A Review of Physical Activity in Pancreatic Ductal Adenocarcinoma: Epidemiology, Intervention, Animal Models, and Clinical Trials

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, and the increasing incidence of PDAC may be related to the prevalence of obesity. Physical activity (PA), a method known to mitigate obesity by increasing total energy expenditure, also modifies multiple cellular pathways associated with cancer hallmarks. Epidemiologic evidence has shown that PA can lower the risk of developing a variety of cancers, reduce some of the detrimental side effects of treatments, and improve patient’s quality of life during cancer treatment. However, little is known about the pathways underlying the correlations observed between PA interventions and PDAC. Moreover, there is no standard dose of PA intervention that is ideal for PDAC prevention or as an adjuvant of cancer treatments. In this review, we summarize relevant literature showing how PDAC patients can benefit from PA, the potential of PA as an adjuvant treatment for PDAC, the studies using preclinical models of PDAC to study PA, and the clinical trials to date assessing the effects of PA in PDAC.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease that became the third leading cause of cancer-related death in the US in 2020, and has an average five-year survival rate of less than 10% ¹. PDAC is projected to become the second leading cause of cancer-related death by 2030². Low survival rates of PDAC patients are often attributed to a combination of factors, including the absence of preventive measures, late stage diagnosis, and the lack of effective treatment options. Currently, no interventions to prevent PDAC are available. Therefore, understanding and preventing known risk factors is critical to the prevention of this deadly disease.

Obesity is a major risk factor for many cancers including PDAC ^3–6. A case-control study showed that the death rate from all cancers increased by 52% in men and 62% in women with a body mass index (BMI) greater than 40 kg/m² compared to normal subjects ⁷. Moreover, the relative risk of PDAC increased 1.12-fold for each 5 kg/m² increase in BMI ⁸ and the survival rate decreased in subjects whose BMI was over 25 kg/m² from the ages of 30 to 79 ⁹. These studies suggest that maintaining a healthy weight may reduce the risk of developing cancers associated with obesity, such as PDAC.

Increasing physical activity (PA) could be a practical approach for weight loss with the goal of modulating molecular mechanisms associated with decreasing tumor development and growth^10–13 to reduce cancer risk ^{12, 14, 15}. The intensity of PA in humans is expressed in metabolic equivalents of task (METs), defined as the energy it takes for an adult to sit quietly and is roughly equivalent to the expenditure of one kilocalorie per kilogram of body weight per hour ¹⁶. Activities that expend three to six METs, such as brisk walking, are considered “moderate activities,” and those that expend more than six METs, like running are considered “vigorous activities” ¹⁷. The World Health Organization guidelines recommend that adults (18–64 years) engaged in 150 minutes of moderate activity or 75 minutes of vigorous activity per week ¹⁷. On the other hand, cancer patients or survivors are recommended to exercise three times per week for about 30 minutes and perform resistance training twice a week for a minimum of 120 minutes of activity ¹⁸. However, for some cancer patients, achieving these recommendations can be difficult especially for those that develop of a secondary wasting disorder called cachexia.

Cachexia is a metabolic syndrome commonly found in PDAC patients that lowers their survival ^{19, 20}. Symptoms of cachexia include muscle and adipose tissue wasting, involuntary weight loss, reduced appetite, insulin resistance, and edema ²¹. Cachexia-related tissue muscle wasting, or atrophy, reduces the ability to perform physical activity or exercise ²². This atrophy is driven by a loss of muscle mass, myofiber size, muscle oxidative capacity and protein synthesis with a concurrent increase in protein breakdown ²². In preclinical studies, physical activity or exercise training counteracts muscle atrophy^{23, 24}. Studies in humans are small and less clear about the effectiveness of physical activity with or without nutritional supplementation on muscle wasting in cachexia^25–27. However, larger clinical trials, like the Norwegian MENAC study on exercise, nutrition, and anti-inflammatory medications, are under way in cachectic pancreatic cancer patients to examine the effects of a multimodal therapy on cachexia (EUCTR2013–002282-19). These trials aim to better understand PA outcomes, like improved muscle atrophy or increased patient survival ^{22, 28}.

Despite the recommended PA guidelines, it remains poorly understood whether PA: can benefit patients at risk of developing PDAC, be beneficial as an adjuvant treatment of PDAC, and be accurately modeled using preclinical models of PDAC. To investigate these knowledge gaps, we performed a literature search on Google Scholar and Pubmed using the following keywords: “physical activity”, “pancreatic ductal adenocarcinoma”, “pancreatic cancer”, “sports”, “leisure time physical activity” and “physical exercise” from 1995 to April, 2021. Moreover, to summarize the clinical trials in these setting to date, we searched the clinicaltrials.gov website, the World Health Organization (WHO) database, and the European Society of Medical Oncology (ESMO) using the following criteria: “physical activity” OR “exercise” AND “pancreatic cancer”. We summarize and discuss the studies that resulted from these searches in this review. We also highlight the most commonly utilized methods to study the effects of PA in the preclinical setting and the ongoing clinical trials conducted to explore the effects of PA on multiple aspects of PDAC. Additionally, we summarize the general findings of the pre-clinical and clinical studies in PDAC (Figure 1), bringing attention to the overlaps and gaps in research between them.

Figure 1:

Overview of how PA affects pre-clinical and clinical models. Created with Biorender.com

Pancreatic Cancer Risk Factors and their Relationship with Physical Activity

There are multiple risk factors of PDAC that are either modifiable or non-modifiable ^{29, 30}. Among the modifiable risk factors, PA may be beneficial at mitigating their risk. Below, we detail some of the risk factors of PDAC and the evidence for PA as a countermeasure.

Smoking:

Tobacco smoking is a modifiable and independent risk factor of PDAC ^31–33 for which some of the mechanisms have been recently summarized ³⁴. One of the side effect of smoking is the development of bronchial asthma. A prospective study observed a positive association between bronchial asthma and the risk of pancreatic cancer (HR=2.16, 95% CI 1.17–3.98). Moderate/heavy PA in these patients suggested a decreased risk of pancreatic cancer (HR=0.42, 95% CI 0.22–0.83) however it was not directly correlated with improvements in the bronchial asthma ³⁵.

