Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life

Cancer Treatment Reviews xxx (2014) xxx–xxx

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Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv

General and Supportive Care

Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life Gregory Carter a,⇑, Kerrie Clover b, Ben Britton b, Alex J. Mitchell c, Martin White d, Nicholas McLeod e, Jim Denham f, Sylvie D. Lambert g a

Centre for Translational Neuroscience and Mental Health, School of Medical Practice and Population Health, Faculty of Health, University of Newcastle, NSW, Australia Psycho-Oncology Service, Calvary Mater Newcastle, School of Psychology, Faculty of Science and Information Technology, Centre for Translational Neuroscience & Mental Health Research, University of Newcastle, Australia c Depart of Cancer & Molecular Medicine, Leicester Royal Infirmary & University of Leicester, Leicester LE5 1WW, United Kingdom d Consultant Urologist, New Lambton, Newcastle, NSW, Australia e John Hunter Hospital, New Lambton, Newcastle, NSW, Australia f Faculty of Health and Medicine, Prostate Cancer Trials Group, School of Medicine and Public Health, University of Newcastle, NSW, Australia g Ingram School of Nursing, McGill University, Canada b

a r t i c l e

i n f o

Article history: Received 28 August 2014 Received in revised form 27 October 2014 Accepted 3 November 2014 Available online xxxx Keywords: Prostate cancer Active Surveillance Distress Depression Anxiety Stress Quality of life Wellbeing

a b s t r a c t Background: Active Surveillance (AS) is recommended for the treatment of localised prostate cancer; however this option may be under-used, at least in part because of expectations of psychological adverse events in those offered or accepting AS. Objective: (1) Determine the impact on psychological wellbeing when treated with AS (non-comparative studies). (2) Compare AS with active treatments for the impact on psychological wellbeing (comparative studies). Method: We used the PRISMA guidelines and searched Medline, PsychInfo, EMBASE, CINHAL, Web of Science, Cochrane Library and Scopus for articles published January 2000–2014. Eligible studies reported original quantitative data on any measures of psychological wellbeing. Results: We identified 34 eligible articles (n = 12,497 individuals); 24 observational, eight RCTs, and two other interventional studies. Studies came from North America (16), Europe (14) Australia (3) and North America/Europe (1). A minority (5/34) were rated as high quality. Most (26/34) used validated instruments, whilst a substantial minority (14/34) used watchful waiting or no active treatment rather than Active Surveillance. There was modest evidence of no adverse impact on psychological wellbeing associated with Active Surveillance; and no differences in psychological wellbeing compared to active treatments. Conclusion: Patients can be informed that Active Surveillance involves no greater threat to their psychological wellbeing as part of the informed consent process, and clinicians need not limit access to Active Surveillance based on an expectation of adverse impacts on psychological wellbeing. Ó 2014 Elsevier Ltd. All rights reserved.

Introduction Radical prostatectomy and radiation therapy are the most common active treatments for localised prostate cancer [1]. In Europe 70% and the US 90% receive active treatment [2]. Active treatments are largely curative, however there is concern about overtreatment, since many cases will never become life-threatening [2]. Moreover, active treatments lead to permanent, serious adverse ⇑ Corresponding author at: Locked Bag #7, Hunter Region Mail Centre, NSW 2310, Australia. Tel.: +61 (0) 240144926; fax: +61 (0) 240144933. E-mail address: [email protected] (G. Carter).

effects, especially erectile dysfunction and urinary incontinence, which are distressing and compromise quality of life [1]. Up to 20% of newly diagnosed localised prostate cancer patients show clinically important levels of psychological distress [3] and partners’ distress sometimes exceed the patients’ distress [4,5] . Prostate cancer prevalence in the USA has more than doubled since the introduction of the prostate specific antigen (PSA) test and cases detected by PSA ‘‘screening’’ are problematic. Many would have remained asymptomatic without the advent of PSA testing and most would not have a mortality benefit from active treatment [6]. Paradoxically, without PSA testing, they would have not been offered active treatment and would not have been at risk

http://dx.doi.org/10.1016/j.ctrv.2014.11.001 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

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G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

of adverse effects of treatment or threats to their psychological wellbeing. With the increase in asymptomatic ad hoc PSA testing more men are diagnosed with localised disease; and with their partners, have been confronted with complex treatment decision-making. Although shared treatment decision-making is a cornerstone of patient-centred care, often these decisions have to be made quickly after diagnosis and men and their partners report feeling overwhelmed, confused and struggle with making the ‘best’ decision [7]. In a large study of men with localised disease, only 9% of men who would be eligible for Active Surveillance actually made that choice for treatment [8]. Active Surveillance is an alternative treatment [9], which involves regular clinical monitoring, with progression to active treatment for signs of disease progression, detected by repeat prostate biopsies supplemented by regular clinical review and monitoring of prostate specific antigen (PSA) levels [2]. Active Surveillance is a strategy to defer (sometimes indefinitely) radical prostatectomy or radiotherapy in men with curable, low risk prostate cancer, aiming to avoid overtreatment in those who don’t need it. There is a variety of standardised protocols available for Active Surveillance e.g. the 2008 UK NICE guidelines, which advise ‘‘Men with low-risk localised prostate cancer who are considered suitable for radical treatment should first be offered active surveillance. It is particularly suitable for men with clinical stage T1c, Gleason score 3 + 3 and PSA density <0.15 ng/ml who have cancer in less than 50% of their biopsy cores, with <10 mm of any core involved.’’ [10]. Intervention with active treatment is then offered for a PSA doubling time of less than 3 years (depending on patient age, comorbidities, or grade progression to a pattern of predominantly Gleason 4) [11]. Active Surveillance was first described in 2001 [6] and in the time before Active Surveillance a ‘‘Watchful Waiting’’ approach (or even no treatment) was the main alternative to active treatment for localised disease [12]. Watchful Waiting is currently the strategy used to avoid radical treatment in (usually elderly) patients. Watchful Waiting is a strategy of accepting that a patient has prostate cancer for which surgery or radiotherapy is inappropriate (e.g. serious co-morbid illness and/or less than 5 year life expectancy). Management is aimed at treatment of symptomatic progression e.g. lymph node or bony metastatic disease, which may be treated with androgen deprivation therapy [2,6]. The potential benefits of Active Surveillance are that side effects of treatment can be postponed or avoided, with little to no impact on future cure rates [2] for lower treatment cost. However, it is possible that being diagnosed with prostate cancer, yet recommending no immediate active treatment might be more distressing to men and their partners than choosing and receiving active treatment [2]. This concern about the possibility of increased distress may be a reason why Active Surveillance is not more frequently offered by clinicians or chosen by patients. If we knew precise estimates of the risk of developing psychological symptoms based on choice of treatment, this would help in the explanation of risk and benefits to patients (and their partners). If there was no greater impact on psychological wellbeing in Active Surveillance compared to active treatment, with equivalent mortality and reduced or delayed physical adverse effects, then there might be greater provision of Active Surveillance by clinicians and greater acceptance by patients, resulting in substantial reduction in health costs and patient adverse effects. Aims (1) Determine the impact on psychological wellbeing (distress, psychological symptoms, mental health function, or quality of life) when treated with Active Surveillance (non-comparative studies).

