Psychological burden and depressive symptoms in caregivers of hemato-oncological patients: the role of medical visits

Cancer is an established leading cause of death worldwide, with its global incidence increasing to >18 million of new cases in 2020, which was associated with a mortality rate of nearly 1 in every 6 cases.¹ At the same time, cancer treatments are dramatically improving, and the number of people surviving and living with cancer has been on the rise in the past 2 decades. Hence, the disease, once considered acute, is now frequently regarded as chronic. However, the remarkable ongoing breakthrough in cancer treatment strategies has its downside; many patients end up with long-term disabilities and complex conditions demanding close physical and psychological support.² This situation places extensive burden on informal caregivers (eg, spouses, children, parents, and friends), who have to provide a broad spectrum of assistance to their loved ones suffering from a chronic disease for a long period.

Increased caregiver burden is shown to be associated with several factors, such as severity of illness and symptoms, types of administered treatments, their side effects, and costs.^3-5 The burden is also reported to correlate with a requirement for more intensive home care, especially in patients with functional decline.^6,7 Along with factors related to the nature of the patient illness, caregiver own characteristics may contribute to the burden. Studies suggest that higher burden is linked with being a spouse of the patient, a sole caregiver, as well as with having a low income and a low educational level.^8,9 Two recently published reports emphasize that the caregiver burden is experienced at all disease stages and is associated with psychological distress.^10,11 Although depressive symptoms in caregivers of solid tumor patients are well described,^12-14 the information regarding depressive symptoms among caregivers of patients with hematological malignancies is limited.¹⁵ Because the latter patients constitute 6.5% of all patients with cancer worldwide,¹⁶ studies addressing the burden and its link with depressive symptoms in this population are eagerly awaited. Moreover, the available data about burden and depressive symptoms mainly come from the hematopoietic stem cell transplantation setting, representing a highly specific patient subset.^17-19 Further research aiming to identify factors influencing the link between burden and depressive symptoms in informal caregivers of other hematological patients is warranted.

It is important to assess the interplay between patient and caregiver characteristics, caregiver burden and depressive symptoms, and the effects of medical visits on caregiver burden and depressive symptoms. The impact of medical visits in the context of caregiver burden acquires particular significance, because major advances in cancer therapies have led to care transition from the inpatient to the outpatient setting. Hence, the critical role of caregivers becomes even more essential, given the vital importance of their presence at these visits. The unique trajectory of hematological malignancies, associated with numerous lines of therapy, multiple relapses, and prognostication difficulties,²⁰ poses a special set of challenges for informal caregivers. The goal of this study is to explore the diverse array of interconnected factors contributing to extensive burden among informal caregivers of hematological patients to develop strategies to reduce this burden.

The following overarching research questions have been posed in this study:

1. What are the associations between patient characteristics and caregiver burden and depressive symptoms?

2. What are the associations between caregiver characteristics and caregiver burden and depressive symptoms?

3. What are the associations between medical visits and caregiver burden and depressive symptoms?

4. Does caregiver burden mediate the link between patient characteristics and caregiver depressive symptoms?

5. Does caregiver burden mediate the link between medical visits and caregiver depressive symptoms?

The study was approved by the institutional review board of the Rambam Health Care Campus (Haifa, Israel; approval number 0095-19-RMB). All participants signed the informed consent form before inclusion. Medical staff explained to potential participants that participation was voluntary and their decision to participate would not influence their treatment. To gain a broad understanding of patient and caregiver perspectives, all caregivers and patients diagnosed with a hematological malignancy, who were on active treatment during the recruitment period (August 2020 to February 2021), could read Hebrew, and understand the consent form and the questionnaire, were considered eligible for participation. All patients were aged >18 years. The caregiver was defined as a person identified by the patient as primarily responsible for his/her care. Patients and caregivers completed separate questionnaires by themselves once during the study period. The visit length (ie, how many minutes a patient stayed in the hospital during the visit) was variable (90-240 minutes) and depended on the treatment type. All visits were conducted in-person, 90% for anticancer therapy and the rest for symptom management. Caregivers did not attend every visit. Because the study did not include any intervention, no further inclusion or exclusion criteria were applied.

