P < .001). Longer survival was associated with multiplelines of therapy; however, these results should be interpreted with caution, andno causal relationship can be inferred.This retrospective observational study was designed to evaluate overall survivalin a real-world patient population and to identify predictive factors associatedwith receipt of second-line therapy. A retrospective analysis of electronicmedical records  was conducted among patientsinitiating first-line therapy from January 1, 2013, through April 30, 2018.Eligible patients were diagnosed with advanced gastric, gastroesophagealjunction, or esophageal adenocarcinoma and ≥18 years of age at the time oftreatment initiation. Patients alive 45 days after discontinuation of first-linetherapy were considered potentially eligible for continued therapy and werecategorized into those who received and those who did not receive second-linetherapy. Survival analyses were conducted using Kaplan-Meier method and log-ranktest without adjusting for any baseline covariates. Factors associated withfurther treatment were evaluated using logistic regression. A total of 3850patients met eligibility criteria. Among the 2516 patients available to receivesecond-line therapy, 1515 (60.2%) received second-line therapy and 1001 (39.8%)did not receive further therapy. Among those potentially eligible to receivesecond-line therapy, median survival was 15.4 months  from initiation of first-line therapy for those who receivedsecond-line therapy and 10.0 months (95% CI: 9.3-10.7) for those who did not.Longer duration of first-line therapy (≥169 vs ≤84 days), HER2-positive tumors,initially diagnosed with stage IV disease, less weight loss during first-linetherapy, and younger age were associated with receipt of second-line therapy(all  Unfortunately for patients diagnosed with metastatic disease,potentially curative surgical resection is not an option.2 National Comprehensive Cancer Network (NCCN) category 1 evidence supportsfirst- and second-line systemic therapy for patients with unresectable locallyadvanced, metastatic, or recurrent disease.4 In the first-line setting, the NCCN guidelines recommend 2-drug cytotoxictherapy. Two gastric cancer regimens are preferred by the NCCN: fluoropyrimidineplus cisplatin (category 1) or fluoropyrimidine plus oxaliplatin .4 Modified dosing of the DCF regimen or substitution of cisplatin with oxaliplatin are considered category 2Aevidence for GEJ and esophageal cancers (squamous and adenocarcinoma).3 Additionally, trastuzumab is recommended to be added to first-linechemotherapy for patients whose tumors overexpress HER2. In the second line, 5preferred regimens are supported by category 1 evidence for gastric, GEJ, oresophageal adenocarcinoma: ramucirumab plus paclitaxel or single-agent ramucirumab,docetaxel, paclitaxel, or irinotecan.4 Pembrolizumab is supported by category 2A evidence for the second-line orsubsequent treatment of tumors with high-microsatellite instability (MSI-H) or fordeficient mismatch repair tumors and in the third-line or later setting forPD-L1–positive adenocarcinoma.4Gastric, gastroesophageal junction (GEJ), and esophageal cancers carry a very poorprognosis, particularly when diagnosed at stage IV . The5-year relative survival rate for patients diagnosed with gastric/GEJ or esophagealcancers is 31.5% and 20.7%, respectively.59 In the REGARD trial, ramucirumab monotherapy reduced all-cause mortality by22% compared to placebo plus best supportive care  and reduced the risk of disease progression or deathby 52%  in patients with gastric or GEJ adenocarcinoma.5 An open-label, randomized study of irinotecan versus BSC in patients withgastric or GEJ adenocarcinoma found that irinotecan improved OS ; PFS was not compared.7 COUGAR-02 was an open-label, randomized trial comparing docetaxel to activesymptom control in patients with gastric, GEJ, or esophageal adenocarcinoma. Thisstudy also demonstrated OS improvement associated with docetaxel ; PFS was not compared between the groups.8 A Cochrane review of 11 randomized trials including 1347 participants found asignificant improvement in OS chemotherapy and/or targeted therapy versus BSC orcontrol in the second-line treatment of patients with esophageal or GEJ cancer . Five trials (883 participants) provided datasupporting the benefit in PFS for second-line treatment as well .9 Despite the mounting evidence for benefit of second-line therapy in clinicaltrials, such evidence for a real-world population is lacking.The survival benefit of second-line therapy is supported by numerous randomizedclinical trials.1012 The reasons associated with treatment discontinuation at first-line therapyare unclear. Potential reasons could include comorbidities or declining healthleading to inability to receive further treatment, patient death, or patient orphysician choice. Identifying the factors associated with the receipt of second-linetherapy in real-world population is a critical step in developing strategies toincrease adherence of patients and providers to this recommended practice.Retrospective observational studies report that less than 50% of patients receivesecond-line treatment for advanced or metastatic gastric cancer.This retrospective observational study was designed to examine whether the clinicalbenefit of continued therapy would be demonstrated in an unselected, real-worldpopulation. Additionally, this study was designed to identify factors associatedwith receipt of second-line therapy to inform potential strategies to improve therate of continued therapy among eligible patients with gastroesophagealadenocarcinoma.The Flatiron Health database is a longitudinal, demographically, andgeographically diverse database derived from electronic medical record (EMR)data. The Flatiron Health database at the time of this study included data fromover 255 cancer clinics representing 1.7 million patients with active cancer.The Flatiron Health Advanced Gastric/Esophageal Cohort is a subset of theoverall Flatiron Health database that includes a geographically diverse randomsample of over 7500 patients with advanced gastric/GEJ/esophageal cancer atFlatiron community oncology and academic cancer cancers in the United States .Patients in the database are diagnosed with stage IV disease or with distantrecurrence, a second locoregional recurrence after any initial stage atdiagnosis (gastric only), a first locoregional recurrence that was notcompletely resected , or no surgical resection of the primary tumor. Thedatabase includes patients whose advanced cancer diagnoses occurred on or afterJanuary 1, 2011, and who have 2 or more visits documented in the EMR during thattime period. The database includes both structured and unstructured EMR dataelements curated via technology-enabled abstraction, such as patientdemographics ,community versus academic facility, clinical diagnostic codes, laboratory data,HER2 expression testing and status, medications ordered and/or administered,line of therapy (derived), month and year of death, and clinical characteristicsincluding cancer stage at diagnosis, tumor histology, and Eastern CooperativeOncology Group performance status. This data set is deidentified, and provisionsare in place to prevent reidentification in order to protect patients’confidentiality. This noninterventional study does not qualify as human subjectsresearch in accordance with the US Code of Federal Regulations (CFR), 45 CFR46.102(f) and is thereby exempt from institutional review board (IRB)evaluation.13 Patients diagnosed with squamous carcinomas or who were younger than theage of 18 years at the initiation of first-line therapy were also excluded.Radiation therapy is not recorded in the database; therefore, it was assumedthat patients receiving weekly carboplatin + paclitaxel were likely receivingconcurrent radiation therapy.Patient records eligible for inclusion were those in the Flatiron advancedgastric/esophageal cohort who had a primary diagnosis of gastric, GEJ, oresophageal adenocarcinoma. As described earlier, this database is limited topatients with advanced or metastatic cancers, data specific to care ofearly-stage disease or treatment in the adjuvant or neoadjuvant setting are notincluded. All patients in this study must have initiated first-line therapy onor after January 1, 2013, to ensure the study included a current cohort ofpatients. Flatiron oncologist-defined, rule-based lines of therapy were used toidentify lines of therapy. In general, a change in a line of therapy is definedbased on the addition of new chemotherapy agents and gap periods in which notreatment was received. The rules used to define lines of therapy in Flatironare consistent with other published approaches.P values were calculated to evaluate differences incharacteristics between patients who received second-line therapy and those whodid not (among those eligible for second-line therapy) using ttest/F test for continuous variables and χ2 test for categoricalvariables. Predictors of second-line treatment were evaluated usingmultivariable logistic regression. The regression model was built to predict theprobability of patients receiving second-line treatment (vs no second-linetreatment). The candidate covariates included age-group (18-64 vs 65+), gender, race , practice type (community vs academic), disease site, HER2 status , advanced diagnosis (stage IV at diagnosis vsrecurrent/unresectable disease), body mass index , prior resection (yes vs no), weight lossduring first-line therapy , duration fromadvanced diagnosis date to start of first-line therapy (<70 days vs 71-100 vs100-200 vs >200 days), duration of first-line therapy (≤84 days vs 85-168days vs ≥169 days), and creatinine level. Stepwise variable selection procedurewas used to identify factors significantly associated with the outcome withentry significance level of 0.15 and stay significance level of 0.1.This study was designed as a descriptive, noncomparative analysis. Descriptivestatistics were reported using mean, standard deviation, median, and range forcontinuous variables and frequency counts and percentages for categoricalvariables. Patients were assumed to be eligible for second-line therapy if theywere alive at least 45 days after completion of first-line therapy and haddiscontinued first-line treatment prior to April 30, 2018 (the date of lastavailable record). The selection of 45 days was based on the optimal date thatwould exclude the sickest patients who were likely never candidates forsecond-line therapy while not creating bias by retaining patients unable toinitiate 2L therapy. Patients were assumed to have discontinued first-linetherapy if either they had initiated a subsequent line of therapy or if they hadnot received therapy within at least 30 days prior to the last data available inthe database or end of follow-up. The end of first-line therapy was defined asthe last administration date of first-line therapy. In the case of oralmedications, 30 days were added to the last refill date. UnadjustedTo reduce the risk of immortal time bias, survival analyses between those who didand did not receive second-line therapy excluded any patient who was stillreceiving first-line therapy as of April 30, 2018  or who had died during or within 45 days of completingfirst-line therapy. Overall survival from the start of 1L therapy was estimatedusing Kaplan-Meier