Physical Activity and Mortality in Cancer Survivors: A Systematic Review and Meta-Analysis

Abstract

The role of physical activity (PA) in cancer prevention is well recognized, with recent publications by the World Cancer Research Fund/American Institute for Cancer Research (1) and the 2018 Physical Activity Guidelines for Americans Report highlighting its importance to global health (2). Since the mid-2000s, there has been an exponential increase in studies evaluating the link between PA and survival outcomes that has resulted in some reviews on this topic (3). Although published reviews have explored the relationship between PA and survival (cancer-specific or all-cause mortality) following breast (4–9), colorectal (6,10), or all cancer (11,12), to date there have been no systematic reviews and meta-analyses examining all available cancer sites (including all-cancer as well as specific cancer sites) with cancer-specific and all-cause mortality outcomes. In addition, cardiovascular disease (CVD) is receiving increasing research attention as a leading cause of mortality for those with cancer. Yet, despite the known benefits through PA on CVD risk and survival, there are no available reviews evaluating cardiovascular mortality following any cancer.

In part, as a consequence of the exponential growth in PA and cancer survival epidemiological research, the momentum behind endorsing and promoting PA in the prevention and management of cancer has also grown (13). Concurrently, however, concerns have been raised about whether there is sufficient evidence to support the benefits of PA participation for all people with cancer or, alternatively, whether the evidence supports benefit through PA only for specific cancer types or subgroups within cancer types (that is, is dependent on sex, body mass index (BMI), menopausal status, or subtypes within a specific cancer). In addition, the extent to which the evidence can guide recommendations around PA domain (ie, total, recreational [leisure time], occupational, household) and dose of PA and for whom is unclear (14). Hence, there is a need for rigorous review of the rapidly evolving evidence base. As such, the primary objective of this systematic review and meta-analysis was to evaluate the association between prediagnosis and postdiagnosis PA and survival (primary outcomes: cancer-specific mortality, all-cause mortality, and CVD mortality) for all cancer and by specific cancer sites by using data from all available observational epidemiologic studies and randomized, controlled trials. Secondary objectives included assessing these associations by sex, BMI, menopausal status, and colorectal cancer subtype; evaluating the associations between different domains of PA (ie, total, recreational [leisure time], occupational, household) and survival outcomes; and determining the dose-response relationship between PA and cancer survival.

Methods

This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (15). Additionally, the protocol was registered in PROSPERO (registration number: CRD42018103290).

Results

Literature Search

We identified 15 760 records from our database search, five from PubMed e-alerts, and 31 through other sources such as reference lists, relevant review articles, and literature summary documents maintained by authors (Figure 1). After removing duplicates, 11 996 titles or abstracts remained and 967 were eligible for full-text screening. Full-text screening by two independent reviewers resulted in 97.5% agreement on inclusion or exclusion (kappa = 0.857). A total of 136 studies remained for inclusion in this systematic review and meta-analysis.

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Figure 1.

Flow diagram showing inclusion and exclusion of studies. PA = physical activity.

Primary Results

Figures 2 and ​and33 display forest plots of the summary hazard ratios for the highest vs lowest amount of prediagnosis and postdiagnosis PA for all cancers and specific cancer sites on cancer-specific mortality and all-cause mortality, respectively. Evidence from 136 studies contributed to findings showing reduced hazards of mortality for those in the highest vs lowest levels of prediagnosis and/or postdiagnosis total or recreational PA for all cancers combined (cancer-specific mortality: hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.79 to 0.86, and HR = 0.63, 95% CI = 0.53 to 0.75, respectively). Statistically significantly reduced hazards were also found for 11 cancer types depending on timing of PA (prediagnosis and postdiagnosis) and mortality outcome (cancer-specific and all-cause mortality). Specifically, higher prediagnosis PA was protective against cancer-specific mortality following breast, colorectal, hematologic, liver, lung, and stomach cancer, and higher postdiagnosis PA was protective against cancer-specific mortality following breast, colorectal, and prostate cancer (Figure 2). For all-cause mortality, higher prediagnosis PA was protective against breast, colorectal, hematologic, and prostate cancer, and higher postdiagnosis PA was protective following breast, childhood, colorectal, gynecologic, glioma, hematologic, kidney, lung, prostate, and stomach cancer (Figure 3). Breast and colorectal cancer sites had the largest number of contributing studies, and results suggest that greater reductions were observed for postdiagnosis PA both for cancer-specific and all-cause mortality (HR = 0.58–0.63) compared with mortality reductions observed with prediagnosis PA (HR = 0.80–0.86). Summary estimates did not differ by time scale (Supplementary Table 1, available online), and thus healthy cohorts and cancer survival cohorts were combined in the results. Further, removal of randomized, controlled trials did not change the results (data not shown).

