single center was conducted to identify 144 patients with fibrotic HP. Semiquantitative scores of lung abnormalities on HRCT were evaluated. Patients with corticosteroid treatment (PDN group) and without the treatment (non-PDN group) were matched using a propensity score method. Survival rates and serial changes in pulmonary function, and annual changes in HRCT scores werecompared between pair-matched patients. Results: In the matched analysis, 30 of the PDN group were matched with 30 of the non-PDN group, the majority of which comprised ILD without extensive fibrosis. The survival rate was significantly better in the PDN group (P = 0.032for the stratified Cox proportional hazards model; HR, 0.250). Absolute changes in %FVC at 6, 12, and 24 months from baseline were significantly better in the PDN group. Fewer cases experienced annual deterioration in HRCT scores in the non-PDN group for ground-glass attenuation, consolidation, reticulation, traction bronchiectasis and honeycombing. Conclusions: Fibrotic HP without extensive fibrosis may receive benefits from corticosteroid treatment in terms of improvements in survival rate and pulmonary function decline and inhibition of fibrotic progression. We propose that early initiation of corticosteroid be considered for fibrotic HP when worsening fibrosis is observed.

scholarly journals Efficacy of treatment with corticosteroids for fibrotic hypersensitivity pneumonitis: a propensity score-matched cohort analysis

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Masaru Ejima ◽  
Tsukasa Okamoto ◽  
Takafumi Suzuki ◽  
Tatsuhiko Anzai ◽  
Kunihiko Takahashi ◽  
...  
Keyword(s):  
Propensity Score ◽  
Hypersensitivity Pneumonitis ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Cohort Analysis ◽  
Corticosteroid Treatment ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Matched Cohort ◽  
Propensity Score Method

Abstract Background Fibrotic hypersensitivity pneumonitis (HP) is a chronic interstitial lung disease caused by allergic responses to repeated exposures to a causative antigen. Therapeutic evidence of the use of corticosteroids to treat fibrotic HP remains lacking, although corticosteroids are recognized as a major treatment option. The purpose of this study was to evaluate the efficacy of corticosteroid treatment in patients with fibrotic HP in a propensity score-matched cohort. Methods A retrospective review of the medical records from 2005 to 2019 in a single center was conducted, and 144 patients with fibrotic HP were identified. Semiquantitative scores for lung abnormalities on HRCT were evaluated. Patients who received (PDN group) and did not receive (non-PDN group) corticosteroid treatment were matched using a propensity score method. Survival rates, serial changes in pulmonary function and annual changes in HRCT scores were compared in the matched cohort. Results In the matched analysis, 30 individuals in the PDN group were matched with 30 individuals in the non-PDN group, the majority of whom had ILD without extensive fibrosis. The survival rate was significantly better in the PDN group (P = 0.032 for the stratified Cox proportional hazards model; HR, 0.250). The absolute changes in FVC at 6, 12, and 24 months from baseline were significantly better in the PDN group. Fewer patients in the PDN group experienced annual deterioration, as reflected in the HRCT score, due to ground-glass attenuation, consolidation, reticulation, traction bronchiectasis and honeycombing. Conclusion We demonstrated that corticosteroids improved survival and slowed fibrotic progression in a matched cohort, the majority of whom had ILD without extensive fibrosis. Fibrotic HP with less severe fibrosis may benefit from corticosteroid treatment. We propose that the early initiation of corticosteroids should be considered for fibrotic HP when worsening fibrosis is observed.

Comorbidities and Myelodysplatic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2789-2789 ◽  
Author(s):  
Kiran Naqvi ◽  
Guillermo Garcia-Manero ◽  
Sagar Sardesai ◽  
Jeong Oh ◽  
Sherry Pierce ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Median Survival ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Hazards Model ◽  
Kaplan Meier ◽  
Comorbidity Scores ◽  
Severe Comorbidity

