Proportion Of Treatment Effect Research Articles

Statistical Methods to Evaluate Surrogate Markers.

There is tremendous interest in evaluating surrogate markers given their potential to decrease study time, costs, and patient burden. The purpose of this statistical workshop article is to describe and illustrate how to evaluate a surrogate marker of interest using the proportion of treatment effect (PTE) explained as a measure of the quality of the surrogate marker for: (1) a setting with a general fully observed primary outcome (eg, biopsy score); and (2) a setting with a time-to-event primary outcome which may be censored due to study termination or early drop out (eg, time to diabetes). The methods are motivated by 2 randomized trials, one among children with nonalcoholic fatty liver disease where the primary outcome was a change in biopsy score (general outcome) and another study among adults at high risk for Type 2 diabetes where the primary outcome was time to diabetes (time-to-event outcome). The methods are illustrated using the Rsurrogate package with a detailed R code provided. In the biopsy score outcome setting, the estimated PTE of the examined surrogate marker was 0.182 (95% confidence interval [CI]: 0.121, 0.240), that is, the surrogate explained only 18.2% of the treatment effect on the biopsy score. In the diabetes setting, the estimated PTE of the surrogate marker was 0.596 (95% CI: 0.404, 0.760), that is, the surrogate explained 59.6% of the treatment effect on diabetes incidence. This statistical workshop provides tools that will support future researchers in the evaluation of surrogate markers.

Time to Complete Response within 24 Months As a Good Surrogate Marker of 8 Year-Progression Free Survival in Extranodal Marginal Zone Lymphoma

Background: Extranodal marginal zone lymphoma (EMZL) represents the most common marginal zone lymphoma (MZL) subtype and it generally has a very indolent course, thus requiring long and costly trials to provide evidence on novel therapies. The IELSG-19 open-label phase 3 trial was conducted at 78 centers in six countries and showed the advantage of double therapy (rituximab-chlorambucil) over single therapy (rituximab or chlorambucil). Based on this trial, we assessed whether time to complete response within 24 months (TTCR24) could be a surrogate marker of progression-free survival (PFS) in EMZL. Methods: We used a recently developed method which derives conditional survival estimates under a landmark Cox proportional hazards model. This method allows us 1) to estimate surrogacy via the proportion of treatment effect explained by surrogate information and 2) to decompose this proportion between information gathered on the true outcome and the incremental value of the surrogate outcome alone. True outcome was 8 year-PFS and candidate surrogate marker was TTCR24. For both outcomes, treatment effect was defined using restricted mean survival time difference (RMST) between the two study arms: the difference in mean progression-free survival time restricted at 8 years and the difference in mean time to CR. Results: Among 401 patients (median follow-up: 7.4 years), 8y-PFS was not achieved in the combined therapy arm vs 8.35 years in the single therapy arm. At 2 years, TTCR24 was 83% vs 65%, while 2y-PFS was 87% vs 75%, respectively. In terms of RMST, patients under double therapy had a shorter TTCR24 by 3.8 months and a longer PFS by 11 months, compared to patients under single therapy. The estimated proportion of treatment effect on 8y-PFS explained by TTCR24 was 95% (95% CI: 0.27,1.87). When decomposed, the proportion of treatment effect on 8y-PFS was explained by PFS24 was 75% (95% CI: 0.31, 1.27) and the incremental value of TTCR24 was 20% (95% CI: -0.23,0.86). Conclusion: We found that TTCR24 predicted 95% of the treatment effect on 8y-PFS and, when used as surrogate marker, it could reduce the needed follow-up time of a phase 3 trial by four. From this, one could conclude that a new therapy in EMZL would be effective if it offers a significantly shorter TTCR than the one obtained by rituximab-chlorambucil (5.5 months). Although this single-trial approach suffers of the lack of a trial-level evidence, there are, to date, too few MZL phase 3 trials to undertake a meta-analysis. The very strong surrogacy offered by TTCR24 could make it the most relevant surrogate marker in EMZL in the coming years.

Identifying surrogate markers in real-world comparative effectiveness research.