(2) Compare Active Surveillance with active treatments for the impact on psychological wellbeing (comparative studies). Evidence acquisition We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline for the conduct and reporting of this systematic review [13]. Eligibility criteria We included studies that reported original quantitative data on the impact of choosing Active Surveillance for men with localised prostate cancer. We included studies regardless of sample size, study design, and method of measurement of psychological impact and studies which included some (a minority) patients on Active Surveillance who did not have localised disease. We also accepted any approximations to Active Surveillance including Watchful Waiting. We conceptualised psychological wellbeing broadly. We included any psychological symptoms (e.g. distress, psychological distress, decisional distress, anxiety or depression symptoms scores or mental illness diagnosis), mental health functioning or mental health related disability, and quality of life or health related quality of life (HRQoL). Studies that included measures of decisional distress or decisional satisfaction with the treatment decision taken were also included. We included studies that reported on the same samples or sub-sets of other samples and studies published in either English or French. We excluded studies focusing only on decision-making processes regarding treatment and studies that were reported only in conference abstracts. Information sources We searched Medline, PsychInfo, EMBASE, CINHAL, Web of Science and Scopus from January 2000 to January 2014. We searched the Cochrane Trials Database and retrieved the systematic review ‘‘Psychosocial interventions for men with prostate cancer’’ [14], which we searched for relevant trials. We also hand searched key journals in the field; reviewed the reference lists of each paper retrieved; and used the ‘find similar’ and ‘find citing’ functions for seminal papers in Web of Science and PubMed.

Records identified through database searching (n=738)*

Records identified through other sources (n=16)

Records screened on basis of title & abstract (n=754) Records excluded (n=705) Full-text articles assessed for eligibility (n=49) Full-text articles excluded (n=15) Studies included for quality assessment and narrative synthesis of findings (n=34) Review article n=3 Not psychosocial n=4 Not AS n=7 Qualitative n=1 Fig. 1. Study selection. ⁄Excluding duplicates and including search of electronic databases and of Cochrane database of clinical trials (psychosocial interventions for men with prostate cancer).

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

Search The search terms were developed from those terms used in key papers in this area. The ‘Active Surveillance’ search terms were: active surveillance.mp, exp Watchful Waiting/. The active treatment terms were: exp Radiotherapy, exp prostatectomy AND exp Prostate-Specific Antigen/. The terms for psychological impact were: Anxiety/, exp Depression/, exp Adaptation, Psychological/or distress.mp. or coping.mp. or exp Stress, Psychological/OR exp ‘‘Quality of Life’’/. The terms for prostate cancer were: prostate cancer.mp. or exp Prostatic Neoplasms/Diet Therapy, Drug Therapy, Radiotherapy, Surgery, Therapy]/. Study selection A subset of titles and abstracts from one database (Medline, n = 50) was independently examined by two reviewers (KC, SL) to identify articles for full review. Inter-rater reliability was very good (kappa = 0.92); and so all the remaining titles and abstracts were subsequently screened for relevance according to the inclusion criteria by a single reviewer (KC). Data collection process We assessed potential bias in randomised controlled trials (RCT) based on the Cochrane recommendations [15]. We did not expect to find many RCTs, which addressed the outcomes of interest even as secondary study outcomes, so we were prepared to include observational studies (classified as cross-sectional, casecontrol and cohort designs) [16] in this review. There is no standard method or single tool for assessing quality and susceptibility to bias in observational studies [17], ‘‘Data collection forms may need to be customised to the research question being investigated. Because of the diversity of potentially eligible studies and the ways in which they are reported, developing the data collection form can require several iterations in the course of reviewing a sample of primary studies. It is almost impossible to finalise these forms in advance.’’ [18]. The Cochrane guidelines offer a tool for the assessment for risk of bias in cohort studies, which we used in part to develop a standardised form used in our rating of quality and risk of bias. http://bmg.cochrane.org/ sites/bmg.cochrane.org/files/uploads/Tool%20to%20Assess%20Risk %20of%20Bias%20in%20Cohort%20Studies.pdf. Two independent reviewers (GC, KC) extracted data using a standardised collection form. The form was pilot tested with five key studies and refined accordingly. The quality of observational studies was assessed by reporting of: year of publication, study design, sample size and setting, socio-demographic and clinical eligibility characteristics (including details of prostate cancer), response rates, the use of valid measures, and the analysis strategy; and we made an overall quality rating and individual quality ratings of: external validity, eligibility, response rates, measures used and analysis as: low (L), medium (M), high (H) and unknown or unclear (U); or as present (Y) or absent (N) as applicable. For studies with any comparative component, we also noted the presence of a power calculation. For any RCT we rated the quality of randomisation and the blindness of the rater for the primary outcome. Discordant ratings between two independent reviewers were resolved through discussion and consensus. We assessed external validity by the representativeness of those invited to participate (sampling frame) to the entire population from which they were recruited; and of those participating (response rate and retention rate). We assessed internal validity by use of validated measures for the main outcomes and the use

