Falls prechemotherapy and toxicity-related hospitalization during adjuvant chemotherapy for breast cancer in older women: Results from the prospective multicenter HOPE trial.

BACKGROUND: Older women with breast cancer frequently experience toxicity-related hospitalizations during adjuvant chemotherapy. Although the geriatric assessment can identify those at risk, its use in clinic remains limited. One simple, low-cost marker of vulnerability in older persons is fall history. Here, the authors examined whether falls prechemotherapy can identify older women at risk for toxicity-related hospitalization during adjuvant chemotherapy for breast cancer. METHODS: In a prospective study of women >65 years old with stage I-III breast cancer treated with adjuvant chemotherapy, the authors assessed baseline falls in the past 6 months as a categorical variable: no fall, one fall, and more than one fall. The primary end point was incident hospitalization during chemotherapy attributable to toxicity. Multivariable logistic regression was used to examine the association between falls and toxicity-related hospitalization, adjusting for sociodemographic, disease, and geriatric covariates. RESULTS: Of the 497 participants, 60 (12.1%) reported falling before chemotherapy, and 114 (22.9%) had one or more toxicity-related hospitalizations. After adjusting for sociodemographic, disease, and geriatric characteristics, women who fell more than once within 6 months before chemotherapy had greater odds of being hospitalized from toxicity during chemotherapy compared to women who did not fall (50.0% vs. 20.8% experienced toxicity-related hospitalization, odds ratio, 4.38; 95% confidence interval, 1.66-11.54, p = .003). CONCLUSIONS: In this cohort of older women with early breast cancer, women who experienced more than one fall before chemotherapy had an over 4-fold increased risk of toxicity-related hospitalization during chemotherapy, independent of sociodemographic, disease, and geriatric factors.

Outcome prioritization and preferences among older adults with cancer starting chemotherapy in a randomized clinical trial.

INTRODUCTION: Older adults with cancer facing competing treatments must prioritize between various outcomes. This study assessed health outcome prioritization among older adults with cancer starting chemotherapy. METHODS: Secondary analysis of a randomized trial addressing vulnerabilities in older adults with cancer. Patients completed three validated outcome prioritization tools: 1) Health Outcomes Tool: prioritizes outcomes (survival, independence, symptoms) using a visual analog scale; 2) Now vs. Later Tool: rates the importance of quality of life at three times-today versus 1 or 5 years in the future; and 3) Attitude Scale: rates agreement with outcome-related statements. The authors measured the proportion of patients prioritizing various outcomes and evaluated their characteristics. RESULTS: A total of 219 patients (median [range] age 71 [65-88], 68% with metastatic disease) were included. On the Health Outcomes Tool, 60.7% prioritized survival over other outcomes. Having localized disease was associated with choosing survival as top priority. On the Now vs. Later Tool, 50% gave equal importance to current versus future quality of life. On the Attitude Scale, 53.4% disagreed with the statement "the most important thing to me is living as long as I can, no matter what my quality of life is"; and 82.2% agreed with the statement "it is more important to me to maintain my thinking ability than to live as long as possible". CONCLUSION: Although survival was the top priority for most participants, some older individuals with cancer prioritize other outcomes, such as cognition and function. Clinicians should elicit patient-defined priorities and include them in decision-making.

External Validation of Risk Factors for Unplanned Hospitalization in Older Adults With Advanced Cancer Receiving Chemotherapy.

BACKGROUND: Older adults (age ≥65 years) receiving chemotherapy are at risk for hospitalization. Predictors of unplanned hospitalization among older adults receiving chemotherapy for cancer were recently published using data from a study conducted by the Cancer and Aging Research Group (CARG). Our study aimed to externally validate these predictors in an independent cohort including older adults with advanced cancer receiving chemotherapy. METHODS: This validation cohort included patients (n=369) from the GAP70+ trial usual care arm. Enrolled patients were aged ≥70 years with incurable cancer and were starting a new line of chemotherapy. Previously identified risk factors proposed by the CARG study were ≥3 comorbidities, albumin level <3.5 g/dL, creatinine clearance <60 mL/min, gastrointestinal cancer, ≥5 medications, requiring assistance with activities of daily activities (ADLs), and having someone available to take them to the doctor (ie, presence of social support). The primary outcome was unplanned hospitalization within 3 months of treatment initiation. Multivariable logistic regression was applied including the 7 identified risk factors. Discriminative ability of the fitted model was performed by calculating the area under the receiver operating characteristic (AUC) curve. RESULTS: Mean age of the cohort was 77 years, 45% of patients were women, and 29% experienced unplanned hospitalization within the first 3 months of treatment. The proportions of hospitalized patients with 0-3, 4-5, and 6-7 identified risk factors were 24%, 28%, and 47%, respectively (P=.04). Impaired ADLs (odds ratio, 1.76; 95% CI, 1.04-2.99) and albumin level <3.5 g/dL (odds ratio, 2.23; 95% CI, 1.37-3.62) were significantly associated with increased odds of unplanned hospitalization. The AUC of the model, including the 7 identified risk factors, was 0.65 (95% CI, 0.59-0.71). CONCLUSIONS: The presence of a higher number of risk factors was associated with increased odds of unplanned hospitalization. This association was largely driven by impairment in ADLs and low albumin level. Validated predictors of unplanned hospitalization can help with counseling and shared decision-making with patients and their caregivers. CLINICALTRIALS: gov identifier: NCT02054741.

