International Review of Psychiatry, February 2014; 26(1): 31–43

Review of psychotherapeutic interventions on depression in cancer patients and their impact on disease progression

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INGRID BARRERA & DAVID SPIEGEL 1Department of Psychiatry and Behavioral Science, Miller School of Medicine, University of Miami, Miami, Florida, USA, and 2Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California, USA

Abstract Depression, ranging from mild to severe, is the most frequently found psychological symptom among individuals with cancer. Depression in cancer patients has been known to mitigate emotional distress, quality of life, adherence to medical treatment, and overall health outcomes. Specifically, depression has been associated with impaired immune response and with poorer survival in patients with cancer. Various studies have found that psychotherapeutic interventions are effective in reducing symptoms of depression, which in turn could affect disease progression and mortality. This paper provides updated information on psychotherapeutic interventions geared towards cancer patients suffering from depressive disorders, and its impact on disease progression. PubMed, Cochrane Library database, PsycINFO and PsycARTICLES databases were searched from January 1980 through August 2013 using key words: psychotherapy, treatment, oncology, cancer, psycho-oncology, psychosocial issues, psychosocial stress, depression, mood disorder, and psychoneuroimmunology.

Introduction Cancer is the second leading cause of death in the USA, while depression is the leading cause of disability. Major depression is known to increase morbidity and mortality in several medical disorders (Evans et al., 1999); in cancer patients in particular, depressive disorders are a common form of psychological distress (Akechi et al., 2001; Kugaya et al., 2000; Okamura et al., 2000) and are even more frequent in patients with advanced cancer (Bukberg et al., 1984; Kugaya et al., 2000). In fact, depression, ranging from mild to severe, is the most frequently found psychological symptom among individuals with cancer (Mitchell et al., 2011; Newport & Nemeroff, 1998, 1999). In fact, up to 38% of patients with cancer meet criteria for a diagnosis of major depression (Massie, 2004). Although depression is two to three times more common in women than in men in the general population, Miller et al. (2011) found that there were no significant gender differences in depression within the cancer population. Prevalence rates of depression in patients with cancer are significantly higher than the prevalence rates of depression in the general US population (Kessler et al., 1994). McDaniel et al. (1995) report that the

prevalence rates for depression in patients with cancer range from 1.5% to 50%, and Newport and Nemeroff (1998) believe it ranges from 23% to 60%. More recent studies report that the prevalence of depression is three-fold higher in cancer patients (Waraich et al., 2004). This extreme variability is also seen in other studies and may relate to the use of different diagnostic approaches (e.g. inclusive/symptomatic versus exclusive/categorical) within epidemiological studies (Guo et al., 2006). Variability may also be related to the following factors: (1) differences in type of cancer (depression rates are generally highest in pancreatic, oropharyngeal, and breast carcinomas; and lowest in lymphoma, leukaemia, and gastric cancers (McDaniel et al., 1995)), (2) staging (Newport & Nemeroff, 1998), (3) severity of illness (rates of depression tend to increase with increase disease severity (Ciaramella & Poli, 2001)), and (4) type of treatment (anti-cancer treatments frequently associated with depression include cytokines (Musselman et al., 1998; Newport & Nemeroff, 1998; Capuron et al., 2001; Musselman et al., 2001a, McDaniel et al., 1997). Depression has a negative impact on outcome in cancer diagnoses in general (Wells et al., 1989).

Correspondence: Dr Ingrid Barrera, Department of Psychiatry and Behavioral Science, Miller School of Medicine, University of Miami, 1120 NW 14th Street, Miami, Florida 33136, USA. Tel: (205) 243-2301. E-mail: [email protected] (Received 26 September 2013; accepted 5 November 2013) ISSN 0954–0261 print/ISSN 1369–1627 online © 2014 Institute of Psychiatry DOI: 10.3109/09540261.2013.864259