Abstract Abstract 2789 Poster Board II-765 Background: Cancer patients often experience comorbidities that may affect their therapeutic options, prognosis, and outcome (1). Limited studies have evaluated the characteristics and impact of comorbidities in myelodysplastic syndromes (MDS). The aim of this study was to determine the effect of comorbidities on the survival of patients with MDS. Methods: We reviewed the medical records of 500 consecutive MDS patients who presented to MD Anderson Cancer Center from January 2002 to June 2004. The Adult Comorbidity Evaluation-27 (ACE-27), a validated 27-item comorbidity index for cancer patients (2), was used to assess the severity of comorbid conditions. For each patient, we obtained demographic data and specific staging information based on the International Prognostic Scoring System (IPSS). We also collected information on stem cell transplantation (SCT), mortality and survival. Kaplan-Meier methods and log-rank tests were used to assess survival. Multivariate analysis was performed using the Cox Proportional Hazards Model. Results: Of the 500 patients included in this study, 327 (65.4%) were male, and 436 (87.9%) were white; median age at presentation was 66.6 years (17.7, 93.5); mean duration of follow-up was 23.5 months (0, 88). A total of 49% of patients had IPSS intermediate-1 or lower risk. The ACE-27 comorbidity scores were as follows: none, 106 patients (21.2%); mild, 213 (42.6%); moderate, 108 (21.6%); and severe, 73 (14.6%). Three hundred and eighty one (76.2%) patients died, and 44 (8.8%) patients underwent SCT. Overall median survival using the Kaplan-Meier method was 17.6 months. Median survival according to ACE-27 scores was: 27.9 months for no comorbidity, 18.9 months for mild comorbidity, 15.2 months for moderate comorbidity, and 9.7 months for severe comorbidity. This trend reached statistical significance (p < 0.0001). The median survival by IPSS ranged from 40.9 months for patients in the low risk group versus 8.1 months for those in the high risk category (p < 0.0001). The hazards ratio obtained from the multivariate Cox Proportional Hazards Model was 1.5 and 2.0 for moderate and severe comorbidity scores when adjusted for age and IPSS (p < 0.0001). A linear trend was also observed between the severity of comorbidity and having received SCT (p = 0.001). Of the 44 patients who had SCT, 21 (47.7%) died. The median survival of patients who did not undergo stem cell transplantation ranged from 22.7 months for patients with no comorbidity to 9.3 months for patients with severe comorbidity (p = 0.0002). Conclusion: Comorbidities had a significant impact on the survival of patients with myelodysplastic syndrome. Patients with higher ACE-27 comorbidity scores had a shorter survival than those with no comorbidity, independent of their age and the IPSS risk group. Also patients with comorbid conditions received SCT less often than those without comorbidity. A comprehensive assessment of comorbidity is therefore needed to determine the prognosis in patients with MDS. References: (1) Extermann M. Measurement and impact of comorbidity in older cancer patients. Crit Rev Oncol Hematol. 2000;35:181-200. (1) Piccirillo JF, Tierney RM, Costas I, et al. Prognostic importance of comorbidity in a hospital-based cancer registry. JAMA. 2004;291:2441-47. Disclosures: No relevant conflicts of interest to declare.

Frequency of use and outcome of surgical resection in the management of malignant mesothelioma in a community-based population: Results in 5,937 patients

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7510-7510
Author(s):  
R. M. Flores ◽  
E. Riedel ◽  
J. S. Donington ◽  
L. Krug ◽  
K. Rosenzweig ◽  
...  
Keyword(s):  
Surgical Resection ◽  
Median Survival ◽  
Malignant Pleural Mesothelioma ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Univariate Analysis ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Pleural Mesothelioma ◽  
Tertiary Referral

7510 Background: Multimodality therapy of mesothelioma patients treated at specialized tertiary hospitals report surgical resection rates of 42% (Flores RM et al. Prognostic Factors in the Treatment of Malignant Pleural Mesothelioma at a Large Tertiary Referral Center. J Thorac Oncol 2007;2(10):957–965.). Treatment strategies in the community are less well defined and surgical expertise is not readily available. We undertook this study to evaluate the rate of surgical resection and its association with survival in a non-tertiary based population. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was searched from 1990 - 2004. Variables analyzed included age, sex, race, year of diagnosis, laterality, vital status, stage, surgery, and reasons for no surgery. The association of resection on overall survival was estimated by the Kaplan-Meier method and examined in a Cox proportional hazards model adjusting for covariates. Results: Pathologically proven malignant pleural mesothelioma was identified in 5,937 patients: 1,166 women, 4,771 men; median age was 70 years. Surgical resection rate was 11% (n=636). Univariate analysis demonstrated a median survival of 13 months with surgical resection and a median survival of 7 months in the non-resected group (p<0.0001). Multivariate analysis demonstrated improved survival for surgically resected patients (HR 0.7, p<0.0001), controlling for age, gender, and stage. Conclusions: Surgical resection was associated with improved survival when controlling for age, stage, and gender. However, the rate of surgical resection was much lower in the community when compared to tertiary referral centers. Treatment efforts should be focused on a multidisciplinary approach which includes surgical evaluation. No significant financial relationships to disclose.