Risk Factors for Hospitalizations Among Older Adults with Gastrointestinal Cancers.

BACKGROUND: Older adults (≥65 years) with gastrointestinal (GI) cancers who receive chemotherapy are at increased risk of hospitalization caused by treatment-related toxicity. Geriatric assessment (GA) has been previously shown to predict risk of toxicity in older adults undergoing chemotherapy. However, studies incorporating the GA specifically in older adults with GI cancers have been limited. This study sought to identify GA-based risk factors for chemotherapy toxicity-related hospitalization among older adults with GI cancers. PATIENTS AND METHODS: We performed a secondary post hoc subgroup analysis of two prospective studies used to develop and validate a GA-based chemotherapy toxicity score. The incidence of unplanned hospitalizations during the course of chemotherapy treatment was determined. RESULTS: This analysis included 199 patients aged ≥65 years with a diagnosis of GI cancer (85 colorectal, 51 gastric/esophageal, and 63 pancreatic/hepatobiliary). Sixty-five (32.7%) patients had ≥1 hospitalization. Univariate analysis identified sex (female), cardiac comorbidity, stage IV disease, low serum albumin, cancer type (gastric/esophageal), hearing deficits, and polypharmacy as risk factors for hospitalization. Multivariable analyses found that patients who had cardiac comorbidity (OR 2.48, 95% CI 1.13-5.42) were significantly more likely to be hospitalized. CONCLUSION: Cardiac comorbidity may be a risk factor for hospitalization in older adults with GI cancers receiving chemotherapy. Further studies with larger sample sizes are warranted to examine the relationship between GA measures and hospitalization in this vulnerable population.

Patient-Defined Goals and Preferences Among Adults With Advanced Neuroendocrine Tumors.

BACKGROUND: Patient preferences (quantity vs quality of life; present vs future health) have not been investigated in patients with neuroendocrine tumors (NETs). The goal of this cross-sectional study was to evaluate patient values toward treatment goals and competing health outcomes among adults with NETs. PATIENTS AND METHODS: Patients with well-differentiated, grade 1 or 2, advanced NETs starting a new systemic therapy completed 4 tools: (1) Health Outcomes Tool, which ranks the importance of 4 outcomes (survival, function/independence, freedom from pain, freedom from symptoms); (2) Attitude Scale, which identifies the extent to which patients agree with statements related to health outcomes; (3) Now versus Later Tool, which ranks the relative importance of quality of life (QoL) now versus 1 and 5 years from now; and (4) Prognosis and Treatment Perceptions Questionnaire, which identifies the amount of information the patient prefers to receive about their disease and treatment, the patient's treatment goal, the patient's perception of the physician's treatment goal, and self-reported health status. RESULTS: We recruited 60 patients with NETs (50.0% aged ≥65 years; 96.7% with stage IV disease). Primary tumor locations included the gastrointestinal tract (41.7%), pancreas (30.0%), and lung (21.7%). A plurality of patients reported maintaining independence as their most important health outcome (46.7%), followed by survival (30.0%), freedom from pain (11.7%), and freedom from symptoms (11.7%). A total of 67% of patients agreed with the statement, "I would rather live a shorter life than lose my ability to take care of myself"; 85.0% agreed with the statement, "It is more important to me to maintain my thinking ability than to live as long as possible." When asked to choose between current QoL versus QoL 1 year or 5 years in the future as more important, 48.3% and 40.0% of patients valued their QoL 1 year and 5 years in the future, respectively, more than their current QoL. Only 51.7% of patients believed their physician's treatment goals aligned with their own. CONCLUSIONS: Adult patients with NETs strongly value independence over survival. More communication between patients with NETs and their physicians is needed to ensure that patient preferences are incorporated into treatment plans.

Cross-sectional clinical cancer genomics community of practice survey analysis of provider attitudes and beliefs regarding the use of deceased family member tissue to guide living family member genetic cancer risk assessment.

