Sage Journals: Discover world-class research

Abstract

Background. As part of a new standard of quality cancer care, the Institute of Medicine has recommended inclusion of therapies that address psychosocial needs of cancer patients. A range of psychosocial therapies for managing acute and chronic stress have been developed for patients with cancer, based on the scientific framework of psychoneuroimmunology (PNI). The current review aimed to identify studies of new and emerging PNI-based psychosocial therapies in patients with cancer that have used neuroendocrine–immune biomarkers as outcomes. Specifically, this review aimed to evaluate studies based on the cancer populations involved, types of psychosocial therapies, and PNI measures employed. Methods. Methodology was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The PubMed, EMBASE, PsychINFO, CINAHL, and Google Scholar online databases were searched using combinations of keywords obtained from previous reviews of psychosocial interventions. Studies from 2001 to 2012 were included if they (a) were published in English, (b) used experimental or quasi-experimental designs, (c) evaluated psychosocial therapies, (d) involved cancer patients, and (e) reported results on at least one neuroendocrine or immune outcome measure. The search strategy identified 403 records and 2 stages of screening were used to eliminate irrelevant studies. Results. A total of 24 cancer-specific studies of psychosocial therapies that used PNI-based outcome measures were included in this review. Most studies included early-stage breast cancer patients, and 2 major types of therapies emerged, cognitive–behavioral therapies and complementary medical therapies. Durations of interventions ranged widely, from 1.3 hours over a single week to 27 hours over 18 weeks. Considerable diversity in PNI outcomes made statistical comparisons problematic. Studies of cognitive–behavioral therapies were found to have reported the most success in impacting PNI-based measures, which were typically functional measures of the immune system, for example, cytokines. Conclusions. Several issues related to research methodology are discussed. Most important, studies examining dose–response associations and resource allocation are needed to guide future research. A standardized panel of psychosocial instruments and biomarkers for PNI-based studies would enhance comparability of findings across studies when evaluating this body of research and assist with integrating psychosocial therapies into the standard of cancer care.

Keywords

cancer psychoneuroimmunology psychosocial interventions complementary therapies biomarkers neuroendocrine–immune outcomes literature review

Introduction

Over the past few decades, a variety of therapies have been developed to address the psychological and social (ie, psychosocial) aspects of illness for patients with cancer.^1-3 These psychosocial therapies, also referred to as psychosocial interventions by researchers, involve a wide range of activities, such as educating patients, enhancing coping skills, and providing supportive care to cancer patients.^3,4 The Institute of Medicine (IOM) has recommended that the standard of quality cancer care must now include services and interventions to address the psychosocial needs of cancer patients.⁵ However, studies of psychosocial therapies have used a wide variety of health outcomes, ranging from measures of psychosocial well-being and biological function to more global outcomes such as survival rates and health care utilization, to assess their therapeutic effectiveness in the cancer population.^2,6

To advance the science and delivery of psychosocial therapies, it is critical to review the literature and determine how these therapies have influenced specific health outcomes of persons with cancer. An important set of health outcomes that has gained considerable attention from researchers are related to the physiological stress response, which includes measures of psychosocial function as well as certain biological measures, collectively referred to as biomarkers.^7-9 Stress has been implicated in an array of negative impacts on the physical and mental health of individuals and is especially relevant to the cancer population.^10,11 The interdisciplinary field of research called psychoneuroimmunology (PNI) has provided an important framework for understanding the impact of stress on persons with cancer.^9,12

Stress and Psychoneuroimmunology

Patients with cancer are known to endure psychosocial–emotional suffering and physical distress, which collectively act as chronic stress stimuli.⁵ Chronic stress has a considerable negative impact on biological function, and most important, on the neuroendocrine and immune systems.¹³ The 2 major physiological pathways related to stress responses that have been extensively researched include the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic–adrenal–medullary (SAM) axis.¹⁴ Biochemical mediators released through these pathways (eg, cortisol from HPA axis and epinephrine from the SAM axis) increase the release of certain signaling molecules of the immune system, notably pro-inflammatory cytokines, such as interleukin-1 (IL-1) and IL-6.¹⁵ Continued exposure to high concentrations of stress mediators causes decreased expression of glucocorticoid receptors, thereby leading to cortisol resistance, which ultimately inhibits cortisol from exerting its downregulating action on the HPA axis.¹⁶ Normal cortisol regulation of the immune system response is lost, leading to a pro-inflammatory state and immune system dysregulation.^15,16

Additionally, there is emerging evidence that implicates other physiological pathways in stress responses such as (a) the parasympathetic nervous system, which involves the neurotransmitter acetylcholine and influences regional immune response through the vagus nerve and (b) the peripheral nervous system that acts locally to regulate inflammation by releasing neuropeptides such as substance P from peripheral sensory nerves.^15,17,18 Evidence also indicates a direct interaction between the brain and pro-inflammatory cytokines that negatively affects psychosocial functioning by inducing “sickness behavior” and depression.^19,20 The aim of PNI researchers is to study these bidirectional interactions among the psychosocial, neuroendocrine, and immunologic systems.^18,19

Stress and PNI in Patients With Cancer

The PNI framework is particularly relevant to persons with cancer since research indicates that dysfunction of the neuroendocrine system, such as abnormal cortisol rhythms, has been associated with increased mortality rates in patients with cancer.²¹ Also, chronic stress can further magnify existing impairment of immune function in cancer patients due to (a) the cancer itself, through the production of dysfunctional immune cells and (b) immune suppression caused by treatments such as chemotherapy and radiotherapy.^22,23 Dysregulation of the immune system has critical consequences for the cancer population, such as increasing susceptibility to infection and the progression of cancer, thereby increasing the likelihood of cancer recurrence and development of secondary cancers.^5,24,25 Researchers have recognized these negative health consequences of psychosocial stressors and have designed psychotherapeutic interventions based on the tenets of PNI to reduce stress and restore neuroendocrine and immune system regulation in patients with cancer.^26,27

PNI-Based Psychosocial Therapies

Although studies supporting a relationship between psychosocial stress and adverse health outcomes have been published since the 1940s, substantial progress in PNI research occurred only after 1980.⁸ A study published by Spiegel et al¹ drew considerable attention to psychosocial intervention research, as it reported an increased survival rate in breast cancer patients who participated in a group-therapy psychosocial intervention. The effects of group therapy on increased survival rate were later attributed to neuroendocrine–immune mechanisms described in the PNI framework.²⁸ Though the study by Spiegel et al study was controversial and replication studies of their group-therapy intervention failed to demonstrate increased survival,^29,30 researchers became interested to explore the neuroendocrine–immune effects of a variety of psychosocial therapies,²⁷ such as cognitive–behavioral stress management (CBSM) and supportive therapy in persons with cancer.²⁷ Subsequent systematic reviews of PNI-based psychosocial therapies have been conducted,^27,31 but these reviews have lacked a comprehensive approach toward identifying and appraising eligible studies.

Gaps in Literature: Lack of Comprehensive Reviews

Previous reviews have lacked breadth and depth in their approach toward evaluating PNI-based psychosocial therapies with regard to (a) review methodology, (b) limited cancer types evaluated, (c) limited descriptions of the types of therapies, and (d) lack of specificity in reporting PNI-measures

Review Methodology

Although early reviews, published in the 1990s,^3,32,33 of psychosocial therapies indicated that the PNI framework could be used to explain the benefits (eg, increased survival) of psychosocial interventions for cancer patients, these reviews did not use statistical methods to assess the PNI effects of psychosocial interventions. A systematic review published in 2002⁶ used a more rigorous methodology provided by the evidence-based medicine approach, which involved assessing results of rigorous randomized controlled trials. This review concluded that not a single psychosocial intervention strategy could be recommended for improving immune function in cancer patients.⁶ However, the review authors, Newell et al,⁶ made their conclusion based on a small sample of 4 qualifying studies that measured PNI outcomes.^34-37 The National Cancer Policy Board criticized this review in a report published in 2004,⁴ and determined that, because of very narrow methodological specifications, many valuable effects of psychosocial interventions, which includes PNI effects, may have been “missed or undervalued.”^4(p97) Other health researchers have also suggested that the evidence-based methodology may be too restrictive for evaluating psychosocial therapies and have advocated for reviewers to ensure methodological diversity (described below) in the inclusion of psychosocial interventions.^38,39

Cancer Population

Reviews of PNI-based psychosocial therapies have most commonly reported studies conducted for a specific cancer population, most often women with breast cancer.^27,40,41 Reviews that adopt this narrow focus eliminate studies conducted in other cancer populations and this limits the reach of psychosocial therapies for persons with cancer.

Types of Therapies

A wide variety of therapies have been developed for addressing the psychosocial aspects of cancer. A meta-review of psychological interventions identified 79 distinct modalities of psychosocial therapies,⁴² ranging from education to breathing exercises. However, reviewers have not appraised the details of psychosocial therapies in terms of their individual components and activities, methods of delivery or duration of the interventions.⁴² Health researchers have been recommended to pay attention to the aforementioned details of psychosocial therapies in recently provided recommendations for reviewing complex interventions: assessment and trials implementation of services (COMPASS).^42,43

PNI Measures Employed

Reviews of psychosocial therapies that included studies that used PNI biomarkers as outcomes, have not detailed the specifics of the PNI biomarkers and psychometric scales employed.^27,41 Also, researchers in this field have noted that many psychosocial interventions claiming to work through PNI mechanisms have not measured actual PNI biomarkers.^3,27,44 For example, even though the landmark study by Spiegel et al¹ alluded to PNI mechanisms,²⁸ it has been noted that biomarkers associated with PNI systems were not obtained as outcome measures in the original study.²⁷ Recent reviews of research studies designed to determine relationships between psychosocial factors and survival outcomes of patients with cancer continue to suggest PNI mechanisms of actions.^45,46 However, these reviews^45,46 have included research that did not use PNI-based biomarkers as outcome measures, and thus calling into question the validity of the claims regarding PNI effects of therapies targeting psychosocial variables in persons with cancer.

