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Physical Activity Decreases the Risk of Cancer Reclassification in Patients on Active Surveillance: A Multicenter Retrospective Study - Full-Text Article

Background: Physical activity (PA) is associated with favorable outcomes in prostate cancer (PCa) patients. We assessed its effect on the risk of PCa reclassification (PCaR) during active surveillance.

Methods: Anthropometric, demographic, and clinical data concerning men diagnosed with a low-risk PCa and initially managed with active surveillance at the two participating institutions were retrospectively collected. The Physical Activity Scale for the Elderly (PASE) was used for patients’ self-assessment of their daily exercise and their consequent stratification into three groups: sedentary (PASE ≤ 65), moderately active (65 < PASE < 125), active (PASE ≥ 125). Kaplan–Meier model was used to evaluate the predictive role of PA on PCaR, computed at 2, 5, 10 years after diagnosis; differences between lifestyle groups were assessed using the log-rank and uni-/multivariable Cox analyses applied to identify predictors of reclassification.

Results: Eighty-five patients were included in the analysis, with a median age of 66 years (IQR: 59–70); 16% were active, 45% were former smokers, and 3 presented with metabolic syndrome (MetS). Prostate-specific antigen (PSA) density was 0.12 (IQR: 0.07–0.15); 34 men showed a PSA doubling time <10 years. The Median PASE score was 86 (IQR: 61.5–115.8): 24 patients were sedentary, 46 moderately active, and 15 active. At a median follow-up of 37 months (IQR: 14–53), 25% of patients experienced PCaR. These were less physically active (PASE score 69.3 vs 87.8; p = 0.056) and presented with significantly smaller prostates (46 ml vs 50.7 ml; p = 0.001) and a higher PSAD (0.14 vs 0.10; p = 0.019). At 2 years, the risk of reclassification was 25 ± 5%, while it was 38 ± 7% at both 5 and 10 years. The risk was significantly different in the three PA groups (Log Rank p = 0.033). PASE score was the only independent predictor of PCaR (HR: 0.987; 95%CI: 0.977–0.998; p = 0.016).

Conclusions: PA influences PCa evolution, as increasing levels are associated with a significantly reduced risk of tumor reclassification among patients undergoing active surveillance.

INTRODUCTION

Prostate cancer (PCa) represents a major healthcare concern worldwide, with over 191,000 estimated new cases in the United States in 2020.1 Since the introduction of prostatespecific antigen (PSA) screening, its incidence has risen dramatically but we have also witnessed a considerable stage/risk migration, with up to 67% of men diagnosed with limited-volume, low-grade diseases of uncertain biologic significance.2 Considering the remarkable morbidity associated with prostate surgery and radiation,3 most patients with low-risk cancer are nowadays managed expectantly.4 However, about one-quarter of men reclassify to higher-risk disease within 3 years after commencing active surveillance (AS) and nearly 50% within 5 years.5

Since surveillance not only reduces PCa burden for the individual but also represents a cost-effective treatment option for the healthcare system,6 there is growing interest in identifying modifiable factors that influence disease progression as this will lead to valuable forms of tertiary prevention. According to meta-analytic data, intense physical exercise increases the quality of life and decreases physiological distress in men with PCa, while its efficacy in preventing disease reclassification is still debated:7-11 we assessed whether physical activity (PA) levels could affect this risk in patients undergoing AS.

MATERIALS AND METHODS

Patients and dataset After institutional board approval, we identified men diagnosed with low-risk PCa and initially managed with AS12 at two participating institutions within the study period (January 2006 to September 2019). Patients lost to followup and those who voluntarily discontinued surveillance were excluded. Informed consent was obtained at the time of the scheduled appointments/visits.