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Severe symptoms of depression are often associated with prolonged hospital stays, poorer quality of life, decreased treatment compliance (Koenig et al., 1992; Grassi et al., 1996; Colleoni et al., 2000; Prieto et al., 2002; Li et al., 2011), and can lead to suicide (Henriksson et al., 1995; Li et al., 2011). In fact, in the USA, patients with cancer have nearly twice the incidence of suicide than those in the general population; however, suicide rates differ depending on cancer type (Misono et al., 2008) Moreover, there is mounting evidence that co-morbid depression predicts shorter survival in patients with cancer (Satin et al., 2009; Giese-Davis et al., 2011; Cohen et al., 2012). Stommel et al. (2002) found that patients with a history of depressive symptoms are at a 2.6 times increased risk of dying from their cancer within the first 19 months after diagnosis than are patients without a history of depression. Watson et al. (1999) hypothesize that this finding may be due to a decrease in self-care and compliance with anti-cancer treatments in patients with co-morbid depression. Faller et al. (1999) found that in a study including 103 patients with cancer, a depressive style was associated with decreased survival time, even when other major risk factors such as tumour stage and histological classification were taken into account. There is recent evidence that worsening depression predicts shorter survival in patients with breast cancer, independent of other known risk factors (Giese-Davis et al., 2011). This makes the management of depression in patients with cancer of great importance for both quality and potentially quantity of life. Despite higher rates of depression in the cancer patient population, depression is often underdiagnosed and undertreated in these patients, possibly due to the fact that many of the symptoms of cancer, as well as the side effects of its treatment, can mimic depressive symptomatology (i.e. fatigue, insomnia, cognitive impairment, cachexia, decrease in appetite, and decrease in energy) (Guo et al., 2006; Musselman et al., 1996). Even more ‘classic’ symptoms of depression such as hopelessness, suicidal ideation, and passive death wishes can too easily be ‘rationalized’ by medical staff as a response to the disease and its prognosis rather than a symptom of a treatable co-morbid psychiatric illness. Thus depression is often underdiagnosed and undertreated by professionals when working with this population. Raison & Miller (2003) note: ‘The widespread tendency to excuse depression as a natural reaction to cancer and the overlap between sickness and depressive symptoms both highlight the importance of accurately assessing depression in the context of neoplastic illness’ (p. 285); in addition, appropriate adequate treatment is also required. The appropriate diagnostic approach may vary in relation to its purpose. In research settings it may be more useful

to use an exclusive approach (excluding symptoms that are directly related to cancer or the side effects of the treatments, i.e. fatigue and decreased appetite) to emphasize precision (Raison & Nemeroff, 2000). An inclusive approach, on the other hand, counts all relevant symptoms towards a diagnosis of depression without regard to whether these symptoms stem from a mood disorder or physical illness. This inclusive approach is likely to be beneficial in a clinical setting because it is clinically important to deliver early, effective interventions to reduce depressive symptoms in patients with cancer. After doing a systematic review of 24 studies, Williams and Dale (2006) found that although there are a limited number of high quality Randomized control trials regarding pharmacological and psychotherapeutic interventions for patients with cancer, there is some evidence that: (1) antidepressants are effective in reducing the incidence of diagnosed cases of depression as well as symptoms of depression, and (2) psychotherapeutic interventions are effective in reducing symptoms of depression. Raison & Nemeroff (2000) report that while there is a shortage of well-controlled studies, the available research indicates that depression that occurs in patients with cancer is responsive to treatment with antidepressant medications. Paroxetine was found to be effective in reducing the incidence of depression diagnoses in patients with malignant melanoma who were receiving high-dose interferon alpha therapy (Musselman et al., 2001a) and in breast cancer patients receiving chemotherapy (Roscoe et al., 2005). Additionally, studies have found that in addition to relieving depressive symptoms, antidepressants have also been found to improve other symptoms associated with cancer and its treatment including hot flushes (Loprinzi et al., 2000, 2002; Stearns et al., 2000) and neuropathic pain (Max et al., 1992; Semenchuk et al., 2001; Sumpton & Moulin, 2001). Psychotherapeutic treatment of depression in cancer patients A number of studies support the benefit of psychosocial interventions in treating depression in patients with cancer. Even at the end of life, the provision of psychosocial support may not only be kind, but it may also be more medically effective than continuing anticancer treatment alone (Spiegel, 2011). For example, Temel et al. (2010) showed in a randomized clinical trial that palliative care for end-stage nonsmall-cell lung cancer patients resulted in significantly reduced depression and pain, as well as 2.5 months longer survival. Psychotherapy can alleviate depressive symptoms and improve coping in patients with cancer (Ross et al., 2002). In a Cochrane database meta-analysis including six studies, Akechi