Comprehensive Approach to Literature Review

Thus, we aimed to conduct a comprehensive approach to review the current literature to better inform researchers, health practitioners, and policy makers about PNI effects of psychosocial therapies for persons with cancer and help advance evidence for including psychosocial therapies within oncology research and practice. To this end, we followed directives for conducting evidence reviews of psychosocial interventions provided by the IOM,^4,5 the World Health Organization,³⁹ and the COMPASS checklist proposed by Hodges et al.⁴² We operationalized these directives for the current review by (a) having methodological diversity in study designs, (b) including all cancer populations, (c) examining details of the types of psychosocial therapies, (d) identifying the specific PNI outcome measures employed, and (e) examining the implications of the results of studies with regard to a PNI causal framework that can validly explain the mechanisms of action of psychosocial therapies.

We aimed to assess the current state-of-the-science (studies published after 2001) for PNI-based psychosocial therapies to answer the following questions (Qs):

Q1: Population. In which cancer populations, in terms of type and stage of cancer, have psychosocial interventions using PNI-based measures been conducted?

Q2: Types of therapies. What types of psychosocial therapies (that used PNI-based outcomes measures) have been delivered for cancer patients? Particularly,

(a) What activities (eg, relaxation training) did the therapies employ?

(b) What were the method(s) of delivery (eg, individual/group-based) and personnel involved?

Q3: PNI measures. Which specific measures of PNI subsystems were used as outcomes for psychosocial interventions in the cancer population?

Method

Methodology for the review process was based on guidelines provided in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.⁴⁷ Authors also reviewed methodological recommendations for conducting literature reviews put forth by the Cochrane Collaboration,⁴⁸ the IOM committee on standards for systematic reviews of comparative effectiveness research,⁴⁹ and the assessment of multiple systematic reviews (AMSTAR) checklist.⁵⁰ Methods involved developing a systematic (a) search strategy and (b) selection criteria, along with (c) screening and identification procedures to eliminate irrelevant studies, which were followed by (d) data extraction procedures.

Search Strategy

The following electronic databases were searched online during November and December of 2012 to identify the studies: PubMed/Medline, EMBASE, PSYCINFO, CINAHL, and Google Scholar. Studies were considered if they were published from January 2001 to November Week 4, 2012. The search terms (keywords) from a previous systematic review⁶ and a meta-analysis⁵¹ of psychological interventions were included in our search strategy.

There were 3 categories of keywords (described in italics) used in combinations to identify relevant studies related to (a) cancer: cancer, neoplas*, oncolog*; (ii) psychosocial intervention: psych*, psychosoc*, interven*, psychotherapy, psycholog*, cognitive therapy, behav* therapy, self-help-groups, support group*, relax*, hypno*, meditat*, imagery, stress, psychological, counsel*, group therap*, family therapy, depressive disorder therapy, treatment(s), therapy/therapies; and (c) PNI measures: leukocyte, lymphocyte, natural killer cell, interferon, interleukin, tumor necrosis factor, cortisol, neuroendocrine, hormonal, psychoneuroimmunology, immune function, where * represents wildcard characters. Additionally, the reference sections of all relevant articles were examined to identify any additional relevant studies. This electronic search strategy yielded 403 research records, from which 112 duplicate records were eliminated. The remaining 291 records were screened based on our selection criteria to find eligible studies.

Selection Criteria

A set of 5 independent selection criteria related to (a) time frame and language, (b) study design, (c) cancer population, (d) types of therapies, and (e) PNI-based measures, were used to identify, screen and select eligible studies corresponding with the aims of this review.

Time Frame and Language

Only studies published in peer-reviewed journals after January 2001 until November 2012 were included in this review. For a comprehensive review of psychosocial therapies for cancer patients that used PNI-based measures published before 2001, refer to Andersen.²⁶ The searches were conducted in English and all the studies included in this review were either published in English or translated into English language by the publishers of the journal.

Study Design

We included true experimental designs, that is, randomized controlled trials (RCTs), as well as studies with rigorous quasi-experimental designs,⁵² such as nonrandomized controlled trials (NRCTs) and pretest–posttest measurement designs. RCTs had to include the number of cancer patients included in the intervention group and in the control group. Nonexperimental designs, such as correlational research studies, were excluded.

Selection criteria relevant to the specific research questions of this review were as follows.

Cancer Population

Interventions conducted with participants diagnosed with cancer at any stage beyond initial diagnosis were included. Since this review aimed to evaluate the impact of psychosocial therapies on the health of patients actually diagnosed with cancer; interventions conducted exclusively with family members or caregivers of cancer patients were excluded.

Types of Therapies

To guide our inclusion of psychosocial therapies, we adopted the IOM’s definition of psychosocial health interventions, which involved therapies that help patients “to optimize biomedical health care and to manage the psychological/behavioral and social aspects of illness and its consequences so as to promote better health.”^5(p69) This IOM definition inherently encompasses therapies employing cognitive and behavioral therapeutic activities, such as coping skills training. However, we also included therapies that emphasized integrative concepts of healing body, mind, and spirit, which were classified under complementary medical therapies by the National Cancer Institute.^53,54 Interventions that exclusively involved behavioral regimens, such as physical exercise, were excluded because the IOM definition required psychosocial therapies to address psychological and or social problems related to illness. Interventions delivered by any health professional, and in any setting, using any method of delivery or duration, were included.

PNI-Based Measures

We included only those psychosocial intervention studies that reported results of at least one neuroendocrine or immune outcome measure, as well as described the PNI framework in the paper’s background section. Studies that merely referred to the PNI framework but only measured psychological constructs (eg, depression) or global outcomes (eg, survival) were excluded.

Screening and Identification Procedures

The 291 research records obtained from the search strategy underwent 2 stages of screening. Details of the screening and identification process are outlined in Figure 1. In the first stage of screening, the title and abstracts of the research records were evaluated according to our five criteria. In this stage, 246 of 291 records were eliminated leaving us with 45 records. These 45 records entered the second stage of screening, where full-text articles were further evaluated for final eligibility. The second screening stage eliminated an additional 23 of 45 studies leaving 22 studies (Figure 1). However, our review of the reference lists of full-text research articles obtained during second screening, led us to 4 additional studies found eligible for review. Therefore, finally 26 articles were identified and included for review procedures. We noted that in this sample of 26 articles, there were 2 pairs of manuscripts (2 RCTs^55,56 and 2 pretest–posttest studies^46,51) that had reported results during different phases of the same larger intervention. These 2 pairs of articles were collapsed and considered to be single studies; which led to 24 original studies (reported in 26 manuscripts) obtained at the end of the search and selection process. For the review procedures, information was extracted from all 26 manuscripts.

Figure 1.

Flowchart of identification, screening, and selection process.

Data Extraction Procedures

The reviewers prepared a detailed data extraction manual. This manual was applied to the sample of 26 articles. Data were extracted and entered into an Excel spreadsheet. Studies were categorized based on the strength of their study design as suggested by the evidence-based approach for therapeutic interventions previously suggested by some health scientists.^57,58 This categorization involved placing RCTs first, followed by NRCTs, and finally pretest–posttest studies. One RCT that reported results from only their intervention group participants was included in the pretest–posttest study group for review procedures.⁵⁹ Data from the manuscripts of the 2 RCTs^55,56 and 2 pretest–posttest studies^46,51 that reported findings from the same intervention, were pooled and reported collectively in their respective study groups.

The following data were obtained from the research articles: (a) first author, year of publication; (b) stage and type of cancer; (c) number of participants in the intervention group; (d) the type of control condition and number of participants in control group; (e) the type and duration of intervention and length of each session; (f) psychosocial measure(s) used; (g) neuroendocrine measure(s) used; and (h) immunological measure(s) used. Other noteworthy points (eg, adequacy of sample size, analysis of mediators) were included as (i) additional remarks. Since this review aimed to appraise studies with regard to the specific research questions (stated above), methodological quality scores were not assigned to the studies.

Results

This review included results from 19 RCTs, 1 NRCT, and 4 pretest–posttest studies of PNI-based psychosocial therapies conducted in the cancer population. Table 1 gives an outline of the type and duration of the interventions and their effects on the respective psychosocial, neuroendocrine and immunological measures used. Specific findings related to the research questions posed by this review are presented below.

Table 1.

Summary of Psychosocial Therapies for Cancer Patients Using Psychoneuroimmunology (PNI)-Based Outcome Measures

