Endpoint In Cancer Clinical Trials Research Articles

Comparison of volumetric methods for tumor measurements on two and three dimensional MRI in adult glioblastoma

Change in tumor size is a frequent endpoint in cancer clinical trials, but whether change in size should be measured using volume on two-dimensional (2D) or three-dimensional (3D) images is not certain. We compared volumetric measurements on post-contrast 2D and high-resolution 3D T1-weighted MR images (T1WI) in evaluating tumor response in glioblastoma multiforme (GBM). Tumor volume measurements were performed on 86 MRI studies from 37 adult patients with GBM on post-contrast 5mm 2D T1WI and isotropic high-resolution T1WI. The means of the two volumes were compared and their association was analyzed. There is no significant difference between volumes measured on 2D and 3D in 86 scans (Z = 0.63, p = 0.53), and a high correlation was revealed between them (r = 0.95, 95% CI: 0.93-0.97, p < 0.001). When the percentage changes were categorized into traditional tumor response criteria (complete response/partial response/stable disease/progressive disease), the kappa coefficient between the volume on 2D and volume on 3D was 0.80 (95% CI: 0.57-1.03, p < 0.05) with an overall agreement of 84%. Volume on post-contrast 2D T1WI appears comparable to volume on 3D T1WI and should be a practical alternative to volume on 3D in evaluating tumor response.

Joint modeling of progression‐free survival and death in advanced cancer clinical trials

Progression-related endpoints (such as time to progression or progression-free survival) and time to death are common endpoints in cancer clinical trials. It is of interest to study the link between progression-related endpoints and time to death (e.g. to evaluate the degree of surrogacy). However, current methods ignore some aspects of the definitions of progression-related endpoints. We review those definitions and investigate their impact on modeling the joint distribution. Further, we propose a multi-state model in which the association between the endpoints is modeled through a frailty term. We also argue that interval-censoring needs to be taken into account to more closely match the latent disease evolution. The joint distribution and an expression for Kendall's tau are derived. The model is applied to data from a clinical trial in advanced metastatic ovarian cancer.

Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials

The identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. A putative surrogate endpoint must be validated at both individual-level and trial-level before it can be used to replace the clinical endpoint in a future clinical trial. Recently, meta-analytic methods for evaluating potential surrogates have become widely accepted in cancer clinical trials. In this review, after addressing multiple complications and general issues surrounding surrogate endpoints, we review various proposed and adopted meta-analytic methodologies pertaining to the application of these methods to oncology clinical trials with different tumor types. In oncology, several applications have successfully identified useful surrogates. For example, disease-free survival and progression-free survival have been validated through meta-analyses as acceptable surrogates for overall survival in adjuvant colon cancer and advanced colorectal cancer, respectively. We also discuss several limitations of surrogate endpoints, including the critical issues that the extrapolation of the validity of a surrogate is always context-dependent and that such extrapolation should be exercised with caution.

Validation of novel imaging methodologies for use as cancer clinical trial end-points

The success or failure of a clinical trial, of any phase, depends critically on the choice of an appropriate primary end-point. In the setting of phases II and III cancer clinical trials, imaging end-points have historically, and continue presently to play a major role in determining therapeutic efficacy. The primary goal of this paper is to discuss the validation of imaging-based markers as end-points for phase II clinical trials of cancer therapy. Specifically, we outline the issues that must be considered, and the criteria that would need to be satisfied, for an imaging end-point to supplement or potentially replace RECIST- defined tumour status as a phase II clinical trial end-point. The key criteria proposed to judge the utility of a new end-point primarily relate to its ability to accurately and reproducibly predict the eventual phase III end-point for treatment effect, which is usually assessed by a difference between two arms on progression free or overall survival, both at the patient and more importantly at the trial level. As will be demonstrated, the level of evidence required to formally and fully validate a new imaging marker as an appropriate end-point for phase II trials is substantial. In many cases, this level of evidence will only become available by conducting a series of coordinated prospectively designed multicentre clinical trials culminating in a formal meta-analysis. We also include a discussion of situations where flexibility may be required, relative to the ideal rigorous evaluation, to accommodate inevitable real-world feasibility constraints.

