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Established prognostic factors for head and neck squamous cell carcinoma (HNSCC) mostly consist of clinical and tumor features assessed before treatment. We report a novel application of DNA methylation in peripheral blood before and after radiation therapy to further improve outcomes stratification.Peripheral blood samples from patients with nonmetastatic HNSCC were obtained for methylation analysis 1 week before and 1 month after radiation therapy. Patients were randomized 1:1 to a Discovery Cohort or a Validation Cohort. In the Discovery Cohort, associations between genome-wide methylation change (posttreatment minus pretreatment) and recurrence-free survival (RFS) as well as overall survival (OS) were evaluated using Cox regression. A methylation risk score (MRS) was then constructed from methylation levels at the top associated sites, filtered for residing within the regulatory regions of genes expressed in cells of hematopoietic lineage. The prognostic value of MRS was separately assessed in the Discovery and Validation Cohorts.Between December 2013 and September 2018, 115 patients participated in this study. Human papilloma virus negative status, oral cavity cancer, gastrostomy tube insertion, and higher neutrophil count before radiation therapy were associated with shorter RFS and OS (P.05). Genes downstream of the methylation sites comprising MRS are HIF1A, SF1, LGALS9, and FUT5, involved in hypoxia response, blood cell maturation, and immune modulation. High MRS (in the top third) was significantly associated with worse RFS (hazard ratio [HR], 7.1; 95% confidence interval [CI], 1.4-35.5; P = .016) and OS (HR, 15.9; 95% CI, 1.6-153.6; P = .017) in the Discovery Cohort, independent of the aforementioned risk factors. These findings were replicated in the Validation Cohort, for which high MRS also independently predicted worse RFS (HR, 10.2; 95%, CI 2.4-43.4; P = .002) and OS (HR, 3.7; 95% CI, 1.3-10.4; P = .015).We successfully trained and validated a signature of DNA methylation in peripheral blood before and after radiation therapy that stratified outcomes among patients with HNSCC, implicating the potential for genomics-tailored surveillance and consolidation treatment.

BACKGROUND Patients with colorectal cancer (CRC) receiving chemotherapy often experience psychoneurological symptoms (PNS, i.e., fatigue, depression, anxiety, sleep disturbance, pain, and cognitive dysfunction) that negatively impact both patients’ and their caregivers’ health outcomes. Limited information is available on PNS management for CRC patient and caregiver dyads. OBJECTIVE The purposes of this study are to: 1) develop a web-based dyadic intervention for patients with CRC receiving chemotherapy and their caregivers (CRCweb); and 2) evaluate the feasibility, acceptability, and preliminary effects of CRCweb among patient-caregiver dyads in a cancer clinic. METHODS A mixed methods approach will be used. Semi-structured interviews among eight dyads will be conducted to develop CRCweb. A single-group pre- and post-test clinical trial will be employed to examine the feasibility, acceptability, and preliminary effects of the intervention (CRCweb) among 20 dyads. Study assessments will be conducted pre- (T1) and post-intervention (T2). Content analysis will be performed for semi-structured interviews. Descriptive statistics will be calculated separately for patients and caregivers, and pre-post paired t-tests will be used to evaluate treatment effects. RESULTS This study was funded in November 2022. As of April 2023, we have completed the Institutional Review Board approval and clinical trial registration and are currently recruiting patient-caregiver dyads in a cancer clinic. The study is expected to be completed in October 2024. CONCLUSIONS Developing a web-based dyadic intervention holds great promise to reduce PNS burden for patients with CRC receiving chemotherapy and their caregivers. The findings from this study will advance intervention development and implementation of symptom management and palliative care for cancer patients and their caregivers. CLINICALTRIAL ClinicalTrials.gov identifier, NCT05663203

Patients with gastrointestinal cancers experience diurnal variations in fatigue severity during chemotherapy that decrease their functional status and quality of life.Study purposes were to identify subgroups of patients with distinct co-occurring morning and evening fatigue profiles and evaluate for differences among these subgroups in demographic, clinical, stress, and symptom characteristics.Patients with gastrointestinal cancers (n = 405) completed questionnaires 6 times over 2 cycles of chemotherapy. The Lee Fatigue Scale was used to evaluate diurnal variations in fatigue severity. Latent profile analysis was used to identify subgroups of patients with distinct co-occurring morning AND evening fatigue profiles. Differences among the subgroups in demographic, clinical, stress, and symptom characteristics at enrollment were evaluated using parametric and nonparametric analyses.Two classes were identified, namely: low morning and moderate evening fatigue (ie, Low-Moderate, 60.0%) and high morning and high evening fatigue (ie, Both High, 40.0%). Compared with the Low-Moderate class, the Both High class was significantly younger, female, unmarried, and unemployed and lacked regular exercise. In addition, they had childcare responsibilities, lower annual income, lower functional status, higher comorbidity burden, and self-reported anemia and depression. Patients in the Both High class reported higher levels of anxiety, depressive symptoms, sleep disturbance, pain, and stress, and lower levels of energy and cognitive function.Findings provide new insights into the risk factors for higher levels of co-occurring morning and evening fatigue in patients with gastrointestinal cancers.Clinicians can use this information to identify high-risk patients and develop personalized symptom management interventions.

To examine colorectal cancer (CRC) survivors' symptom characteristics (occurrence, frequency, and severity) during acute cancer survivorship.A cross-sectional study of 117 CRC survivors was conducted at a National Cancer Institute-designated cancer center in South Florida.Symptom characteristics were assessed by the Therapy-Related Symptom Checklist. Participants completed a 25-item demographic questionnaire. Mann-Whitney U and Kruskal-Wallis H tests assessed between-group differences based on sex, age, education, and months since diagnosis. Exploratory factor analysis was performed to identify preliminary symptom clusters.117 CRC survivors completed the study (age range = 21-88 years, 56% male, and 79% stage IV). Common symptoms included peripheral neuropathy, fatigue/feeling sluggish, and skin changes. Significance was found between months since diagnosis and number of symptoms (p = 0.03), suggesting that symptoms accumulate with time. Chemotherapy (85%) was the most common treatment type, and exploratory factor analysis identified two chemotherapy-related symptom clusters.Nurses are poised to identify, prevent, and promote self-management skills to reduce symptoms.

