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Exercise medicine as adjunct therapy during RADIation for CAncer of the prostaTE to improve treatment efficacy – protocol for the ERADICATE study: a phase II randomised controlled trial

BMC Cancer volume 25, Article number: 160 (2025) Cite this article

Abstract

Background

Tumour hypoxia resulting from inadequate perfusion is common in many solid tumours, including prostate cancer, and constitutes a major limiting factor in radiation therapy that contributes to treatment resistance. Emerging research in preclinical animal models indicates that exercise has the potential to enhance the efficacy of cancer treatment by modulating tumour perfusion and reducing hypoxia; however, evidence from randomised controlled trials is currently lacking. The ‘Exercise medicine as adjunct therapy during RADIation for CAncer of the prostaTE’ (ERADICATE) study is designed to investigate the impact of exercise on treatment response, tumour physiology, and adverse effects of treatment in prostate cancer patients undergoing external beam radiation therapy (EBRT).

Methods

The ERADICATE study is a two-arm, parallel group, phase II randomised controlled trial. Fifty patients diagnosed with prostate cancer will be randomised (1:1) to either an exercise intervention group (EBRT + exercise) or a usual care control group (EBRT only) for the duration of treatment (i.e., 2 to 8 weeks of EBRT). The exercise intervention will be clinic-based and supervised by exercise physiologists. Exercise sessions will include moderate- to vigorous-intensity aerobic and resistance exercise conducted two to three times per week for 60 min per session. Treatment response (primary outcome) will be assessed by change in tumour apparent diffusion coefficient derived from magnetic resonance imaging. Secondary outcomes will include acute and chronic changes in tumour perfusion and hypoxia, treatment-related toxicity, body composition, physical function, and quality of life. Survival outcomes will be assessed as exploratory endpoints. Study measurements will be conducted at baseline (i.e., prior to commencing EBRT), immediately after completion of EBRT, and during follow-up at 3 months as well as 2 years and 5 years post treatment. The study was approved by the Human Research Ethics Committee at Edith Cowan University.

Discussion

The ERADICATE study will investigate exercise as a novel therapeutic approach for sensitising prostate cancer to EBRT by targeting a known mechanism of treatment resistance. Improving treatment efficacy of EBRT with exercise may result in better patient outcomes clinically, while also addressing adverse effects of treatment and quality of life in prostate cancer patients.

Trial registration

The study was registered on the Australian New Zealand Clinical Trials Registry (ACTRN12624000786594) on 26/06/2024.

Background

Hypoxia is a common feature of many solid tumours and a major limiting factor in radiation therapy that contributes to treatment resistance [1]. In prostate cancer, tumour hypoxia is an established prognostic marker that has been associated with a more aggressive tumour phenotype and shorter time to biochemical recurrence [2,3,4,5]. Moreover, local disease persistence after treatment with radiation therapy for localised prostate cancer has been shown to increase the risk of developing metastases [6]. Consequently, patients require further treatment to manage the recurring or progressing cancer, resulting in additional adverse effects and negatively impacting quality of life.

The tumour vascular microenvironment plays an important role in facilitating the therapeutic effect of localised and systemic cancer treatments such as chemo- and radiation therapy [1, 4, 7]. Poorly regulated and rapid angiogenesis is a characteristic feature of cancer that results in malformed and dysfunctional tumour blood vessels [8, 9]. As a result of the structurally and functionally abnormal vascular network, tumour perfusion becomes heterogeneous, which diminishes the supply of oxygen to some or all parts of the tumour, ultimately resulting in hypoxic areas [10, 11]. Importantly, hypoxic cancer cells are more resistant to radiation therapy than cancer cells with adequate oxygenation [4]. Hence, strategies that aim to improve perfusion and reduce hypoxia in the tumour microenvironment have great potential to sensitise cancer cells to radiation, thereby enhancing the response to treatment and improving patient outcomes.