Alcohol:

Epidemiological human studies ^{32, 36–42} and preclinical studies in mice using models expressing oncogenic Kras ⁴³ have linked alcohol consumption to an increased risk of pancreatic cancer. In addition, alcohol consumption is a risk factor for chronic pancreatitis (CP) development ⁴⁴, which promotes chronic inflammation in the pancreas and also increases the risk of pancreatic cancer. The pooled analysis conducted by Perreault et al. showed that people who met the PA recommendations can nearly attenuated the associations between alcohol intake and mortality risk of cancers ⁴⁵, however the study did not report on pancreatic cancer specifically.

Obesity:

Obesity is another modifiable risk factor of pancreatic cancer ^{30, 46}. The connection between pancreatic cancer and obesity has been well established ^47–50. PA can reduce obesity by increasing the bodies energy expenditure and decreasing general adiposity ⁵¹, which may be contributing to reduce pancreatic cancer risk. It is proposed that the expansion of the adipose tissue promotes tumor development through the deposition of fibrosis, connective tissue, and the activation of inflammatory pathways among others ^{47, 52}. However, whether increased PA could decrease the risk of pancreatic cancer by blocking these pathways induced by increased adiposity is unclear. Therefore, these topics and associations merit further investigation since weight loss via bariatric surgery has been associated with a decreased cancer incidence, particularly obesity-associated cancers such as pancreatic cancer⁵³.

Non-genetic chronic pancreatitis:

The risk of CP is associated with smoking and heavy alcohol consumption ^{54, 55}. The inflammatory state that partially characterizes CP can promote metaplasia and neoplastic transformation, leading to pancreatic cancer development ^{56, 57}. A meta-analysis showed that CP patients have almost an eight-fold increased risk of PDAC five year after diagnosis ⁵⁸. However, limited evidence was found in our search regarding the contribution of increased PA in reducing the risk of CP-associated with PDAC development.

Diabetes:

Diabetes mellitus is another known risk factor for pancreatic cancer ⁵⁹. High glucose levels increased O-linked N-acetylglucosaminylation and promoted de novo KRAS mutations ⁶⁰, which is present in more than 95% of PDAC ⁶¹. Diabetes or impaired glucose tolerance could be found in 50–80% of pancreatic cancer patients when diagnosed ⁵⁹. Pannala et al. showed that in pancreatic cancer patients, 74% of diabetes were new-onset diabetes mellitus, meaning that diabetes developed no more than two years before the cancer diagnosis ⁶². High diabetes prevalence, especially new-onset diabetes mellitus is unique to pancreatic cancer patients ⁶³. Researchers are currently identifying novel biomarkers to screen pancreatic cancer in patients with new-onset diabetes mellitus ^{64, 65}. PA may delay or prevent diabetes development ⁶⁶ and improve blood glucose control ⁶⁷ in diabetes patients. In a large cohort study from Japan, Iwasaki et al. suggested that fast walking was preventive for new-onset diabetes (OR=0.93, 95% CI 0.88–0.98) ⁶⁸. Not many studies describe the association between type 1 diabetes and pancreatic cancer. One cohort study using data from five countries showed that the HR associated with type I diabetes with pancreatic cancer was 1.53 in men (95% CI 1.30–1.79) and 1.25 in women (95% CI 1.02–1.53) ⁶⁹. However, overall it is still unclear whether PA can reduce the risk of pancreatic cancer after the onset of diabetes and further studies are needed.

Mitigating Pancreatic Cancer Risk with Physical Activity

Moderate- or vigorous- intensity activities as defined by the 2008 physical activity guidelines for americans ⁷⁰ have been associated with longevity in cancer patients ⁷¹. Moreover, several large cohorts or case control studies have demonstrated an inverse relationship between PA and pancreatic cancer (including PDAC) incidence and/or mortality in men and women. A meta-analysis of 26 independent studies concluded that, although there was significant heterogeneity between studies (due to study design, the median age of the population, and confounding variables used for adjustment), the overall protective association between leisure time PA and pancreatic cancer was 11% ⁷². Interestingly, low or moderate intensity PA was more beneficial than vigorous activity in lowering the risk of pancreatic cancer ⁷³. A cohort study that included 43,479 men indicated that a moderate range of MET hours (42–62.9 MET hrs/week) was more beneficial (hazard ratio [HR] = 0.59) than a low range (< 20.9 MET hrs/week; HR = 1) or a high range (> 63 MET hrs/wk; HR = 0.90) of MET hours. The range of 42–62.9 MET hours/week provided an optimal inverse correlation risk for pancreatic cancer ⁷⁴. Song and Giovannucci further divided participants in the two nationwide cohorts into a low-risk group (nonsmokers, with no or moderate alcohol consumption, a BMI between 18.5–27.5, and 150 minutes of moderate or 75 minutes of vigorous PA weekly) and a high-risk group (those who failed to meet all four of the low-risk-group criteria). According to the analysis, both the incidence rate and mortality rate of pancreatic cancer were lower in the low-risk group ⁷⁵. Moreover, the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study showed that healthy life style habits including increased PA were inversely associated with pancreatic cancer risk in European adults ⁷⁶. Together, these studies illustrate that increased PA may lower the risk of developing pancreatic cancer. However, several limiting factors made it hard to understand the true protective effect of PA, which included study design, age of the patient population, measurement of PA, and confounding variables used for analysis adjustments. In some studies, it was also hard to discern whether other well-known pancreatic cancer risk factors discussed above were confounding factors in interpreting the effects of PA in PDAC. Future research should consider all risk variables to improve the interpretation of the studies on the effects of PA in pancreatic cancer.

Effects of Physical Activity on PDAC Tumor Growth

Although preventing PDAC is ideal, the cancer diagnosis may still occur before a PA intervention could begin. Therefore, many researchers have focused on studying whether PA can be used as an adjuvant therapy for PDAC in combination with standard of care to slow or reverse its growth in both pre-clinical models and clinical trials.

