Efficacy and Mechanisms of Aerobic Exercise on Cancer Initiation, Progression, and Metastasis: A Critical Systematic Review of In Vivo Preclinical Data

Structured exercise training (hereto referred to as exercise) is considered an integral component of “standard of care” therapy in primary and secondary prevention of numerous common chronic conditions (1–4). In comparison, the role of exercise has received surprisingly little attention in individuals at high-risk or after a diagnosis of cancer. Over the past two decades, however, an increasing number of groups are investigating the effects of general physical activity as well as exercise in the oncology setting, a field now commonly referred to as “Exercise–Oncology” (5).

A strong body of observational evidence indicates that higher levels of self-reported exercise, physical activity, as well as cardiorespiratory fitness (i.e., objective assessment of exercise exposure) are inversely associated with the primary incidence of several forms of cancer. This evidence base is summarized by several excellent systematic reviews and meta-analyses (6–9). For example, exercise participation consistent with the national guidelines (i.e., 150 minutes of moderate-intensity or 75 minutes of vigorous-intensity exercise per week) is associated, on average, with 25%, and 30% to 40% risk reductions in breast and colon cancers, respectively, compared with inactivity. There is also evidence of a linear dose–response relationship in prevention of breast and colon cancer. On this basis, the evidence for the exercise–prevention relationship is categorized as “convincing” for breast and colon cancer by several national agencies, and regarding as “encouraging” or “promising” for the prevention of prostate, lung, and endometrial cancers (10, 11). On the basis of this data, several phase II randomized controlled trials (RCT) were initiated, predominantly in breast cancer prevention, to investigate the effects of highly structured exercise on modulation of host-related factors (e.g., adiposity, circulating factors including sex-steroid and metabolic sex hormones, and the immune–inflammatory axis) that may underpin the exercise–cancer prevention relationship (6, 12–14). In general, exercise was associated with modest changes in markers of adiposity and select circulating factors (6, 12, 13). Whether the observed alterations are of biologic or clinical importance remains to be determined, as only one trial to date has investigated the exercise-induced changes in circulating factors occuring in conjunction with changes in factors/pathways in the organ/tissue of primary interest (i.e., colon crypts; ref. 15). Whether exercise reduces cancer incidence or modulates established surrogate markers of cancer incidence has not been investigated.

In patients with cancer, a steadily growing and ever diversifying series of studies indicate that, in general, exercise is a tolerable adjunct therapy associated with significant benefit across a wide range of symptom control variables both during and after primary adjuvant therapy (5, 16, 17). These data combined with the powerful inverse relationships with primary cancer incidence has led researchers to investigate whether exercise influences disease outcomes after diagnosis (18, 19). Although not nearly as mature as the evidence in the prevention setting, emerging observational data suggest that regular exercise exposure is associated with between a 10%–50% reduction in the risk of recurrence and cancer-specific death in patients with colorectal, breast, and prostate cancer (reviewed in ref. 20), compared with inactivity.

In the development of potential drug candidates, data from observational studies is insufficient to support the initiation of human trials; appropriate preclinical evidence is first required prior to human testing (21). While exercise is not a drug and exhibits a markedly different safety profile than most anticancer agents, the use of preclinical models are of critical importance to confirm the biological plausibility, establish the therapeutic window of efficacy, a biologically effective dose, and identify predictors of response (22). This evidence, combined with data from epidemiologic and molecular epidemiologic studies facilitates the design of early “signal-seeking” clinical studies and ultimately definitive RCTs. Accordingly, we conducted a critical systematic review of in vivo preclinical studies across the cancer continuum (i.e., prevention through metastasis). A secondary purpose was to provide recommendations to facilitate the standardization of the conduct of in vivo exercise–oncology studies as well as directions for future research.

