Using Bayesian hierarchical modeling for performance evaluation of clinical trial accrual for a cancer center.

Introduction: Slow patient accrual in cancer clinical trials is always a concern. In 2021, the University of Kansas Comprehensive Cancer Center (KUCC), an NCI-designated comprehensive cancer center, implemented the Curated Cancer Clinical Outcomes Database (C3OD) to perform trial feasibility analyses using real-time electronic medical record data. In this study, we proposed a Bayesian hierarchical model to evaluate annual cancer clinical trial accrual performance. Methods: The Bayesian hierarchical model uses Poisson models to describe the accrual performance of individual cancer clinical trials and a hierarchical component to describe the variation in performance across studies. Additionally, this model evaluates the impacts of the C3OD and the COVID-19 pandemic using posterior probabilities across evaluation years. The performance metric is the ratio of the observed accrual rate to the target accrual rate. Results: Posterior medians of the annual accrual performance at the KUCC from 2018 to 2023 are 0.233, 0.246, 0.197, 0.150, 0.254, and 0.340. The COVID-19 pandemic partly explains the drop in performance in 2020 and 2021. The posterior probability that annual accrual performance is better with C3OD in 2023 than pre-pandemic (2019) is 0.935. Conclusions: This study comprehensively evaluates the annual performance of clinical trial accrual at the KUCC, revealing a negative impact of COVID-19 and an ongoing positive impact of C3OD implementation. Two sensitivity analyses further validate the robustness of our model. Evaluating annual accrual performance across clinical trials is essential for a cancer center. The performance evaluation tools described in this paper are highly recommended for monitoring clinical trial accrual.

Improving the efficiency of clinical trials by standardizing processes for Investigator Initiated Trials.

Early phase clinical trials are the first step in testing new medications and therapeutics developed by clinical and biomedical investigators. These trials aim to find a safe dose of a newly targeted drug (phase I) or find out more about the side effects and early signals of treatment efficacy (phase II). In a research institute, many biomedical investigators in oncology are encouraged to initiate such trials early in their careers as part of developing their research portfolio. These investigator-initiated trials (IITs) are funded internally by the University of Kansas Cancer Center or partially funded by pharmaceutical companies. As financial, administrative, and practical considerations play an essential role in the successful completion of IITs, it is imperative to efficiently allocate resources to plan, design, and execute these studies within the allotted time. This manuscript describes monitoring tools and processes to improve the efficiency, cost-effectivness, and reliability of IITs. The contributions of this team to processes such as: participant recruitment, feasibility analysis, clinical trial design, accrual monitoring, data management, interim analysis support, and final analysis and reporting are described in detail. This manuscript elucidates how, through the aid of technology and dedicated personnel support, the efficiency of IIT-related processes can be improved. Early results of these initiatives look promising, and the Biostatistics and Informatics team intends to continue fostering innovative methodologies to enhance cancer research by improving the efficiency of IITs.

Accrual Prediction Program: A web-based clinical trials tool for monitoring and predicting accrual for early-phase cancer studies.

BACKGROUND: Monitoring subject recruitment is key to the success of a clinical trial. Accordingly, researchers have developed accrual-monitoring tools to support the design and conduct of trials. At an institutional level, delays in identifying studies with high risk of accrual failure can lead to inefficient and costly trials with little chances of meeting study objectives. Comprehensive accrual monitoring is necessary to the success of the research enterprise. METHODS: This article describes the design and implementation of the University of Kansas Cancer Center Accrual Prediction Program, a web-based platform was developed to support comprehensive accrual monitoring and prediction for all active clinical trials. The Accrual Prediction Program provides information on accrual, including the predicted completion date, predicted number of accrued subjects during the pre-specified accrual period, and the probability of achieving accrual targets. It relies on a Bayesian accrual prediction model to combine protocol information with real-time trial enrollment data and disseminates results via web application. RESULTS: First released in 2016, the Accrual Prediction Program summarizes enrollment information for active studies categorized by various trial attributes. The web application supports real-time evidence-based decision making for strategic resource allocation and study management of over 120 ongoing clinical trials at the University of Kansas Cancer Center. CONCLUSION: The Accrual Prediction Program makes accessing comprehensive accrual information manageable at an institutional level. Cancer centers or even entire institutions can reproduce the Accrual Prediction Program to achieve real-time comprehensive monitoring and prediction of subject accrual to aid investigators and administrators in the design, conduct, and management of clinical trials.