One of the first pre-clinical animal studies to demonstrate the benefits of exercise in reducing pancreas tumors evaluated the protective effects of voluntary wheel running in male Lewis and female F344 rats injected with azaserine, a pancreatic carcinogen. Voluntary wheel running in these rats reduced the growth rate of azaserine-induced pancreatic foci for four months after carcinogen initiation ⁷⁷. A study using voluntary wheel running prior to subcutaneously implanting PANC-1 tumor cells into mice showed that PA inhibited tumor growth ⁷⁸. In this study, voluntary wheel running was started one week before tumor cell implantation and lasted 63 days. After tumor cell injection, the Panc-1 tumors in the mice with access to running wheels grew at a slower rate (0.00476cm² per day) compared to the control mice (0.00654cm² per day) ⁷⁸. These results suggest that voluntary wheel running could delay PDAC tumor growth in pre-clinical mouse models; however, these results have not been validated using genetically engineered mouse models of PDAC and/or in combination with PDAC treatment regimens. Moreover, these results are only modest and tested only one human pancreatic cancer cell line.

Aerobic exercise can also play a role in remodeling the tumor microenvironment. Florez Bedoya et al. reported that exercise remodels the tumor vasculature in a patient-derived xenograft mouse model of PDAC and in PDAC patients ⁷⁹. The increased shear stress via aerobic exercise can cause tumor vessel remodeling through calcineurin-NFAT-TSP1 signaling in endothelial cells and improve the delivery of gemcitabine in a PDAC tumor-bearing mouse model ⁸⁰. The evidence suggests that PDAC patients could benefit from PA, clinically.

Although several studies have demonstrated some of the positive effects of exercise in delaying PDAC growth, the underlying mechanisms of these effects are unclear. Several molecular mechanisms had linked PA to cancer prevention and treatment ^{81, 82}. Among them are molecular mechanisms related to changes in metabolism, systemic immune function ^{10, 13}, tumor microenvironment ¹¹, and some other hallmarks of cancer ¹². Metabolically, PA increased a tumoricidal immune response by reducing glucose consumption ⁸³ and tumor proliferation by altering gene expression of fatty acid metabolism pathways ⁸⁴. However, many of these mechanisms have not been verified in PDAC as a result of PA. Therefore, further studies on these phenomena are needed to explore the molecular mechanisms of how PA could reduce the risk of PDAC or delay tumor growth in particular using genetically engineered mouse models of PDAC that recapitulate various stages of the disease.

Effects of Physical Activity in Combination with PDAC Treatments

Although PA may have direct anti-tumor effects for some cancer types, PA may also help improve some of the side effects cancer patients experience as a result of cancer treatments. PA interventions can mitigate common chemotherapy side effects like fatigue and tissue wasting, improve better outcomes, treatment completion rates, and quality of life during and after treatment ^85–96. The safety and efficacy of PA in PDAC patients that undergo adjuvant treatment were first reported by Cormie et al. ⁹⁷. In the study, a 49-year-old male PDAC patient whose tumor was surgically removed three months before the PA intervention and who received adjuvant chemotherapy and radiotherapy tolerated the exercise program well. The exercise program also had a positive impact on several outcomes, including physical capacity and functional ability ⁹⁷. A single-arm prospective trial showed that PDAC patients who were able to adhere to a home-based exercise program during preoperative therapy increased their capacity for PA and the exercise program had no related adverse effects ⁹⁸ (Table 1, NCT02295956). Moreover, PDAC patients receiving preoperative chemotherapy and/or chemoradiation showed that light PA increased weekly was correlated with increased health-related quality of life (HRQOL) (β = 0.03, p = 0.02), while sedentary activities were associated with decreased HRQOL ((β = −0.02, p = 0.01) ⁹⁹ (Table 1, NCT02295956). A study by Niels et al. reported that a well-tolerated and feasible PA program in advanced PDAC patients could improve medical treatment outcomes, improve oxygen uptake, and quality of life (QoL) in pre-operative patients before liver metastasis resection¹⁰⁰ (Table 1, NCT02940067). Even less strenuous activity, like progressive mobilization after pancreatic cancer surgery, reported benefits by increasing oxygenation when performed on the same day of the surgery, compared to patients mobilized a day after the surgery¹⁰¹ (Table 1, NCT03466593). Moreover a post-operative randomized control trial (RCT) suggested that three months of resistance training improve patients’ sleep problems and fatigue¹⁰² (Table 2, NCT01977066). They also showed improved muscle strength but no significant effects on body composition after six months of resistance training. In this trial, loss of muscle mass was a predictor of poor overall survival, suggesting that training to maintain muscle mass and avoid muscle wasting from malnutrition or cachexia benefited patients¹⁰³ (Table 2, NCT01977066). A recent systematic review conducted by Luo et al. ¹⁰⁴ also suggested that exercise is a safe and feasible treatment for PDAC patients and may positively affect several physical and psychological outcomes. So far the improvements to patient outcomes as a result of PA may be due to several aspects such as, tumor vasculature remodeling, lowered inflammation, and metabolic improvements, however there might be many undiscovered mechanisms that require further research. While most PA intervention studies in PDAC are associated with improved quality of life, fatigue, and functional capacity, most of the conclusions are drawn from studies with low levels of evidence like case series and case reports. However, another systematic review of exercise efficacy in PDAC also suggested a significant lack of high-quality evidence from RCTs, which severely limits the interpretation of the results from many of the studies conducted on this topic ¹⁰⁵. In addition, even the few RCTs that investigate the role of PA in pancreatic cancer patients have significant variations in the type of intervention modality, including the type and duration of the physical activity (aerobic and resistance, 1–5X per week, etc.), outcomes measured (VO₂ peak, VO₂ max, 6 min walk test, body composition, fatigue, etc.) and the frequency of these measurements. The heterogeneity of the studies and the lack of high-quality evidence delays reaching a consensus on the most appropriate PA intervention for these patients. Therefore, well-designed clinical trials are needed to address the limitations of current studies and determine the efficacy and prescription of PA for pancreatic cancer patients ¹⁰⁵. We recorded the primary outcome measures in the studies we found from our search in Tables 1–5. Our findings highlight the heterogeneity in study design of these trials in the different patient settings.

