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.

Brain white matter microstructural changes in chemotherapy-treated older long-term breast cancer survivors.

PURPOSE: To assess white matter microstructural changes in older long-term breast cancer survivors 5-15 years post-chemotherapy treatment. METHODS: Breast cancer survivors aged 65 years or older who underwent chemotherapy (C+) and who did not undergo chemotherapy (C-) and age- and sex-matched healthy controls (HC) were enrolled at time point 1 (TP1) and followed for 2 years for time point 2 (TP2). All participants underwent brain MRI with diffusion tensor images and neuropsychological (NP) testing with the NIH Toolbox Cognition Battery. Tract-based spatial statistics (TBSS) analysis was performed on the diffusion tensor images to assess white matter microstructural changes with the fractional anisotropy (FA) parameter. RESULTS: There were significant longitudinal alterations in FA within the C+ group over time. The C+ group showed diminished FA in the body and genu of corpus callosum, anterior corona radiate, and external capsule on both the whole brain and region of interest (ROI) based analyses after p < 0.05 family-wise error (FWE) correction. However, there were no significant group differences between the groups at TP1. Additionally, at TP1, a positive correlation (R = 0.58, p = 0.04) was observed between the FA value of the anterior corona radiata and the crystallized composite score in the C+ group. CONCLUSIONS: Brain white matter microstructural alterations may be the underlying neural correlates of cognitive changes in older breast cancer survivors who had chemotherapy treatment years ago.

Anxiety, Depression, and Coping Strategies during Chemotherapy Treatment: A Comparison of Older and Younger Adults with Advanced Cancer in Brazil.

We sought to examine differences in anxiety, depression and coping strategies among younger (<64-year old) and older (≥65-year old) patients. Patients were assessed at baseline (T1), mid-point (T2) and on the last day of treatment (T3) using the Hospital Anxiety and Depression Scale and the Ways of Coping. A linear mixed modeling approach was used. The study included 200 patients (gender: 70% women; diagnosis: 30% breast, 22% hematological, 18% gastrointestinal; disease stage: 60% advanced). Older patients who used an emotion-focused coping strategy had a greater decrease in anxiety at T3 compared to those that used problem-focused coping (p = .002).

Differences of biopsychosocial distress and requests for psychological assistance between Asian American and non-Hispanic White oncology patients.

OBJECTIVE: The purpose of this study was to compare Asian American (AA) to non-Hispanic White (NHW) cancer patients regarding biopsychosocial distress and requests for psychological assistance. METHODS: This retrospective study included 5627 eligible patients, newly diagnosed with cancer, who completed the 30-item SupportScreen® survey of biopsychosocial distress. The top 10 sources of high distress were assessed. Distress domains (Emotional, Physical/Functional, and Practical) were examined by race/ethnicity. Requests for psychological assistance were also explored by ethnic groups. RESULTS: Overall, the top 10 sources of high distress were similar between groups and approximately half consisted of concerns regarding physical symptoms. All patients preferred "talking" as their method of receiving assistance for these items. Ratings of emotional, practical, and physical/functional distress were similar between AA and NHW patients. However, AAs (vs. NHWs) requested more assistance regarding physical/functional and practical distress. No difference was observed between these two groups regarding requests for emotional support. CONCLUSIONS: Overall, our study suggests that healthcare providers should be aware of the physical and practical needs of AA cancer patients and provide culturally sensitive care that addresses these needs.

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 to 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 & 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 6 local gyrus regions including the right fusiform, paracentral, precuneus, superior, middle temporal gyri and left pars opercularis gyrus, and it had decreased gyrification in 2 local gyrus regions from TP1 to TP2 (p < 0.05, Bonferroni corrected). The C- and HC groups showed decreased gyrification only (p < 0.05, Bonferroni corrected). In C+ group, changes in right paracentral gyrification and crystalized composite scores were negatively correlated (R = -0.76, p = 0.01). Conclusions: Altered gyrification could be the neural correlate of cognitive changes in older chemotherapy-treated long-term breast cancer survivors.

Implementation and evaluation of a remote geriatric assessment and intervention program in Brazil.