method and log-rank test without adjusting any baselinecovariates. Additional analyses explored differences between patients who haddied during the period from initiation to the date of last infusion offirst-line therapy and those who did not die during this period.Due to the lack of data regarding radiation therapy in the EMR database,sensitivity analyses were conducted to estimate the impact of potential receiptof radiation therapy. For patients receiving weekly carboplatin plus paclitaxel,it was assumed for the sensitivity analyses that these patients were receivingconcurrent radiotherapy. The lines of therapy were recoded excluding thoserecords where chemoradiation was a line of therapy. Therefore, a patientreceiving chemoradiation would have been recategorized from first-linecarboplatin plus paclitaxel to line zero chemoradiation. Survival analyses wererepeated using the revised rules to determine the stability of results ifpossible miscategorization occurred in the absence of radiation therapydata.There were 7566 patients in the Flatiron database available for analysis. Of these,3850 met eligibility criteria and were included in the study . The priThe median OS from start of first-line therapy for patients who received second-linetherapy was 15.4 months (95% CI: 14.6-16.0), and for those who did not receivesecond-line therapy, median OS was 10.0 months  and did not meet the stepwise selectioncriteria, the Flatiron data are more than 90% community-based practices, and thedata set may not be appropriate to study this question due to the very small samplefrom academic practice settings.Importantly, the factors that may contribute to patients receiving subsequent careare critical. In this study, 451 (19.9%) patients were excluded from the survivalanalysis as if they died during first-line therapy, representing a much smallerproportion versus the 2516 patients that were alive and not continuing to receivetherapy after first-line therapy. These patients can be partly accounted for bythose with aggressive disease biology in which rapid cancer progression likelyimpacted the ability to receive further therapy. While the Flatiron database doesnot capture tumor genomic profiling given biomarker testing outside HER2 forfirst-line therapy remains experimental, certain oncogene amplifications such asIn multivariable analysis, tumor HER2 positivity was associated with higherlikelihood of receiving second-line therapy. HER2 overexpressing gastroesophagealcancers derive benefit from the addition of trastuzumab to first-line therapy. Whilehypothesis generating, improved categorization of biomarkers to develop successfulmolecularly targeted strategies to improve first-line treatment outcomes andincrease the chance of receiving subsequent lines of therapy. Duration of first-linetherapy was also found to be significant, which could be affected by improvedclinical and supportive care but also could be associated with time to progressivedisease. The available EMR data sets did not contain data on disease progression, sothis could be a factor unaccounted for in the analysis. Importantly, patient weightloss during first-line therapy is a potentially modifiable factor that providerscould address during first-line care to ensure patients maintain body weight duringinitial treatment. There is a need to further investigate this finding to understandwhether the study of interventions to support patient body weight after advancedgastric cancer diagnosis are warranted.Despite the limitations of retrospective analyses with regard to causal inference,this study provides evidence regarding a potential association between survivaloutcomes and therapy after first-line treatment among patients able to receivesubsequent treatment. There is a need to ensure patients receive the best possibleoutcomes of treatment by providing category 1 evidence-based care whenever possibleand to consider taking a sequential approach to therapy to ensure as many patientsas possible remain well enough to continue therapy if and when first-line therapyfails.Click here for additional data file.SUPPLEMENTAL_TABLES for Real-World Outcomes and Factors Associated With theSecond-Line Treatment of Patients With Gastric, Gastroesophageal Junction, orEsophageal Adenocarcinoma by Afsaneh Barzi, Lisa M. Hess, Yajun E. Zhu, Astra M.Liepa, Tomoko Sugihara, Julie Beyrer and Joseph Chao in Cancer Control


This cross-sectional study analyzes the association of rural-to-urban migration in China with mental health among migrants and their left-behind family members. What is the association of rural-to-urban migration in China with symptoms of depression among migrants and their left-behind family members?In this study of cross-sectional data from the 2015 China Health and Retirement Longitudinal Survey including 14 332 middle-aged and older adults, rural-to-urban migration was associated with higher depressive symptoms, and a similar association was found among left-behind spouses.Mental health policy in China should address the increased risk of symptoms of depression among migrants and their left-behind family members. There were an estimated 247 million rural-to-urban migrant workers in China in 2016, yet at a national level, there is scant evidence on the association of migration with mental health among migrants and their left-behind family members.To examine the association of rural-to-urban migration with symptoms of depression among migrants and left-behind family members aged 45 years and older.Using representative cross-sectional data of 14 332 middle-aged and older adults from the 2015 China Health and Retirement Longitudinal Survey, regression analyses were conducted to examine the association of depressive symptoms with rural-to-urban migration status in urban areas and the association of depressive symptoms with left-behind status in rural areas. The statistical analysis was performed from January to August 2018.hukou [household registration record]) in urban areas and left-behind status (defined as having a spouse or child living in another area) in rural areas.Migration status  scale.P = .03; standard errors clustered at the household level henceforth). Compared with intact-family rural residents, left-behind spouses had higher CES-D-10 scores after adjustment for covariates .A total of 14 332 middle-aged and elderly participants  were included, of whom 4404 (30.7%) lived in urban areas and 9928 (69.3%) lived in rural areas. In urban areas, 1607 participants (36.2%) were rural-to-urban migrants, and the remaining 2797 participants (72.8%) were local residents. In rural areas, 3405 participants (34.3%) were left-behind family members, and the remaining 6523 participants (65.7%) were not. Compared with urban residents, rural-to-urban migrants had higher CES-D-10 scores after adjustment for covariates (β = 0.74; 95% CI, 0.08-1.40; Rural-to-urban migration in China was associated with poor mental health for migrants and their left-behind spouses. Short-term policies, such as building community social facilities, may prove effective, but long-term solutions should address issues related to economic and social exclusions and the lack of a social security system in rural China. The associations of migration could go beyond happiness, well-being, and life satisfaction: migration could also be associated with worse health outcomes, including mental health outcomes.Rural-to-urban migration in China has been a major driving force behind its economic growth in the past few decades. Beyond economic implications, there has been an increasing interest from research and policy communities to understand the association of rural-to-urban migration with various well-being outcomes in China. The 2018 World Happiness Report2 In addition, the literature offers limited evidence on the channels through which migration and mental health are associated. To date, most studies in the literature focus on the hukou system, the Chinese household registration system, which is primarily based on place of birth and hence divided into 2 broad categories: urban and rural. Hukou affiliation is linked to the provisioning of social services .3 This implies that rural-to-urban migrants are generally excluded from social welfare services,6 with a potential impact on mental health, particularly for women and now-older migrants who moved during the earlier, more restrictive hukou environment.9 For older rural-to-urban migrants who faced a more restrictive system, this may be associated with poorer mental health compared with their younger counterparts. A 2014 study2 of a single city in China supports this notion, but nationally representative samples have not been explored, to our knowledge.Despite increased interest, the literature on the association of rural-to-urban migration with mental health and the channels through which rural-to-urban migration and mental health are associated is limited, particularly for older adults. To our knowledge, most of the literature has focused on the migration and mental health nexus of younger migrants.11 The existing studies in China suggest that older left-behind or empty-nest parents have higher levels of depressive symptoms. Higher depressive symptoms may be attributed to lowered social capital, worse economic status, and increased loneliness.14 More evidence from a nationally representative survey is needed to examine the mental health status of left-behind family members and the potential mitigation mechanisms, such as remittances or close emotional ties.16The large wave of rural-to-urban migration has also created a group of left-behind parents, spouses, and older adults. This issue has been explored in other Asian countries, but, to our knowledge, most of the studies in the Chinese context have been small and nonrepresentative.17 Studies have shown that increased social participation is associated with higher subjective well-being and can mediate the association of resources with well-being for retired people.20 It is important to examine whether this is also the case for elderly migrant groups.Additionally, further evidence is needed to distill policies relevant for strengthening the mental health of elderly rural-to-urban migrants. For example, more emphasis may be needed on community building and promotion of social support networks.This study had 3 objectives. The first was to examine the association of migration status with depressive symptoms in urban areas. The second was to examine the association of left-behind status with depressive symptoms in rural areas. The third was to explore factors that could contribute to or mitigate the disparities in depressive symptoms associated with rural-to-urban migration.21 The CHARLS is a nationally representative survey of individuals in China aged 45 years and older, providing rich data to serve the needs of scientific research on older adults. The national baseline survey for the CHARLS was conducted between June 2011 and March 2012 and included 17 708 individual participants. Samples were chosen through multistage probability sampling. In the first stage, 150 county-level units were randomly chosen with a probability-proportional-to-size sampling technique from a sampling frame containing all county-level units except Tibet. The sample was stratified by region, within region by urban districts or rural counties, and per capita