Table 1.

Clinical Trials of PDAC and Physical Activity for Pre-Operative Patients (N/A: Not applicable)

Study Title	Conditions & Diseases	Interventions	Study Population	Primary Outcome Measure	Phase	ID Number
Pilot Study of a Multimodal Prehabilitation Pancreatic Cancer Program	Pancreatic Ductal Adenocarcinoma	Exercise Program, Nutrition Program	40	Number of participants to complete prehabilitation program	N/A	NCT03865875
Exercise and Nutrition to Improve Pancreatic Outcomes	Pancreatic Cancer	Nutritional Counseling, Standard Exercise, Enhanced Exercise	60	Quality of Life (QOL), change in body weight, physical performance, fatigue	N/A	NCT03256201
PancFit: Multimodal Exercise During Preoperative Therapy for Pancreatic Cancer	Pancreatic Cancer	Questionnaires, Nutritional Counseling, Physical Assessments	128	Change in 6 Minute Walk Test (6MWT)	N/A	NCT03187951
Improving Outcomes in Cancer Patients With a Nutritional and Physical Conditioning Prehabilitation Program	Pancreatic Cancer, Liver Cancer, Bile Duct Cancer, Hepatobiliary Cancer, Surgery	Exercise, Nutrition, Relaxation Techniques	60	6MWT	N/A	NCT03475966
Monitoring Heart Rate Variability for the Early Detection of Pancreatic Cancer	Pancreatic Ductal Adenocarcinoma	Activity monitor, Quality-of-Life Assessment, Questionnaire Administration	750	Magnitude of heart rate variability (HRV) decline (Stage I) Compliance statistics for wristband use (Stage II)	N/A	NCT04400903
Re-Defining Frailty and Improving Outcomes Through Prehabilitation in Patients With Pancreatic, Liver, or Gastric Cancer, The RIOT Trial	Adult Liver Carcinoma, Gastric Carcinoma, Malignant Solid Neoplasm, Pancreatic Carcinoma	Best Practice Behavioral, Exercise Intervention, Physical Therapy, Questionnaire Administration	50	Frailty assessment	N/A	NCT04602026
Walking for Recovery From Surgery in Improving Quality of Life in Older Adults With Lung or Gastrointestinal Cancer and Their Family Caregivers	Adult Liver Carcinoma, Caregiver, Colorectal Carcinoma, Lung Carcinoma, Malignant Digestive System Neoplasm, Pancreatic Carcinoma	Exercise Intervention, Quality-of-Life Assessment, Survey Administration	50	6MWT, daily steps, timed-up and go	N/A	NCT03267524 144
HOPE - A Study to Evaluate the Effect of a Prehabilitation Program on GI Cancer Patients Planning to Undergo Surgery	Pancreatic Cancer, Esophageal Cancer, Gastric Cancer	Nutritional Intervention, Physical Activity Intervention	60	Frailty Measurement weight loss, grip strength, and prealbumin serum level	4	NCT03642093
Preoperative Exercise in Pancreatic Cancer	Pancreatic Cancer	Exercise Program, Standard Care	3	Change in 400-meter walk time	N/A	NCT02648880
Preoperative Rehabilitation During Neoadjuvant Therapy for Pancreatic Cancer	Pancreatic Cancer	Questionnaires, Exercise, Nutrition Counseling, Phone Calls, Booklet	75	Feasibility of Prehabilitation Program Among Pancreatic Patients	1	NCT02295956 98, 99, 145
Enhancing Fitness Before Pancreatic Surgery	Pancreatic Cancer Chronic Pancreatitis	MedEx: A Combination of Dietary and Exercise Interventions over Four Weeks Before Scheduled Pancreatic Surgery	20	Peak power - measured using cardiopulmonary exercise testing	N/A	NCT02940067 100, 146, 147
Effects of Prehabilitation and Early Mobilization for Patients Undergoing Pancreas Surgery.	Pancreas Cancer	Prehabilitation, Routine Care, Extra Early Mobilization, Standard Mobilization	245	Postoperative complications, Partial Pressure of Oxygen (PaO2)	N/A	NCT03466593 101
Exercise medicine as chemotherapy adjunct: the feasibility and efficacy of a multicomponent program in pancreatic cancer patients receiving neoadjuvant therapy (The EXPAN Project)	Pancreatic Cancer	Resistance Training, Aerobic Exercise or Adapted Sport-Related Drills	40	Feasibility, Safety	1	ACTRN12620001081909148
A phase II study about the efficacy of an intervention of exercise therapy on the adjuvant chemotherapy for pancreatic cancer: Exercise-PC Study - Exercise impact on adjuvant chemotherapy for pancreatic cancer	Invasive Ductal Adenocarcinoma of Pancreas	Exercise Therapy	44	The completion rate of four courses of S-1 adjuvant chemotherapy.	2	JPRN-UMIN000030124

Table 2.

Clinical Trials of PDAC and Physical Activity for Post-Operative Patients (N/A: Not applicable)