BACKGROUND: This study sought to determine the feasibility and acceptability of a remote geriatric assessment (GA) and implementation (GAIN) program in Brazil. The authors also explored the effect of this program on health-related quality of life (HR-QOL) outcomes 3 months after initiating treatment. METHODS: This is a longitudinal study enrolling older adults (65+ years), diagnosed with any type of solid tumor, scheduled to initiate chemotherapy in a networked Brazilian cancer center. The GA was performed through telehealth. We assessed the feasibility of the remote GA, acceptability to patients, and changes in patient-centered outcomes (HR-QOL, mood, function) from baseline to month 3. Linear mixed model analysis was done, adjusting for age, gender, race, income, and disease stage. RESULTS: Fifty-six patients completed all intended assessments. Notably, the threshold of feasibility was 70% and there was 92% complete adherence. Average age was 76 years old (SD = 7.2). Most patients were female (57%), married (59%), and had a college degree (46%). The most common diagnoses were gastrointestinal (39%) and gynecological cancers (18%); most were diagnosed at an advance disease stage (77%). A total of 32 patients were referred to a remote appointment and 86% followed this recommendation(s). Significant improvement in Functional Assessment of Cancer Therapy - General FACT-G (mean difference, 6.04; p < .001), Geriatric Depression Scale (mean difference, -0.86; p = .008), and instrumental activities of daily living ratio (mean difference, 0.17; p < .001) were found. CONCLUSION: Remote GAIN is feasible and acceptable to older adults with cancer receiving treatment in Brazil. The authors also found significant improvement in HR-QOL outcomes over time. Notably, this GAIN program could guide early detection of chemotherapy toxicity and improving patient-reported outcomes in low-resource environments.

Association of time intervals in cancer screenings and older participants' characteristics, in a nationally representative sample.

INTRODUCTION: Health agencies and guidelines have proposed various recommendations regarding breast and prostate cancer screening intervals for older adults. However, there is limited data about factors that could impact older individuals' adherence to these guideline-based intervals. This study emphasized the differences in screening rates between men and women undergoing screening for breast (mammogram) and prostate (prostate-specific antigen [PSA] test) cancer. It also investigated the socio-demographic and emotional factors associated with screening time intervals. MATERIALS AND METHODS: This cross-sectional design study used data from the National Social Life Health and Aging Project Wave 3 (NSHAP-W3, 2015). The outcome measures were screening time intervals (PSA test or mammogram). Individuals were asked, "About how long has it been since you last had a screening?" Response categories ranged from 1 = within the past year to 5 = never. Differences in screening time intervals were evaluated and displayed by age group (PSA vs. mammogram). The association between the outcome measures and participants' characteristics was evaluated via ordinal logistic regression. RESULTS: There were 2320 participants included: 52% women and 48% men. They had a mean age of 66.9 years old, were mostly White (74%) and college graduates (68%). The average time interval between screenings was greater for PSA testing than mammography (mean [M] = 2.28 vs. M = 1.89, p < 0.001). The middle age groups (PSA: 60-79 and mammogram: 65-74), had significantly more frequent screenings compared to the youngest group (50-54). In contrast, older (80+) individuals did not display shorter screening time intervals compared to the youngest group. Furthermore, shorter time intervals between screenings were associated with higher household income (mammogram: odds ratio [OR] = 0.804; PSA: OR = 0.785, p < 0.05), African American descent (mammogram: OR = 0.458, p < 0.001), and higher frequency of physical activity (PSA: OR = 0.921, p = 0.030). Lastly, women who responded "yes" to skipping care due to lack of insurance reported longer periods between mammograms (OR = 1.784, p = 0.002). DISCUSSION: Findings from this real-world US population representative database highlight the role of age, income, and insurance in the timing between screenings; participants aged between 60 and 79 years old, African American women, and physically active men are more likely to pursue earlier screening. These results emphasize the importance of socioeconomic and lifestyle factors when seeking to impact screening timing.

Cortical thinning in chemotherapy-treated older long-term breast cancer survivors.