Research in animal models of prostate cancer has shown that exercise can impact vascularisation, modulate perfusion, and reduce hypoxia in the tumour microenvironment [12]. For example, treadmill exercise in male rats has been shown to acutely increase tumour perfusion by up to 200% and reduce hypoxia by as much as 50% [13, 14]. Studies have also shown that repeated treadmill exercise as well as wheel running over the course of several weeks can increase tumour blood flow and reduce hypoxia [15, 16]. Imaging studies revealed that blood flow was uniformly increased throughout the tumour microenvironment in animals that exercised, whereas tumours from sedentary control animals were heterogeneously perfused [15]. In addition, decreased fluctuations in tumour microvascular partial pressure of oxygen have also been observed after regular exercise, suggesting beneficial tumour vascular adaptations [16]. However, it is currently unknown if acute and chronic changes in tumour perfusion and hypoxia as well as tumour vascular adaptations beyond the immediate post-exercise window also occur in humans in response to exercise and whether such changes would translate to improved treatment outcomes for cancer patients.

The purpose of this study is to investigate exercise as a potential novel therapeutic approach for sensitising prostate cancer to external beam radiation therapy (EBRT) and thus enhance the efficacy of treatment in prostate cancer patients by improving blood flow and oxygen delivery to the tumour. Further, we will assess the impact of exercise on treatment-related adverse effects, physical function, body composition, and quality of life during and after radiation therapy. In addition, survival outcomes will be assessed as exploratory endpoints. We hypothesise that exercise will improve tumour perfusion and result in a reduction in hypoxia in the tumour microenvironment, which will sensitise cancer cells to radiation therapy and result in an enhanced treatment response.

Methods

Trial design

The ‘Exercise medicine as adjunct therapy during RADIation for CAncer of the prostaTE’ (ERADICATE) study is a two-arm, parallel group, phase II randomised controlled trial designed to investigate the effects of exercise on treatment efficacy (including possible underlying biological mechanisms associated with tumour perfusion and hypoxia) as well as patient-reported outcomes and treatment toxicity in prostate cancer patients undergoing EBRT. The study protocol was developed in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) 2013 statement [17]. A schematic overview of the study design is shown in Fig. 1, and the study measurements, outcomes, and schedule are summarised in Table 1. Assessments will be conducted at baseline (i.e., before the start of EBRT), postintervention (within 1 week after completion of EBRT), and 3 months after completion of EBRT. An additional assessment will be conducted after 4 weeks of EBRT in participants who have > 20 radiation fractions (patient-reported outcomes only). Follow-ups will be completed at 2 years and 5 years posttreatment (clinical endpoints only). Depending on the duration of the radiation therapy treatment, the exercise intervention (or control condition) will be 2 to 8 weeks. The study was registered on the Australian New Zealand Clinical Trials Registry (registration number: ACTRN12624000786594).

Fig. 1
figure 1

Study design. Abbreviations: MRI, magnetic resonance imaging; PSA, prostate-specific antigen.

Full size image
Table 1 Schedule of enrolment, interventions, and assessments
Full size table

Recruitment and eligibility criteria

Participants will be recruited by their treating oncologist or prostate cancer specialist nurse during initial consultation visits at hospitals and cancer treatment centres in Perth, WA, Australia. With permission of the patient, clinicians will refer potential participants to the study coordinator for eligibility screening. Patients can also self-refer if they become aware of the study through other channels such as the clinical trials registry.

Inclusion criteria

Individuals must satisfy the following criteria for study inclusion: (1) have a diagnosis of prostate cancer; (2) be scheduled for EBRT with curative intent (conventional, hypofractionated and stereotactic body radiotherapy); and (3) receive approval from their treating oncologist to participate in the study.

Exclusion criteria

Individuals are not eligible for the study if they meet any of the following exclusion criteria: (1) have had a previous radical prostatectomy; (2) engage in regular exercise, defined as undertaking structured (i.e., planned and individualised) aerobic or resistance exercise on 2 or more days per week within the past 3 months; (3) have an acute illness or any musculoskeletal, cardiovascular, or neurological disorder that is a safety concern for exercise testing or training; or (4) have any contraindication to magnetic resonance imaging (MRI).

