On Overall Survival Hazard Ratio Research Articles

Assessing the real-world effectiveness of 8 major metastatic breast cancer drugs using target trial emulation

BackgroundDemonstration of trial emulation ability to benchmark randomised controlled trials (RCTs) from real-world data (RWD) is required to increase confidence in the use of routinely collected data for decision making in oncology. MethodsTo assess the frequency with which emulation findings align with RCTs regarding effect size on overall survival (OS) in metastatic breast cancer (MBC), 8 of 13 pre-selected pivotal RCTs in MBC were emulated using data from 32,598 patients enrolled in the French ESME-MBC cohort between January 1, 2008 and December 31, 2021. Adjustment methods and confounders were selected a priori for each emulation; stabilized weight was the reference method to mitigate confounding. Concordance in OS hazard ratios with associated 95% confidence intervals between RCTs and emulations were assessed used predefined metrics based on statistical significance, estimates, and standardized differences. ResultsThe effect sizes were consistent with RCT results in 7 out of the 8 emulations; 4 emulations achieved full statistical significance agreement; 5 emulations had a point estimate included in the RCT CI (estimate agreement); 6 emulations reported no significant differences between RCT and emulation (standardized difference agreement). Discrepancies related to residual confounders and significant shifts in prescription practices post-drug approval may arise in some cases. ConclusionTarget trial emulation from RWD combined with appropriate adjustment can provide conclusions similar to RCTs in MBC. In oncology, this methodology offers opportunities for confirming the impact on long-term survival, for expanding indications in patients excluded from RCTs and for comparative effectiveness in single-arm trials using external control arms.

Adverse Events in Targeted Therapy for Unresectable Hepatocellular Carcinoma Predict Clinical Outcomes.

To assess the impact of adverse event (AE) severity, caused by targeted therapy, on overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC), a total of 183 patients with HCC treated with atezolizumab plus bevacizumab (40), lenvatinib (57), sorafenib (79), cabozantinib (3), ramucirumab (3), and regorafenib (1) were included in this study. Age-, AFP-, and ALBI score-adjusted hazard ratios (HRs) of AE grades 1 to 3 versus grade 0 for OS and PFS were calculated using Cox proportional hazards models. The linear trend of the HRs was assessed by calculating the p values for this trend. The most common AEs were appetite loss (AE grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). The adjusted HRs for OS of these AEs were 0.532-1.450-2.361 (p for trend 0.037), 1.057-1.691-3.364 (p for trend 0.004), 1.176-0.686-0.281 (p for trend 0.002), 0.639-0.759-1.820 (p for trend 0.462), 1.030-0.959-0.147 (p for trend 0.011), and 0.697-0.609 (p for trend 0.119), respectively. Those for PFS of the corresponding AEs were 0.592-1.073-2.811 (p for trend 0.255), 1.161-1.282-4.324 (p for trend 0.03), 0.965-0.781-0.655 (p for trend 0.095), 0.737-0.623-2.147 (p for trend 0.153), 1.061-0.832-0.800 (p for trend 0.391), and 1.412-0.560 (p for trend 0.081), respectively. Appetite loss and general fatigue negatively affected clinical outcomes, whereas hypertension, HFS, proteinuria, and hypothyroidism had positive effects.

A Retrospective Study of Pediatric Patients With Low- or Intermediate-Risk Acute Myeloid Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation for the AML-05 Study Conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group

The AML-05 study aimed to examine the efficacy and safety of a therapeutic strategy based on risk stratification for low-, intermediate-, or high-risk acute myeloid leukemia (AML) pediatric patients. Allogeneic hematopoietic cell transplantation (allo-HCT) was not indicated for low- or intermediate-risk AML patients in first complete remission. The present retrospective study for the AML-05 study aimed to identify prognostic factors for survival and to determine optimal allo-HCT according to multivariate analysis on overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), and cumulative incidence of nonrelapse mortality for and between low- and intermediate-risk AML group patients in the AML-05 study who had undergone allo-HCT after its completion and relapse. The unique patient numbers (UPNs) of the AML-05 study were matched with the Transplant Registry Unified Management Program (TRUMP)-registered numbers, and the tied data on the AML-05 study's UPNs and the TRUMP-registered numbers were analyzed. The primary endpoint was 3-yr OS. Among 443 AML patients in the AML-05 study, 79 (32 low-risk AML and 47 intermediate-risk AML) were analyzed. The following statistically favorable prognostic factors were identified by multivariate analysis on the low- and intermediate-risk AML groups, respectively: UCB (OS—hazard ratio [HR], 0.105; 95% CI, 0.011 to 0.941; P = .004 and EFS—HR, 0.065, 95% CI, 0.007 to 0.577, P = .014) and late relapse (OS—HR, 0.212; 95% CI, 0.072 to 0.626; P = .005 and EFS—HR, 0.236; 95% CI, 0.088 to 0.630; P = .004). Three-year OS, 3-yr EFS, and 3-yr CIR were significantly different between the low- and intermediate-risk AML groups. UCB may be a safe and beneficial donor source for low-risk AML patients, while late relapse was a favorable prognostic factor for intermediate-risk AML patients. Intermediate-risk AML patients with late relapse and low-risk AML patients may benefit from allo-HCT after relapse.

Dexamethasone in Patients with Glioblastoma: A Systematic Review and Meta-Analysis.