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of appropriate statistical tests for the research question. We also assessed internal validity by addressing possible confounding. This included reporting of the recruitment of comparison groups from the same population, adjustment for confounding by study design (e.g. stratification at recruitment) or by analysis (e.g. multivariate analyses). For longitudinal studies this included the report of participants lost from the study (retention rate) and accounting for these losses in analyses. Results The search strategy retrieved 754 (non-duplicate) records with 34 ultimately selected for the study (Fig. 1). Overlapping populations Multiple reports of the same samples were identified for three articles in one study series Prostate Cancer Research International Active Surveillance (PRIAS) [19–21]; two other PRIAS reports [22,23]; two from the European Randomized Study of Screening for Prostate Cancer (ERSPC) [21,24]; two reports from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) project [25,26]; two reports on the US Prostate Cancer Outcomes Study (PCOS) [27,28]; four reports for the Scandinavian Prostate Cancer Groups Study Number 4 (SPGC-4) [29–32]; two reports on the Prostate Cancer Lifestyle Trial (PCLT) [33,34]; and a sample overlap was identified in two other reports [35,36]. Study characteristics There were twenty-four observational studies, eight RCTs, and two other interventional studies. Studies came from North America (n = 16), Europe (n = 14) Australia (n = 3) and North America/Europe (n = 1). Studies recruiting patients from population based PSA ‘‘screening’’ included those from PRIAS and ERSPC and an unnamed study from the USA [37]. We identified n = 12,497 individual patients reported across all studies. Only a minority of studies (5/34) were rated as being of high overall quality. However, most studies (26/34) used validated instruments. A substantial minority (14/34) used watchful waiting or no active treatment rather than Active Surveillance. Studies restricted to AS populations – psychological and quality of life outcomes There were nine studies restricted to samples undergoing AS (n = 7), WW (n = 2) or no treatment (n = 0), of which five reported psychological outcome measures [19,20,24,26,35] and four reported quality of life outcomes [22,23,25,36] (Table 1). We estimate there were n = 407 and n = 566 unique individuals, respectively. The overall quality of the studies was rated as high (n = 0), medium (n = 6) and low (n = 3). Main findings Five studies measured psychological outcomes (no treatment n = 1, WW = 0, AS n = 4). Two cross sectional studies reported low proportions above threshold for anxiety (14–17%) and depression (6–8%) [19,24]. One longitudinal study reported that a transition from AS to ‘‘active treatment’’ was associated with an increase in PSA levels and an increase in cancer anxiety scores, whilst those remaining on AS showed a reduced rate of anxiety over time [26]; and one longitudinal study reported improvement in anxiety and fear of progression of prostate cancer over time [20]. Four studies measured Quality of Life outcomes (no treatment n = 1, WW n = 1, AS n = 2). Three cohort studies where one showed

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

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Author, year, country

Study design

Sample size & setting

Eligibility cancer features

Response rate

Measures

Comment

Quality scores overall other

Main findings

Psychological symptoms Seiler 2012; Switzerland

Cross sectional

n = 133

Response 133/ 283 (47%)

Validated HADS (8–10 borderline & >10 clinical)

Couples only

Low

Below reference (patients)

ERSPC

Couples only Recruitment U Power N

Life expect >10 years Gleason63 + 3 62 +ve cores <50% tumour PSAD <0.15 ng/mL/ cc Or patient choice

Primary outcome anxiety and HRQoL in partners Variable follow-up

External L Eligibility L Response L Measures H

Response 129/ 150 (86%)

n = 19

Diagnosis 66 month stage 6T2 PSA <10 ng/ mL PSAD <0.2 ng/ mL/cc <2 +ve biopsy Gleason < 6 (3+3) >65 years

Power N

PCa Dx

van den Bergh et al. 2009; Netherlands

Cross sectional

Comparison to literature controls

n = 129

Power N

PRIAS

Wallace 2003; USA

Latini 2007; USA

van den Bergh 2010; Netherlands

Cross sectional

Cohort

n = 105

Max 3 year

Follow up

national observational registry Power N

CaPSURE Cohort

n = 150

9 month follow up QoL ‘‘side study’’

MAX-PC (P27) EORTC QLQ-C30

STAI-6 (>44) CES-D (P16)

Response U

Response 105/ 296 (35%)

Diagnosis 66 month

Response 129/ 150 (86%) Retention 108/ 150 (72%)

PSA <10 ng/ mL PSAD <0.2 ng/ mL/cc

Primary outcomes psychological (4)

Medium External L Eligibility H

Depression (92%) Anxiety (83%)

Response M

Uncertainty (81%)

Analysis: mean scores v reference values

MAX-PC (P27)

Multivariate Y

Measures H Analysis H

PCa anxiety (93%) All four variables (65%)

Validated STAI SF-36 QLI-CV

Not AS (No Rx)

Low External L Eligibility M Response L

Results unclear

MUIS-C (Uncertainty) F&L AS Not Validated

Small sample Multiple instruments and analyses Possible overlap with Hegarty et al. (2008) Primary outcome – transition from AS to active treatment

Measures H Analysis L Medium External M Eligibility L

Anxiety: 3 items with 5 point Likert scale; transformed to 0–100 score

Multivariate Y

Validated

Primary outcomes psychological

STAI-6 (>44)

Analysis: comparison baseline v f-up

CES-D (P16)

Multivariate Y

Power N PRIAS

Analysis H

DCS (>37.5)

Biopsy proven localised PCa Chose AS No transition to active Rx > 6 month P3 anxiety rating

stage 6T2

Validated

Multiple tests Multivariate Y

HADS-A (86%) HADS-D (not stated) MAX-PC (92%) Partners had higher anxiety & depression scores than patient Partners worse on HRQoL High partner anxiety predicted by partner global health and emotional function BELOW reference for

DCS (>37.5)

Cancer anxiety change scores independently predicted transition from AS to active treatment

Response L Measures L Analysis H Medium External L Eligibility H Response M Measures H Analysis H

Baseline % over threshold Anxiety 17% Depression 6% Follow-up: Anxiety & depression scores sig improved vs baseline % over threshold Anxiety 12%

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

Table 1 Studies of Active Surveillance (AS) populations for psychological symptoms or QoL outcomes.

Quality of life (or mental functioning) Hegarty 2008; USA & Cross sectional Ireland

n = 29 Ireland = 10; USA = 19 Power Y

>65 years On AS PCa ‘‘biopsy’’

MAX-PC (P27)

Response Ireland 10/92 (10.9%) USA U

Plan n = 100

Arredondo 2004 (reprinted 2008); USA

Cohort Follow up

n = 310

Median 1.6 year Max 5 years

observational registry: 33 sites Power N

CaPSURE Vasarainen 2012; Finland

Cohort (+population controls) Single centre

Validated SF-36 MUIS-C (uncertainty) F&LAS

Low External L Eligibility L Response L

Validated

Not AS (No Rx) Primary outcomes QoL Multiple instruments and analyses Descriptive Older 65 years Possible sample overlap with Wallace et al. (2003) WW not AS

SF36

Mixture of new and existing cases

Eligibility M Response L

Multivariate models

QLI-CV

Biopsy proven localised PCa

Chose WW

Response Baseline 310/451 (69%) Retention Yr 5: 57/451 (13%)

Depression 8%

Measures M Analysis L

Medium External M

n = 124

Stage 6T2

Response 105/ 124 (85%)

Validated

Sub group study

Measures H Analyses M Medium

Power N

PSA <10 ng/ mL PSAD <0.2 ng/ mL/cc <2 +ve biopsy

Retention 75/124 (60%)

SF-36 (mean scores on 8 subscales, 0–100)

Univariate Y

External L

Multivariate Y

Eligibility M

Follow up 1 year (min) PRIAS (Finnish subgroup)

Response M

Gleason <6

Measures H

Analysis M

Bellardita 2013; Italy

Cohort

n = 103

Clinically localised

Response 154/ 220 (70%)

Validated

Outcome Low QoL (< 25th%)

Medium

Dichotomised scores

External L

SCL-90

Univariate Y

Eligibility H

FACT-P

Multivariate Y Primary (model) predictors of low HRQoL

Response M Measures H

PSA 610 ng/ mL Follow up 10 months

Single Italian centre

PSAD <0.2 ng/ mL/cc

PRIAS

Power N

6 2 +ve cores Gleason 3+3=6

QoL side study

Retention 103/ 220 (59%)

Mini-MAC

Results unclear

Analysis H

Baseline MCS 52.4 (8.25)

Follow-up: No sig change MCS

Baseline: Mean score all domains sig better in AS vs ‘‘population controls’’.