Randomisation and blinding

Following confirmation of eligibility and informed consent, participants are enrolled in the study and undergo a baseline assessment (see Table 1 and ‘Measurements’ section below for details). After completion of the baseline assessment (including baseline imaging), participants are randomised to either the intervention group (radiation therapy + exercise) or the control group (radiation therapy only) using a 1:1 allocation ratio, with group allocation being stratified by treatment duration, that is, ≤ 5 or > 5 radiation fractions. The allocation sequence was computer-generated using an online software application (i.e., Sealed Envelope) [18] and comprises random permuted blocks with block sizes of 2 and 4 to reduce predictability. Moreover, randomisation will be performed in REDCap [19, 20] and, therefore, study investigators as well as research staff (including study coordinators and research assistants) are blinded to group allocation until after the baseline assessment. Investigators conducting MR image analysis will remain blinded to group allocation as well as the assessment timepoints throughout the study. Due to the nature of the intervention, trial participants will be aware of their group allocation.

Intervention and control group

Exercise session before and after treatment

To assess exercise-induced acute changes in tumour perfusion and hypoxia, MRI scans of the prostate will be performed immediately prior to and following a single exercise session. This assessment will be conducted before and after radiation therapy treatment. The exercise session will comprise 15 min of aerobic step exercise or cycling on a stationary ergometer (Ergoselect 1, Ergoline GmbH) at a target intensity of ≥ 70% of age-predicted maximal heart rate (calculated as 220–age [years]). Step exercise will be performed using a height adjustable (15–20 cm) aerobic step (Orbit Fitness). Heart rate will be continuously recorded during exercise using a heart rate monitor with chest strap (Polar H10, Polar Electro) and supplemented with a subjective rating of perceived exertion (RPE, 0–10 Borg scale) at the end of exercise (target RPE of 5–6) [21]. Further, pulse rate and blood pressure will be measured before and after exercise as well as before and after each MRI scan using an automatic blood pressure monitor (Welch Allyn ProBP 2000, Welch Allyn). The exercise session will be delivered face-to-face and supervised by an exercise physiologist to monitor fidelity and ensure participant safety.

Exercise program during treatment

The exercise intervention during radiation therapy treatment will consist of a progressive aerobic and resistance exercise program conducted in a clinic-based setting. Face-to-face 1-hour exercise sessions (including a 5-minute warm-up and cool-down) will be undertaken 2 to 3 times per week for the duration of treatment (i.e., 2 to 8 weeks). The exercise sessions will be planned around radiation therapy times to accommodate individual treatment schedules. All exercise sessions will be either individually supervised or conducted in small groups of up to 4 participants with an exercise physiologist. Moderate- to vigorous-intensity aerobic exercise (e.g., walking or cycling) will be performed at an intensity of 65–85% of age-predicted maximal heart rate (calculated as 220–age [years]) for 15–20 min per session, followed by 30–35 min of resistance exercise. The resistance exercise component of the program will include 6–8 machine-loaded and dumbbell exercises that involve major upper- and lower-body muscle groups, including leg press and leg curl, calf raises, chest press, seated row, lateral raises, triceps extension, and biceps curl. Each exercise will be performed for 2–3 sets at a load of 8–12 repetitions per set (i.e., 8–12 repetition maximum). The load will be increased by 5–10% when a participant can successfully complete 2 additional repetitions on the last set of an exercise for 2 consecutive sessions.

Control group

After randomisation, participants allocated to the control group will be advised to maintain their usual activities during treatment; no exercise prescription or recommendation will be provided to them during this period. However, following completion of their radiation therapy treatment, participants in the control group will undergo a similar individualised exercise program that matches the duration of their radiation therapy treatment (i.e., 2 to 8 weeks).

Measurements

Primary outcome

Response to radiation therapy

Tumour apparent diffusion coefficient (ADC) will be used as a surrogate marker to assess treatment response and will be measured before and immediately after radiation therapy as well as 3 months after completion of treatment using diffusion-weighted MRI. ADC has prognostic value in prostate cancer patients treated with radiation therapy, that is, patients with disease progression have lower mean ADC values [22] and changes in ADC values during treatment represent a reproducible biomarker to monitor the response to radiation therapy in prostate cancer [23,24,25]. All scans will be performed on the same 3 Tesla human MRI scanner (MAGNETOM Vida XT, Siemens Healthineers) using a standardised image acquisition sequence. MRI data analysis will be performed using syngo.via software (Siemens Healthineers).