Glioblastomas are the most common primary central nervous system (CNS) tumors. Although modern management strategies have modestly improved overall survival, the prognosis remains dismal, with treatment side effects often impinging on the clinical course. Glioblastomas cause neurological dysfunction by infiltrating CNS tissue and via perifocal oedema formation. The administration of steroids such as dexamethasone is thought to alleviate symptoms by reducing oedema. However, despite its widespread use, the evidence for the administration of dexamethasone is limited and conflicting. Therefore, we aimed to review the current evidence concerning the use and outcomes of dexamethasone in patients with glioblastoma. We performed a systematic review and meta-analysis according to the PRISMA-P guidelines. We performed a restricted search using the keywords "Dexamethasone" and "Glioblastoma" on PubMed, Web of Science, Cochrane Library, and Academic Search Premier. We included studies reporting on overall survival (OS) and progression-free survival (PFS) in glioblastoma patients receiving higher or lower dexamethasone doses. The risk of bias was assessed using ROBINS-I. We performed a meta-analysis using a random effects model for OS and PFS. Twenty-two retrospective studies were included. Higher doses of dexamethasone were associated with poorer OS (hazard ratio 1.62, confidence interval 1.40-1.88) and PFS (1.49, 1.23-1.81). OS remained worse even when studies corrected for clinical status (1.52, 1.38-1.67). Despite the widespread use of dexamethasone in glioblastoma patients, its use is correlated with worse long-term outcomes. Consequently, Dexamethasone administration should be restricted to selected symptomatic patients. Future prospective studies are crucial to confirm these findings.

Macroscopic type is implicated in the prognostic impact of initial chemotherapy on peritoneal lavage cytology-positive gastric cancer with no other noncurative factors.

Initial chemotherapy (Initial-C) followed by surgery is a promising treatment strategy for peritoneal lavage cytology-positive gastric cancer (CY1 GC) with no other noncurative factors. The aim of this study was to investigate the survival advantage of Initial-C compared to initial surgery (Initial-S) for this disease according to the macroscopic type, which was associated with prognosis and the efficacy of chemotherapy in GC. One hundred eighty-nine patients who were diagnosed with CY1 GC with no other noncurative factors at four institutions from January 2007 to December 2018 were enrolled. The patients were divided into a macroscopic type 4 group (N = 48) and a non-type 4 group (N = 141). The influence of initial treatment on overall survival (OS) in each group was evaluated. In the type 4 group, the 5-year OS rates of Initial-C (N = 35) and Initial-S (N = 13) were 11.6% and 0%, respectively (P = 0.801). The multivariate analysis could not show the survival advantage of Initial-C. In the non-type 4 group, the 5-year OS rates of Initial-C (N = 41) and Initial-S (N = 100) were 48.4% and 29.0%, respectively (P = 0.020). The multivariate analysis revealed that Initial-C was independently associated with prolonged OS (hazard ratio, 0.591; 95% confidence interval, 0.375-0.933: P = 0.023). Initial-C improves the prognosis of non-type 4 CY1 GC with no other noncurative factors. On the other hand, further development of effective chemotherapeutic regimens and innovative treatment strategies are required for type 4 CY1 GC.