Mental health mean score (SD): AS = 81 (15) .(Pop mean not stated approx 78 from graph) Follow-up: Mental Health no sig change vs baseline. Mean (SD) = 81 (14) AS better than population controls No demographic or clinical predictors of QoL score Baseline to follow up: no change Emotional Wellbeing on FACT-P and Anxious preoccupation on Mini-MAC Low HRQoL predictors: lack of partner & impaired mental health Poor global QoL predictors: impaired mental health & time Dx to enrolment Better QoL: physician influence on choice AS, partner present & >18 biopsy specimens

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

⁄

Epstein criteria: No Gleason score >3, 62 +ve biopsy cores, <50% tumour involvement biopsy cores, PSA density <0.15 ng/mL. Studies: CaPSURE Cancer of the Prostate Strategic Urologic Research Endeavor; ERSPC: European Randomized Study of Screening for Prostate Cancer; PRIAS: Prostate Cancer Research International Active Surveillance. Instruments: CES-D: Centre for Epidemiological Studies – Depression; DCS: Decisional Conflict Scale; EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire; F&LAS: Folkman & Lazarus Appraisal Scale; FACT-P: Functional Assessment of Cancer Therapy – Prostate version; HADS: Hospital Anxiety & Depression Scale; SCL-90: Symptom Checklist-90; MAX-PC: Memorial Anxiety in Prostate Cancer; Mini-MAC: Mini-Mental Adjustment to Cancer, MUIS-C: Mishel Uncertainty in Illness Scale; QLI-CV: Quality of Life – Cancer Version; SF36: Short-Form 36, contains Mental Component Summary (MCS) scale and Role Emotional (RE) subscale; STAI: Spielberger State-Trait Anxiety Inventory, UCLA-PCI: UCLA Prostate Cancer Index.

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Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

< 2 +ve biopsy Gleason <6

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G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

normal Quality of life (mental function) [25], one reported equivalent or better scores than population norms at baseline and followup [23], and two showed no significant change in quality of life (mental health function) from baseline to follow-up [22,25]. Studies reporting decisional stress as an outcome (non-comparative and comparative) Five studies reported ‘‘decisional stress’’, ‘‘decisional conflict’’ or ‘‘decisional satisfaction’’ as the primary outcome (no treatment n = 1, WW n = 0, AS n = 4). There were n = 3733 individual patients. The overall quality was rated as high (n = 0), medium (n = 2) and low (n = 3). Three studies used cross-sectional and two used cohort designs. Main findings Three cross sectional studies showed high decisional satisfaction, low decisional conflict or being ‘‘comfortable with decision to select AS’’ [38–40]; whilst one reported more decisional worry in the AS compared with the RP group, but no difference in decisional satisfaction [39]. One cohort study showed high satisfaction for treatment choice for AS and for the whole sample [41]; whilst one study showed the ‘‘no treatment’’ group were less satisfied than the ‘‘active treatment’’ group [27] (see Table 2). Comparative treatment studies – psychological and quality of life There were 20 studies which compared AS (or WW or no treatment) with active treatments, or compared treatments within an AS population. Ten were observational and ten were interventional, with eight of the interventional studies using RCT designs (Table 3). For the ten observational studies (no treatment n = 2, WW n = 4, AS n = 4); for the eight RCTs (no treatment n = 0, WW n = 5, AS n = 3); and for two other treatment designs (no treatment n = 0, WW n = 0, AS n = 2). The observational studies reported n = 9381, RCTs n = 812 and others n = 9 individuals. In this section the quality ratings were high (n = 5), medium (n = 5) and low (n = 10). For the observational studies, three used cross sectional, one a matched case–case and six a cohort design. For the interventional studies, eight used a RCT design, with four studies from the SPCG-4 using WW groups compared to radical prostatectomy for localised disease; three studies using AS populations only, one of dutasteride v placebo, two studies of AS plus a lifestyle intervention v AS; and one study of psycho-social intervention v treatment as usual in a WW population. The quality ratings for the interventional studies were high (n = 1), medium (n = 1) and low (n = 8). Main findings There was no significant difference in psychological symptoms or quality of life for the AS, WW or no treatment condition, compared to other treatment modalities for seven studies [28,42–47]. In two studies AS showed better outcomes than hormonal therapy, with no differences to the other active treatment modalities [37,48]. In a single study, AS showed better outcomes on emotional function, social function and role function than active treatments [49]. The four SPCG-4 reports, showed no differences for WW v radical prostatectomy for depression, anxiety or quality of life [29–32]. In the other four RCT interventional studies, three were restricted to AS populations. The two lifestyle intervention studies plus AS showed no differences in mental health scores or quality of life compared to AS alone [33,34]. There were modest benefits in favour of the dutasteride arm compared to placebo for anxiety and fear of recurrence, (as well as benefits in terms of reductions of prostate cancer progression) [50]. In the RCT of psychosocial

intervention compared to usual care and restricted to WW participants, there were reported benefits in favour of the psycho-social intervention for quality of life and having a ‘‘new view’’ on life measured by the GTUS, but with no differences in mood profile scores [51]. Two other interventional studies; one compared treatment groups from two primary studies [21] and one used a single subject pre–post design [52]. AS compared with prostatectomy or radiotherapy showed benefit in favour of AS for depression at 6 months and 12–18 months, a benefit in favour of radical treatment for anxiety at 6 months but not different at 12–18 months, and no difference for mental health function at 6 months and 12–18 months [21]. The pre–post study showed no change in quality of life for baseline to 5 week follow-up [52]. Discussion Main findings In the studies of AS populations, a minority had symptoms of depression or anxiety [19,24,42]; were over threshold for depression or anxiety [20,46,48]; and after follow-up had no change [46,48] or modest improvement in depression and anxiety scores [20]. The quality of life studies showed either ‘‘normal’’ levels of MCS scores at baseline and follow-up for AS [22,25], or better scores at baseline and at follow-up than population controls [23]. Decisional stress or satisfaction, decisional conflict was low and decisional satisfaction was usually high, with no changes over follow-up [27,38–41]. Taken together, this is modest evidence to suggest that there is little or no adverse impact on wellbeing after choosing or being treated with Active Surveillance. Active Surveillance patients mostly had equivalent levels of anxiety, depression, emotional functioning and quality of life to other treatment modalities at baseline; and no differences at end of treatment, or after follow-up compared to prostatectomy or radiotherapy [28,42–47]. The interventional studies showed no differences in anxiety or depression for WW v radical prostatectomy [29–32]. These findings suggest there is modest evidence that psychological wellbeing is no different for those receiving AS compared to those receiving active treatment. Future research It is unlikely that there will be many future studies using RCT designs of Active Surveillance v radical treatments, which means that good quality observational studies may be needed to further address the issue of wellbeing in Active Surveillance populations. Most studies used appropriate and validated instruments for measurement of psychological symptoms and quality of life, although there was a considerable diversity in the instruments used. For future research some agreement to use a core group of instruments in psychological wellbeing studies would be potentially useful. Analyses that were restricted to comparisons of differences on mean scores or cut points or thresholds without any reference to clinically meaningful levels are of limited use. ‘‘Future research should report clinically relevant differences or clinically significant differences, appropriate to the research question. This will vary depending on the construct examined and the instrument used. Clinical relevance is often greater for threshold scores rather than mean differences in scores, e.g. using the threshold of >3 on the Distress Thermometer to identify clinically relevant distress. Prevalence of psychiatric disorder (e.g. anxiety and depression) should use accepted diagnostic thresholds and contextualise rates by comparison with community populations. Clinically significant differences or clinically meaningful change scores should be

