Abstract
Introduction:
Depression and anxiety are prevalent in older adults with cancer but are often undertreated. Older adults are also at increased risk of chemotherapy toxicity (CT). This study evaluated the impact of depression and anxiety symptoms on severe CT risk in older adults with cancer.
Methods:
This is a secondary analysis of a randomized trial (2:1) evaluating geriatric assessment-driven interventions (GAIN) versus standard of care (SOC) to reduce grade 3+ CT in older adults with cancer. Mental health was assessed using Mental Health Inventory (MHI)-13. CT was graded by NCI Common Terminology Criteria for Adverse Events v 4.0.
Results:
A total of 605 patients enrolled (402 GAIN; 203 SOC). Overall, 35% were depressed and 47% anxious. Patients with depression had increased CT in SOC (70.7% vs 54.3%, p=0.02), but not in GAIN (54.3% vs. 48.5%, p=0.27). CT was more likely in SOC patients with depression (OR 2.03, 95% CI 1.10–3.72). This association persisted after adjusting for Cancer and Aging Research Group toxicity score (OR=1.98, 95% CI 1.07–3.65), and for demographic, disease, and treatment factors (OR=2.00, 95% CI 1.03–3.85). Depression and CT were not associated in GAIN (OR 1.26, 95% CI 0.84–1.91). Anxiety and CT were not associated in either arm.
Conclusion:
Elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer, which was mitigated with geriatric assessment-interventions. This suggests that treating depression symptoms may lower toxicity risk. Future studies are needed to confirm and investigate the impact of depression specific interventions on outcomes.
Keywords: Depression, anxiety, older adults with cancer, chemotherapy toxicity, mental health
Précis:
Depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer. This risk is mitigated in those who received geriatric assessment- driven interventions.
Introduction
Mental health disorders, including depression and anxiety, are more prevalent in patients with cancer compared to the general population.1 Compared to the 5% prevalence rate of depression in the broader population of community-dwelling older adults, as many as 13% and 21% of older adults with cancer have depression and anxiety, respectively.2,3 These mental health disorders are associated with increased health care costs in this vulnerable population and account for 5.5% of unplanned presentations to the hospital in patients receiving chemotherapy.4,5 Depression and anxiety are further associated with decreased adherence to therapy, lower health-related quality of life (HRQOL), increased hospital length of stay, and shortened survival in older adults with cancer.6–12 Despite these consequences, mental health concerns are often undertreated during cancer care for older adults, with lower psychosocial service referral rates found in older patients.1,13 In addition, these studies do not provide a mechanism for the association of depression and anxiety with these poor outcomes. We note that severe chemotherapy toxicities require hospitalization for management and can impact HRQOL.14 It is unclear how comorbid mental health symptoms may influence chemotherapy tolerability and toxicity.
Older adults are at increased risk of chemotherapy toxicity.15 A tool to help evaluate mental health along with other vulnerabilities that place older adults at increased risk of poor health outcomes is a geriatric assessment (GA). National guidelines recommend evaluation with a GA for all patients over age 65 receiving systemic cancer therapies.16,17 Two large randomized controlled trials have shown that identifying and addressing vulnerabilities based on a GA reduces chemotherapy-related toxicities 10–20% and increases treatment adherence.18,19
These trials considered GA interventions overall, but they did not examine the specific contributions of interventions related to mental health. Studies specifically investigating the connection between mental health and chemotherapy-related toxicity in older adults are limited. The goal of this study is to evaluate the impact of depression and anxiety symptoms on risk of severe chemotherapy-related toxicities in older adults with cancer prior to starting a new chemotherapy regimen.