CD5 Expression in Mature T Cell Lymphoma

Background Mature T-cell lymphoma (TCL), an aggressive and heterogenous group of T cell neoplasms, constitutes less than 15% of adult non-Hodgkin lymphomas. CD5 is an inhibitory T cell receptor molecule expressed on mature T cells. CD5 expression has been associated with worse outcomes in B-cell malignancies, however this association has not been explored in TCL. Furthermore, CD5 has become a promising immunotherapeutic target for TCL. We herein aimed to characterize CD5 expression in TCL subtypes at diagnosis and relapse, and its association with clinical features and outcomes in a single center cohort. Methods We retrospectively identified 109 patients (pts) diagnosed with non-cutaneous and non-leukemic mature TCL, with data on CD5 expression on tumor tissue by immunohistochemistry (IHC) and/or flow cytometry (FC), from the electronic medical records at the Hospital of the University of Pennsylvania (HUP). CD5 positivity (CD5+) was defined as any percentage of CD5+ malignant cells on FC and/or IHC. Chi-square test was used to compare baseline pt characteristics at the initial presentation between CD5 expression groups. Treatment response (TR) was defined as achieving complete or partial response by the end of initial treatment. Logistic regression models were used to assess the impact of clinical parameters on the overall TR rate and odds ratios (OR) were computed. Cox proportional hazards models were used to evaluate the effects of clinical parameters on overall survival (OS) and progression-free survival (PFS) and were reported as hazard ratios (HR). We also conducted Kaplan-Meier (KM) analyses for OS and PFS by CD5 expression status. The OR and HR are reported with 95% CI in brackets. P-values <0.05 were considered significant. All analyses were conducted in SAS version 9.4 (SAS Institute Inc). Results We collected and evaluated data from a total of 109 adult pts diagnosed with TCL at HUP between 1/1/05-1/1/21. Median age at diagnosis was 58 (range: 19 - 86 years); 56% were men; the most common diagnosis was ALCL (n=37) followed by nodal TFH lymphoma (n=29), PTCL-NOS (n=16), ENKTCL (n=13) and other extranodal (EN) TCL (n=14) (Table.1). Compared to CD5- pts, a higher percentage of CD5+ pts were diagnosed at age >60 (CD5-:34.7%, CD5+:55.0%, p=0.0343), and stage 3 or 4 (CD5-:46.9%, CD5+:70%, p=0.0142), but fewer CD5+ pts had EN involvement at diagnosis (CD5-:77.6%, CD5+:50%, p=0.0031). CD5 was also differentially expressed by TCL subtypes: nearly all TFH TCL (93.1%) and PTCL-NOS expressed CD5 (87.5%), whereas CD5 was less commonly expressed in ALCL (39.4%,), other ENTCL (27.8%), and ENKTCL (7.7%) (p<0.0001). In addition, on univariate analysis (UVA), CD5 expression was associated with stage 3 or 4 (p=0.014), age >60 (p=0.034), and less common EN involvement (p=0.031), but not with treatment response, relapse or survival. On UVA for treatment response, established risk factors such as ≥ 2 EN involvement (OR=0.25 [0.09, 0.6], p=0.0243) and high LDH (OR=0.26 [0.08, 0.85], p=0.0267), were shown to be negative predictors. Multivariate analysis (MVA) for response also predicted high LDH as a negative predictor (OR=0.29 [0.08,0.99], p=0.0477). CD5 expression was not associated with treatment response on either UVA (OR=1.18 [0.50, 2.78], p=0.7042) or MVA (OR=1.00 [0.33,3.60], p=0.9969). On UVA, CD5 positivity did not impact OS (HR=1.2 [0.7,2.0], p=0.6118) nor PFS (HR=1.5 [0.7,3.0], p=0.2862), while worse outcomes were associated with established risk factors, including ECOG performance status ≥ 2 (OS HR=2.0 [1.0-3.8], p=0.0440), ≥2 EN involvement (OS HR=3.1 [1.7-5.7], p=0.0002; PFS HR 13.1 [2.9-59.9], p=0.0009), and B symptoms (OS HR=2.1 [1.2-3.7], p=0.0117). TFH TCL was also found to be associated with worse OS (HR= 2.6 [1.3-5.5], p=0.0101). In our cohort of 35 pts with CD5 expression data at relapses, 100% pts remained CD5+ (n=19), 68.75% pts remained CD5- (n=11), but 31.25% pts gained CD5 expression (n=5), and none lost CD5 expression. Based on KM analyses, CD5 expression did not impact PFS or OS (Fig. 1). Conclusions In this cohort of 109 TCL pts, CD5 expression was common in TFH TCL, PTCL-NOS, ALCL, and ENTCL, and was retained or gained at relapse, thus supporting its potential as a therapeutic target. CD5 expression was associated with advanced age and stage, while EN involvement was less common. CD5 expression was not associated with a differential treatment response, PFS, nor OS.

Elevate-TN: Impact of First-Year Dose Modifications in Patients with Treatment-Naive Chronic Lymphocytic Leukemia Treated with Acalabrutinib

Background: Acalabrutinib (acala), a second-generation Bruton tyrosine kinase inhibitor (BTKi), with or without obinutuzumab (obin), demonstrated superior progression-free survival (PFS) compared with obin plus chlorambucil in patients with treatment-naive (TN) chronic lymphocytic leukemia (CLL) in the phase 3 ELEVATE-TN (NCT02475681) trial. Despite the long-term benefits observed with acala therapy, data from real-world studies in patients with CLL demonstrate that 22% of patients discontinue acala treatment for any reason in the first year of treatment across therapy lines (Roeker et al. Blood. 2022). To assess the impact on survival outcomes of acala discontinuation and dose modifications occurring in the first year of treatment, we conducted a post hoc analysis in patients treated in the acala-containing arms of ELEVATE-TN. Methods: Patients who received acala 100 mg twice daily with or without obin (fixed duration, up to 6 cycles) with at least 1 year of follow-up were included in this analysis. The impact of dose reductions, treatment breaks, or treatment discontinuations in the first year on overall survival (OS) was assessed. Protocol-specified dose-modification guidelines that included dose reductions, breaks, and discontinuations depending on severity and frequency were applied to patients with apparent treatment-related toxicity. To assess the impact of dose reductions, breaks, or discontinuations, patients were divided into 4 dose-modification subgroups: 1) patients with no dose reductions/breaks >14 days during the first year; 2) patients with dose reductions >14 days, but no breaks >14 days during the first year; 3) patients with breaks >14 days, but who continued treatment in the first year; and 4) patients who discontinued treatment during the first year. Results: With a median follow-up of 60 months, 358 patients (n=179, acala monotherapy; n=179, acala-obin) with ≥1 year of follow-up were included in this analysis. In the first year, 269 (75%) patients had no dose reductions/breaks >14 days, 11 (3%) patients had dose reductions >14 days but no breaks >14 days, 32 (9%) patients had breaks >14 days but continued treatment, and 46 (13%) patients discontinued treatment. Reasons for treatment discontinuation during the first year were adverse events (n=26), disease progression (n=7), physician decision (n=5), consent withdrawn (n=3), death (n=2), loss to follow-up (n=1), and other (n=2). Patients who discontinued treatment within the first year had inferior OS compared with patients who did not require dose reductions or breaks (OS hazard ratio [HR]: 8.39, 95% confidence interval [CI]: 3.96-17.8, P<0.0001; Figure 1). In contrast, patients who had dose reductions or breaks >14 days but did not discontinue treatment had statistically similar OS to patients who did not require dose reductions or breaks. Within the group that had no dose reductions or treatment breaks >14 days, there was no difference in the proportion of patients treated with acala monotherapy (n=133) and acala-obin (n=136). However, OS outcomes in this subgroup of patients with no treatment modifications were superior in patients treated with acala-obin compared with those treated with acala monotherapy (HR: 0.37, 95% CI 0.15-0.87, P=0.0183; Figure 2). Conclusions: This post hoc analysis of acala-treated patients with TN CLL in ELEVATE-TN demonstrated superior OS in patients who did not have dose reductions or breaks compared with patients who discontinued treatment within the first year. OS outcomes in patients who required dose reductions or breaks but did not discontinue treatment in the first year were similar to those in patients who did not require dose modification. Accepting the limitations of retrospective analysis, these data suggest that patients who are unable to tolerate standard-dose acala or who require treatment breaks may benefit from continuing or resuming treatment at a reduced dose rather than stopping treatment altogether. For patients who do not require dose modifications, ongoing follow-up of the ELEVATE-TN trial suggests durable and incrementally improved OS benefit from the addition of obin to acala.