scholarly journals Prognosis of Stage IIB early gastric cancer has a unique and dismal property putatively requiring post operative adjuvant chemothrapy

2017 ◽  
Author(s):  
Hideki Ushiku ◽  
Keishi Yamashita ◽  
Akira Ema ◽  
Natsuya Katada ◽  
Kei Hosoda ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Prognostic Factors ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Cancer Prognosis ◽  
Node Metastasis ◽  
Dismal Prognosis

Abstract Background Pathological T1 (pT1) gastric cancer showed excellent prognosis, however lymph node metastasis sometimes reflects patients with dismal prognosis. In this study, we investigated prognosis of pT1 gastric cancer with lymph node metastasis to identify prognostic factors. Patients and Methods Among 1,442 gastric cancer patients between 2002 and 2010, 73 (5%) of pT1 with lymph node metastasis were identified. Univariate prognostic factors were applied to multivariate Cox proportional hazards model. Results (1) Among the 1,442 patients, pT1 was composed of 333 patients with pT1a and 423 patients with pT1b, which included 9 (2.7%) and 64 cases (15.1%) with lymph node metastasis, respectively. (2) Ten (13.7%) patients of the 73 patients with lymph node metastasis showed tumor relapse.　　Univariate negative prognostic factors were tumor size (p=0.03), intraoperative bleeding (p=0.03), and perioperative transfusion (POT)(p=0.001), as well as 14th JGCA Stage (p&lt;0.0001), and multivariate analysis identified 14th JGCA Stage (p=0.0004) and POT (p=0.03) as independent prognostic factors. (3) pT1 gastric cancer representing pN3 (Stage IIB) was rare (n=4) and unique entity from a prognostic point of view, exhibiting dismal prognosis (0% at 5 years). We thereafter identified 17 such cases from 5,204 gastric cancer including the earliest cases. Prognosis of such 17 patients was very unique, in that recurrences occurred even 5 years after curative operation, and the frequent recurrent sites were bone. Conclusion pT1 gastric cancer prognosis is robustly affected by pN3 and POT, and Stage IIB disease showed unique prognosis requiring special attention even after 5 years of operation.

Comorbidities and Overall Survival In Myelodysplastic Syndromes (MDS): Development of a Prognostic Model Incorporating IPSS and Age with ACE-27 Comorbidity Index

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 605-605 ◽  
Author(s):  
Kiran Naqvi ◽  
Maria E Suarez-Almazor ◽  
Sagar Sardesai ◽  
Jeong Oh ◽  
Carlos Vigil ◽  
...  
Keyword(s):  
Median Survival ◽  
Prognostic Model ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Risk Group ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Hazards Model ◽  
Kaplan Meier ◽  
Comorbidity Scores