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Psychotherapy, cancer & disease progression et al. (2008) found that compared to standard treatment, psychotherapy interventions were associated with a significant decrease in depressive symptoms among patients with incurable cancer and non-clinically diagnosed depression. The authors conducted a systematic review of randomized controlled trials to study the impact of psychotherapy on depression in patients with incurable (advanced) cancer. The population studied included adults of either gender with a primary diagnosis of incurable cancer. Among these studies, four implemented supportive psychotherapy, one implemented cognitive behavioural therapy, and one implemented problem-solving therapy, neither one showing higher efficacy than the other. It is important to note that none of the studies focused on patients with clinically diagnosed depression; therefore the effectiveness of psychotherapy for the treatment of depression in cancer patients could not be established. When compared with standard treatment, psychotherapy interventions were associated with a significant decrease in depressive symptoms (SMD ⫽ ⫺ 0.44, 95% CI ⫽ ⫺ 0.08 to ⫺ 0.80) among patients with advanced cancer and nonclinically diagnosed depression. There are a wide variety of psychotherapies and other psychological interventions that have been found effective in the treatment and management of depressive symptoms. Many of these have been slightly modified from their original form in order to be more applicable to the specific issues that cancer patients face (i.e. death anxiety). The following therapeutic techniques are particularly applicable to patients with cancer because they highlight coping with lifestyle changes, management of quality of life, and/or possible end of life issues. These interventions can be delivered both in a group and/or individual format. The most common interventions include: • Cognitive behavioural psychotherapy: A therapeutic modality geared towards increasing patient awareness of how thoughts (cognitions) can influence emotions, which in turn influences behaviour. The therapy is time-limited, and it includes psycho-education as well as homework assignments (i.e. thought records and other tools to help the person identify thoughts that may have a negative impact). There are a number of different types of cognitive therapies, but they all follow the same premise: a person’s cognitive distortions lead to irrational thinking, which can lead to dysfunctional behaviour (Horne & Watson, 2011). • Supportive-expressive group therapy (SEGT): A standardized treatment for patients with lifethreatening illness that encourages the expression of feelings and concerns regarding the illness and its impact on their lives in a supportive group environment (Classen & Spiegel, 2011; Spiegel

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et al., 1981; Spiegel & Classen, 2000). The goal/ purpose of the intervention is to increase social support, encourage emotional expression, help individuals cope with fears of death and dying, restructure life priorities, improve communication with family and healthcare professionals, and improve control of pain and anxiety. Problem solving therapy: A brief psychological intervention, usually offered in a 4–8 session format. The goal is for the clinician and patient to collaborate in identifying different problems in the patient’s life and trying to solve/approach the problems in a more structured format, while additionally teaching the patient general coping skills. Cognitive-existential group therapy (CEGT): Kissane et al. (1997) developed this treatment modality specifically for women receiving adjuvant chemotherapy with the intention of promoting active coping and social support. CEGT focuses on the following goals: Promoting a supportive environment, facilitating the grieving process, reframing negative thinking, enhancing coping and problem-solving skills, fostering hope, and setting priorities for the future. Supportive therapy: A therapeutic intervention geared towards helping patients cope with difficult emotions, while teaching them how to effectively manage their distress (Ledenberg & Holland, 2011). Mindfulness-based stress reduction: The use of mindfulness-based interventions, in conjunction with relaxation training, are also increasingly used with this patient population (Carlson et al., 2003, 2004; Carlson & Garland, 2005). This intervention involves teaching exercises adapted from Buddhist practices designed to still the mind, scan the body, and become more open to feelings and thoughts rather than struggling with them. Recent research has shown this approach to provide improved control of stress, quality of life, and social support (Carlson et al., 2013)

It is difficult to compare the effectiveness of each of the above interventions because the therapies have individual variations and furthermore, the populations that they study vary in degree of depressive symptomatology, cancer type, staging, treatment type, and other such factors. Psychotherapeutic effects on disease progression Could psychotherapeutic support for cancer patients actually impact the course of illness in cancer diagnosis? This question has been examined in 15 controlled trials. Eight of these studies showed prolonged

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survival time in cancer patients treated with both standard care and psychosocial treatments; the other seven studies showed no difference. It is difficult to make inferences as to what makes the studies successful or not, given that they are not comparable due to variability in cancer types, disease progression, treatment, and variability in population. Nevertheless, none of the studies revealed a deleterious effect of psychosocial intervention on survival time. Increasing evidence supports the idea that ‘in the absence of other more targeted and effective treatments, supportive care makes a difference to longevity’ (Spiegel, 2011). An initial clinical trial demonstrated that women with metastatic breast cancer randomized to a year of weekly supportive-expressive group therapy lived 18 months longer than control patients, and that the difference in survival was not due to differences in initial disease severity or subsequent chemo- and radiotherapy (Spiegel et al., 1989). In the spirit of further examining the relationship between group psychotherapy and breast cancer survival, Spiegel et al. (2007) repeated the study a decade later with the hope of replicating their earlier finding that intensive group therapy extended survival time of women with metastatic breast cancer. The results of the latter study did not fully replicate earlier findings and revealed no overall effect of the group therapy intervention on survival. However, post-hoc exploratory moderator analysis revealed a significant overall interaction between oestrogen-receptor (ER) status and experimental group (p ⫽ 0.002). More specifically, among the 25 ER-negative participants, those randomly assigned to the intervention group survived significantly longer (median of 29.8 months) than those in the control group (median of 9.3 months). The ER-positive participants showed no such intervention effect. The authors noted that the group of women who did benefit from the group therapy intervention (ER-negative group) had more limited anti-cancer treatment options and had a poorer prognosis. In other words, ER-negative women do not have the same advantage as do ER-positive women in the availability of highly effective hormonal treatments. Thus, the authors hypothesized that the differential intervention effects found in the study may be related to more room for the impact of other treatments (e.g. chemotherapy or the effects of psychosocial interventions on the body’s stress response systems) in the ER-negative group. Major advances in hormonal and chemotherapies have improved overall survival for women with ERpositive metastatic breast cancer (Peto et al., 2000), but these anti-oestrogen treatments have not benefited women with ER-negative tumours (Davies et al., 2011; Peto et al., 2000) It is therefore possible that the earlier improvement in survival time had