Cognitive decline is an increasing issue for cancer survivors, especially for older adults, as chemotherapy affects brain structure and function. The purpose of this single center study was to evaluate alterations in cortical thickness and cognition in older long-term survivors of breast cancer who had been treated with chemotherapy years ago. In this prospective cohort study, we enrolled 3 groups of women aged ≥ 65 years with a history of stage I-III breast cancer who had received adjuvant chemotherapy 5 to 15 years ago (chemotherapy group, C +), age-matched women with breast cancer but no chemotherapy (no-chemotherapy group, C-) and healthy controls (HC). All participants underwent brain magnetic resonance imaging and neuropsychological testing with the NIH Toolbox Cognition Battery at time point 1 (TP1) and again at 2 years after enrollment (time point 2 (TP2)). At TP1, there were no significant differences in cortical thickness among the 3 groups. Longitudinally, the C + group showed cortical thinning in the fusiform gyrus (p = 0.006, effect size (d) = -0.60 [ -1.86, -0.66]), pars triangularis (p = 0.026, effect size (d) = -0.43 [-1.68, -0.82]), and inferior temporal lobe (p = 0.026, effect size (d) = -0.38 [-1.62, -0.31]) of the left hemisphere. The C + group also showed decreases in neuropsychological scores such as the total composite score (p = 0.01, effect size (d) = -3.9726 [-0.9656, -6.9796], fluid composite score (p = 0.03, effect size (d) = -4.438 [-0.406, -8.47], and picture vocabulary score (p = 0.04, effect size (d) = -3.7499 [-0.0617, -7.438]. Our results showed that cortical thickness could be a candidate neuroimaging biomarker for cancer-related cognitive impairment and accelerated aging in older long-term cancer survivors.

Signal Variability and Cognitive Function in Older Long-Term Survivors of Breast Cancer with Exposure to Chemotherapy: A Prospective Longitudinal Resting-State fMRI Study.

The purpose of this study was to assess the effect of chemotherapy on brain functional resting-state signal variability and cognitive function in older long-term survivors of breast cancer. This prospective longitudinal study enrolled women age ≥ 65 years of age who were breast cancer survivors after exposure to chemotherapy (CH), age-matched survivors not exposed to chemotherapy, and healthy controls. Participants completed resting-state functional brain MRI and neurocognitive testing upon enrollment (timepoint 1, TP1) and again two years later (timepoint 2, TP2). There were 20 participants in each of the three groups at TP1. The CH group showed a significant decrease in SDBOLD (blood-oxygen-level-dependent signal variability in standard deviation) in the right middle occipital gyrus (ΔSDBOLD = -0.0018, p = 0.0085, q (pFDR) = 0.043 at MNI (42, -76, 17)) and right middle temporal gyrus (ΔSDBOLD = -0.0021, p = 0.0006, q (pFDR) = 0.001 at MNI (63, -39, -12)). There were negative correlations between the crystallized composite scores and SDBOLD values at the right inferior occipital gyrus (correlation coefficient r = -0.84, p = 0.001, q (pFDR) = 0.016) and right middle temporal gyrus (r = -0.88, p = 0.000, q (pFDR) = 0.017) for the CH group at TP1. SDBOLD could be a potentially useful neuroimaging marker for older long-term survivors of breast cancer with exposure to chemotherapy.

Emotional Distress and Financial Toxicity in Younger Adult Patients Undergoing Oncologic Surgery.

BACKGROUND: There has been an alarming increase in the number of young adults (YA) diagnosed with cancer. The emotional, psychosocial, and financial distress experienced by newly diagnosed YA undergoing cancer surgery remains largely unknown. METHODS: A validated biopsychosocial distress screening tool (SupportScreen) was administered to patients diagnosed with cancer before surgery between 2009 and 2017 in a National Cancer Institute Comprehensive Cancer Center. Patients were stratified into YA less than or equal to 45 years and older adults (OA) above 45 years. Descriptive statistics and logistic regression were used to analyze distress outcomes. RESULTS: In total, 4297 patients were identified, with YA comprising 13.3% (n=573) of the cohort. YA reported higher emotional distress, including increased anxiety (33.8% vs 27.4%, P =0.002), greater fear of procedures (26.7% vs 22%, P =0.018), and difficulty managing emotions (26% vs 20.7%, P =0.006). YA struggled more frequently to manage work/school (29.5% vs 19.3%, P <0.001), finding resources (17.8% vs 11.8%, P <0.001), changes in physical appearance (22.2% vs 13.4%, P <0.001), fatigue (36% vs 27.3%, P <0.001), and ability to have children (18.4% vs 3%, P <0.001). Financial toxicity was significantly higher in the YA group (40.5% vs 28%, P <0.001). While income level was strongly protective against emotional distress and financial toxicity in OAs, it was less protective against the risk of financial toxicity in YA. Younger age was an independent predictor of financial toxicity in a model adjusted to income (odds ratio=1.52, P =0.020). CONCLUSIONS: YA in the prime of their personal and professional years of productivity require special attention when undergoing surgical evaluation for cancer. Resource allocation and counseling interventions should be integrated as part of their routine care to expedite their return to optimal physical and holistic health and mitigate psychosocial distress and financial toxicity.