In comparative effectiveness research (CER), leveraging short-term surrogates to infer treatment effects on long-term outcomes can guide policymakers evaluating new treatments. Numerous statistical procedures for identifying surrogates have been proposed for randomized clinical trials (RCTs), but no methods currently exist to evaluate the proportion of treatment effect (PTE) explained by surrogates in real-world data (RWD), which have become increasingly common. To address this knowledge gap, we propose inverse probability weighted (IPW) and doubly robust (DR) estimators of an optimal transformation of the surrogate and the corresponding PTE measure. We demonstrate that the proposed estimators are consistent and asymptotically normal, and the DR estimator is consistent when either the propensity score model or outcome regression model is correctly specified. Our proposed estimators are evaluated through extensive simulation studies. In two RWD settings, we show that our method can identify and validate surrogate markers for inflammatory bowel disease (IBD).

Causal Effects of Financial Education Intervention Aimed at University Students on Financial Knowledge and Financial Self-Efficacy

Based on a randomized controlled experiment among final-year undergraduate students, we provide an assessment of the treatment effects of financial education intervention focused on debt-financed graduate education decision-making. Specifically, this study finds positive treatment effects on both college seniors’ objective financial knowledge and subjective financial knowledge and self-confidence (i.e., perceived financial self-efficacy). Individual financial well-being is thought to be enhanced by improved financial knowledge test scores and perceived financial self-efficacy. In addition, we carry out a causal mediation analysis to investigate the extent to which objective financial knowledge plays a mediating role in the effect of financial education treatment on the intervention outcome (perceived financial self-efficacy). The mediation proportion, the proportion of treatment effect on outcome explained by the intermediate variable of financial knowledge, is around 21%, which is important. Thus, policies that aim to improve financial capabilities among college students through financial education programs should be aware that financial literacy is a significant antecedent of (a prerequisite for) financial self-efficacy.

A Surrogate Measure for Time-Varying Biomarkers in Randomized Clinical Trials

Clinical trials with rare or distant outcomes are usually designed to be large in size and long term. The resource-demand and time-consuming characteristics limit the feasibility and efficiency of the studies. There are motivations to replace rare or distal clinical endpoints by reliable surrogate markers, which could be earlier and easier to collect. However, statistical challenges still exist to evaluate and rank potential surrogate markers. In this paper, we define a generalized proportion of treatment effect for survival settings. The measure’s definition and estimation do not rely on any model assumption. It is equipped with a consistent and asymptotically normal non-parametric estimator. Under proper conditions, the measure reflects the proportion of average treatment effect mediated by the surrogate marker among the group that would survive to mark the measurement time under both intervention and control arms.

Testing for heterogeneity in the utility of a surrogate marker.

In studies that require long-term and/or costly follow-up of participants to evaluate a treatment, there is often interest in identifying and using a surrogate marker to evaluate the treatment effect. While several statistical methods have been proposed to evaluate potential surrogate markers, available methods generally do not account for or address the potential for a surrogate to vary in utility or strength by patient characteristics. Previous work examining surrogate markers has indicated that there may be such heterogeneity, that is, that a surrogate marker may be useful (with respect to capturing the treatment effect on the primary outcome) for some subgroups, but not for others. This heterogeneity is important to understand, particularly if the surrogate is to be used in a future trial to replace the primary outcome. In this paper, we propose an approach and estimation procedures to measure the surrogate strength as a function of a baseline covariate W and thus examine potential heterogeneity in the utility of the surrogate marker with respect to W. Within a potential outcome framework, we quantify the surrogate strength/utility using the proportion of treatment effect on the primary outcome that is explained by the treatment effect on the surrogate. We propose testing procedures to test for evidence of heterogeneity, examine finite sample performance of these methods via simulation, and illustrate the methods using AIDS clinical trialdata.

Impact of bone mineral density in reducing fracture risk in patients receiving alendronate plus alfacalcidol therapy