on gross domestic product. The final sample included 150 counties in 28 provinces. In the second stage, the survey used villages in rural areas and communities in urban areas as primary sampling units. Three primary sampling units were selected within each county-level unit using probability-proportional-to-size sampling. Finally, 80 households were randomly sampled in each primary sampling unit, from which those with an age-eligible member (≥45 years) were approached by survey collectors for participation. Written informed consent and individual information were collected through computer-assisted personal interviewing. Since CHARLS Wave1 was completed in 2012, 2 follow-up surveys have been conducted to date, one in 2013 (CHARLS Wave2) and another in 2015 (CHARLS Wave3), which tracked previous respondents and included a small share of new respondents. We used the most recent data from the 2015 wave for our study. The 2015 wave included 20 284 participants in total, from which we selected 14 332 after excluding 615 age-ineligible participants, 2484 participants in semiurban areas, and 2853 participants with missing values. We split the data into an urban subsample for the analysis of rural-to-urban migrants vs urban residents and a rural subsample for the analysis of left-behind rural family members vs intact-family rural residents. Ethical approval for primary data collection was obtained from the Ethical Review Committee at Peking University in 2011. Our research involved secondary analysis of deidentified established data sets and was not subject to ethical approval or informed consent according to London School of Economics and Political Science22 research ethics policy and procedures. Results were reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline for cross-sectional studies.Our sample came from the household questionnaire administered in the 2015 China Health and Retirement Longitudinal Study (CHARLS).24 Respondents were asked to rate how often they experienced depressive symptoms in the last week, with 0 indicating rarely, 1 indicating some days (1-2 days), 2 indicating occasionally (3-4 days), and 4 indicating most of the time (5-7 days). The responses were summed to produce a score from 0 to 30. A binary measure for scoring 10 or greater was used as a robustness check.24Depressive symptoms were measured with the 10-item Center for Epidemiologic Studies Depression (CES-D-10) scale.25 Out of the concern that urban areas by this definition include the outskirts of city and town areas that were in fact rural in nature,26 we excluded the outskirt areas and restricted the urban sample to the central areas of cities and towns. Migration status was defined by respondents’ current place of residence and their current hukou status. Individuals were categorized as rural-to-urban migrants if they lived in an urban area and currently had rural hukou. Individuals were categorized as urban residents if they lived in an urban area and had nonrural hukou. In further analysis, we divided rural-to-urban migrants by sex.We based our analysis of migrants on the urban subsample. Urban and rural area definitions were provided in the CHARLS according to the guidelines by the China National Bureau of Statistics.We based our analysis of left-behind family members on the rural subsample. Left-behind spouses were people living in a rural area who did not live with their spouse. Left-behind parents were people who had no children living nearby (in the same household or community) and at least 1 child who was not living in the same community. A left-behind family member was defined as being either a left-behind spouse or left-behind parent. Other rural residents were categorized as intact-family rural residents. Left-behind spouses and left-behind parents were not necessarily mutually exclusive.Covariates were selected to control for potential confounding related to socioeconomic status and physical health. Socioeconomic variables included sex, age, marital status (currently married or not), education levels , and a continuous variable of logarithm of per-capita household expenditure (coded as 0 if not reported). Physical health indicators included a binary variable of having fallen down in the last 2 years , a binary variable of experiencing any physical function difficulty in 10 daily tasks , and a binary indicator of having been diagnosed as having 1 or more of 13 listed long-term conditions . A binary variable was also included to indicate if physical function difficulty information was not reported.We further considered variables about economic and social exclusion in parts of the analysis. For rural-to-urban migrants, these included a binary variable indicating owning their current residence, a binary variable indicating having any savings, a binary variable indicating engaging at least weekly in 1 or more of 8 listed social activities , a community social facilities index  indicating the availability of 1 or more of 14 listed facilities in the village or community , and years since migration. For left-behind family members, these included 2 variables of receiving support: a binary variable indicating having received financial support (in cash or in kind) from children, and a binary variable indicating seeing children at least once per year.t tests to test the differences.We started by presenting descriptive statistics. First, we showed regional variations in depressive symptoms among provinces by plotting the provincial CES-D-10 mean score on a map. We divided the provincial mean CES-D-10 scores into quartiles, then visualized the data by displaying the results on a thematic map. Second, we reported unconditional subgroup means in urban and rural areas separately. Specifically, for the urban subsample, we compared the mean CES-D-10 scores and the proportions of CES-D-10 scores of 10 or greater of rural-to-urban migrants with urban residents, and for the rural subsample, we compared mean CES-D-10 scores of left-behind with intact-family rural residents. We used Least squares regression analyses were conducted to assess the association of migration or left-behind status with depressive symptoms. To allow for error terms to be associated within the household, we clustered standard errors at the household level to avoid overstating estimation precision. Survey sampling weights were applied in all regressions. Analyses were performed using Stata statistical software version 14.2 (StataCorp).Next, we explored what factors might be associated with the potential disparities in depressive symptoms by migration status. We regressed CES-D-10 scores based on rural-to-urban migrant status, while also controlling for a range of socioeconomic and health status covariates. In recognition of regional disparities of economic and social development, we further controlled for province fixed effects. We further examined heterogeneity by replacing the rural-to-urban migrant variable with 2 variables, one indicating a male migrant and the other indicating a female migrant.To assess potential migration-associated depressive symptoms pathways, we focused on the economic and social exclusion of migrants by regressing an economic or social exclusion indicator based on migration status. The indicators included whether the respondent owned the property of current residence, whether the respondent had any individual savings, and a social activity index. We next considered what factors might reduce the risk of depressive symptoms for migrants. Focusing on the migrant subsample, we analyzed if certain factors  were associated with lower depressive symptoms among migrants.Last, we examined whether migration was associated with increased depressive symptoms for left-behind family members. In the rural sample, we regressed CES-D-10 scores based on left-behind status and covariates. In an alternative specification, we replaced the left-behind status variable with left-behind spouse status or left-behind parent status. In the left-behind sample, we regressed CES-D-10 based on 2 variables indicating financial and emotional support and covariates to understand the association of depressive symptoms with familial support for left-behind family members.P values were 2-tailed. Statistical significance was set at less than .05.A total of 14 332 middle-aged and elderly participants  were included, of whom 4404 (30.7%) lived in urban areas and 9928 (69.3%) lived in rural areas. In urban areas, 1607 participants (36.2%) were rural-to-urban migrants, and the remaining 2797 participants (72.8%) were local residents. In rural areas, 3405 participants (34.3%) were left-behind family members, and the remaining 6523 participants (65.7%) were not. Descriptive statistics for urban, rural, and all participants are shown in 27Graphical evidence suggested there were wide variations in depressive symptoms among provinces in China, with the mean (SD) provincial CES-D-10 score ranging from 4.41 (3.86) points to 12.32 (6.96) points. There was a geographical trend that depressive symptoms increased from east to west . This roP = .23), which is 10% of 1 SD of the whole distribution (6.54 points). The difference between CES-D-10 scores of female migrants and female urban residents was higher , or 27% of 1 SD. Male migrants had a probability (SD) of 0.22 (0.42) of reporting high depressive symptoms (CES-D-10 score ≥10) compared with their urban counterparts’ probability (SD) of 0.17 (0.37). Among female migrants, the probability (SD) of reporting high depressive symptoms was 0.40 (0.49) compared with their urban counterparts’ probability (SD) of 0.26 (0.44).Rural-to-urban migrants reported higher mean CES-D-10 scores than urban residents among both men and women. Without adjusting for covariates, male migrants’ CES-D-10 scores were greater than male urban residents’ scores . Compared with intact-family rural residents, left-behind spouses had higher CES-D-10 scores after adjustment for covariates . Being a woman and being in poor physical health  were associated with reporting higher depressive symptoms. Older age, being married, having higher education levels, and having higher living standards (indicated by household expenditure) were associated with reporting lower depressive symptoms. Estimated coefficients for covariates are reported in P = .01). Compared with male urban residents and conditional on covariates and provincial fixed effects, male migrants also had higher CES-D-10 scores .P < .001) lower probability of owning current residence, 10.3%  lower probability of having any savings, and 8.6%  lower probability of engaging in weekly social activities. Statistical significance remained for these 3 multiple tests after applying Bonferroni correction. Compared with migrants who did not live in a community with community facilities, migrants living in a community with community facilities had lower CES-D-10 scores . More years since migration was not associated with CES-D-10 .P = .03), as did left-behind parents , although the difference was not significant. Among the left-behind sample, compared with people who did not receive financial support from family, people who received financial support from family had lower CES-D-10 scores , and compared with not seeing children at least once per year, left-behind people who did see their children at least once per year had lower CES-D-10 scores .Finally, we explored the mental health associations among the family members left behind because of spouse or adult child migration, as reported in Based on our analysis of data from the 2015 CHARLS survey, we report a number of important findings. Our analysis found that rural-to-urban migration was associated with higher depressive symptoms in middle and old age. This association was particularly strong among female migrants. We also found that migration was positively associated with economic deprivation (proxied by house ownership and savings) and social exclusion , suggesting these factors were likely channels underlying the association of migration with depressive symptoms. We also found that community building  could mitigate the negative association of migration with depressive symptoms, in that migrants living in communities with more social facilities had lower depressive symptoms than migrants living in communities with fewer social facilities. Additionally, we found that being a left-behind spouse was associated with higher depressive symptoms and that among left-behind parents, receiving more familial support from children financially or emotionally was associated with lower depressive symptoms than receiving less familial support.hukou system and the marginalization of women within the system. Existing research argues that migrant women have multiple marginalized identities and thus are more likely to be exposed to social and economic inequality compared with their male counterparts.28 Although we were not able to show causal effects, our findings support the notion that female migrants may be at higher risk of depression than their male counterparts.Previous analyses have argued that female migrants have worse mental health status because of the nature of the hukou system acts as an institutional barrier to integration.29 Previous studies have explored the urban economic and social exclusion of rural-to-urban migrants and the ways in which they are excluded.6 One study that used subjective measures of socioeconomic status showed that migrants had higher likelihood of economic isolation,30 while another found migration led to divided social identities and social stigma.31 Our results support the literature that suggests that economic and social deprivation could translate into poor mental health. From a policy perspective, it is important to understand what resources and facilities might mitigate the negative association of migration with mental health. We contributed to this question by showing that the availability of community social facilities could be associated with better mental health outcomes among migrants.33We explored the roles of economic and social exclusions in understanding the association of migration with depressive symptoms. These 2 mechanisms are particularly relevant to rural-to-urban migrants in China where the 34 Within this context, intergenerational support structures, such as financial support and regular visits from children, play an important role for the mental health of the rural left-behind elderly population.While we did not find evidence that left-behind family members were associated with worse mental health status overall, we did observe that left-behind spouses were associated with higher depressive symptoms and left-behind parents were not. Among left-behind parents, our results suggest that familial support is important for lowering depressive symptoms. Because of the lack of a comprehensive pension system in rural China, family support is the primary source of support for elderly rural residents.There are a few strengths of our work. First, this analysis is the first analytical effort on the mental health and migration nexus of middle-aged and elderly Chinese people relying on a well-established nationally representative data set, to our knowledge. Second, in performing our analysis, we also explored some of the factors that could be associated with lower mental health outcomes among elderly migrants, such as socioeconomic exclusion. Relevant to policy making, we also explored whether the availability of community social facilities could help limit the negative association of migration with mental health. Third, we emphasized that migration was not only associated with the mental health of the migrants themselves but also with the mental health of family members that were left behind. We further explored the association of familial support with the mental health of left-behind family members.This study also had limitations. First, although we tried to control for as many confounding covariates and regional variations as possible, there were unobservable factors that might be associated with migration and mental health that we were not able to account for. Thus, our interpretation of the results was not causal. Although we did not establish causality, we did show a pattern of association of migration with mental health status. Second, our data only included individuals aged 45 years and older, so we were unable to examine how the mental health of left-behind children might be associated with the rural-to-urban migration of their parents.Mental health policy in China should address the issue that migrants and some of their left-behind family member may be at higher risk of poor mental health. Effectively addressing this issue requires more broad policy coordination to deal with economic and social exclusions associated with rural-to-urban migration. While this will be a long-term task, our findings regarding the association of community-based social facilities with mental health provides support to the notion that community-based social facilities could contribute to improving mental health of elderly migrants by facilitating opportunities for interaction with others and increasing feelings of self-determination. Community building projects should be continued, and access to community centers for rural-to-urban migrants should be facilitated. Additionally, familial support was associated with the mental health of left-behind family members. Although emotional support may be irreplaceable, the lack of a formal social security system in rural areas could be a factor in why left-behind rural residents rely on their children for financial support. Establishing a social security system in rural areas could be a path to economic security and mental well-being for rural residents.


A dose-response relationship was found between spironolactone use and risk of ESRD and HKAH. There were no statistical differences in MACE, HHF, all-cause mortality and cardiovascular mortality between spironolactone users and non-users. Conclusion: Spironolactone represented a promising treatment option to retard CKD progression to ESRD amongst stage 3–4 CKD patients, but strategic treatments to prevent hyperkalemia should be enforced.Background: Spironolactone, a non-selective mineralocorticoid receptor antagonist, can protect against cardiac fibrosis and left ventricular dysfunction, and improve endothelial dysfunction and proteinuria. However, the safety and effects of spironolactone on patient-centered cardiovascular and renal endpoints remain unclear. Methods: We identified predialysis stage 3–4 chronic kidney disease (CKD) patients between 2000 and 2013 from the Longitudinal Health Insurance Database 2005 (LHID 2005). The outcomes of interest were end-stage renal disease (ESRD), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), hyperkalemia-associated hospitalization (HKAH), all-cause mortality and cardiovascular mortality. The Fine and Gray sub-distribution hazards approach was adopted to adjust for the competing risk of death. Results: After the propensity score matching, 693 patients with stage 3–4 CKD were spironolactone users and 1386 were nonusers. During the follow-up period, spironolactone users had a lower incidence rate for ESRD than spironolactone non-users (39.2 vs. 53.69 per 1000 person-years) and a higher incidence rate for HKAH (54.79 vs. 18.57 per 1000 person-years). The adjusted hazard ratios for ESRD of spironolactone users versus non-users were 0.66 (95% CI, 0.51–0.84;  Chronic kidney disease (CKD), having an increasing prevalence rate of about 10% worldwide as a result of longevity and ongoing epidemic of diabetes mellitus (DM), is an emerging global health concern and associated with the risk of premature cardiovascular disease (CVD) and mortality . The aboAmong the available treatment options to retard renal function decline, blockade of renin-angiotensin-aldosterone system (RAAS) by angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) has been widely used for their potentially beneficial effects on renal and cardiovascular outcomes in both diabetic and non-diabetic patients ,5. The rSeveral studies on the effects of MRA were conducted amongst CKD patients in the past one decade. A 2014 meta-analysis, updated from a 2009 meta-analysis, included 1549 patients of 27 studies and demonstrated that addition of MRA to ACEI or ARB (or both) in mild to moderate CKD patients resulted in the reduction of proteinuria and blood pressure, but precluded conclusive evidence regarding the risk of major cardiovascular events or end-stage renal disease (ESRD) . The higThe National Health Insurance Research Database (NHIRD) of Taiwan, which included the healthcare utilization data covering 99% of Taiwanese population, was released for the purpose of scientific research. The Longitudinal Health Insurance Database 2005 (LHID 2005), which contained the information of 1 million people, was randomly selected from the NHIRD and was used as the research database for our study. LHID 2005 contained the comprehensive de-identified healthcare information on demographic, outpatient visit, inpatient care, prescription drugs and medical procedures from 1996 to 2013. The Bureau of Taiwan Health Insurance adopted the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes for medical coding. The drugs were classified according to the Anatomical Therapeutic Chemical (ATC) classification system. This study was approved by the Institutional Review Board (IRB) of the Changhua Christian Hospital  and conducted in accordance with the declaration of Helsinki. The written informed consents were waived for a retrospective study in Taiwan.From 1996 to 2013, we identified 21,693 patients with CKD who were defined as having at least one record of a CKD diagnostic code made by a nephrologist per month for at least three consecutive months. We used a 4-year look-back (1996–1999) period to determine patients with incident CKD by excluding pre-existing CKD diagnosis. In addition, incident CKD patients who had incomplete demographic data; were aged <18 years, >100 years; had advanced CKD (stage 5), acute kidney injury, end-stage renal disease; or had a follow-up time of <90 days were also excluded. The remaining incident CKD patients represented moderate to severe (stage 3–4) CKD patients. Among them, patients who had received spironolactone within 90 days after CKD diagnosis were considered as spironolactone users, whereas the remaining patients were considered as non-users. Because we used drug prescription information within 90 days after CKD diagnosis to ascertain spironolactone use, the 91st day after CKD diagnosis was defined as the index date.The outcomes of interest were ESRD requiring renal replacement