American College of Radiology Annual Progress Report: 2009 Formula Grant

Transcription

1 American College of Radiology Annual Progress Report: 2009 Formula Grant Reporting Period July 1, 2012 June 30, 2013 Formula Grant Overview The American College of Radiology (ACR) received $2,043,960 in formula funds for the grant award period January 1, 2010 through December 31, Accomplishments for the reporting period are described below. Research Project 1: Project Title and Purpose Novel Methods for Cancer Clinical Trial Design and Analysis - Clinical trials provide the critical evidence necessary to advance treatment for cancer. With the ever growing number of promising interventions, there is a need for improvements in trial design in order to a) obtain answers more quickly, b) conserve and optimize resources, and c) make better choices of what treatments to pursue in further evaluation. In addition, as treatment regimens become more complex and multimodal, the ability to accurately characterize whether anticipated benefits with respect to specific disease event reduction have occurred requires extensions of standard analytic methods. To address these needs, we propose a series of methodological projects aimed at addressing current questions in clinical trial design and analysis. These projects encompass a range of needs that apply broadly to cancer clinical trials and research in general. Anticipated Duration of Project 1/1/ /31/2013 Project Overview Three specific investigations are proposed as follows: Aim 1: Development and Use of an Efficient Phase II/III Transition Design The traditional paradigm for therapy development involves a pilot safety and efficacy trial (phase II) followed by a definitive Phase III comparative trial if warranted. This development model is intensive with respect to the time and logistical overhead involved in conducting sequential studies, and too often leads to failure in Phase III despite promising Phase II data on seemingly similar targeted populations. We propose to evaluate and implement a novel Phase II/III transition design that has thus far been little used in the oncology setting. Aim 2: Alternative Metrics for Time to Event Endpoints in Phase II and III Trials Phase II trials have traditionally been formulated as one-sample designs where all patients receive the treatment of interest. While statistical power for comparison to fixed benchmark values can be adequate American College of Radiology 2009 Formula Grant Page 1

2 within a feasible sample size, the design suffers from dependence on historical comparisons that may not prove reliable. An alternative is a randomized Phase II design, where either a) treatment arms are not formally compared, but rather the arm that prevails to any degree is taken as more favorable with respect to further development, or b) adequately powered comparisons for simple endpoints such as fixed-time proportions failure-free are feasible. We propose analytic development of an approach using quantile (median, etc) estimation and comparison in the randomized Phase II setting. The approach is equally applicable to Phase III trials, and may have particular advantages in the presence of non-proportionality. Aim 3: Estimating Treatment and Covariate Effects Under Competing Risks Competing risks, whereby patients are subject to multiple potential failure types, with only one of these occurring as the primary first failure, are ubiquitous in cancer. In addition to multiple cancer-specific events (i.e., local, regional, distant recurrence), patients may experience second primary cancers or deaths from other causes that preclude any cancer event. While correct estimation of eventspecific probabilities of occurrence for competing risks is straightforward, inference in the presence of competing risks remains more challenging. We propose to investigate and compare different recently developed competing risks modeling methods. Principal Investigator James J Dignam, PhD Group Statistician, Radiation Therapy Oncology Group American College of Radiology 1818 Market Street, Suite 1600 Philadelphia, PA Other Participating Researchers Ed Zhang, PhD - employed by American College of Radiology Maria Kocherginsky, PhD - employed by University of Chicago Expected Research Outcomes and Benefits Cancer clinical trials are a critical component of cancer care and as all reliable treatment options arise through this process, it is only through systemic and comprehensive evaluation in a trial setting that the risks and benefits of any option can be assessed. However, the process can be slower than desired, is always process intensive, and requires the greatly valued contribution of patient participants, who are seeking the best possible option for their personal situation while at the same time contributing to research. In addition, an increasing array of agents in which to try in some disease settings further strains the development system. A more efficient treatment evaluation strategy could improve both knowledge acquisition and patient care. Previous proposals to accelerate the development process have often been too ambitious, and remain unused. We propose three areas of research that have immediate practical implications for cancer clinical trials. The integrated Phase II/III design fits well into the current framework while at the same time offering the opportunity to improve it, and thus is more likely to become widely used. More informative and reliable endpoints for Phase II trials are needed, as typical response endpoints often fail to correlate adequately with survival and also do not fully apply to many American College of Radiology 2009 Formula Grant Page 2