Secondary outcomes

Tumour perfusion and hypoxia

Arterial spin labelling (ASL), using the flow-sensitive alternating inversion recovery method [26] will be acquired using a single-slice through the primary tumour to provide tumour perfusion estimates without requiring an intravenous contrast agent [27]. VERDICT MRI (Vascular, extracellular, and restricted diffusion for cytometry in tumours) is used to obtain vascular volume fraction estimates from diffusion MRI data [28, 29]. Oxygen-enhanced MRI (OE-MRI) will be used to assess tumour hypoxia using both Blood Oxygen Level Dependent (BOLD) and Tissue Oxygen Level Dependent (TOLD) measures. Quantitative R2* (for BOLD) and R1 (for TOLD) maps are acquired before and after the patient has been breathing 100% medical oxygen for five minutes.

These measurements will be conducted immediately before and after a single bout of exercise prior to commencing radiation therapy treatment to investigate acute responses to exercise. This pre- to post-exercise assessment will be repeated after completion of radiation therapy treatment to investigate chronic adaptations of the tumour vascular microenvironment in response to regular exercise; in addition, we will investigate moderating effects of the exercise program on acute responses in tumour perfusion and hypoxia. The pre- to posttreatment change in resting (i.e., pre-exercise) MRI parameters will be used as proxy for tumour vascular adaptations. All scans will be performed as described above and analysed using publicly available state-of-the-art software from the research community to calculate quantitative and semi-quantitative parameters of tumour perfusion and hypoxia in regions of interest. Exploratory analyses will be performed to investigate associations between tumour perfusion/hypoxia parameters and patient/tumour characteristics such as body composition, lesion size, or tumour grade.

Prostate-specific antigen

Serum prostate-specific antigen levels will be assessed before and after radiation therapy as well as 3 months after completion of treatment. Blood samples will be collected, processed, and analysed by a National Association of Testing Authorities accredited pathology laboratory.

Physical function

Physical function will be measured before and after radiation therapy using a series of standard tests. Assessments will comprise the 400-meter walk test for cardiorespiratory fitness [30], a 1-repetition maximum (1RM) chest press and leg press for upper and lower limb muscle strength [30], the 5-repetition sit-to-stand test as a measure of functional capacity [30], and the timed up-and-go test to assess mobility [31]. Tests will be performed in triplicate, except for the 400-meter walk and 1RM tests.

Body composition and anthropometry

Whole-body lean and adipose tissue mass, percent body fat, as well as appendicular skeletal muscle mass will be assessed before and after radiation therapy using dual-energy X-ray absorptiometry (Horizon A, Hologic) [32]. In addition, body weight and height will be measured using an electronic scale and stadiometer (Seca 763, Seca), respectively.

Treatment toxicity and quality of life

Treatment-related adverse effects and symptoms will be monitored using a set of validated questionnaires. These patient-reported outcomes will be assessed before and after radiation therapy and additional assessments will be conducted after 4 weeks of radiation therapy (only for patients with > 20 radiation fractions) as well as 3 months after completion of treatment. The assessments will include outcomes in health-related quality of life using the Medical Outcomes Study Questionnaire Short Form 36 [33], treatment-related adverse effects (including urinary, bowel, sexual, and hormonal symptoms) using the Expanded Prostate Cancer Index Composite as well as the International Prostate Symptom Score [34, 35], fatigue using the Functional Assessment of Chronic Illness Therapy – Fatigue Scale [36], and sleep quality using the Pittsburgh Sleep Quality Index [37].

