Background
Up to 60% of all new cancer diagnoses and 70% of all cancer-related deaths occur among adults aged ≥65 years.1 Older adults with cancer are at high risk of treatment-related toxicity and inferior survival, yet neither chronologic age nor clinician-assessed performance status (PS) adequately captures this vulnerability.2 A geriatric assessment (GA) is a multidimensional tool to uncover this vulnerability or frailty and predicts the risk of morbidity and mortality among older adults with cancer.3–5 A growing body of literature shows that GA can predict chemotherapy-related toxicity,5,6 as well as mortality,4 guide clinical decision-making,7 and improve patient satisfaction8 among older adults with cancer. Specifically among gastrointestinal cancers, a GA has been shown to predict postsurgical complications among older adults with colorectal cancer9 and gastroesophageal10 and hepatocellular carcinoma,11 as well as chemotherapy-related toxicity12 and short- and long-term mortality.13–15 Given these substantial benefits, ASCO16 and NCCN guidelines17 currently recommend that all older adults with cancer undergo a GA.
However, the association between chronologic age and GA impairments and frailty remains understudied. Furthermore, ASCO recommends a GA should be performed among all older adults with cancer aged >65 years, yet the rationale for this age cutoff remains unclear. Because patients with cancer are known to undergo accelerated aging through multiple mechanisms,18 extrapolating from the age cutoff used in the general population may be inaccurate. In this study, we examined the association between chronologic age and GA-identified impairments and frailty among adults aged ≥60 years with gastrointestinal malignancies.
Patients and Methods
Study Population
Using participants from the University of Alabama at Birmingham (UAB) Cancer and Aging Resilience Evaluation (CARE) Study, an ongoing prospective registry enrolling older adults (≥60 years old) undergoing cancer care at UAB Hospitals and Clinics,19,20 we identified patients diagnosed with a gastrointestinal malignancy presenting to our medical oncology clinic for an initial consultation. We chose 60 years of age as a criterion for enrollment in this registry given the uncertainty surrounding the “right” age cutoff and to allow for meaningful age-related subanalyses, such as the current study.21 The UAB Institutional Review Board (IRB-300000092) approved this study.
Geriatric Assessment
We conducted patient-reported GAs as previously described (supplemental eTable 1; available with this article at JNCCN.org).19,20 Our GA comprised the following domains: functional status, comorbidity, cognition, mental health status, nutrition, social support, and health-related quality of life, consistent with recommendations from the International Society of Geriatric Oncology (SIOG).3 We assessed functional status using the Older Americans Resources and Services (OARS) instrumental activities of daily living (IADLs),22 OARS activities of daily living (ADLs),22 patient-reported ECOG PS,23 and number of falls within the last 6 months.24 Nutritional status was evaluated using an abridged version of patient-generated subjective global assessment (PG-SGA).25 Comorbidity assessment was performed using number of medications26 and OARS comorbidity assessment.22,27 We assessed social support using Medical Outcomes Study-Social Support Survey,28 mental health status using the Patient-Reported Outcomes Measurement Information System (PROMIS) Anxiety and Depression measures,29,30 and cognition using the PROMIS Cognitive Function measure.31 Lastly, health-related quality of life was examined using the PROMIS 10-item Global Health tool.32 The GA was completed by the patient. However, if the patient had any vision issues, a member of the study personnel or a primary caregiver could ask the patient the GA questions.
GA Impairments
Based on the GA evaluation, patients were classified as having GA impairment if they met ≥2 of the following criteria33: ≥1 falls in the last 6 months, significant limitation in walking 1 block, impairment in ≥2 IADLs, any ADL impairment, significant weight loss (3% in 3 months or 6% within 6 months), presence of ≥4 comorbidities, poor social support for physical activity, significant interference in social activity, presence of anxiety (T-score ≥60) or depression (T-score ≥60), cognitive impairment (T-score ≤60), or polypharmacy (≥9 medications).
