Browsing by Author "Deal, Allison M."

Now showing 1 - 7 of 7
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    A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer
    (Oxford University Press, 2024) Sanoff, Hanna K.; Deal, Allison M.; Patel, Jai; Sorah, Jonathan D.; Gaddy, Jacquelyne; O’Neil, Bert; Turk, Anita; Irvin, William; Boles, Jeremiah; Lee, Michael S.; McRee, Autumn; Wardell, Alexis C.; Weck, Karen E.; Basch, Ethan; Wood, William A.; Innocenti, Federico; Medicine, School of Medicine
    Background: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. Methods: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). Results: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. Conclusions: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.
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    A randomized double-blind placebo-controlled trial of intravenous thiamine for prevention of delirium following allogeneic hematopoietic stem cell transplantation
    (Elsevier, 2021) Nakamura, Zev M.; Deal, Allison M.; Park, Eliza M.; Quillen, Laura J.; Chien, Stephanie A.; Stanton, Kate E.; McCabe, Sean D.; Heiling, Hillary M.; Wood, William A.; Shea, Thomas C.; Rosenstein, Donald L.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Objective: To determine if high dose intravenous (IV) thiamine can prevent delirium during hospitalization following allogeneic HSCT. Secondarily, we evaluated the effects of high dose IV thiamine on thiamine levels and explored risk factors for delirium. Methods: Randomized, double-blind, placebo-controlled trial in patients undergoing allogeneic HSCT at a U.S. academic medical center between October 2017 and March 2020. 64 participants were randomized 1:1 to thiamine 200 mg IV three times daily for 7 days or placebo. We used the Delirium Rating Scale to assess for delirium. Delirium incidence was compared between groups using the chi-square test. Group differences in time to onset and duration of delirium were compared using the Kaplan-Meier method. Fisher's Exact and Wilcoxon Rank Sum tests were used to examine associations between pre-transplantation variables and delirium. Results: 61 participants were analyzed. Delirium incidence (25% vs. 21%, Chi-square (df = 1) = 0.12, p = 0.73), time to onset, duration, and severity were not different between study arms. Immediately following the intervention, thiamine levels were higher in the thiamine arm (275 vs. 73 nmol/L, t-test (df = 57) = 13.63, p < 0.0001), but not predictive of delirium. Variables associated with delirium in our sample included disease severity, corticosteroid exposure, infection, and pre-transplantation markers of nutrition. Conclusion: High dose IV thiamine did not prevent delirium in patients receiving allogeneic HSCT. Given the multiple contributors to delirium in this population, further research regarding the efficacy of multicomponent interventions may be needed.
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    Coronary Artery Calcifications and Cardiac Risk after Radiotherapy for Stage III Lung Cancer
    (Elsevier, 2022) Wang, Kyle; Malkin, Hayley E.; Patchett, Nicholas D.; Pearlstein, Kevin A.; Heiling, Hillary M.; McCabe, Sean D.; Deal, Allison M.; Mavroidis, Panayiotis; Oakey, Mary; Fenoli, Jeffrey; Lee, Carrie B.; Klein, J. Larry; Jensen, Brian C.; Stinchcombe, Thomas E.; Marks, Lawrence B.; Weiner, Ashley A.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Purpose: Heart dose and heart disease increase the risk for cardiac toxicity associated with radiation therapy. We hypothesized that computed tomography (CT) coronary calcifications are associated with cardiac toxicity and may help ascertain baseline heart disease. Methods and materials: We analyzed the cumulative incidence of cardiac events in patients with stage III non-small cell lung cancer receiving median 74 Gy on prospective dose-escalation trials. Events were defined as symptomatic effusion, pericarditis, unstable angina, infarction, significant arrhythmia, and/or heart failure. Coronary calcifications were delineated on simulation CTs using radiation software program (130 HU threshold). Calcifications were defined as "none," "low," and "high," with median volume dividing low and high. Results: Of 109 patients, 26 had cardiac events at median 26 months (range, 1-84 months) after radiation therapy. Median follow-up in surviving patients was 8.8 years (range, 2.3-17.3). On simulation CTs, 64 patients (59%) had coronary calcifications with median volume 0.2 cm3 (range, 0.01-8.3). Only 16 patients (15%) had baseline coronary artery disease. Cardiac events occurred in 7% (3 of 45), 29% (9 of 31), and 42% (14 of 33) of patients with no, low, and high calcifications, respectively. Calcification burden was associated with cardiac toxicity on univariate (low vs none: hazard ratio [HR] 5.0, P = .015; high vs none: HR 8.1, P < .001) and multivariate analyses (low vs none: HR 7.0, P = .005, high vs none: HR 10.6, P < .001, heart mean dose: HR 1.1/Gy, P < .001). Four-year competing risk-adjusted event rates for no, low, and high calcifications were 4%, 23%, and 34%, respectively. Conclusions: The presence of coronary calcifications is a cardiac risk factor that can identify high-risk patients for medical referral and help guide clinicians before potentially cardiotoxic cancer treatments.
