Pre-planned Sensitivity Analysis Research Articles

Prostate cancer detection and complications of MRI-targeted prostate biopsy using cognitive registration, software-assisted image fusion or in-bore guidance: a systematic review and meta-analysis of comparative studies.

Three primary strategies for MRI-targeted biopsies (TB) are available: Cognitive TB (COG-TB), MRI-US Fusion TB (FUS-TB), and In Bore TB (IB-TB). Despite nearly a decade of practice, a consensus on the preferred approach is lacking, with previous studies showing comparable PCa detection rates among the three methods. We conducted a search of PubMed, EMBASE, PubMed, Web of Science, and Scopus databases from 2014 to 2023, to identify studies comparing at least two of the three methods and reporting clinically significant PCa (csPCa) detection rates. The primary and secondary outcomes were to compare the csPCa and insignificant prostate cancer (iPCa, ISUP GG 1) detection rates between TB techniques. The tertiary outcome was to compare the complication rate between TB techniques. Detection rates were pooled using random-effect models. Planned sensitivity analyses included subgroup analysis according to the definition of csPCa and positive MRI, previous biopsy status, biopsy route, prostate volume, and lesion characteristics. A total of twenty studies, involving 4928 patients, were included in the quantitative synthesis. The meta-analysis unveiled comparable csPCa detection rates among COG-TB (0.37), FUS-TB (0.39), and IB-TB (0.47). iPCa detection rate was also similar between TB techniques (COG-TB: 0.12, FUS-TB: 0.17, IB-TB: 0.18). All preplanned sensitivity analyses were conducted and did not show any statistically significant difference in the detection of csPCa between TB methods. Complication rates, however, were infrequently reported, and when available, no statistically significant differences were observed among the techniques. This unique study, exclusively focusing on comparative research, indicates no significant differences in csPCa and iPCa detection rates between COG-TB, FUS-TB, and IB-TB. Decisions between these techniques may extend beyond diagnostic accuracy, considering factors such as resource availability and operator preferences. Well-designed prospective studies are warranted to refine our understanding of the optimal approach for TB in diverse clinical scenarios.

Risk of acute kidney injury in critically-ill patients with COVID-19 compared with seasonal influenza: a retrospective cohort study

The SARS-CoV-2 virus can bind to angiotensin-converting enzyme 2 receptors on host renal cells and may cause acute kidney injury (AKI). The comparative risks of AKI in patients severely ill with COVID-19 and influenza A have not been examined. This is a retrospective cohort study including patients with positive PCR results for SARS-CoV-2 or influenza A virus admitted to the intensive care units (ICUs) of 15 public hospitals in Hong Kong between 1st January 2013 and 30th April 2023. Patients who were already on chronic dialysis or had missing values in the confounder model were excluded. Data were retrieved from Hong Kong Hospital Authority's electronic healthcare records. The primary outcome was incident AKI during ICU stay. Secondary outcomes included acute kidney disease (AKD) and hospital mortality. All analyses were examined in multivariable regression adjusting for potential confounders (age, sex, baseline eGFR, PaO2/FiO2 ratio, baseline comorbidities, APACHE IV predicted risk of death, Charlson Comorbidity Index, emergent hospital admission, admission from elderly home, reason for ICU admission, presence of bacterial co-infections, use of medications [including vasopressors, antiviral medications, steroids and nephrotoxic antibiotics], as well as anaemia and leucocytosis). Patients were matched in a 1:1 ratio using a propensity score generated based on the full confounder model. The analyses were repeated using inverse probability weighting and in propensity-score matched cohorts. A total of 5495 ICU patients were identified. After excluding 1093 (19.9%) patients who met the exclusion criteria and 74 (1.3%) patients who had one or more missing values in the logistic regression model, a total of 4328 patients were included in the final analysis, with 2787 (64.4%) patients who tested positive for SARS-CoV-2 reverse transcription (RT)-PCR and 1541 (35.6%) patients who tested positive for influenza A virus RT-PCR. The comorbidity burden was greater in patients with COVID-19 (Charlson Comorbidity Index 3 [2-4] vs. 3 [1-4]), but the median APACHE IV predicted risk of death was significantly lower (0.19 [0.08-0.38] vs. 0.25 [0.11-0.52]). A total of 1053 (37.8%) patients with COVID-19 and 828 (53.7%) patients with influenza A developed AKI of any stage during ICU stay. In adjusted analysis, the risk of AKI was significantly lower in patients with COVID-19 compared with influenza A (adjusted odds ratio 0.51, 95% confidence interval 0.42-0.61, P<0.0001]. The risk of stage 3 AKI and AKD were also significantly lower in patients with COVID-19. These results remained robust in multiple pre-planned sensitivity analyses including inverse probability weighting and propensity score matching. Our results suggest that the risk of AKI in patients severely ill with COVID-19 was lower than in patients with influenza A. The burden of concurrent organ failure complicating respiratory viral infections, such as the higher disease-attributable risk of AKI associated with influenza, should be clarified. An unrestricted philanthropic donation from Mr and Mrs Laurence Tse, The Wai Im Charitable Foundation, Chan Sui Kau Family Benefits and Charitable Foundation, So Ka Wing and Lee Sau Ying Charitable Foundation, Mr & Mrs Tam Wing Fun Edmund Renal Research Fund, the Theme-Based Research Scheme of the Research Grants Council, Hong Kong Special Administrative Region, The Government of the Hong Kong Special Administrative Region; Programme of Enhancing Laboratory Surveillance and Investigation of Emerging Infectious Diseases and Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government; Emergency COVID-19 Project, Major Projects on Public Security, National Key Research and Development Program; Emergency Collaborative Project of Guangzhou Laboratory; the National Key Research and Development Program of China; Sanming Project of Medicine in Shenzhen China; and the High Level-Hospital Program, Health Commission of Guangdong Province, China.