therapy, MACE, HHF, HKAH, all-cause mortality and CVD mortality. MACE was the composite of acute myocardial infarction (ICD-9 code 410) and ischemic stroke (ICD-9 code 433–436). We defined HHF and HKAH as the first listed ICD-9 code 428 or 276.7 of the discharge diagnoses during the follow-up period, respectively. Causes of death were defined by either the main diagnosis for in-hospital death or the first discharge diagnosis of the last hospitalization within three months before death outside the hospital. The end of study was on 31 December 2013. Death was considered a competing event for the occurrence of ESRD, MACE, HHF, and HKAH.Potential relevant confounders included demographic , comorbid diseases defined by at least three corresponding diagnostic codes within 1 year before index date, and long-term medications use, such as anti-hypertensive drugs, anti-diabetic medication, statin, aspirin, NSAIDs and NaHCO3. Charlson comorbidity index scores (CCIs) were used to measure the severity of baseline comorbidities.Data were presented as mean ± standard deviation (SD) for continuous variables and number (percentage) for categorical variables. The distribution of patients’ characteristics between spironolactone users and non-users was compared using chi-squared tests and t-test for categorical and continuous variables, respectively. The propensity score was calculated by performing non-parsimonious multivariate logistic regression using all the patient’s characteristic variable . The resWe calculated the incidence rate (per 1000 person-years) for outcomes of interest. The cumulative incidence of study outcomes over time between spironolactone users and non-users was estimated using modified Kaplan-Meier method (Fine and Gray sub-distribution hazards approach) and compared using Gray’s tests. The Cox proportional hazards regression models were performed to assess the association between spironolactone use and outcomes of interest, with hazard ratio (HR) and 95% confidence interval (CI) to determine the statistical significance. Because death would impede the occurrence of other study outcomes, the Fine and Gray sub-distribution hazards approach was adopted to adjust for the competing risk of death.p-value < 0.05 was considered as significant.To determine the dose-response association, we estimated the risk of clinical outcomes for spironolactone users versus non-users according to the prescribed daily dose  and the cumulative defined daily dose (DDD) during the 90-day exposure period (≤30 or >30 DDD). The spironolactone DDD defined by WHO is 75 mg. Subgroup analyses were performed to assess the effect modification and we tested the association between spironolactone use and study outcomes of statistical significance in different patient groups. Furthermore, we performed a series of sensitivity analyses to obtain a robust result. First, we evaluated misclassification bias by re-defining spironolactone use at interval of 60, 120 and 180 days after CKD diagnosis. Second, we excluded patients in control cohort who received spironolactone during the follow-up period. Third, an as-treat (AT) model was performed to examine the results when patients who switched to receive or discontinue spironolactone were censored. Fourthly, we also checked the cohort effects by dividing all the study patients into two exposure year periods. Lastly, we re-ran the multivariate regression analysis using the raw data before propensity score matching . All statistical analyses were performed using R language and SPSS statistical software, version 20.0 ). Two-tailed p value < 0.001) but an increased prevalence of HKAH  compared with the spironolactone non-users. However, there was no significant difference in prevalence of MACE, HHF and mortality.A flowchart of the subjects’ selection process was shown in p value < 0.001 in p value < 0.001) compared with the spironolactone non-users. After adjustment for all confounders, the association was unchanged . An inverse dose-response relationship was found between spironolactone use and risk of ESRD. Compared with CKD patients not taking spironolactone, patients who took prescribed daily dose of spironolactone ≥25 mg, 12.5–25 mg and <12.5 mg had significantly a lower risk of ESRD with aHR of 0.57 (0.35–0.91), 0.59 (0.39–0.91), and 0.73 (0.52–1.00), respectively .During the follow-up period, spironolactone users had a lower incidence rate for ESRD than spironolactone non-users (39.2 vs. 53.69 per 1000 person-years) . Kaplan-p value < 0.001 in p value < 0.001; aHR, 3.17; 95% CI, 2.41–4.17; p value < 0.001) than spironolactone non-users  . Spironoon-users . In the Kaplan-Meier curves showed non-significant difference in cumulative incidences for MACE, HHF, CVD mortality and all-cause mortality . NonetheThe reduced HRs of ESRD associated with spironolactone use among moderate to severe CKD patients were consistent across most of the patient subgroups, except those with female cohort, no nephrological visit, non-hypertension, DM, stroke, cirrhosis, ACEI/ARB users, while the significant interaction effect was only found between ESRD and DM . MoreoveThe results of a series of sensitivity analyses were shown in As far as we know, the present study was the first and largest study of nationwide cohort population to assess the effects of spironolactone on patient-centered hard endpoints in patients with moderate to severe (stage 3–4) CKD. The most striking finding was, for the first time, that treatment with spironolactone was associated with a lower risk of ESRD but complicated with a higher risk of HKAH. The dose-dependent effect of spironolactone suggested that a lower risk of ESRD was confounded by a higher risk of HKAH while prescribing higher doses of spironolactone. Insignificant associations were found between spironolactone users and non-users in terms of MACE, HHF, all-cause mortality, and cardiovascular mortality. The associations were further consolidated by the consistent results throughout the sensitivity tests and in most subgroups of patients.n = 18–208) with variable methodology and most of them had stage 1–3 CKD. Data were not available on long-term patient-focused outcomes, including cardiovascular events, ESRD, and mortality in any of the trials. Currie et al. demonstrated that combined use of MRA with ACEI and/or ARB significantly lowered proteinuria with a higher risk of hyperkalemia, but was associated with a small, non-significant decline in renal function in a recent meta-analysis [A growing body of clinical evidence has been emerging in support of the independent role of aldosterone in the development and progression in cardiovascular and kidney disease ,12,13. TThe hyperkalemia risk induced by spironolactone may be mitigated by replacement with nonsteroidal MRA which reportedly had a promising reduction in albuminuria with a lower risk of side effects in patients with diabetic nephropathy . FurtherMineralocorticoid receptors (MR) are expressed in podocytes, mesangial cells and endothelial cells and smooth muscle cells of murine vasculature . Renal MRecently, Tseng et al. reported the use of spironolactone in advanced (stage 5) CKD patients resulted in higher risks of all-cause mortality, HHF, and infection related mortality and non-significant associations with MACE, CVD mortality and HKAH whereas the impact on ESRD was not evaluated . They atThe present study is the first large-scale nationwide one to investigate the effects of spironolactone on several clinical endpoints in stage 3–4 CKD patients. The selection bias was minimized due to the use of medical claim data of NHIRD, which covered more than 99% of Taiwanese residents. In addition, a longer follow-up time and more enrolled patients than previously published trials allowed us to assess the risks and benefits associated with spironolactone in the long run. Furthermore, the robustness of our findings was strengthened by performing propensity-score matching process, sensitivity analyses and subgroup tests. However, some limitations should also be addressed. First, some residual confounding factors may affect our outcomes despite we managed to adjust for clinically important patient characteristics, including socio-economic status, relevant comorbidities and medications usage. The NHIRD also did not contain personal information, which is known as key determinants of clinical outcomes, such as medical adherence, over-the-counter medications, Chinese herbal medicine, tobacco use, and laboratory measurements. A propensity-score matching method was applied to control for the residual confounders. The unmeasured confounders were likely to distribute equally in the spironolactone and control groups. Second, causality cannot be approved in our retrospective observational study. Our national cohort study represented a clinical practice in the real world, unlike the randomized controlled trials where women and high-risk and vulnerable populations are usually excluded. Available evidence also indicated that well-designed observational studies do not systemically overestimate the treatment effects and can yield comparable results to randomized controlled trials .Third, the use status of spironolactone may change over time, biasing the statistical analyses. We defined the spironolactone users by several time intervals and ran the analyses by treating spironolactone use in as-treated model and excluding the control cohort receiving spironolactone during the follow-up period, and checked the cohort effects. All of these tests produced similar results as the primary analyses. Fourthly, there is indication bias inherent to this study because spironolactone was not prescribed with the intention to prevent the progression of CKD. Instead, spironolactone is mainly used as treatment for cirrhosis, resistant hypertension or heart failure and these comorbidities increase the progression of CKD to ESRD. Therefore, the spironolactone users were more frequently co-morbid, especially by cirrhosis, resistant hypertension and heart failure, which was evident from our unmatched data for baseline characteristics. Because the spironolactone users were more comorbid and these comorbidities worsen renal function, the renal protective effect of spironolactone was supposed to augment in the absence of these comorbidities. We also re-ran the multivariate regression analysis using the raw data before propensity score matching and the results were consistent with the primary analyses. Finally, the results of the present study may not be applicable to other population outside Taiwan due to different ethnicity, cultural background and health service systems. It may only apply to stage 3–4 CKD patients, not to advanced (stage 5) CKD.In conclusion, spironolactone represented a promising treatment option to retard CKD progression to ESRD in patients with moderate to severe (stage 3–4) CKD. The HR of ESRD for spironolactone users versus non-users was 0.66 (0.51–0.84) but it also carried a significantly quantifiable risk of HKAH. There was no significant difference in the risks of MACE, HHF, all-cause mortality and CVD mortality between spironolactone users and non-users. Based on the results of our nationwide population-based cohort study, spironolactone can be prescribed for its renoprotective effect in stage 3–4 CKD but strategic treatments to prevent hyperkalemia should be enforced.