No.	First Author, Year	Stage and Type of Cancer	Intervention (n) Control Condition (n)	Type of Therapy and Duration of Intervention	Psychosocial Measure(s)^a	Neuroendocrine Measure(s)^a	Immunological Measure(s)^a
Randomized controlled trials (RCTs)
1	Rosenberg^b, 2002⁷⁸	Prostate cancer survivors	Intervention (n = 15) Assessment only Control (n = 15)	Individual expressive writing intervention; 20 minutes of continuous writing over 4 consecutive days	(↓) BPI (X) MOS-SF-36 (X) SCL-90-R (X) POMS (X) Rumination^c (X) WOC-CA (X) FACT-P		(X) TNFα(X) IL-4(X) IL-10(X) CD4⁺ T cells(X) CD8⁺ T cells
2	Heiney, 2003⁶⁶	Stage I or II breast cancer	Intervention (n = 33)Standard of careControl (n = 33)	Therapeutic group intervention through a telephone conference call; 6 weekly sessions lasting 90 minutes each	(↑) POMS totalPOMS subscale(↑) tension(↑) anger(X) QOL-BCV		(X) CD4⁺ T cells(X) CD8⁺ T cells(X) NK cells
3	Andersen, 2004⁶⁹	Stage II or III breast cancer	Intervention (n = 114)Assessment onlyControl (n = 113)	CBT sessions with trained psychologists in small patient groups; 18 weekly sessions lasting 90 minutes each	(↑) PSS-Family(↓) POMS totalPOMS subscale(↓) anxiety(X) IES		No (↓) LPR to PHA(↑) LPR to Con A(X) T lymphocytes(X) NK Cell count(X) NK Cell lysis
4	McGregor, 2004⁶⁵	Stage I or II breast cancer	Intervention (n = 18)1 day seminarControl (n = 11)	Group-based CBSM program; 10 weekly meetings lasting 120 minutes each	(↑) BFS(X) Distress^d		(↑) LPR to anti CD3(X) Lymphocytes
5	Hernandez-Reif, 2004⁶⁷	Stage I or II breast cancer	Intervention (n = 18)Wait listControl (n = 16)	Individual massage sessions 3 massages a week for 5 weeks with every massage session lasting 30 minutes each	(↓) POMSSTAI subscale(↓) Anxiety SCL-90-R subscale(↓) Depression(↓) Hostility	(↑) Dopamine(↑) SerotoninNo (↑) in Norepinephrine(X) Epinephrine(X) Cortisol	(↑) NK Cells(X) NKCC(X) Lymphocytes
6	Savard, 2005⁸²	Chronic insomnia secondary to breast cancer	Intervention (n = 27)Wait listControl (n = 30)	Group-based CBT for insomnia management; 8 weekly sessions with psychologists lasting 90 minutes each	(X) POMS(X) ISI^e(X) MFI(X) HADS^f		(↑) IFNγ(↓) Lymphocytes(X) WBC(X) Monocytes(X) CD3⁺ T cells(X) CD4⁺ T cells(X) CD8⁺ T cells(X) NK cells(X) IL-1β(X) NK cell activity
7	Savard, 2006⁷⁴	Metastatic breast cancer patients with depression	Intervention (n = 25)Wait listControl (n = 20)	Individually-based CT intervention; 8 weekly sessions with psychologists lasting 60 to 90 minutes each	(↓) HDRS(X) BDI(X) HADS(X) MFI(X) ISI(X) EORTC-QLQ-C33		(X) CD3⁺ T cells(X) CD4⁺ T cells(X) CD8⁺ T cells(X) CD16⁺ T cells(X) Lymphocytes(X) WBC(X) Monocytes(X) IFNγ (X) IL-1β(X) NK cell activity
8	Andersen, 2007⁷¹	Stage II or III breast cancer	Intervention (n = 114)Assessment onlyControl (n = 113)	8-month maintenance phase group CBT intervention, which followed-up patients from the Andersen, 2004 study⁶⁹ 8 monthly CBT sessions with trained clinical psychologists lasting 90 minutes each	(↓) POMS(X) IES		No (↓) LPR to PHA(X) LPR to Con A
9	Nunes, 2007⁶⁴	Stage I or II breast cancer	Intervention (n = 20)Assessment onlyControl (n = 14)	Relaxation and visualization in groups with psychologist; 30-minute sessions delivered daily over 24 consecutive days	(↓) ISSL(↓) STAI(↓) BAI(↓) BDI	(X) Cortisol	(X) LPR to PHA(X) LPR to DEX(X) LPR to CORT
10	Nelson, 2008⁷⁹	Cervical cancer survivors	Intervention (n = 17)Standard of care control (n = 19)	Psychosocial telephone counseling therapy; 6 sessions with psychologists lasting 45 to 50 minutes each	(↑) FACT-Cx	(X) Cortisol(X) DHEA	(↓) IL-10(X) PBMC(X) IFNγ(X) IL-5
11	Lindemalm, 2008⁶³	Early stage breast cancer patients undergoing radio/chemotherapy	Intervention (n = 21)Assessment onlyControl (n = 20)	Support group consisting of oncologists, art therapists, masseuses, and person trained in qigong and mental imagery was offered on a residential basis. Week-long program with a 4-day follow-up 2 months later. No information about duration of sessions	(X) HADS(X) NFQ		(X) NK cells(X) NKCC(X) Lymphocytes(X) IFNγ(X) IL-2(X) IL-4
12	Phillips, 2008⁵⁶ and Antoni, 2009⁵⁵	Stage I, II, and III breast cancer	Intervention (n = 63)1-day education seminarControl (n = 65)	Group-based CBSM program; 10 weekly meetings with psychologists lasting 2 hours each	MOCS subscale(↑) Relaxation^g IES subscale(↓) Intrusion(↓) HAM-Anxiety(X) ABS	(↓) Cortisol	(↑) IL-2(↑) IFNγ(↑) IL2:IL4 ratio(X) IL-4(X) IFNγ: IL4 ratio(X) CD4⁺ T cells(X) CD8⁺ T cells(X) CD56⁺ T cells
13	Rao, 2008⁷²	Stage II and III breast cancer	Intervention (n=45)Supportive therapycontrol (n=53)	Integrated yoga program. 4 individual sessions with yoga instructor at bedside lasting 60 minutes.	(↓) STAI(↓) BDI(↑) FLIC		(↑) CD56⁺ T cells(↓) IgA(X) CD4⁺ T cells(X) CD8⁺ T cells(X) IgG(X) IgM
14	Raghavendra, 2009⁷⁰	Stage II and III breast cancer	Intervention (n = 44)Supportive therapyControl (n = 44)	Yoga education and training program; 6-week program with 3 sessions per week (total 18 sessions) lasting 1 hour each	(↓) HADS(↓) PSS	(↓) Cortisol
15	Oh, 2010⁸⁰	Range of cancers (and stages) including breast, lung, prostate cancers	Intervention (n = 79)Assessment onlyControl (n = 83)	Medical Qigong (MQ) group therapy; 10-week MQ program with Qigong instructor consisting of 2 sessions per week lasting 90 minutes each	(↑) FACT-G(↑) FACT-F(↓) POMS		(↓) CRP
16	Cohen, 2011⁷⁷	Prostate cancer	Intervention (n = 38)Standard of careControl (n = 44)	Individual sessions consisting of CBT with a clinical psychologist and stress management information Two sessions lasting 60 to 90 minutes each	(X) POMS		(↑) NKCC(↑) IL-1β(X) IL-12p70(X) TNFα(X) IFNγ(X) IL-6(X) IL-8(X) IL-10
17	Banasik, 2011⁷⁵	Breast cancer survivors	Intervention (n = 9)^hWait listControl (n = 9)	Iyengar yoga practice consisting of different poses. Group yoga practice sessions twice a week for 8 weeks lasting 90 minutes each	FACT-B subscale(↓) Fatigue(X) FACT-B Total	(X) Cortisol
18	Hsiao, 2012⁷⁶	Breast cancer survivors	Intervention (n = 26)1-session education seminarControl (n = 22)	Body–mind–spirit (BMS) group therapy. Weekly sessions over 8 weeks lasting 2 hours each	MLQ subscale(↑) Search(X) BDI-ii	(↓) Cortisol
19	Baker, 2012⁷³	Stage I, II, and III breast cancer	Intervention (n = 6)^hStandard of carecontrol (n = 6)	Integrated support program consisting of 2 day support workshop with a maximum 12 hours consultation with therapist. Exact duration of intervention not described	(↑) SOSI MFI subscale(↓) Mental fatigue(X) FACT-G total FACT-G subscale(↓) Endocrine-specific symptoms(X) POMS	(X) Cortisol	No (↓) NKCANo (↓) PBMC-arginase(X) CD4⁺ T cells(X) CD8⁺ T cells(X) NK cells
Nonrandomized controlled trial (NRCT)ⁱ
20	Witek-Janusek, 2008⁶²	Early stage breast cancer	Intervention (n = 38)Assessment onlyControl (n = 28)	Group-based MBSR training; 8-weekly (2.5 hours/week) sessions plus 1 full day session held after the fifth week	(↑) QOL-CVIII JCS subscales(↑) Supportant and(↑) Optimistic effectiveness(X) MAAS	(↓) Cortisol	(↑) NKCA(↑) IFNγ(↓) IL-4(↓) IL-6(↓) IL-10
Pretest–postest study designs
21	Bakke, 2002⁶⁸	Stage I and II breast cancer	Total n = 25No control	Individual hypnotic-guided imagery delivered by medical doctor; 8 weekly sessions lasting 60 minutes each	POMS subscale(↓) Depression(X) WCC		(↑) NK cells(X) NKCC
22	Carlson, 2003³² and Carlson, 2004⁸³	Early stage breast and prostate cancer	Total n = 42No control	Group-based MBSR delivered by psychologists; 8 weekly sessions lasting 90 minutes each and a 3 hour silent retreat between weeks 6 and 7.	(↓) SOSI EORTC-QLQ-C30 subscales(↑) Global QOL(↑) Appetite(X) POMS	(X) Cortisol(X) Melatonin(X) DHEAS(X) Cortisol/ DHEAS Ratio	(↑) IFNγ(↑) IL-4T(↑) Eosinophils(↓) Monocytes(X) NK cells
23	Carlson, 2007⁶⁰	Early stage breast and prostate cancer	Total n = 51No control	Group-based MBSR delivered by psychologists; 8 weekly sessions lasting 90 minutes each and a 3-hour silent retreat between weeks 6 and 7	(↓) SOSI(X) POMS(X) EORTC-QLQ- C30	(↓) Cortisol	(↑) Eosinophils(↓) Monocytes(↓) IFNγ T cell production
24	Kang, 2011⁵⁹	Stage I, II, and III breast cancer	Intervention (n = 49)Data from control group not presented	Group-based CBSM intervention; 8 weekly sessions lasting 90 minutes each			(↑)NKCC(↑) LPR to PHA(↑) IL-4(↑) IL-10(X) IL-2(X) IL-6(X) IFNγ

Abbreviations: Interventions: CBSM, cognitive–behavioral stress management; CBT, cognitive–behavioral therapy; CT, cognitive therapy; RVT, relaxation and visualization therapy; BMS, body–mind–spirit; MBSR, mindfulness-based stress reduction. Psychosocial measures: BFS, Benefit Finding Scale; POMS, Profile of Mood States; DES-IV, Differential Emotions Scale–IV; CES-D, Center for Epidemiological Studies Depression Scale; IES, Impact of Events Scale; LOT, Life Orientation Test; MOS-SF36, Medical Outcomes Study–Short Form–36; SCL-90-R, Symptom Checklist–90–Revised; BPI, Brief Pain Inventory; WOC-CA, Ways of Coping Inventory–Cancer Version; FACT-P, Functional Assessment of Cancer Therapy–Prostate; QOL, quality of life; BCV, Breast Cancer Version; ISSL, Inventory of Stress Symptoms Lipp (for adults); PSS-Family, Perceived Social Support from Family; BAI, Beck Anxiety Inventory; STAI, State-Trait Anxiety Inventory; ISI, Insomnia Severity Index; MFI, Multidimensional Fatigue Inventory; HADS, Hospital Anxiety and Depression Scale; HDRS, Hamilton Depression Rating Scale; HAM-Anxiety, Hamilton Rating Scale for Anxiety; ABS, Affects Balance Scale; BDI, Beck Depression Inventory; FLIC, Functional Living Index of Cancer; MLQ, Meaning in Life Questionnaire; EORTC-QLQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; NFQ, Norwegian Fatigue Questionnaire; MOCS, Measure of Current Status; PSS, Perceived Stress Scale; FACT-B, Functional Assessment of Cancer Therapy–Breast; QOL-CVIII, Quality of Life Index–Cancer Version III; MAAS, Mindfulness Attention Awareness Scale; JCS, Jaloweic Coping Scale; WCC, Ways of Coping Checklist; SOSI, Symptoms of Stress Inventory. Neuroendocrine measures: DHEAS, dehydroepiandrosterone sulfate. Immunological measures: NK, natural killer; IFN, interferon; TNF, tumor necrosis factor; IL, interleukin; CD, cluster of differentiation; LPR, lymphocyte proliferative response; NKCC, natural killer cell cytotoxicity; WBC, white blood cells, PHA, phytohaemagglutinin; ConA, Concavalin A; DEX, dexamethasone; CORT, corticosterone.