T-cell trafficking plays an essential role in tumor immunity.

Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or ß7 integrin, a component of the α4ß7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII-/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, ß7 integrin-/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.

Bayesian design for two-arm randomized Phase II clinical trials with endpoints from the exponential family using multiple constraints.

Frequentist design for two-arm randomized Phase II clinical trials with outcomes from the exponential dispersion family was proposed previously, where the total sample sizes are minimized under multiple constraints on the standard errors of the estimated group means and their difference. This design was generalized from an approach specific for dichotomous outcomes. The two previous approaches measure the central tendency of each group and treatment effect based on mean and difference in means. Other measures such as median or hazard ratio are more appropriate under certain situations. In addition, the frequentist approaches assume that unknown parameters are fixed values. This does not reflect the reality that uncertainty always exists for unknowns. Compared to the frequentist methods, the Bayesian approach offers a flexible way to measure central tendency and treatment effect, and incorporate uncertainty in parameters of interest into considerations. In this article, we generalize a Bayesian design for Phase II clinical trials with endpoints in the exponential family from the two previously developed frequentist approaches. The proposed design minimizes the total sample sizes under pre-specified constraints on the expected length of posterior credible intervals for measures of treatment effect and central tendency in each group. The design is applicable for trials with fixed or optimal randomization allocation ratio and can be applied under adaptive procedure. Examples of method implementations are provided for different types of endpoints from the exponential family in both fixed and adaptive settings.

Supplemental Screening With Automated Breast Ultrasound in Women With Dense Breasts: Comparing Notification Methods and Screening Behaviors.

OBJECTIVE: Supplemental screening with ultrasound has been shown to detect additional breast malignancies in women with dense breast tissue and normal mammogram findings. The frequency of supplemental screening with automated breast ultrasound and the effect and type of breast tissue density notification on automated screening breast ultrasound utilization rates are unknown. MATERIALS AND METHODS: We examined normal mammogram results letters for patients with heterogeneously or extremely dense breast tissue between July 1, 2013, and June 30, 2014, by type of results letter, notification method, and sociodemographic characteristics. Logistic regression was used to examine the association between type of results letter and subsequent automated screening breast ultrasound. RESULTS: Among 3012 women with dense breast tissue and normal mammogram findings, 15% returned for supplemental automated screening breast ultrasound within 18 months of results letter notification. Compared with a similarly sized control group of women who did not undergo automated ultrasound, a significantly greater proportion of patients (86.9%) returned for breast ultrasound if they received a results letter indicating breast density in combination with a courtesy phone call (p < 0.001). Patients who received results letters with breast density notification including a statement that they may benefit from additional screening with automated breast ultrasound examination were 9.91 times (95% CI, 6.08-16.16) more likely to return for the examination than patients who did not receive breast density notification or mention of supplemental screening. CONCLUSION: Patient breast density notification and radiologists' recommendations for supplemental screening with breast ultrasound increase patient utilization of automated screening breast ultrasound examinations.

Potential factors associated with perceived cognitive impairment in breast cancer survivors.

PURPOSE: This cross-sectional study was designed to explore potential factors associated with perceived cognitive impairment (PCI) in breast cancer survivors compared to controls and gain insight into perceived levels of severity for cognitive complaints. METHODS: Women (N = 363, 317: breast cancer, 46: healthy controls) completed demographic questionnaire, MD Anderson Symptom Inventory, Attentional Function Index, and Functional Assessment for Cancer Therapy-Cognition. Group classification included pre-chemotherapy, current chemotherapy, and postchemotherapy (<1, >1- < 2, >2- < 5, >5 years). RESULTS: A significant group effect was seen for PCI (F 6, 355 = 7.01, p < 0.0001). Controls reported less PCI than all other groups. Neuropathy was inversely correlated with PCI (r = -0.23; p < 0.0001) for participants with breast cancer. A significant association was demonstrated between exercise frequency and PCI in women exposed to chemotherapy (F 3, 135 = 3.78, p < 0.05). A multiple linear regression model built using forward selection methods explained 24 % of the variance (adjusted R (2)) for PCI in breast cancer participants and included group, body mass index (BMI), exercise, fatigue, and distress. Exercise frequency moderated the relationship between BMI and PCI for breast cancer participants (F 3, 198 = 2.4, p = 0.07) and reduced the negative effects of high BMI. The moderating effect of exercise was significant (F 3, 133 = 3.1, p = 0.03) when limited to participants exposed to chemotherapy. CONCLUSIONS: PCI decreased for women >5 years postchemotherapy. Overweight survivors who exercised frequently reported less PCI than sedentary survivors. Study results provide support for a relationship between BMI and PCI in breast cancer survivors and exercise as a potential intervention for cognitive complaints. Further investigation of the influence of weight and exercise on cognitive function is warranted.