BackgroudChanges in bone mineral density (BMD) are a potential surrogate marker for fracture endpoints in clinical trials. However little is known whether the increase in BMD in response to combination treatment with alendronate plus alfacalcidol is associated with fracture risk reduction. We aimed to evaluate the impact of BMD on fracture risk in osteoporosis patients, using the data from the randomized clinical trial comparing alendronate plus alfacalcidol with alendronate alone. MethodsWe selected 412 patients with two or more prevalent vertebral fractures and who had BMD measurements at baseline and after 6, 12, and/or 24 months out of 2022 patients from the database of the Japanese Osteoporosis Intervention Trial. Patients in this subset who received combination treatment with alendronate plus alfacalcidol had shown a lower risk of fracture than patients treated with alendronate alone. We used Poisson regression model analysis to calculate the proportion of treatment effect (PTE) that was attributable to BMD increases in patients receiving combination treatment. ResultsThe highest PTE attributable to changes in BMD was 1.2% in patients with a BMD increase of 3% or more in the lumbar spine. For BMD measurements of the radius, the highest PTE was 2.8% with a BMD increase of 0% or more. For BMD measurements of the metacarpal bone, the highest PTE was 1.2% with a BMD increase of 3% or more. In patients with a BMD greater than or equal to 70% of the young adult mean in the lumbar spine, the PTE attributable to BMD was 0.2%. In patients with a BMD greater than or equal to 70% of the young adult mean in the radius, the PTE attributable to BMD was 0.3%. ConclusionsThe additional effects of alfacalcidol in reducing fracture risk do not likely result from increased BMD; other mechanisms remain a possibility.

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

ObjectivesTo assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing–remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint.MethodsUsing data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2‐year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2‐year relapses and BVL explained by 6‐month log‐transformed NfL levels with the PTE explained by the number of active lesions over 6 months. We estimated sample size requirements for different treatment effects.ResultsAt Month 6, blood NfL levels (pg/mL, median [range]) were lower in the fingolimod arm (fingolimod (n = 132) 18 [8–247]; placebo (n = 114) 26 [8–159], P < 0.001). NfL at 6 months correlated with number of relapses (r = 0.25, P < 0.001), 6‐month CDW (hazard ratio 1.83, P = 0.012), active lesions (r = 0.46, P < 0.001), and BVL (r = −0.41, P < 0.001) at Month‐24. The PTE (95% CI) on 24‐month relapses and BVL explained by 6‐month NfL was 25% (8–60%) and 60% (32–132%), and by 6‐month active lesions was 28% (11–66%) and 45% (18–115%), respectively. Assuming a 20–40% treatment‐related reduction in NfL levels, 143‐28 patients per arm will be required.ConclusionsBlood NfL may qualify as an informative and easy‐to‐measure endpoint for future Phase 2 clinical studies that captures both inflammatory‐ and noninflammatory‐driven neuroaxonal injury in RRMS.

Assessing the value of a censored surrogate outcome.

Assessing the potential of surrogate markers and surrogate outcomes for replacing a long term outcome is an active area of research. The interest in this topic is partly motivated by increasing pressure from stakeholders to shorten the time required to evaluate the safety and/or efficacy of a treatment or intervention such that treatments deemed safe and effective can be made available to those in need more quickly. Most existing methods in surrogacy evaluation either require strict model assumptions or that primary outcome and surrogate outcome information is available for all study participants. In this paper, we focus on a setting where the primary outcome is subject to censoring and the aim is to quantify the surrogacy of an intermediate outcome, which is also subject to censoring. We define the surrogacy as the proportion of treatment effect on the primary outcome that is explained by the intermediate surrogate outcome information and propose two robust methods to estimate this quantity. We propose both a nonparametric approach that uses a kernel smoothed Nelson-Aalen estimator of conditional survival, and a semiparametric method that derives conditional survival estimates from a landmark Cox proportional hazards model. Simulation studies demonstrate that both approaches perform well in finite samples. Our methodological development is motivated by our interest in investigating the use of a composite cardiovascular endpoint as a surrogate outcome in a randomized study of the effectiveness of angiotensin-converting enzyme inhibitors on survival. We apply the proposed methods to quantify the surrogacy of this potential surrogate outcome for the primary outcome, time to death.

Follow-up infarct volume as a mediator of endovascular treatment effect on functional outcome in ischaemic stroke