A systematic literature search was conducted using OVID MEDLINE (1950 to May 2015), PUBMED (1962 to May 2015), and WEB OF SCIENCE (1950 to May 2015) with MeSH terms and keywords related to exercise, cancer, and animals. Text words were searched and appropriate MeSH terms were found (Supplementary Table S1). When possible, Boolean logic was used with MeSH terms to build searches. All results and reference lists were searched manually. Peer-reviewed research articles involving animals with cancer and exposed to chronic exercise (repeated bouts of more than 3 sessions) adopting either forced (i.e., treadmill running or swimming) endurance (aerobic) training or physical activity (i.e., voluntary wheel running) paradigms were considered eligible. All types of animal models of solid tumors were considered eligible including genetically predisposed models [transgenic, genetically engineered mouse models (GEMM)], orthotopic, subcutaneous, and intravenous injections, tumor transplant, and spontaneous or carcinogen-induced solid tumor models. Studies that included multiple treatments, such as study arms with dietary restrictions, were eligible, as long as it was possible to compare sedentary (control) and exercise alone groups. Studies that evaluated preneoplastic lesions (e.g., aberrant crypt foci, Apc^Min), or hematopoietic and ascites tumors were excluded. Only mouse and rat studies were included. Articles unavailable in English were excluded.

Four authors (K.A. Ashcraft, R.M. Peace, A.S. Betof, and L.W. Jones) assessed study eligibility by reviewing the titles and abstracts of all potential citations according to the inclusion criteria. K.A. Ashcraft, R.M. Peace, M.W. Dewhirst, and A.S. Betof extracted and interpreted data from published articles. When necessary, effort was made to contact authors and acquire publications for evaluation. Studies are summarized by type of exercise model and method of tumor initiation. Exercise characteristics are described using common prescription elements: modality, frequency, duration, intensity, and total length of intervention.

Articles were classified by the endpoints reported in the individual studies: (i) “Incidence” (tumor presence or multiplicity), (ii) “Growth” (data on tumor growth, latency or survival), and (iii) “Metastasis” (evaluation of tumors distinct from the primary tumor or developing following the common metastasis model of intravenous tumor cell injection). Study categorization was not always mutually exclusive; thus, studies that included multiple endpoints applicable to more than one categorization were included in both.

For evaluation of mechanistic findings, an alternative classification was applied on the basis of the initiation of the exercise intervention relative to the time of tumor cell transplant or application of carcinogens. “Prevention” was defined as exercise initiated prior to tumor transplant/induction. “Progression” was defined as exercise initiated ≥3 days post-transplant/induction. Studies involving GEMMs were categorized as prevention studies. Distinguishing between exercise initiation and tumor cell inoculation is important because exercise-induced adaptations prior to tumor injection could “prime” the host and/or tissue microenvironment, making it physiologic or biologically distinct from tumor inoculation into a sedentary host. Mechanistic findings were classified as either intratumoral or systemic.

Studies were assessed for changes in tumor growth (as well as the related parameters of time to tumor-related endpoint, and tumor size/mass at the end of the study), incidence (tumor presence), and multiplicity (number of tumors/metastases). All study results that were reported to be “statistically significant” achieved P < 0.05 according to the authors of the original manuscripts. Preliminary analysis of included studies indicated considerable methodologic heterogeneity in all aspects of study design, end points, and efficacy. As such, it was not possible to compare the efficacy of exercise across cancer setting (i.e., incidence, progression, metastasis), cancer histology, exercise paradigm (i.e., forced vs. voluntary), or exercise dose.

A total of 426 potential citations were initially identified using search terms. After secondary screening, 53 articles were deemed eligible and underwent full review (Supplementary Fig. S1). Classification of articles was as follows: (i) incidence (n = 24; 45.3%; refs. 23–46), growth (n = 33; 62.3%; refs. 24, 26, 34, 37, 39, 40, 42, 44–69), and metastasis (n = 10; 18.9%; refs. 53, 55, 63, 64, 70–75).

Included studies tested the effects of exercise on 15 different tumor types/cell lines, using six different tumor initiation methods (Supplementary Table S2). Details of the exercise prescriptions are summarized in Tables 1, 2, and 3. The most common modalities included voluntary running (n = 22; 41.5%; refs. 24–28, 31, 33, 35, 42, 43, 51, 52, 55, 57, 64–66, 70, 71, 73–75) forced running (n = 25; 47.2%; refs. 26, 29, 36–41, 44–46, 48, 49, 54, 56, 58–60, 63, 67–70, 72, 74), and swimming (n = 10; 18.9%; refs. 23, 30, 32, 34, 47, 50, 53, 54, 61, 62).