been supplanted by better overall survival, with the exception of ER-negative women. This explanation receives some support from other recent studies by independent investigators (Spiegel, 2011). Several other major randomized trials have found a survival advantage for those cancer patients randomized to group and individual psychotherapy. For example, Fawzy et al. (1993) found that a structured 6-week group psychotherapeutic intervention (including education, stress management, coping enhancement strategies, and psychological support) was associated with lower rates of recurrence and significantly lower rates of mortality among patients with malignant melanoma at 6-year follow-up. They emphasized the importance of early intervention in fostering effective coping strategies. In their original study (Fawzy et al., 1990), psychological assessments (including emotional state and coping) and specific immunological measures were examined at various time points. In the 1993 study the authors report on the rates of recurrence and mortality at a follow-up 5 to 6 years after primary surgery. There were no significant differences between intervention and control group participants in gender, Breslow depth, and distribution of melanoma sites. There was, however, a statistically significant difference in age in which the intervention group (M ⫽ 45.7 years) was older than the control group (M ⫽ 39.3 years). Control patients had a higher rate of recurrence (13/34; p ⫽ 0.09) and a statistically significant higher rate of mortality (10/34; p ⫽ 0.03) than intervention patients (7/34 recurrence and 3/34 mortality) at 6-year follow-up. Note, the number of recurrence includes both those who had recurrence and were living at follow-up, as well as those who died after recurrence. Male gender and a greater Breslow depth were found to be predictive of higher rates of recurrence and mortality. Analysis of multiple covariates revealed that only Breslow depth and experimental group (i.e. psychotherapy intervention group versus control group) were significant. The intervention effect remained significant after controlling for Breslow depth. Interestingly enough, higher levels of baseline distress were associated with lower rates of recurrence and mortality. The authors believe this is due to increased motivation from more active behavioural coping strategies. The authors studied a potential immune moderator of this psychotherapy effect. Higher natural killer cell activity (NKCA) at baseline was associated with lower recurrence rates, but not to survival. Although changes in NKCA over 6 months did not significantly influence survival, an increase in active behavioural coping was associated with lower rates of recurrence (p ⫽ 0.06) and was significantly associated with better survival (p ⫽ 0.03). Therefore, psychotherapeutic interventions that foster effective coping appear to have beneficial

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Psychotherapy, cancer & disease progression effects on survival among patients with malignant melanoma. Kuchler and colleagues (2007) found that individual psychotherapy provided at the bedside during both the pre- and post-operative inpatient hospital stay had a significantly beneficial impact on 10-year survival rates in patients with gastrointestinal cancer, who underwent surgery for stomach, pancreatic, primary liver, or colorectal cancer. The original study (Kuchler et al., 1999) found that the patients in the intervention group had a significantly higher rate of survival (69/136; p ⫽ 0.002) than those in the control group (45/135). They also found significant differences in Tumor, node, metastases staging or the residual tumour classification, in favour of the intervention patients. Secondary analyses found that most of the differences in favour of the intervention group occurred in female patients and in those with stomach, pancreatic, primary liver, or colorectal cancer. The individualized psychotherapy included education, a supportive relationship, individualized care based on intake information, encouraged a ‘fighting spirit’, worked to decrease a sense of helplessness/ hopelessness, aided in communication with the medical team, encouraged family and social support, explored patient’s adjustment to the surgery, and assisted the patient in planning for the future. At 10-year follow-up 29/136 patients in the intervention group and 13/135 patients in the control group survived. There was therefore a statistically significant better survival rate in the intervention group as compared to the control group (p ⫽ 0.006). Cox regression models that accounted for TNM staging or the residual tumour classification and tumour site also found significant differences at 10-year followup. An independent randomized trial of psychoeducational groups for women with primary breast cancer found significantly reduced rates of relapse and longer survival (Andersen et al., 2008, 2010). In addition, in a recent randomized clinical trial of palliative care for non-small cell lung cancer, patients who received an average of four visits related to psychosocial issues lived longer than those who received treatment as usual (Temel et al., 2010). Temel and colleagues (2010) reported a clear but apparently paradoxical finding: ‘Despite receiving less aggressive end-of-life care, patients in the palliative care group had significantly longer survival than those in the standard care group (median survival was 11.65 vs. 8.9 months; p ⫽ 0.02)’ (Temel et al., 2010, p. 738). Moreover, they found that those in the palliative care condition reported reductions in depressive symptoms. A recent meta-analysis of 25 independent studies (Satin et al., 2009) found that among cancer patients, depression predicted mortality, but not disease progression. The effect of depression remained even after adjusting for other known risk factors,

