Review of systematic reviews of non-pharmacological interventions to improve quality of life in cancer survivors

1This is a systematic review of reviews and evidence synthesis of non-pharmacological interventions in cancer survivors.

2Longer term studies are needed and studies of greater methodological quality that adopt similar reporting standards.

3Definitions of survivor varied and more studies are needed for different types of cancer, and specifically for patients who have poor quality of life.

4More studies are needed that investigate educational, online and multidisciplinary team-based interventions.

5This review has some limitations in the methodology. Studies not in English and grey literature were not included. This was a review of reviews: we did not review individual studies focused on specific cancers or stage, and we did not reassess the quality of the primary studies included in each review.

6Advances in public awareness, early detection and improved treatments mean that more people are now living with and beyond cancer. For example, Cancer Research UK reports that 50% of people diagnosed with cancer in England and Wales survive 10 years or more, and survival rates have doubled over the last 40 years. This group of survivors includes people at various stages of active treatment, and those in remission, who are gradually restoring their social and occupational roles.

7A significant proportion of cancer survivors experience poor quality of life (QoL). The main causes of poor QoL include depression, anxiety, distress, fear of recurrence and lower levels of social support; impacts on relationships, family and social function; and psychological and social needs, and problems coping. The process of diagnosis and treatment is traumatic and disruptive. It is not unusual for patients with cancer to experience distress. Common experiences for those living with and beyond cancer include reduced physical ability, fatigue, changes in sexual activity and developing other medical conditions that affect function for many years. If a person is suffering from fatigue, depression or anxiety, they are understandably less motivated to visit friends or engage in social activities; the strain on marital relationships may lead to a loss of support: 25% of people who experience difficulties have broken up with their partner as a result of cancer. Thus, the effects of cancer extend beyond the diagnostic and active treatment phases. This review aims to gather the evidence for practitioners, patients and their carers about effective non-pharmacological interventions to improve QoL in cancer survivors. We sought to summarise the effectiveness of non-pharmacological interventions in cancer survivors as part of an (National Institute of Health Research) NIHR-funded programme development grant to inform the design and delivery of a full programme grant.

8This review of reviews examined existing systematic reviews of non-pharmacological interventions that include information on QoL of those living with and beyond cancer.

9The study included any systematic reviews that explicitly reported randomised controlled trials (RCTs). Inclusion criteria were organised in accordance with the patient, intervention, comparison, outcome (PICO) reporting structure (see table 1). The population of interest was people living with and beyond cancer, who were aged 18 years or more, and who had received their cancer diagnosis as adults.

10We defined non-pharmacological interventions as those that did not involve any drug or medicine, but they could include educational, behavioural, psychosocial approaches or physical activity; we excluded complementary and alternative therapies as defined by the NHS Choices resource. However, we included physical activity and psychological approaches that were part of yoga-based interventions after consulting with patients in the development of the review. Comparators were not specified for the purpose of the inclusion criteria of the review of reviews, but comparators reported in the original reviews were considered in the analysis.

11The primary outcome was QoL defined by physical, psychological and social functioning. We reported on studies that used an established and validated measure of global or overall QoL; some of these are cancer-specific. In the literature, the terms ‘Quality of Life’ and ‘Health Related QoL’ are used interchangeably; therefore, both are included under the term ‘QoL’ in this review. The study settings included any healthcare venue, such as hospital inpatient or outpatient services and community services, and also included home and remote e-technology-based interventions.

12We searched the following databases: PubMed, Cochrane Central, EMBASE, MEDLINE, Web of Science, the Cumulative Index to Nursing and Allied Health Literature, and PsycINFO. The final search was from inception to May 2017 and is shown in online supplementary annex 1. We consulted experts in the field to assess completeness of the list of identified reviews, and where necessary contacted authors to secure the full-text versions.

13Two authors (MD, JD) independently screened all titles and abstracts of studies identified by the search strategy against inclusion and exclusion criteria, and when eligibility was determined the full text was read. Discrepancies around inclusion were resolved by discussion or in consultation with a third author when required (KB). We searched the reference lists of all included reviews to identify any further relevant reviews. The research team was not blinded to authors. Citations were downloaded and managed in an EndNote library.