Participants completed a self-report questionnaire that was specially designed for this study. This questionnaire included demographic information (gender, age, and education) and questions about their subjective financial status (how do you perceive your current financial status? [1] not good at all, [2] not so good, [3] relatively good, [4] good, and [5] very good [5]), current medical visit frequency ([1] every day, [2] several times a week, [3] once a week, [4] once every 2 weeks, [5] once a month, and [6] less than once a month), illness duration ([1] <1 month, [2] between 1 and <6 months, [3] between 6 months and <1 year, [4] between 1 and <3 years, [5] between 3 and ≤5 years, and [6] >5 years), cancer recurrence (yes/no), physical functioning ([1] physically independent, [2] need a little help, [3] need some help, [4] need a lot of help, and [5] cannot get out of bed), and self-rated health ([1] very poor, [2] poor, [3] average, [4] good, and [5] very good). Additionally, participants completed 2 validated questionnaires regarding depressive symptoms^21,22 and burden.^23,24 Depressive symptoms were measured using the short form of the Center for Epidemiologic Studies Depression (CESD) scale.²⁵ The Hebrew version of the CESD scale used in this study was originally adapted from English by Shmotkin and Keinan.²⁶ Patients and caregivers were given the following instructions: “Below is a list of the ways you might have felt or behaved. Please tell how often you have felt this way during the past week.” The list comprised 10 items including, for example, “I felt fearful” or “I felt hopeful about the future.” The reliability in the evaluated sample was 0.747 for caregivers and 0.828 for patients. Answers ranged from “not at all” (1) to “all the time” (4).

The burden was measured using the 12-item Zarit Caregiver Burden Interview. Caregivers were given the following instructions: “Below is a list of statements that reflect how people sometimes feel when taking care of another person. After reading each statement, indicate how often you experience the feelings listed by circling the number that best corresponds to the frequency of these feelings.” The list comprised 12 items including, for example, “not enough time for myself” or “lost control of life.” The sample reliability was 0.854 for caregivers. Answers ranged from “not at all” (1) to “very much” (4).

These 2 questionnaires were selected, because they are widely used in studies evaluating psychosocial outcomes of cancer.

Data were analyzed using IBM SPSS-25. Pearson correlations were computed to examine univariate associations between variables and to identify the variables that had significant contribution to caregiver burden and depressive symptoms. These significant contributors were included in the multivariable model. Mediation models were calculated with the PROCESS procedure, Model 4, with 5000 bootstrap samples and a 95% confidence interval.²⁷ The PROCESS procedure is a tool used to examine the effect of ≥1 mediating or moderating variables on the association between independent and dependent variables.²⁷ Because the number of patient participants was higher (n = 115) than that of caregiver participants (n = 70), descriptive data about patients and caregivers were provided separately. Additionally, patients and caregivers were analyzed as dyads (n = 70). If the patient or caregiver data were missing, the dyad was not included in the analyses.

The study included patients (n = 115) and their caregivers (n = 70) recruited at the Rambam Hematology Ambulatory Unit (Table 1). The average age of patients was 62.8 + 14.5 years; 47% of them (n = 54) were males. Approximately 42% of patients were diagnosed with multiple myeloma, ∼36% with non-Hodgkin lymphoma, and the rest with Hodgkin lymphoma (7%), chronic lymphocytic leukemia (5%), myelodysplastic syndromes (4%), acute promyelocytic leukemia (2%), or others. The illness duration varied, with a range of <6 months (20%), between 6 months and <1 year (11%), between 1 and <3 years (24%), between 3 and ≤5 years (13%), and >5 years (32%). Almost half of the patients (49%) had a relapsed disease. The following treatment modalities were applied: ∼42% of patients received chemotherapy, 44% immunotherapy, and 9% underwent radiotherapy. The rest of the patients were visiting the clinic for the standard-of-care follow-up, for example, after hematopoietic stem cell transplantation or for the administration of fluids, electrolytes, or cellular therapies. In terms of physical functioning, 63% reported that they were physically independent, 24% reported that they needed a little help, 11% reported that they needed some help, and 2.7% reported that they needed a lot of help or could not get out of bed. Relatedly, self-rated physical health was described by patients as very poor (1%), poor (14%), average (41%), good (36%), or very good (8%). The average depression score was 21.5 + 5.4, with as many as 61.5% of patients reporting the presence of significant depressive symptoms, defined as a CESD score >20.