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

Author, year, country

Study design

Sample size setting & power

Eligibility cancer features

Response rate

Measures

Comment

Quality scores overall other

Main findings

Davison 2011; Canada

Cross sectional

n = 73

Early stage PCa

Response 73/121 (60%)

Non-validated

Primary outcome

Most were comfortable with decision for AS

Clinician identification1 centre Power N

Biopsy confirmed T1–2, NX/NO, MX/MO On AS 6 10 years

Low External L Eligibility U Response M

Goh 2012; USA

Cross sectional

n = 34 support group phone survey Pilot

Decision making

PCa ‘‘Biopsy confirmed’’

Single item for anxiety being on AS

Response U

Validated DCS

Different periods since Dx Univariate Y Small sample

Multiple predictors Power N

Sidana 2012; USA

Hoffman 2003; USA

Anandadas 2011; UK

Cross sectional

Cohort Follow up 24 months PCOS (USA)

Cohort

Follow-up 3,5,12,24 month

n = 493 n = 26 AS n = 397 RP n = 52 RT Single pathology database Power N n = 2365 n = 230 NoRx

<50 years

n = 1373 RP n = 583 RT n = 179 HT Strata sampling Power Y n = 768

60–89 years Some ethnicities excluded

Biopsy proven

n = 61 AS

T1/T2

n = 305 RP n = 402 RT n = 165 BT Power N

PSA <20 lg/L Gleason 67 Referred for active Rx

Gleason = 6 Localised PCa

Biopsy confirmed T1/T2

SE, HMI-5, CMS MUIS, MAX-PC

Multivariate Y

Eligible 986/1551 (64%) Response 493/986 (50%) Analysed 488/493 (99%)

Non-validated

Primary outcome

Response 2365/3073 (77%)

Not validated

Information preferences and decision making Univariate Y

Satisfaction only

Response 768/821 (94%) Retention (QoL subgroup) 354/821 (43%) 2 year 242/821 (29%)

Non validated

Two item satisfaction measure

NoRx not AS Primary outcome treatment satisfaction Dichotomised scores Univariate Y Multivariate Y

Primary outcome reason for Rx choice Post Rx satisfaction in sub-group Univariate Y AS not intended in sampling

Most had low levels of anxiety about PCa progressing

Measures L Analysis L Low

External L Eligibility L Response U Measures M Analysis M Low External L Eligibility L Response M Measures L Analysis L Medium External M Eligibility M Response M Measures L Analyses M Medium

Decisional satisfaction high (93%)

Decisional conflict – low No sig predictors of decisional satisfaction or conflict Decisional satisfaction – high (Whole sample – 89%) AS more decisional worry v RP No difference in satisfaction

No Rx least satisfied group High satisfaction predicted by perception cancer free; bowel & bladder control; erectile function; good general health& social support

Satisfaction with treatment choice – high (AS and whole sample)

External L Eligibility L Response H Measures H Analysis L

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

No difference in satisfaction between groups

Instruments: DCS: Decisional Conflict Scale, SE: Self Efficacy of Prostate Cancer Symptom Management Scale, CMS: Fife Constructed Meaning Scale, HMI-5: Mental Health Index -5, MUIS: Mishel Uncertainty in Illness Scale, MAXPC: Memorial Anxiety in Prostate Cancer. Interventions: NoRx: No treatment, WW: Watchful Waiting; AS: Active Surveillance, RT: Radiotherapy (external beam), RP: Radical Prostatectomy, HT: hormonal therapy, BT: Brachytherapy. Studies: PCOS: Prostate Cancer Outcomes Study (USA).

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Table 2 Studies for decisional stress/satisfaction outcomes: Quality review and main findings.

8

Author, year, country

Study design

Observational studies Smith 2000; USA Cross sectional 6 month–6 years post Dx Volunteers 50+ in serial screening program at one university centre

Burnet 2007; UK

Cross sectional

Sample size & setting

Eligibility cancer features

Response rate

Measures

Comment

Quality rating

Main findings

n = 2234

New Dx

1651/2234 (74%)

Validated SF-36 (role emotional subscale)

Observation not AS

Medium

n = 1584 RP

PCa (all stages)

Not just localised PCa

External L

Sig diffs between Rx groups. HT lower vs observation, RP, RT, HT Role emotional (group adjusted mean) Observation = 91 RP = 86 RT = 85 HT = 76

n = 281 RT n = 210 Observation n = 119 HT n = 40 Other Power N n = 329

n = 100 AS n = 81 Current RT or HT n = 148 Post RT or HT

Vanagas 2013; Lithuania

Cross sectional

n = 61 (12%)

Thong 2009; Netherlands

Matched case-case design Matched cancer stage, tumour grade, age at Dx and years since Dx.