Proposal for Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials: The STEEP System

Standardized definitions of breast cancer clinical trial end points must be adopted to permit the consistent interpretation and analysis of breast cancer clinical trials and to facilitate cross-trial comparisons and meta-analyses. Standardizing terms will allow for uniformity in data collection across studies, which will optimize clinical trial utility and efficiency. A given end point term (eg, overall survival) used in a breast cancer trial should always encompass the same set of events (eg, death attributable to breast cancer, death attributable to cause other than breast cancer, death from unknown cause), and, in turn, each event within that end point should be commonly defined across end points and studies. A panel of experts in breast cancer clinical trials representing medical oncology, biostatistics, and correlative science convened to formulate standard definitions and address the confusion that nonstandard definitions of widely used end point terms for a breast cancer clinical trial can generate. We propose standard definitions for efficacy end points and events in early-stage adjuvant breast cancer clinical trials. In some cases, it is expected that the standard end points may not address a specific trial question, so that modified or customized end points would need to be prospectively defined and consistently used. The use of the proposed common end point definitions will facilitate interpretation of trial outcomes. This approach may be adopted to develop standard outcome definitions for use in trials involving other cancer sites.

11 INVITED Functional imaging in drug development - a primary of secondary endpoint in cancer clinical trials

11 INVITED Functional imaging in drug development - a primary of secondary endpoint in cancer clinical trials

Prostate cancer clinical trial end points: "RECIST"ing a step backwards.

To relate clinical issues to the clinical manifestations of prostate cancers across disease states using the eligibility and outcome criteria defined by Response Evaluation Criteria in Solid Tumors (RECIST). The manifestations of prostate cancer that characterize localized, recurrent, and metastatic disease were considered using the eligibility criteria for trials defined by RECIST. To do so, we analyzed the sites, size, and distribution of lesions in patients enrolled on contemporary Institutional Review Board-approved trials for progressive castrate and noncastrate metastatic disease. Prostate-specific antigen (PSA) levels were also assessed. RECIST-defined outcome measures for tumor regression were then applied to the metastatic patient cohorts, and separately to the states of a rising PSA (noncastrate and castrate) and localized disease. Only 43.5% of men with castrate metastatic and 16% of noncastrate metastatic disease had measurable target lesions > 2 cm in size. Overall, 84.4% of the target lesions were lymph nodes, of which 67.7% were > or = 2 cm in the long axis. There are no target lesions in patients in the states of a rising PSA and localized disease, making them ineligible for trials under these criteria. PSA-based eligibility and outcomes under RECIST conflict with established reporting standards for the states of a rising PSA and castrate metastatic disease. The clinical manifestations of prostate cancer across multiple disease states are not addressed adequately using the eligibility criteria and outcomes measures defined by RECIST. Important treatment effects are not described. Trial eligibility and end points based solely on tumor regression are not applicable to the majority of the clinical manifestations of prostate cancers representing all clinical states. Treatment effects can be described more precisely if eligibility criteria are adapted to the clinical question being addressed and clinical state under study, focusing on the duration of benefit defined biochemically, radiographically, and/or clinically.

Combining Distribution- and Anchor-Based Approaches to Determine Minimally Important Differences

Health-related quality of life (HRQOL) is an important endpoint in cancer clinical trials and in cancer treatment in general; however, the meaningfulness of HRQOL scores may not be apparent to clinicians or researchers. Minimally important differences (MIDs) can enhance the interpretability of HRQOL scores by identifying differences likely to be meaningful to patients and clinicians. This article's objective is to describe and provide examples of approaches we have used to identify MIDs for instruments in the Functional Assessment of Chronic Illness Therapy (FACIT) measurement system. Distribution- and anchor-based approaches are described and illustrated. We also discuss the importance of assessing the appropriateness of anchors, and we provide suggestions for combining results into a single range of plausible MIDs. MIDs for FACIT instruments established to date are summarized, and general guidelines that can be used to estimate MIDs for other FACIT instruments are provided. Applications of MIDs in research are illustrated.

Timing of quality of life assessment in cancer clinical trials: fine tuning remains a challenge

Timing of quality of life assessment in cancer clinical trials: fine tuning remains a challenge

Methodological issues in assessing health-related quality of life of colorectal cancer patients in randomised controlled trials

Although health-related quality of life (HRQOL) is increasingly reported as an important endpoint in cancer clinical trials, questions still remain about the quality of its reporting. The aim of this study was to evaluate the level of reporting of HRQOL in randomised controlled trials (RCTs) of colorectal cancer (CRC). A systematic literature search from 1980 to March 2003 was undertaken on a number of databases. Identified eligible studies were selected and then evaluated on a broad set of HRQOL predetermined criteria by four reviewers. Thirty-one randomised controlled trials involving 9683 colorectal cancer patients were identified. Nearly all studies dealt with metastatic patients and principally compared different chemotherapy regimens. The HRQOL tool most often used was the European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), which was used in 48% of the studies. Some methodological limitations were identified: 39% of the RCTs did not report HRQOL compliance at baseline and 52% did not give details on missing data. A rationale for using a specific HRQOL measure was given in only 10% of the studies. Whilst HRQOL assessment is a potential valuable source of information in understanding the impact of colorectal cancer, a number of methodological shortcomings have to be further addressed in future studies.