BACKGROUND The authors measured epigenetic age acceleration (EAA) during and after cancer treatment and its association with inflammation and fatigue, which is a debilitating symptom in patients with cancer. METHODS Patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 6 months and 12 months postradiotherapy. Blood DNA methylation was assessed using a proprietary bead chip (the Illumina MethylationEPIC BeadChip). EAA was calculated using the Levine epigenetic clock (DNAmPhenoAge), adjusted for chronological age. Fatigue was assessed using the Multidimensional Fatigue Inventory-20. Inflammatory markers were measured using standard techniques. RESULTS Most patients (N = 133) were men, White, had advanced disease, and received concurrent chemoradiation. EAA changes over time were significant, with the largest increase (4.9 years) observed immediately after radiotherapy (P < .001). Increased EAA was associated with elevated fatigue (P = .003) over time, and patients who had severe fatigue experienced 3.1 years higher EAA than those who had low fatigue (P < .001), which was more prominent (5.6 years; P = .018) for patients who had human papillomavirus-unrelated disease at 12 months posttreatment. EAA was also positively associated with inflammatory markers, including C-reactive protein (CRP) and interleukin-6 (IL-6), over time (P < .001), and patients who had high CRP and IL-6 levels exhibited increases of 4.6 and 5.9 years, respectively, in EAA compared with those who had low CRP and IL-6 levels (P < .001). CRP and IL-6 mediated the association between EAA and fatigue (CRP: 95% CI, 0.060-0.279; IL-6: 95% CI, 0.024-0.220). CONCLUSIONS Patients with head and neck cancer experienced increased EAA, especially immediately after treatment completion. EAA was associated with greater fatigue and inflammation, including 1 year after treatment. Inflammation may be a target to reduce the impact of age acceleration on poor functional outcomes.

Background Nurses’ palliative and hospice care-specific education is associated with the quality of palliative and hospice care that influences health outcomes of patients with life-limiting illnesses and their caregivers. However, China lacks measures available to assess nurses’ educational needs in palliative and hospice care. The End-of-Life Professional Caregiver Survey (EPCS) is a psychometrically reliable self-reporting scale to measure multidisciplinary professionals’ palliative and hospice care educational needs. This study was performed to explore the psychometric properties of the Chinese version of the EPCS (EPCS-C) among Chinese nurses. Methods We translated and culturally adapted the EPCS into Chinese based on Beaton and colleagues’ instrument adaptation process. A cross-sectional study design was used. We recruited 312 nurses from 1482 nurses in a tertiary hospital in central China using convenience sampling to complete the study. Participants completed the EPCS-C and a demographic questionnaire. Exploratory and confirmatory factor analysis was carried out to test and verify the construct validity of the nurse-specific EPCS-C. Cronbach’s alpha coefficient was used to appraise the reliability of the nurse-specific EPCS-C. Results A three-factor structure of EPCS-C was determined, including cultural, ethical, and national values; patient- and family-centered communication; and effective care delivery. The exploratory factor analysis explained 70.82% of the total variances. The 3-factor solution of the nurse-specific EPCS-C had a satisfactory model fit: χ2 = 537.96, χ2/df = 2.96, CFI = 0.94, RMSEA = 0.079, IFI = 0.94, and GFI = 0.86. Cronbach’s alpha coefficient of the overall questionnaire was 0.96. Conclusions The nurse-specific EPCS-C showed satisfactory reliability and validity to assess nurses’ palliative and hospice care educational need. Further research is required to verify the reliability and validity of the EPCS-C in a larger sample, especially the criterion-related validity.

Objective Fatigued cancer patients often have high peripheral inflammation; however, the biological mechanisms of this association remain unclear. We examined whether decreased sensitivity of immune cells to the anti-inflammatory effects of glucocorticoids may contribute to inflammation and fatigue in head and neck cancer (HNC) patients during treatment. Methods HNC patients without distant metastasis and with curative intent (n = 77) were studied 1 week before intensity-modulated radiotherapy (IMRT) and 1 month after IMRT. At each time point, fatigue was measured by the Multidimensional Fatigue Inventory-20 along with plasma inflammation markers and glucocorticoid receptor (GR) sensitivity as determined by in vitro dexamethasone suppression of lipopolysaccharide-induced interleukin 6. Linear regression models were used. Results In contrast to our hypothesis, GR sensitivity increased during treatment; however, increased fatigue was associated with a lesser increase in GR sensitivity from baseline to 1 month after IMRT (unstandardized estimate = 4.07, p = .02). This effect was more prominent in human papillomavirus-unrelated HNCs (unstandardized estimate = 8.22, p = .002). Lower increases in GR sensitivity were also associated with increased inflammation at 1 month after IMRT as represented by C-reactive protein, interleukin 6, and tumor necrosis factor α. Addition of inflammation markers to models of GR sensitivity predicting fatigue indicated that these inflammation markers were stronger predictors of fatigue than GR sensitivity. Conclusions Lower increases in GR sensitivity during HNC treatment were significantly predictive of increased fatigue and inflammation markers. Inflammation markers in turn predicted fatigue above and beyond levels of GR sensitivity. Our findings indicate that HNC patients with cancer-related fatigue may exhibit a decreased capacity for glucocorticoids to regulate inflammatory processes, as evidenced by a lower increase in GR sensitivity. Larger studies are necessary to verify the findings.

Background We assessed locoregional control with omission of intentional primary site radiation after transoral robotic surgery (TORS) and quantified nontargeted primary site dose. Methods Following Institutional Review Board (IRB) approval, patients treated with primary TORS resection for squamous cell carcinomas of the oropharynx were reviewed. Patients with cT1-2 tumors, >2 mm margins, in whom the surgeon resected the primary without revising specimen-driven margins, qualified for omission of primary site radiation. Results From 2014 to 2019, 112 patients met criteria. Fifty-nine (52%) patients did not receive radiation targeting the primary site; of whom, 22 received no radiation. In this group, there were no local failures; mean age was 58 years and median follow-up was 25 months. Thirty-seven patients received adjuvant radiation targeting the neck, mean bystander dose to the primary site was 28.8 Gy (range, 13.3-50.6 Gy). Conclusion In a 59 patient population, omission of radiation to the primary site after TORS resulted in no locoregional failures.