Methods
This study is a secondary analysis of the prospective single-center randomized controlled trial assessing whether GA-driven interventions (GAIN) reduce grade 3 or higher chemotherapy-related toxicities in older adults with cancer (NCT02517034).18 All patients underwent a baseline, pre-chemotherapy GA, which included the Mental Health Inventory (MHI). Patients were randomized in a 2:1 ratio to either the intervention or standard of care. For the patients in the intervention arm, a multidisciplinary team reviewed the patient’s baseline GA and provided recommendations for interventions and referrals. Subsequently, an embedded nurse practitioner discussed GA results with the patient and the treating oncologist and implemented the recommendations. In the standard of care arm, patients’ baseline GA results were provided to the treating oncologist without input from the multidisciplinary team. All participants provided written informed consent. The protocol was approved by the City of Hope Institutional Review Board. Full details of the methods have been previously published.18
Eligibility
Eligible patients were aged 65+ years, with any stage solid malignancy, and starting a new chemotherapy-containing regimen at City of Hope. Study questionnaires were available in English, Spanish, or Chinese, and patients fluent in these languages were eligible. Six hundred and five patients were included, 402 were randomized to the intervention arm and 203 to the standard of care arm. Full details of the consort diagram have been previously published.18
Measures
The GA covered the following domains, consistent with current national guidelines: mental health, physical function, cognition, nutrition, social support, and medications.16,17 The MHI-17 was utilized for mental health evaluation. Patients were able to complete the GA on paper or on a touchscreen tablet. The Cancer and Aging Research Group (CARG) chemotherapy toxicity score was calculated (online calculator available at www.mycarg.org. This risk calculator incorporates measures from the GA including patient-reported (fall history, hearing problems, ability to walk one block, ability to take their own medicine, and health limitation on social activities) as well as objective measures (chronologic age, gender, height, weight, cancer type, type and dose of chemotherapy, hemoglobin, and creatinine clearance). Patients received chemotherapy under the management of their treating oncologist and were followed throughout treatment or up to six months from starting chemotherapy, whichever occurred first.
Mental Health Inventory-13
The original MHI has 31 items and generates 4 sub-domains. The full MHI was developed for use in older adults from the general population, not cancer patients specifically. An abbreviated version, the MHI-17, was then developed as part of the Medical Outcomes Study to assess psychological distress and wellbeing.20 Notably, the MHI-17 does not distinguish depression from behavioral/emotional control as a separate psychological domain. During a recent psychometric validation of the MHI-17 in older adults with cancer, four items were removed due to being multivalued or not directly reflecting depression or anxiety, with the resulting development of the MHI-13.21 Based on this work, we chose to use MHI-13 to assess depression and anxiety symptoms in the current study. For both depression and anxiety, individual items were scored from 0 to 5, except in 2 items where the maximum score was 4, and then summed to create the total summary score. Summary scores were converted to T-scores using a conversion table provided by Pergolotti et al.21 Higher scores indicate higher levels of depression or anxiety symptoms. Based on current evidence, dichotomized depression and anxiety variables were created using the cutoff points of 12 for summary score (57.8 for T-score) and 6 for the summary score (55.1 for T-score), respectively.21 Responses for individual questions are provided in supplementary Tables 1 and 2.
Grade 3+ Chemotherapy Toxicity
The primary outcome for this analysis was the incidence of grade 3+ chemotherapy-related toxicity, graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.22 Each patient’s clinical course was carefully reviewed through medical records. Toxicities were graded independently by 2 physicians who were blinded to randomization arm; medical record identifiers were removed to ensure blinding and minimize bias.
Statistical analysis
Descriptive statistics were calculated for patient demographics and baseline tumor/treatment characteristics. Distribution of each individual item on the MHI-13 are summarized and presented in Supplemental Table 1. Chi-square test was used to compare the incidence of grade 3+ chemotherapy-related toxicities between those with and without depression and anxiety for the overall sample and for each of the two arms. The Kruskal-Wallis test was used to compare MHI-13 depression and anxiety summary and T-score between those with and without grade 3+ chemotherapy-related toxicities overall and separately for the two arms. Associations between dichotomized MHI-13 depression and anxiety with grade 3+ chemotherapy-related toxicities were examined using univariate and multivariable logistic regressions. Informed by prior research, age, cancer stage, cancer type, and chemotherapy regimen are known as potential risk factors for grade 3+ toxicities and were thus included as covariates in the multivariable model. Additionally, the CARG-chemotherapy toxicity score, a recognized predictor for grade 3+ toxicity, was adjusted for in the multivariable logistic regression analysis.15,23 Potential confounders of depression (function by instrumental activities of daily living, activities of daily living; cognition; social activity; social support) were adjusted for in the multivariable logistic regression analysis. Furthermore, we classified patients with grade 3+ chemotherapy-related toxicity into 3 distinct categories: with hematologic toxicity but no non-hematologic toxicity (hematologic toxicity only); with non-hematologic toxicity but no hematologic toxicity (non-hematologic toxicity only); with both hematologic toxicity and non-hematologic toxicity (both hematologic and non-hematologic toxicity). Multinominal logistic regression was used to compare the incidence of the 3 types of toxicities between patients with and without depression and anxiety in each arm. A two-sided p-value <0.05 was considered statistically significant. Statistical analyses were performed using SAS® software version 9.4 (Cary, NC: SAS Institute Inc.).