(↑) Significantly higher in intervention group compared with control group in RCTs and in postintervention compared with preintervention in pretest–posttest studies. (↓) Significantly lower in intervention group compared with control group in RCTs and in postintervention compared with preintervention in pretest–posttest studies. (X) No differences between intervention and control groups in RCTs and between postintervention and preintervention in pretest–posttest studies.

Only a smaller subset of the sample completed immune measures.

Rumination measured using 10 items from a study assessing moderating effects of goal beliefs that influence rumination, depression, and physical complaints.

A distress index was developed using descriptive adjectives from scales developed in a previous research published by Carver et al.

(↓) ISI mediated: (↑) IFNγ, (↑) WBC, and (↑) lymphocytes.

(↓) HADS mediated: (↑) IFNγ, (↑) WBC, and (↑) lymphocytes

(↑) Relaxation did not mediate (↓) cortisol.

Considerably underpowered study.

Participants self-selected either treatment or control group.

Q1: Cancer Population

Most studies consisted exclusively of women diagnosed with breast cancer (18/24, 75%). The studies of women with breast cancer consisted of 9 studies that had patients with early stage breast cancer (stage I or II)^60-68 and 7 studies that included patients with stage III breast cancer.^55,59,69-73 Only 1 study included patients with metastatic breast cancer (stage IV)⁷⁴ and 2 studies included breast cancer survivors.^75,76 The next most common type of cancer population was patients with prostate cancer (4/24, 16.7%). In terms of prostate cancer staging, 3 studies included patients with early-stage localized prostate cancer patients,^60,61,77 while 1 study had prostate cancer survivors.^77,78 In the aforementioned studies, 2 studies used a mixed population of patients with early-stage breast and prostate cancer.^60,61 Only 8.3% (2/24) of PNI-based psychosocial therapies included persons with cancers other than breast and or prostate cancer. These studies consisted of one study of cervical cancer survivors⁷⁹; and another study involving mixed cancer populations, including persons with lung and colorectal cancers, as well as persons with prostate and breast cancers in the entire range of cancer stages, including cancer survivors.⁸⁰

Q2: Types of Psychosocial Therapies

The 2 major types of therapies identified were (a) cognitive–behavioral therapies (15/24, 62.5%) and (b) complementary medical therapies (9/24, 37.5%). Each study was assessed for the types of therapeutic activities employed in the psychosocial intervention.

Q2a: What Activities Did the Therapies Employ?

All studies used more than one therapeutic activity during the delivery of their intervention. Table 2 presents a complete list of activities employed in each study. The 2 most common activities, used by more than half of all psychosocial therapies reviewed, were relaxation training and education (Table 2). Descriptions of the kinds of activities used by psychosocial therapies for cancer patients elucidated by the IOM⁵ and National Institutes of Health^53,81 were reviewed to guide categorization of interventions. Studies were either classified as a cognitive–behavioral therapy or a complementary medical therapy based on the activities involved in the intervention.

Table 2.

Activities Involved in Psychoneuroimmunology-Based Psychosocial Therapies.^a

	Study Number^b (Type of Therapies) Using Specified Activities
Name of Activity	Cognitive–Behavioral	Complementary Medical	% of Studies^c
Relaxation training	3, 4, 8, 9, 11, 12, 16, 19, 21, 24,	13, 14, 15, 17, 18, 20, 22, 23	75% (18/24)
Breathing exercises/techniques (eg, deep breathing)	4, 8, 9, 12, 16, 19, 21, 24	13, 14, 15, 17, 18, 20, 22, 23	67% (16/24)
Imagery/guided imagery and visualizations	4, 8, 9, 12, 16, 21, 24	14, 18, 20, 22, 23	50% (12/24)
Progressive muscle relaxation	3, 4, 8, 9, 12, 16, 21, 24		33% (8/24)
Psycho-education	2, 3, 4, 6, 8, 9, 11, 12, 16, 19, 21, 24	15, 18, 20, 22, 23	71% (17/24)
Coping skills training (eg, problem solving, setting goals)	2, 3, 4, 7, 8, 10, 12, 16, 24	13, 14, 18	50% (12/24)
Cognitive restructuring	4, 6, 7, 8, 12, 16, 24	20, 22, 23	42% (10/24)
Yoga training (eg, asanas)	19	13, 14, 15, 17, 20, 22, 23	33% (8/24)
Group social support	2, 3, 4, 8, 12, 24	20, 22, 23	38% (9/24)
Personal stress awareness	2, 3, 7, 12, 16	20, 22, 23	33% (8/24)
Expressing emotions and feelings	1, 2, 4, 8, 12, 24	18	29% (7/24)
Meditation	4, 8, 9, 12	13, 14, 15	29% (7/24)
Physical exercise	3, 11, 19, 24	17	21% (5/24)
Emphasizing the mind–body connection		17, 18, 20, 22, 23	21% (5/24)
Qigong training	11, 19	15, 18	8% (4/24)
Mindfulness meditation training		18, 20, 22, 23	8% (4/24)
Conflict resolution and anger management	12, 4, 8, 12		8% (4/24)
Assertiveness training	3, 4, 8, 12		8% (4/24)
Individual supportive care	16, 19		8% (2/24)
Massage		5, 18	8% (2/24)
Diet/nutritional advice	3, 19		8% (2/24)
Art therapy	11, 19		8% (2/24)
Counseling for relationship and sexual problems	10		4% (1/24)
Forgiveness therapy		18	4% (1/24)
Stimulus control	6		4% (1/24)
Expressive writing	1		4% (1/24)
Insomnia management (sleep restriction)	6		4% (1/24)
Hypnosis/hypnotherapy	21		4% (1/24)
Communication skills training	3		4% (1/24)
Specialized homecare and leisure activities	11		4% (1/24)

Activities listed in this table are based on the types of psychosocial treatments identified in a previous meta-review of psychological interventions in cancer patients.⁴⁰

Study numbers are referenced in the first column of Table 1.

Numbers for percentages reported are rounded off to next integer.

(a) Cognitive–behavioral therapies consisted of interventions that emphasized cognitive and behavioral activities and approaches such as cognitive restructuring, psycho-education, and coping skills training (Table 2). Some studies delivered highly structured cognitive–behavioral programs, such as CBSM, that were specifically designed to meet the psychosocial needs of breast cancer patients.^65,69,74 Few studies used supportive care activities such as individual supportive care, home care and group social support (Table 2). Several studies also included progressive muscle relaxations, meditation, abdominal breathing, and guided imagery (Table 2).

There were 3 cognitive–behavioral studies that particularly emphasized visualizations. Of these, 2 studies asked patients to mentally visualize personal and metaphorical images of their immune systems effectively removing cancer cells from their bodies,^64,68 while the third study employed hypnosis to guide visualizations.⁶⁸ Another intervention included cognitive–behavioral activities specifically tailored for insomnia and sleep management, for example, stimulus control.⁸² One study used an expressive writing intervention that asked patients to write about their experience with prostate cancer and its treatment and other traumatic and upsetting experiences in their lives.⁷⁸ Finally, a cognitive–behavioral study also included counseling for relationship and sexual problems faced by their participants.⁷⁹

(b) Complementary medical therapies involved activities such as yoga, meditation, qigong, mindfulness-based stress reduction (MBSR) and massage (Table 2). In this group of therapies, 5 studies emphasized stress management through meditation. One yoga study combined activities including breathing exercises, meditations, a set of yoga postures (asanas), along with relaxation and mental imagery.⁷⁰ Another study delivered an integrated yoga program at the bedside before and after a surgical operation and provided patients with audiotapes of instruction for yoga exercises to be practiced at home.⁷² The other 3 studies delivered a structured MBSR program^60-62,83 previously developed by another researcher.⁸⁴ MBSR consisted of teaching participants to achieve mindfulness, defined as a “non-elaborative, non-judgmental present-centered awareness”^85(p232) and help participants enhance the acceptance of their life experiences.⁸⁴ Participants learned MBSR through the use of breath awareness, sitting and walking meditations, and yoga techniques and were also provided with educational materials and workbooks to help them with cognitive reappraisals and in practicing mindfulness in daily life.

There were 3 complementary therapies that encouraged stress reduction through either active behavioral practices, such as body movements, or passive behavioral techniques such as massage. One yoga intervention consisted exclusively of performing poses from the “Iyengar yoga” tradition, that were executed slowly with the help of props to maintain proper orientation and posture.⁷⁵ One study of medical qigong consisted of body movements during specific standing postures along with meditation training, visualization, and a range of breathing exercises, including chest and abdominal breathing.⁸⁰ One massage intervention employed a protocol that consisted of a combination of massage and acupressure techniques that promoted relaxation.⁶⁷ Finally, one study emphasized a body–mind–spirit connection and combined yoga and massage techniques with psychosocial approaches such as forgiveness therapy.⁷⁶

Q2b: What Were the Method(s) of Delivery?