Background: Metabolic differences between human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) and smoking-associated HNSCC may partially explain differences in prognosis. The former relies on mitochondrial oxidative phosphorylation (OXPHOS) while the latter relies on glycolysis. These differences have not been studied in blood. Methods: We extracted metabolites using untargeted liquid chromatography high-resolution mass spectrometry from pretreatment plasma in a cohort of 55 HPV-associated and 82 smoking-associated HNSCC subjects. Metabolic pathway enrichment analysis of differentially expressed metabolites produced pathway-based signatures. Significant pathways (P < 0.05) were reduced via principal component analysis and assessed with overall survival via Cox models. We classified each subject as glycolytic or OXPHOS phenotype and assessed it with survival. Results: Of 2,410 analyzed metabolites, 191 were differentially expressed. Relative to smoking-associated HNSCC, bile acid biosynthesis (P < 0.0001) and octadecatrienoic acid beta-oxidation (P = 0.01), were upregulated in HPV-associated HNSCC, while galactose metabolism (P = 0.001) and vitamin B6 metabolism (P = 0.01) were downregulated; the first two suggest an OXPHOS phenotype while the latter two suggest glycolytic. First principal components of bile acid biosynthesis [HR = 0.52 per SD; 95% confidence interval (CI), 0.38–0.72; P < 0.001] and octadecatrienoic acid beta-oxidation (HR = 0.54 per SD; 95% CI, 0.38–0.78; P < 0.001) were significantly associated with overall survival independent of HPV and smoking. The glycolytic versus OXPHOS phenotype was also independently associated with survival (HR = 3.17; 95% CI, 1.07–9.35; P = 0.04). Conclusions: Plasma metabolites related to glycolysis and mitochondrial OXPHOS may be biomarkers of HNSCC patient prognosis independent of HPV or smoking. Future investigations should determine whether they predict treatment efficacy. Impact: Blood metabolomics may be a useful marker to aid HNSCC patient prognosis.

PURPOSE: Epigenetic age acceleration (EAA) is robustly linked with mortality and morbidity. This study examined risk factors of EAA and its association with overall survival (OS), progression-free survival (PFS), and quality of life (QOL) in patients with head and neck cancer (HNC) receiving radiotherapy. METHODS AND MATERIALS: Patients without distant metastasis were enrolled and followed before and end of radiotherapy, and 6-months and 12-months post-radiotherapy. EAA was calculated with DNAmPhenoAge at all four times. Risk factors included demographics, lifestyle, clinical characteristics, treatment-related symptoms, and blood biomarkers. Survival data were collected until August 2020; QOL was measured using Functional Assessment of Cancer Therapy–HNC. RESULTS: Increased comorbidity, HPV-unrelated, and severer treatment-related symptoms were associated with higher EAA (p=0.03 to

Background and PurposeTo compare the effects of missing-data imputation techniques, mean imputation, group mean imputation, regression imputation, and multiple imputation (MI), on the results of exploratory factor analysis under different missing assumptions.MethodsMissing data with different missing assumptions were generated from true data. The quality of imputed data was examined by correlation coefficients. Factor structures were compared indirectly by coefficients of congruence and directly by factor structures.ResultsMI had the best quality and matching factor structure to the true data for all missing assumptions with different missing rates. Mean imputation had the least favorable results in factor analysis. The imputation techniques revealed no important differences with 10% of data missing.ConclusionMI showed the best results, especially with larger proportions of missing data.

Purpose/objective(s) Clinical outcomes for limited stage small cell lung cancer (LS-SCLC) remain suboptimal. Standard of care chemoradiation with platinum/etoposide and thoracic radiation to 45 Gy delivered twice daily followed by prophylactic cranial irradiation yields a median overall survival of 30 months. LU005 is a randomized phase II/III trial designed to test the addition of atezolizumab to concurrent chemoradiation. Materials/methods Patients with LS-SCLC (Tx-T4, N0-N3, M0) are randomly assigned in a 1:1 ratio to either standard chemoradiation, consisting of thoracic radiation (45 Gy twice daily or 66 Gy daily) with concurrent platinum/etoposide chemotherapy, or the experimental arm, consisting of the same chemoradiation regimen plus the addition of atezolizumab delivered concurrently with thoracic radiation, every 3 weeks for 12 months duration. Thoracic radiation begins with the second cycle of chemotherapy in both treatment arms. Stratification variables include radiation schedule (once daily vs. twice daily), chemotherapy (cisplatin vs. carboplatin), gender, and performance status (PS 0/1 vs. 2). Prophylactic cranial radiation is recommended for patients who have a response to treatment. The phase II primary endpoint is progression free survival (PFS) and the phase III primary endpoint is overall survival (OS). The overall sample size for phase II/III will be 506. Secondary endpoints include objective response rates, local control, distant metastases free, and quality of life. Correlative studies will include blood and tissue based tumor mutational burden analysis, with the hypothesis that higher mutational burden will predict for improved PFS in the experimental arm. Results As of 3/01/2021, 374 sites are approved to enroll patients. Two-hundred patients have been accrued. Current enrollment is ahead of projected accrual. Conclusion LU005 is a randomized II/III trial testing the addition of atezolizumab to standard chemoradiation for LS-SCLC. Accrual remains robust in spite of the ongoing COVID 19 pandemic. Funding This project was supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech.

Purpose/objective(s) Established risk factors for head and neck cancer recurrence include clinical and tumor features assessed prior to treatment. We report the first use of DNA methylation in peripheral blood before and after radiotherapy (RT) to further improve risk stratification. Materials/methods Peripheral blood samples were obtained from patients with non-metastatic squamous cell carcinoma (SCC) of the head and neck for methylation analysis, 1 week before initiation and 1 month after completion of RT. Patients were randomized to a discovery cohort or validation cohort. In the discovery cohort, associations between methylation change at 807,100 genomic sites (post-treatment minus pre-treatment) and progression-free survival (PFS) as well as overall survival (OS) were evaluated using Cox regression, adjusted for clinicopathologic covariates. A risk score (RS) was then constructed from methylation levels at the top associated sites, filtered for residing within regulatory elements of genes that are predominantly expressed in bone marrow, lymphoid tissue, or blood cells. The prognostic value of RS was separately assessed in the discovery cohort and validation cohort. Results Between December 2013 and September 2018, 115 patients enrolled in this study (Table) and consist of mostly males (72%) with locally advanced disease (91%). HPV negative status, oral cavity cancer, PEG tube insertion, and higher neutrophil count before RT were associated with shorter PFS and OS (P 10, P = 0.016) and OS (HR > 10, P = 0.017) in the discovery cohort, independent of the aforementioned risk factors. These findings were further replicated in the validation cohort where high RS also independently conferred poorer PFS (HR > 10, P = 0.002) and OS (HR 6.3, P = 0.015). Conclusion We successfully trained and validated a signature of DNA methylation in peripheral blood before and after RT that stratified outcomes among patients with head and neck SCC, implicating the potential for genomics-tailored consolidation treatment and surveillance. Efforts toward methylation analysis at additional post-treatment time points are ongoing.