Cost-Effectiveness of Epcoritamab in Relapsed or Refractory Diffuse Large B-Cell Lymphoma after at Least Two Lines of Therapy in the United States

Introduction: Epcoritamab (SC) is a CD3xCD20 bispecific antibody developed using the DuoBody ® platform for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL), not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy in the US. In the single-arm, phase I/II, EPCORE-NHL-1trial (NCT03625037), epcoritamab (SC) demonstrated deep and durable responses and manageable safety in patients withr/r DLBCL. This study evaluated the cost-effectiveness of epcoritamab versus gemcitabine-oxaliplatin plus rituximab (R-GemOx) and the chimeric antigen receptor T-cell (CAR T) therapy axicabtagene ciloleucel (axi-cel) for adult patients with r/r DLBCL and no prior CAR T therapy from a US health system perspective. Methods: A partitioned survival model with three health states (progression-free [PF], progressive disease [PD], and death) based on overall survival (OS) and progression-free survival (PFS) was developed. OS, PFS, time to treatment discontinuation (TTD), health utilities, and adverse events of epcoritamab were informed by the corresponding patient level data from EPCORE-NHL-1 (data cut-off: June 2022). In the model base case, parametric survival models were chosen to extrapolating OS and PFS as well as TTD for epcoritamab based on statistical fit and plausibility on long-term clinical estimates. Two separate unanchored matching-adjusted indirect comparison (MAIC) analyses were conducted to assess the relative effectiveness of epcoritamab versus R-GemOx or axi-cel. In the first analysis, epcoritamab patients were matched with SCHOLAR-1 patients for comparison with R-GemOx (OS hazard ratio [HR] 0.288, 95% confidence interval [CI] 0.162-0.511). SCHOLAR-1 was chosen because it was the largest patient-level pooled retrospective analysis for r/r DLBCL, pooling outcomes from 2 large RCTs and 2 academic databases. In the second analysis, epcoritamab patients were matched with ZUMA-1 for comparison with axi-cel (OS HR 0.695, 95% CI 0.351-1.376). ZUMA-1 was chosen because it had long-term efficacy data reported. Patients in PF health states were assumed cured beyond two years when the risk of mortality became comparable to the general population (standard mortality ratio of 1.41 to be more conservative and consistent with prior NICE technology assessment submissions) and no further drug costs of epcoritamab were incurred. Health utilities for PF (0.825) and PD (0.779) health states were estimated using linear mixed-effects models based on EQ-5D-3L data collected from EPCORE-NHL-1 and a published US value set. Drug acquisition and administration costs and other resource use and cost data were based on package inserts, US standard sources, and literature. The model reported costs, life years (LYs), quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB) at a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per QALY. All outcomes and costs were discounted by 3% annually. Probabilistic and one-way sensitivity analyses were conducted to assess the robustness of the results. Results: Over a lifetime horizon, epcoritamab was estimated to result in a mean gain of 4.26 LYs and 2.70 QALYs with additional costs of $285,093 versus R-GemOx, leading to an ICER of $105,502 per QALY; epcoritamab was estimated to dominate axi-cel by gaining 2.12 LYs and 1.29 QALYs while saving $180,518 costs. When drug acquisition costs (e.g. axi-cel one-time treatment cost) are not included in the sensitivity analyses, model results were most sensitive to OS HR, age, and HR to adjust background mortality for the cured population for comparison with R-GemOx; and to OS HR, PFS HR, and age for comparison with axi-cel. Epcoritamab was highly cost-effective compared to R-GemOx and aix-cel when WTP threshold was $150,000 per QALY or higher. This study had several limitations including unanchored MAIC approach used and the relatively short follow-up time and small (effective) sample size of the survival data of epcoritamab. Conclusion: Epcoritamab provides substantial LYs and QALYs gains versus R-GemOx and axi-cel and can be considered cost-effective compared to R-GemOx and axi-cel for the treatment of r/r DLBCL in the US.

Impact of Removal of Lymph Nodes on Survival in Stage I-III Gastric Signet-Ring Cell Cancer: The More, the Better?