Next-generation tumor tissue sequencing techniques may result in the detection of putative germline pathogenic variants (PVs), raising the possibility that germline cancer predisposition could be identified from archival medical tissue samples of deceased relatives. The approach, termed traceback, is designed to inform risk management recommendations for living family members. Provider perspectives regarding traceback testing have not yet been explored, so we conducted a cross-sectional survey of Clinical Cancer Genomics Community of Practice providers regarding their attitudes and beliefs toward traceback testing. Self-reported demographics, provider characteristics, attitudes and perceived barriers were collected. We evaluated responses in the context of whether providers had previous experience with traceback testing. Data were analyzed using chi-square and Fisher's exact testing. Among 207 respondents (of 816 eligible), most were women (89.4%), white (85.5%), and not Hispanic or Latino (89.7%). US-based providers represented the majority of respondents (87.4%). Relatively, few providers 32 of 207 (15.5%) had previous experience with traceback. Among the individuals without experience in traceback, 84.0% thought there would be barriers to implementation; however, only 68.8% of individuals with previous traceback experience agreed (p = .04). Respondents in both groups thought that traceback would be valuable in their practice (82.6%, p = .22) and that they would feel comfortable discussing the concept (83.6%, p = .83), interpreting the results (72.2%, p = .24), and discussing the results with their patients (80.7%, p = .38). Patient interest and cost were seen as less of a barrier by those with experience with traceback testing. Recurrent themes obtained in open-ended responses are also presented. Overall, providers believe that traceback would be a valuable tool in their practice. Individuals with previous experience identified less barriers with implementation of this testing, highlighting an area for future research and education.

Associations between nutritional factors and chemotherapy toxicity in older adults with solid tumors.

BACKGROUND: Nutritional status can directly affect morbidity and mortality in older adults with cancer. This study evaluated the association between pretreatment body mass index (BMI), albumin level, and unintentional weight loss (UWL) in the prior 6 months and chemotherapy toxicity among older adults with solid tumors. METHODS: This was a secondary analysis of a prospective, multicenter study involving chemotherapy-treated patients 65 years old or older. Geriatric assessment, BMI, albumin level, and UWL data were collected before treatment. Multivariable logistic regression models evaluated the associations between nutritional factors and the risk of grade 3 or higher (grade 3+) chemotherapy toxicity. RESULTS: Seven hundred fifty patients with a median age of 72 years (range, 65-94 years) and mostly stage IV disease were enrolled. The median pretreatment BMI and albumin values were 26 kg/m2 (range, 15.1-52.1 kg/m2 ) and 3.9 mg/dL (range, 1.0-5.0 mg/dL), respectively. Nearly 50% of the patients reported UWL, with 17.6% reporting >10% UWL. Multivariable analysis revealed no association between >10% UWL and a risk for grade 3+ chemotherapy toxicity (adjusted odds ratio [AOR], 0.87; P = .58). Multivariable analysis showed a trend toward an association between a BMI ≥ 30 kg/m2 and a decreased risk of grade 3+ chemotherapy toxicity (AOR, 0.65; P = .06), whereas a low albumin level (≤3.6 mg/dL) was associated with a higher risk of grade 3+ chemotherapy toxicity (AOR, 1.50; P = .03). An analysis of the joint effect of BMI and albumin demonstrated the lowest risk of grade 3+ chemotherapy toxicity among patients with high BMIs (≥30 kg/m2 ) and normal albumin levels (AOR, 0.41; P = .008). CONCLUSIONS: Among older adults with solid tumors, higher BMIs and normal albumin levels are associated with a lower risk of grade 3+ chemotherapy toxicity. Additional research is warranted to define the clinical significance of nutritional markers and to inform future interventions.

Lung Cancer in Nonelderly Patients: Facility and Patient Characteristics Associated With Not Receiving Treatment.