Objectives: Patients with head and neck cancer experience neuropsychological symptoms (NPS) (i.e., depression, fatigue, sleep disturbance, pain, and cognitive dysfunction) during radiation therapy (RT) that decrease their functional status and quality of life. The purposes of this study were to examine and visualize the relationships among NPS within networks over time and evaluate demographic and clinical characteristics associated with symptom networks. Methods: A total of 192 patients (mean age 59.5±10.1 years, 75% male, 81% White) completed symptom questionnaires four times, namely, before RT (T1), 1 month (T2), 3 months (T3), and 1 year (T4) after RT. Network analysis was used to explore relationships among the five common NPS. Centrality indices, including strength, closeness, and betweenness, were used to describe the degrees of symptom interconnection. The network comparison test was used to assess the differences between two symptom networks. Results: Depression (reported by 13%-24% of patients) was associated with the other four symptoms, and fatigue (reported by 54%-77% of patients) was associated with the other three symptoms across four times. Based on centrality indices, depression (rstrength=1.1-1.4, rcloseness=0.07-0.08, rbetweeness=4-12) was the most central symptom in all four symptom networks, followed by fatigue (rstrength=0.8-1.0, rcloseness=0.05-0.06, rbetweeness=0-2). Higher levels of stress and no alcohol use were associated with stronger symptom networks in network global strength (low stress: 1.49 vs. moderate to high stress: 1.92; p=0.02; no alcohol use: 2.38 vs. alcohol use: 1.75; p=0.01), but not in network structure or edge strength prior to RT. No significant differences were found in other time points. Conclusions: Network analysis provided a novel approach to gain insights into the relationships of co-occurring NPS and identify central symptoms and associated characteristics. Clinicians can use this information to develop personalized symptom management interventions that target central symptoms and interactions within a network. Citation Format: Yufen Lin, Deborah W. Bruner, Sudeshna Paul, Andrew H. Miller, Nabil F. Saba, Kristin A. Higgins, Dong M. Shin, Wenhui Zhang, Christine Miaskowski, Canhua Xiao. Neuropsychological symptoms in patients with head and neck cancer undergoing radiation therapy: A network analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 500.

Colorectal cancer (CRC) survivors are living longer; therefore, factors that improve outcomes, like symptom management and quality of life (QoL), have increasingly become important. This study examined CRC survivors' symptom(s) characteristics, positive psychology (benefit finding and post-traumatic growth), and QoL, and determined whether positive psychology mediates symptom(s) and QoL relationship during acute cancer survivorship.A cross-sectional study of 117 CRC survivors was conducted at a National Cancer Institute-Designated Cancer Center. Data were collected by demographic questionnaire, Therapy-Related Symptom Checklist, QoL Inventory, and positive psychology assessed by Carver Benefit-Finding Scale and Post-Traumatic Growth Inventory. Descriptive statistics, between-group differences, multiple linear regression, and mediation analyses were performed.Top common symptoms were peripheral neuropathy, fatigue/feeling sluggish, skin changes, sleep disturbances, and weakness. Psychological distress symptoms were reported in 38.46% of CRC survivors, and moderate-to-high positive psychology (3.21 ± 1.09) and QoL (5.15 ±0 .52) levels were reported during acute cancer survivorship. Significant (p 0.05) relationships were observed between QoL and (a) number of symptoms, (b) psychological distress symptoms, (c) benefit finding, (d) post-traumatic growth, and (e) positive psychology. Positive psychology partially mediated the relationship between symptom frequency and QoL (p 0.05).Our study's findings suggest that CRC survivors positively cope with their cancer and treatment, and positive psychology partially mediates the relationship between symptoms frequency (almost daily and daily vs. random) and QoL across acute cancer survivorship. Identifying how CRC survivors adjust to their cancer may help healthcare teams provide tailored self-management skills to promote QoL and reduce symptom burden throughout cancer survivorship.

Introduction Sleep disturbance is a prominent concern in patients with cancer with detrimental effect on health outcomes. Although inflammation has been proposed as a potential mechanism of sleep disturbance, there is a dearth of longitudinal data supporting the relationship between cancer-related sleep disturbance and inflammatory markers. The goal of this prospective longitudinal study was to examine the change in sleep quality and its association with inflammatory markers in patients undergoing radiation therapy for head and neck cancer. Methods A total of 176 patients who had head and neck cancer without distant metastases were assessed before, immediately after, and at 3 and 12 months after radiotherapy. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI). Peripheral blood inflammatory markers were measured using standard techniques at the same four assessment times. Generalized estimating equations with exchangeable within-subject correlation matrix were used to analyze repeated measures. Results The participants were mostly middle-aged White (79.5%) men (74.0%) who were married or living with significant others (70.0%) and received concurrent chemoradiotherapy (80.1%). Using the PSQI of 5 as the cut-off, 66.3% of the participants were poor sleepers at baseline, and this rate increased to 82.8% immediately after, then dropped to 56.8% at 3 months and 46.2% 12 months after therapy. Being single (p=0.007), taking antidepressants (p=0.020), and with feeding tube (p=0.01) were identified to be significantly associated with poor sleep quality over time. Controlling for relevant demographic and clinical factors, changes in sleep quality were associated with changes of circulating levels of two inflammatory markers, C-reactive protein (CRP) and interlukin-1 receptor antagonist (IL-1ra). Increased CRP and IL-1ra levels were associated with higher PSQI global scores (beta=0.826, p=0.007 for CRP; beta=1.412, p=0.050 for IL-1ra), indicating worse sleep quality. Conclusion Patients with head and neck cancer experienced poor sleep quality, especially immediately after treatment completion and in those who were single, depressed, or with feeding tube. Inflammation is associated with cancer-related sleep disturbance and both sleep and inflammation may be potential targets to promote health outcomes in patients with cancer. Support (If Any) The study was supported by NIH/NINR K99/R00NR014587, NIH/NINR R01NR015783, NIH/NCI P30CA138292.