Results
Overall, 605 patients participated in the study with a median age of 71 years (range 65–91) (Table 1). Over half of the patients were female (59%), majority were White (79%), and non-Hispanic (81%). The most common cancer types in order of prevalence were gastrointestinal, breast, lung, genitourinary and gynecological. The majority of patients had stage IV cancers (71%), received multi-drug chemotherapy regimen (64%), and over one-third had upfront chemotherapy dose reductions (39%).
Table 1.
Demographics, Disease and Treatment Characteristics, and Geriatric Assessment Variables
| GAIN (n=402) n (%) | SOC (n=203) n (%) | Overall (n=605) n (%) | |
|---|---|---|---|
| Demographics | |||
| Age (years) | |||
| Median (Range) | 71 (65–91) | 72 (65–88) | 71 (65–91) |
| Sex | |||
| Female | 235 (58.5%) | 122 (60.1%) | 357 (59.0%) |
| Race | |||
| White | 316 (78.6%) | 160 (78.8%) | 476 (78.7%) |
| Asian | 58 (14.4%) | 32 (15.8%) | 90 (14.9%) |
| Black | 27 (6.7%) | 9 (4.4%) | 36 (6.0%) |
| Ethnicity | |||
| Hispanic | 74 (18.4%) | 43 (21.2%) | 117 (19.3%) |
| Non-Hispanic | 328 (81.6%) | 160 (78.8%) | 488 (80.7%) |
| Disease Characteristics | |||
| Cancer Type | |||
| Gastrointestinal | 135 (33.6%) | 67 (33.0%) | 202 (33.4%) |
| Breast | 93 (23.1%) | 43 (21.2%) | 136 (22.5%) |
| Lung | 61 (15.2%) | 36 (17.7%) | 97 (16.0%) |
| Genitourinary | 63 (15.7%) | 28 (13.8%) | 91 (15.0%) |
| Gynecological | 35 (8.7%) | 19 (9.4%) | 54 (8.9%) |
| Other | 15 (3.7%) | 10 (4.9%) | 25 (4.1%) |
| Cancer Stage | |||
| I/II/III | 115 (28.6%) | 58 (28.6%) | 173 (28.6%) |
| IV | 287 (71.4%) | 145 (71.4%) | 432 (71.4%) |
| Treatment Characteristics | |||
| Number of Chemotherapy Agent(s) | |||
| Single | 129 (32.1%) | 66 (32.5%) | 195 (32.2%) |
| Multiple | 256 (63.7%) | 132 (65.0%) | 388 (64.1%) |
| Initial Dose Reduction | 148 (36.8%) | 87 (42.9%) | 235 (38.8%) |
| CARG-Toxicity Risk Score | |||
| Median (range) | 7 (0–20) | 7 (2–18) | 7 (0–20) |
| Low (0–5) | 111 (27.6%) | 50 (24.6%) | 161 (26.6%) |
| Medium (6–9) | 180 (44.8%) | 93 (45.8%) | 273 (45.1%) |
| High (10+) | 111 (27.6%) | 60 (29.6%) | 171 (28.3%) |
|
Geriatric Assessment Covariates
(mean, SD) |
|||
| Activities of Daily Living | 59.7 (30.5) | 55.7 (29.7) | 58.3 (30.3) |
| Instrumental Activities of Daily Living | 12.2 (2.6) | 12.2 (2.3) | 12.2 (2.5) |
| Severe cognitive impairment (n, %) | 27 (6.7) | 15 (7.4) | 42 (6.9) |
| Social Activity | 48.3 (23.7) | 47.9 (23.6) | 48.2 (23.7) |
| Social Support | 84.8 (19.2) | 85.8 (17.7) | 85.1 (18.7) |
Abbreviations: GAIN, Geriatric Assessment INtervention; SOC, standard of care; SD, standard deviation; CARG, Cancer and Aging Research Group.