Patients with breast cancer experience a variety of disease symptoms and treatment-related side effects that can adversely affect functioning. The breast cancer experience may differ across disease stages and biomarker subtypes. This study identified relevant disease symptoms, treatment-related side effects, and physical functioning impacts in women with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer.One-on-one concept elicitation interviews were conducted with 15 patients with HR+/HER2- advanced breast cancer. Open-ended questions about patient experience with breast cancer and its treatment were drawn from a semi-structured interview guide. All interviews were audio-recorded and transcribed verbatim, and codes were used to document and organize patient descriptions of their experiences. Coded concepts were defined, supported by exemplary patient quotes, and analyzed for frequency of mention and saturation. Five interviews with experienced oncologists were conducted to supplement the concept elicitation interviews.n = 5 each, 100%), while the ability to work  and walk  were reported impacts, aligning with those concepts reported by patients. The resulting concepts were organized into a patient-based conceptual model.The average age of the patients was 66 years. Most (53%) self-identified as White/Caucasian; 40%, as Black/African American. Patients were reported to have metastases to bone (87%), liver (20%), lung (13%), skin (7%), and lymph nodes (7%). The most frequently reported disease-related concepts were fatigue and lump in breast (47% each) and pain (40%), while the most frequently reported treatment-related side effects were hair loss (67%), fatigue/tiredness (47%), and nausea (40%). Patients identified 10 concepts associated with both breast cancer and its treatment, including fatigue/tiredness, shortness of breath, weakness, and nausea. The most frequently reported impacts on physical function included working around home (73%), walking (73%), and cooking (53%). The most frequently reported symptoms and side effects from the expert perspective included fatigue, pain, and hot flashes .The online version of this article (10.1186/s41687-019-0098-1) contains supplementary material, which is available to authorized users. For patients with hormone receptor positive (HR+)/human epidermal growth factor receptor-2 negative (HER2-) advanced  breast cancer, standard treatments include endocrine monotherapy or targeted therapy with an anti-estrogen in patients with non-visceral or asymptomatic visceral tumors . DiseaseBecause treatment for HR+/HER2- advanced breast cancer is rarely curative, understanding the most relevant disease-related symptoms, treatment-related side effects, and impacts, particularly those on physical functioning, is essential for promoting and maintaining high levels of quality of care in this patient population. In order to evaluate treatment benefits from the patient perspective, it is necessary to understand the most important and relevant aspects of the HR+/HER2- advanced breast cancer experience.In its 2009 Patient-Reported Outcome (PRO) Guidance to Industry, the United States Food and Drug Administration (FDA) acknowledged the value of the patient perspective in evaluating drug efficacy to support labelling claims . In oncoTo direct and inform the research described in this paper, a targeted review of the scientific literature was first conducted to identify and describe the patient experience of advanced breast cancer from the perspective of the peer-reviewed literature. The literature review identified several qualitative studies that sought to provide findings on the relevant and important disease-related symptoms, treatment-related side effects, and impacts of breast cancer from the patient perspective. For example, two semi-structured interview studies and one study that involved essay writing all identified pain and lack of energy (fatigue) as key symptoms or side effects among women with metastatic breast cancer –9. OtherAlthough patient experiences with advanced breast cancer have been researched, there is a need to understand patient experiences across biomarkers, which can differ substantially due to various sites of metastases, disease history, and treatment options , 11. UndQualitative concept elicitation interviews were conducted with patients with HR+/HER2- advanced  breast cancer. Interviews with experienced oncologists were also conducted to supplement findings from the patient perspective.Concept elicitation interviews were conducted to collect and document information about the important and relevant disease-related symptoms, treatment-related side effects, and physical functioning impacts from the perspective of patients with HR+/HER2- advanced breast cancer. Patients were also administered selected PRO measures to evaluate their understanding of the content; results of that activity are beyond the scope of the present paper and will be published elsewhere.Approval to execute the study was received from Quorum Independent Review Board on 27 June 2016. All patients completed and signed statements of informed consent prior to their participation and, once enrolled, completed a Demographic Health and Information Form. A clinician-completed Subject Clinical Screener was used to collect clinical data about patients enrolled in the study.Patients were recruited in person by clinicians at four different clinical sites in the United States (US) from June 2016 to December 2016. Clinicians reviewed patient charts and communicated with a third-party recruitment agency regarding patient eligibility. Patients were considered eligible for participation if they had clinical confirmation of HR+/HER2- advanced breast cancer not amenable to curative treatment by surgery or radiotherapy and were willing and able to participate in a 90-min interview. Additional clinical targets were identified  to align the qualitative study population with clinical trials, as recommended by the FDA’s 2009 PRO guidance . Recruit“You mentioned [Symptom A]. Can you tell me more about this? Are [Symptom A] and [Symptom B] the same or different?”“Can you describe any changes to your daily life, if any, that you have experienced due to [patient’s term for breast cancer]? If so, how? What do you think causes [the impact]?”One-on-one patient interviews were conducted in person or over the telephone. The interviews were approximately 90 min long, and the concept elicitation portion lasted approximately 45 min. Trained interviewers followed a semi-structured interview guide developed to solicit spontaneous responses through open-ended questions about the topics of disease-related symptoms, treatment-related side effects, and physical functioning impacts experienced by patients. The interview guide contained questions designed to allow patients to provide detailed descriptions of these topics, such as:“Has your breast cancer spread to any other parts of your body? What symptoms do you have in [metastatic site]?”Some follow-up questions drew from the literature review and interviews with experienced oncologists to ensure concerns specific to the population were captured:Interviews were audio-recorded, transcribed, anonymized , and imported into ATLAS.ti, a computerized qualitative data analysis package  , to faciTo evaluate saturation, disease-related symptom, treatment-related side-effect, and physical functioning impact concept emergence was documented across sets of successive interviews. The first 25% of interviews were compared with the next 25% of interviews to see what, if any, new concepts emerged, followed by comparing the third 25% against the first 50%, and the final 25% against the first 75% –18. SatuTo organize and catalog patients’ descriptions of their HR+/HER2- advanced breast cancer experience, concepts were analyzed qualitatively by examining specific words and phrases used by the patient regarding relevant characteristics of each concept  and quantitatively by overall frequency of report . The frequency with which a concept was reported by patients as most bothersome or occurring most frequently was also analyzed quantitatively. This approach allowed for the concepts that are important and relevant to the patients’ HR+/HER2- advanced breast cancer experience to emerge by observing and examining the patient voice. Data collected from the interviews were organized into concept description tables and were used to construct an HR+/HER2- advanced breast cancer conceptual model.Concept elicitation interviews with five oncologists experienced in the area of advanced breast cancer were conducted to support the patient interview findings by defining and describing disease-related symptom concepts, treatment-related side-effect concepts, and impact concepts from the perspective of therapeutic area experts. Experienced oncologists were identified by study sponsor-employed clinicians. The interviews were conducted over the telephone by trained interviewers, followed a semi-structured interview guide, and were approximately 60 min in length. The interviews were audio-recorded, transcribed, anonymized, and analyzed using semi-quantitative and qualitative data analytic methods via ATLAS.ti Version 7.5 or later . Conceptn = 12.4). Six patients (40%) self-identified as black or African American, eight (53%) self-identified as white/Caucasian, and one (7%) selected “Other” in response to race. The majority of patients reported completing some college or beyond  and reported their overall health status as “good” or “fair”   and had an Eastern Cooperative Oncology Group score of 0–1  and/or cyclin-dependent kinase (CDK 4/6) inhibitor treatment . Finally, the majority of patients’ breast cancer had metastasized to the bone .Most patients were post-menopausal n = 1, 80% andn = 7 each, 47%) and pain  were the three most frequently reported. Patients also identified 43 concepts that they attributed to be treatment-related side effects. The three most frequently reported treatment-related side effects were hair loss , fatigue/tiredness , and nausea . Fatigue/tiredness, general pain, nausea, shortness of breath, weakness, diarrhea, lymphedema, weight loss, neck swelling, and cough were identified as both disease- and treatment-related experiences. Due to some overlap in patients’ attribution of disease- and treatment-related concepts, analyses were performed to identify the most frequently reported concepts overall, which included fatigue/tiredness , hair loss , and general pain and lump in breast . The overall most frequently reported