Study Title	Conditions & Diseases	Interventions	Study Population	Primary Outcome Measure	Phase	ID Number
PRECISE: Pancreatic Cancer and Exercise	Pancreas Adenocarcinoma	Exercise	10	Participants adhering, participants acceptability	N/A	NCT04305067
Diet and Exercise After Pancreatic Cancer	Pancreatic Cancer	Diet + Exercise	50	Adherence, adverse events	N/A	NCT03187028
Adapted Physical Activity in Patients With Resected Pancreatic Cancer (APACaPOp PRODIGE-56 Study): a National Multicenter Randomized Controlled Phase II Trial	Pancreas Cancer	Unsupervised Adapted Physical Activity (APA) program, Supervised APA program	252	Month 6 (M6), Health-Related quality of life (HRQoL)	N/A	NCT03400072
Improving Outcomes in Cancer Patients With a Nutritional and Physical Conditioning Prehabilitation Program	Pancreatic Cancer, Liver Cancer, Bile Duct Cancer, Hepatobiliary Cancer	Exercise, Nutrition Relaxation techniques	60	6MWT	N/A	NCT03475966
Association Between Health Care Provider (HCP)-Assessed ECOG Performance Status (PS) and Overall Survival, and Objectively Measure of Physical Activity (PA) Levels in Advance-cancer Patients”	Pancreatic Adenocarcinoma, Pancreatic Neuroendocrine Carcinoma and 45 more	Exercise Intervention, Health Telemonitoring, Quality-of Life Assessment, Questionnaire Administration	590	Study Completion, Physical Activity (PA) Assessment, ECOG (Eastern Cooperative Oncology Group) Performance Status	N/A	NCT01365169
Resistance Training Intervention to Improve Physical Function in Patients With Pancreatic Cancer Receiving Combination Chemotherapy or Have Undergone Surgery, PancStrength Study	Advanced Pancreatic Adenocarcinoma, Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8	Educational Intervention Quality-of Life Assessment, Questionnaire Administration, Resistance Training	75	Safety of the tele-resistance training (RT) program, Post-exercise muscle soreness, Body composition, Aerobic fitness	N/A	NCT04837118
Walking for Recovery From Surgery in Improving Quality of Life in Older Adults With Lung or Gastrointestinal Cancer and Their Family Caregivers	Adult Liver Carcinoma, Caregiver, Colorectal Carcinoma Lung Carcinoma, Malignant Digestive System Neoplasm, Pancreatic Carcinoma	Exercise Intervention, Quality-of Life Assessment, Survey Administration	80	6MWT, daily steps, timed-up and go	N/A	NCT03267524 144
Exercise Intervention Study for Pancreatic Cancer Patients	Pancreatic Cancer	Six months Supervised Resistance Training, Six months Home-Based Exercise Training	65	Physical functioning score, as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) EORTC QLQ-C30	N/A	NCT01977066 102, 103
A validation study of biomarkers to predict responders to non-pharmacological multimodal program for advanced cancers - NEXTAC-Three	Non-Small-Cell Lung and Pancreatic Cancer	Nutritional Counseling, Home-based Exercise Intervention, Physical Activity Intervention	100	Positive predictive value	N/A	JPRN-UMIN000033574
A Randomized Phase II study of the nutritional and exercise treatment for the elderly patients with advanced non-small-cell lung and pancreatic cancer - NEXTAC-TWO study	Non-Small-Cell Lung and Pancreatic Cancer	Nutritional Counseling, Home-based Exercise Intervention, Physical Activity Intervention, Usual Care	130	Disability-free survival	2	JPRN-UMIN000028801149
A Feasibility study of the nutritional and exercise treatment for the elderly patients with advanced non-small-cell lung and pancreatic cancer - NEXTAC-ONE study	Non-Small-Cell Lung and Pancreatic Cancer	Early Multimodal Intervention (Nutritional Intervention, Home-Based Muscle Training, and Lifestyle Intervention to Promote Physical Activity)	30	Attendance rate for exercise and nutritional sessions in 8 weeks	N/A	JPRN-UMIN000023207150
Post-operative high intensity interval training in patients undergoing major foregut cancer surgery, investigating the effect on the 6 minute walk test: A randomised controlled trial	Liver Cancer, Gastric Cancer, Pancreatic Cancer, Oesophageal Cancer, Oesophago-gastric Junction Cancer	Exercise, Usual Care	60	6 Minute Walk Test Grip Strength Test.	N/A	ACTRN12620000315910
The influence of exercise on blood glucose control and the anti-oxidative ability of the blood in patients after pancreatectomy: a randomized controlled trial	Pancreatic Disease, mainly Neoplastic Tumors of the Pancreas	Pancreatectomy, Followed by Exercise	40	Measurement of blood glucose levels, HBA1c, albumin and uric acid, 12 weeks after the initiation of exercise (once every 4 weeks interval)	N/A	ISRCTN10827174

Table 5.

Clinical Trials of PDAC and Physical Activity: Without Specified Patient Setting (N/A: Not applicable)

Study Title	Conditions & Diseases	Interventions	Study Population	Primary Outcome Measure	Phase	ID Number
Early Palliative Care for Patients With Advanced Pancreatic Cancer.	Pancreatic Cancer	Early Palliative Care	250	Adjusted mean change in global health status/QOL score at 12 weeks	N/A	NCT04632303
Brown Adipose Tissue Activity and Energy Metabolism in Cachexia	Cachexia, Neoplasms Pulmonary Disease, Chronic Obstructive Pancreatic Neoplasms	Radiation, Abdominal Subcutaneous Adipose Tissue Biopsy, Blood Sampling, Indirect Calorimetry, Device: Accelerometry, Double-Labeled Water	16	Brown adipose tissue (BAT) activity measured by PET(-MRI) (Positron Emission Tomography – Magnetic Resonance Imaging)	N/A	NCT02500004 153
Effect of exercise on sarcopenia in patients with pancreatic cancer	Pancreatic Cancer	Physical Exercise and Standard Therapy	40	Evaluation for sarcopenia using bioimpedance analysis	N/A	JPRN-UMIN000029271154
Effect of exercise on sarcopenia in patients with pancreatic cancer	Pancreatic Cancer	Physical Exercise and Standard Therapy	40	Evaluation for sarcopenia using bioimpedance analysis	N/A	JPRN-UMIN000029272155
A feasibility study of Multimodal Exercise/Nutrition/Anti-inflammatory treatment for Cachexia – the pre-MENAC study - Pre-MENAC Study	Non-operable Stage III/IV Non-Small Cell Lung Cancer, Pancreatic Cancer	Celecoxib CAS Number: 194044-54-7, 100mg	40	Is a multimodal intervention for cancer cachexia feasible?	2	EUCTR2010-022897-14-GB
PreMENAC: Multimodal Exercise/Nutrition/Anti-inflammatory treatment for Cachexia: A feasibility study (phase II) - Pre - MENAC	Non-operable Stage III/IV Non-Small Cell lung Cancer, Pancreatic Cancer	Celecoxib CAS Number: 194044-54-7, 100mg	40	The overall objectives are the feasibility of patient recruitment, compliance to the multimodal intervention as well as the assessment of possible contamination of the control group.	2	EUCTR2010-022897-14-NO
A Feasibility Study of Multimodal Exercise/Nutrition/Anti-inflammatory Treatment for Cachexia - the Pre-MENAC Study	Non-Operable Stage III/IV Non-Small Cell Lung Cancer, Pancreatic Cancer	Multimodal intervention Other Standard of care	46	Feasibility of recruitment and retention	N/A	EUCTR2013-002282-19/NCT01419145156–158