14Two authors (EM, EH) independently extracted data from each of the eligible reviews into a purpose-built, predesigned, structured template. The data extraction forms were then summarised in a table and reviewed independently by a third reviewer (KB). Extracted data included the following information:Publication details: author, year, title, journal, country and format of publication.Study characteristics: number of primary studies, total number of participants, range of publication dates, gender, age range of participants and socioeconomic data, primary cancer site, length of time since final cancer treatment, and type of treatment.Intervention design and evaluation: setting, description of the intervention and its components: physical components, psychosocial components, educational components; duration of intervention, follow-up, number of treatment contacts, type of practitioner providing treatment, mode of delivery of intervention, and any outcomes.Documents: availability of treatment manuals.Results: main outcome measures, secondary outcome measures, narrative findings, adherence levels, patient satisfaction and effect sizes against intervention components.

15Publication details: author, year, title, journal, country and format of publication.

16Study characteristics: number of primary studies, total number of participants, range of publication dates, gender, age range of participants and socioeconomic data, primary cancer site, length of time since final cancer treatment, and type of treatment.

17Intervention design and evaluation: setting, description of the intervention and its components: physical components, psychosocial components, educational components; duration of intervention, follow-up, number of treatment contacts, type of practitioner providing treatment, mode of delivery of intervention, and any outcomes.

18Documents: availability of treatment manuals.

19Results: main outcome measures, secondary outcome measures, narrative findings, adherence levels, patient satisfaction and effect sizes against intervention components.

20The methodological quality of the systematic reviews was evaluated using Assessing Methdological Quality of Systematic Reviews (AMSTAR), a measurement tool for the assessment of multiple systematic reviews that has good reliability and validity (table 2). The AMSTAR checklist used can be found at https://amstar.ca/Amstar_Checklist.php.

21The intervention components were listed, followed by a narrative synthesis. This included understanding components of the interventions, exploring patterns of findings across studies and within primary reviews, and giving greater weight to studies of higher quality in the interpretation of the findings, especially if there were contradictions between the findings of reviews. Ultimately, the purpose was to put into text format the key findings from the most robust evidence available, to guide treatment and future research recommendations. The synthesis set out reported effect sizes across studies, means and SD. Meta-analysis was not undertaken, due to heterogeneity of methods, outcomes and absence of reported effect sizes (10 reviews did not provide effect sizes). The publications were segmented into those reporting meta-analyses to which the greatest weighting was given in the synthesis; some reviews did not undertake or report meta-analyses but rather reported each study, trends and the range of effect sizes; a third group reported no effect sizes but provided narrative statements.

22Patients and carers (and respective organisations) were involved in the design and development of the programme development grant application (from which this review is one output). Patients and carers attended all the steering group meetings and were an integral part of the research team, commenting on and critiquing the inclusion and exclusion criteria, outcome selection, and the acceptability and likely value of interventions. As part of the steering group, they received and commented on study progression, emergent findings and reports. They are integral to the dissemination plans, including sharing the publication, but also helping craft lay summaries of the overall research project and key findings. A public-patient representative (EH) performed the data extraction together with research and clinical colleagues, and coauthored and edited the review. Public-patient representatives were also part of the steering group and informed the design and delivery of the review.

23Electronic database searches yielded 14 430 unique reviews. From this 290 were included from the title search, followed by 47 from the abstract search. After scrutinising the full texts, 21 of eligible published reviews were included in this review (figure 1). The 26 excluded studies are listed in an online supplementary file. The quality scores are shown in table 2.

24The types of interventions, settings, cancer type, measures of QoL and the key narrative findings are reported in table 3.

25The number of patients included in the reviews ranged from 262 to 7164. Thirteen reviews covered mixed tumour groups, seven specifically focused on breast cancer and one on prostate cancer.

26Face-to-face delivery of interventions was often combined with online delivery (three reviews); others included telephone communication (five reviews) and printed information (two reviews). Four reviews included interventions that provided supplementary compact discs, manuals or video tools. Two reviews were from inpatient rehabilitation. None of the reviews reported the use of structured manuals, and interventions were often not fully described or broken down into different components, nor was there attention to a mechanism or theory of change.