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    Longitudinal patient-reported outcomes on genotype-guided irinotecan dosing: feasibility and clinical relevance
    (Oxford University Press, 2024) Sorah, Jonathan D.; Deal, Allison M.; Stein, Sophia I.; Jonsson, Mattias; Innocenti, Federico; Turk, Anita; Boles, Jeremiah C.; Irvin, William; Basch, Ethan M.; Sanoff, Hanna K.; Wood, William A.; Medicine, School of Medicine
    Introduction: Standard investigator-based adverse events (AE) assessment is via CTCAE for clinical trials. However, including the patient perspective through PRO (patient-reported outcomes) enhances clinicians' understanding of patient toxicity and fosters early detection of AEs. We assessed longitudinal integration of PRO-CTCAE within clinical workflow in a phase II trial. Materials and methods: As a sub-study in a phase II trial of genotype-directed irinotecan dosing evaluating efficacy in patients with metastatic colorectal cancer receiving FOLFIRI and bevacizumab, patients reported on 13 AEs generating a PRO-CTCAE form. The primary objective was to estimate forms completed by patients and clinicians at least 80% of time. Secondary objectives were estimating concordance and time to first score of specific symptoms between patient and clinician pairs. Results: Feasibility of longitudinal PRO-CTCAE integration was met as 96% of patients and clinician-patient pairs completed at least 80% of PRO-CTCAE forms available to them with 79% achieving 100% completion. Concordance between patient and clinician reporting a severe symptom was 73% with 24 disconcordant pairs, 21 involved patients who reported a severe symptom that the clinician did not. Although protocol-mandated dose reductions were guided by CTCAE not PRO-CTCAE responses, the median time to dose reduction of 2.53 months, and the time-to-event curve closely approximated time to patient-reported toxicity. Conclusion: Longitudinal integration of PRO-CTCAE paired CTCAE proved feasible. Compared to clinicians, patients reported severe symptoms more frequently and earlier. Patient-reported toxicity more closely aligned with dose decreases indicating incorporation into routine clinical practice may enhance early detection of toxicity improving patient safety and quality of life.