BACKGROUND: In elderly patients with lung cancer, race/ethnicity is associated with not receiving treatment; however, little attention has been given to nonelderly patients (aged ≤65 years) with a range of disease stages and histologies. Nonelderly patients with lung cancer have superior survival at NCI-designated Comprehensive Cancer Centers (CCCs), although the reasons remain unknown. PATIENTS AND METHODS: A retrospective cohort study was conducted in 9,877 patients newly diagnosed with small cell or non-small cell lung cancer (all stages) between ages 22 and 65 years and reported to the Los Angeles County Cancer Surveillance Program registry between 1998 and 2008. Multivariable logistic regression examined factors associated with nontreatment. RESULTS: In multivariable analysis, race/ethnicity was associated with not receiving cancer treatment (black: odds ratio [OR], 1.22; P=.004; Hispanic: OR, 1.17; P=.04), adjusting for patient age, sex, disease stage, histology, diagnosis year, distance to treatment facility, type of facility (CCC vs non-CCC), and insurance status. With inclusion of socioeconomic status (SES) in the model, the effect of race/ethnicity was no longer significant (black: OR, 1.02; P=.80; Hispanic: OR, 1.00; P=1.00). Factors independently associated with nontreatment included low SES (OR range, 1.37-2.15; P<.001), lack of private insurance (public: OR, 1.71; P<.001; uninsured: OR, 1.30; P<.001), and treatment facility (non-CCC: OR, 3.22; P<.001). CONCLUSIONS: In nonelderly patients with lung cancer, SES was associated with nontreatment, mitigating the effect of race/ethnicity. Patients were also at higher odds of nontreatment if they did not have private insurance or received cancer care at a non-CCC facility. These findings highlight the importance of understanding how both patient-level factors (eg, SES, insurance status) and facility-level factors (eg, treatment facility) serve as barriers to treatment of nonelderly patients with lung cancer.

Assessing brain volume changes in older women with breast cancer receiving adjuvant chemotherapy: a brain magnetic resonance imaging pilot study.

BACKGROUND: Cognitive decline is among the most feared treatment-related outcomes of older adults with cancer. The majority of older patients with breast cancer self-report cognitive problems during and after chemotherapy. Prior neuroimaging research has been performed mostly in younger patients with cancer. The purpose of this study was to evaluate longitudinal changes in brain volumes and cognition in older women with breast cancer receiving adjuvant chemotherapy. METHODS: Women aged ≥ 60 years with stage I-III breast cancer receiving adjuvant chemotherapy and age-matched and sex-matched healthy controls were enrolled. All participants underwent neuropsychological testing with the US National Institutes of Health (NIH) Toolbox for Cognition and brain magnetic resonance imaging (MRI) prior to chemotherapy, and again around one month after the last infusion of chemotherapy. Brain volumes were measured using Neuroreader™ software. Longitudinal changes in brain volumes and neuropsychological scores were analyzed utilizing linear mixed models. RESULTS: A total of 16 patients with breast cancer (mean age 67.0, SD 5.39 years) and 14 age-matched and sex-matched healthy controls (mean age 67.8, SD 5.24 years) were included: 7 patients received docetaxel and cyclophosphamide (TC) and 9 received chemotherapy regimens other than TC (non-TC). There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group pre-chemotherapy (p > 0.05). Exploratory hypothesis generating analyses focusing on the effect of the chemotherapy regimen demonstrated that the TC group had greater volume reduction in the temporal lobe (change = - 0.26) compared to the non-TC group (change = 0.04, p for interaction = 0.02) and healthy controls (change = 0.08, p for interaction = 0.004). Similarly, the TC group had a decrease in oral reading recognition scores (change = - 6.94) compared to the non-TC group (change = - 1.21, p for interaction = 0.07) and healthy controls (change = 0.09, p for interaction = 0.02). CONCLUSIONS: There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group; however, exploratory analyses demonstrated a reduction in both temporal lobe volume and oral reading recognition scores among patients on the TC regimen. These results suggest that different chemotherapy regimens may have differential effects on brain volume and cognition. Future, larger studies focusing on older adults with cancer on different treatment regimens are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01992432 . Registered on 25 November 2013. Retrospectively registered.

Association between patient-reported hearing and visual impairments and functional, psychological, and cognitive status among older adults with cancer.

BACKGROUND: Hearing and visual impairments are common among community-dwelling older adults, and are associated with psychological, functional, and cognitive deficits. However, to the authors' knowledge, little is known regarding their prevalence among older patients with cancer. METHODS: The current study was a secondary analysis combining 2 prospective cohorts of adults aged ≥65 years with solid tumors who were receiving chemotherapy. The authors assessed the association between patient-reported hearing and/or visual impairment (defined as fair/poor grading by self-report) and physical function, instrumental activities of daily living (IADLs), anxiety, depression, and cognition. Descriptive analyses were conducted to summarize patient and treatment characteristics. One-way analysis of variance and chi-square tests were conducted as appropriate to examine differences between patients with and without sensory impairments. Logistic regression was used to analyze associations between sensory impairments and outcomes. RESULTS: Among 750 patients with a median age of 72 years who had solid tumors (29% with breast/gynecological tumors, 28% with lung tumors, and 27% with gastrointestinal tumors), approximately 18% reported hearing impairment alone, 11% reported visual impairment alone, and 7% reported dual sensory impairment. Hearing impairment was associated with IADL dependence (odds ratio [OR], 1.9), depression (OR, 1.6), and anxiety (OR, 1.6). Visual impairment was associated with IADL dependence (OR, 1.9), poor physical function (OR, 1.9), and depression (OR, 2.5). Dual impairment was associated with IADL dependence (OR, 2.8), anxiety (OR, 2.3), depression (OR, 2.5), and cognitive impairment (OR, 3.2). CONCLUSIONS: Sensory impairment is common among older adults with cancer. Patients with sensory impairment are more likely to have functional, psychological, and cognitive deficits. Interventions aimed at improving the vision and hearing of older adults with cancer should be studied. Cancer 2018. © 2018 American Cancer Society.