Studies delivered their respective psychosocial therapies to participants either within a group-setting (15/24, 62.5%) or on an individual basis (9/24. 37.5%). On average, 7 participants were included in the group-based therapies, but group size ranged between 3 and 15 participants. Most studies involved in-person interactive (21/24, 87.5%) sessions with participants. There were 3 studies that did not involve any personal interactions with participants (3/24, 12.5%). Of these, 2 studies delivered their intervention exclusively through phone-conversations^66,79 and one study delivered an expressive writing therapy through oral and written instructions given to the patients and followed-up with patients through a phone call.⁷ The interventions delivered entirely through phone conversations consisted of one study that used a telephone conference call to deliver group therapy,⁶⁶ and another study that conducted individual telephone counseling sessions with participants.⁷⁹ It was noteworthy that 2 studies provided therapy sessions on the morning of scheduled surgery to mentally prepare patients for surgical procedures,^72,77 and one supportive therapy intervention was provided to participants on a residential basis.⁶³

Who delivered the therapies? Half the psychosocial therapies were delivered by clinical psychologists, while 3 therapies were delivered by nurses, and 2 therapies involved physicians (Table 1). Supportive care services were delivered by a variety of health professionals, including group therapists, social workers, art therapists, and visualization specialists.^63,66 The complementary medical therapies, also employed a variety of allied health professionals, such as clinical massage therapists and instructors trained in yoga and qigong techniques.^63,67,70,75

Q2c: What Were the Durations of the Interventions?

The average duration of interventions using PNI-based psychosocial therapies (taken over all 24 studies) was roughly a total of 10 hours (600 minutes). The 10 hours of psychosocial intervention were delivered over an average period of 8 weeks consisting of approximately 8 therapy sessions, with each session lasting for about 70 to 75 minutes. However, the duration of interventions, including the time required for each session varied considerably among the studies. The briefest intervention was expressive writing, which lasted for a total of 1.3 hours (80 minutes) over a single week, with 4 sessions taking 20 minutes per session over 4 consecutive days.⁷⁸ In contrast, the lengthiest intervention was 20 times greater in duration, and consisted of a cognitive–behavioral therapy intervention of 27 hours (1620 minutes) over 18 consecutive weeks, with 18 therapy sessions that lasted about 90 minutes per session.⁶⁹

Q3: Psychoneuroimmunologic Measures

Only a third of studies (8/24) in this review collected outcome measures for all 3 PNI subsystems. All studies, except one (23/24) used at least one psychosocial measure. With regard to PNI biomarkers, less than half (11/24) the studies employed biomarkers of the neuroendocrine system, as opposed to the majority (22/24) of studies that used some type of immune biomarker.

Psychosocial Measures (P)

All studies used self-report scales to measure participants’ psychosocial profiles, except one study that did not report measures of any psychosocial construct.⁵⁹ The most commonly employed measure of psychosocial outcomes was the profile of mood states, Profile of Mood States (11/24, 45.8%) scale. Most studies measured negative psychological states such as depression, negative mood, distress, and anxiety.^{63,65,66,69,70,75} Even though most interventions aimed to reduce stress in patients, only three studies actually used psychometric measures of stress.^64,70,73 Studies also assessed psychosocial well-being and function by measuring of quality of life and functional assessments related to cancer treatments and living with cancer.^61,66,80 Some studies were interested in the psychological coping response of participants and measured constructs such as benefit finding⁶⁵ (ie, perceived benefits arising from the experience of being diagnosed and treated for breast cancer) and coping with illness.^62,78 Finally, 3 studies used measures that were closely related to the constructs emphasized in the therapies; for example, the cognitive–behavioral intervention aimed at improving sleep behavior measured the severity of insomnia,⁸² one CBSM intervention measured the specific psychosocial skills that were targeted by the CBSM program⁵⁶ and one MBSR study measured mindfulness attention and awareness.⁶²

Neuroendocrine Measures (N)

The glucocorticoid stress hormone, cortisol, was the most common neuroendocrine measure, used in all 11/24 research studies that had neuroendocrine parameters (45.8%). Studies measured cortisol levels in the participants’ blood using radioimmunoassay techniques^56,62 or in saliva using enzyme-linked immunosorbent assay techniques.^60,70,75,83 Other neuroendocrine parameters measured included (a) catecholamine stress hormones, including epinephrine, norepinephrine in urine⁶⁷; (b) neurotransmitters, including urinary dopamine and serotonin⁶⁷ and salivary melatonin⁸³; and (c) serum levels of the corticosteroid hormone, dehydroepiandrosterone sulfate.⁸³

Immunological Measures (I)

The 22 of 24 studies that reported immunological measures (91.7%) obtained blood samples for immune analysis. The most commonly measured immune outcome was the cytotoxic function of natural killer cells (9/24, 37.5%). Most studies typically evaluated both types of immune measures,⁵¹ including enumeration of immune cells, for example, T lymphocyte counts, and functional measures of the immune system,⁵² for example, cytokine levels (15/24, 62.55%). However, 6 studies exclusively used functional immune measures (6/24, 25%) and 1 study measured only certain immune cell counts (4.2%), namely CD4⁺ and CD8⁺ T lymphocytes and natural killer cells.⁶⁶ Only a couple of studies did not use any type of immune outcome measure (2/24, 8.3%). We noted that only one study measured the inflammatory biomarker, C-reactive protein⁸⁰ and another study measured serum immunoglobulin (Ig) levels (IgG, IgM, and IgA).⁷²

Efficacy of Psychosocial Therapies for Patients With Cancer

Because of the wide diversity of interventions and PNI measures reported, statistical comparisons required for a meta-analysis were not possible. Hence, limited comment can be made about the statistical evidence for the efficacy of psychosocial therapies on PNI measures. However, we do deliberate over studies that reported significant changes in PNI outcome measures. First, with respect to psychosocial measures, 20 studies that included 13 RCTs, 1 NRCT, and 3 pretest–posttest studies reported significant effects on at least one psychosocial measure (Table 1). Second, in terms of neuroendocrine outcomes, 6 studies reported significant results for changes in at least 1 neuroendocrine measure, including 4 RCTs, 1 NRCT, and 1 pretest–posttest study (Table 1). Finally, regarding immune measures, 16 studies reported effects on at least one immune measure, which included 11 RCTs, 1 NRCT, and 4 pretest–posttest studies (Table 1).

Effectiveness with respect to types of therapies indicated that more than half the studies using cognitive–behavioral therapies (10/15, including 8 RCTs) reported significant findings for at least one neuroendocrine or immune outcome measure. One cognitive–behavioral intervention reported a significant effect on an immune outcome up to twelve months after initiating the intervention.⁷¹ Some cognitive–behavioral therapies statistically modeled the variables in the PNI framework and demonstrated that psychosocial constructs had an influence on immune outcomes. For example, one study reported that benefit finding was correlated with an increase in the T lymphocyte proliferative response to anti-CD3,⁶⁵ and another study showed that anxiety and depression mediated the increase in blood levels of the cytokine, interferon-γ.⁸² Thus, several studies of cognitive–behavioral therapies reported significant effects on neuroendocrine–immune function through PNI interactions in patients with cancer.

Regarding complementary medical therapies, two thirds of the studies (6/9) showed significant effects on at least one neuroendocrine or immune outcome measure. Though therapies involving yoga, qigong, and massage were evaluated using RCT designs, only 2 RCTs that included the aforementioned therapeutic activities reported significant effects on functional immune measures.^72,80 MBSR was not evaluated using a RCT study design; however, all 3 studies that used MBSR, involving 1 NRCT⁶² and 2 pretest–posttest studies, had significant impacts on PNI biomarkers.^60,61 This suggests that complementary medical therapies are emerging psychosocial therapies, which require more investigation regarding their impact on PNI-based outcomes in patients with cancer.

Discussion

Publications of PNI-based psychosocial interventions for persons with cancer have markedly grown over the past decade. The past review of this literature (published in 2002) identified only 8 studies of PNI-based psychosocial therapies.²⁶ In this review, we found that studies of PNI-based psychosocial therapies were most commonly conducted in women with early-stage breast cancer, included either cognitive–behavioral or complementary medical therapies, and employed a wide variety of psychosocial, neuroendocrine, and immune outcomes (Tables 1 and 2). No conclusive statement could be made regarding the effectiveness of both types of psychosocial therapies for their impact on PNI outcomes in persons with cancer. However, this review recognized that unique challenges are posed to studies investigating PNI effects of psychosocial therapies in persons with cancer, such as inadvertent interaction effects between the various therapeutic activities and a wide scale for the duration of the interventions. Also, the lack of standardization among available psychosocial instruments and neuroendocrine–immune biomarkers make it difficult for researchers to choose appropriate PNI outcome measures. In the following discussion, specific implications of the findings of this review for forthcoming research are elaborated with regard to this review’s research questions.

Implications for Cancer Populations

Conducting Studies Across Cancer Stages for Persons With Varied Cancer Types

This review found that very few studies of psychosocial therapies were conducted for persons having a cancer diagnosis other than breast or prostate cancer. Also, only a small number of interventions included patients with late stage cancer and cancer survivors. The IOM has indicated that persons diagnosed with all types of cancers have unmet psychosocial needs across the cancer care continuum, especially cancer survivors.^5,86 Moreover, researchers have indicated that PNI-based psychosocial therapies can be especially helpful for persons with cancers in body tissues that influence PNI interactions, such as adrenal glands and bone marrow.⁹ Cancers of the lung and colorectal cancer comprise a significant disease burden in males and females combined, as indicated by the Centers for Disease Prevention and Control.⁸⁷ Therefore, longitudinal research studies are needed that include patients from the time of cancer diagnosis until the end of survivorship in varied cancer populations, which will provide valuable information about PNI effects of psychosocial therapies across the cancer care continuum.^9,88-90

Implications for Types of Therapies

Evaluating Dose–Response Effects of Therapies

An average dose effect of psychosocial therapies on PNI outcomes was not estimated because of the wide variation in the total duration of the interventions (1.3-27 hours). Most psychosocial therapies included combinations of several different therapeutic activities (Table 2), leading to wide ranges in the durations of interventions. However, evidence-based rationales for combining specific psychosocial therapeutic activities (eg, by describing their additive affects) were lacking. Also, since psychosocial therapies are typically designed for patient training, patients are expected to practice the learned activities to evoke and/or sustain the effects over time. Quantitative evidence regarding dose–response associations between (a) type of therapeutic activities and PNI outcomes and (b) extent and duration of practice of specific therapeutic activities and PNI outcomes, can help guide clinical decisions regarding choosing therapeutic activities and the overall duration of psychosocial interventions.⁹¹ Therefore, future studies should employ data collection procedures regarding adherence to intervention activities over time and assess dose–response effects of PNI-based psychosocial therapies in persons with cancer.