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indicating that depression may have a causal role in this finding. Nevertheless the significant finding for mortality, but not for disease progression, may be related to the limited number of studies (only three available statistically comparable articles regarding the relationship between depression and disease progression in cancer patients) and associated lower power. Based on these three studies, depressive symptoms were not shown to significantly predict cancer progression (risk ratio [RR] unadjusted ⫽ 1.23; 95% CI 0.85–1.77; p ⫽ 0.28). However, regarding mortality, the rates were up to 25% higher in patients experiencing depressive symptoms (RR unadjusted ⫽ 1.25; 95% CI 1.12–1.40; p ⬍ 0.001). These three independent studies measured the presence of major and minor depressive episodes (based on DSM-III-R and DSM-IV) and they found that mortality rates were up to 39% higher in patients diagnosed with major or minor depression (RR unadjusted ⫽ 1.39; 95% CI 1.10–1.89; p ⫽ 0.03). The authors concluded that since adjustment for known prognostic variables did not alter these associations, depression may play a causal role in cancer mortality. In a well-conducted study with a null outcome, Kissane and colleagues (2007) found that a supportive-expressive group therapy (SEGT) intervention did not prolong survival in women with histologically confirmed stage IV metastatic breast cancer; however, it did improve quality of life including improvement of existing depression and prevention of new cases of depression. They conducted a multi-centre randomized controlled study on survival, psychosocial outcomes, and treatment adherence in women with metastatic breast cancer in which they examined the effect of a weekly SEGT intervention (as compared to a relaxation-only control group). While SEGT did not prolong survival (median survival was 24.0 months in the intervention group and 18.3 months in the control group), SEGT did improve and prevent new depressive disorders (p ⫽ 0.002), it reduced hopelessness/helplessness (p ⫽ 0.004), trauma symptoms (p ⫽ 0.04), and improved social functioning (p ⫽ 0.03). As a post hoc analysis, the researchers examined the contribution of depression to treatment adherence and found that depressed patients received significantly less anti-cancer treatment (26.9 months) than non-depressed patients (38.0 months; p ⫽ 0.03). In a related study, Kissane and colleagues (2004) found that while cognitiveexistential group therapy (CEGT) intervention did not prolong survival in women with early stage breast cancer (stage I or II), the intervention was associated with beneficial psychosocial effects including significant reductions in anxiety (p ⫽ 0.05, twosided) and improved family functioning (p ⫽ 0.07, two-sided); which in turn translates into improved quality of life.

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Similarly, in a multi-centre randomized controlled study, Goodwin and colleagues (2001) found that supportive-expressive group therapy (geared towards survival, mood, and perceived pain) did not prolong survival in women with metastatic breast cancer. However, there was an unusual lack of parity between the treatment and control groups in baseline psychological functioning. The treatment group was substantially more depressed than the control group at baseline, a difference which in itself may have contributed to mortality in this group (Giese-Davis et al., 2011). Women in the SEGT branch had more improvement in psychological symptoms (i.e. those who were initially more distressed experienced a benefit from intervention, while those who were initially less distressed did not (p ⱕ 0.003)). Additionally, women in the SEGT reported a lower level of worsening pain than the controls (p ⫽ 0.04). There was no significant difference in reported suffering or overall survival. Up to this point, there has been a general consensus that a variety of psychosocial interventions have been beneficial in improving overall quality of life, depressed mood, anxiety, distress, pain, and social support in patients with cancer (Goodwin et al., 2001; Spiegel, 2002). However, the question of whether psychosocial interventions can impact disease progression and overall survival in patients with cancer has been more controversial. As noted above, there are mixed findings regarding how psychotherapeutic interventions impact survival rate; while some studies demonstrated that psychotherapy impacts disease progression, others found no survival benefit for those treated with psychotherapy. Nevertheless, the outcomes of these studies were not random, meaning no studies showed that attention to depression and mortality shortens survival (Spiegel, 2011). Surveillance, Epidemiology and End Results (SEER) Program data involving 7,334,889 patients has provided recent support regarding the influence of psychosocial factors on disease progression in patients with cancer (Aizer et al., 2013). The study demonstrated that in comparison to their single peers, married cancer patients were significantly less likely to present with metastatic disease, were more likely to receive definitive therapy, and were less likely to die of their cancer. The authors concluded, ‘For prostate, breast, colorectal, oesophageal, and head/neck cancers, the survival benefit associated with marriage was larger than the published survival benefit of chemotherapy.’ Furthermore, there is a strong consensus that psychosocial interventions have a positive effect on quality of life and overall psychological functioning in patients with cancer. Based on the literature, it will be important to further examine the question of whether psychosocial support can extend survival time in patients with cancer, and, if so, how that might occur physiologically.