There is an ongoing debate over the prognostic value of the number of examined lymph nodes (ELNs) in cases of gastric signet-ring cell cancer (GSRCC). In this study, we sought to evaluate the correlation between the number of ELNs and the prognosis of GSRCC and identify the optimal number of ELNs. A total of 1020 patients diagnosed with GSRCC between 2011 and 2018 in the National Cancer Center database were identified. Clinicopathological characteristics were retrospectively collected, and optimal cutoff values of ELNs were calculated by using X-tile. The impact of different ELNs on overall survival (OS) was compared by using Kaplan-Meier curves. We used univariate and multivariate Cox and subgroup analyses to explore the relationship between ELNs and OS. Furthermore, nonlinear correlations were investigated by using restricted cubic splines (RCSs). X-tile showed that the optimal cutoff value of ELNs was 22. The 5-year OS was higher for patients with ELNs > 22 (vs. ELNs ≤ 22, 66.9% vs. 74.9%, P = 0.026). Multivariate Cox analyses showed that high ELNs were associated with superior OS (hazard ratio = 0.56, 95% confidence interval 0.43-0.74, P < 0.001). In subgroup analyses, the significant association between tumor size > 4cm, and TNM III stage was still observed. The RCS regression model showed a U-shaped dose-response nonlinear relationship between ELNs and OS; the inflection point, as well as the lowest risk points, corresponded to 44-52 ELNs. A U-shaped, nonlinear correlation with inflection points of 44-52 ELNs between ELNs and prognosis in GSRCC was identified.

Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer

ObjectiveTo determine the impact on overall survival (OS) and patient-reported outcomes (PROs) of combining atezolizumab with standard therapy for newly diagnosed stage III/IV ovarian cancer. MethodsThe placebo-controlled double-blind randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial (NCT03038100) assigned eligible patients to 3-weekly atezolizumab 1200 mg or placebo for 22 cycles with platinum-based chemotherapy and bevacizumab. Coprimary endpoints were progression-free survival (already reported) and OS in the PD-L1-positive and intent-to-treat (ITT) populations, tested hierarchically. Prespecified PRO analyses focused on disease-related abdominal pain and bloating symptoms (European Organisation for Research and Treatment of Cancer QLQ-OV28), functioning, and health-related quality of life (HRQoL) (QLQ-C30). ResultsAfter 38 months’ median follow-up, the OS hazard ratio in the PD-L1-positive population was 0.83 (95% CI, 0.66–1.06; p = 0.13); median OS was not estimable with atezolizumab versus 49.2 months with placebo. The hazard ratio for OS in the ITT population was 0.92 (95% CI, 0.78–1.09; median 50.5 versus 46.6 months, respectively). At week 9, similar proportions of patients in both arms of the neoadjuvant cohort showed ≥10-point improvement from baseline in abdominal pain and bloating, functioning, and HRQoL. In the primary surgery cohort, similar proportions of patients in each arm had improved, stable, or worsened physical and role function and HRQoL from baseline over time. Neither cohort showed differences between arms in treatment-related symptoms or overall side-effect bother. ConclusionsIncorporation of atezolizumab into standard therapy for newly diagnosed ovarian cancer does not significantly improve efficacy or impose additional treatment burden for patients.ClinicalTrials.gov registration: NCT03038100.

Cross-sectional analysis characterizing the use of rank preserving structural failure time in oncology studies: changes to hazard ratio and frequency of inappropriate use

BackgroundRank preserving structural failure time (RPSFT) is a statistical method to correct or adjust for crossover in clinical trials, by estimating the counterfactual effect on overall survival (OS) when control arm patients do not receive the interventional drug when their tumor progresses. We sought to examine the strength of correlation between differences in uncorrected and corrected OS hazard ratios and percentage of crossover, and characterize instances of fundamental and sequential efficacy.MethodsIn a cross-sectional analysis (2003–2023), we reviewed oncology randomized trials that used RPSFT analysis to adjust the OS hazard ratio for patients who crossed over to an anti-cancer drug. We calculated the percentage of RPSFT studies evaluating a drug for fundamental efficacy (with or without a standard of care (SOC)) or sequential efficacy and the correlation between the OS hazard ratio difference (unadjusted and adjusted) and the percentage of crossover.ResultsAmong 65 studies, the median difference between the uncorrected and corrected OS hazard ratio was −0.1 (quartile 1, quartile 3 : −0.3 to −0.06). The median percentage of crossover was 56% (quartile 1, quartile 3: 37% to 72%). All studies were funded by the industry or had authors who were employees of the industry. Twelve studies (19%) tested a drug’s fundamental efficacy when there was no SOC; 34 studies (52%) tested a drug’s fundamental efficacy when there was already a SOC; and 19 studies (29%) tested a drug’s sequential efficacy. The correlation between the uncorrected and corrected OS hazard ratio difference and the percentage of crossover was 0.44 (95% CI: 0.21 to 0.63).ConclusionsRPSFT is a common tactic used by the industry to reinterpret trial results. Nineteen percent of RPSFT use is appropriate. We recognize that while crossover can bias OS results, the allowance and handling of crossover in trials should be limited to appropriate circumstances.

CtDNA as a prognostic biomarker in resectable CLM: Systematic review and meta-analysis.