Evolving Racial/Ethnic Disparities in AML Survival in the Novel Therapy Era: Real-World Evidence of Improved Survival in Older Patients with the Largest Improvement in Non-Hispanic Black Patients

Introduction: The approval of venetoclax (VEN)-based frontline therapy for acute myeloid leukemia (AML) in November 2018 marks a new era of AML care. Racial/ethnic disparities have been increasingly recognized in AML with historically inferior outcomes reported in non-Hispanic Black (NHB) patients relative to non-Hispanic White (NHW) patients. The advances of novel therapeutics offer an unprecedented opportunity to narrow the care gaps between patient groups; but they also create new challenges related to testing, clinical decision-making, and care coordination. Currently, little is known about the impact of race/ethnicity on the recent advances in AML management. We performed a retrospective analysis leveraging real-world data to examine the magnitude and mechanisms of racial/ethnic disparities in modern AML care. Methods: Adult patients from Flatiron Health, a nationwide, electronic health record derived, de-identified database, with AML diagnosed between January 2014 to December 2018 (Pre era) and January 2019 to October 2022 (Post era) who identified as NHW, NHB or Hispanic and received at least one line of anti-leukemic therapy were included. Overall survival (OS) was defined from the time of therapy initiation to the time of death. Multivariable Cox regression models were used to compare the hazards of death for NHB and Hispanics relative to NHW. Predicted survival curves were then computed. Pre-planned sensitivity analyses including patients with 1) no ethnicity information, 2) no anti-leukemic therapy, and 3) care gap &amp;gt;100 days from diagnosis to induction were performed. Results: 2998 patients in Pre era (2566 NHW, 221 NHB, 211 Hispanics) and 2098 patients in Post era (1809 NHW, 162 NHB, 127 Hispanics) were included. Older patients with more comorbidities and worse disease biology (Table 1) were treated in Post era. After adjusting for race/ethnicity, age and Hematopoietic Cell Transplant Specific Comorbidity Index (HCT-CI), patients in Post era had a 10% decrease in the hazard of death compared to Pre era (HR 0.90, 95% CI 0.83-0.96). The difference was driven by OS benefits observed in patients aged &amp;gt;70 years (HR 0.82, 95% CI 0.75-0.91). NHB and Hispanics were younger at diagnosis than NHW in both eras. Lower socioeconomic status was observed in NHB and Hispanics. No difference in ELN2017 risk stratification was observed (Table 1). After adjusting for age and HCT-CI, NHB had a 22% increased hazard of death compared to NHW in Pre era (HR 1.22, 95% CI 1.04-1.43); whereas Hispanics had comparable outcomes (HR 1.01, 95% CI 0.84-1.21). Strikingly, the survival disparity between NHB and NHW in Pre era was not observed in Post era with predicted 2-yr OS rate being 45.3% and 39.9%, respectively (HR 0.86, 95% CI 0.69-1.08) (Figure 1). Predicted 2-yr OS rates improved for NHB patients in both ≤70 years (42.3% vs. 53.2%) and &amp;gt;70 years group (13.6% vs. 37.0%). No significant change in OS was observed in Hispanics between Pre and Post era (Figure 1). Results of all sensitivity analyses were consistent with primary analyses. Molecular testing at diagnosis significantly differed by eras across race/ethnicity groups (overall 66.4% vs. 82.9%, p&amp;lt;0.001). In contrast, molecular testing occurred more frequently in NHB at relapse in Post era (45.6% vs. 65.4%, p=0.020). Despite being older, more NHW received allogeneic transplant than NHB in Pre era (25.8% vs. 18.6%, p=0.046). In Post era, NHW were more likely to receive VEN-based induction therapy (46.9%, 37.0%, 35.4% in NHW, NHB and Hispanic, respectively, p= 0.003). Among patients who were tested and qualified, no difference was observed in the use of gemtuzumab ozogamicin, CPX-351, FLT3 inhibitors or IDH1/2 inhibitors across race/ethnicity. Conclusions: In this large, real-world dataset, we demonstrate OS improvements in the era of modern AML care, particularly among patients &amp;gt;70 years though their outcomes remain inferior to younger patients. Intriguingly, the largest OS improvement was observed in NHB, where the OS disparity between NHB and NHW in Pre era appears to have been mitigated. Hispanics have not experienced similar OS improvement in modern AML care. Ongoing analyses are focused on examining the mechanisms of survival trends observed with focus on assessing the contribution(s) of patient-, disease biology- and treatment-related factors in order to identify potential targets for intervention. • Dr. Kelly Getz and Dr. Catherine Lai contributed equally

