Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue

BACKGROUND: Common acute-term side effects of brain radiotherapy (RT) include fatigue, drowsiness, decreased physical functioning, and decreased quality of life (QOL). We hypothesized that armodafinil (a wakefulness-promoting drug known to reduce fatigue and increase cognitive function in breast cancer patients receiving chemotherapy) would result in reduced fatigue and sleepiness for patients receiving brain RT. METHODS: A phase II, multi-institutional, placebo-controlled randomized trial assessed feasibility of armodafinil 150 mg/day in participants receiving brain RT, from whom we obtained estimates of variability for fatigue, sleepiness, QOL, cognitive function, and treatment effect. RESULTS: From September 20, 2010, to October 20, 2012, 54 participants enrolled with 80% retention and 94% self-reported compliance. There were no grade 4-5 toxicities, and the incidence of grade 2-3 toxicities was similar between treatment arms, the most common of which were anxiety and nausea (15%), headaches (19%), and insomnia (20%). There were no statistically significant differences in end-RT or 4 week post-RT outcomes between armodafinil and placebo in any outcomes (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, Brief Fatigue Inventory, Epworth Sleepiness Scale, FACT-Brain, and FACIT-cognitive function). However, in participants with more baseline fatigue, those treated with armodafinil did better than those who received the placebo on the end-RT assessments for several outcomes. CONCLUSION: Armodafinil 150 mg/day was well tolerated in primary brain tumor patients undergoing RT with good compliance. While there was no overall significant effect on fatigue, those with greater baseline fatigue experienced improved QOL and reduced fatigue when using armodafinil. These data suggest that a prospective, phase III randomized trial is warranted for patients with greater baseline fatigue

Addressing cancer survivors\u27 cardiovascular health using the Automated Heart Health Assessment (AH-HA) EHR tool: Initial protocol and modifications to address COVID-19 challenges

BACKGROUND: The purpose of this paper is to describe the Automated Heart-Health Assessment (AH-HA) study protocol, which demonstrates an agile approach to cancer care delivery research. This study aims to assess the effect of a clinical decision support tool for cancer survivors on cardiovascular health (CVH) discussions, referrals, completed visits with primary care providers and cardiologists, and control of modifiable CVH factors and behaviors. The COVID-19 pandemic has caused widespread disruption to clinical trial accrual and operations. Studies conducted with potentially vulnerable populations, including cancer survivors, must shift towards virtual consent, data collection, and study visits to reduce risk for participants and study staff. Studies examining cancer care delivery innovations may also need to accommodate the increased use of virtual visits. METHODS/DESIGN: This group-randomized, mixed methods study will recruit 600 cancer survivors from 12 National Cancer Institute Community Oncology Research Program (NCORP) practices. Survivors at intervention sites will use the AH-HA tool with their oncology provider; survivors at usual care sites will complete routine survivorship visits. Outcomes will be measured immediately after the study visit, with follow-up at 6 and 12 months. The study was amended during the COVID-19 pandemic to allow for virtual consent, data collection, and intervention options, with the goal of minimizing participant-staff in-person contact and accommodating virtual survivorship visits. CONCLUSIONS: Changes to the study protocol and procedures allow important cancer care delivery research to continue safely during the COVID-19 pandemic and give sites and survivors flexibility to conduct study activities in-person or remotely

Genomic predictors of patterns of progression in glioblastoma and possible influences on radiation field design