Frailty Index
We constructed a frailty index (the CARE Frailty Index) using the principle of deficit accumulation approach originally described by Rockwood and Mitnitski34 and following the standard procedures outlined by Searle et al.35 Similar methods have been used by Guerard et al4 and Cohen et al36 to construct frailty indices that have been shown to be predictive of chemotherapy toxicity36 and all-cause mortality4 among older adults with cancer. We selected 44 GA variables from the CARE questionnaire, each of which captured a health deficit, and recoded responses using the convention that 0 indicated the absence of the deficit and 1 indicated the presence of deficit; for variables that included a single intermediate response (eg, “sometimes” or “maybe”), we used an additional value of 0.5. We then combined these individual scores into an aggregate frailty score reflecting the overall proportion of deficits (range, 0–1), where 0 = no deficit present and 1 = all 44 deficits present. We then categorized patients as robust (<0.2), prefrail (0.2–0.35), and frail (>0.35), as previously described.35 In case of missing response data, we required that responses to at least 30 items be present to construct a valid frailty index. An index constructed with at least 30 variables has been previously shown to be sufficiently accurate for predicting adverse outcomes among older adults.37 Additional details regarding our definition for GA impairment and construction of the CARE Frailty Index are provided in supplemental eAppendices 1 and 2.
Statistical Analysis
We compared baseline characteristics between the 3 age groups (60–64, 65–74, and ≥75 years) using appropriate bivariate statistical tests, namely, analysis of variance/Kruskal Wallis for continuous variables and chi-square test/Fisher exact test for categorical variables depending on their underlying distribution. To measure the correlation between the number of geriatric impairments (a ranked variable) and chronologic age (continuous variable), we used Spearman rank correlation coefficient and tested the alternative hypothesis that the Spearman ρ was significantly different from 0. We compared the difference in proportion of various GA impairments and frailty categories among increasing age groups (60–64, 65–74, and ≥75 years) using chi-square tests of trend. To evaluate the difference between number of GA impairments across the 3 age groups, we used a nonparametric extension of Wilcoxon rank-sum test.38 All statistical tests were 2-sided and the level of significance was 0.05. We used STATA, version 13 (StataCorp LLC) for all statistical analysis.
Results
Of the 523 consecutive adults aged ≥60 years with gastrointestinal malignancy seen for initial consultation at the UAB medical oncology clinic between September 2017 and October 2019, 455 (87%) enrolled in the CARE registry and underwent GA (supplemental eFigure 1). Of these, 367 (81%) had not started any systemic therapy, whereas the remaining (19%) had previously received treatment elsewhere. The median age of the entire cohort at the time of GA was 68 years (interquartile range [IQR], 64–74 years); 55% were male and 72% were non-Hispanic White. Overall, 28% of the 455 patients were aged 60–64 years, 47% were aged 65–74 years, and 25% were aged ≥75 years. Common cancer types included colorectal (33%) and pancreatic (24%); 46% had stage IV disease. The demographic and clinical characteristics were similar across the 3 age groups, with the exception of marital status and cancer stage, as summarized in Table 1. Compared with nonparticipants, patients enrolled in the CARE registry had similar age, sex, and cancer stage, with the exception of a higher proportion of nonresponders among patients with hepatobiliary and pancreatic cancer (supplemental eTable 2).
Distribution of Baseline Demographic and Clinical Characteristics
Relationship Between Chronologic Age and Geriatric Impairments
There was no significant correlation between chronologic age and number of geriatric impairments (Spearman ρ, 0.07; P=.16). Notably, even in the age group of 60–64 years, 61.4% of patients had GA impairments. This was not significantly different compared with patients aged 65–74 years (66.2%) and ≥75 years (70.5%; P=.11). We found similar rates of impairments in IADLs, ADLs, nutritional status, falls, cognitive, anxiety, depression, polypharmacy, and patient-reported ECOG PS across the age groups. However, there was a higher comorbidity burden (≥3) in the older group (39%, 56%, and 56% among ages 60–64 years, 65–74 years, and ≥75 years, respectively; P<.01) (Table 2). The increased comorbidity burden in the older age groups was mainly driven by a higher proportion of patients reporting arthritis, hypertension, and glaucoma (supplemental eTable 3).