Gray matter density reduction associated with adjuvant chemotherapy in older women with breast cancer.

PURPOSE: The purpose of this study was to evaluate longitudinal changes in brain gray matter density (GMD) before and after adjuvant chemotherapy in older women with breast cancer. METHODS: We recruited 16 women aged ≥ 60 years with stage I-III breast cancers receiving adjuvant chemotherapy (CT) and 15 age- and sex-matched healthy controls (HC). The CT group underwent brain MRI and the NIH Toolbox for Cognition testing prior to adjuvant chemotherapy (time point 1, TP1) and within 1 month after chemotherapy (time point 2, TP2). The HC group underwent the same assessments at matched intervals. GMD was evaluated with the voxel-based morphometry. RESULTS: The mean age was 67 years in the CT group and 68.5 years in the HC group. There was significant GMD reduction within the chemotherapy group from TP1 to TP2. Compared to the HC group, the CT group displayed statistically significantly greater GMD reductions from TP1 to TP2 in the brain regions involving the left anterior cingulate gyrus, right insula, and left middle temporal gyrus (pFWE(family-wise error)-corrected < 0.05). The baseline GMD in left insula was positively correlated with the baseline list-sorting working memory score in the HC group (pFWE-corrected < 0.05). No correlation was observed for the changes in GMD with the changes in cognitive testing scores from TP1 to TP2 (pFWE-corrected < 0.05). CONCLUSIONS: Our findings indicate that GMD reductions were associated with adjuvant chemotherapy in older women with breast cancer. Future studies are needed to understand the clinical significance of the neuroimaging findings. This study is registered on ClinicalTrials.gov (NCT01992432).

Factors associated with falls in older adults with cancer: a validated model from the Cancer and Aging Research Group.

BACKGROUND: Falls in older adults with cancer are common, yet factors associated with fall-risk are not well-defined and may differ from the general geriatric population. This study aims to develop and validate a model of factors associated with prior falls among older adults with cancer. METHODS: In this cross-sectional secondary analysis, two cohorts of patients aged ≥ 65 with cancer were examined to develop and validate a model of factors associated with falls in the prior 6 months. Potential independent variables, including demographic and laboratory data and a geriatric assessment (encompassing comorbidities, functional status, physical performance, medications, and psychosocial status), were identified. A multivariate model was developed in the derivation cohort using an exhaustive modeling approach. The model selected for validation offered a low Akaike Information Criteria value and included dichotomized variables for ease of clinical use. This model was then applied in the validation cohort. RESULTS: The development cohort (N = 498) had a mean age of 73 (range 65-91). Nearly one-fifth (18.2%) reported a fall in the prior 6 months. The selected model comprised nine variables involving functional status, objective physical performance, depression, medications, and renal function. The AUC of the model was 0.72 (95% confidence intervals 0.65-0.78). In the validation cohort (N = 250), the prevalence of prior falls was 23.6%. The AUC of the model in the validation cohort was 0.62 (95% confidence intervals 0.51-0.71). CONCLUSION: In this study, we developed and validated a model of factors associated with prior falls in older adults with cancer. Future study is needed to examine the utility of such a model in prospectively predicting incident falls.

Association of pre-chemotherapy peripheral blood pro-inflammatory and coagulation factors with reduced relative dose intensity in women with breast cancer.