BACKGROUND: With an expectation of excellent locoregional control, ongoing efforts to de-intensify therapy for patients with HPV associated squamous cell oropharyngeal cancer necessitate a better understanding of the metastatic risk for patients with this disease. The objective was to determine what factors affect the risk of metastases in patients with squamous cell cancers of the oropharynx METHODS: Under a shared use agreement, 547 RTOG 0129 and 0522 patients with non. metastatic oropharyngeal squamous cell cancers who had known p16 status and smoking status were analyzed to assess the association of clinical features with the development of distant metastases. Factors analyzed included p16 status, gender, T stage, N Stage, age, and smoking history. RESULTS: Multivariable analysis of 547 patients with a median follow-up of 4.6 years revealed that age ≥ 50 (HR=3.28, p=0.003), smoking > 0 pack-years (HR=3.09, p

PURPOSE: Recent evidence supports a key role of gut microbiome in brain health. We conducted a pilot study to assess associations of gut microbiome with cancer-related fatigue and explore the associations with DNA methylation changes. METHODS: Self-reported Multidimensional Fatigue Inventory and stool samples were collected at pre-radiotherapy and one-month post-radiotherapy in patients with head and neck cancer. Gut microbiome data were obtained by sequencing the 16S ribosomal ribonucleic acid gene. DNA methylation changes in the blood were assessed using Illumina Methylation EPIC BeadChip. RESULTS: We observed significantly different gut microbiota patterns among patients with high vs. low fatigue across time. This pattern was characterized by low relative abundance in short-chain fatty acid—producing taxa (family Ruminococcaceae, genera Subdoligranulum and Faecalibacterium, all p < 0.05), with high abundance in taxa associated with inflammation (genera Family XIII AD3011 and Erysipelatoclostridium; all p < 0.05) for high-fatigue group. We identified nine KEGG Orthology pathways significantly different between high- vs. low-fatigue groups over time (all p < 0.001), including pathways related to fatty acid synthesis and oxidation, inflammation, and brain function. Gene set enrichment analysis (GSEA) was performed on the top differentially methylated CpG sites that were associated with the taxa and fatigue. All biological processes from the GSEA were related to immune responses and inflammation (FDR < 0.05). CONCLUSIONS: Our results suggest different patterns of the gut microbiota in cancer patients with high vs. low fatigue. Results from functional pathways and DNA methylation analyses indicate that inflammation is likely to be the major driver in the gut-brain axis for cancer-related fatigue.

Most survivors of childhood cancer experience subsequent chronic conditions but little is known about concurrent symptoms. This study seeks to identify late effect symptom clusters among young pediatric cancer survivors. Survivors ≥ 18 or parents of survivors

Simple Summary Patients with head and neck cancers (HNCs) report a cluster of psychoneurological symptoms (i.e., the PNS cluster), including pain, fatigue, sleep disturbance, depressive symptoms, and cognitive dysfunction across different treatments. The aim of this longitudinal study was to examine associations between the gut microbiome and the PNS cluster in 13 patients with HNCs pre- and post-radiotherapy. Patients with the high PNS cluster showed a greater decrease in microbial evenness than those with the low PNS cluster from pre- to post-radiotherapy. The high and low PNS clusters showed significant gut microbiome dissimilarities. Patients with the high PNS cluster had higher abundances of Bacteroidetes, Ruminiclostridium9, Tyzzerella, Eubacterium_fissicatena, and DTU089. Patients with the low PNS cluster had higher abundances in Lactococcus, Phascolarctobacterium, and Desulfovibrio. Glycan metabolism and vitamin metabolism were different between the high and low PNS clusters pre- and post-radiotherapy. Abstract Cancer patients experience a cluster of co-occurring psychoneurological symptoms (PNS) related to cancer treatments. The gut microbiome may affect severity of the PNS via neural, immune, and endocrine signaling pathways. However, the link between the gut microbiome and PNS has not been well investigated in cancer patients, including those with head and neck cancers (HNCs). This pilot study enrolled 13 patients with HNCs, who reported PNS using the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (CTCAEs). Stool specimens were collected to analyze patients’ gut microbiome. All data were collected pre- and post-radiation therapy (RT). Associations between the bacterial abundances and the PNS clusters were analyzed using the linear discriminant analysis effect size; functional pathway analyses of 16S rRNA V3-V4 bacterial communities were conducted using Tax4fun. The high PNS cluster had a greater decrease in microbial evenness than the low PNS cluster from pre- to post-RT. The high and low PNS clusters showed significant differences using weighted UniFrac distance. Those individuals with the high PNS cluster were more likely to have higher abundances in phylum Bacteroidetes, order Bacteroidales, class Bacteroidia, and four genera (Ruminiclostridium9, Tyzzerella, Eubacterium_fissicatena, and DTU089), while the low PNS cluster had higher abundances in family Acidaminococcaceae and three genera (Lactococcus, Phascolarctobacterium, and Desulfovibrio). Both glycan metabolism (Lipopolysaccharide biosynthesis) and vitamin metabolism (folate biosynthesis and lipoic acid metabolism) were significantly different between the high and low PNS clusters pre- and post-RT. Our preliminary data suggest that the diversity and abundance of the gut microbiome play a potential role in developing PNS among cancer patients.

Jiewei Chen,1,2,* Qingmei He,2,* Jun Liu,1,2,* Yongbo Xiao,1 Canhua Xiao,3 Keming Chen,1 Dan Xie,1,2 Xinke Zhang1,2 1Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, People’s Republic of China; 3Department of Pathology, Qingyuan People’s Hospital, Qingyuan, 511581, People’s Republic of China *These authors contributed equally to this work Purpose: The aim of this study was to investigate the degree of infiltration of CD8+ tumor-infiltrating lymphocytes (TILs) including high and low density in lung sarcomatoid carcinoma (LSC) and their clinicopathological significance.Patients and methods: The density of CD8+ TILs in paraffin-embedded tissue sections from 100 LSC patients was detected by immunohistochemical staining, and the relationship of CD8+ TILs with clinicopathological features and prognosis was analyzed.Results: The chi-squared test showed that the degree of infiltration of CD8+ TILs was significantly correlated with the clinicopathological stage and T stage of LSC (P