Consecutive patients – single NHS Trust Power Y n = 514

Variable follow-up 98% T1/T2

Localised PCa cT1/2, N0/NX, M0/MX Mean interval since Dx AS = 29 month, On Rx = 34 month Post Rx = 56 month

Response 329/ 493 (67%)

All PCa:

Response 514/ 650 (79%)

Validated

Inception time U

High

HADS

On treatment & post- treatment groups

External M

No sig differences between Rx groups on anxiety or depression Anxiety: AS = 21%,

Eligibility H Response M

Depression: AS = 4%

Anxiety P8, Depression P8

Univariate and multivariate

Measures H

Validated

Inception time U

All PCa stages

Multi site 6 Consecutive hospital patients – after Rx Power Y

ICD C-61 >18 years

EORTC QLQ-C30

AS

n = 142

‘‘Newly’’ Dx PCa Stage 62

(mean standardised score 0–100) Validated

n = 71 No Rx

Response AS 71/128 (56%)

SF-36 (MCS)

QoL-CS

No Rx Not AS Recruited from registry untreated pts that would have been eligible for AS given contemporary protocols. Multiple outcomes

Grade 62

Bacon 2001; USA

Follow-up 8 years (mean) Cohort

Mean follow-up Varied by treatment group

n = 71 RT (matched) Cancer Registry (population based) Southern Netherlands Power N n = 842 Baseline

n = 146 Follow-up n = 31 WW

WW +/

Localised PCa

Incident cases Medical records

Eligibility L Response M Measures H Analyses M

Response Baseline 842/ 1201 (71%) Response follow-up 146/ 842 (17%)

Validated SF36

Analyses H Low

External M Eligibility L Response M Measures H Analysis L Medium

AS sig better role function, emotional function and social function than other Rx groups Emotional function means: AS = 84, chemo = 46; surgery = 63; combined = 68; RT = 76; HT = 80 No sig difference AS v RT on mental health scores or QoL

External M

Eligibility L Response L Measures H Analyses L

TURP not AS

WW not AS

Low

Baseline: no difference

Small sample WW High SES cohort

External L Eligibility L Response L Measures H Analyses M

MCS scores (mean, SD) WW = 55 (52–58) RP = 55 (54–55) RT = 53 (52–54) HT = 52 (49–54) Follow-up: No sig difference

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

Table 3 Quality review and main findings: comparison of AS (or WW) with other treatments – observational and interventional trials.

Male professionals

RP = 31 month ER = 32 month

40–75 years Health Professionals Follow-up Study Power N n = 2306 n = 379 WW

Cohort Stratified sample of 5672/11137 (64%) Follow-up 24 month

Steginga 2004; Australia

n = 324 HT n = 533 RT

PCOS (USA)

n = 1070 RP Power N

Cohort Follow-up

n = 111

12 months post-Rx decision

n = 28 WW n = 21 RT n = 62 RP 2 Hospitals & 4 private urology clinics

Sample unclear Variable follow-up period Dichotomised outcome scores Multiple comparisons

New Dx PCa (all stages) < 6 month Dx 39–89 years and 60– 89 years (Seattle) Some ethnicities excluded ‘‘localised’’ newly diagnosed

Contact 4736/ 5672 (84%)

Response 6/ 12 month 3533/4736 (75%) Response 24 month 306/ 4736 (49%) Response 111/ 131 (93%)

Retention 104/ 131 (79%)

Power N

Validated SF-36 (Role Emotional subscale)

Cohort

n = 193

Biopsy PCa

Follow up

n = 61 WW

No metastases

12 months Consecutive patients – multisite

n = 38 RP

Newly diagnosed

n = 56 HT

Response 193/ 211 (91%)

Retention 172/ 211 (82%)

WW not AS All PCa Multiple outcomes

Medium External M Eligibility M

Multivariate models

Response M Measures H

Baseline: not given 2 years: no sig difference between RP, RT, WW & HT in role emotional Role emotional (adjusted mean whole sample) = 80

Analyses M

Validated IES-R (avoidance & intrusion) High >20 Moderate 9–19 Adjustment (PAIS) cutoff not stated Satisfaction (SLS) cutoff not stated DCS total (High >2.5)

UCLA-PCI

Couper 2009; Australia

WW vs RP on MCS (in multivariate analysis adjusted for Gleason score)

WW not AS

High

Baseline: no sig differences WW vs RP or RT

Primary outcome Psychological symptoms & decisional distress Dichotomous outcomes

External M Eligibility H Response H Measures H

Total group . Avoidance: High 24%; Mod 41%

Multiple outcomes

Analyses H

Univariate Y Multivariate Y Significance adjusted for multiple tests

Validated

WW not AS

High

BSI (Depression, Anxiety, higher indicates worse function) SF-36 (Mental Health)

Same time of inception

External M

Multiple statistical tests Univariate

Eligibility H Response H Measures H

Intrusion: high 16%; mod 43% Decision Conflict: 63% Adjustment: 65% 12 month: avoidance, intrusion, satisfaction, decision uncertainty, PCa uncertainty, satisfaction all sig better vs baseline. No sig change in adjustment. No sig predictors of psych outcomes. Avoidance: high 12%; Moderate 22% Intrusion: High 2%; moderate 30% Decision conflict: 44% Adjustment: 42% Baseline: no sig difference WW vs RP or other treatment. HT had worse depression, anxiety & other QoL domains vs WW 12 month: No sig difference WW vs RP or other treatment.

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

(continued on next page)

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Penson 2003; USA

WW = 15 month

10

Author, year, country

Study design

Sample size & setting

Eligibility cancer features

Response rate

Measures

Comment

n = 38 OET

Quality rating

Main findings

Analyses M

Depression: WW = 0.17 (0.3); RP = 0.29 (0.4); HT = 0.36 (0.5) Anxiety: WW = 0.15 (0.2); RP = 0.26 (0.4); HT = 0.29 (0.4) MCS: WW = 83 (15); RP = 79 (15); HT = 78 (15) Baseline: no sig difference between any treatment group and community controls on MCS AS = 51.4; population controls = 52.5

Power N

Smith 2009; Australia

Punnen 2013; USA

Cohort

n = 2031

New diagnosis T1a to T2c

Baseline Follow-up 3 year PCOS (AUS)

n = 970 RP n = 289 RT+/ AD n = 200 AS n = 62 HT 3 years: No sig difference between any treatment group and community controls on MCS n = 105 BT n = 495 controls

no metastases <70 years

Cohort

New Dx localised PCa State registry vs community controls (random selection with matching) Power N n = 679

Baseline

Response 2031/ 3195 (64%)

Validated

AS not defined

High

SF12

Primary outcome QoL Control data at 3 years extrapolated from 1 year & 5 year data Multivariate models

External M Eligibility H Response M Measures H Analyses H

Baseline 1995/ 3195 (62%)

Retention 1 yr 1599/3195 (50%) 3 years 1493/ 3195 (47%)

New Dx PCa

Response

Validated

Stage of disease unclear

Medium

n = 122 AS

No stage reported

Baseline 679/ 864 (77%) Retention

Inception defined by treatment

External L

Follow-up

n = 557 RP

RP v AS

PHQ-9 (moderate >9) GAD-7 (moderate >9) DT (>3)

1 year 1–3 year

University clinic Power N

Randomised controlled trials Steineck 2002; RCT RP v WW Sweden Follow-up Mean 4 years SPCG-4