ObjectiveThe putative mechanism for the favourable effect of endovascular treatment (EVT) on functional outcome after acute ischaemic stroke is preventing follow-up infarct volume (FIV) progression. We aimed to assess to what extent difference in FIV explains the effect of EVT on functional outcome in a randomised trial of EVT versus no EVT (MR CLEAN).MethodsFIV was assessed on non-contrast CT scan 5–7 days after stroke. Functional outcome was the score on the modified Rankin Scale at 3 months. We tested the causal pathway from intervention, via FIV to functional outcome with a mediation model, using linear and ordinal regression, adjusted for relevant baseline covariates, including stroke severity. Explained effect was assessed by taking the ratio of the log odds ratios of treatment with and without adjustment for FIV.ResultsOf the 500 patients included in MR CLEAN, 60 died and four patients underwent hemicraniectomy before FIV was assessed, leaving 436 patients for analysis. Patients in the intervention group had better functional outcomes (adjusted common odds ratio (acOR) 2.30 (95% CI 1.62–3.26) than controls and smaller FIV (median 53 vs. 81 ml) (difference 28 ml; 95% CI 13–41). Smaller FIV was associated with better outcome (acOR per 10 ml 0.60, 95% CI 0.52–0.68). After adjustment for FIV the effect of intervention on functional outcome decreased but remained substantial (acOR 2.05, 95% CI 1.44–2.91). This implies that preventing FIV progression explains 14% (95% CI 0–34) of the beneficial effect of EVT on outcome.ConclusionThe effect of EVT on FIV explains only part of the treatment effect on functional outcome.Key Points• Endovascular treatment in acute ischaemic stroke patients prevents progression of follow-up infarct volume on non-contrast CT at 5–7 days.• Follow-up infarct volume was related to functional outcome, but only explained a modest part of the effect of intervention on functional outcome.• A large proportion of treatment effect on functional outcome remains unexplained, suggesting FIV alone cannot be used as an early surrogate imaging marker of functional outcome.

A comparison of surrogate endpoints for all cause mortality in men with localized unfavorable-risk prostate cancer.

21 Background: Several surrogates for prostate cancer-specific mortality exist, but whether these are surrogates for all cause mortality (ACM), and how their performance compares, is unknown. We investigated the relative efficacy of 4 candidate surrogates for ACM using the proportion of treatment effect (PTE) metric. Methods: Two-hundred and six men with localized unfavorable-risk prostate cancer were randomized to radiation therapy (RT) or RT and 6 months of androgen-deprivation therapy (ADT) from 1995 to 2001 and followed for a median of 16.62 years. Among the 159 men with no or minimal comorbidity, a significant reduction in the risk of death was observed in those randomized to RT and ADT versus RT alone; these 159 men formed the study cohort. In order to assess whether the candidate surrogated satisfied Prentice’s criteria for surrogacy, Cox regression analyses were performed to assess the risk of death for each of the candidate surrogates and treatment before and after adjusting for prostate-specific antigen (PSA), age at randomization, T category, and Gleason score. Results: PSA nadir &gt; 0.5 ng/mL, PSA doubling time &lt; 9 months and interval to PSA failure &lt; 30 months met Prentice’s criteria for surrogacy (P = 0.01, 0.003, and 0.03 for the surrogate covariate in the multivariable model, respectively) for ACM, while PSA failure did not (P = 0.10). For the three surrogates, the PTE values were 103.86%, 43.09%, and 41.26%, respectively. Conclusions: A PSA nadir value of &gt; 0.5 ng/mL following RT and ADT identified men prior to PSA failure who were at high-risk for death and therefore could be used to select men for entry, at the time of PSA nadir and before PSA failure, onto randomized trials evaluating the impact on survival of salvage ADT with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer. By enriching study cohorts with men who have achieved a surrogate endpoint for ACM, one can enhance the likelihood that the study will be able to observe whether survival is prolonged when novel treatment is added to ADT, as compared to ADT alone, in an abbreviated time period. Clinical Trial Number: NCT00116220

Surrogacy analysis of prostate-specific antigen (PSA) decline for improved overall survival (OS) with enzalutamide (ENZ) in AFFIRM.