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Figure 2.

Summary hazard ratios for the highest vs lowest levels of prediagnosis and postdiagnosis physical activity and cancer-specific mortality by cancer site (each estimate denotes a separate meta-analysis performed; if only one estimate is present, then no meta-analyses were conducted and the individual point estimate is reported). ^aRefs. (25,26,28,29,31,34–39,41,42,44–46,48–50,52,54,55,57,59,62–64,66–71). ^bRefs. (29,72). ^cRefs. (29). ^dRefs. (28,31,73–75,78,80,81,83–85,89,91–93,96,97,100–102,105,106,108). ^eRefs. (26,28,31,113,114,117–120,122–124,128,129). ^fRefs. (29,31). ^gRefs. (29,31,132,143,145). ^hRefs. (29,31). ⁱRefs. (25,26,29,137–139). ^jRefs. (29,31). ^kRefs. (28,29,31). ^lRefs. (25,26,28,29,31). ^mRefs. (142). ⁿRefs. (25,26,29,31,147–150). ^oRefs. (29,31,151–154,157–159). ^pRefs. (25,26,29,31). ^qRefs. (33,51,55,58). ^rRefs. (9,76,79,80,82,88,89,93,94,96,100,104,108). ^sRefs. (113,115,116,118,120,122). ^tRefs. (32). ^uRefs. (139). ^vRefs. (155–157,159). CI = confidence interval.

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Figure 3.

Summary hazard ratios for the highest vs lowest levels of prediagnosis and postdiagnosis physical activity and all-cause mortality in cancer survivors by cancer site (each estimate denotes a separate meta-analysis performed; if only one estimate is present, then no meta-analyses were conducted and the individual point estimate is reported). ^aRefs. (60). ^bRefs. (77,78,80,81,83–86,89,91,92,96,97,100–102,105,108,110). ^cRefs. (113,118–120,122–124,128–130). ^dRefs. (27). ^eRefs. (132,144–146). ^fRefs. (32,137,138). ^gRefs. (27,142). ^hRefs. (157,159). ⁱRefs. (27). ^jRefs. (33,43,51,55,56,58). ^kRefs. (9,33,76,79,80,82,87–89,94–96,100,103,107–109). ^lRefs. (112). ^mRefs. (33,113,115,116,118,120,122,126,127,131). ⁿRefs. (30). ^oRefs. (33,111,134,146). ^pRefs. (135). ^qRefs. (136,139). ^rRefs. (139). ^sRefs. (140,141). ^tRefs. (33,155–157,159). ^uRefs. (30). CI = confidence interval.

When considering the association between PA and CVD mortality and given the small number of studies, prediagnosis and postdiagnosis PA were combined to create a single estimate. The summary hazard ratios for all-cancer (n = 3), childhood cancer (n = 1), and colorectal cancer (n = 4) were 0.60 (95% CI = 0.50–0.73), 0.89 (95% CI = 0.49–1.61), and 0.60 (95% CI = 0.40–0.91), respectively. No cancer sites were found to have statistically significant increased mortality hazards (for any mortality outcome) associated with higher levels of PA (Supplementary Table 2, available online).

After visual examination of funnel plots and P values from the Begg and Egger tests, there was evidence for publication bias only for postdiagnosis PA and colorectal cancer-specific mortality (P < .05) (results not shown).

Dose-Response Analyses

We restricted the analysis of dose-response to breast cancer studies because few studies examined these associations for other cancer sites. There was a linear association between prediagnosis PA dose and all-cause mortality (P for nonlinearity = .53) (Figure 4C). Evidence of nonlinear associations was found (P for nonlinearity <.05) between prediagnosis and postdiagnosis PA and breast cancer-specific mortality (Figure 4, A and B, respectively) and postdiagnosis PA and all-cause mortality (Figure 4D). As seen in Figure 4B, the dose-response curve for postdiagnosis PA and all-cause mortality shows the largest reductions in mortality. Compared with no recreational PA, 5, 10, 20, 30, and 65 MET hours per week reduced all-cause mortality by 22%, 43%, 59%, 69%, and 108%, respectively. The steep reductions in mortality seen in Figure 4, A, B, and D, become less pronounced when PA dose is 10–15 MET hours per week or greater. The upper bounds of Figure 4C are less precise because of few contributing studies at higher levels of PA.