3 modern therapeutic agents. Analytic methods that can more directly assess risks, benefits, and effects on intended targets will increase the efficiency of trials and produce more informative reports. This investigation will provide a concrete demonstration of the worth of these innovative concepts, furthering knowledge in cancer research and treatment. Summary of Research Completed James Dignam, PhD, Radiation Therapy Oncology (RTOG) Group Statistician and Associate Professor of Biostatistics at the University of Chicago, is now the PI of this project and has replaced Meihua Wang, PhD, who is no longer employed by the ACR/RTOG. Aim 1: Development and Use of an Efficient Phase II/III Transition Design In the last progress report, we indicated that the manuscript for this project had been submitted to the journal Clinical Trials and had received a largely favorable review. We revised the manuscript and resubmitted it to Clinical Trials. After additional review, the paper was formally accepted in August 2012 and was published in December Citation: Wang M, Dignam JJ, Zhang QE, Degroot JF, Mehta MP, Hunsberger S. Integrated phase II/III clinical trials in oncology: A case study. Clin Trials. 9: , Aim 2: Alternative Metrics for Time to Event Endpoints in Phase II and III Trials Following last year s methodologic developments and simulations related to estimation of the difference in medians between two survival functions, we sought and developed clinical examples to illustrate the method. Specifically, we sought data with properties such non-proportionality and early censoring (before the median) in order to challenge the new method. To reiterate the method, complete survival times for censored observations are first imputed by drawing from the conditional distribution given survival up to the time of censoring. The difference in medians and the variance of this quantity are estimated using the formulae in Price and Bonett (2002), and Rubin s multiple imputation approach (1987) is used to obtain the total variance from which confidence intervals are derived. First, we impute survival times for each censored observation conditional on the Kaplan-Meier estimates Sj(t) in each group j = 1, 2, and then use complete data methods to construct the confidence interval for the difference in medians. Using the multiple imputation approach of Rubin (1978), each censored observation is imputed M times. Estimates from these M complete data sets are then combined to obtain a point estimate and the associated variance. We have sought data examples with specific features to evaluate the method. Two of these are presented briefly here, and two additional and most important examples are currently being analyzed, but must await publication of the primary results before these can be reported here. The first example is from NSABP R-01, a randomized trial in rectal cancer. The survival curves show reasonable proportionality that diminishes with time, and a minimal amount of censoring before the median difference, our target quantity for estimation. We focus on the subset of male patients, in whom a significant advantage for chemotherapy was noted. The median difference and associated variance were estimated by the proposed method and compared to two others American College of Radiology 2009 Formula Grant Page 3

4 [Wang and Hettmansperger (shift model) 1990 and Su and Wei (purely nonparametric) 1993]. As seen in Figure 1, the proposed method has a slightly narrower confidence interval length than the Su and Wei method, but like it includes zero. The Wang and Hettmansperger method has the narrowest length and does not include zero. The second example uses a much smaller dataset from a University of Chicago clinical trial of bevacizumab in mesothelioma, where there was a large difference in outcomes based on vascular endothelial growth factor (VEGF) status that was statistically significant according to the logrank test. Figure 2 shows the three methods applied to this dataset. Here, the proposed method has the narrowest confidence interval length. Thus, this easy to compute method performs comparably with less restrictive assumptions than Wang and Hettmansperger and similar confidence interval width to Su and Wei, and appeared to do particularly well in a small sample. The additional examples will involve much more extensive censoring before the median, one of the principal motivations for derivation of this method. We anticipate completion of these and the manuscript in Figure 1: Median difference estimates for NSABP R-01 data. Shown are estimates for the difference in median survival time by treatment arm according to the newly derived methods and two previously proposed methods. American College of Radiology 2009 Formula Grant Page 4