Association between requests for supportive care assistance and patients' characteristics, prior to treatment in a comprehensive cancer center.

PURPOSE: Patients with cancer experience a wide array of distress symptoms (emotional, practical, physical, and functional), which often hinders their quality of life and survival. Unfortunately, only a small proportion of these patients request assistance for these problems. This study explored the relationship between requests for supportive care assistance and distress of patients newly diagnosed with cancer. METHODS: This study was conducted at city of hope, an NCI-designated comprehensive cancer center, and included 2658 patients treated between 2009 and 2017. Patients were asked to complete a 30-item biopsychosocial problem-related distress survey via SupportScreen® , prior to any treatment. Correlations between requests for assistance and distress domains were evaluated. Primary types of requests were examined for all patients, and general linear modeling was used to determine the significant predictors of requests for assistance. p-values <0.05 were considered significant. RESULTS: Strong correlations were observed between distress subscales and requests for assistance (r ranging from 0.67 to 0.69). The primary types of requests varied by domain: items such as feeling anxious or fearful, finances, and sleep ranked first within the emotional, practical, and physical-functional domains respectively (∼20% requests for each item). Verbal assistance was generally preferred to the written form of assistance, with the exception of a few items, including finances. Overall, household income of <$100,000 and completing the survey in Spanish were significant predictors of requests for assistance. Regarding the practical and physical-functional domains, having an advanced stage of disease was significantly related to an increase in demands for assistance. Being older was associated to a decrease in requests for assistance vis-à-vis both the emotional and physical functional subscales. CONCLUSION: We demonstrated that distress levels were strongly correlated with requests for assistance. Patients' clinical and demographic characteristics such as age, household income, disease stage and survey language were associated with inquiries for psychosocial support, highlighting the importance of targeting interventions towards those most likely to need them, to better aim patients' needs. Therefore, tailoring supportive care assistance to patients' characteristics could help boost the frequency of requests, reduce distress burden, and improve health outcomes.

Hyperthermic Intraperitoneal Chemotherapy-Induced Molecular Changes in Humans Validate Preclinical Data in Ovarian Cancer.

PURPOSE: Hyperthermic intraperitoneal chemotherapy (HIPEC) confers a survival benefit in epithelial ovarian cancer (EOC) and in preclinical models. However, the molecular changes induced by HIPEC have not been corroborated in humans. PATIENTS AND METHODS: A feasibility trial evaluated clinical and safety outcomes of HIPEC with cisplatin during optimal cytoreductive surgery (CRS) in patients with EOC diagnosed with stage III, IV, or recurrent EOC. Pre- and post-HIPEC biopsies were comprehensively profiled with genomic and transcriptomic sequencing to identify mutational and RNAseq signatures correlating with response; the tumor microenvironment was profiled to identify potential immune biomarkers; and transcriptional signatures of tumors and normal samples before and after HIPEC were compared to investigate HIPEC-induced acute transcriptional changes. RESULTS: Thirty-five patients had HIPEC at the time of optimal CRS; all patients had optimal CRS. The median progression-free survival (PFS) was 24.7 months for primary patients and 22.4 for recurrent patients. There were no grade 4 or 5 adverse events. Anemia was the most common grade 3 adverse event (43%). Hierarchical cluster analyses identified distinct transcriptomic signatures of good versus poor responders to HIPEC correlating with a PFS of 29.9 versus 7.3 months, respectively. Among good responders, significant HIPEC-induced molecular changes included immune pathway upregulation and DNA repair pathway downregulation. Within cancer islands, % programmed cell death protein 1 expression in CD8+ T cells significantly increased after HIPEC. An exceptional responder (PFS 58 months) demonstrated the highest programmed cell death protein 1 increase. Heat shock proteins comprised the top differentially upregulated genes in HIPEC-treated tumors. CONCLUSION: Distinct transcriptomic signatures identify responders to HIPEC, and preclinical model findings are confirmed for the first time in a human cohort.