Cell-free circulating tumor DNA (ctDNA) is synthesized by tumor cells, including metastatic tumors, and circulates in the bloodstream. Evidence suggests that ctDNA is a potential predictive and prognostic biomarker for colorectal cancer (CRC), but its predictive efficacy in detecting CRC liver metastasis (CLM) remains unclear. Additionally, its utility in the clinical setting needs further investigation. We conducted a meta-analysis to determine the utility of ctDNA as a biomarker for predicting the prognosis of CLM and investigate the relationship between CLM and ctDNA positivity. A literature search was performed in electronic databases to identify relevant studies published up to March 19, 2022. We retrieved data on overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) for both ctDNA-positive and ctDNA-negative colorectal liver metastasis (CLM) patients from the selected articles. Hazard ratios (HRs) were also calculated for these survival outcomes analysis was also performed. The stability of the combined meta-analysis was verified by sensitivity analysis and publication bias evaluation. Ten trials were included, and 615 patients were evaluated. In patients with CLM, pooled HRs revealed a substantial link between ctDNA positivity and RFS/DFS. Subgroup analysis revealed that ctDNA had a prospective detection value. Sensitivity analysis and publication bias evaluation indicated stable results. Although the results on pooled HR for OS suggested that ctDNA-positive patients had a shorter survival time, their pooled HRs had a relatively evident heterogeneity, and sensitivity analysis and publication bias evaluation indicated that pooled HRs were extremely unstable. In conclusion, our results demonstrate that ctDNA appears to be a prognostic biomarker for resectable CLM patients.

Geriatric nutritional risk index after neoadjuvant chemoradiotherapy and survival in older patients with advanced rectal cancer.

To investigate the clinical impact of malnutrition on the survival of older patients with advanced rectal cancer who underwent neoadjuvant chemoradiotherapy. We investigated the clinical significance of the geriatric nutritional risk index (GNRI) in 237 patients aged over 60years with clinical stage II/III rectal adenocarcinoma who were treated with neoadjuvant long-course chemoradiotherapy or total neoadjuvant therapy followed by radical resection from 2004 to 2017. Pre-treatment and post-treatment GNRI were evaluated, with patients split into low (< 98) and high (≥ 98) GNRI groups. The prognostic impact of pre-treatment and post-treatment GNRI levels on overall survival (OS), post-recurrence survival (PRS), and disease-free survival (DFS) was evaluated using univariate and multivariate analyses. Fifty-seven patients (24.1%) before neoadjuvant treatment and 94 patients (39.7%) after neoadjuvant treatment were categorized with low GNRI. Pre-treatment GNRI levels were not associated with OS (p = 0.80) or DFS (p = 0.70). Patients in the post-treatment low GNRI group had significantly poorer OS than those in the post-treatment high GNRI group (p = 0.0005). The multivariate analysis showed that post-treatment low GNRI levels were independently associated with poorer OS (hazard ratio, 3.06; 95% confidence interval, 1.55-6.05; p = 0.001). Although post-treatment GNRI levels were not associated with DFS (p = 0.24), among the 50 patients with recurrence, post-treatment low GNRI levels were associated with poorer PRS (p = 0.02). Post-treatment GNRI is a promising nutritional score associated with OS and PRS in patients over 60years with advanced rectal cancer treated with neoadjuvant chemoradiotherapy.

Optimal medical management in patients undergoing peripheral vascular interventions for chronic limb-threatening ischemia is associated with improved outcomes

ObjectiveOptimizing medical management and risk factor modification are underused strategies in patients with chronic limb-threatening ischemia (CLTI), despite evidence of improved outcomes. The Vascular Quality Initiative (VQI) registry is a tool to improve quality of vascular care. In this study, we used the VQI to evaluate trends in medical management in patients with CLTI undergoing peripheral vascular interventions (PVI), and the impact of changes in management on overall survival (OS), amputation-free survival (AFS), and limb salvage (LS). MethodsPatients undergoing index PVI for CLTI between 2012 and 2016, with ≥24 months of follow-up were identified from the national VQI registry. Patient details including smoking status and medication use, OS, LS, and AFS were analyzed with linear-by-linear association, t test, and logistic regression. ResultsThere were 12,370 PVI completed in 11,466 patients. There was a significant increase in infrapopliteal interventions (from 29.8% to 39.0%; P < .001) and PVI performed for tissue loss (from 59.1% to 66.5%; P < .001). The percentage of current smokers at time of PVI decreased (from 36.2% to 30.7%; P = .036). At discharge, statins were initiated in 25%, aspirin in 45%, and P2Y12 therapy in 58% of patients not receiving these medications before PVI. Over the course of follow-up, dual antiplatelet therapy (DAPT) (from 41.1% to 48.0%; P < .001), angiotensin-converting enzyme (ACE) inhibitor (from 46.2% to 51.3%; P < .001), and statin (from 70.4% to 77.5%; P < .001) use increased. Combined DAPT, ACE inhibitor and statin use increased from 33.6% to 39.6% (P ≤ .001). Significant improvement in 24-month OS and AFS was noted (OS, from 90.9% to 93.7% [P = .002]: AFS, from 81.2% to 83.1% [P = .046]), but not LS (from 89.6% to 89.0%; P = .83). Combined therapy with P2Y12 inhibitors, statins and ACE inhibitors was an independent predictor of improved OS (hazard ratio, 0.61; 95% confidence interval, 0.39-0.96; P = .034). DAPT was independent predictor of improved LS (hazard ratio, 0.83; 95% confidence interval, 0.79-0.87; P < .007). ConclusionsAntiplatelet, ACE inhibitor, and statin use increased over the study period and was associated with improved OS and AFS. LS trends did not change significantly over time, possibly owing to the inclusion of patients with a greater disease burden or inadequate medical management. Medical management, although improved, remained far from optimal and represents an area for continued development.

