Effect of the Rehabilitation Program, ReStOre, on Serum Biomarkers in a Randomized Control Trial of Esophagogastric Cancer Survivors

Susan A Kennedy, Stephanie L Annett, Margaret R Dunne, Fiona Boland, Linda M O'Neill, Emer M Guinan, Suzanne L Doyle, Emma K Foley, Jessie A Elliott, Conor F Murphy, Annemarie E Bennett, Michelle Carey, Daniel Hillary, Tracy Robson, John V Reynolds, Juliette Hussey, Jacintha O'Sullivan, Susan A Kennedy, Stephanie L Annett, Margaret R Dunne, Fiona Boland, Linda M O'Neill, Emer M Guinan, Suzanne L Doyle, Emma K Foley, Jessie A Elliott, Conor F Murphy, Annemarie E Bennett, Michelle Carey, Daniel Hillary, Tracy Robson, John V Reynolds, Juliette Hussey, Jacintha O'Sullivan

Abstract

Background: The Rehabilitation Strategies Following Esophagogastric cancer (ReStOre) randomized control trial demonstrated a significant improvement in cardiorespiratory fitness of esophagogastric cancer survivors. This follow-up, exploratory study analyzed the biological effect of exercise intervention on levels of 55 serum proteins, encompassing mediators of angiogenesis, inflammation, and vascular injury, from participants on the ReStOre trial.

Methods: Patients >6 months disease free from esophagogastric cancer were randomized to usual care or the 12-week ReStOre program (exercise training, dietary counselling, and multidisciplinary education). Serum was collected at baseline (T0), post-intervention (T1), and at 3-month follow up (T2). Serum biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA).

Results: Thirty-seven patients participated in this study; 17 in the control arm and 20 in the intervention arm. Exercise intervention resulted in significant alterations in the level of expression of serum IP-10 (mean difference (MD): 38.02 (95% CI: 0.69 to 75.35)), IL-27 (MD: 249.48 (95% CI: 22.43 to 476.53)), and the vascular injury biomarkers, ICAM-1 (MD: 1.05 (95% CI: 1.07 to 1.66)), and VCAM-1 (MD: 1.51 (95% CI: 1.04 to 2.14)) at T1. A significant increase in eotaxin-3 (MD: 2.59 (95% CI: 0.23 to 4.96)), IL-15 (MD: 0.27 (95% CI: 0 to 0.54)) and decrease in bFGF (MD: 1.62 (95% CI: -2.99 to 0.26)) expression was observed between control and intervention cohorts at T2 (p<0.05).

Conclusions: Exercise intervention significantly altered the expression of a number of serum biomarkers in disease-free patients who had prior treatment for esophagogastric cancer.

Impact: Exercise rehabilitation causes a significant biological effect on serum biomarkers in esophagogastric cancer survivors.

Clinical trial registration: ClinicalTrials.gov (NCT03314311).

Keywords: biomarker analysis; cancer rehabilitation; cancer survivorship; cardiorespiratory fitness; esophagogastric cancer; exercise training; multidisciplinary rehabilitation treatment.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Kennedy, Annett, Dunne, Boland, O’Neill, Guinan, Doyle, Foley, Elliott, Murphy, Bennett, Carey, Hillary, Robson, Reynolds, Hussey and O’Sullivan.

Figures

Figure 1
Figure 1
Multiplex ELISA analysis of Vascular injury panel. Data at immediately post 12-week intervention (Time 1; T1) and at 3-month follow-up (Time 2; T2) was analyzed using linear regression models, adjusting for baseline values (T0). A significant increase in serum (A) ICAM-1 and (B) VCAM-1 expression was observed at T1 (*p ≤ 0.05).
Figure 2
Figure 2
Exercise intervention increases IP-10 and Eotaxin–3 expression. Data at immediately post 12-week intervention (Time 1; T1) and at 3-month follow-up (Time 2; T2) was analyzed using linear regression models, adjusting for baseline values (T0). A significant increase in serum (A) IP-10 expression was observed at T1 between control and intervention cohorts while a significant increase in (B) Eotaxin-3 was observed at T2 (*p ≤ 0.05).
Figure 3
Figure 3
Exercise intervention increases IL-27 expression at T1. Data at immediately post 12-week intervention (Time 1; T1) and at 3-month follow-up (Time 2; T2) was analyzed using linear regression models, adjusting for baseline values (T0). A significant increase in serum IL-27 expression was observed at T1 between control and intervention cohorts (*p ≤ 0.05).
Figure 4
Figure 4
Exercise intervention decreases bFGF expression at T2. Data at immediately post 12-week intervention (Time 1; T1) and at 3-month follow-up (Time 2; T2) was analyzed using linear regression models, adjusting for baseline values (T0). A significant decrease in serum bFGF expression was observed at T2 between control and intervention cohorts (*p ≤ 0.05).
Figure 5
Figure 5
Exercise intervention increases IL-15 expression at T2. Data at immediately post 12-week intervention (Time 1; T1) and at 3-month follow-up (Time 2; T2) was analyzed using linear regression models, adjusting for baseline values (T0). A significant increase in serum IL-15 expression was observed at T2 between control and intervention cohorts (*p ≤ 0.05).

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