Exercise compliance and physical activity

Attendance, adherence, and compliance, as well as tolerability of the exercise program will be assessed and recorded throughout the intervention period. Attendance is defined as the percentage of attended exercise sessions versus the total number of allocated exercise sessions based on the duration of radiation therapy. Adherence will be defined as the percentage of exercise sessions completed as prescribed (considering exercise volume and intensity) versus the number of attended exercise sessions. Compliance will be defined as the percentage of exercise dose completed versus the exercise dose prescribed [38, 39]. The reason(s) for non-attendance and non-adherence will be documented by the supervising exercise physiologist. Tolerability of the exercise program will be assessed by recording the rating of perceived exertion at each exercise session using the modified 0–10 Borg category-ratio scale [21]. In addition to the recorded exercise dose during each session, physical activity not performed as part of the exercise program (including that in the control group) will be self-reported and monitored using the short version of the International Physical Activity Questionnaire [40].

Adverse events

The incidence and severity of adverse events during exercise testing and training will be captured by the supervising exercise physiologist using a dedicated tracking log and identified through review of medical records. Adverse events will be actively monitored by investigators and graded using the Common Terminology Criteria for Adverse Events (version 5.0) [41].

Exploratory outcomes

Clinical endpoints

Biochemical recurrence and progression-free survival will be extracted from medical records and assessed at 2 years and 5 years after completion of radiation therapy.

Other measures

Demographics and medical history

Patient demographic information and medical history will be collected at baseline using a self-report questionnaire. Data pertaining to a patient’s cancer and treatment will be extracted from their medical records.

Cardiovascular measures

Resting pulse rate and blood pressure will be assessed before and after radiation therapy using an automatic oscillometric blood pressure monitor (Welch Allyn ProBP 2000, Welch Allyn). Three consecutive measurements will be performed on the non-dominant arm in the supine position after 5 min of rest, with 30 s between each measurement.

Sample size determination

Based on previous research [23,24,25], we calculated a standard deviation of change in ADC of up to 0.195 × 10−3 mm2 × s−1. Therefore, a sample size of 44 participants (22 per group) is required to detect a clinically meaningful between-group difference in ADC of 0.17 × 10−3 mm2 × s−1 with 80% power and a type I error probability of 0.05 (two-tailed). This sample size is also sufficient to detect significant differences in secondary outcomes of the study [42]. To account for 10% attrition, a total of 50 participants (25 per group) will be recruited.

Statistical analysis

Data will be analysed using IBM SPSS Statistics (IBM Corp) and/or R (The R Foundation). Normal distribution of data will be evaluated with the Shapiro-Wilk test. For baseline demographic and clinical data, descriptive statistics will be used to characterise each study group as well as the overall trial population. Continuous variables will be presented as means and standard deviations or medians and interquartile range, while categorical variables will be presented as frequencies and proportions. To compare MRI parameters (i.e., tumour perfusion and hypoxia) between pre- and post-exercise scans for acute changes, analyses will include paired t-tests or the Wilcoxon signed-rank test, as appropriate. Furthermore, correlation and regression analyses will be performed to examine the association between MRI parameters and patient/tumour characteristics. Linear mixed models or generalised linear mixed models with patient as random effect will be used to compare MRI parameters (including ADC), physical function, body composition, prostate-specific antigen, and patient-reported outcomes between groups over time; group and time will be included as fixed effects in the model. The Kaplan-Meier method with log-rank test will be used to analyse survival outcomes. In addition, Cox proportional hazard regression will be used to estimate the hazard ratio between study arms. All outcomes will be analysed using an intention-to-treat approach. Exercise adherence and compliance as well as adverse events will be analysed using descriptive statistics and reported accordingly. Between-group differences in adverse events will be assessed using the chi-square test or Fisher’s exact test. Tests will be two-tailed and considered statistically significant if P < 0.05.

Discussion

There is evidence from animal research to suggest that exercise may have additive, sensitising, or synergistic effects with radiation therapy, as well as systemic cancer treatments, that increase the effectiveness of treatment through modulation of tumour perfusion and hypoxia. However, this area of research has been mainly preclinical and is largely unexplored in the clinical setting. Increasing the effectiveness of existing and established cancer therapies may result in better treatment outcomes for patients. Alternatively, patients may derive the equivalent therapeutic effect at a lower treatment dose, for example, in cases where the dose must be reduced due to treatment-related adverse effects, when tumours are better accessible via improved vascularisation and enhanced perfusion. This research will provide novel insights into how exercise affects tumour physiology and the response to treatment as well as management of treatment toxicity in prostate cancer patients during and after EBRT.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