Distribution of baseline depression and anxiety scores is presented in Table 2. Overall, 35% of patients (n=215) were classified as having depression, and 47% as having anxiety (n=283). No significant differences for depression and anxiety were observed between the two arms at baseline. Among the 75 patients with depression in the standard of care arm, 25 (33.0%) received referral to mental health services; among the 140 patients with depression in the GA-intervention arm, 117(83.6%) received a mental health referral. Among the 98 patients with anxiety in the standard of care arm, 27 (27.6%) received referral to mental health services; among the185 patients with anxiety in the GA-intervention arm, 142 (76.8%) received a mental health referral.
Table 2.
Distribution of MHI-13 Depression and Anxiety
| SOC (N=203) | GAIN (N=402) | Total (N=605) | p value | |
|---|---|---|---|---|
| Depression Score | 0.60 | |||
| Summary Score Mean (SD) | 10.3 (7.82) | 9.9 (7.65) | 10.0 (7.70) | |
| Summary Score Median (range) | 9 (0–41) | 8 (0–41) | 8 (0–41) | |
| T-Score mean (SD) | 54.0 (9.95) | 53.4 (10.15) | 53.6 (10.08) | |
| Depression * | 0.61 | |||
| No | 127 (62.9%) | 260 (65%) | 387 (64%) | |
| Yes | 75 (37.1%) | 140 (35%) | 215 (35.5%) | |
| Anxiety Score | 0.88 | |||
| Summary Score Mean (SD) | 6.0 (4.44) | 5.9 (4.30) | 5.9 (4.34) | |
| Summary Score Median (Range) | 5 (0–20) | 5 (0–20) | 5 (0–20) | |
| T-score Mean (SD) | 54.2 (10.23) | 54.1 (9.80) | 54.1 (9.94) | |
| Anxiety * | 0.56 | |||
| No | 104 (51.5%) | 217 (54%) | 321 (53.1%) | |
| Yes | 98 (48.5%) | 185 (46%) | 283 (46.8%) |
3 patients with missing MHI-13 depression score; 1 patient with missing MHI-13 anxiety score.
MHI-13 depression summary score >=12 (T-score >=57.8); MHI-13 Anxiety summary score >=6 (T-score >=55.1)
Table 3 presents the association between MHI-13 depression and anxiety and grade 3+ chemotherapy toxicity in each arm. When considered as a continuous variable, patients with grade 3+ chemotherapy toxicity exhibited a trend for higher depression scores at baseline, but this relationship was not statistically significant. However, when dichotomized, patients with depression were significantly more likely to have grade 3+ chemotherapy-toxicity in the standard care arm (70.7% vs 54.3%, p=0.02), but not in the GA-intervention arm (54.3% vs. 48.5%, p=0.27). When treatment arms are considered separately, in the standard of care arm, patients with depression were twice as likely to have grade 3+ chemotherapy toxicity (univariate OR 2.03, 95% CI 1.10–3.72) comparing to those without depression. No significant association was observed in the intervention arm (univariate OR 1.26, 95% CI 0.84–1.91). Interaction between these were not statistically significant (p=0.21). In the standard of care arm, the association between depression and grade 3+ chemotherapy toxicity persisted after adjusting for CARG toxicity score (adjusted OR=1.98, 95% CI 1.07–3.65), as well as for demographic, disease, and treatment factors (adjusted OR=2.00, 95% CI 1.03–3.85). When adjusting for functional, cognitive, and social support variables, the association was attenuated (OR: 1.82, 95% CI: 0.87–3.80).
Table 3.