Moreover, our review revealed the efficacy of brief and relatively inexpensive psychosocial therapies, which require minimal input from trained health professionals. One study consisted of 3 hours of therapeutic interaction with a psychologist only and demonstrated significant changes in immune outcomes.⁷⁷ Another study of expressive writing lasted for less than 1.5 hours,⁷⁸ and although no effect on PNI biomarkers was reported in the study reviewed here, in another study, this low-cost and short-duration therapy has demonstrated an improvement in immune response when delivered to patients who were positive for infection with HIV.⁹² Future research could usefully target comparisons of dose response and explore optimal resources needed to produce changes in PNI effects in the cancer population.

Using Technology to Deliver Therapies

Only two studies in this review used communication technology to deliver their psychosocial interventions through telephone conversations.^66,79 One of the most significant changes in individual lifestyles and societies in the modern world has been the use of computer technology and the Internet. Studies of psychosocial therapies such as expressive writing have been delivered to cancer patients through the internet, but have not measured PNI outcomes.⁹³ A review of internet interventions in the oncology setting has suggested that cancer patients report Internet-based delivery to be acceptable and feasible, and psycho-oncology researchers have suggested that more psychosocial interventions should be delivered using the Internet in the cancer population.⁹⁴ An important step toward advancing the delivery of psychosocial therapies for persons with cancer is by using technology to deliver therapies.

Implications for PNI Measurement

Measuring Appropriate Psychosocial Outcomes

This review noted that certain psychosocial outcomes were associated with physiological responses measured by PNI biomarkers. For example, even though benefit finding was reported to mediate neuroendocrine and immune outcomes,⁶⁵ the intervention that increased relaxation reported no apparent mediating effect on cortisol.⁵⁶ This suggests that targeting certain psychosocial processes, such as coping, may be effective in influencing physiological stress responses and immune function. In contrast, targeting other psychological outcomes such as relaxation or positive attitude may not influence physiological processes, even though they may provide some benefit to the overall psychosocial profile of the patient. Identifying reliable and valid psychometric instruments for psychosocial constructs that are responsive and appropriate for PNI-based psychosocial therapies is an important next step in this area of research.

Triangulating Measures of Neuroendocrine Outcomes

In relation to neuroendocrine measures, most studies evaluated the effect of psychosocial therapies on the HPA axis by measuring levels of cortisol. Only one study used the biomarkers, epinephrine and norepinephrine, that could be associated with the SAM axis.⁶⁷ Extensive evidence has been put forth indicating that the SAM axis/sympathetic nervous system plays an important role in neuro-immune regulation.¹⁴ Hence, future studies of PNI-based psychosocial therapies should also incorporate biomarkers of the SAM axis. While many indicators of SAM responses are difficult to measure, one noninvasive method of measuring SAM axis response is provided by recent progress in PNI measurement related to validation of the salivary enzyme, α-amylase (sAA).⁹⁵ Levels of sAA correlate with blood levels of norepinephrine, lending credence to consideration of sAA as a biomarker for the SAM axis.⁹⁶ Forthcoming research should emphasize triangulation of neuroendocrine biomarkers to assess effects of psychosocial therapies on the SAM axis.

Employing Functional Measures of Immune Response

This review noted that 10 RCTs reported significant changes in functional measures of the immune system (eg, cytotoxicity levels of natural killer cells⁷⁷), in contrast to only 2 RCTs that reported a significant change in immune cell counts (ie, lymphocytes and natural killer cells^67,82). This finding is consistent with previous PNI research in persons with cancer¹¹ and in persons with HIV infection,^97,98 where functional changes in the immune system were detected before or instead of changes in immune cell counts. Hence, PNI-based psychosocial therapies may be most effective in influencing functional measures of the immune response, with minimal effects on immune cell counts, and future studies should employ functional immune outcome measures. Since immune measurement in patients with cancer involves several complex procedures, researchers may refer to the guidelines for measuring immune response previously given by leading PNI researchers.^99,100

Implications for Validating the PNI Causal Framework

Understanding mechanisms of action of psychosocial therapies, by using PNI as a causal framework, is critical for advancing the science of psychosocial therapies. Though quality of the research methods used by studies was not assessed in this review, 5 major methodological implications become apparent, which affect validity of evidence for the PNI causal framework. These implications were related to (a) employing outcome measures related to PNI processes, (b) defining the direction of change in PNI outcomes, (c) demonstrating statistical interactions between PNI subsystems, (d) accounting for missing data for PNI biomarkers, and (e) collecting data regarding integrity of biomarkers collection procedures.

Employing outcome measures related to PNI processes

This review noted that very few studies specifically used outcome measures that were the focus of their intervention, such as the insomnia management cognitive–behavioral intervention.⁸² In studies of PNI-based psychosocial therapies, different types of psychosocial factors may trigger differential PNI responses and several other external factors can influence the findings of a particular study. Therefore, future studies should employ PNI measures associated with the specific aims of individual PNI-based psychosocial therapies, which will provide evidence for the PNI causal framework. This will also assist future reviewers who will collectively appraise findings across studies that use PNI process–related outcomes and provide a comprehensive understanding of the PNI effects of psychosocial therapies in persons with cancer.

Defining the direction of change in PNI outcomes

We noted that some studies did not clearly report the direction in which they expected their PNI outcome measures to change. Postulating a trend in PNI outcomes is difficult in the cancer population, because factors such as stage of disease and treatment variations (eg, chemotherapy vs radiation) can affect PNI measures, particularly immune outcomes.^26,99 Future studies should choose PNI outcome measures that are appropriate for their specific cancer population and type of intervention. Also, epidemiological evidence regarding the mean PNI measures for specific populations is needed, which will enable researchers to better estimate the direction of change in PNI outcomes.

Demonstrating statistical interactions between PNI subsystems

This review noted that very limited studies reported statistical analyses of interactions between the three subsystems of the PNI framework. Researchers have advocated using advanced statistical methods (eg, structural equation modeling), as well as identifying mediators and moderators of outcomes of psychosocial therapies to understand specific therapies’ mechanisms of action.^101,102 Forthcoming studies of psychosocial therapies should attempt to demonstrate changes in psychosocial outcome measures to predict changes (or show associations) in neuroendocrine–immune biomarkers over time to provide evidence for their PNI mechanism of action.

Accounting for missing data for PNI biomarkers

Some studies in this review were able to collect PNI biomarkers in only a smaller subset of their original sample. Having a smaller sample size to report certain outcomes, such as PNI biomarkers, can decrease the power of the statistical tests used to report results of those outcomes.⁵¹ However, since PNI biomarkers need to be collected over multiple time points, often through blood draws, studies of PNI-based psychosocial therapies are faced with the likelihood of having missing data. Hence, future interventions should account for attrition and missing data during their power analysis (eg, by oversampling) stage and establish a plan for handling missing data.

Collecting data regarding integrity of biomarkers collection procedures

Although most studies reported the timing for collecting biomarkers, only few studies employed measures of adherence to the PNI-measurement protocol. For example, one study gave participants wrist watches with preset alarms and asked participants to record the time when they provided saliva samples on measurement tracking forms.⁷⁵ Another study used a sophisticated method of tracking the date and time of sample collection, which involved the use of MEMS IV tracking caps on the saliva collection containers that have microcircuits to record time and date.⁷⁹ Research shows that considerable methodological variation exists in relation to timing of collection PNI biomarkers, for example large diurnal variations cortisol production.¹⁰³ Therefore, forthcoming research should collect data to assess the integrity of measurement protocols when collecting time-sensitive PNI-based outcomes in psychosocial interventions.

Future Directions for Oncology Research and Practice

Remarkable advances have occurred in innovative medical technologies and therapies for patients with cancer⁵ such as targeted chemotherapy,¹⁰⁴ robotic surgery,¹⁰⁵ and positron imaging tomography/positron emission tomography scans for radio-imaging.¹⁰⁶ However, psychosocial therapies have not witnessed the same advancement in scientific support and technological delivery.⁵ Therefore, the IOM has recommended that researchers, health practitioners, and policy makers in the oncology setting consider (a) taking steps to enhance the science of psychosocial therapies, (b) identifying ways to link cancer patients with appropriate therapies and services which suit their specific psychosocial needs, and (c) making psychosocial therapies and services part of the standard of quality cancer care.^5,107 Results from this review demonstrate that some psychosocial therapies such as cognitive–behavioral therapies have the potential to influence PNI-based outcomes.

Nevertheless, it is important to note that discordance related to the efficacy of such psychosocial therapies, continues in the literature. A systematic review of PNI-based psychosocial interventions for breast cancer patients published in 2009 concluded that there is evidence to suggest that cognitive–behavioral therapies impact neuroendocrine and immune measures.²⁷ However, other researchers that reviewed the same literature published a critical review in 2010 reporting that the evidence for psychological interventions having clinically significant impacts on the immune function of cancer patients is still “limited and unconvincing.”^108(p21) Therefore, researchers in this field are encouraged to pay greater attention to methodological and implementation aspects of PNI-based psychosocial therapies.

Based on this review, we suggest that studies of psychosocial therapies that involve PNI outcomes need to consider (a) clearly defining activities and therapies involved in the intervention; (b) specifying duration of the interventions and time estimated for each session, including time for booster session(s); (c) considering the timing of the intervention delivery with regard to treatment regimens (ie, chemotherapy/ surgery); (d) monitoring adherence to the intervention protocol; and (e) evaluating sustainability of the intervention in routine clinical practice. Also, this review supports IOM’s recommendation for developing “standard outcome measures”^5(p15) for evaluating the efficacy of psychosocial therapies and services for cancer patients. A concerted effort is needed to use similar approaches with regards to populations, descriptions of the therapies (including components and activities involved), psychometric instruments for psychosocial measures, and biomarkers for neuroendocrine–immune outcomes. Such efforts will contribute toward building a convincing empirical evidence-base for the effectiveness of PNI-based psychosocial therapies.

Limitations

No statistical findings for the efficacy of the interventions or meta-analyses have been presented. Considerable diversity in the therapies and outcome measures made comparisons and statistical evaluations across all studies problematic. Therefore, since this is a relatively new area of research, faced with challenges related to scientific methodology and service delivery, practitioners should view the results with caution when recommending psychosocial therapies for improving PNI-based outcomes in cancer patients.