Health related quality of life in prostate carcinoma patients: a systematic review of randomized controlled trials.

Health related quality of life (HRQOL) is increasingly reported as an important endpoint in cancer clinical trials. However, evidence suggests that HRQOL reporting is often inadequate. Given this, the authors undertook a systematic review to evaluate HRQOL assessment methodology and reported outcomes of randomized controlled clinical trials (RCTs) with prostate carcinoma patients. A comprehensive search of the literature from 1980 to 2001, mainly on the following databases, was undertaken: MedLine, Cancerlit, and the Cochrane Controlled Trials Register. Studies were identified according to a predefined coding scheme, including HRQOL measure, cultural validity, compliance data reported and the clinical significance of the results. Twenty-five RCTs were identified, involving 8015 patients primarily with metastatic cancer. Bicalutamide was the medical treatment against which most treatment comparisons were made. Limitations identified included the fact that only 44% of the studies gave a rationale for selecting a specific HRQOL measure, 64% of the studies failed to report information about the administration of the HRQOL measure, and 56% failed to report compliance at baseline. The measure most often used was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Care 30 (EORTC QLQ-C30), although some studies used non-validated HRQOL tools. The current study revealed a lack of a uniform approach to HRQOL assessment and several methodologic limitations. It is possible that such methodologic limitations have influenced trial findings for HRQOL outcomes.

Health related quality of life assessment methodology and reported outcomes in randomised controlled trials of primary brain cancer patients

Over the last 20 years, the assessment of quality of life (QOL) has become an important endpoint in cancer clinical trials, helping us to understand patient survival and QOL experiences and aiding clinicians in providing the best possible treatment and care, with the least toxicity and ill-effects. In primary brain cancer, these are critical issues. Survival is often limited and treatment difficult to tolerate. In recent years, some authors have questioned the methodological quality of the investigations and the reporting of QOL assessments from randomised controlled trials (RCTs), of cancer patients yet this assessment has never specifically focused on brain cancer. This paper therefore reports a systematic review of the research methodology and QOL assessment reporting in brain cancer patients in RCTs. The search was mainly performed on the following databases: Medline, Cancerlit and the Cochrane Controlled Trials Register. We identified only five RCTs, enrolling a total of 1026 patients. In many of these studies, we had identified methodological limitations which would hinder the interpretation of the results. These included a lack of detailed reporting regarding missing data, use of poorly validated tools, and general limitations regarding the presentation and interpretation of the results. Based on the results of our review, we make recommendations for future investigations to avoid these shortcomings.

The Influence of handling censored data on estimating progression-free survival in cancer clinical trials (JCOG9913-A).

Progression-free survival (PFS) is a common endpoint in cancer clinical trials. This study was undertaken to assess the impact of data errors and data handling on the statistical estimation of PFS. Data from four trials conducted by the Japan Clinical Oncology Group were examined. Three types of data handling methods were defined: (1) data handling method A (METHOD-A), the collected event data are used as much as possible, (2) METHOD-C, only reliable data with firm evidence are used, and (3) METHOD-B is intermediate between METHOD-A and METHOD-C. To assess the impact of each of the three methods, Kaplan-Meier survival curves, median PFS, proportion of PFS, log-rank p values and hazard ratios were estimated. In three trials that collected PFS data periodically, no remarkable differences in median PFS and the proportion of PFS were observed. In one trial with non-periodic data cleaning, however, the ratio of median PFS by METHOD-C to that by METHOD-B was 0.85, the maximum difference of proportion of PFS between METHOD-C and METHOD-B was 12.0% and the largest spread in PFS curves amongst the three methods was observed in this trial. In all trials, log-rank p values and hazard ratios for between arm comparisons did not differ between the three methods. Periodic data management can reduce errors in comparisons of PFS and is a critical requirement when using PFS as a major endpoint. Furthermore, proper data handling is essential in the estimation of patient benefit and caution is needed when making clinical decisions based on PFS.

Endpoints in cancer clinical trials: is there a need for measuring quality of life?

A review of the possible reasons to measure quality of life in cancer patients as well as reasons not to measure it is presented. These are considered in the context that standard endpoints already exist in cancer clinical trials and have served us well. Quality-of-life assessments might best be utilized in trials in which survival differences between treatments are expected to be small, which is frequently the case. Although more data are required to establish properly the true value of quality-of-life measurement in cancer clinical trials, such measurements should be encouraged.