Depression and Anxiety in relation to Grade 3+ Chemotherapy Toxicity
| SOC | GAIN | |||||
|---|---|---|---|---|---|---|
|
| ||||||
| Grade 3+ toxicity | Grade 3+ toxicity | |||||
|
| ||||||
| No (n=80) | Yes (n=123) | P value | No (n=199) | Yes (n=203) | P value | |
|
| ||||||
| Depression Score | ||||||
| Summary Score Mean (SD) | 9.5 (7.46) | 10.8 (8.03) | 9.4 (7.34) | 10.5 (7.93) | ||
| Summary Score Median | 8.0 (0–41) | 9.5 (0–39) | 0.25 | 8 (0–36) | 8.5 (0–41) | 0.20 |
| T-Score mean (SD) | 53.3 (9.23) | 54.4 (10.41) | 52.6 (10.09) | 54.1 (10.17) | ||
|
| ||||||
| Depression | ||||||
| No | 58 (45.7%) | 69 (54.3%) | 134 (51.5%) | 126 (48.5%) | ||
| Yes* | 22 (29.3%) | 53 (70.7%) | 0.02 | 64 (45.7%) | 76 (54.3%) | 0.27 |
|
| ||||||
| Anxiety Score | ||||||
| Summary Score Mean (SD) | 5.8 (4.22) | 6.1 (4.59) | 5.7 (4.41) | 6.0 (4.19) | ||
| Summary Score Median | 5.0 (0–20) | 5.0 (0–19) | 0.75 | 5.0 (0–19) | 5.0 (0–20) | 0.33 |
| T-Score mean (SD) | 53.8 (9.93) | 54.4 (10.45) | 53.6 (10.10) | 54.5 (9.51) | ||
|
| ||||||
| Anxiety * | ||||||
| No | 42 (40.4%) | 62 (59.6%) | 111 (51.2%) | 106 (48.8%) | ||
| Yes* | 38 (38.8%) | 60 (61.2%) | 0.82 | 88 (47.6%) | 97 (52.4%) | 0.47 |
Defined as: MHI-13 depression summary score >=12 (T-score >=57.8); MHI-13 Anxiety summary score >=6 (T-score >=55.1).
No association was observed between anxiety and grade 3+ chemotherapy toxicity in either arm. Patients with anxiety did not have higher odds of grade 3+ chemotherapy toxicity in either standard of care (univariate OR=1.07, 95% CI 0.61–1.88) or intervention arm (univariate OR=1.15, 95% CI 0.78–1.71).
While looking at categories of grade 3+ toxicities (hematologic, non-hematologic, or both), depression and anxiety were each associated with risk of hematologic and non-hematologic toxicity together (depression: OR 1.82, 95% CI 1.08–3.06; anxiety: OR 1.68, 95% CI 1.01–2.81) in the GA-intervention arm (Table 4). Depression was also associated with increased odds of hematologic only toxicities (OR 2.50, 95% CI 1.13–5.56) in the standard of care arm. There were no associations between anxiety and hematologic only or non-hematologic only toxicity in either standard of care or GA-intervention arms.
Table 4.
Univariate Associations of Depression and Anxiety with type of Grade 3+ Chemotherapy Toxicity
| Grade 3+ toxicity | ||||
|---|---|---|---|---|
| Total without Grade 3+ toxicity | Hematologic only | Non-Hematologic only | Both* | |
| Depression | ||||
| GAIN | ||||
| No | 134 (51.5%) | 30 (11.54%) | 51 (19.62%) | 45 (17.31%) |
| Yes** | 64 (45.7%) | 15 (10.71%) | 22 (15.71%) | 39 (27.86%) |
| OR (95% CI) | 1.05 (0.53–2.08) | 0.90 (0.51–1.62) | 1.82 (1.08–3.06) | |
| SOC | ||||
| No | 58 (45.7%) | 20 (15.75%) | 33 (25.98%) | 16 (12.60%) |
| Yes** | 22 (29.3%) | 19 (25.33%) | 20 (26.67%) | 14 (18.67%) |
| OR (95% CI) | 2.50 (1.13–5.56) | 1.60 (0.76–3.35) | 2.31 (0.97–5.50) | |
| Anxiety | ||||
| GAIN | ||||
| No | 111 (51.2%) | 27 (12.44%) | 43 (19.82%) | 36 (16.59%) |
| Yes** | 88 (47.6%) | 18 (9.73%) | 31 (16.76%) | 48 (25.95) |
| OR (95% CI) | 0.84 (0.44–1.63) | 0.91 (0.53–1.56) | 1.68 (1.01–2.81) | |
| SOC | ||||
| No | 42 (40.4%) | 19 (18.27%) | 28 (26.92%) | 15 (14.42%) |
| Yes** | 38 (38.8%) | 20 (20.41%) | 25 (25.51%) | 15 (15.31%) |
| OR (95% CI) | 1.16 (0.54–2.50) | 0.99 (0.49–1.98) | 1.11 (0.48–2.56) | |
Both = those with both hematologic and nonhematologic toxicity
as defined by MHI-13
Discussion
The current study showed that elevated depression symptoms are associated with increased risk of severe chemotherapy toxicities in older adults with cancer.. This risk was mitigated in those in the GA-intervention arm, which suggests that addressing elevated depression symptoms may lower the risk of toxicities. Overall, elevated anxiety symptoms were not associated with risk for severe chemotherapy toxicity. However, in a subgroup analysis, elevated anxiety symptoms were associated with increased risk of hematologic and non-hematologic toxicities together; notably, this was a small subgroup.