Play brick therapy to aid the social skills of children and young people with autism spectrum disorder: the I-SOCIALISE cluster RCT

Background Social skills interventions are commonly recommended to help children and young people with autism spectrum disorder develop social skills, but some struggle to engage in these interventions. LEGO® (LEGO System A/S, Billund, Denmark) based therapy, a group social skills intervention, aims to be more interesting and engaging. Objective To evaluate the clinical effectiveness of LEGO® based therapy on the social and emotional skills of children and young people with autism spectrum disorder in school settings compared with usual support. Secondary objectives included evaluations of cost-effectiveness, acceptability and treatment fidelity. Design A cluster randomised controlled trial randomly allocating participating schools to either LEGO® based therapy and usual support or usual support only. Setting Mainstream schools in the north of England. Participants Children and young people (aged 7–15 years) with autism spectrum disorder, their parent/guardian, an associated teacher/teaching assistant and a facilitator teacher/teaching assistant (intervention schools only). Intervention Schools randomised to the intervention arm delivered 12 weekly sessions of LEGO® based therapy, which promotes collaborative play and encourages social problem-solving in groups of three children and young people with a facilitator (trained teacher or teaching assistant). Participants received usual support from school and community services. Participants in the control arm received usual support only. Research assistants and statisticians were blind to treatment allocation. Main outcome measure The social skills subscale of the Social Skills Improvement System (SSIS), completed by the children and young people’s unblinded teacher pre randomisation and 20 weeks post randomisation. The SSIS social skills subscale measures social skills including social communication, co-operation, empathy, assertion, responsibility and self-control. Participants completed a number of other pre- and post-randomisation measures of emotional health, quality of life, loneliness, problem behaviours, academic competence, service resource utilisation and adverse events. Results A total of 250 children and young people from 98 schools were randomised: 127 to the intervention arm and 123 to the control arm. Intention-to-treat analysis of the main outcome measure showed a modest positive difference of 3.74 points (95% confidence interval –0.16 to 7.63 points, standardised effect size 0.18; p = 0.06) in favour of the intervention arm. Statistical significance increased in per-protocol analysis, with a modest positive difference (standardised effect size 0.21; p = 0.036). Cost-effectiveness of the intervention was found in reduced service use costs and a small increase in quality-adjusted life-years. Intervention fidelity and acceptability were positive. No intervention-related adverse events or effects were reported. Conclusions The primary and pre-planned sensitivity analysis of the primary outcome consistently showed a positive clinical difference, with modest standardised effect sizes of between 0.15 and 0.21. There were positive health economics and qualitative findings, corroborated by the difference between arms for the majority of secondary outcomes, which were not statistically significant but favoured the intervention arm. Post hoc additional analysis was exploratory and was not used in drawing this conclusion. Given the small positive change, LEGO® based therapy for children and young people with autism spectrum disorder in schools should be considered. Limitations The primary outcome measure was completed by an unblinded teacher (rather than by the facilitator). Future work The study team recommends future research into LEGO® based therapy, particularly in school environments. Trial registration This trial is registered as ISRCTN64852382. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Public Health Research programme (NIHR award ref: 15/49/32) and is published in full in Public Health Research; Vol. 11, No. 12. See the NIHR Funding and Awards website for further award information.

Postoperative outcomes of pediatric patients with perioperative COVID-19 infection: a systematic review and meta-analysis of observational studies.

To quantify the risk of adverse postoperative outcomes in pediatric patients with COVID-19 infection. We searched PubMed, Embase, Cochrane Library from December 2019 to 21 April 2023. Observational cohort studies that reported postoperative early mortality and pulmonary complications of pediatric patients with confirmed COVID-19-positive compared with COVID-19-negative were eligible for inclusion. We excluded pediatric patients underwent organ transplantation or cardiac surgery. Reviews, case reports, letters, and editorials were also excluded. We used the Newcastle-Ottawa Scale to assess the methodological quality and risk of bias for each included study. The primary outcome was postoperative early mortality, defined as mortality within 30days after surgery or during hospitalization. The random-effects model was performed to assess the pooled estimates, which were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). 9 studies involving 23,031 pediatric patients were included, and all studies were rated as high quality. Compared with pediatric patients without COVID-19, pediatric patients with COVID-19 showed a significantly increased risk of postoperative pulmonary complications (PPCs) (RR = 4.24; 95% CI 2.08-8.64). No clear evidence was found for differences in postoperative early mortality (RR = 0.84; 95% CI 0.34-2.06), postoperative intensive care unit (ICU) admission (RR = 0.80; 95% CI 0.39-1.68), and length of hospital stay (MD = 0.35, 95% CI -1.81-2.51) between pediatric patients with and without COVID-19. Perioperative COVID-19 infection was strongly associated with increased risk of PPCs, but it did not increase the risk of postoperative early mortality, the rate of postoperative ICU admission, and the length of hospital stay in pediatric patients. Our preplanned sensitivity analyses confirmed the robustness of our study findings.

Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial.

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

Real World Effectiveness of "7 + 3" Intensive Chemotherapy Vs Venetoclax and Hypomethylating Agent for Initial Therapy in Adult Acute Myeloid Leukemia

Introduction Initial treatment selection for older adults with AML remains challenging. Historically, clinicians and patients had to choose between intensive chemotherapy (7 + 3), low intensity therapy or best supportive care. Approval of venetoclax and a hypomethylating agent (ven/HMA, NCT02993523) for those ≥75 years or with major comorbidities has offered higher response rates and improved survival vs. low intensity therapy. Use has expanded to other groups like younger patients with high risk disease or patients with "borderline" induction fitness. Prospective comparisons have yet to complete, so we examined retrospective outcomes for older patients receiving either 7 + 3 or ven/HMA as initial therapy. Methods We included patients from both the University of Pennsylvania ("HUP", n=187) and the Flatiron Health electronic health record derived, de-identified database with incident AML diagnosed between January 2017 and 2021, and 7 + 3 (7 days of cytarabine and 3 days of anthracycline) or ven/HMA (azacitadine or decitabine) as initial therapy (n=621). Only patients presumably eligible for 7 + 3 were included (age 60-75, estimated glomerular filtration rate > 30 mL/min, alanine transaminase, aspartate transaminase, bilirubin < 1.5x upper limit of normal (ULN), no history of systolic heart failure). Primary endpoint of overall survival (OS) had 80% power for hazard ratio (HR) 0.74 with alpha 0.05. OS was analyzed by Kaplan-Meier method and compared using log-rank test. Pre-planned sensitivity analyses included multiple imputation (MI) with inverse-probability of treatment weighting (IPTW) to address missingness and balance baseline covariates. Results 305 patients received 7 + 3 and 503 received ven/HMA. Baseline covariates showed ven/HMA patients were older, sicker and had worse disease biology (table 1). Underscoring this imbalance in age and comorbidity, allogeneic transplant rates were 31% vs 16% for 7 + 3 and ven/HMA respectively (p<0.0005). More than 40% of initial 7 + 3 patients received second-line ven/HMA while less than 10% of ven/HMA patients received second line 7 + 3 or CPX-351. In unadjusted analysis, median OS (mOS) was 14 months for all patients and 22 months for 7 + 3 versus 10 months for ven/HMA (HR 0.52, 95% confidence interval CI 0.41-0.67, p-value <0.005, Fig 1). No subset had statistically significant higher OS with ven/HMA compared to 7 and 3; in multi-variate analysis controlling for all covariates with univariate p-value < 0.20 induction choice did not affect overall survival (limited to complete cases n=229, HR 0.72, p-value 0.21). Missing values in the HUP dataset were <5% for all baseline covariates; Flatiron dataset missing values ranged from 0-40% for covariates (e.g., sex and baseline LDH respectively). After balancing covariates and adjustment for missing values, survival remained superior in the 7+3 group (HR 0.71, p-value 0.026, 95% CI 0.53-0.94) (absolute standardized differences for all baseline variables were below 0.10). Regarding safety, early mortality was higher for ven/HMA (13% vs 6%, p=0.003). However, rates of febrile neutropenia and culture positive infection were higher for 7 + 3. Length of stay, including any admission prior to next cycle, was longer for 7 + 3 in the HUP cohort (among patients admitted for induction: average 25 days for ven/HMA vs 34 days for 7 and 3 p=0.0012; an additional 20% of ven/HMA patients were managed entirely outpatient). Conclusion In this large, multi-center real word study, of patients presumed to be eligible for either approach we found superior outcomes for 7 + 3. However, there was significant confounding by indication and imbalance between the groups. Adjusting for these differences, OS was still higher for 7 + 3 (p=0.026). In this real world dataset, the 7 + 3 cohort outperformed historical benchmarks (e.g., NCT02085408) in OS and early mortality, perhaps reflecting improved later lines of therapy and patient selection. Given the significant confounding by indication, uneven cross-over and greater lab-based AEs/longer length of stays for intensive chemotherapy, prospective studies (such as NCT04801797) must confirm superiority of intensive chemotherapy. Careful attention to factors predictive of response to non-7 + 3 based therapy may be as important as the characterization of side effects, quality of life and impact on allotransplant to select optimal therapies for all adult AML patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cost-utility analysis of cemented hemiarthroplasty versus hydroxyapatite-coated uncemented hemiarthroplasty for the treatment of displaced intracapsular hip fractures : the World Hip Trauma Evaluation 5 (WHiTE 5) trial.