concepts are reported with exemplary patient quotes in Table A total of 50 sign, symptom, and treatment-related side-effect concepts were elicited spontaneously from patients during the qualitative interviews. Patients identified 14 unique concepts that they attributed to be disease-related signs or symptoms; fatigue and lump in breast . The disease-related symptoms or treatment-related side effects that patients reported to be “most bothersome” were varied; shortness of breath , followed by fatigue/tiredness, general pain, and vomiting  were mentioned as “most bothersome” by more than one patient each. All of the “most frequent” concepts were also reported by patients as the most bothersome, with the exception of vomiting  characteristic of their disease, with general pain reported by the greatest number of patients as occurring frequently n = , 20%. Thn = 26, 72%). Most frequently, patients reported that their condition affected concepts within the activities of daily living domain  and the general physical functioning domain  , relationships  , work  , and sleep    Table . Patientwork n = 1, 73% anThe 50 sign, symptom, and side effect concepts and 36 impact concepts reported by subjects during the concept elicitation portion of the interviews were organized into a patient-based conceptual model Fig. .Fig. 1PaOf the 50 sign, symptom, and treatment-related side-effect concepts that were elicited spontaneously from subjects during the qualitative interviews, 48 (96%) were elicited in the first 75% of interviews. A total of 26 physical function impacts were elicited from subjects, 23 (88%) of which were elicited in the first 75% of interviews. Based on these saturation results, it was determined that an adequate number of interviews had been conducted.n = 5 each, 100%), followed by neurologic symptoms  and shortness of breath . In relation to treatment-related side effects, a total of 37 concepts were identified; the most frequently reported were fatigue , hot flashes , arthralgia , hair loss , mouth sores , neuropathy , and vaginal dryness . Oncologists reported that both disease-related symptoms and treatment-related side effects can lead to a variety of impacts on patients, most notably physical functioning, and specifically the ability to work , ability to walk , and decreased motor function . The impact on social functioning/relationships was also frequently discussed, such as the ability to engage with family and friends  , patients reported fatigue as either the first or second most important symptom or concern to monitor [N = 70), fatigue was the most commonly reported symptom and most important to patients [The intent of the present research was to identify the important and relevant disease-related symptoms, treatment-related side effects, and physical functioning impacts from the perspective of patients with HR+/HER2- advanced breast cancer, supported by the perspective of experienced oncologists. The present study suggests, similar to other research –9, that  monitor . Garcia  monitor . Similarpatients .The present study also found that patients attributed many concepts to both the condition and its treatment, and in some cases, patients were unable to attribute a particular concept specifically to their disease or its treatment. The challenges of distinguishing between disease- and treatment-related symptoms were not unique to the current study or to breast cancer. Indeed, prior research by Cleeland et al. (2010) has noted that cancer-related disease and treatment symptoms do not occur in isolation, but instead occur simultaneously, and that this should be taken into consideration when trying to measure the patient experience . RosenbeThe results of the current research were combined into a concept tracking matrix Table , which dLimitations of this study include several challenges in generalizing findings to the wider advanced breast cancer population. Although saturation was determined to have been achieved for symptoms/side effects, suggesting that these concepts are the key features of the HR+/HER2- advanced breast cancer experience, there is a possibility that because of the specific breast cancer subtype and treatments received, these results may not be generalizable to the wider advanced breast cancer population. Treatment-related concepts may vary based on treatment regimen, dose, sequence, and schedule . FurtherAnother potential limitation of the current study was the sole focus on physical functioning-type impacts during the patient interviews. Although other types of impacts were spontaneously elicited and reported in the findings, these were not explored in as much depth, given time limitations and the focus of this study. The focus on physical functioning was driven from a PRO measurement perspective; previous literature indicated that it is a core contributor to patient HRQoL, and less susceptible to confounding sources other than the disease or its treatment , thus taDocumenting and describing the relevant sign, symptoms, and impacts from the patient perspective contributes to a deeper understanding of the specific patient experience of HR+/HER2- advanced breast cancer and can provide avenues to identify and target the measurement of treatment outcomes. Recent emphasis on PROs from the FDA, particularly in oncology , 5, highResults of qualitative interviews with patients, supported by interviews with experienced oncologists, indicate that individuals with HR+/HER2- advanced breast cancer experience a myriad of concepts related to both disease and treatment, with fatigue/tiredness, hair loss, general pain, and lump in breast reported most frequently and shortness of breath, fatigue/tiredness, general pain, and vomiting reported as the most bothersome. Further, the results of the concept elicitation activities described herein indicate that HR+/HER2- advanced breast cancer affects individuals’ ability to function physically, such as walking, ability to do housework, and ability to cook, as well as impacting other areas of their lives , such as family, social life, work, and emotional well-being.Additional file 1:Table S3. HR+ and HER2- advanced breast cancer health and well-being impact concept descriptions. (DOCX 20 kb)Additional file 2:Table S1. HR+ and HER2- advanced breast cancer disease-related and treatment-related concept frequencies and descriptions. (DOCX 17 kb)Additional file 3:Table S2. HR+ and HER2- advanced breast cancer physical function impact concept frequencies and descriptions. (DOCX 17 kb)


IMPORT LOW demonstrated noninferiority of partial-breast and reduced-dose radiotherapy versus whole-breast radiotherapy for local relapse and similar or reduced toxicity at 5 years. Comprehensive patient-reported outcome measures collected at serial time points are now reported.IMPORT LOW recruited women with low-risk breast cancer after breast-conserving surgery. Patients were randomly assigned to 40 Gy whole-breast radiotherapy (control), 36 Gy whole-breast and 40 Gy partial-breast radiotherapy (reduced-dose), or 40 Gy partial-breast radiotherapy only  in 15 fractions. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 and Breast Cancer–Specific Module, Body Image Scale, protocol-specific items, and the Hospital Anxiety and Depression Scale were administered at baseline, 6 months, and 1, 2, and 5 years. Patterns of moderate/marked adverse effects (AEs) were assessed using longitudinal regression models, and baseline predictors were investigated.P < .001 for each), whereas breast shrinkage increased (P < .001). Analysis by treatment group showed average number of AEs per person was lower in partial-breast  and reduced-dose  versus whole-breast group and decreased over time in all groups. Younger age, larger breast size/surgical deficit, lymph node positivity, and higher levels of anxiety/depression were baseline predictors of subsequent AE reporting.A total of 41 of 71 centers participated in the patient-reported outcome measures substudy; 1,265 (95%) of 1,333 patients consented, and 557 (58%) of 962 reported no moderate/marked AEs at 5 years. Breast appearance change was most prevalent and persisted over time (approximately 20% at each time point). Prevalence of breast hardness, pain, oversensitivity, edema, and skin changes reduced over time (Most AEs reduced over time, with fewer AEs in the partial-breast and reduced-dose groups. Baseline predictors for AE reporting were identified. These findings will facilitate informed discussion and shared decision making for future patients receiving moderately hypofractionated breast radiotherapy. The main objective was to determine whether breast cancer treatment–related AEs improve, persist, or worsen over time to inform future patients. In addition, it was hypothesized that baseline patient-, tumor-, and treatment-specific factors could be identified that influence patterns of patient AE reporting over 5 years.4 All centers were invited to participate in the PROM substudy , and 41 of 71 centers participated. A majority of centers gave no reason for declining to participate, but a few stated lack of local research resources. There was no suggestion of a systematic difference between those centers that did and did not participate. All patients at these 41 centers were invited to participate in the substudy until the designated sample size was obtained.The PROM substudy was conducted in a subset of IMPORT LOW, for which full details of patients and procedures have been published.4 Women were randomly assigned to receive whole-breast radiotherapy or one of the experimental schedules .Details of trial procedures have been published.Patients who consented to participate in the PROM substudy completed a baseline questionnaire booklet prerandomization. Subsequent questionnaires were posted by The Institute of Cancer Research Clinical Trials and Statistics Unit for completion at the patients’ homes at 6 months and 1, 2, and 5 years postrandomization. Questionnaire items investigated are summarized in Appendix 6 Hospital Anxiety and Depression Scale ,7 Body Image Scale,8 and protocol-specific questionnaire items.Patients completed the European Organisation for Research and Treatment of Cancer (EORTC) general cancer scale  and breast cancer–specific module (QLQ-BR23),v none/mild) AEs at each time point was determined, and changes over time were assessed using the χ2 test for trend. A generalized estimating equation model9 including a treatment group/time interaction investigated whether prevalence of moderate/marked AEs over time differed between the treatment groups. A