Psychophysiology: how psychosocial interventions might impact disease progression Although disease outcome is largely accounted for by the specific pathophysiology of the disease, some variability may also be explained by ‘host resistance’ factors, including the response to stress of illness (Spiegel, 2011). Various clinical and epidemiological studies have demonstrated that tumour growth, progression, and metastasis are associated with reported patient stress, depression, and anxiety, as well as with limited perceived social support and poor coping mechanisms (Lillberg et al., 2003; Spiegel, 2002; Spiegel & Giese-Davis, 2003). Pathways linking stress reduction to changes in endocrine, immune and autonomic nervous system function and pathways linking gene expression to cancer progression are being studied (Rutter et al., 2008; Spiegel, 2013).

Stress and cancer Depression while not producing cancer has an impact on cancer progression. It appears that the physiological stress response is one of the probable moderators between depression, psychosocial factors and cancer progression. While few studies have supported a relationship between stress and the onset of cancer, multiple studies have supported a relationship between stress and cancer progression (Powell et al., 2013; Spiegel, 2011). Although the role of psychosocial factors in the initiation of cancer is unclear, there is strong evidence suggesting a connection between psychological factors (e.g. stress, depression, social isolation) and the progression of cancer (Lutgendorf et al., 2010). Stress may be acute or chronic. In acute stress, the fight/flight stress response is elicited by the release of catecholamines (i.e. norepinephrine and epinephrine) from the sympathetic nervous system and the adrenal medulla (Lutgendrof et al., 2010; Sood et al., 2010). Chronic stress is associated with dysregulation of the stress response system (Spiegel, 2011), including changes in multiple neuroendocrine hormones, and this contributes to harmful effects on multiple organ systems (McEwen, 1998). Current evidence suggests that the stress response can impact multiple pathways involved in cancer metastases and progression including immunoregulation, angiogenesis, and tumour invasion (Lutgendorf et al., 2010; Powell et al., 2013). Lack of social support is associated with higher norepinephrine levels in patients with ovarian tumours (Lutgendorf et al., 2011). Other neuroendocrine factors (including dopamine, prolactin, nerve growth factor, substance P, and oxytocin) are also modulated by chronic stress (Seeman & McEwen, 1996; Lutgendorf et al., 2010).

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Sympathetic nervous system and cytokines

Parasympathetic nervous system

Current evidence suggests that the stress response pathways can impact many aspects of the complex process of tumour metastasis. Cancer metastasis is responsible for most cancer-related mortality. However, several steps (e.g. angiogenesis, proliferation, invasion, embolization, and evasion of immune system surveillance) need to occur before metastasis is possible (Fidler, 2003). Angiogenesis is promoted by multiple factors including vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), transforming growth factors alpha and beta, and tumour necrosis factor alpha (Spannuth et al., 2008). This has a variety of psychosocial implications. For instance, poor levels of perceived social support are associated with higher levels of VEGF and IL-6 (Lutgendorf et al., 2011). Musselman et al. (2001b) found in cancer patients that higher than normal plasma IL-6 concentrations were associated with a diagnosis of depression. Furthermore, norepinephrine release, which is associated with the stress response, is also associated with the induction of VEGF expression and IL-6 gene transcription, which promotes growth of a blood supply that supports tumour metastasis (Thaker et al., 2006).This increase in VEGF and associated metastatic growth can be blocked with beta-adrenergic blockers, as well as with short interfering RNA (siRNA), which inhibits the production of norepinephrine (Thaker et al., 2006). As an example of the translation of such laboratory work in animals to the clinical setting, there is now evidence that breast cancer patients who happen to be taking beta-adrenergic blockers (i.e., propranolol) have lower rates of relapse and longer survival (Barron et al., 2011). Studies have also demonstrated the involvement of signal transducers and activators of transcription factor-3 (STAT3) in enhancing stress-mediated tumour-associated angiogenesis (Landen et al., 2007). STAT3 can be activated by growth factors (VEGF) and cytokines (IL-6), as well as by stress hormones (norepinephrine and epinephrine). The ability of a tumour cell to separate from the main tumour, invade the basement membrane, and enter the blood supply represents another important step in metastasis. Sood and colleagues (2006) found evidence that stress hormones can impact this process by increasing matrix metalloprotinease (MMP). For instance, both depression and stress are associated with MMP-9 secretion by tumour-associated macrophages (TAM) in patients with ovarian cancer. In their study, 222 up-regulated gene transcripts were found to be consistent with activation of signalling pathways involved in tumour growth and progression in individuals with ovarian cancer with high levels of depression and low levels of social support.