Benefits of Physical Activity in Pancreatic Cancer Survivors

Cancer survivors tend to experience physical and psychological deconditioning after cancer therapy ^{106, 107}. PA can potentially help patients recover from deconditioning due to its potential to improve common cancer-related disorders, such as fatigue, anxiety, and reduced physical functioning ^{108, 109}. Cancer survivors are encouraged to do moderate-intensity aerobic training at least three times per week, for at least 30 minutes for 8 to 12 weeks to address health-related outcomes after cancer treatment ¹⁸. A telephone survey found that over 70 % of pancreatic cancer survivors are willing to participate in exercise and diet interventions ¹¹⁰. One study pointed out that most cancer survivors are insufficiently active, especially those who are obese ¹¹¹. Moreover, Parker et al. showed that less than one-quarter of patients after PDAC resection met the U.S. exercise guidelines ¹¹². Barriers that keep survivors from regular PA include past exercise experience, motivation, environmental barriers, and logistical barriers ¹¹². Therefore, ways to break exercise barriers and elicit patients’ motivation to increase PA are needed for cancer survivors to experience the benefits of increased PA.

Commonly Used Preclinical Models to Study Physical Activity

Mouse models have been used for decades to study the impact of structured exercise training on a variety of cancers ^{113, 114}. Several techniques are routinely used to study the effects of exercise in mice, such as either voluntary or involuntary running systems including wheel running (voluntary), treadmill running (involuntary), swimming (involuntary), and resistance training (involuntary) (Figure 2). Unfortunately, there are inconsistencies in study design related to how studies used voluntary or involuntary methods of exercise when using preclinical models of cancers to assess the effects of exercise. The exercise methods utilized depends on the investigator’s preferences of the experimental design. However, there are some differences between voluntary and involuntary exercise that influence the interpretation of results and the biological relevance of each model. Kim et al. showed that mice running on wheels had higher average grip strength and a different expression pattern of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α, compared to those mice running on a treadmill ¹¹⁵. However, Conner et al. showed that using electrical shock to train mouse to performed involuntary exercise increased the levels of stress hormones and cytokines after exercise ¹¹⁶. These elevated stress hormones and cytokines might lead to confounding results in the context of cancer research as some of these stress hormones ¹¹⁷ and cytokines ¹¹⁸ are known to affect cancer development.

Figure 2:

Summary of the common methods of pre-clinical PA assessment. Created with Biorender.com

In addition to the variety of exercise techniques to choose from, it is also important to consider the time of day at which the mice exercise. Mice are nocturnal animals and are most active during the night. Therefore, to study PA/exercise using mouse models, some researchers have altered the mouse housing environments to provide a reversed light-dark cycle so that the exercise/PA interventions can occur during the rodent’s night phase when mice are naturally more active ¹¹⁹.

Wheel Running (Voluntary):

Wheel running is one of the two most common forms of exercise training used in preclinical models because it is less labor intensive and reduces the amount of psychological stress experienced by the mice by allowing them to choose the duration and intensity of running. The lack of control over exercise intensity is one of the limitations of using wheel running instead of treadmills; wheel running often prevents the mice from running at their maximal intensity. Moreover, the mice run voluntarily and therefore must be motivated and willing to run when given access to the wheels.

Treadmill Running (Involuntary):

Treadmill running is the other most common form of exercise used in both human clinical studies and murine preclinical studies. One of the primary advantages of using treadmills is the uniformity with which the level of exertion of each experimental group is measured. Treadmill running enables factors such as running duration, intensity, and frequency to be controlled so subjects exercise at maximal or submaximal levels. Unlike voluntary wheel running, treadmill exercise sometimes requires methods like tail tapping, shock grid, air burst, or cold-water jets to encourage the animal to run. These types of methods can aggravate an already stressful experience in these animals, and they have been associated with tumor development and growth ¹²⁰. To avoid stress induced by forced exercise, treadmill running requires the mice to gradually become familiarized with the apparatus. Often, treadmill performance parameters are evaluated based on the duration of running at fixed speeds and/or the gradual increase in speed until each mouse reaches their maximal workload ¹²¹. Among the disadvantages of treadmill exercise are frequent animal handling, the difficulty of motivating mice to exercise, lack of access to food and water during the training periods, and the need for constant investigator vigilance to ensure that the animals run for the entire duration of the exercise regimen. Moreover, researchers have identified strain-related differences in how mice handle treadmill exercises. Lerman et al. showed that C57BL6J mice had the least maximum speed of all the mice strains they tested. ¹²¹.

Swimming (Involuntary):

Swimming is another model used to study PA. Swimming has several advantages over other types of exercise modalities and has been shown to suppress tumor growth in mice ¹²². Swim training is typically performed in a swimming pool at a controlled temperature for less than one hour per day. The initial swim training consists of a gradual increase in workload until a maximal load is obtained. The procedure requires inexpensive equipment and relies on the natural swimming ability of laboratory rodents. Swimming behaviors are affected by diverse factors, such as the diving reflex, mental stress, and episodes of hypoxia associated with diving ¹²³.