We present a retrospective investigation of the role of genomics in the prediction of central versus marginal disease progression patterns for glioblastoma (GBM). Between August 2000 and May 2010, 41 patients with GBM and gene expression and methylation data available were treated with radiotherapy with or without concurrent temozolomide. Location of disease progression was categorized as within the high dose (60 Gy) or low dose (46 Gy) volume. Samples were grouped into previously described TCGA genomic groupings: Mesenchymal (m), classical (c), proneural (pn), and neural (n); and were also classified by MGMT-Methylation status and G-Cimp methylation phenotype. Genomic groupings and methylation status were investigated as a possible predictor of disease progression in the high dose region, progression in the low dose region, and time to progression. Based on TCGA category there was no difference in OS (p = 0.26), 60 Gy progression (PN: 71 %, N: 60 %, M: 89 %, C: 83 %, p = 0.19), 46 Gy progression (PN: 57 %, N: 40 %, M: 61 %, C: 50 %, p = 0.8) or time to progression (PN: 9 months, N:15 months, M: 9 months, C: 7 months, p = 0.58). MGMT methylation predicted for improved OS (median 25 vs. 13 months, p = 0.01), improved DFS (median 13 vs. 8 months, p = 0.007) and decreased 60 Gy (p = 0.003) and 46 Gy (p = 0.006) progression. There was a cohort of MGMT methylated patients with late marginal disease progression (4/22 patients, 18 %). TCGA groups demonstrated no difference in survival or progression patterns. MGMT methylation predicted for a statistically significant decrease in in-field and marginal disease progression. There was a cohort of MGMT methylated patients with late marginal progression. Validations of these findings would have implications that could affect radiation field size

Assessment of Oral Chemotherapy Nonadherence in Chronic Myeloid Leukemia Patients Using Brief Measures in Community Cancer Clinics: A Pilot Study

The purpose of this pilot study was to assess Chronic Myeloid Leukemia (CML) patients’ adherence to, beliefs about, and barriers to oral anticancer agents (OAC) using brief self-report measures in community-based cancer clinics. Patients completed a structured interview including a health literacy assessment, a Brief Medication Questionnaire, two single-item self-report adherence questions, and the Medications Adherence Reasons Scale. Of the 86 participants, 88.4% were white; 55.8% male; mean age, 58.7 years; and 22.1% had limited health literacy. Nonadherence (missing at least one dose in the last week) was reported by 18.6% of participants and associated (p < 0.003) with less-than-excellent perceived ability to take CML medications (16.3%). Black participants reported more difficulty taking CML medications than white participants (28.6% vs. 8.3%, p = 0.053). Among all participants, 43.0% reported their CML medicine was ineffective and 24.4% that taking CML pills was somewhat to very hard. The most common reasons for missing a dose were simply missed it (24.4%) and side effects (18.6%). Most patients perceived their ability to take CML medication was good to excellent, yet nearly one in five reported missing at least one dose in the last week. Brief, no-cost self-report assessments to screen CML patients’ OAC adherence, barriers, and beliefs could facilitate counseling in busy community cancer clinics

Abstract 1615: C-Reactive protein and radiotherapy-induced skin toxicity in breast cancer

Abstract Background: Post-surgery adjuvant radiotherapy (RT) for breast cancer significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASRs) that impact quality of life. Methods: In a large prospective study of 1,000 breast cancer patients undergoing RT, we evaluated an inflammatory biomarker, C-reactive protein (CRP) in predicting RT-induced EASRs. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA CRP assay. RT-induced EASRs were assessed using the Oncology Nursing Society Skin Toxicity Criteria. Association between EASRs and CRP were assessed using logistic regression models after adjusting for potential confounders. Results: The study population includes 405 non-Hispanic White, 280 African Americans, 218 Hispanic Whites, 52 Asians, and 45 others. RT-induced grade 3+ and 4+ skin toxicity at the end of RT were observed in 42% and 15% patients, respectively. CRP levels differ significantly by race/ethnicity at baseline and at the end of RT. RT-induced grade 4+ skin toxicity was significantly associated with: obesity and pre-RT CRP &amp;gt; 2mg/L (OR=3.27; 95%CI=1.88, 5.68), obesity and post-RT CRP &amp;gt; 2mg/L (OR=4.42; 95%CI=2.38, 8.23), or obesity and change of CRP &amp;gt; 1mg/L (OR=3.58; 95%CI=2.00, 6.39). Conclusion: The current data validate our previous findings that the inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity. Impact: Our current findings support the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced EASRs and improve quality of life in breast cancer patients undergoing RT. Citation Format: Jennifer J. Hu, Doug Case, Mark O. Lively, Eunkyung Lee, Cristiane Takita, James J. Urbanic, Glenn J. Lesser, Edward G. Shaw. C-Reactive protein and radiotherapy-induced skin toxicity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1615. doi:10.1158/1538-7445.AM2017-1615</jats:p