Autonomic nervous system dysregulation involving the parasympathetic nervous system has until recently been largely overlooked in relation to cancer progression (Gidron et al., 2005; Giese-Davis, Wilhelm et al., 2006). The parasympathetic nervous system involves self-soothing, the ability to counter sympathetic nervous system arousal-related increases in heart rate, blood pressure, and sweating. Its activity can be easily measured through assessing heart rate variability with respiration (Berntson et al., 1997). These changes in heart rate are largely driven by vagal activity. There is accumulating evidence that parasympathetic vagal feedback circuits involving adrenergic and cholinergic pathways (Olofsson et al., 2012) influence tumour processes via regulation of inflammation (De Couck et al. 2012; Gidron & Ronson 2008; Golan et al. 2009; Mravec et al., 2006, 2008; Mravec & Hulin, 2006; Mravec et al., 2009). Hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal (HPA) axis has been linked to increased levels of depression in patients (McDaniel et al., 1997). The HPA axis is a major hormonal stress response system that releases cortisol, the primary stress hormone. Cortisol mobilizes glucose into the blood, preparing the body to fight or flee. Stress disrupts the diurnal secretion of neuroendocrine hormones, including cortisol, which is typically high in the morning upon awakening and declines rapidly throughout the day. Dysregulation of such neuroendocrine hormones is associated with poorer quality of life and worse outcomes in patients with cancer (Sephton & Spiegel, 2003). Dysregulation of diurnal cortisol patterns has been associated with higher levels of functional disability, depression (Weinrib et al., 2010), fatigue (Bower et al., 2005), and poorer survival in women with breast cancer (Sephton et al., 2000) and lung cancer (Sephton et al., 2013). Other studies have also shown a direct relationship between glucocorticoids and neoplastic growth. For instance, glucocorticoids promote a survival pathway, inhibit apoptosis of a mammary tumour cell line, and down-regulate the expression of DNA repair genes including BRCA1 (Antonova & Mueller, 2008). Immune moderators and mediators and their effect on depression and cancer progression There is bidirectional communication between the neuroendocrine and immune systems. The stress-induced release of catecholamines (norepinephrine and epinephrine) and glucocorticoids has

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been associated with modulation of immune function (Sephton et al., 2009). Chronic stress is known to suppress and dysregulate immune function. The sequelae of the stress-response therefore represents one set of factors that influence cancer biology (Powell et al., 2013). Chronic stress, depression, and social isolation are associated with down-regulation of the cellular immune response, largely through adrenergic and glucocorticoid signalling pathways (McEwen, 1998). Inflammatory cytokines are associated with cancer-related fatigue and depression, and both depression and breast cancer are associated with higher levels of pro-inflammatory cytokines, which, in turn, affect neural function and induce depressive symptoms (Cleeland et al., 2003; Miller et al., 2008; Raison & Miller, 2003; Seruga et al., 2008). Evidence supports that both depression and breast cancer are sources of potent immune modulating cytokines (Cleeland et al., 2003; Miller et al., 2008; Raison & Miller, 2003; Schiepers et al., 2005; Seruga et al., 2008), which can influence both immune and central nervous system function, contributing to a reciprocal feedback loop that can worsen depression and tumour burden. Specific genetic markers, including the serotonin transporter and apolipoprotein E (Beaudreau et al., 2012; Caspi et al., 2003; O’Hara et al., 2007, 2008, 2009), as well as shorter telomeres and reduced telomerase activity (Heaphy et al., 2011; Pooley et al., 2010; Shen et al., 2007; Svenson et al., 2009), contribute to an increased risk of depression and cognitive impairment. These factors are therefore likely to amplify the risk of dysfunction in response to the stress of breast cancer and its treatment. Experimental studies with animal models have shown that chronic stress may contribute to tumour incidence and progression by suppressing type 1 (TH1) cytokines, as well as by cytotoxic activation of T cells and natural killer (NK) cells, thereby impairing antigen presentation and increasing regulatory T cells (Ben-Eliyahu et al., 1991, 1999) Similarly, in patients with breast cancer who have undergone surgery, stress has been associated with reductions in a variety of markers of cellular immunity including lower T-cell production of TH1 cytokines, decreased T-cell response to mitogen stimulation, and impaired NK cell cytotoxicity. NK cells attack transformed and dying cells, including tumour cells, rather than looking for specific antigens. It has been well established that decreasing numbers and cytotoxic activity of natural killer cells are associated with shorter survival in breast cancer (Levy et al., 1985, 1987, 1991). Chronic inflammation, accompanied by persistent increases in free radical-generating granulocytes, monocytes and cytokines (i.e. IL-1 beta, IL-6, and TNF-alpha) is associated with tumour promotion