Resistance Training (Involuntary):

Resistance training is a form of exercise that can strengthen your skeletal muscles by providing progressive overload ¹²⁴. Exercise interventions can benefit cancer patients by improving muscular strength, cardiovascular function, and quality of life.¹²⁵. However, few studies have translated the use of exercise regimes in mice to identify the protective mechanisms of resistance training. The failure to identify protective mechanisms due to resistance training is in part due to the inability to relate exercise prescriptions used in humans to mice and vice versa. For example, a typical form of resistance training for mice is a “squat-like” movement proposed by Tamaki et al. ¹²⁶. The major limitation of this method is the need for electrical stimulation, and this setting cannot be directly used in humans ¹²⁷. Another form of resistance training for mice is climbing a rope with a small weight on their tail to provide a resistance-training stimulus ¹²⁸ which does not have an equivalent exercise in humans.

Although mouse models are an essential and commonly used tool in preclinical studies, their ability to mimic human physiologic changes is still limited. Researchers still face important challenges, such as determining how to design a novel approach to bridge the mouse–human gap and determining how to use the results from current mouse models of exercise to design future human clinical trials to test these interventions.

Translating Preclinical Exercise Findings to the Clinic

Using mouse models to study disease mechanisms is often insightful; however, exercise interventions currently used in human clinical trials for patients with pancreatic cancer are not based on preclinical exercise studies or mechanisms identified in mice. There is a disconnect between translating important findings in mouse exercise studies and designing exercise programs for clinical trials based on these studies. This disconnect is due, in part, to the lack of linear correlation between mouse aerobic or resistance exercise intensity and the human equivalent, i.e. the lack of understanding of what 30 minutes of moderate intensity aerobic exercise in a mouse is equivalent to in a human.

Very few clinical trials have been conducted with patients to determine the effectiveness of incorporating exercise or PA for pancreatic cancer patients ^{97, 129}. A limited number of studies have used animal models to investigate how exercise, or increased PA, affects or prevents pancreatic cancer ^{77, 78}. Thus, despite the epidemiological evidence suggesting that PA decreases the risk of pancreatic cancer, a lack of translation to the clinic has affected the progress of investigating how PA/exercise could provide anti-pancreatic-cancer effects. Zheng et al. showed that exercise was sufficient to suppress tumor growth, increase food consumption, and decrease fat pad size in mice ⁷⁸. This study demonstrated that exercise induced a positive effect by increasing active caspase-3 expression and decreasing the ratio of mitotic to apoptotic cells that lead to inhibition of tumor-growth. Similar studies are needed to further pinpoint the mechanisms by which exercise could inhibit pancreatic cancer growth. Given the limited research on links between the effects of PA and PDAC prevention or PDAC-risk reduction, it is beneficial to review studies of other cancers that have used exercise and PA as means of preventing cancer and reducing tumorigenesis. Recent studies have demonstrated that PA, alone or in combination with pharmacological treatments, has an effect on cancer prevention and prognosis ^{23, 125, 128, 130–132}.

Several mouse models of PDAC also develop cachexia ¹³³. Research on cancer cachexia has demonstrated that appropriate exercise recommendations play an important role in identifying how exercise affects cancer biology and disease progression. For example, voluntary wheel running counteracts cachexia-mediated overload of autophagic flux, which results in rescued muscle mass and function in tumor-bearing mice. Treating with 5-aAminoimidazole-4-carboxamide ribonucleotide or rapamycin trigger autophagic flux and replicate the effects of exercise on muscle mass ²³. Another study has shown that exercise-induced inflammation, via the inflammatory regulator nuclear factor-κB, mediates suppression of the transcription factor paired box 7, and improves muscle mass in cancer cachexia ¹³⁰. These findings indicate the benefits of using exercise to activate the immune system. Unfortunately, many studies on cancer cachexia have noted no changes in muscle size in rodents with cachexia, but exercise before tumor inoculation resulted in improved outcome¹³⁴. This further strengthens the rationale for instituting physical activity or exercise regimens prior to the development of cachexia to reduce its severity.

To better translate these findings, it is vital that the exercise prescribed to mice be purposeful and that there is compatibility between mouse and human responses to exercise and adaptation. Both exercise and tumors are stressors, and, when adapting to exercise, an organism can handle only so much stress before adaptations become unfavorable. It is therefore important to standardize animal-training protocols to evaluate dosages of activity needed for beneficial results without adding too many additional stressors to the cancer patients. Additionally, PA and exercise are different by definition ¹³⁵. Physical activity refers to any movement that results in energy expenditure; whereas, exercise is a subset of physical activity that aims to maintain physical fitness. It is critical to keep this in mind so that findings concluded in mice can be appropriately interpreted and translated to PA or exercise therapies in humans. Although challenging, by closing this gap, this field can move toward recommendations for optimal exercise prescription for cancer patients, and even toward identifying pharmacological exercise mimetics for cancer patients who cannot or will not exercise.

Clinical Trials Investigating Physical Activity Regimens for Pancreatic Cancer Patients

Epidemiological data indicates a protective role of PA for patients with cancer ^136–139. Nonetheless, only a few clinical trials have incorporated PA interventions for patients diagnosed with PDAC which are summarized in Tables 1–5 depending on the patient setting. Among all available clinical trials that met the search criteria, 14 evaluate PA in pre-operative patients, 13 evaluate PA in post-operative patients, 3 evaluate PA in patients with advanced cancer, 7 evaluate PA in patients undergoing chemotherapy or radiotherapy, and 7 did not specified the patient setting (Figure 3A). Different types of PA intervention are used in these trials, 4 use aerobic exercise, 3 use resistance training, and 10 use both aerobic exercise and resistance training (Figure 3B). Unfortunately, the vast majority (23 of 40) do not specify the type of PA intervention which may make it difficult late to make comparisons among trials.

Figure 3:

Summary of the clinical trials. (A) Times of intervention and (B) Types of exercise using in clinical trials. Created with Graphpad Prism 9

Of all the clinical trials, only one trial that involves exercise and pancreatic cancer is a phase 4 trial (Table 1, NCT03642093). The goal of the trial is to evaluate whether a four-week nutritional and PA (walking and inspiratory muscle training) intervention program can alter frailty in upper gastrointestinal surgical oncology patients. Based on the results of the preclinical studies in mice and humans in addition to this phase 4 trial, we expect more interventions like this to become part of approved cancer treatment in the near future. Moreover, we expect to see more unified experimental design among clinical trials to determine the efficacy of PA on PDAC patients.