The average age of participating caregivers was 57.3 + 15.7 years; 58% (n = 41) of them were females (Table 2). Approximately two-thirds (68%) of these individuals had higher education degrees (ie, >12 years of education). In terms of financial status, only 6% of caregivers reported that it was not good at all, and the rest defined it as relatively good (20%), good (51%), or very good (23%). The majority of caregivers (78%) were patients’ spouses, and the rest were their children. Among caregivers, the average burden score was 15.5 ± 5.4, with as many as 79.1% of them reporting a high level of burden, defined as a total Zarit burden score >13. Additionally, caregivers reported high levels of depressive symptoms, with the average depression score of 20.6 ± 3.9, and up to 50.0% of caregivers reported on the occurrence of significant depressive symptoms (CESD score >20).

The first research question dealt with associations between patient characteristics and caregiver burden and depressive symptoms. Caregivers experienced a higher level of burden if the patients were less educated and less healthy in terms of physical health (measured using 2 designated items of physical functioning and self-rated health) and emotional health (measured by the CESD scale). Depressive symptoms were mainly found among caregivers if the patients were less healthy in terms of physical health (measured by the designated self-rated health item) and emotional health (measured by the CESD scale).

The second research question dealt with associations of caregiver characteristics with their burden and depressive symptoms. The only socio-demographic variable that significantly predicted the caregiver burden and depressive symptoms was found to be their gender, with female caregivers reporting higher levels of these variables (Table 2). As expected, a significant link between the caregiver burden and depressive symptoms was observed.

In terms of the third research question, the frequency of medical visits was linked with both caregiver burden and depressive symptoms. The fourth and fifth research questions were analyzed using 3 mediation models, presented in Table 3. Medical visits (Figure 1A), patient self-rated health (Figure 1B), and patient depressive symptoms (Figure 1C) were defined as independent variables, whereas the caregiver burden was defined as a mediator, and the caregiver level of depressive symptoms was defined as an outcome. The findings demonstrated full mediation when the independent variables were patient self-rated health and medical visits. Conversely, when the independent variable was patient depressive symptoms, the mediation was partial. These analyses indicated that the direct effect of patient depressive symptoms on those of a caregiver was significant. However, direct effects of both patient self-rated health and medical visits on caregiver depressive symptoms were nonsignificant, because these effects were fully mediated by the caregiver burden. The indirect effects (ie, the effect of each independent variable on caregiver depressive symptoms through the mediation of the caregiver burden) were found to be significant in all 3 models (Table 3).

This study focused on the identification of variables contributing to the burden and depressive symptoms in informal caregivers of patients, who were managed at the hematology ambulatory unit. Several important findings emerged. First, the levels of both caregiver burden and depressive symptoms were higher among females. Second, the caregiver burden and depressive symptoms were found to be linked to patient self-rated health, depressive symptoms, and the number of medical visits. Third, caregiver burden fully mediated the link between medical visits and caregiver depressive symptoms, as well as the link between patient self-rated health and caregiver depressive symptoms. However, the link between the depressive symptoms of a patient and a caregiver was only partly mediated by caregiver burden. These findings emphasize that to reduce the burden and depressive symptoms among caregivers of hematological patients, it is important to decrease the number and length of medical visits. Additionally, it is essential to identify patients with depressive symptoms and provide intensive psychological support both to them and their caregivers.

The first research question of this study concentrated on the associations between patient characteristics and caregiver burden and depressive symptoms. Although the mean age of the evaluated patients was 62.8 years, it was not found to affect caregiver burden. This result contradicted previous reports demonstrating that older patients had significant caregiving needs, particularly individuals who required assistance with instrumental activities of daily living.^28,29 Our findings might be related to the nature of hematological malignancies, in which, unlike in other types of cancer, the age spectrum of patients is wider, with a greater proportion of young individuals.