BACKGROUND: Chemotherapy decreases the risk of relapse and mortality in early-stage breast cancer (BC), but it comes with the risk of toxicity. Chemotherapy efficacy depends on relative dose intensity (RDI), and an RDI < 85% is associated with worse overall survival. The pro-inflammatory (interleukin (IL)-6, C-reactive protein (CRP)) and coagulation factors (D-dimer) serve as biomarkers of aging. The purpose of this study is to determine if these biomarkers are associated with reduced RDI in women with stage I-III BC. METHODS: This study enrolled women with stage I-III BC. Prior to adjuvant or neoadjuvant chemotherapy, peripheral blood was collected for biomarker measurement. Dose reductions and delays were captured and utilized to calculate the RDI delivered. Univariate and multivariate analyses were performed to describe the association between pre-chemotherapy IL-6, CRP, and D-dimer levels and an RDI < 85%, controlling for relevant tumor and patient factors (age, stage, receptor status, chemotherapy regimen, and pre-chemotherapy physical function and comorbidity). RESULTS: A total of 159 patients (mean age 58 years, range 30-81, SD 11.3) with stage I-III BC were enrolled. An RDI < 85% occurred in 22.6% (N = 36) of patients and was associated with higher pre-chemotherapy IL-6 (OR 1.14, 95% CI 1.04-1.25; p = 0.006) and D-dimer (OR 2.32, 95% CI 1.27-4.24; p = 0.006) levels, increased age (p = 0.001), increased number of comorbidities (p = 0.01), and decreased physical function by the Medical Outcomes Survey Activities of Daily Living (ADL) Scale (p = 0.009) in univariate analysis. A multivariate model, including two biomarkers (IL-6 and D-dimer), age, ADL, BC stage, and chemotherapy regimen, demonstrated a significant association between the increased biomarkers and reduced RDI < 85% (OR 2.54; p = 0.04). CONCLUSIONS: Increased pre-chemotherapy biomarkers of aging (IL-6 and D-dimer) are associated with reduced RDI (<85%). Future studies are underway to validate these findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01030250 . Registered on 3 November 2016.

Association of Pre-Chemotherapy Peripheral Blood Pro-Inflammatory and Coagulation Factors with Physical Function in Women with Breast Cancer.

BACKGROUND: Pro-inflammatory and coagulation factors serve as biomarkers of aging and functional reserve. The purpose of this study was to determine if pro-inflammatory (interleukin-6 [IL-6], C-reactive protein [CRP]), and coagulation (D-dimer) factors were associated with pre-chemotherapy functional status in women with stage I-III breast cancer. PATIENTS AND METHODS: Prior to chemotherapy initiation in patients with stage I-III breast cancer, the following was captured: IL-6, CRP, D-dimer blood levels, and physical function measures including activities of daily living (ADL, subscale of Medical Outcomes Study Physical Health); instrumental activities of daily living (IADL, subscale of the Older Americans Resources and Services Program); Timed Up and Go (TUG); physician-rated Karnofsky Performance Status (KPS); and self-rated KPS. The association of these biomarkers with physical function measures was evaluated. RESULTS: One hundred sixty patients (mean age 58.3 years, range 30-81 years) with stage I-III breast cancer (stages I [n = 34; 21.5%], II [n = 88; 55.7%], III [n = 36; 22.8%]) were enrolled. The group with poorest physical function (defined by ADL <70, IADL <14, and TUG ≥10 seconds) had higher levels of IL-6 (p = .05), D-dimer (p = .0004), and CRP (p = .05). There was no significant association between these biomarkers and KPS. Patients with at least two biomarkers in the highest quartile were more likely to have poorer physical function (odds ration [OR] 18.75, p < .001). In multivariate analysis adjusting for age, stage, number of comorbidities, and body mass index, the association remained (OR 14.6, p = .002). CONCLUSION: Pre-chemotherapy biomarkers of aging are associated with poorer physical function among patients with breast cancer across the aging spectrum. The Oncologist 2017;22:1189-1196 IMPLICATIONS FOR PRACTICE: Commonly used physical function assessment tools may not reflect the diverse nature of physical function and risk for chemotherapy toxicity, particularly in older adults. No laboratory test reflects functional reserve. Pro-inflammatory and coagulation factors, such as IL-6, CRP, and D-dimer, can serve as biomarkers of aging and physical function; however, few studies have evaluated their utility in patients with cancer. This study was designed to understand the association between pre-chemotherapy biomarkers and physical function in women with early stage breast cancer undergoing adjuvant chemotherapy. Results indicate that elevated pre-chemotherapy levels in two of the three peripheral biomarkers are associated with the poorest physical function among patients with breast cancer across the aging spectrum.

Frailty as determined by a comprehensive geriatric assessment-derived deficit-accumulation index in older patients with cancer who receive chemotherapy.