27Ten of the reviews focused on physical interventions, and three focused on yoga; four reviews were of psychosocial or behavioural interventions; and one review focused on online interventions including connecting patients and online education (see tables 3 and 4). One review compared multidimensional versus monodimensional interventions, and one tested multidisciplinary rehabilitation models. Finally, one review focused on the effects of expressive writing. The duration and frequency of the interventions varied greatly from a single 20 min session to 60 weekly sessions.

28The most common components of physical interventions were aerobic exercise and resistance/strength training. Psychological education and cognitive behavioural therapy (CBT) were the most commonly used psychological and educational interventions. Peer support was often used as a psychological and a behavioural intervention. Components of the interventions were thematically organised into two groups (see table 4 for a more detailed itemisation): biological or physical actions (19 types of activity or diet change), and psychological, behavioural or educational (24 types of intervention about mind and body, including CBT, mindfulness-based stress reduction, psychosexual therapy, supporting existing coping methods, emotional support, relaxation, psychotherapy and psychosocial therapy, and interventions focusing on social support, guided imagery, self-management, use of peer support, bibliotherapy, telephone and web-based interventions, and return to work interventions).

29Meta-analyses were reported in 11 reviews and the effect sizes (as reported in the original reviews) are tabulated (table 5). Of six publications providing meta-analyses of physical activity (not including yoga), all found convincing positive associations for studies testing response between 1 and 26 weeks post-treatment. Long-term effects were not tested by all, although Fong et al and Zeng et al did show persistent effects at 6 months and a year, respectively. One review showed uncertain outcomes at 3–6 months, although shorter and longer term outcomes were favourable. This review showed equivocal effects when the intervention group was compared with the control group, once adjusted for QoL and covariates at baseline. The two meta-analyses of yoga interventions showed positive effects, as did a review of CBT. There was no evidence of benefit in QoL following patient education and behavioural interventions.

30Two reviews reported effect sizes from individual studies but did not undertake meta-analyses. Mewes et al’s review of multidimensional rehabilitation included 10 studies, 9 of which had global QoL outcomes; of these, 7 showed benefit, with effect sizes ranging from 0.04 to 0.99 (no CIs reported). Fors et al’s review included six RCTs only, four of which included a QoL measure; two of these showed positive effect sizes (ranging from 0.56, 95% CI 0.09 to 1.03; 0.63, 95% CI: 0.11 to 1.18); one showed improved and one a worsening of QoL as a non-standardised mean score. Five reviews did not report meta-analyses or effect sizes; mostly these provided mean change scores or narrative statements. On the whole these gave a mixed picture, often resorting to subgroup analysis by cancer type or different dimensions of QoL.

31Cramer et al’s high-quality review of 6–12 weeks of yoga in patients with breast cancer showed a large increase in general QoL, a finding that was consistent with reviews by Buffart et al and Culos-Reed et al, which scored lower on the AMSTAR. Mishra et al’s high-quality review of people with multiple cancers, 50% of whom had breast cancer, found that physical activity had a positive effect on global QoL at 3 and 6 months of follow-up, as did Smits et al’s high-quality review of endometrial cancer and Gerritsen and Vincent’s moderate-quality review of mixed cancers. Fong et al’s high-quality review of breast cancer, colorectal, endometrial and mixed cancers similarly found physical interventions improved general QoL on average at 13 weeks of follow-up (range 3–60 weeks). Bourke et al’s review of prostate cancer found personalised lifestyle interventions helpful, and McAlpine et al’s review of mixed cancers including prostate found benefit of activity following medication treatment.