1 year 254/864 (29%) 1–3years 85/ 864 (10%)

a

n = 376

Localised PCa

n = 166 WW

New diagnosis

n = 160 RP Power U

AS = 53.1; population controls = 54.1

T0d, T1,T2 PSA <50 ng/mL < 75 years Life expectancy >10 years

High attrition rate

Variable follow up period Dichotomised outcome scores Univariate analyses

Eligibility H Response M-L Measures H Analyses M

Response

Validated:

WW not AS

Medium

326/376 (87%)WW 166/189 (88%)RP 160/187 (86%)

STAI (>90th percentile) CES-D(>90th percentile)

Primary outcome QoL

External L

Variable follow up period

Eligibility M Response H

Randomisation U Blind N

Dichotomised outcome scores ITT analysis Univariate

Measures H Analyses M

Baseline: no sig difference RP v AS on anxiety, depression, distress Depression: AS 4%, RP 4%

Anxiety: AS 4%, RP 3% Distress: AS 14%, RP 20% 1 year and 1–3 year: no sig difference RP v AS on anxiety, depression, distress 4 years: no sig difference WW vs RP Anxiety (STAI) 10% vs 9%

Depression (CES-D) 11% vs 7%

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

Table 3 (continued)

Johansson 2011; Sweden & Finland

RCT RP v WW Follow-up

n = 376 n = 166 WW

Median 4 years SPCG-4

n = 160 RP Power U

Localised PCa a New diagnosis T0d, T1,T2 PSA <50 ng/mL <75 years Life expectancy >10 years

a

RCT RP v

n = 349

Localised PCa

WW Follow-up

n = 167 WW

New diagnosis

Median 12 years n = 182 RP SPCG-4

Bill-Axelson 2013; Sweden

Power U

T0d, T1,T2 PSA <50 ng/mL < 75 years Life expectancy >10 years

RCT RP v WW

n = 272

Localised PCa

Follow-up Max 8 years SPCG-4

n = 136 WW n = 136 RP

New diagnosis T0d, T1,T2

Power U

PSA <50 ng/mL < 75 years Life expectancy >10 years

Randomised controlled trials in Active Surveillance populations Bailey 2002; USA RCT Psycho-social n = 41 intervention vs usual care Telephone delivered 3 Urologists at one hospital

Response 326/376 (87%) WW 166/189 (88%) RP 160/187 (86%) Randomisation U Blind N Response

167/192(87%) WW 182/208 (80%) RP Retention 81/192 (42%) WW 85/208 (41%) RP Randomisation U Blind N Invited 347/ 695 (50%) Response 272/ 347 (78%) Retention 101/ 136 (74%)

Non validated Study specific. Single item 1–7 score

WW not AS Some (n = 25) WW pts on HT.

Low External L

Primary outcome QoL

Eligibility M Response H

Anxiety >2 Depression >2 QoL 1–5

Variable follow up period Dichotomised scores ITT analysis U

Measures L Analyses L

Non validated

WW not AS Primary outcome QoL

Low

Study specific Single item 1–7 score Anxiety >2

Single item scales

External M

10 weeks

Follow-up: no sig differences WW vs RP Anxiety 43% vs 43%

Eligibility M Response L Dichotomised scores

Depression >2 QoL 6–7

Multiple outcomes

Measures L Analyses M

Depression 52% vs 47% QoL (high) 34% vs 35%

Variable follow up period ITT analysis Y

Non Validated

WW not AS

Low

Study specific: Single item Visual Analogue Scales

Swedish subset Primary outcome distress Dichotomised outcomes

External L Eligibility L Response L Measures L Analyses L

Multiple outcomes Variable follow up GLM Mixed model for missing data ITT analysis N

WW 98/136 (72%) RP Randomisation U Blind N

Follow-up: No sig difference WW vs RP on depression, feeling worried about future or general health distress.

All on WW

Response 41/54 (76%)

Validated:

WW not AS

Low

10 weeks post-intervention

Retention 39/ 54 (72%)

GTUS

Not only localised Pca

External L

Convenience sample

B1, B2 or C1 PCa (97%: T1/T2)

GTUS: Intervention sig better scores on ‘‘new view on life’’ vs control.

Power N

98% PSA <20

Randomisation N

Total and 3 subscales POMS-SF Total & 6 subscales

Blind N Follow-up

No sig differences on anxiety, depression or QoL between patients stratified on time to survey completion (2–3 yr vs 4– 5 yr vs 6–8 yr)

Ave 4 comorbid health conditions

QoL – 2 items current & 6 month, 0–10 scale

Eligibility M Convenience sample Primary outcome living with uncertainty Variable time WW

Response M Measures H

Analyses L Univariate Multiple analyses ITT Analysis N

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

Mean 50 vs 48.

No other sig differences for GTUS POMS-SF: No sig differences QoL scores sig higher in intervention vs control Current QoL = 8.25 vs 7.47 QoL in 6 month = 8.55 vs 7.84 (continued on next page)

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Johansson et al. 2009; Sweden

12

Author, year, country

Study design

Sample size & setting

Eligibility cancer features

Response rate

Measures

Comment

Quality rating

Main findings

Daubenmier 2006; USA

RCT Lifestyle + AS v AS Follow up 1 year

n = 93 n = 44

All on AS Biopsy PCa PSA 4–10 ng/mL Gleason <7

Validated SF-36 (MCS)

Lifestyle intervention in AS Primary outcome lifestyle change

Low External L

Baseline vs 12 month: No differences mental health or QoL

PCLT

Lifestyle + AS n = 49 AS Power N

Response U Retention 82/ 93 (88%) 40/44 (90%) Lifestyle + AS 42/49 (86%)

Eligibility M Response L Measures H Analyses L

SF-36 MCS mean (SD)

Frattaroli 2008; USA

RCT Lifestyle + AS v AS Follow up 2 year PCLT

n = 93 n = 44 Lifestyle +AS n = 49 AS

All on AS Biopsy PCa PSA 4–10 ng/mL Gleason <7

Power N

Fleshner 2012; USA & Canada

RCT Dutasteride + AS v placebo + AS

n = 302

Low volume PCa T1c-T2A

Follow up 3 years

n = 147 Dutasteride + AS

Gleason 5–6

n = 155 placebo +AS

Multicentre

Power Y

REDEEM

Other interventional study designs Kazer 2011; USA Single subject pre-post (pilot) Lifestyle intervention Internet-based Follow up 5 weeks

n = 9 (planned 20) Two academic urology clinics Power N

PSA 6 11 ng/ mL< 50% tumour 48–82 years Dx < 14 months Life expectancy >5 years

Dx PCa All on AS Speaks English Computer access

Adherence to Rx

AS

Initial sample U

Randomisation U Blindness U Response 93/ 181 (51%) Retention 31/ 44 (70%) Lifestyle + AS 28/49 (57%) AS Randomisation U Blindness U Response U