5 Figure 2: Median difference estimates for the UC mesothelioma data. Shown are estimates for the difference in median survival time by treatment arm according to the newly derived methods and two previously proposed methods. Research Project 2: Project Title and Purpose Exploration of the RTOG Clinical Trial Database Beyond Protocol-Specified Endpoints - For over 40 years, the Radiation Therapy Oncology Group (RTOG) has been funded by the National Cancer Institute (NCI) to conduct clinical trials seeking to improve the survival and quality of life of cancer patients. Drawing upon this vast resource of demographic, treatment, outcome, and patient-reported data, the researchers will develop hypotheses and explore correlations that were not defined in the treatment protocols for patients with brain, cervix, gastrointestinal, head and neck, lung, and prostate cancer. These analyses may lead to future protocols and/or better ways to identify high-risk subgroups and screen patients for specific treatment regimens. Anticipated Duration of Project 1/1/ /31/2013 Project Overview RTOG investigators complete analyses and report on the endpoints specified in each NCIapproved protocol. Frequently these analyses raise questions or point to other potential hypotheses that were not included in the original protocol. Likewise, current literature and new research may point to areas of interest or possible correlations that were unknown during the design of the original protocol. The broad objectives of this research proposal are to (i) generate hypotheses and explore correlations that may lead to more efficient clinical trials and more patient-targeted treatments, and (ii) explore novel ways of analyzing the demographic (age, gender, race), treatment (including dose, volume, duration), outcome (survival, disease-free American College of Radiology 2009 Formula Grant Page 5

6 survival, time-to-progression), and quality of life (frequency/severity of adverse events, patientreported outcomes) data in the RTOG database to potentially develop new tools for determining the best treatment regimen for each patient based upon their personal profile. Principal Investigator Kathryn A. Winter, MS RTOG Director, Statistics Radiation Therapy Oncology Group American College of Radiology 1818 Market Street, Suite 1600 Philadelphia, PA Other Participating Researchers Daniel Hunt, PhD, Jonathan Harris, MS, Jennifer Moughan, MS, Rebecca Paulus, MS, Wendy Seiferheld, MS employed by American College of Radiology Expected Research Outcomes and Benefits The identification of pre-treatment patient characteristics and demographics associated with better or worse outcome for cancer patients may allow future researchers to generate new hypotheses to address outcome disparities due to age, race, ethnic origin or gender. Exploring the radiation therapy dose volume histogram data in more detail will help with better definitions of dose constraints in future trials. In addition to aiding in the conduct of clinical trials, this type of research may help to tailor treatments to individual patients based on their demographic and/or treatment characteristics profile. Summary of Research Completed We have begun to analyze the relative contributions of pretreatment characteristics to the survival of patients treated with chemo radiation for unresectable carcinoma of the pancreas. The RTOG trials included in this analysis are: RTOG 0411, 0020, 9812, 9209, 9102, 8801, and Additional statistical analyses were performed on patients with LD-SCLC and LA-NSCLC enrolled on RTOG trials 0212 and The additional analyses were conducted to assess the impact of longitudinal decline in patient-reported quality of life (QOL) on disease relapse and overall survival following curative treatment for limited-disease small cell lung cancer (LD- SCLC) and locally advanced non-small-cell lung cancer (LA-NSCLC). The manuscript reporting these results has been submitted to the Journal of Clinical Oncology. The manuscript reporting the results assessing the impact of PCI on self-reported cognitive functioning (SRCF), a two-item functional scale on the EORTC QLQ-C30 questionnaire, for patients following curative treatment for limited-disease small cell lung cancer (LD-SCLC) and locally advanced non-small-cell lung cancer (LA-NSCLC) is in press with the International Journal of Radiation Oncology Biology Physics. American College of Radiology 2009 Formula Grant Page 6