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Figure 4.

Random-effects dose-response curves for recreational physical activity in breast cancer survivors. A) Prediagnosis physical activity and breast cancer-specific mortality (n = 7 sets of data from six studies); B) postdiagnosis physical activity and breast cancer-specific mortality (n = 7 sets of data from six studies); C) prediagnosis physical activity and all-cause mortality (n = 5 sets of data from four studies); D) postdiagnosis physical activity and all-cause mortality (n = 8 sets of data from seven studies). MET = metabolic equivalent.

Discussion

In this first ever analysis, to our knowledge, of the association between PA and cancer survival that included all cancer sites, we found evidence from 136 studies conducted to date for improved survival outcomes for all cancer and 11 cancer sites associated with prediagnosis or postcancer diagnosis PA. Although the most consistent and strong evidence for a role of PA in cancer survival was found for breast and colorectal cancer, there is also clear evidence for improved prostate cancer-specific survival with postdiagnosis PA. In addition, there is emerging evidence for a beneficial effect of prediagnosis PA on cancer-specific survival for liver, lung, hematologic, esophageal, and stomach cancers. Compared with prediagnosis PA, postdiagnosis PA was associated with greater reductions both in cancer-specific and all-cause mortality, with greater than 30% reductions in hazards for all-cause mortality observed in studies of all cancer, breast, colorectal, female reproductive, glioma, kidney, lung, prostate, and stomach cancers (HR = 0.58–0.76).

This study extends the results found in previous meta-analyses of PA and cancer survival (5,6,8–12), with our results for breast and colorectal cancer similar in magnitude to those previously reported (4–6,10) (prediagnosis and postdiagnosis PA HR = ∼ 0.80 and 0.60, respectively, for cancer-specific and all-cause mortality). Findings reported here also indicate that PA contributes to survival benefits for prostate, lung, liver, hematologic, stomach, esophageal, and female reproductive cancers. Conversely, there was no evidence of harm from higher PA levels, even for cancers associated with poor prognosis (eg, lung cancer) or melanoma, which is the only cancer site for which higher levels of PA have been associated with higher risk of development.

Using data from studies involving women with breast cancer, we found a nonlinear relationship between increasing postdiagnosis PA levels and breast cancer-specific and all-cause mortality hazards, up to about 10–15 MET hours per week. This level is consistent with approximately 150 weekly minutes of moderate-intensity PA or 75 weekly minutes of vigorous-intensity PA and fits with the amount of PA recommended by the World Health Organization for healthy adults (160). This amount of PA is also typically endorsed and recommended by international cancer and clinical groups for those with cancer (13). Our findings also suggest that the clinical relevance of any potential survival benefit accrued through PA levels beyond 15 MET hours per week becomes less clear.

Questions remain regarding what represents the optimal dose, domain, and timing of activity for people with cancer and what these associations are for specific cancer sites or population subgroups. Findings from this meta-analysis show that there is clear evidence that postdiagnosis PA is an important independent prognostic factor distinct from prediagnosis activity levels. In addition, there is some preliminary evidence from three RCTs that exercise during treatment is also an important predictor of mortality outcomes (95,107,136). PA is also beneficial, irrespective of menopausal status, BMI, and sex, although being overweight or obese may attenuate the survival benefit. These findings highlight the need to combine weight (particularly fat mass) loss and PA interventions postcancer for those with BMIs greater than 25 kg/m². Currently, there are insufficient data to support specific recommendations related to domain and dose of activity. For example, from a survival perspective, these epidemiologic findings support a PA dose of at least 10 METs, but not whether that dose is accumulated through recreational, transportation, occupational, or household activity, or mixed mode (aerobic vs resistance vs combined exercise) or specific intensity (moderate vs vigorous vs mixed). Nonetheless, findings are sufficiently compelling to support additional epidemiologic research, particularly on understudied cancer sites, subgroups within cancer sites, and more comprehensive measurement of PA (including during and posttreatment and domain, type, intensity, duration, and frequency). Further, these findings support the need for adequately powered, randomized, controlled exercise interventions that seek to evaluate the impact of modifying recreational PA on cancer outcomes (161–164).