Conclusions

Although there are pieces of evidence showing that PA improves quality of life in PDAC patients and survivors and that PA potentially protects against PDAC growth, the relationship between PA and PDAC-risk reduction remains unexplored ¹⁴⁰. The lack of long-term epidemiologic evidence that supports the beneficial role of PA in PDAC has been hindered by the limited investigations and the low percentage of the population that could be recruited for studies in this area.

Well-designed preclinical studies need to be developed to generate stronger evidence of the role of PA in PDAC. This will be important for justifying the need to increase the number of clinical trials that target PA and the need to recommend PA as a prevention strategy or adjuvant intervention in PDAC. These studies should implement relevant disease mouse models that recapitulate the human disease and PA regimens that can be translated into patients. Moreover, the majority of current epidemiological studies of exercise are undertaken in higher-income regions, and research with more diverse ethnicity and genetic ancestry is needed for evidence based guidelines ¹⁴⁰.

PA may not be feasible for some elder or weaker patients. Hence, finding alternative strategies to mimic the effects of PA are needed. Electrical stimulation of individual or collective muscle groups can improve general muscle strength ^{141, 142} and may be a valuable substitution for exercise in more frail populations ¹⁴³. However, future studies related to the safety and efficacy of electrical stimulation in PDAC patients with or without cachexia are needed before it can become a viable treatment regimen.

Overall, there is abundant evidence that PA promotes health, and it is generally advised for cancer patients ¹⁴⁰. Since PA is usually combined with other supportive cares such as nutritional interventions in cancer patients, these can create confounding factors that make it difficult for us to understand the sole effects of PA on PDAC patients that can then translate the information and specific recommendations for PDAC patients and at-risk individuals. However, because PA is potentially a cost-effective intervention, further research in this area should be encouraged.

Table 3.

Clinical Trials of PDAC and Physical Activity for Patients with Advanced Cancer (N/A: Not applicable)

Study Title	Conditions & Diseases	Interventions	Study Population	Primary Outcome Measure	Phase	ID Number
Evaluation of an Adapted Physical Activity Program in Patients With Unresectable Pancreatic Cancer	Unresectable Locally Advanced Cancer, Metastatic Pancreatic Cancer	Adapted Physical Activity program	317	Fatigue, QOL	N/A	NCT02184663 151
Ambulatory Measurement of Physical Activity in Pancreatic Cancer Patients	Unresectable Pancreatic Adenocarcinoma	Wrist-worn Accelerometer, Auto-questionnaires	30	Average time wearing the accelerometer, in hours	N/A	NCT03490604
Patient Activation Through Counseling, Exercise and Mobilization	Pancreas Cancer, Biliary Tract Cancer, Non Small Cell Lung Cancer, Advanced Cancer	Multimodal and Exercise-based Intervention	99	Lower body strength measured with the 30-second chair stand test	N/A	NCT03411200 152

Table 4.

Clinical Trials of PDAC and Physical Activity for Patients Undergoing Chemotherapy or Radiotherapy (N/A: Not applicable)

Study Title	Conditions & Diseases	Interventions	Study Population	Primary Outcome Measure	Phase	ID Number
Cardiopulmonary Exercise Testing: An Assessment of Patients Fitness for Palliative Chemotherapy for Pancreatic Cancer	Pancreatic Cancer	Cardiopulmonary Exercise Test	100	Survival		NCT03215459
Ambulatory Measurement of Physical Activity in Pancreatic Cancer Patients	Unresectable Pancreatic Adenocarcinoma	Wrist-worn Accelerometer Auto-questionnaires	30	Average time wearing the accelerometer, in hours	N/A	NCT03490604
Randomised Trial Evaluating the Benefit of a Fitness Tracker Based Workout During Radiotherapy	Bronchial Carcinoma, Esophageal Carcinoma, Tumor of the Brain, Head and Neck Cancer, Pancreas Cancer, Sarcoma, Cervix Uteri Cancer	Fitness Tracker Based Activity Training, Booklet “physical training, exercise and cancer” and an Introduction About Physical Activity During Cancer Therapy	201	Evaluation of the impact of an Activity tracker based Fitness programme on the Qualitiy of Life after oncological Therapy	N/A	NCT04517019
Resistance Training Intervention to Improve Physical Function in Patients With Pancreatic Cancer Receiving Combination Chemotherapy or Have Undergone Surgery, PancStrength Study	Advanced Pancreatic Adenocarcinoma, Pancreatic Adenocarcinoma, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8	Educational Intervention Quality-of-Life Assessment, Questionnaire Administration, Resistance Training	75	Safety of the tele-resistance training (RT) program, Post-exercise muscle soreness, Body composition, Aerobic fitness	N/A	NCT04837118
Exercise to Reduce Chemotherapy-Induced Peripheral Neuropathy	Gastrointestinal Cancer, Colorectal Cancer, Pancreatic Cancer, Gastric Cancer, Stomach Cancer, Esophageal Cancer	MI-Walk Intervention Physical Activity Education Pamphlet	54	Sensory neuropathy at 8 weeks	N/A	NCT03515356
Resilience and Exercise in Advanced Cancer Treatment	Pancreatic Adenocarcinoma, Gastric Adenocarcinoma, Adenocarcinoma of the Gastroesophageal Junction	Band Together, Exercise Education	14	Feasibility of Large-Scale Trial: Adherence & Contamination	N/A	NCT02680990
A pilot study to explore efficacy of outpatient cancer rehabilitation for advanced lung or pancreatic cancer under palliative chemotherapy	Advanced or Recurrenced Lung and Pancreatic Cancer	Nutritional Counseling, Home-based Exercise Intervention, Physical Activity Intervention, Usual Care	30	SPPB(Short Physical Performance Battery)	N/A	JPRN-UMIN000036771