7 Research Project 3: Project Title and Purpose Emerging Imaging Technology Clinical Trials in PA: Comparison of Full Field Digital Mammography with Digital Breast Tomosynthesis Imaging: Comparison of Recall Rates - The purpose of this multi-center study, to be conducted as part of the American College of Radiology Imaging Network Pennsylvania, is to evaluate the digital breast tomosynthesis screening recall rates compared to routine 2D projection digital mammography. The goal is to understand if a hybrid combination of 3D tomosynthesis and low dose 2D digital mammography can significantly reduce the recall rate of women from screening mammography without a concomitant reduction of sensitivity of cancer detection. Anticipated Duration of Project 1/1/ /31/2013 Project Overview Previous C.U.R.E. funding established a network of medical centers in Pennsylvania (ACRIN PA) with the broad goal of advancing the role of imaging in the detection and/or treatment of disease by conducting early stage imaging clinical trials. This project seeks to continue the work of that network. A multi-institutional clinical trial is proposed to evaluate the impact of breast tomosynthesis on the recall rate of screening mammography. Study Hypothesis: Digital breast tomosynthesis (DBT) will improve the specificity of breast cancer screening as measured by a reduction in the recall rate while maintaining the sensitivity of cancer detection. This improved accuracy will be achieved by the optimization of the imaging sequence and number of views obtained at a capped radiation dose in the combined DBT and 2D screening sequence. Principal Investigator Mitchell D. Schnall, MD, PhD Professor of Radiology University of Pennsylvania Dept. of Radiology Hospital of the University of Pennsylvania 3400 Spruce St. Philadelphia, PA Other Participating Researchers Emily Conant, MD employed by University of Pennsylvania Andrew Maidment, PhD employed by University of Pennsylvania Constantine Gatsonis, PhD employed by Brown University American College of Radiology 2009 Formula Grant Page 7

8 Expected Research Outcomes and Benefits Screening mammography has been extensively criticized for the high rate of false positive interpretations, a subgroup of which is the recall of patients for additional diagnostic imaging for pseudolesions or superimpositions of normal tissue, perceived on screening mammography to be potentially significant lesions that on additional imaging prove to be normal. With competing parameters of specificity and sensitivity, mammographic screening must both limit missed cancers and reduce false positive call-backs. Tomosynthesis, a new emerging technology that allows the 3D reconstruction of images, has shown early evidence suggesting that it could significantly reduce the rate of false positive recalls from screening without a loss of sensitivity or breast cancer detection. There are few published trials on breast cancer screening with tomosynthesis partly because the optimal procedural metrics for tomosynthesis have not been fully defined. Manufacturers have different platforms that offer different views, different angles, and different dose and exposure levels. The exact number of tomosynthesis views of the mediolateral-oblique (MLO) view only or both MLO and cranio-caudal (CC) tomosynthesis views varies while the screening imaging sequence with or without 2D digital mammography remains controversial. This disparity in image number and image acquisition parameters may alter the balance between specificity and sensitivity and significantly affect radiation dose. The expected outcome of this research is to show that the incorporation of tomosynthesis in the screening paradigm can reduce the number of false positive interpretations without a loss of cancer detection. This improvement in screening specificity must be gained while limiting both the number of imaging views and the radiation dose to the patient. Summary of Research Completed The study closed to accrual on January 6, 2012 with target enrollment achieved. Projected Milestone: July, 2012-June, complete participant follow-up, data cleaning, QC and analysisthe primary aim of the study, the comparison of call-back rates between full field digital mammography (FFDM) and digital breast tomosynthesis (DBT) showed no statistical significant difference. The study was greatly affected by the large variability of call-back rates between readers which ranged greatly from % for FFDM and from % for DBT as shown in Tables 1-3 at the end of the narrative. (Note 558 patients were accrued to the study; the target accrual was 550 cases and 501 had complete data for analysis.) The hypothesis driving the primary aim was that the addition of DBT imaging to FFDM would result in a lower call-back rate in a screening population. For 2 of the 8 readers the hypothesis held true. However, 3 readers experienced minimal change in call-back rate and 3 readers actually experienced an increase in call-back rate with the inclusion of DBT. The overall call back rate was similar between the two modalities for the group as a whole. In retrospect, a stronger design might have been achieved with fewer readers each reading more cases. As shown in tables 1 and 2, some readers read very few cases and did not read a balanced number of FFDM American College of Radiology 2009 Formula Grant Page 8