Emotional problem-related distress screening and its prevalence by cancer type: Assessment by patients' characteristics and level of assistance requested.

OBJECTIVE: Emotional problem-related distress is a common issue faced by patients with cancer. However, patients suffering with this emotional burden do not typically seek assistance. This study sought to determine the prevalence of emotional problem-related distress by cancer type, and identify factors correlated with the level of assistance requested. METHODS: Using the SupportScreen®, patients were screened for emotional problem-related distress at their first or second visit to an NCI designated Comprehensive Cancer Center. General Linear Model was used to test the association between emotional problem-related distress and type of cancer, and the relationship between level of assistance requested and patients' characteristics. RESULTS: A total of 2,421 patients were included in this analysis. Patients were mostly female (62%), diagnosed with breast (24%), gynecological (16%) or gastrointestinal (15%) cancers. Highest levels of emotional problem-related distress were reported by patients diagnosed with lung, gynecological, breast and gastrointestinal cancers. Level of assistance requested were significantly associated with problem-related distress scores (p < 0.001), which were higher among patients with lower household incomes (p < 0.001) and Spanish as primary language (p = 0.001). CONCLUSION: Our study found an association between Level of assistance requested and emotional problem-related distress, which were heightened by lower income and Spanish-speaking. Intervention strategies should be considered to increase access to psychosocial support services.

Certainty of evidence and intervention's benefits and harms are key determinants of guidelines' recommendations.

OBJECTIVE: Many factors are postulated to affect guidelines developments. We set out to identify the key determinants. STUDY DESIGN AND SETTING: a) Web-based survey of 12 panels of 153 "voting" members who issued 2941 recommendations; b) qualitative analysis of 13 panels of 311 attendees (panel members, systematic review teams and observers). RESULTS: Compared with "no recommendations", when intervention's benefit outweigh harms (BH-balance), probability of issuing strong recommendations in favor of intervention was 0.22 (95%CI: 0.08 to 0.36) when certainty of evidence (CoE) was very low; 0.5 (95%CI:0.36 to 0.63) when low; 0.74 (95%CI 0.61 to 0.87) when moderate and 0.85 (95%CI:0.71 to 1.00) when high. No other postulated factor significantly affected recommendations. The findings are consistent with a J- curve model when recommendations are issued in favor but not against an intervention. Panelists often changed their judgments as a result of the meeting discussion (67% for CoE to 92% for balance between benefits and harms). The panels spent over 50% of their time debating CoE; the chairs and co-chairs dominated discussion. CONCLUSIONS: CoE and BH-balance are key determinants of recommendations in favor of an intervention. Chairs and co-chairs dominate discussion. Panelists often change their judgments as a result of panel deliberation.

When are randomized trials unnecessary? A signal detection theory approach to approving new treatments based on non-randomized studies.

