The feasibility and benefit of a brief psychosocial intervention in addition to early palliative care in patients with advanced cancer to reduce depressive symptoms: a pilot randomized controlled clinical trial

There has been much discussion in recent years about the integration of palliative care (PC) in oncology [ 1, 2]. Important clinical trials [ 3– 6] that demonstrate the benefits of the early integration of PC in oncology have been published. Such studies show improvement in patients’ quality of life (QOL) [ 3– 5], lower rates of depressive symptoms [ 3, 5], less aggressive end-of-life care [ 3, 6], greater patients’ [ 4] and caregivers’ [ 7] satisfaction with the care received. Although the aforementioned evidence, PC continues to be offered late even at comprehensive oncological centers [ 8].

Countless barriers hinder the access of patients with advanced cancer to PC [ 9, 10]. Among such barriers, those related to the stigma associated with PC by patients themselves seem relevant in Brazil; many patients believe that PC is merely “a place to die” [ 11]. At earlier stages of diseases, when patients are functionally fitter, many of them do not accept early referral to PC. In addition, the rate of absenteeism among PC consultations is around 25% in our hospital (personal communication). The cognitive-behavioral therapy (CBT) aims to enable individuals to identify and modify their distorted or dysfunctional automatic thoughts [ 12]. A CBT-based intervention, including psychoeducation, would be useful to educate patients about PC, reducing stigmatization and facilitating the early transition to PC.

The Pre-Palliative Emotional Care (PREPArE) trial was designed to develop a strategy to prepare patients before their first visit to a PC service. Our hypothesis was that among non-depressed patients with advanced cancer starting first-line palliative chemotherapy, the early provision of PC would be associated with lower rates of depressive symptoms compared to standard cancer treatment. The inclusion of a brief psychosocial intervention based on CBT [ 12] would be feasible and help reduce the rates of depressive symptoms when systematically combined with early PC.

In the present article, we present the impact of interventions on patients’ emotional domain over time and in greater detail on intervention day 90 measured using several assessment instruments.

Recruitment occurred from August 21, 2014, to August 5, 2015. During this period, 613 patients were screened, 103 were considered potentially eligible, and 63 were finally included (inclusion rate = 10.3%). The main reasons for excluding 510 patients were unavailability to perform the required hospital visits ( n = 299), use of antidepressants ( n = 52), age above 75 years old ( n = 30), diagnosis not compatible with the study criteria ( n = 26), and life expectancy not compatible with the one required for inclusion ( n = 23). The main reasons for refusing participation ( n = 17) were the presence of a limiting comorbidity ( n = 5) and psychological treatment ( n = 4) (Fig. 1). Figure 1 depicts the flowchart of patients through the study according to CONSORT and Table 1 describes the sociodemographic characteristics of the sample.

First, the data were analyzed to establish whether the patients’ characteristics were homogenous across the three arms at baseline; no clinical variable (tumor type, active neoplasm site, educational level, and family income) exhibited differences before intervention, nor did the scores on any of the applied questionnaires (Table 1).

Four patients (arm A, n = 2; Arm B, n = 2) were diagnosed by clinical oncologists with a depressive disorder during the study and started taking antidepressant (sertraline, n = 3; citalopram, n = 1). Of these, none were referred for specialized psychiatric treatment.

In this study, we assessed the feasibility and the efficacy of a brief psychosocial intervention systematically combined with early PC to reduce symptoms of depression 90 days after randomization. To our knowledge, no previous study has tested a brief psychosocial intervention together with early PC in the same clinical context. Depressive symptoms did not significantly differ between the arm that received psychosocial intervention and early PC and the other two arms over time.

Scientific evidence demonstrates the benefits of cognitive-behavioral approaches in the reduction of depressive symptoms among cancer patients [ 24]. A previous study demonstrated a reduction in anxiety and an improvement in QOL scores among end-stage cancer patients receiving CBT. The authors stressed the relevance of fitting interventions to the needs of this particular population of patients [ 25]. A large amount of scientific evidence demonstrates the efficacy of the CBT approach in cancer patients, including improvement in the state of health, changes in behavior, reduction in significant symptoms and depression, and greater independence in symptom management [ 26– 28]. However, there are no reports of studies that use CBT together with early PC in patients with advanced cancer, which we consider to be a population at high risk for the development of depression and anxiety.