Depression and anxiety have previously been associated with poor outcomes in adults with cancer. For instance, depression has been associated with decreased survival, lower health-related quality of life, and increased hospital length of stay.6,7 Similarly, anxiety has been associated with decreased health-related quality of life, increased hospital readmissions, higher healthcare utilization, and higher healthcare costs.6,10,24 The cause of poor health outcomes in adults with cancer and depression and/or anxiety is not fully clear, although it has been associated with nonadherence to treatment, early discontinuation of treatment, and difficulty communicating with the healthcare team.6,25,26 The findings of the current study introduce a new health outcome for older adults with cancer having depressive symptoms – namely, that they are at increased risk of serious chemotherapy-related toxicities. This risk was attenuated when controlling for covariates of depression such as physical function, cognition and social factors. However, these findings warrant future investigations focused on evaluating the impact of mental health on chemotherapy-related toxicities.
With over 50% of older adults experiencing severe or life-threatening chemotherapy toxicities, identifying potentially modifiable risk factors to lower this risk is important.15 Prior studies investigating risks for increased chemotherapy toxicity in older adults with cancer have not shown depression and/or anxiety symptoms to be risk factors.15,27 A major difference is in the tools used in these other studies, which evaluated symptoms over a shorter time period than the MHI. These tools, the Geriatric Depression Scale and the Hospital Anxiety and Depression Scale, evaluate symptoms over the preceding one week whereas the MHI evaluates symptoms over the preceding four weeks. The difference may be that evaluation of depression symptoms over four weeks better captures important fluctuations in mood or longer term symptoms, which increases an older adult’s risk for severe chemotherapy toxicity. Additional differences between the prior studies and the current study have impacted the disparate findings, including differences in the proportions of patients with advanced cancer, line of chemotherapy, specific GA variables analyzed, and birth cohort. However, the findings of this study still warrant future studies designed to assess the impact of mental health on toxicity risk.
Although anxiety has been associated with decreased health-related quality of life and increased healthcare utilization, healthcare costs, and hospital readmissions, our study did not find a correlation with increased grade 3+ chemotherapy toxicities.6,25,26 Our study did show an association with anxiety and hematologic and non-hematologic toxicities together in a subgroup analysis. The limited association between anxiety and grade 3+ chemotherapy toxicities may be due to increased visits with healthcare providers by patients with anxiety, which in turn may allow for early symptom evaluation and management. However, future studies are needed to further investigate the impact of anxiety in older adults with cancer and how often care is sought.
Evaluation of mental health in older adults with cancer is recommended by national guidelines as part of a GA, which also evaluates functional status, cognition, nutrition, social support, comorbidities, and medications.16,17 Interventions based on vulnerabilities identified by GA have been shown to decrease toxicities, which is likely due to a combination of interventions.18,19,28 However, incorporation of GA into busy practices has been limited, with a major reported barrier being time and resource constraints.29 To overcome this barrier, ASCO developed the Practical GA utilizing validated measures.16 This study shows that if unable to perform a full GA, evaluation for depression with MHI-13 may identify older adults at increased risk for severe chemotherapy toxicity. The lack of correlation between depression and chemotherapy toxicity in the GA-intervention arm suggests that referrals to mental health services could mitigate toxicity risk. In fact, the majority of the patients in the GA-intervention arm received a mental health intervention, weakening the strength of the association. Further studies dedicated specifically to investigating the targeting of depression are needed.