ITT Analysis N

Retention 143/ 147 (97%) 148/ 155 (95%) Randomisation H

Validated SF-36

Lifestyle intervention in AS Primary outcome lifestyle change Adherence to Rx

Low External L Eligibility M Response L Measures H

Initial sample U ITT analysis N

Analyses L

Validated

Primary outcome time to progression ITT analysis – used last observation carried forward

High

MAX-PC

Univariate Y

External H

Eligibility H Response H

Baseline: Lifestyle + AS 51 (10); AS 56 (7) 12 month: Lifestyle + AS 51 (9); AS 56 (7) No differences on QoL outcomes Scores/p values not presented

Total MAX-PC scores at 3 years improved for Dutasteride (Placebo no change v Dutasteride decreased 1.5 pts) Fear of recurrence (score) improved for Dutasteride (Placebo no change v Dutasteride decreased 0.6 pts)

Blind Y

3/9 (33%)

Validated UCLA-PCI

Multivariate Y Data monitor Y ITT analysis Y

Measures H Analyses H

Primary outcome

Low

Uncertainty and QoL 14 outcomes 9 participants Univariate Y

External L Eligibility U Response L Measures H Analysis L

No change baseline to follow up for QoL

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

Table 3 (continued)

Non randomised experimental trial AS in PRIAS v Radical Rx in ERSPC

Follow up 6 & 12– 18 months

Screening detected

n = 266

PRIAS or

Response U

Validated

n = 129 AS

ERSPC

Retention U

CES-D

n = 137 Radical Rx (prostatectomy or radiotherapy) Power N

criteria

Primary outcome sexual function overlapping sample of AS with other PRIAS studies

Low

6 month:

External L

AS sig lower on depression vs RP or RT (combined); mean scores AS = 6; RP = 8; RT = 9 AS sig higher on anxiety vs RP or RT (combined);

STAI-6

SF-12 (MCS)

Eligibility L (different inception rules) Response U Measures H Analyses L

Mean scores AS = 36; RP = 30; RT = 34 No sig diff MCS: Mean scores AS = 54; RP = 54; RT = 53 12–18 month: no sig diff anxiety or MCS. AS sig lower on depression vs RP or RT (combined); Mean scores AS = 5; RP = 7; RT = 8

Instruments: BSI-53: Brief Symptom Inventory; CES-D: Centre for Epidemiological Studies – Depression; DCS: Decisional Conflict Scale; DT: Distress Thermometer; GTUS: Growth Through Uncertainty Scale; EORTC QLQ-C30: European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core Questionnaire; GAD-7: Generalised Anxiety Disorder; HADS: Hospital Anxiety & Depression Scale; IES: Impact of Events ScaleRevised; MAX-PC: Memorial Anxiety Scale for Prostate Cancer; PAIS: Health Care Orientation subscale of Psychosocial Adjustment to Illness Scale; PHQ-9: Patient Health Questionnaire; QoL-CS: Quality of Life – Cancer Survivors; SF-12: Medical Outcomes Study Short Form 12, contains Mental Component Summary (MCS) scale; SF36: Medical Outcomes Study Short-Form 36, contains Mental Component Summary (MCS) scale and Role Emotional (RE) subscale; SLS: Satisfaction with Life Scale; STAI: Spielberger State-Trait Anxiety Inventory; STAI-6: Spielberger State-Trait Anxiety Inventory-6; Studies: PCLT: Prostate Cancer Lifestyle Trial; PCOS (USA): Prostate Cancer Outcomes Study (USA), PCOS (AUS) New South Wales Prostate Cancer Outcomes Study (Australia); REDEEM: REduction by Dutasteride of clinical progression Events in Expectant Management; SPCG-4: Scandinavian Prostate Cancer Groups Study Number 4. Interventions: WW: Watchful Waiting, RP: Radical Prostatectomy, OET: other early treatment including radiotherapy, HT hormone therapy, Rx: treatment, RRx: radiotherapy + neoadjuvant HT, Dx: diagnosis. a Localised PCa: Steineck criteria.

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx 13

Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001

van den Bergh 2012; Netherlands

14

G. Carter et al. / Cancer Treatment Reviews xxx (2014) xxx–xxx

reported rather than simple differences in mean scores e.g. in reporting depression response or depression remission. Quality of life scores could also be contextualised by indirect comparison with community populations or populations with chronic medical conditions. Quality of life instruments that are able to generate utility scores (quality adjusted life years) would also provide the basis for making judgements about clinical significance as well as being the basis for cost-utility analyses. Future analyses should also include adjustment for potential confounding.’’We did not identify any studies reporting cost–effectiveness or cost–utility analyses, which should be included in future studies. Strengths and limitations Systematic searches were done according to the PRISMA standards. Inter rater reliability was high for identification of studies and data extraction and quality ratings were done by two independent raters using a standardised format. For the comparative studies the severity of disease (stage of prostate cancer) was essentially similar. The identified studies came from western countries with no coverage of non-western countries or low income countries. Studies in languages other than English or French were not identified. The results in the long term are uncertain because there are few studies of psychological wellbeing in AS populations with long term follow-up. The results are also limited because most comparative studies do not account for men who initially choose Active Surveillance but later opt for early intervention for reasons of adverse impact on psychological wellbeing rather than signs of disease progression. The interpretation of the findings was limited by the heterogeneity of the measures used and the outcomes reported. There was also considerable heterogeneity in the treatment condition of interest, which may affect the generalisability of the results. The older studies of WW (rather than AS) are an important specific example of the heterogeneity of treatment condition(s) studied, although the results indicated that WW also had little or no adverse impact on psychological wellbeing when compared to the active treatments of the day. Conclusions For patients with localised prostate cancer the offer and acceptance of Active Surveillance as a treatment option is not likely to be associated with any substantial adverse effect on wellbeing as measured by psychological symptoms, decisional distress, mental functioning or of quality of life. This information could be conveyed to patients with localised disease as part of the informed consent process for treatment selection. Since there seems to be no greater risk to psychological wellbeing, clinicians might be more inclined to offer Active Surveillance as a specific treatment option and patients might be more confident in selecting Active Surveillance when offered. Conflict of interest All authors have declared that they have no conflicts of interest in regards to this manuscript. Acknowledgments The study was made possible thanks to a grant from the Hunter Translational Cancer Research Unit (HTCRU) and the Priority Research Centre for Cancer (PRC Cancer), University of Newcastle, Australia; and the general support of the Calvary Mater Newcastle.

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Please cite this article in press as: Carter G et al. Wellbeing during Active Surveillance for localised prostate cancer: A systematic review of psychological morbidity and quality of life. Cancer Treat Rev (2014), http://dx.doi.org/10.1016/j.ctrv.2014.11.001