Because cancer is a chronic, incurable disease with a substantial impact on patients’ life routine, family functioning, roles performed, physical functioning, and professional activities, among other areas, patients will expectably exhibit some psychological maladjustment. Some symptoms, such as those of depression and anxiety, are easily found under these circumstances [ 29, 30]. Some authors stress the need to investigate depression at different times to identify a potential healthy adjustment associated with treatment [ 31]. In the present study, we found that both depression and anxiety symptoms improved over time, independent of the interventions received; thus, one may expect such symptoms to naturally decrease over the course of treatment. It should be emphasized that the participants were at the point of starting first-line chemotherapy, i.e., they had already been informed as to the occurrence of relapse or progression of the disease, which most likely elicited higher levels of emotional symptoms. In addition, the feeling/fear of the unknown is frequent at the onset of chemotherapy (“Will I feel sick?”, “How will I feel after treatment?”, etc.). We believe that there is a trend for the improvements in depression and anxiety levels with the progression of treatment.

The tendency of patients subjected to the psychosocial intervention to exhibit higher scores of depression over time compared to the other two arms was a significant and unexpected finding. According to some studies, debriefing, i.e., talking about some traumatic event immediately after it occurs, may intensify uncomfortable symptoms [ 32, 33]. In this regard, one should consider the fact that a diagnosis of cancer is related to a significantly traumatic event [ 34], particularly in the case of advanced and incurable disease. On these grounds, the time of application of the psychosocial intervention, i.e., immediately after diagnosis of cancer relapse/progression, may have worsened some emotional aspects. Future studies including psychological strategies need to consider what the most adequate time for intervention may be. Probably, the most useful protocol would include on-demand psychological intervention, but not systematic as was in our study. However, regarding the emotional functioning domain, arm A responded better than arms B and C. The same held true for anxiety symptoms, albeit with a smaller effect sizes.

We consider the preliminary results of this study very important for the design of a larger multicenter, multinational randomized clinical trial. Regarding feasibility, some aspects warrant discussion. The eligibility criteria are being revised to become less restrictive, since the inclusion rate was only 10.2%. Among other modifications in the research protocol, we plan not to limit age at 75 years, and not to exclude patients because of previous psychiatric conditions. Additionally, aiming to minimize the burden of completing many questionnaires and considering that PHQ-9 and HADS measures a similar construct (depression), we plan to use only HADS in the larger study. Another factor that limited the study feasibility was the high contamination rate found; approximately 30% of the patients allocated to arm C received PC during the study period. This value is slightly more than twice the rate reported in the original study by Temel et al. [ 3]. However, we think that the intention-to-treat analysis used likely reduced the contamination bias. The attrition rate was 15.9% and 38% on days 90 and 180, respectively. Although these rates may be considered high, they are similar (and actually somewhat lower) than those previously described [ 35]. One of the goals of early PC is to help patients navigate the difficult decisions made towards the end of life which would include the decision whether or not to undergo palliative chemotherapy. In order to enhance the benefit of PC, in the subsequent study, we plan to include patients before the decision to receive first-line palliative chemotherapy, and not after starting chemotherapy (as in the present study).

The present study has several limitations, including the fact that it was a single-center study. The study was performed at a hospital that provides adequate psychosocial support as “routine”; thus, findings may be different in less specialized hospitals. Another limitation is the sample size. The study did not reach its enrollment goal and is likely underpowered to evaluate its primary outcome. In addition, due to the restricted eligibility criteria, the findings are difficult to generalize. The focus was on the prevention of depressive symptoms. For this reason, patients with a diagnosis of depression or known to be using antidepressants were excluded. As a result, the depression scores most likely may have been lower than those found in daily clinical practice, leaving little “room” for improvement. In addition, a slight worsening of the clinical condition may be clinically relevant. This fact may be explained by the statistical phenomenon known as regression to the mean, which has potentially significant implications for the interpretation of health-related behaviors [ 36]. Further studies should focus on patients reporting higher scores of anxiety and depression.

Future studies to be conducted with this population group need to revise the eligibility criteria and make them less restrictive. In addition, the need for arm C is questioned due to high contamination rate. The systematic psychosocial and educational intervention was not able to reduce the depression scores after 90 days or over time in patients starting first-line palliative chemotherapy. Assessment of the ES indicates a possible impact of interventions on the emotional functioning domain, which need to be better assessed in future studies. The intervention should be tested on-demand and in subgroups of high risk of anxiety and depression.