9 and DBT cases. When evaluating the actual cases that were called back, there were 17 cases called back from both FFDM and DBT, 12 cases called back from FFDM only and 17 cases called back from DBT only. In the entire population accrued (including the enriched B arm), there were only 6 participants diagnosed with cancer (3 in each arm). Each cancer was detected on both FFDM and DBT imaging. A paired study design was used so that each patient underwent both routine screening digital mammogram (Standard-DM) and a low-dose, combined (DM+DBT) tomosynthesis imaging set (ACRIN Full). Cumulative mean glandular dose (MGD) was calculated in 495 women from exposure parameters of 2262 Standard-DM and 1980 low-dose DM+DBT acquisitions. Extra views in Standard-DM were obtained in some patients at the clinical discretion of reading radiologists or technicians. Sub-screening paradigms were defined based on the combination of images used to determine cumulative MGD values: Standard DM (CC+MLO), ACRIN-Limited (DM: MLO; DBT: MLO+CC), and ACRIN-Full (DM: MLO+CC; DBT: MLO+CC). The ACRIN-Limited MGD at Site A and Site B were 4.94 mgy and 5.29 mgy, respectively, while the Standard-DM MGD was 4.81 mgy and 3.52 mgy at Site A and B, respectively. (Please see Table 4 below) An additional 23.9% and 6.7% Standard-DM views were obtained at site A and B, respectively. After adjusting for extra views, the Standard-DM MGD was 3.85 mgy and 3.28 mgy at Site A and B, respectively. Our hypothesis was that it would be possible to perform the low-dose ACRIN-Limited DBT protocol at a dose comparable to the Standard DM. Comparison of MGD per breast between protocols was made by 2-sided paired Student s t-test. The ACRIN-Limited MGD did not differ significantly from Standard-DM at Site A (p=0.10) but was greater than Standard-DM at Site B (p<0.01). After adjusting for additional Standard-DM views, ACRIN-Limited dose was greater than Standard-DM at both sites (p<0.01). We attribute this difference to the fact that both sites were using very new DM technology that used doses significantly lower than the national average. The following abstract has been accepted for presentation at the American Association of Physicists in Medicine: Evaluation of Image Quality in Digital Mammography and Digital Breast Tomosynthesis: Phantom Observer Study from American College of Radiology Imaging Network PA 4006 Using Maximum Intensity Projection in the Evaluation of Digital Breast Tomosynthesis: A Phantom Observer Study from the American College of Radiology Imaging Network PA 4006 Trial The following abstracts have been submitted to the Radiological Society of North America: ACRIN 4006: A study comparing the screening recall rates from 2D Digital American College of Radiology 2009 Formula Grant Page 9

10 Mammography (DM) versus Combined low dose 2D plus Digital Breast Tomosynthesis (DBT) Effect of Reduced Radiation Dose on Breast Density Estimation in Digital Mammography: Data from the ACRIN 4006 Trial Prediction of False-Positive Recall from Screening Mammography in the ACRIN 4006 trial Using Computer-Extracted Breast Tissue Complexity Features Digital Breast Tomosynthesis Single Slice versus Slab Analysis of Objects: Phantom Observer Study from the American College of Radiology Imaging Network PA 4006 Trial ACRIN PA 4006: Comparison of Dose in Digital Breast Tomosynthesis and Standard Two-View Mammography for Prospective Breast Cancer Screening ACRIN PA 4006: Characterization of Mean Glandular Dose Adjusted to Volumetric Breast Density in a Prospective Digital Breast Tomosynthesis Screening Trial Table 1: FFDM reads and call-back by Reader (Group A only N=501*) Reader ID FFDM # Read FFDM call-back (%) Reader A 48 4 (8.3) Reader B 13 1 (7.7) Reader C 90 3 (3.3) Reader D (9.7) Reader E 42 4 (9.5) Reader F 76 4 (5.3) Reader G 42 1 (2.4) Reader H 87 2 (2.3) Total (5.8) American College of Radiology 2009 Formula Grant Page 10