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    Parenting through grief: A cross-sectional study of recently bereaved adults with minor children
    (Sage, 2021) Park, Eliza M.; Deal, Allison M.; Yopp, Justin M.; Chien, Stephanie A.; McCabe, Sean; Hirsch, Ariella; Bowers, Savannah M.; Edwards, Teresa; Rosenstein, Donald L.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Background: Grieving adults raising parentally-bereaved minor children experience persistently elevated symptoms of depression and grief. However, the factors associated with their mental health outcomes are not well understood. Aim: To investigate the psychosocial and demographic characteristics associated with grief distress and depressive symptom severity in bereaved adults with minor children. Design: Cross-sectional, web-based survey. Setting/participants: Eight hundred forty-five bereaved adults raising minor (age <18 years) children who had experienced the death of a co-parent. Primary outcomes were grief distress (Prolonged Grief Disorder-13), depressive symptoms (Patient-Reported Outcomes Measurement Information System-Depression), and widowed parenting self-efficacy (WPSES). Results: Mean grief scores were 33.5; mean depression scores were 58.3. Among the 690 individuals more than 6 months bereaved, 132 (19.3%) met criteria for prolonged grief disorder. In adjusted models, participants reporting higher grief scores were more recently bereaved, identified as mothers, non-Caucasian, had lower education and income, and had not anticipated their co-parent's death. The statistical modeling results for depression scores were similar to grief scores except that depression was not associated with anticipation of co-parent death. Parents reporting lower WPSES scores had higher grief and depression scores. Retrospective assessments of more intense parenting worries at the time of co-parent death were also associated with higher grief and depression scores. Conclusions: For bereaved adults with minor children, unanticipated co-parent death was linked with higher grief distress but not symptoms of depression. Addressing parenting concerns may represent a common pathway for improving the mental health of parentally-bereaved families.
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    Quality of Life and Health State Utilities in Bladder Cancer
    (IOS Press, 2022-03-11) Smith, Angela B.; McCabe, Sean; Deal, Allison M.; Guo, Amy; Gessner, Kathryn H.; Lipman, Robert; Chisolm, Stephanie; Ahlschlager, Lauren; Gore, John L.; Urology, School of Medicine
    Background: Bladder cancer treatments may variably impact health-related quality of life (QOL). Objective: To characterize the quality of life of patients with bladder cancer at various time points across the continuum of bladder cancer care from non-muscle-invasive disease to metastatic bladder cancer and develop utility scores to inform cost-effective analyses. Methods: We performed a cross-sectional survey of bladder cancer patients in the Bladder Cancer Advocacy Network Patient Survey Network. Participants were classified into mutually exclusive health states based upon non-muscle invasive (NMIBC), muscle-invasive (MIBC), or metastatic bladder cancer and completed surveys of generic cancer and bladder cancer-specific quality of life, financial toxicity, and work impairment. We constructed generalized linear mixed models to identify patient, clinical, and treatment factors associated with quality of life over time and derived health state utilities. Results: Among 911 self-identified patients with bladder cancer, overall QOL scores and function domains were worse among those with advanced cancer. Financial toxicity was similar among non-metastatic disease states. Work and activity impairment increased with advancing disease (13%and 12%among non-recurrent NMIBC to 63%and 31%for metastatic disease respectively; p < 0.01). On multivariable analysis, bowel-related QOL was diminished among patients with MIBC, with urinary symptoms and physical function most diminished among patients with metastatic disease. Patients with metastatic and MIBC experienced worse emotional functioning (p = 0.04; p = 0.048). Health state utilities were calculated, highest among those with non-recurrent NMIBC and lowest among those with metastatic disease. Conclusion: Generic and bladder cancer-specific QOL diminishes with advancing disease. Health state utility estimates derived from this study can inform shared decision making with patients and may be used to inform future cost-effective analyses.
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    TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases
    (Springer, 2014) Anders, Carey; Deal, Allison M.; Abramson, Vandana; Liu, Minetta C.; Storniolo, Anna M.; Carpenter, John T.; Puhalla, Shannon; Nanda, Rita; Melhem-Bertrandt, Amal; Lin, Nancy U.; Marcom, P. Kelly; Van Poznak, Catherine; Stearns, Vered; Melisko, Michelle; Smith, J. Keith; Karginova, Olga; Parker, Joel; Berg, Jonathan; Winer, Eric P.; Peterman, Amy; Prat, Aleix; Perou, Charles M.; Wolff, Antonio C.; Carey, Lisa A.; Medicine, School of Medicine
    Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.