266 Background: ENZ significantly increased OS for men with metastatic castration-resistant prostate cancer (mCRPC) vs. placebo and significantly decreased PSA levels. However, the prognostic significance and role of PSA falls as a surrogate for OS are not established. Methods: Men in the AFFIRM trial were grouped by maximal unconfirmed PSA decline during the 1st 90 days of treatment in a post-hoc analysis. Each PSA decline criterion was assessed for surrogacy for OS by the proportion of treatment effect (PTE)-explained and Prentice criteria. We also assessed the association of PSA decline with OS, progression-free survival (PFS), and pain response. Results: ENZ improved OS (hazard ratio 0.63, p &lt; 0.001) and was associated with higher rates of PSA declines when compared to placebo (odds ratio &gt; 19.0, p &lt; 0.001). Greater declines in PSA were associated with longer OS, PSA PFS, radiographic PFS, and higher pain response when compared with no PSA decline or PSA increase (table). All decline measures from baseline were highly prognostic for OS and several ( &gt; 0%, ≥ 30%, ≥ 50% declines) explained a proportion of the treatment effect (PTE 1.07–1.29, 95% CI lower bounds &gt; 0.63), in which treatment was no longer significant after adjustment for the decline measures (p &gt; 0.20). Full surrogacy was not demonstrated. Conclusions: In AFFIRM, &gt; 0, ≥30%, and ≥50% PSA declines within 90 days of treatment fulfilled Prentice surrogacy criteria 1–3. Prentice 4, equivalency of survival adjusting for PSA decline outcomes, could not be demonstrated. PSA declines are associated with longer PFS and improved pain response. External prospective validation is needed. Clinical trial information: NCT00974311. [Table: see text]

Fingolimod effect on brain volume loss independently contributes to its effect on disability

Background: Brain volume loss occurs in patients with relapsing–remitting MS. Fingolimod reduced brain volume loss in three phase 3 studies. Objective: To evaluate whether the effect of fingolimod on disability progression was mediated by its effects on MRI lesions, relapses or brain volume loss, and the extent of this effect. Methods: Patients (992/1272; 78%) from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study were analyzed. Month-24 percentage brain volume change, month-12 MRI-active lesions and relapse were assessed. The Prentice criteria were used to test surrogate marker validity. The proportion of treatment effect on disability progression explained by each marker was calculated. Results: Two-year disability progression was associated with active T2 lesions (OR = 1.24; p = 0.001) and more relapses during year 1 (OR = 2.90; p < 0.001) and lower percentage brain volume change over two years (OR = 0.78; p < 0.001). Treatment effect on active T2 lesions, relapses and percentage brain volume change explained 46%, 60% and 23% of the fingolimod effect on disability. Multivariate analysis showed the number of relapses during year 1 (OR = 2.62; p < 0.001) and yearly percentage brain volume change over two years (OR = 0.85; p = 0.009) were independent predictors of disability progression, together explaining 73% of fingolimod effect on disability. Conclusions: The treatment effect on relapses and, to a lesser extent, brain volume loss were both predictors of treatment effect on disability; combining these predictors better explained the effect on disability than either factor alone.

Changes in bone mineral density, bone turnover markers, and vertebral fracture risk reduction with once weekly teriparatide

Objective:We aimed to evaluate the surrogacy of bone mineral density and bone turnover markers for incident vertebral fracture using data from 237 patients treated with once weekly 56.5 μg teriparatide or placebo.Methods:This analysis was conducted using data from the Teriparatide Once-Weekly Efficacy Research trial, a randomized, double-blind, placebo-controlled trial for patients with severe osteoporosis in Japan. A total of 237 subjects (placebo group, n = 130; teriparatide group, n = 107) were assessed at baseline and at 72 weeks. Main outcome measures included estimation of the treatment effects of once weekly teriparatide on vertebral fracture risk reduction using percentage changes in lumbar bone mineral density and bone turnover markers.Results:The percentage change in lumbar bone mineral density was 6.69% in the teriparatide group compared with 0.28% in the placebo group (p < 0.01). One incident vertebral fracture occurred in the teriparatide group compared with 16 in the placebo group. The unadjusted and adjusted hazard ratios of the teriparatide group compared with the placebo group were 0.07 (95% confidence interval: 0.01 to 0.56) and 0.64 (95% confidence interval: 0.06 to 6.36), respectively. The proportion of treatment effect explained by changes in lumbar bone mineral density was 83% (Freedman’s method) and 66% (Chen’s method). There were no notable changes in hazard ratios if we adjusted for bone turnover markers.Conclusions:Most of the vertebral fracture risk reduction with once weekly 56.5 μg teriparatide is explained by changes in lumbar bone mineral density rather than changes in bone turnover markers.

Statistical evaluation of surrogate endpoints: a systematic review

Results Prentice’s operational criteria, proportion of treatment effect explained and relative effect were the original techniques for evaluating surrogacy. These led to the development of several approaches for surrogate evaluation, namely; principal stratification, direct and indirect effects, meta-analytical (including the surrogate threshold effect) and information theory. Each methodological approach raises various computational issues in practice and conceptual issues regarding causality, transportability and interpretation.