RATIONALE, AIMS AND OBJECTIVES: New therapies are increasingly approved by regulatory agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) based on testing in non-randomized clinical trials. These treatments have typically displayed "dramatic effects" (ie, effects that are considered large enough to obviate the combined effects of biases and random errors that may affect the study results). The agencies, however, have not identified how large these effects should be to avoid the need for further testing in randomized controlled trials (RCTs). We investigated the effect size that would circumvent the need for further RCTs testing by the regulatory agencies. We hypothesized that the approval of therapeutic interventions by regulators is based on heuristic decision making whose accuracy can be best characterized by the application of signal detection theory (SDT). METHODS: We merged the EMA and FDA database of approvals based on non-RCT comparisons. We excluded duplicate entries between the two databases. We included a total of 134 approvals of drugs and devices based on non-RCTs. We integrated Weber-Fechner law of psychophysics and recognition heuristics within SDT to provide descriptive explanations of the decisions made by the FDA and EMA to approve new treatments based on non-randomized studies without requiring further testing in RCTs. RESULTS: Our findings suggest that when the difference between novel treatments and the historical control is at least one logarithm (base 10) of magnitude, the veracity of testing in non-RCTs seems to be established. CONCLUSION: Drug developers and practitioners alike can use the change in one logarithm of effect size as a benchmark to decide if further testing in RCTs should be pursued, or as a guide to interpreting the results reported in non-randomized studies. However, further research would be useful to better characterize the threshold of effect size above which testing in RCTs is not needed.

Association between hospital anxiety and depression scale and problem-related distress in patients with cancer in a Brazilian private institution.

OBJECTIVE: Emotional symptoms are frequently reported among patients with cancer. We evaluated the association between emotional symptoms and problem-related distress in a sample of patients with cancer about to initiate chemotherapy within a private hospital in Brazil. METHODS: Patients were assessed before initiating chemotherapy, treatment mid-point, and on the last day of treatment for anxiety and depression (Hospital Anxiety and Depression Scale [HADS]) and for problem-related distress (Distress Thermometer Problem List). Problem-related distress variable was computed as the sum of practical, physical, spiritual and familial problems. Mixed-model analysis was applied to determine the association between HADS and problem-related distress, adjusting for age and gender. RESULTS: A total of 655 consecutive patients were enrolled. There was a significant main effect of time (F = 8.99, p = 0.0001), showing that emotional symptoms improve over time. A significant main effect was observed for problem-related distress (F = 371.56, p < 0.0001) revealing that patients with elevated problem-related distress at baseline tend to have higher HADS across the three time points, compared to patients with lower problem-related distress. There was an interaction effect between problem-related distress and time (F = 85.22, p < 0.0001), suggesting that HADS scores decreased differently over time, depending on patients' initial level of problem-related distress. CONCLUSION: Overall, emotional symptoms, while decreasing over time, remained associated with problem-related distress after chemotherapy in Brazil. The potential benefit of implementing a psychosocial intervention remains high throughout cancer treatment.

Association between chemotherapy toxicity risk scores and physical symptoms among older Brazilian adults with cancer.

OBJECTIVE: Utilizing the Cancer and Aging Research Group (CARG) chemotherapy toxicity risk score before starting treatment in older adults with cancer is guideline-recommended. However, this has not been tested in most developing countries. We investigated the use of a Portuguese version of the CARG score, including the association between this score and physical symptoms, among older Brazilian adults with cancer. PATIENTS AND METHODS: We enrolled patients aged ≥65 starting chemotherapy at a public Brazilian hospital. A Portuguese version of the CARG tool was created and linguistically validated. Patients were assessed for chemotherapy toxicity risk using the CARG score, and physical symptoms were evaluated using the Functional Assessment of Cancer Treatment-General (FACT-G) scale. Multivariable logistic regression was used to identify physical symptoms associated with high CARG scores, including pain, nausea, and fatigue. RESULTS: Older patients (65+) with cancer were enrolled (n = 117). Patients were mostly female (57.3%), white (52.1%), married (52.1%), and had less than high school education (75.2%). Breast, gastrointestinal and lung cancers were the most common diagnosis, and 66.7% had metastatic disease. Elevated pain scores (P < .01) were associated with higher chemotherapy toxicity risk scores, even after adjusting for potential confounders. CONCLUSION: We created and implemented a Portuguese language version of the CARG tool. We found that, although physical symptoms are not included in the CARG model, elevated pain was strongly associated with having a high CARG score. As a modifiable risk factor, pain should be addressed among older patients with cancer considering chemotherapy, to help mitigate their risks for toxicity.

US Food and Drug Administration Approvals of Drugs and Devices Based on Nonrandomized Clinical Trials: A Systematic Review and Meta-analysis.