Medical charts were reviewed and the following variables collected in a purpose-built dataset:

  • patients’ characteristics (age, race, body mass index [BMI]), smoking habit (number of cigarettes smoked, duration and eventual smoke cessation), and comorbidities at the time of diagnosis
  • baseline prostate volume (PV), total PSA and density (PSAD)
  • PSA doubling time (PSADT)
  • possible PCa reclassification (PCaR) due to tumor upsizing (>2 positive cores at follow-up biopsies), upgrading, and/or clinical upstaging12
At the time of the last scheduled visits, we provided each enrolled patient with a validated PASE (Physical Activity Scale for the Elderly) questionnaire for the self-assessment of his daily PA:13 this brief and easily scored survey combines information on leisure, household and occupational activities and was specifically designed to assess daily energy expenditure in epidemiologic studies of persons in their 60s and older. Men were asked to recall the average PA during the whole period of AS. The reported scores allowed for PA stratification into three groups: sedentary (PASE ≤ 65), moderately active (65 < PASE < 125), active (PASE ≥ 125).13

Active surveillance inclusion criteria and follow-up schedule Only men with >10 years life-expectancy diagnosed with an ISUP grade 1, ≤2 positive cores, clinical-stage T1c-2a, PSA ≤ 10 ng/mL, and a PSA density <0.2 were deemed eligible for surveillance12 and follow-up visits were scheduled according to PRIAS (Prostate Cancer Research International Active Surveillance) protocol: PSA tests every 3 months, visits every 6, biopsies at 12, 48, and 84 months.12

Study objectives The primary objective was to investigate the association between PA and tumor reclassification while on AS. Other possible predictors of this undesirable outcome were assessed as secondary endpoints.

Statistical analysis Means and standard deviations were calculated and reported for continuous variables and frequencies and proportions for categorical variables Chi square and Mann–Whitney tests were applied to compared categorical and continuous variables, respectively.

Kaplan–Meier method was performed to evaluate the predictive role of PA on PCaR, computed at 2, 5, 10 years after diagnosis; the log-rank test was used to assess statistically significant differences between lifestyle groups.

Univariable and multivariable Cox regression models were performed to identify predictors of tumor reclassification. For all tests, the significance level was set at a p value of <0.05. Statistical analysis was performed using the Statistical Package for Social Science v. 25.0 (IBM, Somers, NY, USA).

RESULTS

Overall, 85 Caucasian patients were included in the analysis: 16% were active smokers, 45% were former smokers, with a median age of 66 years (IQR: 59–70) and BMI of 25.3 (IQR: 23.5–27). At the time of diagnosis, 7 (8%) were obese, 3 (3%) diabetic, 45 (53%) presented with hypertension, and 18 (21%) with hypercholesterolemia (Table 1); MetS was diagnosed in 3 (3%) cases. At the time of diagnosis, median PSAD was 0.12 (IQR: 0.07–0.15) and, during follow-up, 34 (40%) patients showed a PSADT < 10 years. Median PASE score was 86 (IQR: 61.5–115.8): 24 (28%) men were sedentary, 46 (54%) moderately active, and 15 (18%) active. At a median follow-up of 37 months (IQR: 14–53), one out of three patients experienced PCaR and these were less physically active (PASE score 69.3 vs 87.8; p = 0.056) and presented with significantly smaller prostates (PV 46 ml vs 50.7 ml; p = 0.001) and a higher PSAD (0.14 vs 0.10; p = 0.019) compared to those who did not present reclassification (Table 1).

Table 1 Patient characteristics and outcomes according to prostate cancer reclassification (PCaR).
table_1.png

At 2 years, the risk of reclassification was 25 ± 5% while it was 38 ± 7% at both 5 and 10 years (Fig. 1A). The risk was significantly different in the three PA groups (Log Rank p = 0.033), being the highest in the sedentary one (Fig. 1B). At Cox regression analysis, PASE score was the only independent predictor of PCaR (HR: 0.987; 95% CI: 0.977–0.998; p = 0.016) (Table 2).

Table 2 Univariable and multivariable Cox regression analyses to identify predictors of prostate cancer reclassification.
table_2.png

DISCUSSION

All active treatments of PCa are associated with a non-negligible risk of adverse effects including urinary incontinence, erectile dysfunction, cystitis, and proctitis which can result in a substantial reduction in quality of life.3 Since it has been estimated that up to two-thirds of all newly diagnosed cases are low-grade slow-growing tumors with a marginal death rate, men diagnosed with a low-risk PCa are increasingly managed with AS. This paradigm involves regular monitoring with an intent to proceed to curative treatments in case of disease reclassification,4 which occurs to half of men undergoing surveillance within 5 years from diagnosis. In our cohort, the discontinuation rate was 25% at a median follow-up of 37 months (IQR: 14–53), in line with other large series on AS.5

Substantial research interest exists in low-cost, harmless interventions that might defer or even avoid exposing patients to curative-treatment-related toxicity and morbidity.