Conclusion

The turn of the 21st century has given way to a considerable transformation in the understanding of disease and health care, particularly in the oncology setting. In 2001, a National Research Council Committee on Health and Behavior concluded that “health and disease are determined by dynamic interactions among biological, psychological, behavioral, and social factors,”^109(p16) and discussed the implications of PNI for cancer patients. Less than a decade since this report, in 2008, the IOM recommended psychosocial health therapies and services be a part of the standard of cancer care.⁵ Concurrently, the growing field of integrative cancer care, which seeks to synthesize evidence-based therapies that mutually address the physical and psychosocial–spiritual needs of cancer patients, has been generating an extensive evidence base.^110,111 This review provides a systematic appraisal of a diverse range of PNI-based psychosocial therapies developed in a variety of disciplines for patients across the cancer care continuum. This information can assist health practitioners, researchers and policy makers interested in integrative approaches to evaluate the use of psychosocial therapies in the standard of cancer care.

Footnotes

Author’s Note

This research was not conducted using any specific grant funding mechanism. However, this research was conducted using the resources available to the authors through their university.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

References

Spiegel

Kraemer

Bloom

Gottheil

. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet. 1989;334:888-891.

Owen

Klapow

Hicken

Tucker

. Psychosocial interventions for cancer: review and analysis using a three-tiered outcomes model. Psychooncology. 2001;10:218-230.

Fawzy

. Psychosocial interventions for patients with cancer: what works and what doesn’t. Eur J Cancer. 1999;35:1559-1564.

Hewitt

Herdman

Holland

, National Cancer Policy Board, Institute of Medicine, National Research Council. Meeting Psychosocial Needs of Women With Breast Cancer. Washington, DC: National Academies Press; 2004.

Institute of Medicine, Committee on Psychosocial Services to Cancer Patients/Families in a Community Setting, Adler

Page

, eds. Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs. Washington, DC: National Academies Press; 2008.

Newell

Sanson-Fisher

Savolainen

. Systematic review of psychological therapies for cancer patients: overview and recommendations for future research. J Natl Cancer Inst. 2002;94:558-584.

Segerstrom

Miller

. Psychological stress and the human immune system: a meta-analytic study of 30 years of inquiry. Psychol Bull. 2004;130:601-630.

Kiecolt-Glaser

McGuire

Robles

Glaser

. Psychoneuroimmunology and psychosomatic medicine: back to the future. Psychosom Med. 2002;64:15-28.

Artherholt

Fann

. Psychosocial care in cancer. Curr Psychiatry Rep. 2012;14:23-29.

10.

Andersen

Kiecolt-Glaser

Glaser

. A biobehavioral model of cancer stress and disease course. Am Psychol. 1994;49:389-404.

11.

Kiecolt-Glaser

Robles

Heffner

Loving

Glaser

. Psycho-oncology and cancer: psychoneuroimmunology and cancer. Ann Oncol. 2002;13(suppl 4):165-169.

12.

Ader

Cohen

. Psychoneuroimmunology: conditioning and stress. Annu Rev Psychol. 1993;44:53-85.

13.

Glaser

Kiecolt-Glaser

. Stress-induced immune dysfunction: implications for health. Nat Rev Immunol. 2005;5:243-251.

14.

Cohen

Janicki-Deverts

Miller

. Psychological stress and disease. JAMA. 2007;298:1685-1687.

15.

Sternberg

. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol. 2006;6:318-328.

16.

Webster Marketon

Glaser

. Stress hormones and immune function. Cell Immunol. 2008;252:16-26.

17.

Rosas-Ballina

Tracey

. The neurology of the immune system: neural reflexes regulate immunity. Neuron. 2009;64:28-32.

18.

Levite

, ed Nerve-Driven Immunity Neurotransmitters and Neuropeptides in the Immune System. New York, NY: Springer; 2012.

19.

Irwin

Cole

. Reciprocal regulation of the neural and innate immune systems. Nat Rev Immunol. 2011;11:625-632.

20.

Dantzer

. Cytokine, sickness behavior, and depression. Neurol Clin. 2006;24:441-460.

21.

Sephton

Sapolsky

Kraemer

Spiegel

. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92:994-1000.

22.

Aziz

Rowland

. Trends and advances in cancer survivorship research: challenge and opportunity. Semin Radiat Oncol. 2003;13:248-266.

23.

Costanzo

Sood

Lutgendorf

. Biobehavioral influences on cancer progression. Immunol Allergy Clin North Am. 2011;31:109-132.

24.

Thaker

Lutgendorf

Sood

. The neuroendocrine impact of chronic stress on cancer. Cell Cycle. 2007;6:430-433.

25.

Antoni

Lutgendorf

. Psychosocial factors and disease progression in cancer. Curr Dir Psychol Sci. 2007;16:42-46.

26.

Andersen

. Biobehavioral outcomes following psychological interventions for cancer patients. J Consult Clin Psychol. 2002;70:590-610.

27.

McGregor

Antoni

. Psychological intervention and health outcomes among women treated for breast cancer: a review of stress pathways and biological mediators. Brain Behav Immun. 2009;23:159-166.

28.

Spiegel

Sephton

Terr

Stites

. Effects of psychosocial treatment in prolonging cancer survival may be mediated by neuroimmune pathways. Ann N Y Acad Sci. 1998;840:674-683.

29.

Boesen

Johansen

. Impact of psychotherapy on cancer survival: time to move on? Curr Opin Oncol. 2008;20:372-377.

30.

Kissane

. Letting go of the hope that psychotherapy prolongs cancer survival. J Clin Oncol. 2007;25:5689-5690.

31.

Chaturvedi

Venkateswaran

. New research in psychooncology. Curr Opin Psychiatry. 2008;21:206-210.

32.

Bauer

. Psychoneuroimmunology and cancer: an integrated review. J Adv Nurs. 1994;19:1114-1120.

33.

Fawzy

Arndt

Pasnau

. Critical review of psychosocial interventions in cancer care. Arch Gen Psychiatry. 1995;52:100-113.

34.

Fawzy

Kemeny

Fawzy

. A structured psychiatric intervention for cancer patients: II. Changes over time in immunological measures. Arch Gen Psychiatry. 1990;47:729-735.

35.

Lekander

Fürst

Rotstein

Hursti

Fredrikson

. Immune effects of relaxation during chemotherapy for ovarian cancer. Psychother Psychosom. 1997;66:185-191.

36.

Davis

IV . Effects of biofeedback and cognitive therapy on stress in patients with breast cancer. Psychol Rep. 1986;59:967-974.

37.

Richardson

Post-White

Grimm

Moye

Singletary

Justice

. Coping, life attitudes, and immune responses to imagery and group support after breast cancer treatment. Altern Ther Health Med. 1997;3(5):62-70.

38.

Kelly

Mackenbach

, Universidad del Desarrollo, National Institute for Health and Clinical Excellence, Measurement and Evidence Knowledge Network, WHO Commission on Social Determinants of Health. The Social Determinants of Health: Developing an Evidence Base for Political Action: Final report to World Health Organization, Commission on the Social Determinants of Health from Measurement and Evidence Knowledge Network. Chile; United Kingdom: Universidad del Desarrollo; National Institute for Health and Clinical Excellence; 2007.

39.

Braveman

Egerter

Woolf

Marks

. When do we know enough to recommend action on the social determinants of health? Am J Prev Med. 2011;40(1 suppl 1):S58-S66.

40.

Edwards

Hulbert-Williams

Neal

. Psychological interventions for women with metastatic breast cancer. Cochrane Database Syst Rev. 2008;(3):CD004253.

41.

Luecken

Compas

. Stress, coping, and immune function in breast cancer. Ann Behav Med. 2002;24:336-344.

42.

Hodges

Walker

Kleiboer

. What is a psychological intervention? A metareview and practical proposal. Psychooncology. 2011;20:470-478.

43.

Taft

Bandyopadhyay

. Introduction to COMPASS: navigating complexity in public health research. BMC Public Health. 2011;11(suppl 5):S1.

44.

Antoni

Lechner

Kazi

. How stress management improves quality of life after treatment for breast cancer. J Consult Clin Psychol. 2006;74:1143-1152.

45.

Sprehn

Chambers

Saykin

Konski

Johnstone

. Decreased cancer survival in individuals separated at time of diagnosis. Cancer. 2009;115:5108-5116.

46.

Spiegel

. Mind matters in cancer survival. Psychooncology. 2012;21:588-593.

47.

Moher

Liberati

Tetzlaff

Altman

; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

48.

Higgins

JPT

Green

, Cochrane Collaboration. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: Wiley-Blackwell; 2008.

49.

Institute of Medicine, Committee on Standards for Systematic Reviews of Comparative Effectiveness Research, Board on Health Care Services, Eden

Levit

Berg

Morton

, eds. Finding What Works in Health Care: Standards for Systematic Reviews. Washington, DC: National Academies Press; 2011.

50.

Shea

Grimshaw

Wells

. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7(1):10.

51.

Miller

Cohen

. Psychological interventions and the immune system: a meta-analytic review and critique. Health Psychol. 2001;20:47-63.

52.

Petticrew

Roberts

. Evidence, hierarchies, and typologies: horses for courses. J Epidemiol Community Health. 2003;57:527-529.

53.

US Department of Health and Human Services. Thinking About Complementary and Alternative Medicine: A Guide for People With Cancer. Bethesda, MD: National Institutes of Health, National Cancer Institute, National Center for Complementary and Alternative Medicine; 2005.

54.

National Cancer Institute, Office of Cancer Complementary Alternative Medicine. NCI’s Annual Report on Complementary and Alternative Medicine: Fiscal Year 2010. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health; 2012.

55.

Antoni

Lechner

Diaz

. Cognitive behavioral stress management effects on psychosocial and physiological adaptation in women undergoing treatment for breast cancer. Brain Behav Immun. 2009;23:580-591.

56.

Phillips

Antoni

Lechner

. Stress Management intervention reduces serum cortisol and increases relaxation during treatment for nonmetastatic breast cancer. Psychosom Med. 2008;70:1044-1049.

57.

Sackett

Rosenberg

Gray

Haynes

Richardson

. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312:71-72.

58.

Evans

. Hierarchy of evidence: a framework for ranking evidence evaluating healthcare interventions. J Clin Nurs. 2003;12:77-84.