This study has limitations. The thresholds for depression and anxiety used on MHI-13 were based on an English-speaking population whereas this study also included Chinese and Spanish speaking patients. The percentage of these individuals are 3.8% and 10.4% respectively, reducing the likelihood of a substantial impact on our findings. However, the threshold scores for depression and anxiety in non-English speakers may differ, and these findings would need to be confirmed due to potential differences across different language groups. Although the rate of anxiety in this study was higher than in the literature for older adults with cancer, this may be attributed to a number of additional factors.2 For example, this study cohort included a higher population of patients with advanced cancer, likely receiving palliative-intent chemotherapy, and receiving first line chemotherapy. These factors may contribute to increased anxiety at baseline. Depression and anxiety were not evaluated by a mental health professional or evaluated using a structured interview to assess formal DSM-5 diagnostic criteria for depressive or anxiety disorders. Another limitation is that psychiatric medication use at the time of baseline GA was not included in the analysis. The MHI-13 is a screening tool, and patients who are identified as having depression or anxiety symptoms should undergo further, more detailed, evaluation. As the current study is a secondary analysis of a randomized controlled trial where patients may have received multiple interventions impacting the levels of depression and anxiety, it isn’t known which components of the interventions affected mental health. Future studies designed to confirm (or reject) our findings and investigate the impact of mental-health specific interventions on chemotherapy toxicity risk are needed.
Conclusion
Older adults with cancer who have elevated symptoms of depression when starting a new cytotoxic chemotherapy have an increased risk of severe chemotherapy-related toxicities, suggesting the importance of screening older patients for such symptoms. Future studies will need to confirm this finding, including the incorporation of more extensive mental health tools into evaluations, and ultimately, the impact of specific interventions for depression and anxiety on outcomes. In the meantime, it is important to identify mental health concerns when starting chemotherapy for older adults.
Supplementary Material
Acknowledgements
We dedicate this research to the memory of Dr. Arti Hurria, our friend, colleague, mentor, and original principal investigator of the GAIN study, who we tragically lost in November 2018.
Funding:
This research project was supported by the UniHealth Foundation (PI: A.Huria/W.Dale). Support was also provided by City of Hope’s Center for Cancer and Aging and the NIH (R33AG059206 [PI: W. Dale], K24AG055693 [PI: W. Dale]).
Anahid Hamparsumian is a research fellow in the VA Fellowship in Advanced Geriatrics at the Geriatric Research Education and Clinical Center, Department of Veterans Affairs Medical Center, Los Angeles, CA.
Footnotes
Conflict of Interest: DL: Research funding to institution from AstraZeneca and Brooklyn ImmunoTherapeutics. Consultant for AbbVie, Adagene, AstraZeneca, Delcath, Eisai, Exelixis, Genentech, Ipsen Biopharmaceuticals, Merck, Sumitomo, and TriSalus, all outside of the submitted work. The remaining authors have no conflict of interest to disclose.
Disclosure: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government.
Trial Registration: Clinicaltrials.gov identifier: NCT02517034
References
- 1.Nakash O, Levav I, Aguilar-Gaxiola S, et al. Comorbidity of common mental disorders with cancer and their treatment gap: findings from the World Mental Health Surveys. Psychooncology. 2014;23(1):40–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Weiss Wiesel TR, Nelson CJ, Tew WP, et al. The relationship between age, anxiety, and depression in older adults with cancer. Psycho-Oncology. 2015;24(6):712–717. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Taylor WD. Clinical practice. Depression in the elderly. N Engl J Med. 2014;371(13):1228–1236. [DOI] [PubMed] [Google Scholar]
- 4.Birch K, Chung S, Zion SR, MacEwan JP, Malecki MJ. Incremental Health Care Costs of Anxiety and Depression Among Medicare Beneficiaries With Cancer. JCO Oncol Pract. 2023;19(5):e660–e671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.McKenzie H, Hayes L, White K, et al. Chemotherapy outpatients’ unplanned presentations to hospital: a retrospective study. Support Care Cancer. 2011;19(7):963–969. [DOI] [PubMed] [Google Scholar]
- 6.Arrieta Ó, Angulo LP, Núñez-Valencia C, et al. Association of Depression and Anxiety on Quality of Life, Treatment Adherence, and Prognosis in Patients with Advanced Non-small Cell Lung Cancer. Ann Surg Oncol. 2013;20(6):1941–1948. [DOI] [PubMed] [Google Scholar]