The aim of this study was to compare the cost-effectiveness of cemented hemiarthroplasty (HA) versus hydroxyapatite-coated uncemented HA for the treatment of displaced intracapsular hip fractures in older adults. A within-trial economic evaluation was conducted based on data collected from the World Hip Trauma Evaluation 5 (WHiTE 5) multicentre randomized controlled trial in the UK. Resource use was measured over 12 months post-randomization using trial case report forms and participant-completed questionnaires. Cost-effectiveness was reported in terms of incremental cost per quality-adjusted life year (QALY) gained from the NHS and personal social service perspective. Methodological uncertainty was addressed using sensitivity analysis, while decision uncertainty was represented graphically using confidence ellipses and cost-effectiveness acceptability curves. The base-case analysis showed that cemented implants were cost-saving (mean cost difference -£961 (95% confidence interval (CI) -£2,292 to £370)) and increased QALYs (mean QALY difference 0.010 (95% CI 0.002 to 0.017)) when compared to uncemented implants. The probability of the cemented implant being cost-effective approximated between 95% and 97% at alternative cost-effectiveness thresholds held by decision-makers, and its net monetary benefit was positive. The findings remained robust against all the pre-planned sensitivity analyses. This study shows that cemented HA is cost-effective compared with hydroxyapatite-coated uncemented HA in older adults with displaced intracapsular hip fractures. Cite this article: Bone Joint J2022;104-B(8):922-928.

Trends in and determinants of germline BRCA1/2 testing in patients with breast and ovarian cancer.

10583 Background: Germline BRCA1/2 testing (GT) is instrumental in identifying patients with breast and ovarian cancer who may be eligible for biomarker-driven poly ADP ribose polymerase inhibitor (PARPi) therapy. Little is known about recent trends and determinants of GT since PARPi were approved for these patients. Methods: We performed a retrospective cohort study of patients with breast and ovarian cancer who were eligible for GT (diagnosed with breast cancer under age 45, triple negative breast cancer under age 60, male breast cancer or ovarian cancer) between 1/2011 and 3/2020 in the nationwide Flatiron Health EHR-derived deidentified database. Duration of follow-up was at least one year for each patient. Spline regressions estimated the annual prevalence of GT within one year of diagnosis. Multivariable log binomial regressions estimated adjusted relative risks (RR) of GT by patient and tumor characteristics. Multiple imputation with chained equations was conducted for missing data. Results: Among 2,982 eligible patients with breast cancer, 1,682 (56%) underwent GT within one year of diagnosis with a median time of 42 days. GT increased from 37% in 2011 to 68% in 2020, with a significantly higher RR after PARPi were approved for breast cancer in 1/2018 (RR 1.35, 95% CI 1.20-1.51). In multivariable analyses, there were no appreciable differences by sex, race or ethnicity, but there was a negative linear relationship between GT and age (RR 0.93, 95% CI 0.90-0.96 for every 5 years). After adjusting for age, the 87 breast cancer patients with Medicare were also less likely to undergo GT despite being eligible (RR 0.67, 95% CI 0.48-0.95 vs commercial insurance). Among 5,563 eligible patients with ovarian cancer, 1,968 (35%) underwent GT within one year of diagnosis with a median time of 101 days. GT increased from 23% in 2011 to 53% in 2020, with a significantly higher RR after PARPi were approved for ovarian cancer in 12/2014 (RR 2.25, 95% CI 2.01-2.52). Although insurance status was not a significant determinant of GT in patients with ovarian cancer, older age (RR 0.95, 95% CI 0.93-0.97 for every 5 years) and Black race (RR 0.80, 95% CI 0.66-0.98 vs white race) were associated with a lower likelihood of GT in multivariable analyses. All results remained similar in pre-planned sensitivity analyses restricted to the post-PARPi approval period, limiting to patients who remained alive one year after diagnosis and using the non-imputed dataset. Conclusions: GT remains underutilized in patients with breast and ovarian cancer. Although GT has increased since PARPi were approved for this population, significant disparities by age, race and insurance status persist but differ by tumor type. This study is limited by potential misclassification due to missing GT performed outside the Flatiron Health network. Multifaceted patient-, clinician- and system-level strategies are needed to ensure that all eligible patients receive GT.

Assessment of various efficacy outcomes using ERIVANCE-like criteria in patients with locally advanced basal cell carcinoma receiving sonidegib: results from a preplanned sensitivity analysis