Evaluation of Progressive Neuroretinal Rim Loss as a Surrogate End Point for Development of Visual Field Loss in Glaucoma

To evaluate the validity of using progressive loss of neuroretinal rim area as a surrogate end point for the development of visual field loss in glaucoma. Prospective, observational cohort study. The study group included 492 eyes of 328 patients classified with suspected glaucoma at the baseline visit. These eyes had an average of 7.4±2.8 confocal scanning laser ophthalmoscopy (CSLO) images during a mean follow-up time of 6.6±1.6 years. Rim area measurements were acquired with CSLO during follow-up. The visual field end point was considered the development of 3 consecutive abnormal visual fields on standard automated perimetry. Strong predictive ability and large proportion of treatment effect (PTE) explained are requisites for a suitable surrogate end point. A joint longitudinal survival model was used to evaluate the ability of rates of rim area loss in predicting visual field development, adjusting for confounding variables (baseline age, race, and corneal thickness and follow-up measurements of intraocular pressure [IOP] and pattern standard deviation). The PTE was calculated by comparing the effect of IOP on the risk of development of visual field loss when incorporating rim area loss in the same model with the effect of IOP in the model excluding rim area measurements. Predictive strength was measured by survival-adapted R(2) and PTE. Sixty-two of 492 eyes (13%) developed visual field loss during follow-up. The mean rate of rim area change in eyes that developed visual field loss was-0.011 mm(2)/year versus-0.003 mm(2)/year in eyes that did not (P<0.001). In the multivariable model, each 0.01 mm(2)/year faster rate of rim area loss was associated with a 2.94 higher risk of visual field loss (hazard ratio, 2.94; 95% confidence interval, 1.38-6.23; P= 0.005). R(2) values were 62% and 81% for univariable and multivariable models, respectively. The PTE was 65%. Progressive rim area loss was highly predictive of the development of visual field loss in glaucoma and explained a significant PTE on the clinically relevant outcome. These findings suggest that rim area measurements may be suitable surrogate end points in glaucoma clinical trials.

Magnetic resonance active lesions as individual-level surrogate for relapses in multiple sclerosis

Background: Use of quantitative magnetic resonance imaging (MRI) metrics as surrogates for clinical outcomes in multiple sclerosis (MS) trials is controversial. Objectives: We sought to validate, at the individual-patient level, the number of MRI active lesions, as a surrogate marker for relapses in MS. Methods: Individual-patient data from two large, placebo-controlled clinical trials of subcutaneous interferon β-1a in patients with relapsing–remitting or secondary progressive (SP) MS were analysed separately and as pooled data. The four Prentice criteria were applied to assess surrogacy for the number of new T2 MRI lesions. The predictive value of short-term treatment effects on this MRI marker for longer-term clinical relapses was also assessed. Results: All Prentice criteria were satisfied. The number of new T2 MRI lesions correlated with the number of relapses over the follow-up period. The proportion of treatment effect on relapses accounted for by the effect of treatment on new T2 MRI lesions over 2 years was 53% in patients with relapsing–remitting MS, 67% in patients with secondary progressive MS, and 62% in pooled data. In the pooled data, treatment effects on new lesions over 1 year mediated a good proportion (70%) of effects on relapses over the subsequent year. Conclusions: This study provides evidence that new T2 MRI lesion count is a surrogate for relapses in patients with MS treated with interferon or drugs with a similar mechanism of action. Short-term treatment effects on this MRI measure can predict longer-term effects on relapses.