(Coussens & Werb, 2002; Currier & Nemeroff, 2014). Immune and tumour cell secretion of cytokines (i.e. IL-8) and angiogenic factors (i.e. VEGF) have been associated with increased metastasis (Yu & Rak, 2003). Importantly, pro-inflammatory cytokines are known to mediate aspects of depression (Dantzer et al., 2008; Schiepers et al., 2005). In contrast, decreases in anti-inflammatory cytokines (i.e. IL-10) have also been associated with depression (Dhabhar et al., 2009; Fredericks et al., 2009). Myeloid-derived suppressor cells (i.e. MDSC, CD33⫹/CD11b⫹/CD15⫹/CD14⫺/ HLADR) are found in metastatic tumour tissue, and are found in greater numbers among breast cancer patients with depression (Gabrilovich & Nagaraj, 2009; OstrandRosenberg & Sinha, 2009). They are recruited to metastatic sites by cytokines produced by breast cancer cells, and they are specifically stimulated by the cytokines MIF, serpin E1, IL-8, and GM-CSF produced by these cells. They facilitate metastasis by inhibiting the cytotoxicity of natural killer (CD56⫹) and T cells by depleting the tumour microenvironments of arginine (Diaz-Montero et al., 2009; Solito et al., 2011). p53 gene expression There is recent evidence that alterations in p53 function are associated with the transformation of mammary cells into basal-like patterns of carcinogenesis, typical of ER-negative tumours (Pires et al., 2013). Stress and cortisol inhibit p53 gene expression, thereby promoting tumour growth (Feng et al., 2012). Telomeres Telomeres provide a model for how cells become reproductively unstable. Telomeres are the protective nucleoprotein structures capping the ends of eukaryotic chromosomes, consisting of a simple repeat sequence (TTAGGG) and bound proteins. Telomeres naturally shorten as cells divide. With every cell division, the terminus of the telomeric DNA is not replicated due to the ‘end replication problem’. In other words, DNA polymerase cannot replicate the very end of a DNA strand (Blackburn & Collins, 2011). Therefore, cells in older organisms have shorter telomeres than cells in younger ones. Telomeres shorten as mitotic cells divide due to end replication problems with DNA polymerase (Willeit et al., 2010), increasing risk for potentially cancerous mutations (Wu et al., 2003). Because of their protective function, telomeres can prevent genomic instability associated with oxidative stress, cell division, and DNA replication – common problems related to carcinogenesis. This is a complex and

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Psychotherapy, cancer & disease progression multistep process involving the accumulation of chromosomal instability and genetic abnormalities. Telomere shortening is a major cause of chromosomal instability and has been called a ‘hallmark’ of human carcinogenesis (Wu et al., 2003). There is an association between telomere attrition and wellestablished carcinogenic changes such as non-reciprocal translocations and gene copy number changes (Wu et al., 2003). In a well-designed case-controlled study, women with breast cancer had substantially shorter telomeres than did controls (Pooley et al. 2010). A polymorphism on chromosome 14q21 associated with longer leucocyte telomere length has been found to be associated with reduced risk of bladder cancer (Gu et al., 2011). Intensive meditation training has been shown to increase telomerase activity (Jacobs et al., 2011). Thus, telomere length and activity are salient to cancer (Shen et al., 2009; Willeit et al. 2010) and stress (Epel et al., 2004), and are susceptible to influence by psychotherapy (Pooley et al. 2010).

Conclusion Thus there is ample evidence indicating that comorbid depression and cancer are both a serious problem and an opportunity. Studies have shown that adequate treatment and management of depressive symptoms can improve the quality of life, as well as the disease progression in patients with cancer. Breast cancer patients with co-morbid depression tend to have disruption of emotion and cognition that triggers autonomic and HPA axis dysregulation associated with MDSC-induced suppression of protective immunity coupled with excessive enhancement of pro-inflammation and a related reduction in p53 protein, and excessive suppression of protective immunity. In turn, this may lead to more rapid cancer progression and more deleterious effects on brain function than would be observed in either illness alone. On the other hand, depression is a highly treatable illness, both with the psychotherapies outlined here, and with antidepressant medication. Accurate diagnosis of co-morbid depression and vigorous treatment has the potential to improve quality of life for those with cancer, and potentially to extend life as well. Living better may mean living longer. More stringent studies are needed to further examine the effects of both pharmacological and psychotherapeutic interventions among patients with cancer. Major limitations of the studies to date include small sample sizes and lack of consideration for confounding factors. Additional research is needed to compare standardized therapeutic modalities with more specificity than just cancer type.

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Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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