32There was inconsistency across the reviews with regard to the types of exercise interventions that were most effective. Fong et al found aerobic plus resistance training to be significantly more effective than aerobic training alone on many aspects of QoL. However, Zeng et al’s moderate-quality review suggested that single types of exercise interventions (general aerobic, yoga or tai chi) were more effective at increasing QoL at 4–52 weeks after intervention; half of the studies assessed interventions between 8 and 12 weeks. Duijts et al’s study of patients with breast cancer found only small effects of physical activity on QoL (at 8–26 weeks after intervention), and Spence et al’s study of mixed but mostly patients with breast cancer reported evidence that physical activity improved overall QoL, but only four of ten trials maintained the intervention and only a fifth of trials seemed to assess outcome at 3 months and beyond. Zeng et al’s review of patients with breast cancer found small but positive benefits of physical activity on overall QoL. Galvão and Newton’s review of mixed cancers gave preliminary evidence of positive benefits on a Modified Rotterdam QoL measure, but no overall effects were reported. However, Spark et al’s review of patients with breast cancer showed that the impact of physical activity on QoL was not convincing. Although Spark et al did not report effect sizes, two of the studies in that review included QoL measures, both of which reported effect sizes in the original papers: one showed positive benefits on Functional Assessment of Cancer Therapy—General (FACT-G) and Functional Assessment of Cancer Therapy—Breast Cancer at 8 months (effect sizes 9.8–13.4), but not at 24 months of follow-up; the other showed no significant effects on FACT-G overall, but when the cancer-specific FACT-G was assessed at 6-month follow-up, there was benefit (4.9, 0.2–9.6). Ferrer et al’s study of breast, prostate, endometrial, head and neck, ovarian cancers and lymphoma found small but positive effects of exercise at long-term follow-up on multiple measures of QoL. The efficacy of the interventions appeared greater with shorter duration treatments, and if exercise was supervised. Aerobic intensity predicted improvements in QoL.

33Only one of the reviews of psychological and behavioural interventions was classified as high quality: Huang et al’s meta-analysis of patients with breast cancer showed that mindfulness-based stress reduction programmes had a significant effect in improving overall QoL. Duijts et al’s review, on the other hand, concluded that behavioural techniques such as problem solving, stress management and CBT did not significantly improve health-related QoL. Nevertheless, Fors et al’s review of patients with breast cancer showed CBT improved QoL. No meta-analysis or overall effect sizes were reported due to heterogeneity. Further support for CBT came from Osborn et al’s review of group and individually delivered CBT for mixed cancers; individual interventions were more effective than group-based treatment. CBT showed both short-term and long-term improvements in QoL. Five primary papers in one review assessed the effect of social and emotional support as an intervention, four of them finding no effect, and one reporting a significant improvement in QoL on one measure. There was no evidence that psychosocial education increased QoL.

34Khan et al’s high-quality review of patients with breast cancer included just two studies, only one of which provided low-level evidence that multidisciplinary rehabilitation improved participation and social activities. The other showed no significant effects. Mewes et al’s moderate-quality review of breast and other cancers treated by inpatient multidisciplinary rehabilitation demonstrated no differences between multidimensional and single-dimension interventions, with benefits of both on physical outcomes. Bourke et al’s review of prostate cancer survivors examined the effectiveness of multidisciplinary approaches based on findings from three primary studies. They concluded that such interventions showed small benefits for QoL, typically when they involved a smaller number of health professionals, thus allowing more focused tailoring of the interventions.

35The effectiveness of online educational interventions was unclear. McAlpine et al’s review of lung, prostate, head and neck and a smaller number of mixed cancers showed equivocal findings. There were benefits to online education and message boards, but mixed effects for interactive websites, and worse outcomes from one study on email interventions. One interesting review was of expressive writing interventions, but this found no benefit on QoL, although small effects would be undetected. Individuals with low levels of emotional support appeared to benefit more than others.

36Five reviews included reports of adverse events. Of four studies in Buffart et al’s review, one reported back spasm in a yoga class in a patient with a history of back problems. In Cramer et al’s review of three studies reporting adverse events, there was one adverse event (back spasm) in 138 patients. McAlpine et al’s review included two studies that reported adverse effects of online support groups. One of these reported transient helplessness, anxiety, confusion and depression at 6 months, while the other showed poorer QoL despite high levels of reported satisfaction. Zeng et al’s review of 25 trials found one study with reports of exercise-related lymphoedema. In Mishra et al’s review, six studies reported adverse effects including lymphoedema, gynaecological complications and influenza in the exercise group. One study reported back, knee and hip problems. Three participants in one study reported thrombosis and infection following exercise interventions. Another study found hip pain, sciatica, arm discomfort (n=4), knee discomfort (n=10), ankle discomfort (n=3), and foot discomfort (n=8) with asymptomatic ischaemia and conduction problems on ECG. A further study reported lung metastases, pulmonary embolism and palpitations. Another study reported soft tissue injury following exercise, and cholecystitis following stroke. Cancer recurrence, although not a direct effect of interventions, was common and another reason to stop participation in the research.