The patient gender was not identified as a contributing factor to caregiver burden, which was in agreement with prior studies.³⁰ 

In terms of the impact of the patient educational level, caregivers of patients with higher education degrees were found to experience lower levels of burden. This could be related to the fact that educated patients are more likely to use a variety of resources providing detailed information about their disease, its complications, and treatment options, which helps them to adopt realistic expectations regarding their prognosis. In this context, hematological malignancies and the associated treatments may be very aggressive and carry multiple side effects. Patient awareness of such risks makes them more capable of coping with the burden. Additionally, because education is linked with income, patients with higher education degrees can afford to spend more on informal help, thus reducing the burden.

In this study, frequent medical visits are found to lead to more depressive symptoms and higher burden. Treatment and monitoring of hematological malignancies require frequent hospitalizations and visits to the ambulatory unit, which often forces the caregivers to miss workdays. Although, to the best of our knowledge, such results have not been previously reported in this setting, an Indian observational study, including family caregivers of patients with cancer has shown that during chemotherapy, the burden increases when more medical visits and admissions are needed.⁷ Yet, that study has identified mild-to-moderate and moderate-to-severe burden in ∼70 % and 20% of caregivers, respectively. At the same time, in our analysis, as many as ∼80% of the caregivers have reported a high level of burden.³¹ This difference may be explained by the supportive joint family setup that is common in India.

This study has demonstrated that patient self-rated health correlates with caregiver burden and depressive symptoms. To our knowledge, this is the first report of a linkage between these variables. This finding is reasonable, given that as the subjective health of patients deteriorates, they need more help from their caregivers, who, as a result, experience higher levels of burden. Our study has also revealed a relationship between patient depressive symptoms and the extent of burden and depressive symptoms in caregivers. This result is consistent with those from other studies.³² 

In this study, illness duration and recurrence are not found to be linked to burden. This is not in line with previously published reports.³³ A plausible explanation for these differences is associated with the nature of hematological malignancies. The majority of patients in our cohort have been suffering from multiple myeloma and lymphomas, which are considered incurable diseases, with numerous relapses and prolonged treatment periods. Most patients are aware of their disease course and prognosis.

The second research question focused on the evaluation of caregiver characteristics and their associations with burden. The mean age of caregivers was 57.3 years, and it did not appear to be related to caregiver burden or depressive symptoms, which differs from previous studies in which this was more frequently seen in caregivers aged <60 years.^28,34 The lack of associations between caregiver age and burden observed in our study could be attributed to the relatively young age of the analyzed sample.

This study has demonstrated a significant correlation between the female gender of a caregiver and enhanced burden and depressive symptoms, which is consistent with the existing literature.^8,35,36 Such correlation could be primarily related to the fact that women are typically more likely to perform routine family care tasks, which makes them exposed to high caregiving strain, resulting in increased burden. An additional explanation might be that, given the gender-role socialization perspective,³⁷ women feel more comfortable to report about their emotional distress, higher burden, and depressive symptoms.

Regarding the effect of educational level, our study, in which approximately two-thirds of caregivers had higher education degrees, revealed no correlation between this parameter and burden. This result is not in line with previously published data,⁸ in which a lower educational status has been reported to be associated with a higher burden risk, because a lower educational level is linked to lower socio-economic status. Similar to the educational level, marital status and being a spouse of a patient appear to have no effect on the level of caregiver burden. These data are also inconsistent with the literature.⁸ 

Furthermore, as expected, caregivers suffering from enhanced burden have been at a higher risk for depressive symptoms. This result supports previous reports, demonstrating a clear link between the level of caregiver burden and depressive symptoms as well as other psychiatric morbidities.¹⁴ Of note, it might be that depressive symptoms lead to burden and vice versa; hence, further longitudinal studies are warranted to determine the direction of the influence.