BACKGROUND: Frailty has been suggested as a construct for oncologists to consider in treating older cancer patients. Therefore, the authors assessed the potential of creating a deficit-accumulation frailty index (DAFI) from a largely self-administered comprehensive geriatric assessment (CGA). METHODS: Five hundred patients aged ≥65 years underwent a CGA before receiving chemotherapy. A DAFI was constructed, resulting in a 51-item scale, and cutoff values were examined for patients in the robust/nonfrail (cutoff value, 0.0 < 0.2), prefrail (cutoff value, 0.2 < 0.35), and frail (cutoff value, ≥ 0.35) groups. RESULTS: Two hundred and fifty patients (50%) were nonfrail, 197 (39%) were prefrail, and 52 (11%) were frail. Older patients (aged ≥ 80 years) and those who had lower education, were living alone, and had higher stage disease were associated with prefrail/frail status. Prefrail/frail patients were more likely to have grade ≥3 toxicity but not to have a dose delay or reduction, and they were more likely to discontinue drug and be hospitalized. The association with grade ≥3 toxicity was attenuated by controlling for a toxicity risk calculator, but the other outcomes were not. CONCLUSIONS: A deficit-accumulation frailty index can be constructed from a CGA in older patients with cancer and can indicate the frailty status of the population. The frailty status so determined is associated both with outcomes likely because of chemotherapy toxicity and with those likely because of age-related physiologic and functional deficits and thus can be useful in the overall assessment of the patient. Cancer 2016;122:3865-3872. © 2016 American Cancer Society.

Impact of care at comprehensive cancer centers on outcome: Results from a population-based study.

BACKGROUND: Rigorous processes ensure quality of research and clinical care at National Cancer Institute-designated comprehensive cancer centers (NCICCCs). Unmeasurable elements of structure and process of cancer care delivery warrant evaluation. To the authors' knowledge, the impact of NCICCC care on survival and access to NCICCCs for vulnerable subpopulations remain unstudied. METHODS: The current study's population-based cohort of 69,579 patients had newly diagnosed adult-onset (aged 22-65 years) cancers reported to the Los Angeles County cancer registry between 1998 and 2008. Geographic information systems were used for geospatial analysis. RESULTS: With regard to overall survival across multiple diagnoses, patients not receiving their first planned treatment at NCICCCs experienced poorer outcomes compared with those treated at NCICCCs; differences persisted on multivariable analyses after adjusting for clinical and sociodemographic factors (hepatobiliary: hazard ratio [HR], 1.5; 95% confidence interval [95% CI], 1.4-1.7 [P<.001]; lung: HR, 1.4; 95% CI, 1.3-1.6 [P<.001]; pancreatic: HR, 1.5; 95% CI, 1.3-1.7 [P<.001]; gastric: HR, 1.3; 95% CI, 1.1-1.7 [P = .01]; breast: HR, 1.3; 95% CI, 1.1-1.5 [P<.001]; and colorectal: HR, 1.2; 95% CI, 1.0-1.4 [P = .05]). With regard to barriers to care, multivariable analyses revealed that a lower likelihood of treatment at NCICCCs was associated with race/ethnicity (African-American: OR range across diagnoses: 0.4-0.7 [P<.03]; Hispanic: OR range, 0.5-0.7 [P<.04]); lack of private insurance (public: OR range, 0.6-0.8 [P<.004]; uninsured: OR range, 0.1-0.5 [P<.04]); less than high socioeconomic status (high-middle: OR range, 0.4-0.7 [P<.02]; middle: OR range, 0.3-0.5 [P<.001]; and low: OR range, 0.2-0.6 [P<.01]), and residing >9 miles from the nearest NCICCC (OR range, 0.5-0.7 [P<.02]). CONCLUSIONS: Among individuals aged 22 to 65 years residing in Los Angeles County with newly diagnosed adult-onset cancer, those who were treated at NCICCCs experienced superior survival compared with those treated at non-NCICCC facilities. Barriers to care at NCICCCs included race/ethnicity, insurance, socioeconomic status, and distance to an NCICCC.

Chronic myelogenous leukemia stem and progenitor cells demonstrate chromosomal instability related to repeated breakage-fusion-bridge cycles mediated by increased nonhomologous end joining.

Chromosomal aberrations are an important consequence of genotoxic exposure and contribute to pathogenesis and progression of several malignancies. We investigated the susceptibility to chromosomal aberrations in chronic myelogenous leukemia (CML) progenitors after exposure to ionizing radiation. In normal progenitors, ionizing radiation induced both stable and unstable chromosomal lesions, but only stable aberrations persisted after multiple divisions. In contrast, radiation of chronic phase CML progenitors resulted in enhanced generation of unstable lesions that persisted after multiple divisions. CML progenitors demonstrated active cell cycle checkpoints and increased nonhomologous end joining DNA repair, suggesting that persistence of unstable aberrations was the result of continued generation of these lesions. CML progenitors demonstrated enhanced susceptibility to repeated cycles of chromosome damage, repair, and damage through a breakage-fusion-bridge mechanism. Perpetuation of breakage-fusion-bridge cycles in CML progenitors was mediated by classic nonhomologous end joining repair. These studies reveal a previously unrecognized mechanism of chromosomal instability in leukemia progenitors because of continued generation of unstable chromosomal lesions through repeated cycles of breakage and repair of such lesions.