Abstract Abstract 605 Background: Cancer patients often experience comorbidities that may affect their therapeutic options, prognosis, and outcome. Limited studies have evaluated the characteristics and impact of comorbidities in MDS. The aim of this study was to determine the effect of comorbidities on the survival of patients with MDS. Methods: We reviewed the medical records of 600 consecutive MDS patients who presented to MD Anderson Cancer Center from 01–2002 to 06–2004. The Adult Comorbidity Evaluation-27 (ACE-27), a validated 27-item comorbidity index for cancer patients, was used to assess the severity of comorbid conditions. Data on demographic characteristics, International Prognostic Scoring System (IPSS), stem cell transplant (SCT) and outcomes (leukemic transformation and survival) was collected. Kaplan-Meier methods and log-rank tests were used to assess survival. Multivariate analysis was performed using the Cox Proportional Hazards Model. A prognostic model incorporating baseline comorbidities with age and IPSS was developed to predict survival. A score point for each significant factor (age, IPSS and ACE-27 comorbidity score) was obtained by dividing respective coefficients from the multivariate model by 0.3 and rounding to the nearest integer. Results: Of the 600 patients included in this study, 400 (65.7%) were male, and 518 (87.1%) were white; median age at presentation was 66.6 years (range 17.3 – 93.5); median duration of follow-up was 14.8 months (range 0–88). The ACE-27 comorbidity scores were as follows: none, 137 patients (28.8%); mild, 254 (42.3%); moderate, 127 (21.2%); and severe, 82 (13.7%). Four hundred and fifty six (76.0%) patients died, 123 (20.5%) suffered leukemic transformation and 51 (8.5%) patients underwent SCT. Overall median survival using the Kaplan-Meier method was 18.6 months. Median survival according to ACE-27 scores was: 31.8, 16.8, 15.2 and 9.7 months for none, mild, moderate and severe comorbidity scores respectively (p < 0.0001). The adjusted hazards ratios from the multivariate Cox Proportional Hazards Model were 1.3, 1.6 and 2.3 for mild, moderate and severe comorbidity scores when adjusted for age and IPSS (p < 0.0001). A final prognostic model incorporating comorbidity score with age and IPSS was developed. A risk score was derived based on the regression coefficients from the final multivariate model. The score points assigned were: Age > 65 years=2; IPSS of Intermediate-2= 2 and High= 3; ACE-27 score of mild or moderate= 1 and Severe= 3. Based upon their risk scores, patients were categorized into 3 groups: low (0 - 1), intermediate (2 - 4) and high (5 – 8). Almost 50% of the patients in our study were noted to be in the intermediate category with a median survival of 23 months. The model confirmed a better survival in patients in low risk group of 43 months versus 9 months in the high risk group (p < 0.001). Conclusion: Comorbidities had a significant impact on the survival of patients with myelodysplastic syndrome. Patients with higher ACE-27 comorbidity scores had a shorter survival than those with no comorbidity, independent of their age and the IPSS risk group. A comprehensive assessment of comorbidity is therefore needed to determine the prognosis in patients with MDS. Our newly developed prognostic model helps predict survival in such patients based on their comorbidities. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Corticosteroid therapy in critically ill patients with COVID-19: a multicenter, retrospective study

Critical Care ◽  
2020 ◽  
Vol 24 (1) ◽  
Author(s):  
Yiming Li ◽  
Qinghe Meng ◽  
Xin Rao ◽  
Binbin Wang ◽  
Xingguo Zhang ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Corticosteroid Treatment ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Initiation Time ◽  
Icu Admission

Abstract Background Corticoid therapy has been recommended in the treatment of critically ill patients with COVID-19, yet its efficacy is currently still under evaluation. We investigated the effect of corticosteroid treatment on 90-day mortality and SARS-CoV-2 RNA clearance in severe patients with COVID-19. Methods 294 critically ill patients with COVID-19 were recruited between December 30, 2019 and February 19, 2020. Logistic regression, Cox proportional-hazards model and marginal structural modeling (MSM) were applied to evaluate the associations between corticosteroid use and corresponding outcome variables. Results Out of the 294 critically ill patients affected by COVID-19, 183 (62.2%) received corticosteroids, with methylprednisolone as the most frequently administered corticosteroid (175 accounting for 96%). Of those treated with corticosteroids, 69.4% received corticosteroid prior to ICU admission. When adjustments and subgroup analysis were not performed, no significant associations between corticosteroids use and 90-day mortality or SARS-CoV-2 RNA clearance were found. However, when stratified analysis based on corticosteroid initiation time was performed, there was a significant correlation between corticosteroid use (≤ 3 day after ICU admission) and 90-day mortality (logistic regression adjusted for baseline: OR 4.49, 95% CI 1.17–17.25, p = 0.025; Cox adjusted for baseline and time varying variables: HR 3.89, 95% CI 1.94–7.82, p < 0.001; MSM adjusted for baseline and time-dependent variants: OR 2.32, 95% CI 1.16–4.65, p = 0.017). No association was found between corticosteroid use and SARS-CoV-2 RNA clearance even after stratification by initiation time of corticosteroids and adjustments for confounding factors (corticosteroids use ≤ 3 days initiation vs no corticosteroids use) using MSM were performed. Conclusions Early initiation of corticosteroid use (≤ 3 days after ICU admission) was associated with an increased 90-day mortality. Early use of methylprednisolone in the ICU is therefore not recommended in patients with severe COVID-19.