The magnitude of the effect of PA on cancer-specific and all-cause mortality outcomes ranged from 0.46 to 1.19 for prediagnosis PA and cancer-specific survival, whereas for postdiagnosis activity the range was narrower and stronger (0.57–0.79 for cancer-specific survival). The range of effect sizes observed was similar for prediagnosis and postdiagnosis activity when considering all-cause mortality outcomes. For prediagnosis activity, estimates ranged from 0.47 to 0.92, and for postdiagnosis, the range was 0.37–0.96. Of interest, however, was that for cancer sites for which there were greater than 10 contributing point estimates (which occurred for all cancers combined, breast, colorectal, and prostate cancers), there was greater consistency of the evidence. This range of effect sizes for cancer-specific survival was reduced to 0.80–0.90 for prediagnosis PA and 0.62–0.70 for postdiagnosis PA, and for all-cause survival, the range was 0.80–0.82 for prediagnosis PA and 0.58–0.63 for postdiagnosis PA. Hence, as the evidence base is accumulating, despite differences in study populations, study designs, and PA assessment methods, there is remarkable consistency of the effects of prediagnosis and postdiagnosis PA across various cancer sites.

Despite the exponential increase in the number of studies conducted on this topic since the mid-2000s, there is still a paucity of evidence for most cancer sites with only breast, colorectal, and prostate cancers approaching the number of studies required per site for meta-analyses by site and within population subgroups. To understand whether current differences observed in effect size are cancer specific or due to imprecision, more research beyond these top three cancer sites is needed. Additional limitations of this meta-analysis include the heterogeneous PA assessment methods. We mitigated, as much as possible, the impact of different PA assessment methods by selecting, wherever possible, point estimates expressed in units of MET hours per week. In addition, differences in adjustment for confounding and examination of effect modification also make comparisons across studies more challenging and can adversely influence the precision of summary estimates reported. We examined this issue with our quality assessment of the 136 included studies, which determined that these studies, overall, had high quality of conduct, adding credibility to the findings reported here.

We were unable to examine the associations between PA and cancer recurrence, progressions, or other cancer outcomes because of the heterogeneous definitions used across the source studies. Likewise, an interest in precision exercise oncology is to examine how cancer population subgroups, defined by clinical or pathologic characteristics, respond to PA (165). To date, few studies have examined these clinicopathologic subgroups to identify which populations might benefit more from PA. With additional research on this topic and the prerequisite that future studies follow standardized definitions of outcomes (eg, STEEP guidelines) and comprehensively report patient and tumor characteristics, analyses by specific outcomes will also be possible and highly informative (166). Finally, future studies are needed that use the highest quality of PA assessment with objective and self-report measures and the reporting in MET hours per week to permit additional evaluations of the dose-response effects in other cancer sites.

In summary, we found strong evidence that PA before or after cancer diagnosis was associated with statistically significant decreased hazards of cancer-specific and all-cause mortality in at least 11 different cancer sites. In addition, we found that hazard of CVD mortality among cancer survivors was also reduced with PA. As such, these findings confirm the importance of promoting PA after cancer and suggest that in doing so, there is huge potential for patient and public health gain through PA.

Funding

There was no funding source for this study.

Notes

Affiliations of authors: Division of Medical Oncology, Tom Baker Cancer Centre (WYC) and Department of Cancer Epidemiology and Prevention Research (CMF, CRS), CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada; Departments of Oncology and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada (CMF, WYC); Institute of Health and Biomedical Innovation, School of Public Health and Social Work, Queensland University of Technology, Brisbane, Australia (SCH).

CMF, SCH, and CRS designed and conceptualized the study; CRS conducted the literature search and eligibility review, abstracted the study details and results, contacted authors for additional details, conducted the analysis, prepared the tables and figures, and drafted the study methods and results; CMF wrote the final paper with input from SCH and WYC. WYC also provided input on subgroup analyses. All authors reviewed and approved the final draft. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

The authors declare no competing interests.

The authors thank Maryah Liepert for conducting the title and abstract screening and Nathaniel Minichiello, Rebecca Urbat, and Renée Kokts-Porietis for being the second reviewers for full-text screening. We also thank all the authors who provided us unpublished data on request. We also acknowledge Cancer Council Queensland for fellowship funding for SCH.

Supplementary Material

References