59.

Kang

D-H

McArdle

Park

N-J

Weaver

Smith

Carpenter

. Dose effects of relaxation practice on immune responses in women newly diagnosed with breast cancer: an exploratory study. Oncol Nurs Forum. 2011;38:E240-E252.

60.

Carlson

Speca

Faris

Patel

. One year pre–post intervention follow-up of psychological, immune, endocrine and blood pressure outcomes of mindfulness-based stress reduction (MBSR) in breast and prostate cancer outpatients. Brain Behav Immun. 2007;21:1038-1049.

61.

Carlson

Speca

Patel

Goodey

. Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress, and immune parameters in breast and prostate cancer outpatients. Psychosom Med. 2003;65:571-581.

62.

Witek-Janusek

Albuquerque

Chroniak

Durazo-Arvizu

Mathews

. Effect of mindfulness based stress reduction on immune function, quality of life and coping in women newly diagnosed with early stage breast cancer. Brain Behav Immun. 2008;22:969-981.

63.

Lindemalm

Mozaffari

Choudhury

. Immune response, depression and fatigue in relation to support intervention in mammary cancer patients. Support Care Cancer. 2008;16:57-65.

64.

Nunes

Rodriguez

da Silva Hoffmann

. Relaxation and guided imagery program in patients with breast cancer undergoing radiotherapy is not associated with neuroimmunomodulatory effects. J Psychosom Res. 2007;63:647-655.

65.

McGregor

Antoni

Boyers

Alferi

Blomberg

Carver

. Cognitive-behavioral stress management increases benefit finding and immune function among women with early-stage breast cancer. J Psychosom Res. 2004;56:1-8.

66.

Heiney

McWayne

Hurley

. Efficacy of therapeutic group by telephone for women with breast cancer. Cancer Nurs. 2003;26:439-447.

67.

Hernandez-Reif

Ironson

Field

. Breast cancer patients have improved immune and neuroendocrine functions following massage therapy. J Psychosom Res. 2004;57:45-52.

68.

Bakke

Purtzer

Newton

. The effect of hypnotic-guided imagery on psychological well-being and immune function in patients with prior breast cancer. J Psychosom Res. 2002;53:1131-1137.

69.

Andersen

Farrar

Golden-Kreutz

. Psychological, behavioral, and immune changes after a psychological intervention: a clinical trial. J Clin Oncol. 2004;22:3570-3580.

70.

Raghavendra

Vadiraja

Nagarathna

. Effects of a yoga program on cortisol rhythm and mood states in early breast cancer patients undergoing adjuvant radiotherapy: a randomized controlled trial. Integr Cancer Ther. 2009;8:37-46.

71.

Andersen

Farrar

Golden-Kreutz

. Distress reduction from a psychological intervention contributes to improved health for cancer patients. Brain Behav Immun. 2007;21:953-961.

72.

Rao

Nagendra

Raghuram

. Influence of yoga on mood states, distress, quality of life and immune outcomes in early stage breast cancer patients undergoing surgery. Int J Yoga. 2008;1:11-20.

73.

Baker

Harrington

Choi

B-S

Kropf

Muller

Hoffman

. A randomised controlled pilot feasibility study of the physical and psychological effects of an integrated support programme in breast cancer. Complement Ther Clin Pract. 2012;18:182-189.

74.

Savard

Simard

Giguère

. Randomized clinical trial on cognitive therapy for depression in women with metastatic breast cancer: psychological and immunological effects. Palliat Support Care. 2006;4:219-237.

75.

Banasik

Williams

Haberman

Blank

Bendel

. Effect of Iyengar yoga practice on fatigue and diurnal salivary cortisol concentration in breast cancer survivors. J Am Acad Nurse Pract. 2011;23:135-142.

76.

Hsiao

Jow

Kuo

. The effects of psychotherapy on psychological well-being and diurnal cortisol patterns in breast cancer survivors. Psychother Psychosom. 2012;81:173-182.

77.

Cohen

Parker

Vence

. Presurgical stress management improves postoperative immune function in men with prostate cancer undergoing radical prostatectomy. Psychosom Med. 2011;73:218-225.

78.

Rosenberg

Ernstoff

. Expressive disclosure and health outcomes in a prostate cancer population. Int J Psychiatry Med. 2002;32:37-53.

79.

Nelson

Wenzel

Osann

. Stress, immunity, and cervical cancer: biobehavioral outcomes of a randomized clinical trial. Clin Cancer Res. 2008;14:2111-2118.

80.

Butow

Mullan

. Impact of medical Qigong on quality of life, fatigue, mood and inflammation in cancer patients: a randomized controlled trial. Ann Oncol. 2010;21:608-614.

81.

National Institute of Mental Health. Psychotherapies. http://www.nimh.nih.gov/health/topics/psychotherapies/index.shtml. Accessed August 28, 2013.

82.

Savard

Simard

Ivers

Morin

. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer: part II. Immunologic effects. J Clin Oncol. 2005;23:6097-6106.

83.

Carlson

Speca

Patel

Goodey

. Mindfulness-based stress reduction in relation to quality of life, mood, symptoms of stress and levels of cortisol, dehydroepiandrosterone sulfate (DHEAS) and melatonin in breast and prostate cancer outpatients. Psychoneuroendocrinology. 2004;29:448-474.

84.

Kabat-Zinn

. Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness. New York, NY: Delacorte Press; 1990.

85.

Bishop

Lau

Shapiro

. Mindfulness: a proposed operational definition. Clin Psychol Sci Pract. 2004;11:230-241.

86.

Institute of Medicine, Committee on Cancer Survivorship: Improving Care. From Cancer Patient to Cancer Survivor: Lost in Transition. Washington, DC: National Academies Press; 2005.

87.

Cancer Statistics Working Group. United States Cancer Statistics: 1999-2009: Incidence and Mortality Web-Based Report. Atlanta, GA: Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2013.

88.

Robson

Scrutton

Wilkinson

MacLeod

. The risk of suicide in cancer patients: a review of the literature. Psychooncology. 2010;19:1250-1258.

89.

Norredam

Meara

Landrum

Huskamp

Keating

. Financial status, employment, and insurance among older cancer survivors. J Gen Intern Med. 2009;24:438-445.

90.

Andersen

Thornton

Shapiro

. Biobehavioral, immune, and health benefits following recurrence for psychological intervention participants. Clin Cancer Res. 2010;16:3270-3278.

91.

Maracy

Dunn

. Estimating dose-response effects in psychological treatment trials: the role of instrumental variables. Stat Methods Med Res. 2011;20:191-215.

92.

Petrie

Fontanilla

Thomas

Booth

Pennebaker

. Effect of written emotional expression on immune function in patients with human immunodeficiency virus infection: a randomized trial. Psychosom Med. 2004;66:272-275.

93.

Pauley

Morman

Floyd

. Expressive writing improves subjective health among testicular cancer survivors: a pilot study. Int J Mens Health. 2011;10:199-219.

94.

Leykin

Thekdi

Shumay

Muñoz

Riba

Dunn

. Internet interventions for improving psychological well-being in psycho-oncology: review and recommendations. Psychooncology. 2012;21:1016-1025.

95.

Nater

Rohleder

. Salivary alpha-amylase as a non-invasive biomarker for the sympathetic nervous system: current state of research. Psychoneuroendocrinology. 2009;34:486-496.

96.

Thoma

Kirschbaum

Wolf

Rohleder

. Acute stress responses in salivary alpha-amylase predict increases of plasma norepinephrine. Biol Psychol. 2012;91:342-348.

97.

Clerici

Stocks

Zajac

. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest. 1989;84:1892-1899.

98.

McCain

Gray

Elswick

. A randomized clinical trial of alternative stress management interventions in persons with HIV infection. J Consult Clin Psychol. 2008;76:431-441.

99.

Vedhara

Fox

Wang

. The measurement of stress-related immune dysfunction in psychoneuroimmunology. Neurosci Biobehav Rev. 1999;23:699-715.

100.

Vedhara

Wang

. Assessment of the immune system in human psychoneuroimmunology. In: Vedhara

Irwin

, eds. Human Psychoneuroimmunology. Oxford, England: Oxford University Press; 2005:53-80.

101.

Lohr

. What is (and what is not) the meaning of evidence-based psychosocial intervention? Clin Psychol Sci Pract. 2011;18:100-104.

102.

Stanton

Luecken

MacKinnon

Thompson

. Mechanisms in psychosocial interventions for adults living with cancer: opportunity for integration of theory, research, and practice. J Consult Clin Psychol. 2013;81:318-335.

103.

Hansen

ÅM

Garde

Persson

. Sources of biological and methodological variation in salivary cortisol and their impact on measurement among healthy adults: a review. Scand J Clin Lab Invest. 2008;68:448-458.

104.

Han Ang

Dyson

. Classical and non-classical ruthenium-based anticancer drugs: towards targeted chemotherapy. Eur J Inorg Chem. 2006;2006:4003-4018.

105.

Peiretti

Zanagnolo

Bocciolone

. Robotic surgery: changing the surgical approach for endometrial cancer in a referral cancer center. J Minim Invasive Gynecol. 2009;16:427-431.

106.

Kim

Ryu

Gong

Hong

Shong

. 18F-fluorodeoxyglucose uptake in thyroid from positron emission tomogram (PET) for evaluation in cancer patients: high prevalence of malignancy in thyroid PET incidentaloma. Laryngoscope. 2005;115:1074-1078.

107.

Fann

Ell

Sharpe

. Integrating psychosocial care into cancer services. J Clin Oncol. 2012;30:1178-1186.

108.

Coyne

Tennen

. Positive psychology in cancer care: bad science, exaggerated claims, and unproven medicine. Ann Behav Med. 2010;39:16-26.

109.

National Research Council, Committee on Health Behavior: Research Practice and Policy, Board on Neuroscience and Behavioral Health, Institute of Medicine, eds. Health and Behavior: The Interplay of Biological, Behavioral, and Societal Influences. Washington, DC: National Academies Press; 2001.

110.

Block

. Integrative cancer treatment in the 21st century [editorial]. Integr Cancer Ther. 2002;1:3-6.

111.

Geffen

. Integrative oncology for the whole person: a multidimensional approach to cancer care. Integr Cancer Ther. 2010;9:105-121.