11 Table 2: DBT reads and call-back by Reader (Group A only) Reader ID DBT # Read DBT callback (%) Reader A 64 5 (7.8) Reader B 40 4 (10.0) Reader C (13.9) Reader D (7.0) Reader E 34 1 (2.9) Reader F 44 3 (6.8) Reader G 39 1 (2.6) Reader H 94 2 (2.1) Total (6.8) Table 3: Call-back rates per Reader by modality (Group A only) Reader FFDM Call-back(%) DBT Call-back (%) DBT vs FFDM Call-back rate Reader A Down minimally Reader B Up Reader C Up Reader D Down Reader E Down Reader F Up Reader G Up minimally Reader H Down minimally Total Up American College of Radiology 2009 Formula Grant Page 11

12 Table 4: Comparison of Cumulative MGD per Breast by Protocol and Site Research Project 4: Project Title and Purpose Investigation and Analyses of Patient Co-Morbidities in a Survey of Radiation Oncology Facilities in the USA and their Association with Treatment Decisions in Radiation Oncology - The purpose of this project is to describe the distribution of co-morbidities by socio-demographic characteristics such as age, race, geographic region, insurance status and socio-economic status in patients diagnosed with cancer of the breast, cervix, stomach, lung and prostate, to investigate the association of the prevalence of co-morbidities with treatment decisions and variations in compliance with recommended disease management guidelines for such patients, and to examine the interaction of co-morbidities by site and stage of disease with gender, race, and age. Duration of Project 1/1/2010-7/2/2012 Project Overview Since 1973 the American College of Radiology (ACR) has conducted retrospective surveys of the processes of care in radiation oncology through the Quality Research in Radiation Oncology (QRRO, formerly Patterns of Care Study). Detailed information is collected from chart reviews on patient and tumor characteristics, imaging, treatment planning, surgery, radiation and systemic therapy with the purpose of measuring quality of care and comparing care actually received by patients to well-established clinical guidelines. These guidelines base treatment recommendations on tumor and patient characteristics, but provide little guidance on including patient co-morbidities in the treatment decision. Although co-morbidities are not part of the scope of the QRRO study, the current data collection American College of Radiology 2009 Formula Grant Page 12

13 has included detailed data on co-morbidities for patients treated for breast, cervix, gastric and prostate cancers and non-small cell and limited stage small cell lung cancers. This project will investigate co-morbidity data in detail including interaction with other patient characteristics and association with treatment decisions. SPECIFIC AIMS 1. To describe the distribution of co-morbidities by socio-demographic characteristics such as age, race, geographic region, insurance status and socio-economic status in patients diagnosed with cancer of the breast, cervix, stomach, lung and prostate. 2. To investigate the association of the prevalence of co-morbidities with treatment decisions and variations in compliance with recommended disease management guidelines for such patients. 3. To examine the interaction of co-morbidities by site and stage of disease with gender, race, and age. Principal Investigator Jean B. Owen, PhD Senior Director American College of Radiology 1818 Market St., Suite 1600 Philadelphia, PA Other Participating Researchers Alex Ho, MS, MA, Najma Khalid, MS employed by American College of Radiology Expected Research Outcomes and Benefits This project will provide new information on the effect of co-morbidities on treatment decisions for cancer patients and the interaction of co-morbidities with other patient and tumor factors. This will help fill a knowledge gap in the application of nationally recognized treatment guidelines that currently allow vague exceptions to the established standard of care for patients who have multiple confounding medical problems. By providing analyses that help increase understanding of the impact of co-morbidities on treatment decisions, this project will help improve the standard of care for these patients. Summary of Research Completed This project ended on July 2, Although the researchers are no longer associated with the American College of Radiology, they and their collaborators have continued to draft manuscripts reporting the data analyses performed in this project for submission to peer reviewed journals. American College of Radiology 2009 Formula Grant Page 13