BackgroundThe BOLT study for sonidegib, a Hedgehog pathway inhibitor (HHI) approved for patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy, used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation. The ERIVANCE study for vismodegib, another HHI, used a composite RECIST endpoint of ≥30% reduction in externally visible tumor or radiographic dimension, or complete ulceration resolution. This preplanned sensitivity BOLT analysis evaluated efficacy outcomes using ERIVANCE-like criteria in patients with laBCC who received sonidegib 200 mg once daily.MethodsThis phase 2, double-blind study randomized patients 1:2 to sonidegib 200:800 mg daily, respectively. Key endpoints included objective response rate (ORR), duration of response (DOR), complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). laBCC tumors were assessed by both mRECIST and ERIVANCE-like criteria. Per mRECIST, an overall response of CR was based on negative histology; photographic assessment of CR, PR (scar/fibrosis only), SD (scar/fibrosis only), or not available (NA); and a magnetic resonance imaging response of CR or NA. An overall response of CR was primarily based on negative histology using ERIVANCE-like criteria.ResultsPer mRECIST criteria, ORR (95% confidence interval [CI]) by central and investigator review for patients with laBCC (n = 66) was 56.1% (43.3–68.3%) and 71.2% (58.7–81.7%), respectively. CR per central review was achieved in 3 (4.5%) patients and PR, SD, and PD occurred in 34 (51.5%), 23 (34.8%), and 1 (1.5%) patient, respectively. Median (95% CI) DOR was 26.1 months (not estimable [NE]).Using ERIVANCE-like criteria, efficacy outcomes per central and investigator review were higher, with an ORR (95% CI) of 60.6% (47.8–72.4%) and 74.2% (62.0–84.2%), respectively. CR per central review was reached in 14 (21.2%) patients and PR, SD, and PD occurred in 26 (39.4%), 20 (30.3%), and 1 (1.5%) patient, respectively. DOR was unchanged with a median (95% CI) of 26.1 months (NE).ConclusionsOverall, applying ERIVANCE-like criteria to patients with laBCC receiving sonidegib 200 mg daily yielded higher response rates vs mRECIST criteria.Trial registrationBOLT registration: ClinicalTrials.gov (NCT01327053) on March 30, 2011.

Real World Survival Outcomes of CPX-351 Versus Venetoclax and Azacitadine for Initial Therapy in Adult Acute Myeloid Leukemia

Real World Survival Outcomes of CPX-351 Versus Venetoclax and Azacitadine for Initial Therapy in Adult Acute Myeloid Leukemia

26198 Evaluating patient outcomes in the BOLT 42-month trial using modified Response Evaluation Criteria in Solid Tumors methodology: Results from a preplanned analysis

Introduction: Sonidegib is approved in the US to treat locally advanced basal cell carcinoma (laBCC) not amenable to surgery or radiation. The BOLT trial for sonidegib used modified Response Evaluation Criteria in Solid Tumors (mRECIST) for laBCC tumor evaluation, while ERIVANCE trial for vismodegib used RECIST. This preplanned sensitivity analysis in BOLT trial applied RECIST criteria to laBCC tumors.

Association between timely targeted therapy initiation and clinical outcomes in patients with advanced HER2+ gastroesophageal adenocarcinoma.

e16048 Background: Delayed treatment initiation is associated with increased mortality in early-stage cancers. Few studies have examined the impact of timely initiation in advanced cancers. Timely targeted therapy initiation can be especially challenging due to the additional biomarker testing required to identify patients eligible for these treatments. We examined the impact of timely targeted therapy initiation on survival among patients with metastatic HER2+ gastroesophageal adenocarcinoma (GEA). Methods: We performed a retrospective cohort study of patients with metastatic HER2+ GEA treated with first line systemic therapy between 1/2011 and 12/2017 using the nationwide Flatiron Health EHR-derived deidentified database. Timely targeted therapy, defined as initiation of the anti-HER2 monoclonal antibody trastuzumab up to 14 days after first line chemotherapy initiation, was entered as a time-varying exposure on the day of initiation. Patients who initiated trastuzumab after the 14-day cut point or who lacked documentation of having received trastuzumab were classified as having non-timely targeted therapy initiation. Extended Cox regression models were used to compare progression-free (PFS) and overall survival (OS) from the date of first line treatment initiation, adjusted for potential confounders. Pre-planned sensitivity analyses assessed alternative “timeliness” definitions as well as the impact of any trastuzumab administration, regardless of the timing of initiation. Results: We included 459 patients with metastatic HER2+ GEA; 293 (63.8%) received trastuzumab, of whom 223 (76.1%) initiated in a timely manner. The median age was 65.0 years, and patients were predominantly male (82.4%) and non-Hispanic White (78.2%) with an ECOG performance status of 0-1 (85.9%). Relative to non-timely initiation, timely targeted therapy was associated with significantly higher OS (2-year OS 29.6% vs 14.6%; adjusted HR 0.72, 95% CI 0.57-0.91, p = 0.006) and PFS (2-year PFS 8.3% vs 3.9%; adjusted HR 0.78, 95% CI 0.62-0.98, p = 0.030). Results remained similar in sensitivity analyses 1) using alternative “timeliness” definitions (up to 70 days after chemotherapy initiation), and 2) comparing any trastuzumab administration, regardless of the timing of initiation, to no trastuzumab administration (OS - adjusted HR 0.75, 95% CI 0.60-0.95, p = 0.018; PFS - adjusted HR 0.81, 95% CI 0.64-1.02, p = 0.069). Conclusions: OS and PFS were higher among patients with metastatic HER2+ GEA treated with trastuzumab, regardless of the timing of targeted therapy initiation. Although our results provide reassurance to clinicians that delays in targeted therapy may not be detrimental to patient outcomes, efforts should still be made to ensure that all patients with metastatic HER2+ GEA receive first line trastuzumab.

Smoking cessation for improving mental health.

Smoking cessation for improving mental health.

Analysis of the effect of crossover from placebo (PBO) to darolutamide (DARO) on overall survival (OS) benefit in the ARAMIS Trial.