This pilot study examined whether a combined aerobic resistance exercise program reduced fatigue and the potential inflammatory and epigenetic mechanisms in patients with head and neck cancer (HNC) receiving intensity-modulated radiotherapy. The exercise group (N=12) received a 3-month supervised aerobic resistance exercise intervention that was initiated before a 6-week radiotherapy regimen; the control group (N=14) received standard care. Fatigue was measured using Multidimensional Fatigue Inventory-20; physical function measures included a 6-minute walk distance (6MWD), chair stands, bicep curls, and hand grip strength. Inflammatory markers and DNA methylation data were acquired using standardized protocol. Patients were mostly white (93%) and male (81%) with a mean age of 57 years. At the end of the intervention, the exercise group had a marginal decrease in fatigue compared with the control (−5.0 vs. 4.9; P = 0.10). The exercise group had a significantly greater improvement in 6MWD (29.8 vs. −55.5 meters; P = 0.04), and a marginally smaller decline in hand grip (−0.3 vs. −5.8 lbs; P = 0.05) at the end of the intervention than the control. No significant difference in inflammatory markers was observed between groups. Lower plasma interleukin (IL) 6, IL1 receptor antagonist, tumor necrosis factor α (TNFα), soluble TNF receptor II and C-reactive protein were significantly associated with increased 6MWD, chair stand, and bicep curl at the end of the intervention (p

BACKGROUND Human papillomavirus (HPV) infection has contributed to an increased incidence of squamous cell carcinoma of the head and neck (SCCHN). Fatigue is a major side effect of SCCHN and its treatment. However, to the authors' knowledge, the association between HPV and fatigue has not been examined to date, nor is it known whether HPV influences biological mechanisms of fatigue, including inflammation. METHODS Patients with SCCHN who were without distant metastasis were assessed at baseline (pre-radiotherapy) and 1 month and 3 months postradiotherapy. Fatigue was measured using the Multidimensional Fatigue Inventory. Peripheral inflammation was assessed by plasma C-reactive protein (CRP), interleukin 1 receptor antagonist (IL-1ra), soluble tumor necrosis factor receptor 2 (sTNFR2), and IL-6. Mixed effect models were used to examine associations. RESULTS A total of 94 patients who were newly diagnosed were enrolled; 53% had HPV-related tumors. Patients with HPV-unrelated tumors had higher fatigue and higher plasma CRP, sTNFR2, and IL-6 over time, especially at baseline and 3 months after intensity-modulated radiotherapy compared with those with HPV-related tumors (all P

Radiation (RT) dose to the central nervous system (CNS) has been implicated as a contributor to treatment-related fatigue in head and neck cancer (HNC) patients undergoing radiation therapy (RT). This study evaluates the association of RT dose to CNS structures with patient-reported (PRO) fatigue scores in a population of HNC patients.At pre-RT (baseline), 6th week of RT, and 1-month post-RT time points, Multidimensional Fatigue Inventory (MFI-20) scores were prospectively obtained from 124 patients undergoing definitive treatment for HNC. Medulla, pons, midbrain, total brainstem, cerebellum, posterior fossa, and pituitary dosimetry were evaluated using summary statistics and dose-volume histograms, and associations with MFI-20 scores were analyzed.Maximum dose (Dmax) to the brainstem and medulla was significantly associated with MFI-20 scores at 6th week of RT and 1-month post-RT time points, after controlling for baseline scores (p0.05). Each 1Gy increase in medulla Dmax resulted in an increase in total MFI-20 score over baseline of 0.30 (p=0.026), and 0.25 (p=0.037), at the 6th week of RT and 1-month post-RT, respectively. Each 1Gy increase in brainstem Dmax resulted in an increase in total MFI-20 score over baseline of 0.30 (p=0.027), and 0.25 (p=0.037) at the 6th week of RT, 1-month post-RT, respectively. Statistically significant associations were not found between dosimetry for the other CNS structures and MFI-20 scores.In this analysis of PRO fatigue scores from a population of patients undergoing definitive RT for HNC, maximum dose to the brainstem and medulla was associated with a significantly increased risk of acute patient fatigue.

BackgroundPsychosocial and inflammatory factors have been associated with fatigue in breast cancer survivors. Nevertheless, the relative contribution and/or interaction of these factors with cancer-related fatigue have not been well documented.MethodThis cross-sectional study enrolled 111 stage 0–III breast cancer patients treated with breast surgery followed by whole breast radiotherapy. Fatigue was measured by the total score of the Multidimensional Fatigue Inventory-20. Potential risk factors included inflammatory markers (plasma cytokines and their receptors and C-reactive protein; CRP), depressive symptoms (as assessed by the Inventory of Depressive Symptomatology–Self Reported), sleep (as assessed by the Pittsburgh Sleep Quality Index) and perceived stress (as assessed by the Perceived Stress Scale) as well as age, race, marital status, smoking history, menopause status, endocrine treatment, chemotherapy and cancer stage. Linear regression modeling was employed to examine risk factors of fatigue. Only risk factors with a significance level post-hoc mediation model using PROCESS SPSS was conducted to examine the association among depressive symptoms, sleep problems, stress, inflammation and fatigue.ResultsAt 1 year post-radiotherapy, depressive symptoms (pp = 0.015; interleukin-1 receptor antagonist: p = 0.014; soluble tumor necrosis factor receptor-2: p = 0.009 in separate models) were independent risk factors of fatigue. Mediation analysis showed that depressive symptoms also mediated the associations of fatigue with sleep and stress.ConclusionsDepressive symptoms and inflammation were independent risk factors for cancer-related fatigue at 1 year post-radiotherapy, and thus represent independent treatment targets for this debilitating symptom.

Background Is posttreatment functional status prognostic of overall survival in patients with head and neck cancer (HNC). Methods In an HNC clinical trial, 495 patients had two posttreatment functional assessments measuring diet, public eating, and speech within 6 months. Patients were grouped by impairment (highly, moderately, modestly, or not impaired) and determined if they improved, declined, or did not change from the first assessment to the second. Multivariable Cox models estimated overall mortality. Results Across all three scales, the change in posttreatment patient function strongly predicted overall survival. In diet, patients who declined to highly impaired had three times the mortality of patients who were not impaired at both assessments (hazard ratio [HR] = 3.60; 95% confidence interval, 2.02-6.42). For patients improving from highly impaired, mortality was statistically similar to patients with no impairment (HR = 1.38; 95% CI, 0.82-2.31). Conclusions Posttreatment functional status is a strong prognostic marker of survival in patients with HNC.

Fatigue is one of the most prevalent and debilitating symptoms that breast cancer patients experience. Cancer-related fatigue (CRF) can persist for many years after treatment has ended, and it is not relieved by either rest or sleep. Fatigue negatively affects quality of life and physical function and may result in decreased adherence to medical treatment. Increasing evidence shows that fatigue is prognostic of survival. In this chapter, we discuss the prevalence, biological mechanisms, and predictors of fatigue in women with breast cancer who receive radiotherapy. The impact of radiation dose and modality on the development of fatigue, as well as interventions for fatigue, are also reviewed.