A phase I study of intraperitoneal nanoparticulate paclitaxel (Nanotax®) in patients with peritoneal malignancies.

PURPOSE: This multicenter, open-label, dose-escalating, phase I study evaluated the safety, tolerability, pharmacokinetics and preliminary tumor response of a nanoparticulate formulation of paclitaxel (Nanotax®) administered intraperitoneally for multiple treatment cycles in patients with solid tumors predominantly confined to the peritoneal cavity for whom no other curative systemic therapy treatment options were available. METHODS: Twenty-one patients with peritoneal malignancies received Nanotax® in a modified dose-escalation approach utilizing an accelerated titration method. All patients enrolled had previously received chemotherapeutics and undergone surgical procedures, including 33 % with optimal debulking. Six doses (50-275 mg/m(2)) of Cremophor-free Nanotax® were administered intraperitoneally for one to six cycles (every 28 days). RESULTS: Intraperitoneal (IP) administration of Nanotax® did not lead to increases in toxicity over that typically associated with intravenous (IV) paclitaxel. No patient reported ≥Grade 2 neutropenia and/or ≥Grade 3 neurologic toxicities. Grade 3 thrombocytopenia unlikely related to study medication occurred in one patient. The peritoneal concentration-time profile of paclitaxel rose during the 2 days after dosing to peritoneal fluid concentrations 450-2900 times greater than peak plasma drug concentrations and remained elevated through the entire dose cycle. Best response assessments were made in 16/21 patients: Four patients were assessed as stable or had no response and twelve patients had increasing disease. Five of 21 patients with advanced cancers survived longer than 400 days after initiation of Nanotax® IP treatment. CONCLUSIONS: Compared to IV paclitaxel administration, Cremophor-free IP administration of Nanotax® provides higher and prolonged peritoneal paclitaxel levels with minimal systemic exposure and reduced toxicity.

A multicenter pilot study examining the role of circulating tumor cells as a blood-based tumor marker in patients with extensive small-cell lung cancer.

BACKGROUND: Small-cell lung cancer (SCLC), a variant of lung cancer marked by early metastases, accounts for 13% of all lung cancers diagnosed in US. Despite high response rates to treatment, it is an aggressive disease with a median survival of 9-11 months for patients with extensive stage (EX-SCLC). Detection of circulating tumor cells (CTCs) is a novel laboratory technique currently in use to determine response to therapy and to predict prognosis in breast, colorectal, and prostate cancer. We initiated a pilot study to analyze the role of CTCs as a biomarker of response and relapse in patients with EX-SCLC. METHODS: We collected blood samples from chemotherapy naïve patients with EX-SCLC prior to initiation of therapy, after completion of systemic therapy, and follow-up every 6-8 weeks and at relapse. The number of CTCs was determined using the cell search system in a central laboratory. The study was conducted in four different sites, and it was reviewed and approved by respective research review committees and IRBs. RESULTS: We enrolled 26 patients with EX-SCLC, 1 was excluded due to ineligibility, all were treated with platinum and etoposide. We observed partial response in 16 patients, stable disease in 3 patients, 1 patient with disease progression, and 6 patients were not assessed (5 deceased, 1 not available). The overall median number of CTCs in 24 patients measured at baseline and post-tx was 75 (range 0-3430) and 2 (range 0-526), respectively. A significant reduction in CTCs from baseline to post-treatment was identified for 15 subjects; the median reduction was 97.4% (range -100 to +100%, p < 0.001). Higher baseline CTCs and percentage change in post-treatment CTCs were associated with decreased survival. CONCLUSION: We demonstrated that it is feasible to detect CTCs in EX-SCLC. If validated in other prospective studies, CTCs could be a useful biomarker in the management of EX-SCLC by predicting patients' clinical responses to therapy.

Extrapulmonary small cell carcinoma: the University of Kansas experience and review of literature.