Poisson model adjusted for time and treatment group assessed whether average number of moderate/marked AEs per person changed over time and whether this varied according to treatment group. Separate generalized estimating equation models for each AE were fitted including terms for time and treatment group to investigate whether baseline factors predicted reporting of moderate/marked AEs over 5 years. Full details of methodology are available in the Data Supplement.All analyses conducted in the whole cohort were adjusted for treatment group. The prevalence of moderate/marked (v 60 years); however, other baseline characteristics were similar between those who did and did not consent (P = .006). There was a high proportion of completed questionnaires at all time points  consented. Most women had small (approximately 1 cm), grade 1 or 2 estrogen receptor–positive and human epidermal growth factor receptor 2–negative, node-negative tumors and received adjuvant hormonal therapy . Baselin consent . Patiente points .In the whole cohort, 557 (58%) of 962 patients reported no AEs at 5 years. Overall breast appearance change was the most prevalent AE reported at each time point and persisted over time  and reduced-dose  groups compared with the whole-breast group.Overall, in patients who reported at least one AE at year 5, the median number of AEs per person at this time point was three ; for the whole-breast group, this was three  compared with two  for both test groups. The average number of AEs reported per person at each time point was lower in the partial-breast . Prevalence of moderate/marked breast hardness, pain, oversensitivity, edema, skin changes (P < .001 for each), and arm/shoulder pain (P = .002) reduced over time  trial,13 used the QLQ-BR23 subscale, but only at baseline and 2 years after completion of treatment. Patients were randomly assigned to partial-breast IMRT using 30 Gy in five fractions over 1 week versus 50 Gy in 25 fractions over 5 weeks to the whole breast with an optional tumor bed boost. The partial-breast group showed improvement in PROM at 2 years, whereas breast and arm symptoms worsened in the whole-breast radiotherapy group. This difference from other reported studies may be related to the higher biologically equivalent dose with 50 Gy in 25 fractions in the whole-breast radiotherapy group compared with 40 Gy in 15 fractions in other studies. It may also reflect the smaller number of patients completing PROM questionnaires at both time points in the Florence study (205 [39%] of 520).A fourth study, the Florence trial,10 also demonstrated that breast shrinkage was the only patient-reported AE showing an increase in prevalence in the 5 years after completion of radiotherapy. The results of the Cambridge IMRT trial11 suggested an increase in breast shrinkage over time as reported by patients, but this did not reach statistical significance. In the START-B trial, patients reported significantly less breast shrinkage in the hypofractionation group compared with the control group.10 In IMPORT LOW, there was less patient-reported breast shrinkage in the reduced-dose and partial-breast groups compared with the whole-breast group; however, this did not reach statistical significance.4As per IMPORT LOW, START-BThis increase in the prevalence of breast shrinkage over time is likely to be an effect of both fibrosis and atrophy, which are recognized late normal tissue pathophysiologic consequences of radiotherapy. Therefore, the question arises of whether breast shrinkage reported by patients may be the most appropriate end point for assessing dose-volume response within breast radiotherapy trials.10 and Cambridge IMRT11 trials also reported breast appearance change as the most prevalent PROM, which remained stable over time. The cumulative incidence across the 5-year period in these trials was similar to that in IMPORT LOW: approximately 20% and 18% in START-B and Cambridge IMRT, respectively. This stable reporting of breast appearance over the 5-year period may reflect the dynamic interaction of some surgical changes resolving while some radiotherapy-related changes develop over time.IMPORT LOW showed that breast appearance change was the most commonly reported AE, and reporting remained stable over time, with significantly lower rates in the partial-breast group. Both START-B14 testing partial-breast radiotherapy using three-dimensional conformal radiotherapy versus whole-breast radiotherapy. Patients randomly assigned to whole-breast radiotherapy showed relatively stable reporting of breast cosmesis using the EORTC cosmetic rating system15 over the 5-year period, whereas those in the partial-breast group reported significantly worse cosmesis, which seemed to increase with time. The reasons for worse cosmesis in the partial-breast radiotherapy group are unclear, but it may be related to a higher biologically equivalent dose, especially if incomplete normal tissue repair after twice-daily irradiation is considered.16In contrast, different results were found in an interim analysis of the RAPID  study,11; however, this trial included women younger than 50 years of age, so the study population was different from that of IMPORT LOW.The IMPORT LOW analysis showed that certain baseline factors were associated with some patient-reported AEs. One of these factors was younger age, within the context of a cohort of perimenopausal/postmenopausal women. This observation raised the question of whether association resulted from biologic differences  or perception of AEs in the younger age group. Firstly, younger age was only associated with items in the Body Image Scale that relate to patient perception of attractiveness and sexuality. In contrast, the Cambridge IMRT trial showed that younger age was associated with increased rates of patient-reported skin changes and breast hardness4 Similarly, in the EORTC boost versus no boost trial,17 age was not a predictor of clinician-assessed fibrosis. Taken together, these observations suggest that it was the perception of younger women within IMPORT LOW driving increased body image AE reporting rather than a biologic effect.Previously published results from IMPORT LOW show that there was no significant association found between age and AEs reported by clinicians or from photographs over 5 years.11Larger breast size was a significant predictor of patient-reported AEs within IMPORT LOW. Patients with larger breasts were more likely to report skin changes and feeling self-conscious/dissatisfied with their appearance and body. In the Cambridge IMRT study, larger breast volume was also a main risk factor influencing patient-reported breast-related AEs.Larger surgical deficit predicted for increased breast appearance change and breast shrinkage in IMPORT LOW. In addition, poor baseline surgical cosmesis  predicted for increased skin changes and breast hardness within the Cambridge IMRT trial.12Positive axillary lymph nodes predicted for worse arm/shoulder AE reporting. Similarly, the GEC-ESTRO trial reported worse arm symptom scores at baseline in patients who underwent axillary node dissection and at 3 and 6 months after whole-breast radiotherapy.18 It has been reported that pretreatment psychological status may affect perception of cosmetic outcome from breast-conserving surgery and radiotherapy.19In IMPORT LOW, 23% and 8% of patients were identified as being at high risk of anxiety and depression, respectively, based on baseline HADS subscale scores, and these women were more likely to report AEs. Anxiety predicted for almost all AEs, whereas association with depression was not consistently statistically significant, possibly because of a small number of patients identified as being at high risk of clinical depression. Baseline prevalence of high-risk anxiety and depression was higher in the START trials  but was not investigated as a predictor of AEs.Limitations include lack of baseline data regarding patient smoking, comorbidity, postoperative breast infections, and seromas, because effects of these factors were not proven to be associated with AEs during the setup of the trial. In addition, there is a possibility of reporting bias, because patients were not blinded to treatment allocation. There is an inherent risk of informative censoring with PROM questionnaire return; for example, patients with certain baseline characteristics may be more or less likely to return questionnaires. In IMPORT LOW, there were no significant differences in a majority of baseline characteristics of those who did or did not return questionnaires at 5 years, with the exception of higher baseline HADS anxiety and depression subscale scores in those who did not return their year-5 questionnaires. Bias may also arise because patients who have worse AEs may be more or less inclined to report or may represent a different subpopulation. In IMPORT LOW, we found patients who reported at least one AE at year 2 were more likely to return questionnaires at year 5; therefore, it is possible that the prevalence of AEs was overestimated in this analysis. Finally, IMPORT LOW was conducted in a lower-risk population and therefore may not be generalizable to all patients with early breast cancer.These results demonstrate that a majority of AEs reported reduce over time. This information can provide reassurance for patients considering either whole-breast or partial-breast radiotherapy using moderately fractionated IMRT. Furthermore, baseline factors that predict AEs may be considered before radiotherapy and contribute to the informed discussion and shared clinician-patient decision-making process. Finally, this comprehensive serial analysis of PROMs adds further support to the hypothesis that partial-breast radiotherapy using moderately fractionated IMRT has less toxicity compared with whole-breast irradiation.In conclusion, IMPORT LOW provides a unique opportunity to investigate the breadth and depth of data from a longitudinal analysis of PROMs in a large partial-breast radiotherapy trial. The results provide reassurance for future patients receiving either whole-or partial-breast moderately hypofractionated radiotherapy that treatment sequelae usually improve over time, with more than half of patients reporting no moderate/marked AEs at 5 years. Furthermore, patients receiving partial-breast radiotherapy reported fewer AEs compared with whole-breast radiotherapy using this technique. In addition, baseline factors that predict AEs can be assessed before radiotherapy, allowing tailoring of risk-benefit discussions for individuals.