Overall and Domain-Specific Geriatric Impairment and Frailty
Relationship Between Chronologic Age and Frailty
Overall, 37% (n=108) of the cohort were frail, whereas 30% (n=128) were prefrail and 33% (n=143) had robust frailty status. Compared with those who were prefrail or robust, patients who were frail were more likely to have an ECOG PS ≥2 (68% vs 26% vs 4%, respectively; P<.001) and a higher cancer stage (52% vs 42% vs 42%, respectively; P=.03), but did not differ significantly by treatment status (22% vs 20% vs 16%, respectively, were already on treatment; P=.44).
We then compared the rates of frailty categories across the different age groups. Notably, 26% and 35% of patients aged 60–64 years had evidence of prefrail and frail status. This was not significantly different compared with the proportion of patients with prefrail and frail status in the 65–74 age group (30% and 36%, respectively) and ≥75 age group (33% and 40%, respectively) (P=.45).
Discussion
In this study comprising an unselected cohort of older adults aged ≥60 years with gastrointestinal malignancies, we found no significant relationship between chronologic age and the presence of geriatric impairments or frailty. Furthermore, we found comparable prevalence of GA impairments and frailty in the 60–64 age group compared with those aged ≥65 years, suggesting that the traditional cutoff of 65 years for conducting comprehensive GA may not be accurate, and even patients aged <65 years could benefit from GA evaluation.
There is no universal agreement on the age at which a person becomes old. In the United States, age ≥65 years is generally considered the chronologic definition of an older adult, similar to what is used for Medicare eligibility. Accordingly, consensus recommendations for GA from ASCO and SIOG use 65 years as the age cutoff.3,16,17 However, emerging evidence suggests that cancer diagnosis and/or treatment can accelerate the human aging process through multiple mechanisms, including DNA damage and induction of aging-related biologic pathways, such as telomerase activity, DNA hypermethylation, and stem cell exhaustion.18 Hence, the age cutoffs assumed for the general population may not apply to patients with cancer. We postulate that this phenomenon may account for the high prevalence of GA impairments in our cohort aged <65 years.
In a prior study, Aleixo et al21 reported the prevalence of GA impairments among patients aged <65 years with early-stage breast cancer. Patients aged 50 to 64 years had a high prevalence of falls in the past 6 months (15%), abnormal timed up-and-go test >14 seconds (12%), and impaired IADLs (17%). However, patients aged 50 to 64 years comprised <10% of the study population and were derived from exercise intervention trials and compared with patients aged ≥65 years derived from a prospective registry, thus raising a possibility of selection bias. In comparison, our entire cohort includes unselected patients from a cancer registry who underwent initial consultation at the gastrointestinal oncology clinic. However, we report similar findings, with comparable rates of GA impairments and frailty among patients in the 60–65 age group.
Limitations of our study include being a single-institution analysis limited to gastrointestinal malignancies, and therefore our findings may not be generalizable to other settings/populations. The reason for limiting our study to gastrointestinal malignancies was to eliminate the possibility of selection bias as mentioned earlier. Nevertheless, we recognize that our cohort is still quite diverse and there may be substantial variation in the proportion of patients with GA impairment and frailty within individual cancer types and cancer stages. Almost half of our patients had stage IV disease, which may explain the high rate of GA impairments in our study. Notably, another study among patients with early-stage breast cancer reported similar findings.21 All patients who underwent GA evaluation did so at the time of initial contact with the UAB health system. Consequently, not all patients who presented for an initial appointment were previously untreated, and approximately 20% had already undergone cancer therapy at another facility. Furthermore, by limiting our sample to patients completing GA at their initial visit, we may have excluded patients with severe illness requiring hospitalization for urgent treatment or hospice care, such as those with more aggressive malignancies, including hepatobiliary and pancreatic cancers. This may have potentially biased our findings. We did not have data on treatment-related toxicity, treatment discontinuation, or healthcare utilization, which need to be explored in future studies.
Conclusions
Our study adds to the growing body of evidence that chronologic age is an imperfect marker of presence of GA impairment and frailty. Furthermore, GA impairments are seen even among adults aged <65 years, and GA may aid in the clinical management of even younger populations than previously considered.
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