Though extrapulmonary small cell carcinoma was first described over 80 years ago, definitive treatment recommendations are lacking. The treatment strategies commonly utilized are extrapolated from pulmonary small cell carcinoma experience. A better understanding of this entity is needed to improve management approach. The University of Kansas tumor registry was reviewed from 1990 to 2013. Thirty-five cases met the inclusion and exclusion criteria for review. Age, gender, smoking status, weight loss, metastatic disease-related data, stage, performance status (PS), treatment received, and survival data were collected. Patients were evaluated with a variety of primary locations of disease including GI tract (29%), GU tract (35%), Gyn organs (17%), head and neck (14%), and unknown primary (9%). Several sites of metastatic disease were noted, with 57 and 43% of patients meeting criteria for limited disease (LD) and extensive disease (ED), respectively. Chemotherapy, surgery, and radiation were used in several different regimens, with small cell lung cancer-type regimens incorporating a platinum and etoposide being the most common (74%). Patients with LD had a median survival of 36 months compared with 5 months in patients with ED (p<0.0001). Among different primary sites, patients with GU and Gyn LD tumors had best median survival of 36 months. Among other variables that were examined with respect to their poor prognostic significance, PS>2 (p=0.001) and one or fewer number of treatment modalities especially in LD (p=0.0005) were found to be associated significantly with mortality. GI and GU tract tumors were the most common primary sites of disease in our retrospective review. Survival varied according to stage, PS, site of primary disease, use of chemotherapy, and number of treatment modalities used. Further studies are needed to better understand this rare disorder and optimize management approach.

Combined use of multiday palonosetron with aprepitant and low-dose dexamethasone in prevention of nausea and emesis among patients with multiple myeloma and lymphoma undergoing autologous hematopoietic stem cell transplant: A pilot study.

BACKGROUND: The current standard for prevention of chemotherapy-induced nausea/vomiting in autologous stem cell transplant only achieves 4-20% emetic control. OBJECTIVES: To assess emetic responses to multiday palonosetron, aprepitant, and low-dose dexamethasone among patients with myeloma and lymphoma undergoing autologous hematopoietic stem cell transplant. METHODS: Oral aprepitant 125/80/80 mg was administered with intravenous dexamethasone 4 mg and palonosetron 0.25 mg on days -3, -2, -1 for multiple myeloma and days -7 through -3 for lymphoma. Palonosetron was repeated day +3 in both groups. RESULTS: A total of 20 patients were enrolled and 18 analyzed. None experienced emetic failure with complete control achieved in 78, 33, and 17% in the acute, delayed, and extended phases, respectively. Nausea occurred in 78% although not significant in 61%, with median Nausea Visual Score of 4.5. Quality of life correlated with emetic and nausea control. Eight patients developed grade 2-3 nonhematologic toxicities with only one event attributed to the study medications. CONCLUSIONS: This triplet regimen was feasible with acceptable safety profile in the autologous hematopoietic stem cell transplant setting. Emetic control was best achieved in the acute phase. Lesser degree of emetic and nausea control in the delayed and extended phases impacted quality of life. Our results warrant further evaluation in a larger autologous hematopoietic stem cell transplant population.

Predictors of early versus late smoking abstinence within a 24-month disease management program.

INTRODUCTION: Standard smoking cessation treatment studies have been limited to 6- to 12-month follow-up, and examination of predictors of abstinence has been restricted to this timeframe. The KanQuit study enrolled 750 rural smokers across all stages of readiness to stop smoking and provided pharmacotherapy management and/or disease management, including motivational interviewing (MI) counseling every 6 months over 2 years. This paper examines differences in predictors of abstinence following initial (6-month) and extended (24-month) intervention. METHODS: Baseline variables were analyzed as potential predictors of self-reported smoking abstinence at Month 6 and at Month 24. Chi-square tests, 2-sample t tests, and multiple logistic regression analyses were used to identify predictors of abstinence among 592 participants who completed assessment at baseline and Months 6 and 24. RESULTS: Controlling for treatment group, the final regression models showed that male gender and lower baseline cigarettes per day predicted abstinence at both 6 and 24 months. While remaining significant, the relative advantage of being male decreased over time. Global motivation to stop smoking, controlled motivation, and self-efficacy predicted abstinence at 6 months but did not predict abstinence at Month 24. In contrast, stage of change was strongly predictive of 24-month smoking status. CONCLUSIONS: While the importance of some predictors of successful smoking cessation appeared to diminish over time, initial lack of interest in cessation and number of cigarettes per day strongly predicted continued smoking following a 2-year program.