There is grounded evidence that PA influences tumor evolution, as increasing levels are associated with a reduced risk for tumor diagnosis, recurrence, and disease-specific death;14 in particular, observational studies have already shown that vigorous exercise after diagnosis is most consistently associated with favorable oncologic outcomes.15-19 For these reasons, exercise has been included in the ASCO (American Society of Clinical Oncology) Clinical Practice Guidelines on PCa. However, its role in the setting of AS is still debated. While three retrospective studies found no7 or weak association,8,9 the Prostate Cancer Lifestyle Trial proved that 12 months of moderate exercise, together with a low-fat vegan diet and stress management strategies, effectively limited the rising of serum PSA levels (4% reduction in the intervention group vs 6% increase in the control group; p = 0.016)10 and significantly reduced the odds of reclassification at 2 years (5% vs 27%; p < 0.5).11 In the present study, patients that required a curative treatment were less physically active than those in the nonPCaR group, although the difference did not reach statistical significance (p = 0.056). According to our KM model, the risk of tumor reclassification was significantly dissimilar in the three PASE groups (Log Rank p = 0.033), being the highest in the sedentary group (Fig. 1B). This finding was further confirmed at Cox regression analysis which identified the PASE score as the only independent predictor of cancer reclassification (HR: 0.987; 95%CI: 0.977–98; p = 0.016) (Table 2). Our findings are consistent with previous trials indicating that increasing participation in recreational PA only slightly reduces the risk of PCa progression while a remarkable inverse association with vigorous exercise exists.8

fig_1.png
Fig. 1 Kaplan-Meier analyses. A prostate cancer reclassification probabilities over time, (B) predictive role of physical activity on the risk of prostate cancer reclassification.

Although the different mechanisms underlying this protective role are yet to be elucidated, it is postulated that a number of inter-related pathways may contribute.14 First, exercise seems capable of modulating gene expression: the GEMINAL study pointed out that 3 months of diet and daily brisk walking increased telomere length20 and modulated the expression of genes involved in protein intracellular transportation, metabolism, and phosphorilation.21 Likewise, Magbanua et al. showed that engaging in ≥3 h per week of high-intensity training increased the expression of specific anti-oncogenes in prostate tissues.22 Second, increased levels of PA could improve insulinresistance and interfere with the levels of various circulating tumor-promoting proteins (such as insulin-like growth factor-1 which has both mitogenic and antiapoptotic effects), as testified by the increased apoptotic rate among LNCaP cells incubated with serum drawn from daily trained low-risk-PCa-patients.10 Third, intensive physical exercise hypertrophies skeletal muscles and reduces adiposity, thus decreasing blood levels of proinflammatory adipokines.23 Other pathways such as reduced oxidative stress inflammation and increased immune surveillance have also been hypothesized.14

Since the World Health Organization defines PA as any body movement produced by skeletal muscles that require energy expenditure,14 we asked the patients to self-assess it using the PASE. This brief and easily scored survey was specifically conceived to assess PA in epidemiological studies of persons in their 60s and older and was already used in other studies investigating the association between daily energy expenditure and prostatic diseases.24,25 It was systematically developed and validated and combines information on leisure, household, and occupational activities. Although a risk of overestimation exists when daily energy expenditure is self-assessed through questionnaires because of the social desirability bias, Washburn et al. already provided evidence of a significant correlation between the PASE score, general health status, and specific physiologic measures such as age, sickness profile score, strength, static balance, and resting heart rate.13

Smoking habit is another modifiable factor linked to prostatic diseases as it was not only associated with lower urinary tract symptoms and benign prostatic hyperplasia26 but also to PCa progression and death.27 Its specific role in the setting of surveillance is still unclear though Burton et al. demonstrated that current smokers undergoing AS had higher PSA levels and faster yearly increase than never-smokers.28 According to our analysis, however, smoking status did not predict the risk for PCaR (p = 0.931), in line with other studies assessing the role of different lifestyle characteristics on disease progression.8,9