240 Background: DARO is a structurally distinct androgen receptor inhibitor approved for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) based on significantly prolonged metastasis-free survival compared with PBO (median 40.4 vs 18.4 months; hazard ratio [HR] 0.41; 95% confidence interval [CI] 0.34–0.50; P &lt; 0.0001) and a favorable safety profile in the phase III ARAMIS trial. Following unblinding at the primary analysis, crossover from PBO to DARO was permitted for the subsequent open-label treatment phase. Sensitivity analyses were performed to assess the effect of PBO–DARO crossover on OS benefit. Methods: Patients (pts) with nmCRPC receiving androgen deprivation therapy were randomized 2:1 to DARO (n = 955) or PBO (n = 554). In addition to OS, secondary endpoints included times to pain progression, first cytotoxic chemotherapy, first symptomatic skeletal event, and safety. The OS analysis was planned to occur after approximately 240 deaths, and secondary endpoints were evaluated in a hierarchical order. Iterative parameter estimation (IPE) and rank-preserving structural failure time (RPSFT) analyses were performed as pre-planned sensitivity analyses to adjust for the treatment effect of PBO–DARO crossover. The IPE method used a parametric model for the survival times and iteratively determined the model parameter describing the magnitude of the treatment effect, whereas a grid search and non-parametric log-rank test were used for the RPSFT analysis. The IPE and RPSFT analyses both generated a Kaplan–Meier curve for the PBO arm that predicts what would have been observed in the absence of PBO–DARO crossover. Results: After unblinding, 170 pts (30.7% of those randomized to PBO) crossed over from PBO to DARO; median treatment duration from unblinding to the final data cut-off was 11 months. Final analysis of the combined double-blind and open label periods was conducted after 254 deaths (15.5% of DARO and 19.1% of PBO pts) and showed a statistically significant OS benefit for DARO vs PBO (HR 0.69; 95% CI 0.53–0.88; P = 0.003). Results from the IPE (HR 0.66; 95% CI 0.51–0.84; P &lt; 0.001) and RPSFT (HR 0.68; 95% CI 0.51–0.90; P = 0.007) analyses were similar to those from the intention-to-treat population, showing that the impact of PBO–DARO crossover was small. Additional analyses accounting for the effect of PBO–DARO crossover will be presented. The safety profile of DARO continued to be favorable at the final analysis, and discontinuation rates at the end of the double-blind period remained unchanged from the primary analysis (8.9% with DARO and 8.7% with PBO). Conclusions: Early treatment with DARO in men with nmCRPC is associated with significant improvement in OS regardless of pts crossing over from PBO to DARO. The safety profile of DARO remained favorable at the final analysis. Clinical trial information: NCT02200614.

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).

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]

Impact of subsequent immune checkpoint inhibitor treatment on overall survival with avelumab vs docetaxel in platinum-treated advanced NSCLC: Post hoc analyses from the phase 3 JAVELIN Lung 200 trial

ObjectivesThe JAVELIN Lung 200 phase 3 trial did not meet its primary endpoint of improving overall survival (OS) with avelumab vs docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report post hoc analyses assessing the effects of subsequent immune checkpoint inhibitor (ICI) treatment on OS. Material and methodsPatients with stage IIIB/IV NSCLC progressed following platinum-doublet therapy were randomized to receive avelumab or docetaxel. OS was analyzed in the PD-L1+ population (≥1% of tumor cells) and full analysis set (PD-L1+ or PD-L1−). Effects of subsequent ICI (after permanent discontinuation of study treatment) on OS were analyzed using a preplanned naive sensitivity analysis and post hoc inverse probability of censoring weighting (IPCW) analysis. Subgroups with or without subsequent ICI treatment were analyzed using descriptive statistics. ResultsIn the avelumab and docetaxel arms, a subsequent ICI was received by 16/396 (4.0 %) and 104/396 (26.3 %) after a median of 10.5 months (range, 3.9–20.4) and 5.7 months (range, 0.1–24.4), respectively. Some subgroups showed trends for higher subsequent ICI treatment, including patients with non-squamous NSCLC (avelumab arm, 4.3 % vs docetaxel arm, 32.1 %) or with a baseline ECOG performance status of 0 (6.3 % vs 31.3 %); those enrolled in the early recruitment wave (11.6 % vs 54.3 %), or enrolled in the US/Western Europe (2.8 % vs 45.5 %) or Asia (11.0 % vs 35.4 %); and non-white patients (10.1 % vs 35.0 %). The hazard ratio for OS with avelumab vs docetaxel was lower in the IPCW analysis than in the naive sensitivity analysis (PD-L1+ population: 0.80 [95 % CI, 0.62−1.04] vs 0.86 [95 % CI, 0.68−1.09], respectively). ConclusionIn the JAVELIN Lung 200 trial, avelumab showed clinical activity as second-line treatment for patients with advanced NSCLC. Post hoc analyses suggest that the primary OS analysis may have been confounded by subsequent ICI use in the docetaxel arm. ClinicalTrials.gov identifier: NCT02395172.