Background: Human papillomavirus (HPV) status and tobacco use are the strongest prognostic factors of survival for squamous cell carcinoma of the head and neck (SCCHN). Patients with HPV-related SCCHN live more than twice as long as patients with tobacco-related SCCHN. The underlying metabolic dysregulation characterizing these two clinically distinct groups may pose exciting translational targets that are yet unknown. Using a metabolome-wide approach, we investigated the metabolic differences of HPV vs smoking-related SCCHN in a large patient population. We then linked those metabolic differences to patient survival. Methods: We recruited 137 patients from Emory University hospitals and clinics: 55 HPV-positive never smokers (i.e., HPV-related SCCHN) and 82 HPV-negative current or former smokers (i.e., smoking-related SCCHN). We performed untargeted high-resolution metabolomics using liquid chromatography-mass spectrometry on pre-treatment patient plasma at the Emory Clinical Biomarkers Laboratory. Our statistical approach has three steps. 1) Metabolite feature selection: We aggregated the results from two selection algorithms (5-fold cross-validated partial least squares discriminant analysis and support vector machine) to determine the metabolites that differentiated HPV vs smoking-related SCCHN. 2) Metabolic pathway analysis (Mummichog): We identified statistically significant (P Citation Format: Ronald C. Eldridge, Karan Uppal, Jonathan Beitler, Kristin Higgins, Evanthia C. Wommack, Dong M. Shin, Nabil F. Saba, Andrew Miller, Deborah W. Bruner, Canhua Xiao. Metabolic differences between human papillomavirus-related and smoking-related squamous cell carcinoma of the head and neck independently predict overall patient survival [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-033.

Purpose: The purpose of this study was to examine the impact of radiation therapy on quality of life (QOL) of breast cancer patients during and until 1 year after radiation therapy treatment. Methods and materials: Thirty-nine breast cancer patients treated with breast-conserving surgery were enrolled in a prospective study before whole breast radiation therapy (50 Gy plus a 10-Gy boost). No patient received chemotherapy. Data were collected before, at week 6 of radiation therapy, and 6 weeks and 1 year after radiation therapy. The primary outcome variable was quality of life (QOL), measured by Medical Outcomes Study 36-Item Short Form Version 2 (SF-36). Risk factors potentially associated with total SF-36 scores and its physical and mental health component summary scores were also examined, including age, race, marital status, smoking history, menopausal status, endocrine treatment, cancer stage, sleep abnormalities (assessed by the Pittsburgh Sleep Quality Index), and perceived stress levels (assessed by the Perceived Stress Scale). Mixed effect modeling was used to observe QOL changes during and after radiation therapy. Results: Total SF-36 scores did not change significantly during and up to 1 year after radiation therapy compared with baseline measures. Nevertheless, increased body mass index (BMI) and increased perceived stress were predictive of reduced total SF-36 scores over time (P = .0064, and P < .0001, respectively). In addition, increased BMI was predictive of reduced physical component summary scores of the SF-36 (P = .0011), whereas increased perceived stress was predictive of worse mental component summary scores (P < .0001). Other proposed potential risk factors including skin toxicity from radiation therapy were not significant. Conclusions: Radiation therapy did not worsen QOL in breast cancer patients. However, pre-radiation therapy patient characteristics including BMI and perceived stress may be used to identify women who may experience decreased physical and mental function during and up to 1 year after radiation therapy.

Patients with head and neck cancer (HNC) receiving intensity-modulated radiation therapy (IMRT) have particularly high rates of fatigue, and pre- and post-radiotherapy fatigue are prognostic factors for pathologic tumor responses and poor survival. Although inflammation has been proposed as one of the potential mechanisms of fatigue in cancer patients, findings have not been consistent, and there is a dearth of longitudinal studies. Accordingly, we conducted a prospective study in 46 HNC patients pre- and one-month post-IMRT. Fatigue was measured by the Multidimensional Fatigue Inventory (MFI)-20 at both time points along with the assessment of peripheral blood inflammatory markers including interleukin (IL)-6, soluble tumor necrosis factor receptor 2, and C-reactive protein (CRP) and gene expression. Generalized estimating equations were used to examine the association between inflammatory markers and fatigue. Gene enrichment analysis using MetaCore software was performed using up-regulated genes that were significantly associated with IMRT and fatigue. Significant associations between fatigue and IL-6 as well as CRP, which were independent of time, were observed. In addition the change in fatigue from pre- to post-IMRT was positively associated with the change in IL-6 and CRP. Analysis of up-regulated gene transcripts as a function of IMRT and fatigue revealed overrepresentation of transcripts related to the defense response and nuclear factor kappa B. In conclusion, our findings support the hypotheses that inflammation is associated with fatigue over time in HNC patients. Future studies on how inflammation contributes to fatigue as well as strategies targeting inflammation to reduce fatigue are warranted.

TPS9082 Background: Limited stage small cell lung cancer (LS-SCLC) is treated with standard of care platinum/etoposide (EP) and thoracic radiation therapy (TRT) with curative intent, however the majority of patients are not cured and median overall survival is approximately 30 months. Addition of atezolizumab to chemotherapy in extensive stage SCLC has improved progression free and overall survival in a non-curative setting leading to hope that addition of an immune checkpoint inhibitor to standard chemoradiotherapy could benefit LS-SCLC patients. LU005 is a randomized phase II/III trial of standard concurrent chemoradiation with or without atezolizumab for patients with LS-SCLC. Methods: Patients are randomly assigned in a 1:1 ratio to standard EP chemotherapy with concurrent TRT (45 Gy BID or 66 Gy QD) with or without atezolizumab beginning concurrently with TRT, and continued every 3 weeks for up to 12 months. Eligible patients have LS-SCLC, PS 0-2, adequate organ function, no concerning comorbidities (including no active autoimmune disease) and are eligible for TRT. Patients are randomized prior to their second cycle of EP and thoracic radiation begins with the second overall cycle of chemotherapy (first cycle of study therapy) in both treatment arms. Prophylactic cranial radiation (PCI) is recommended for patients who respond to treatment. The phase II/III primary endpoints are progression free (PFS) and overall survival (OS) respectively. Secondary endpoints include objective response rates, local and distant disease control, and quality of life/patient reported outcomes assessment. Translational science component includes blood and tissue based immune related assays. This study activated in May 2019. 50 of 506 planned patients have been accrued as of 2/1/2020. Supported by grants U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U23CA180803 (IROC) from the National Cancer Institute (NCI) and Genentech. *Authors Ross and Higgins are co-first authors and contributed equally to this work. Clinical trial information: NCT03811002.