Abstract 16998: Gender and Age Specific Baseline Predictors of MACE in PEACE Trial Identified by Machine Learning

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Victoria Xin ◽  
Scout Hayashi ◽  
Anwar Husain ◽  
Ahmed A Hasan ◽  
Amit Dey ◽  
...  
Keyword(s):  
Machine Learning ◽  
Proportional Hazards Model ◽  
Coronary Revascularization ◽  
Stable Coronary Artery Disease ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Therapeutic Interventions ◽  
Data Repository ◽  
Age Group ◽  
Gender And Age

Introduction: The NHLBI supported Prevention of Events with Angiotensin-Converting Enzyme (ACE) Therapy trial (PEACE) (NCT00000558) found that the addition of ACE inhibitor trandolapril to conventional therapy in 8290 patients with stable coronary artery disease and preserved ejection fraction provided no benefit against MACE (cardiovascular death, nonfatal myocardial infarction, or the need for coronary revascularization), the composite primary endpoint. We reused publicly available individual patient-level PEACE data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses by machine learning (ML) using random survival forest (RSF) to identify gender and age group specific predictors for MACE. Methods: RSF was performed on 50 baseline variables for the MACE outcome in male and female and in age group (<60, 60-69, >69) cohorts. The top ten predictors identified in each cohort were included in a multivariate analysis using a Cox proportional hazards model with a multiple regression approach. Results: The top 10 predictors for the MACE selected by RSF are shown in Figure 1. Expected cardiovascular (CV) risk predictors like blood pressure, Canadian CV Society angina classification (CCS), age, and a history of various CV procedures consistently emerge amongst the top ten predictors of the primary MACE outcome across all gender and age specific subgroups. Interestingly, RSF also identified renal function biomarkers like serum potassium and glomerular filtration rate as common top ten predictors. Conclusion: Using ML, we uncovered in an unbiased fashion, gender and age groups specific unanticipated top predictors for MACE in PEACE trial. This underscores the value of gender and age specific predictors to examine the efficacy and outcomes of therapeutic interventions in advancing precision and personalized medicine.

Final analysis results from TITAN: A phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) receiving androgen deprivation therapy (ADT).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 11-11
Author(s):  
Kim N. Chi ◽  
Simon Chowdhury ◽  
Anders Bjartell ◽  
Byung Ha Chung ◽  
Andrea Juliana Pereira de Santana Gomes ◽  
...  
Keyword(s):  
Repeated Measures ◽  
Proportional Hazards Model ◽  
Final Analysis ◽  
Cox Proportional Hazards Model ◽  
Phase Iii ◽  
Rank Test ◽  
Mixed Effect ◽  
End Points ◽  
Risk Of Death

11 Background: TITAN evaluated APA or PBO added to ADT in pts with mCSPC. Pts with high- and low-volume disease, prior docetaxel, prior treatment for localized disease, and prior ADT (≤ 6 mos) were eligible. At the first interim analysis, with 22.7 mos median follow-up, APA significantly improved dual primary end points of overall survival (OS) (hazard ratio [HR] 0.67) and radiographic progression-free survival (rPFS) (HR 0.48) compared with PBO (Chi et al. NEJM. 2019). At that time, OS analysis was first planned interim while rPFS was final. TITAN was unblinded, allowing pts without progression who were still receiving PBO to cross over to APA. Herein, we report the final analysis of efficacy and safety results from TITAN. Methods: 1052 mCSPC pts were randomized 1:1 to receive APA (240 mg QD) or PBO plus ADT. Time-to-event end points were analyzed by Kaplan-Meier method and Cox proportional hazards model. A preplanned sensitivity analysis for OS, accounting for crossover using inverse probability censoring weighted (IPCW) log-rank test, was conducted. No formal statistical retesting was performed; nominal p values were reported without multiplicity adjustment. Change from baseline in Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score was assessed using a mixed-effect repeated-measures model. Results: With 44 mos median follow-up, 405 OS events had occurred. After unblinding, 208 PBO pts (39.5%) crossed over to APA. Median treatment duration was 39.3 mos for the APA group, 20.2 mos for the entire PBO group, and 15.4 mos for the PBO→APA crossover group. OS was superior in the APA group compared with the PBO group despite crossover (Table). 48-mo survival rates were 65% (APA) vs 52% (PBO). Other end points also favored APA vs PBO (Table). Health-related quality of life (HRQoL), per total FACT-P, was maintained in the APA group through the study and was not different from the PBO group. Safety was consistent with previous reports. Conclusions: With close to 4 yrs of follow-up, the final analysis of TITAN demonstrated that in a broad population of pts with mCSPC, APA plus ADT provides an improvement in OS with a 35% reduction in risk of death, which increased to 48% reduction after adjusting for pts who crossed over from PBO to APA. In addition, there was consistent benefit with APA in other end points, including delaying castration resistance, and HRQoL continued to be maintained with an acceptable safety profile. Clinical trial information: NCT02489318. [Table: see text]

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