Importance: The size of estimated treatment effects on the basis of which the US Food and Drug Administration (FDA) has approved drugs and devices with data from nonrandomized clinical trials (non-RCTs) remains unknown. Objectives: To determine how often the FDA has authorized novel interventions based on non-RCTs and to assess whether there is an association of the magnitude of treatment effects with FDA requirements for additional testing in randomized clinical trials (RCTs). Data Sources: Overall, 606 drug applications for the Breakthrough Therapy designation from its inception in January 2012 were downloaded from the FDA website in January 2017 and August 2018, and 71 medical device applications for the Humanitarian Device Exemption from its inception in June 1996 were downloaded in August 2017. Study Selection: Approved applications based on non-RCTs were included; RCTs, studies with insufficient information, duplicates, and safety data were excluded. Data Extraction and Synthesis: Data were extracted by 2 independent investigators. A statistical association of the magnitude of estimated effect (expressed as an odds ratio) with FDA requests for RCTs was assessed. The data were also meta-analyzed to evaluate the differences in odds ratios between applications that required further testing and those that did not. The results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Main Outcomes and Measures: Disease, laboratory, and patient-related outcomes, including disease response or patient survival, were considered. Results: Among 677 drug and medical device applications, 68 (10.0%) were approved by the FDA based on non-RCTs. Estimates of effects were larger when no further RCTs were required (mean natural logarithm of the odds ratios, 2.18 vs 1.12; odds ratios, 8.85 vs 3.06; P = .03). The meta-analysis results confirmed these findings: estimated effects were approximately 2.5-fold higher for treatments or devices that were approved based on non-RCTs than for treatments or devices for which further testing in RCTs was required (6.30 [95% CI, 4.38-9.06] vs 2.46 [95% CI, 1.70-3.56]; P < .001). Overall, 9 of 677 total applications (1.3%) that were approved on the basis of non-RCTs had relative risks of 10 or greater and 12 (1.7%) had relative risks of 5 or greater. No clear threshold above which the FDA approved interventions based on the magnitude of estimated effect alone was detected. Conclusions and Relevance: In this study, estimated magnitudes of effect were larger among studies for which the FDA did not require RCTs compared with studies for which it did. There was no clear threshold of treatment effect above which no RCTs were requested.

Accuracy of a Novel Handheld Wireless Platform for Detection of Cardiac Dysfunction in Anthracycline-Exposed Survivors of Childhood Cancer.

Purpose: Childhood cancer survivors are at risk for anthracycline-related cardiac dysfunction, often developing at a time when they are least engaged in long-term survivorship care. New paradigms in survivorship care and chronic disease screening are needed in this population. We compared the accuracy of a novel handheld mHealth platform (Vivio) as well as echocardiography for assessment of cardiac function [left ventricular ejection fraction (EF)] in childhood cancer survivors with cardiac magnetic resonance (CMR) imaging (reference).Experimental Design: Cross-sectional study design was used. Concurrent evaluation of EF was performed using Vivio, two-dimensional (2D) echocardiography, and CMR. Differences in mean EF (2D echocardiography vs. CMR; Vivio vs. CMR) were compared using Bland-Altman plots. Linear regression was used to evaluate proportional bias.Results: A total of 191 consecutive survivors participated [50.7% female; median time from diagnosis: 15.8 years (2-44); median anthracycline dose: 225 mg/m2 (25-642)]. Echocardiography overestimated mean EF by 4.9% (P < 0.001); linear regression analysis confirmed a proportional bias, when compared with CMR (t = 3.1, P < 0.001). There was no difference between mean EF derived from Vivio and from CMR (-0.2%, P = 0.68). The detection of cardiac dysfunction via echocardiography was poor when compared with CMR [Echo EF < 45% (sensitivity 14.3%), Echo EF < 50% (sensitivity 28.6%)]. Sensitivity was substantially better for Vivio-based measurements [EF < 45% or EF < 50% (sensitivity 85.7%)].Conclusions: This accessible technology has the potential to change the day-to-day practice of clinicians caring for the large number of patients diagnosed with cardiac dysfunction and heart failure each year, allowing real-time monitoring and management of their disease without the lag-time between imaging and interpretation of results. Clin Cancer Res; 24(13); 3119-25. ©2018 AACR.