Many other non-modifiable factors have been examined in order to assess their possible association with tumor reclassification during surveillance.29-32 However, their relevance in clinical practice is limited as these could help to select patients eligible for an expectant management but will not lead to valuable forms of tertiary prevention. Age, race, PV, total PSA at baseline are some of the most broadly investigated. It is widely accepted that young age at diagnosis is associated with a higher risk of PCa progression29 since more aggressive disease stems from the increased genetic burden in early-onset tumors. A significant inverse correlation between age and the risk of AS discontinuation has also been described,9 in contrast with our findings (Tables 1 and 2). Although large prospective studies supporting the safety of AS have included few African American men and albeit these patients may be more likely to harbor aggressive elements, the preponderance of evidence demonstrates that surveillance remains a viable and safe treatment option also in this specific racial group.31 Furthermore, PSAD is a strong predictor of upgrading and upstaging at final pathology30 and it also predicts tumor reclassification during AS:32 among other nonmodifiable factors, it plays a key role in selecting PCa patients eligible for expectant management strategies.

There is grounded evidence that PSAD is a strong predictor of upgrading and upstaging at pathology examination after radical prostatectomy30 and it also plays a role in foreseeing tumor reclassification while in AS,32 as confirmed by our univariate Cox regression analysis (Table 2).

MetS is a complex, highly prevalent, pandemic disorder. Together with its main components (central obesity, insulin resistance/diabetes, dyslipidemia, and hypertension) it is strongly associated with PCa aggressiveness.33,34 Its specific role in the setting of AS is still under investigation and results from a recent retrospective study based on 3662 patients eligible for surveillance but treated with radical prostatectomy showed that this disease was independently associated with 42% increased risk of upgrading (OR: 1.42, 95%CI: 1.19–1.69; p = 0.0001).35 Interestingly, in our cohort, its prevalence was extremely limited (3%), compared to Italian standards (≃20%)33,34 and this could be explained by the increased risk of MetS patients being diagnosed with a high-risk PCa33,34 which would contraindicate expectant management options.

The first limitation of the present study is its retrospective nature and, mainly, the retrospective assessment of the average PA during the whole period of AS. Moreover, the limited size of the sample may not have provided adequate power and a sub-analysis of patients based on their level of PA is unsuitable. In addition, all the included patients were Caucasian and this may limit the generalizability of our findings. Furthermore, PA data were selfreported and thus subject to the social desirability bias. Although PASE score was proven to be a reliable tool to assess daily work-related and leisure activities and was found significantly associated with objective indirect physical exercise measures like peak oxygen uptake, resting systolic blood pressure, and balance,13 it does not assess the intensity of PA and exercise; further studies should consider the use of the broadly available personal accelerometers and heart rate monitors.

CONCLUSIONS

Post-diagnosis PA influences PCa evolution, as increasing levels are associated with a reduced risk of tumor reclassification among patients undergoing AS. If confirmed by larger randomized controlled trials, embracing an active lifestyle may represent a valuable form of tertiary prevention, a low-cost and harmless intervention capable of deferring or even avoiding curative-treatment-related toxicity and morbidity.

Compliance with ethical standards

Conflict of interest: The authors declare no competing interests.
Ethics approval and consent to participate: The retrospective study was performed in accordance with the Declaration of Helsinki. Review board approval was acquired; informed consent for the retrospective study was obtained from all the participants.
Informed consent: Informed consent for the submission and publication of the study was obtained from all individual participants included.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Authors: Aldo Brassetti,1 Mariaconsiglia Ferriero,1 Giorgio Napodano2, Roberto Sanseverino,2 Fabio Badenchini,3 Gabriele Tuderti,1 Umberto Anceschi,1 Alfredo Bove,1 Leonardo Misuraca,1 Riccardo Mastroianni,4 Flavia Proietti,4 Michele Gallucci,1,4 Giuseppe Simone1

  1. Department of Urology, IRCCS “Regina Elena” National Cancer Institute, Rome, Italy
  2. Department of Urology, “Umberto I” Hospital, Nocera Inferiore, Italy
  3. Department of Urology, Istituto Nazionale Tumori di Milano, Milan, Italy
  4. Department of Urology, “Sapienza” University of Rome, Rome, Italy
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Prostate Cancer and Prostatic Diseases; Received: 15 October 2020 / Revised: 13 April 2021 / Accepted: 23 April 2021 / Published online: 18 May 2021

Read an Editorial on this Article: Role of Physical Activity and Its Link with Lower Rates of Progression in Men on Active Surveillance - Editorial