1RM:

1-repetition maximum

ADC:

Apparent diffusion coefficient

ASL:

Arterial spin labelling

BOLD:

Blood oxygen level dependent

DXA:

Dual-energy X-ray absorptiometry

EBRT:

External beam radiation therapy

EPIC:

Expanded prostate cancer index composite

ERADICATE:

Exercise medicine as adjunct therapy during RADIation for CAncer of the prostaTE

FACIT-Fatigue:

Functional assessment of chronic illness therapy – fatigue scale

IPAQ:

International physical activity questionnaire

IPSS:

International prostate symptom score

MRI:

Magnetic resonance imaging

OE:

Oxygen-enhanced

PSA:

Prostate-specific antigen

PSQI:

Pittsburgh sleep quality index

REDCap:

Research electronic data capture

RPE:

Rating of perceived exertion

SF-36:

36-item short form health survey

SPIRIT:

Standard protocol items: recommendations for interventional trials

TOLD:

Tissue oxygen level dependent

VERDICT:

Vascular, extracellular, and restricted diffusion for cytometry in tumours

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Acknowledgements

Not applicable.

Funding

Funding for grant IIG_FULL_2023_011 was obtained from World Cancer Research Fund (WCRF UK), as part of the World Cancer Research Fund International grant programme. This activity is supported by the Western Australian Future Health Research and Innovation Fund (Grant ID: WANMA/Ideas2023-24/10). Dr Oliver Schumacher was supported by a Cancer Council WA Post-Doctoral Research Fellowship (Award ID: 1228).

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Authors and Affiliations

  1. Exercise Medicine Research Institute, Edith Cowan University, 270 Joondalup Drive, Joondalup, WA, 6027, Australia

    Oliver Schumacher, Robert U. Newton, Colin Tang, Raphael Chee, David Joseph, Dennis R. Taaffe & Daniel A. Galvão

  2. School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia

    Oliver Schumacher, Robert U. Newton, Colin Tang, Raphael Chee, David Joseph, Dennis R. Taaffe & Daniel A. Galvão

  3. 5D Clinics, Claremont, WA, Australia

    Colin Tang & David Joseph

  4. Radiation Oncology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia

    Colin Tang

  5. GenesisCare, Joondalup, WA, Australia

    Raphael Chee

  6. Western Australia National Imaging Facility, University of Western Australia, Perth, WA, Australia

    Sjoerd B. Vos

  7. Envision Medical Imaging, Wembley, WA, Australia

    Ronny S. Low

Authors
  1. Oliver Schumacher
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  2. Robert U. Newton
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  3. Colin Tang
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  4. Raphael Chee
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  5. Sjoerd B. Vos
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  6. Ronny S. Low
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  7. David Joseph
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  8. Dennis R. Taaffe
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  9. Daniel A. Galvão
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Contributions

O.S., R.U.N., D.R.T., and D.A.G. developed the study concept and design. C.T., R.C., and S.B.V. contributed to the design of the study. C.T., R.C., and D.J. will recruit participants for the study. O.S., R.U.N., S.B.V., D.R.T., and D.A.G. will implement the study and oversee data acquisition. O.S., S.B.V., R.S.L., and D.R.T. will be responsible for data analysis. All authors will contribute to data interpretation. O.S. drafted the manuscript, and all authors contributed to the revision of the work. All authors read and approved the final version of the manuscript.

Corresponding author

Correspondence to Daniel A. Galvão.

Ethics declarations

Ethics approval and consent to participate

The study described in this protocol was approved by the Human Research Ethics Committee at Edith Cowan University (reference number: 2023-04149-SCHUMACHER). All participants are required to provide written informed consent to participate in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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Schumacher, O., Newton, R.U., Tang, C. et al. Exercise medicine as adjunct therapy during RADIation for CAncer of the prostaTE to improve treatment efficacy – protocol for the ERADICATE study: a phase II randomised controlled trial. BMC Cancer 25, 160 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-13555-9

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12885-025-13555-9

Keywords

BMC Cancer

ISSN: 1471-2407

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