- 7.Klepin HD, Sun C-L, Smith DD, et al. Predictors of Unplanned Hospitalizations Among Older Adults Receiving Cancer Chemotherapy. JCO Oncol Pract. 2021;17(6):e740–e752. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Brown LF, Kroenke K, Theobald DE, Wu J, Tu W. The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. Psychooncology. 2010;19(7):734–741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Prieto JM, Blanch J, Atala J, et al. Psychiatric morbidity and impact on hospital length of stay among hematologic cancer patients receiving stem-cell transplantation. J Clin Oncol. 2002;20(7):1907–1917. [DOI] [PubMed] [Google Scholar]
- 10.Nipp RD, El-Jawahri A, Moran SM, et al. The relationship between physical and psychological symptoms and health care utilization in hospitalized patients with advanced cancer. Cancer. 2017;123(23):4720–4727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wang YH, Li JQ, Shi JF, et al. Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies. Mol Psychiatry. 2020;25(7):1487–1499. [DOI] [PubMed] [Google Scholar]
- 12.McFarland DC, Saracino RM, Miller AH, Breitbart W, Rosenfeld B, Nelson C. Prognostic implications of depression and inflammation in patients with metastatic lung cancer. Future Oncol. 2021;17(2):183–196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ellis J, Lin J, Walsh A, et al. Predictors of referral for specialized psychosocial oncology care in patients with metastatic cancer: the contributions of age, distress, and marital status. J Clin Oncol. 2009;27(5):699–705. [DOI] [PubMed] [Google Scholar]
- 14.Basch E, Deal AM, Kris MG, et al. Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial. J Clin Oncol. 2016;34(6):557–565. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Hurria A, Togawa K, Mohile SG, et al. Predicting Chemotherapy Toxicity in Older Adults With Cancer: A Prospective Multicenter Study. J Clin Oncol. 2011;29(25):3457–3465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Dale W, Klepin HD, Williams GR, et al. Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update. J Clin Oncol. 2023:JCO2300933. [DOI] [PubMed] [Google Scholar]
- 17.Dotan E, Walter LC, Beechinor R, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Older Adult Oncology V.1.2024.. Published 2023. Accessed 12/8/23, 2023. [Google Scholar]
- 18.Li D, Sun CL, Kim H, et al. Geriatric Assessment-Driven Intervention (GAIN) on Chemotherapy-Related Toxic Effects in Older Adults With Cancer: A Randomized Clinical Trial. JAMA Oncol. 2021;7(11):e214158. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Mohile SG, Mohamed MR, Xu H, et al. Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study. Lancet. 2021;398(10314):1894–1904. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Stewart AL WJ. Measuring Functioning and Well-being: the Medical Outcomes Study Approach. Durham, NC: Duke University Press; 1992. [Google Scholar]
- 21.Pergolotti M, Langer MM, Deal AM, Muss HB, Nyrop K, Williams G. Mental status evaluation in older adults with cancer: Development of the Mental Health Index-13. J Geriatr Oncol. 2019;10(2):241–245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Insittute. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. Published 2021. Accessed. [Google Scholar]
- 23.Hurria A, Mohile S, Gajra A, et al. Validation of a Prediction Tool for Chemotherapy Toxicity in Older Adults With Cancer. J Clin Oncol. 2016;34:2366–2371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Dai D, Coetzer H, Zion SR, Malecki MJ. Anxiety, Depression, and Stress Reaction/Adjustment Disorders and Their Associations with Healthcare Resource Utilization and Costs Among Newly Diagnosed Patients With Breast Cancer. J Health Econ Outcomes Res. 2023;10(1):68–76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Lin C, Clark R, Tu P, Bosworth HB, Zullig LL. Breast cancer oral anti-cancer medication adherence: a systematic review of psychosocial motivators and barriers. Breast Cancer Res Treat. 2017;165(2):247–260. [DOI] [PubMed] [Google Scholar]
- 26.Schag CAC, Heinrich RL. Anxiety in medical situations: Adult cancer patients. J Clin Psychol. 1989;45(1):20–27. [DOI] [PubMed] [Google Scholar]
- 27.Extermann M, Boler I, Reich RR, et al. Predicting the Risk of Chemotherapy Toxicity in Older Patients: The Chemotherapy Risk Assessment Scale for High-Age Patients CRASH) Score. Cancer. 2012;118:3377–3386. [DOI] [PubMed] [Google Scholar]
- 28.Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363(8):733–742. [DOI] [PubMed] [Google Scholar]
- 29.Gajra A, Jeune-Smith Y, Fortier S, et al. The Use and Knowledge of Validated Geriatric Assessment Instruments Among US Community Oncologists. JCO Oncol Pract. 2022;18(7):e1081–e1090. [DOI] [PubMed] [Google Scholar]
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