Screening for depression in children and adolescents: a protocol for a systematic review update

BackgroundMajor depressive disorder is common, debilitating, and affects feelings, thoughts, mood, and behaviors. Childhood and adolescence are critical periods for the development of depression and adolescence is marked by an increased incidence of mental health disorders. This protocol outlines the planned scope and methods for a systematic review update that will evaluate the benefits and harms of screening for depression in children and adolescents.MethodsThis review will update a previously published systematic review by Roseman and colleagues. Eligible studies are randomized controlled trials (RCTs) assessing formal screening in primary care to identify children or adolescents not already self-reporting symptoms of, diagnosed with, or treated for depression. If no or only a single RCT is available, we will consider controlled studies without random assignment. Studies of participants with characteristics associated with an elevated risk of depression will be analyzed separately. Outcomes of interest are symptoms of depression, classification of major depressive disorder based on a validated diagnostic interview, suicidality, health-related quality of life, social function, impact on lifestyle behavior (e.g., substance use, school performance, lost time at work, or school), false-positive results, overdiagnosis, overtreatment, labeling, and other harms such as those arising from treatment. We will search MEDLINE, Embase, PsycINFO, CINAHL, the Cochrane Library, and grey literature sources. Two reviewers will independently screen the titles and abstracts using the liberal accelerated method. Full-text screening will be performed independently by two reviewers using pre-specified eligibility criteria. Data extraction and risk of bias assessments will be performed independently by two reviewers. Pre-planned analyses, including subgroup and sensitivity analyses, are detailed within this protocol. Two independent reviewers will assess and finalize through consensus the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, and prepare GRADE evidence profiles and summary of findings tables for each outcome of interest.DiscussionThe systematic review will provide a current state of the evidence of benefits and harms of depression screening in children and adolescents. These findings will be used by the Canadian Task Force on Preventive Health Care to inform the development of recommendations on depression screening.Systematic review registrationPROSPERO CRD42020150373

BILCAP trial and adjuvant capecitabine in resectable biliary tract cancer: reflections on a standard of care

ABSTRACT Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies comprising ampulla of Vater cancer, gallbladder cancer, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma; unfortunately, the incidence of distant and locoregional recurrence remains high in resected BTCs, with approximately 60–70% of the patients who will experience disease relapse. Until a few years ago, adjuvant treatment was mainly based on the results of a meta-analysis including heterogeneous retrospective studies and showing a survival benefit in the selected populations of resected BTC patients with node-positive disease and/or R1 resection. More recently, the results of several prospective randomized clinical trials have been presented and published. Among these, although the randomized phase III BILCAP trial comparing adjuvant capecitabine versus placebo failed to meet its primary endpoint by intention-to-treat analysis, the preplanned sensitivity analysis highlighted a survival benefit, leading to the wide adoption of capecitabine as adjuvant treatment. However, several unanswered questions remain, including the following: may standard capecitabine represent the effective, real standard of care in this setting? Herein, we discuss the results of the BILCAP study, with a particular focus on the impact the trial had in everyday clinical practice worldwide.

Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.

6002 Background: SOLO2 (ENGOT ov-21; NCT01874353) showed that maintenance therapy with the PARP inhibitor olaparib in pts with platinum-sensitive relapsed ovarian cancer (PSROC) and a BRCA mutation (BRCAm) led to a statistically significant improvement in median progression-free survival (PFS) of 13.6 months vs placebo (hazard ratio [HR] 0.30). Time to second progression or death significantly improved (Pujade-Lauraine et al Lancet Oncol 2017) and a quality-adjusted PFS benefit was seen (Friedlander et al Lancet Oncol 2018) with maintenance olaparib vs placebo. We report the preplanned final OS analysis for SOLO2. Methods: Pts with PSROC and a BRCAm who had received ≥2 lines of treatment and were in response to their most recent platinum-based chemotherapy received maintenance olaparib (300 mg bid tablets) or placebo. Pts were stratified by response to previous chemotherapy (complete vs partial) and length of platinum-free interval (&gt;6–12 months vs &gt;12 months). OS was a secondary endpoint. The only preplanned OS sensitivity analysis was an OS analysis in the Myriad germline BRCAm subset (Myriad BRAC Analysis test). Results: At final data cut-off (Feb 3, 2020), median follow-up was 65 months in both treatment arms. A long-term treatment benefit was seen with olaparib vs placebo with an OS HR of 0.74 (95% confidence interval [CI] 0.54–1.00) in the full analysis set (FAS; unadjusted for crossover; 38.4% of placebo pts crossed over to a PARP inhibitor) (Table). At 5 years: by Kaplan-Meier estimates, 28.3% of pts in the olaparib arm vs 12.8% of pts in the placebo arm were alive and had still not received subsequent treatment; 42.1% of olaparib pts vs 33.2% of placebo pts were alive. The long-term tolerability profile of olaparib was generally consistent with that reported previously. Conclusions: In the final analysis of SOLO2, maintenance olaparib provided an unprecedented improvement of 12.9 months in median OS vs placebo. This is the first study with olaparib tablets, and the first since Study 19 (NCT00753545), to provide long-term follow-up and final OS data in pts with PSROC and a BRCAm. Clinical trial information: NCT01874353. [Table: see text]