The evidence base of US Food and Drug Administration approvals of novel cancer therapies from 2000 to 2020.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non-pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression-free survival and tumor response were summarized in meta-analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33-4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72-0.79, I2 = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000-2005; 41% in 2016-2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

Adjuvant chemoradiotherapy versus chemotherapy or radiotherapy in advanced endometrial cancer: a systematic review and meta-analysis.

Endometrial cancer is one of the most common gynecological cancer in the world. However, the available adjuvant therapies, chemotherapy (CT) and radiotherapy (RT), demonstrated several limitations when used alone. Therefore, we conducted a meta-analysis to investigate the clinical effectiveness of chemoradiotherapy (CRT) based on overall survival (OS) and disease-free survival (DFS). A literature search was performed on five databases and one clinical trial registry to obtain all relevant articles. Search for studies was completed on September 9, 2021. A meta-analysis was conducted to determine the overall hazard ratio with the 95% Confidence Interval. A total of 17 articles with 23,975 patients in the CRT vs RT group and 50,502 patients in the CRT vs CT group were included. The OS Hazard Ratios (HR) of CRT compared to RT was 0.66 (95% CI [0.59-0.75]; P < 0.00001). Compared to CT, the OS HR was 0.70 (95% CI [0.64-0.78]; P < 0.00001). CRT also significantly improved the DFS compared to CT only (HR 0.79, 95% CI [0.64-0.97]; P = 0.02) However, CRT did not improve the DFS compared to RT only, with HR of 0.71 (95% CI [0.46-1.09]; P = 0.12). Adjuvant CRT can significantly improve OS compared to CT or RT alone and improve the DFS compared to CT alone in patients with advanced endometrial cancer. Further research is needed to identify the optimal CRT regimen, and to whom CRT will be most beneficial.

Characterizing Mature T-Cell Lymphoma Patients' Outcomes By Race

Background Mature T-cell lymphomas (TCL) are a rare and aggressive group of non-Hodgkin lymphomas with significant geographic variability. Data on TCL patient outcomes by race are limited, and minority populations are often underrepresented in TCL clinical trials in North America and Europe. Herein, we describe outcomes in patients with newly diagnosed TCL from an urban US tertiary care center based on race. Methods We retrospectively identified 125 patients with non-cutaneous and non-leukemic mature TCL diagnosed between 1/1/2009-12/31/2021 from the electronic medical records at the Hospital of the University of Pennsylvania. In a univariate model stratified by self-reported race, we compared baseline patient characteristics at initial presentation, treatment patterns (including first line (1L) therapy, use of CNS prophylaxis and hematopoietic cell transplant (HCT), number of subsequent lines of treatment), and disease outcomes. Multivariate Cox proportional hazards models controlling for race, sex, age, ECOG score, LDH level, initial stage of disease, presence of B symptoms, hemoglobin, platelet count, IPI score, number of sites of extranodal involvement (ENI), histology, and 1L treatments (CHOP, CHOEP, other intensive treatment, radiation only, as well as palliative care), and receipt of HCT were implemented to further investigate the impact of these clinical parameters on overall survival (OS) and progression-free survival (PFS). P-values <0.05 were considered significant. Hazard ratio (HR) is reported with 95% CI in brackets. Results We collected and evaluated data from 94 White patients, 21 Black patients and 10 patients of other races. Patients of other races comprised less than 10% of our cohort and were omitted from the analysis due to inadequate statistical representation. Compared to White patients, Black patients demonstrated comparable baseline characteristics at initial presentation, except for lower incidence of TCL with T-follicular helper phenotype (p=0.013), poor performance status (ECOG ≥ 2; p=0.005), and ≥2 sites of ENI (p=0.002). Treatment patterns for Black and White patients, including 1L chemotherapy, radiation therapy, CNS prophylaxis, HCT, and subsequent lines of treatment were not significantly different. On univariate analysis, response rates to initial therapy, PFS, and OS were similar for Black and White patients (Table 1). On multivariate analysis, race did not significantly impact OS (HR 0.72 [0.29-1.80], p=0.480) or PFS (HR 0.50 [0.17-1.47], p=0.206), though worse outcomes were observed with other established risk factors, including ECOG ≥ 2 (OS HR 3.32 [1.43-7.73], p=0.005), elevated LDH (OS HR 3.25 [1.37-7.71], p=0.008; PFS HR 2.29 [1.00-5.21], p=0.0.049), and low platelet count (OS HR=2.84 [1.22-6.60], p=0.015; PFS HR 2.73 [1.13-6.62], p=0.026). However, advanced stage was associated with better OS (HR 0.22 [0.09 -0.58], p=0.002). For both races, HCT in 1st remission was associated with significantly improved PFS (HR 0.03 [0.03-0.33], p=0.004) but not OS (HR 0.57 [0.14-2.35] p=0.44) (Table 2). Conclusion In this cohort of patients with TCL treated at an urban US tertiary care center with demographics reflective of the national population, we did not find outcomes affected by race despite the higher incidence of poor risk baseline prognostic factors in Black patients. Treatment patterns, including intensive therapy, use of transplant, and number of subsequent therapies, were also not affected by race in our cohort. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Importance of triple tumor markers as biomarkers in patients with pancreatic ductal adenocarcinoma.