Cardiovascular risk factors in hematopoietic cell transplantation survivors: role in development of subsequent cardiovascular disease.

Hematopoietic cell transplantation (HCT) recipients may be at an increased risk of developing hypertension, diabetes, and dyslipidemia (referred to as cardiovascular risk factors [CVRFs]); and these factors can potentially increase the risk of cardiovascular disease (CVD). We examined the incidence and predictors of CVRFs and subsequent CVD in 1885 consecutive 1+year survivors of HCT performed at City of Hope between 1995 and 2004. Ten-year cumulative incidence of hypertension, diabetes, dyslipidemia, and multiple (≥ 2) CVRFs was 37.7%, 18.1%, 46.7%, and 31.4%, respectively. The prevalence of CVRFs was significantly higher among HCT recipients compared with the general population; contributed to largely by allogeneic HCT recipients. Older age and obesity at HCT were associated with increased risk of CVRFs. History of grade II-IV acute graft versus host disease was associated with an increased risk for hypertension (relative risk [RR] = 9.1, P < .01), diabetes (RR = 5.8, P < .01), and dyslipidemia (RR = 3.2, P < .01); conditioning with total body irradiation was associated with an increased risk of diabetes (RR = 1.5, P = .01) and dyslipidemia (RR = 1.4, P < .01). There was an incremental increase in 10-year incidence of CVD by number of CVRFs (4.7% [none], 7.0% [1 CVRF], 11.2% [≥ 2 CVRFs], P < .01); the risk was especially high (15.0%) in patients with multiple CVRFs and pre-HCT exposure to anthracyclines or chest radiation.

Effect of chemotherapy on hippocampal volume and shape in older long-term breast cancer survivors.

Purpose: The objective of this study was to assess changes in hippocampal volume and shape in older long-term breast cancer survivors who were exposed to chemotherapy 5-15 years prior. Methods: This study recruited female long-term breast cancer survivors aged 65 years or older with a history of chemotherapy (C+), age-matched breast cancer survivors who did not receive chemotherapy (C-), and healthy controls (HC). The participants were recruited 5-15 years after chemotherapy at time point 1 (TP1) and were followed up for 2 years at time point 2 (TP2). Assessments included hippocampal volume and shape from brain MRI scans and neuropsychological (NP) tests. Results: At TP1, each of the three groups was comprised of 20 participants. The C+ group exhibited a hippocampal volume loss estimated in proportion with total intracranial volume (ICV) in both the left and right hemispheres from TP1 to TP2. Regarding the hippocampal shape at TP1, the C+ group displayed inward changes compared to the control groups. Within the C+ group, changes in right hippocampal volume adjusted with ICV were positively correlated with crystalized composite scores (R = 0.450, p = 0.044). Additionally, in C+ groups, chronological age was negatively correlated with right hippocampal volume adjusted with ICV (R = -0.585, p = 0.007). Conclusion: The observed hippocampal volume reduction and inward shape deformation within the C+ group may serve as neural basis for cognitive changes in older long-term breast cancer survivors with history of chemotherapy treatment.

Altered gyrification in chemotherapy-treated older long-term breast cancer survivors.

PURPOSE: The purpose of this prospective longitudinal study was to evaluate the changes in brain surface gyrification in older long-term breast cancer survivors 5-15 years after chemotherapy treatment. METHODS: Older breast cancer survivors aged ≥ 65 years treated with chemotherapy (C+) or without chemotherapy (C-) 5-15 years prior and age- and sex-matched healthy controls (HC) were recruited (time point 1 (TP1)) and followed up for 2 years (time point 2 (TP2)). Study assessments for both time points included neuropsychological (NP) testing with the NIH Toolbox cognition battery and cortical gyrification analysis based on brain MRI. RESULTS: The study cohort with data for both TP1 and TP2 consisted of the following: 10 participants for the C+ group, 12 participants for the C- group, and 13 participants for the HC group. The C+ group had increased gyrification in six local gyral regions including the right fusiform, paracentral, precuneus, superior, middle temporal gyri and left pars opercularis gyrus, and it had decreased gyrification in two local gyral regions from TP1 to TP2 (p < .05, Bonferroni corrected). The C- and HC groups showed decreased gyrification only (p < .05, Bonferroni corrected). In the C+ group, changes in right paracentral gyrification and crystalized composite scores were negatively correlated (R = -0.76, p = .01). CONCLUSIONS: Altered gyrification could be the neural correlate of cognitive changes in older chemotherapy-treated long-term breast cancer survivors.