Genome-wide enriched pathway analysis of acute post-radiotherapy pain in breast cancer patients: a prospective cohort study

Adjuvant radiotherapy (RT) can increase the risk of developing pain; however, the molecular mechanisms of RT-related pain remain unclear. The current study aimed to identify susceptibility loci and enriched pathways for clinically relevant acute post-RT pain, defined as having moderate to severe pain (pain score ≥ 4) at the completion of RT. We conducted a genome-wide association study (GWAS) with 1,344,832 single-nucleotide polymorphisms (SNPs), a gene-based analysis using PLINK set-based tests of 19,621 genes, and a functional enrichment analysis of a gene list of 875 genes with p < 0.05 using NIH DAVID functional annotation module with KEGG pathways and GO terms (n = 380) among 1112 breast cancer patients. About 29% of patients reported acute post-RT pain. None of SNPs nor genes reached genome-wide significant level. Four SNPs showed suggestive associations with post-RT pain; rs16970540 in RFFL or near the LIG3 gene (p = 1.7 × 10 ), rs4584690, and rs7335912 in ABCC4/MPR4 gene (p = 5.5 × 10 and p = 7.8 × 10 , respectively), and rs73633565 in EGFL6 gene (p = 8.1 × 10 ). Gene-based analysis suggested the potential involvement of neurotransmitters, olfactory receptors, and cytochrome P450 in post-RT pain, whereas functional analysis showed glucuronidation (FDR-adjusted p value = 9.46 × 10 ) and olfactory receptor activities (FDR-adjusted p value = 0.032) as the most significantly enriched biological features. This is the first GWAS suggesting that post-RT pain is a complex polygenic trait influenced by many biological processes and functions such as glucuronidation and olfactory receptor activities. If validated in larger populations, the results can provide biological targets for pain management to improve cancer patients' quality of life. Additionally, these genes can be further tested as predictive biomarkers for personalized pain management

A Randomized Double-Blind Placebo-Controlled Trial of Fruit and Vegetable Concentrates on Intermediate Biomarkers in Head and Neck Cancer

Background. Head and neck cancer (HNC) patients are at an increased risk for developing second primary tumors (SPTs). Diets rich in fruits and vegetables (FVs) may lower HNC risk. FV concentrates may offer a potential alternative to increasing FV intake. Methods. We conducted a randomized, double-blind, placebo-controlled trial to evaluate whether Juice PLUS+ (JP; a commercial product with multiple FV concentrates) has an effect on p27 and Ki-67, biomarkers associated with the risk of SPTs. During 2004-2008, we randomized 134 HNC patients to 12 weeks of JP (n = 72) or placebo (n = 62). Oral cavity mucosal biopsies and whole blood were obtained at baseline and after 12 weeks. All participants were given the opportunity to receive JP for 5 years following the end of the intervention period, and they were followed yearly for the development of SPTs. Results. After 12 weeks, patients on JP had significantly higher serum α-carotene ( P = .009), β-carotene ( P < .0001), and lutein ( P = .003) but did not differ significantly in p27 ( P = .23) or Ki-67 ( P = .95). JP use following the initial 12-week trial was not significantly associated with SPT prevention. Conclusions. Despite increased serum micronutrient levels, our results do not suggest a clinical benefit of JP in HNC patients. Future studies should focus on longer intervention periods and/or modified supplement formulations with demonstrated chemopreventive properties