There is an urgent need to establish biomarkers for the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate the usefulness of the combined assessment of carbohydrate antigen 19-9 (CA19-9), carcinoembryonic antigen (CEA), and duke pancreatic monoclonal antigen type 2 (DUPAN-2) in PDAC. We retrospectively investigated the impact of three tumor markers on overall survival (OS) and recurrence-free survival (RFS). Patients were classified into two groups: upfront surgery (US) and neoadjuvant chemoradiation (NACRT) groups. In total, 310 patients were evaluated. In the US group, patients who had all three elevated markers showed a significantly worse prognosis than the others (median: 16.4months, P=.005). In the NACRT group, patients who had elevated CA 19-9 and CEA levels after NACRT had significantly worse prognosis than the others (median: 26.2months, P < .001). The elevated DUPAN-2 levels before NACRT were associated with significantly worse prognosis than normal levels (median: 44.0 vs 59.2 months, P=.030). Patients who had elevated DUPAN-2 levels before NACRT with elevated CA 19-9 and CEA levels after NACRT showed extremely poor RFS (median: 5.9months). Multivariate analysis revealed that a modified triple-positive tumor marker indicating elevated DUPAN-2 levels before NACRT and elevated CA19-9 and CEA levels after NACRT was an independent prognostic factor of OS (hazard ratio: 2.49, P=.007) and RFS (hazard ration: 2.47, P=.007). The combined evaluation of three tumor markers may provide useful information for the treatment of patients with PDAC.

Postoperative tegafur-uracil for stage I lung adenocarcinoma: first real-world data with an exploratory subgroup analysis.

The effect of postoperative tegafur-uracil on overall survival (OS) after resection of stage I adenocarcinoma has been shown in clinical trials. The purpose of this study was to investigate whether findings from randomized trials of adjuvant tegafur-uracil are reproducible in a real-world setting. A retrospective cohort study was performed using a multi-institutional database that included all patients who underwent complete resection of pathological stage I adenocarcinoma between 2014 and 2016. Survival outcomes for patients managed with and without tegafur-uracil were analyzed using the Kaplan-Meier method and a Cox proportional hazards model for the whole patient cohort and in a selected cohort based on eligibility criteria of a previous randomized trial. Propensity score matching was used to adjust for confounding effects. After propensity score matching, the hazard ratios for OS were 0.57 (95% confidence interval (CI) 0.29-1.14, P = 0.11) in the whole cohort and 0.69 (95% CI 0.32-1.50, P = 0.35) in the selected cohort. The effects of tegafur-uracil in this retrospective study appear to be consistent with those found in randomized clinical trials. These effects may be maximized in patients aged from 45 to 75years.

Abstract 2727: Overexpression of protocadherin related 15 (PCDH15) gene predicts better prognosis in low-grade glioma patients

Abstract Background: Gliomas are the most common tumors arising from the brain. According to the WHO classification, gliomas are divided into low- and high-grade gliomas based on their aggressiveness and degrees of differentiation. Protocadherin Related 15 (PCDH15) gene is a member of the cadherin superfamily that encode membrane proteins involved in cell-cell adhesion. In this study, we aimed to investigate the prognostic value of PCDH15 expression in Low-Grade Gliomas (LGG) and Glioblastoma Multiforme (GBM). Methods: We conducted a bioinformatics analysis for PCDH15 in LGG and GBM patients’ data using their respective datasets from the Cancer Genomic Atlas (TCGA). GEPIA and GENT2 web-based tools were used to confirm the differential expression of PCDH15 in LGG and GBM patients in comparison with normal brain tissue. We used the cBioPortal database to compare PCDH15 expression across molecular and histological glioma subtypes. Also, the SurvExpress tool was used to assess the prognostic value of PCDH15 on overall survival (OS). To further understand the underlying molecular biology of PCDH15’s function, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted for significantly co-expressed genes (|spearman correlation coefficient|≥ 0.5) with PCDH15 using the DAVID 6.8 bioinformatics tool. Results: LGG and GBM both had statistically significant differences in PCDH15 expression compared with normal brain tissue. PCDH15 expression was significantly higher in LGG patients compared with GBM patients (mean log2 (TPM + 1): 9.5 vs 5.6, P &amp;lt; 0.0001), with the highest expression in patients with mutated IDH genes. In the LGG cohort, higher PCDH15 expression was associated with longer OS (hazard ratio: 2.44, 95% confidence interval: 1.69 - 3.53, P = 1.949E-6) while no significant difference was found in the GBM cohort (hazard ratio: 1.07, 95% confidence interval: 0.74 - 1.53, P = 0.7304). GO analyses for co-expressed genes in LGG indicated a role in the biological process (BP) DNA-templated regulation of transcription with a cellular component (CC) in the nucleus and the molecular functions (MF) “histone demethylase activity”, “hydrolase activity, acting on acid anhydrides” and “zinc ion binding”. While in GBM, GO analysis showed enrichment in the BP terms, “neuron cell-cell adhesion”, “positive regulation of synapse assembly”, and the CC terms, “cell junction”, “axon”, “plasma membrane”. KEGG pathway analysis did not retrieve any significantly enriched pathways in both diseases. Conclusion: Our findings demonstrate a unique pattern of PCDH15 overexpression in low-grade gliomas which was translated into a substantial impact on patients’ survival. Functional enrichment analysis indicated transcription regulation as a potential mechanism for PCDH15 in LGG, further supporting PCDH15's potential as a therapeutic target. Citation Format: Hassan Mohammed Abushukair, Bayan Osama Abu Alragheb. Overexpression of protocadherin related 15 (PCDH15) gene predicts better prognosis in low-grade glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2727.