Finally, this has been the first study, to our knowledge, examining whether patient characteristics (ie, medical visits, patient self-rated health, and patient depressive symptoms) have a direct effect on caregiver depressive symptoms or whether this effect is mediated by caregiver burden. Serial mediation models, developed for each evaluated variable (Figure 1), demonstrated full mediation when the independent variables were patient self-rated health (Figure 1B) and medical visits (Figure 1A). In contrast, when the independent variable was patient depressive symptoms (Figure 1C), the mediation was partial. These results suggest that medical visits and patient subjective health do not have a direct impact on caregiver depressive symptoms. In fact, they affect caregiver burden, which then affects caregiver depressive symptoms. These findings are particularly salient because they highlight that a reduction in medical visits, using such services as telemedicine,^38,39 can diminish caregiver burden, which, in turn, can improve caregiver depressive symptoms. Furthermore, Mooney et al have recently reported on an “Oncology hospital-at-home program” that could become a promising model of oncological care delivery, allowing to reduce the use of unplanned health care and related costs.⁴⁰ Such approach might also have a positive impact on the burden of informal caregivers.

The onset of the COVID-19 pandemic and the associated social distancing requirements have considerably affected the delivery of oncological care, forcing physicians to promptly adapt to the new circumstances and reduce the number of medical visits and admissions without compromising patient outcomes. Our analyses suggest that it is also important to expand this strategy beyond pandemic and apply such tools as virtual care and telemedicine to cut down medical visits and thus decrease caregiver burden and depressive symptoms. To that end, attempts to minimize the number of visits to hematology ambulatory unit should be made. Yet, when medical visits are required (eg, for antineoplastic therapy administration), it is important to make a deliberate effort to shorten the visit (eg, by minimizing the waiting time and replacing IV with subcutaneous therapy administration). An alternative solution that may decrease caregiver burden and depressive symptoms is to increase the number of involved caregivers in a rotatory way. This option is highly recommended by our social workers to new patients and their families because of the findings of this study.

This pilot study has several limitations. The number of participants is relatively small, which could explain the reason for some differences in results between our study and previously published data. This is a single-center study, mainly representing the population of Northern Israel. This population is heterogeneous and includes Jews and Arabs, with each ethnic group being further subdivided into several diverse component groups. Patients with acute leukemia are underrepresented in this study because most of them were treated as inpatients during the study period. The use of novel agents that are usually administered in the outpatient setting (eg, venetoclax and azacitidine) was not common in Israel at that time. Physical functioning and financial status of patients were assessed subjectively. However, subjective assessments (rather than objective ones) capture patient's personal perception of both issues, which can significantly influence their decision-making process and psychological well-being.⁴¹ Patients and caregivers completed the study questionnaires only once, and we did not collect data regarding visit length, reason (treatment, examination, and follow-up), the attendance of caregivers during previous visits ,and whether their presence was required or voluntary. Additionally, this study focused on the primary caregiver as identified by the patients. In some cases, several caregivers may be involved with the same patient; hence, the associations between gender and caregiver burden and depressive symptoms may be confounded by the number of caregivers patients had. Finally, the majority of caregivers in this research had high educational status, which might lead to underrepresentation of certain deprived population groups. Further studies with large number of patients with a wide variety of hematological malignancies should be conducted to validate our pilot study findings.

In conclusion, this study provides new insights into the burden and depressive symptoms experienced by informal caregivers of patients with hemato-oncological malignancies treated at a hematology ambulatory unit, emphasizing the impact of medical visits. The high frequency of medical visits has been found to correlate with the exacerbation of caregiver depressive symptoms through the mediation of caregiver burden. Therefore, reduction in the number and length of such visits could essentially decrease the burden and depressive symptoms of caregivers, without compromising patient outcomes. Psychosocial support by health care professionals should be offered for both patients and their informal caregivers to improve the understanding and acceptance of the illness and provide tools to cope with the struggles that accompany the disease.

The authors acknowledge with thanks the assistance of Sonia Kamenetsky in the preparation of the manuscript.

Contribution: A.A.A.W. and R.E.-B. designed the study, interpreted the data, and wrote the manuscript; M.F. and G.A.K. collected the data; N.A.H. designed the study, collected and interpreted the data, and wrote the manuscript; and all the authors reviewed and approved the final version of the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Netanel A. Horowitz, Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8 Ha'Aliya St, Haifa 3109601, Israel; email: n_horowitz@rambam.health.gov.il.