Purpose: A meta-analysis of sociodemographic variables and their association with late (>180 days from start of radiation therapy[RT]) bowel, bladder, and clustered bowel and bladder toxicities was conducted in patients with high-risk (clinical stages T2c-T4b or Gleason score 8-10 or prostate-specific antigen level >20) prostate cancer. Methods and materials: Three NRG trials (RTOG 9202, RTOG 9413, and RTOG 9406) that accrued from 1992 to 2000 were used. Late toxicities were measured with the Radiation Therapy Oncology Group Late Radiation Morbidity Scale. After controlling for study, age, Karnofsky Performance Status, and year of accrual, sociodemographic variables were added to the model for each outcome variable of interest in a stepwise fashion using the Fine-Gray regression models with an entry criterion of 0.05. Results: A total of 2432 patients were analyzed of whom most were Caucasian (76%), had a KPS score of 90 to 100 (92%), and received whole-pelvic RT+HT (67%). Of these patients, 13 % and 16% experienced late grade ≥2 bowel and bladder toxicities, respectively, and 2% and 3% experienced late grade ≥3 bowel and bladder toxicities, respectively. Late grade ≥2 clustered bowel and bladder toxicities were seen in approximately 1% of patients and late grade ≥3 clustered toxicities were seen in 2 patients (

Purpose A preliminary report of patient reported outcomes (PROs) between men receiving high-dose radiation therapy (RT) on RTOG 0126, a phase III dose-escalation trial treated with either 3-dimensional conformal RT (3D-CRT) or intensity modulated RT (IMRT).

An overview of proceedings, findings, and recommendations from the workshop on "Advancing Symptom Science Through Symptom Cluster Research" sponsored by the National Institute of Nursing Research (NINR) and the Office of Rare Diseases Research, National Center for Advancing Translational Sciences, is presented. This workshop engaged an expert panel in an evidenced-based discussion regarding the state of the science of symptom clusters in chronic conditions including cancer and other rare diseases. An interdisciplinary working group from the extramural research community representing nursing, medicine, oncology, psychology, and bioinformatics was convened at the National Institutes of Health. Based on expertise, members were divided into teams to address key areas: defining characteristics of symptom clusters, priority symptom clusters and underlying mechanisms, measurement issues, targeted interventions, and new analytic strategies. For each area, the evidence was synthesized, limitations and gaps identified, and recommendations for future research delineated. The majority of findings in each area were from studies of oncology patients. However, increasing evidence suggests that symptom clusters occur in patients with other chronic conditions (eg, pulmonary, cardiac, and end-stage renal disease). Nonetheless, symptom cluster research is extremely limited and scientists are just beginning to understand how to investigate symptom clusters by developing frameworks and new methods and approaches. With a focus on personalized care, an understanding of individual susceptibility to symptoms and whether a "driving" symptom exists that triggers other symptoms in the cluster is needed. Also, research aimed at identifying the mechanisms that underlie symptom clusters is essential to developing targeted interventions.

In this article, we address statistical techniques appropriate for examining longitudinal changes in cancer symptom clusters. When the cluster structure is not pre-determined, researchers may examine symptom clusters either at each time point or use composite scores to examine the symptom clusters across time points. When the cluster structures are pre-determined, the statistical techniques depend on the research assumptions or purposes. Multilevel modeling, generalized estimating equations, latent growth curve modeling, and multivariate repeated-measure analysis of variance are good choices for exploring whole cluster changes over time. Alternately, confirmatory factor analysis and path analysis are appropriate techniques for examining changes in symptom relationships within clusters over time. Each technique is described, with examples and strengths and weaknesses.

Purpose: Cancer mortality is estimated using underlying cause of death. For instance, to estimate the risk of head and neck cancer (HNC) mortality attributed to smoking, ‘death by HNC’ is the outcome (ie, smoking → HNC death). This conventional approach has notable flaws. It relies on accurate reporting on cause of death, a potential source of misclassification, and it excludes any mortality effects in cancer patients who die from other causes, a potential source of selection bias. Regarding HNC, 80% of all patients are excluded using this approach. These potential biases may result in underestimating cancer mortality from important public health factors such as smoking, obesity and physical activity. To overcome these biases, we are proposing a new approach to estimate cancer mortality. The method uses a causal mediation model and we demonstrate it in a smoking and HNC example. Methods: The model estimates cancer mortality through a mediated pathway. In our example, smoking is the exposure, incident HNC is the mediator, and all-cause mortality is the outcome (smoking → HNC incidence → all deaths). The mediated effect is the risk of mortality attributed to HNC, which in turn, is attributed to smoking. We compare the results in the mediation model to the conventional approach using Aalen’s additive hazards, which estimates the absolute increase in deaths in smokers compared to non-smokers; the mediation model also uses logistic regression for the HNC mediator. Both models are adjusted for age, sex, race, body mass index, diet, alcohol use, physical activity, marital status, education, and reported health. We used the NIH-AARP Diet and Health cohort, which has smoking information at baseline, and cancer incidence and mortality during follow-up on 518,100 U.S. subjects. Results: In the study, 2,279 subjects developed HNC during follow-up, among whom, 508 (22%) died from HNC; 125,442 subjects died from any cause. Under the conventional method, 11.0 more deaths (per 100,000 person-years) are attributed to HNC from current smokers relative to never smokers (95% CI: 8.0, 13.9); 1.8 deaths in former smokers (95% CI: 0.4, 3.2). Under the mediation method, 13.4 more deaths are attributed to HNC from current smokers relative to never smokers (95% CI: 9.3, 16.8); 2.2 deaths in former smokers (95% CI: 1.2, 3.4). Comparing the two estimates, the conventional approach underestimates HNC mortality attributed to smoking by 18%. Noteworthy, the underestimate for current smokers manifests primarily in men, while the underestimate for former smokers manifests primarily in women. Conclusions: The mediation method overcomes limitations in prior approaches of cancer mortality. In our example, the method estimated a stronger effect on HNC mortality by smoking. Further study is warranted as published estimates of cancer mortality by notable public health risk factors (eg, smoking, obesity, physical activity) may be underestimating their impact. Citation Format: Ronald C. Eldridge, W. Dana Flanders, Colin Adler, Deborah W. Bruner, Canhua Xiao. Are we underestimating cancer mortality? A mediation model shows a larger impact from smoking [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2418.