Surrogate end points for overall survival and local control in neoadjuvant rectal cancer trials: statistical evaluation based on the FFCD 9203 trial

BackgroundIn resectable rectal cancer trials, pathological parameters are early preoperative treatment efficacy measures. Their validation as surrogate end points for long-term clinical outcomes would allow to reduce trial duration. The aim was to evaluate potential surrogates for overall survival (OS) and local control (LC) in preoperative T3/T4 rectal cancer trials. Candidate variables included ypT and ypN stages, T downstaging, tumor regression grade (TRG), and circumferential resection margin (CRM) status. Patients and methodsIn the Fédération Francophone de Cancérologie Digestive (FFCD) 9203 trial, 742 eligible patients were randomly assigned to receive preoperative radiotherapy with or without concurrent chemotherapy. Surrogacy was evaluated using Prentice criteria and the proportion of treatment effect (PTE) explained by each potential surrogate. ResultsNone of the candidate surrogates fulfilled all Prentice criteria. Data analyses did not provide interpretable PTE measures for OS. Regarding LC, the highest PTE was reached by TRG, which explained 12% of the effect on local recurrence. This proportion may not exceed 41% [95% confidence interval (CI) -1% to 41%]. PTE explained by the CRM status was associated with a wide uncertainty (95% CI -81% to 105%), which does not exclude a potentially high degree of surrogacy. ConclusionIn the FFCD 9203 trial, pathological parameters were not surrogate for OS or LC.

Circulating Levels of Soluble KIT Serve as a Biomarker for Clinical Outcome in Gastrointestinal Stromal Tumor Patients Receiving Sunitinib following Imatinib Failure

To evaluate changes in circulating levels of soluble KIT (sKIT) extracellular domain as a potential biomarker for clinical outcome in gastrointestinal stromal tumor patients treated with the multitargeted tyrosine kinase inhibitor sunitinib following imatinib failure in a previously reported phase III study. Patients received sunitinib 50 mg/d (n = 243) or placebo (n = 118) daily in 6-week cycles (4 weeks on, 2 weeks off treatment). Plasma sKIT levels were sampled every 2 weeks in cycle 1 and on days 1 and 28 of subsequent cycles; analyzed by ELISA; and evaluated using Prentice criteria, Cox proportional hazards models, and proportion of treatment effect (PTE) analysis. From 4 weeks on treatment and onward, significant differences were shown between treatment groups (P < 0.0001) in sKIT level changes from baseline (median levels decreased with sunitinib and increased with placebo). Decreases in sKIT levels were a significant predictor of longer time to tumor progression (TTP). Patients with reduced levels at the end of cycle 2 had a median TTP of 34.3 weeks versus 16.0 weeks for patients with increased levels [hazard ratio, 0.71; 95% confidence interval (95% CI), 0.61-0.83; P < 0.0001], and changes in sKIT levels replaced treatment as a stronger predictor of TTP (PTE, 0.80; 95% CI, 0.34-3.70), showing even greater surrogacy on cycle 3 day 1 (PTE, 0.98; 95% CI, 0.39-3.40). The results suggest that circulating plasma sKIT levels seem to function as a surrogate marker for TTP in gastrointestinal stromal tumor patients. Additional studies are warranted to confirm and expand these findings.

Risk factors for stroke and lipid-lowering effect of pravastatin on the risk of stroke in Japanese patients with hypercholesterolemia: Analysis of data from the MEGA Study, a large randomized controlled trial

BackgroundThe aims of this study were to clarify the risk factors for stroke, and to investigate the effect of low-density lipoprotein cholesterol (LDL-C) lowering with pravastatin on the risk of stroke, in Japanese mild-to-moderately hypercholesterolemic patients enrolled in the MEGA Study. MethodsMultivariate Cox proportional hazard model was used to determine the baseline risk factors for stroke. The proportion of treatment effect (PTE) explained by on-treatment LDL-C levels was estimated. ResultsIn 7832 patients at risk, a total of 99 strokes were observed during the 5-year follow-up period. Significant relationships were observed between stroke and traditional risk factors such as male sex, advanced age, low high-density lipoprotein cholesterol (HDL-C), high lipoprotein(a) (Lp[a]), hypertension, diabetes, obesity, and smoking. In the pravastatin group, hazard ratio (HR) for stroke adjusted by on-treatment lipid level was lower than the unadjusted value versus control (HR [95%CI], 0.48 [0.26–0.87] and 0.59 [0.38–0.92], respectively)—giving a negative PTE of −38.6% and suggesting that the risk reduction could not be explained by LDL-C lowering alone. ConclusionsMale sex, aging, hypertension, diabetes, low HDL-C, high Lp(a), obesity, and smoking were determined as risk factors for stroke in Japanese patients with hypercholesterolemia, and the observed risk reduction could not be explained by pravastatin's LDL-C-lowering effect alone, suggesting pleiotropic effects.