37Twenty-one reviews were included and showed a lack of definitive and consistent evidence across 465 primary studies, of which 362 were RCTs. In part this is explained by substantial variation in study designs and outcome measures used to indicate QoL. All systematic reviews of physical activity demonstrated improved overall QoL, but few studies assessed long-term outcomes beyond 3 months, and even fewer assessed outcomes beyond a year after the intervention. More focused research and a consistent approach are required to explore the effect on the subdomains of QoL. A higher quality review suggests that aerobic plus resistance training provides maximum improvements in QoL. There was more evidence of physical rather than psychological or other types of interventions.

38One of the included reviews for psychological or behavioural interventions was of high quality. CBT is effective for improving QoL in the short and long term, especially when provided as an individual intervention. There is not much evidence to support comparative effectiveness of intervention modalities such as group versus individual, monodimensional versus multidimensional or multidisciplinary; further work is needed to examine these different approaches. Given the accessibility of social media and its popularity, the findings that email contact was related to poorer QoL need further investigation; although interactive websites were beneficial, the overall findings about digital interventions were equivocal.

39The current review has some limitations in the methodology. Studies not in English and grey literature were not included due to time constraints as the review was undertaken as part of a programme development grant to inform the design of a future research programme application.

40We encountered some methodological limitations in included reviews. Some used multiple outcomes and often had a very broad understanding of QoL and used diverse measures of QoL. There was no consistent reporting standard.

41We did not consider outcomes such as well-being or the multiple subdomains of QoL to avoid the risk of generating findings due to multiple testing in smaller subsamples in underpowered analyses. Some reviews included few primary papers. We examined the sample sizes of RCTs included in reviews and whether there seemed to be any relationship with AMSTAR ratings. We found no obvious relationship, given AMSTAR scores refer to review quality rather than the quality of or sample size of individual RCTs. A review of primary RCTS might help to better understand and report robust findings from RCTs with large and adequate sample sizes, findings which may otherwise be less visible in a review of reviews.

42We found little overlap between reviews (tabulation available on request), reflecting their specific inclusion and exclusion criteria and interest in very specific interventions and cancer types. We did not evaluate the methodological quality or bias of the original studies within each systematic review. Ten reviews planned to assess publication bias; three of these could not perform any specific tests of bias due to small samples. Consequently seven studies tested for publication bias. Three of these reported that publication bias was not significant. Four reviews reported significant publication bias suggesting caution in assuming there is definitive evidence for exercise and CBT.

43The physical and psychosocial concerns of patients at different time periods of the cancer experience will vary greatly, and interventions effective at one stage may not be suitable for another. Most reviews defined ‘survivors’ as those who had completed active treatment before the onset of the study. Some specified a time frame, from immediately after surgery to 15 years after active treatment. One review defined survival as being from diagnosis onwards. Another included terminal stages of cancer. The majority of the reviews incorporated studies combining patients during and post-treatment. These differing definitions of living with and beyond cancer make comparison difficult, and a standardised approach to trials and reporting of studies is needed.

44Interventions were offered to patients based on their diagnosis of cancer, rather than low QoL, which may have led to underestimation of potential beneficial effects. Future research should consider the effectiveness of interventions targeting people living beyond all types of cancer and with poor overall QoL.

45Systematic reviews of patients with cancer and their QoL showed that effective interventions included physical activity, CBT and mindfulness-based stress reduction training. Personalised lifestyle interventions showed promise, as did social and emotional support. Educational and information provision appears ineffective, and there were few studies of electronic interventions. Currently, there is no standard study design, outcome selection or reporting convention adopted across these reviews. No single intervention can be recommended to those patients with a poor QoL following cancer treatment as interventions were not targeting poorer QoL, but cancer survivors in general.