In incidence studies, 58% reported that exercise inhibited tumor initiation or multiplicity (23–25, 27, 28, 31, 33, 35, 36, 41, 43–46), 8% reported that exercise accelerated tumor incidence (26, 42), and 3% found null effects (29, 30, 32, 34, 37–40). In the growth category, exercise was associated with tumor inhibition in 64% of studies (24, 39, 47–54, 58–63, 65–69), while 21% (37, 40, 44, 55–57, 64) and 9% (26, 34, 42) of studies reported null and accelerated tumor growth, respectively. Finally, in the tumor metastasis category, three studies utilized models in which metastases arose from a primary tumor; of these, two reported non-significant inhibition of tumor growth (55, 64), while the other found accelerated tumor growth with exercise (53). Eight studies utilized intravenously injected tumor cell model of metastases. MacNeil and Hoffman-Goetz found that exercise did not alter retention of lung tumor cells, but increased the median number of lung metastases (74). Conversely, Jadeski and Hoffman-Goetz reported that exercise decreased retention of lung tumor cells, but had no effect on the number of lung metastases (72). One additional paper reported no difference in tumor cell retention in the lungs (71), whereas three papers reported no effect of exercise on lung metastasis (64, 70, 73). Two papers reported that exercise inhibited lung metastasis multiplicity (63) or total volume (75).

Mechanistic findings are summarized in Table 4 and Fig. 1. Studies were classified as prevention (n = 20; 37.7%), progression (n = 26; 49.1%), or metastasis (n = 7; 13.2%). Eight prevention studies (40%) reported significant effects of exercise in modulation of local immune response, tumor metabolism, and tumor physiology/angiogenesis. Ten progression studies (38.5%) examined mechanisms underlying the effects of exercise on tumor progression (32, 41, 42, 44, 52, 55, 57, 61, 68, 69). The mechanisms examined included multiple different factors/pathways such as apoptosis, perfusion, and immune cell infiltration. Only one metastasis study examined changes in tumor biology: Higgins and colleagues found that exercise favored a proapoptotic environment (75), reflecting changes in immune cell populations/function, tumor physiology, and signaling cascades.

Correlative systemic pathways examined are summarized in Table 4. Ten prevention (24, 28, 29, 40, 46–49, 59, 62), seven progression (23, 31, 37, 42, 51, 55, 64, 76), and five metastasis studies (70–72, 74, 75) reported significant effects of exercise on changes in systemic effectors, predominantly changes in factors involved in immune surveillance or metabolism.

The findings of this critical review indicate that the current evidence base is plagued by heterogeneity in all aspects of study methodology and data reporting. Unfortunately, such heterogeneity precludes rigorous evaluation of essential questions such as the biologically effective exercise dose to modulate specific tumor pathways or inhibit tumor growth, the effects of manipulating exercise intensity or duration or the differential impact of exercise across tumor subtypes (22). Nevertheless, our review did permit identification of the most salient methodologic issues that prudent investigators may consider when designing in vivo preclinical exercise–oncology studies. These aspects are described in the proceeding sections and summarized in Table 5. 

The components of the exercise prescription being investigated in preclinical studies should mirror, as closely as possible, exercise prescription parameters tested in human studies (22). Key parameters include: (i) modality/paradigm (i.e., forced vs. voluntary), (ii) dose (i.e., intensity, session duration, frequency of training sessions/week, and length of treatment), and (iii) schedule (i.e., time of initiation).

A foremost decision is the use of forced versus voluntary exercise paradigms. An often overlooked key point is that voluntary wheel running is a model of physical activity, whereas forced paradigms are a model of exercise training (i.e., structured and purposeful physical activity). Observational (epidemiologic) studies typically measure both physical activity and exercise, whereas efficacy-based clinical trials largely examine highly structured exercise training. The decision of which exercise modality is selected should depend on whether the investigators envisage the study findings directly informing clinical translation or plausibility/mechanisms of a clinical observation.

An important caveat to consider in all exercise paradigms is the degree of associated negative stress, as evidenced by exercise-induced increases in serum corticosterone and fecal corticosterone metabolites (77, 78), as observed in both voluntary and forced exercise paradigms. Furthermore, voluntary running may result in “addictive behavior” with negative effects on the hypothalamic–pituitary–adrenal (HPA) axis and animal health (79). Human studies have taught us that exercise induces spikes in cortisol at the beginning of exercise and immediately after bout of exercise ceases (80). Stress-induced activation of the HPA axis may accelerate tumor growth (81), and have diverse effects on the immune response (reviewed in ref. 82), thereby confounding the efficacy of exercise on tumor growth characteristics. HPA-mediated changes on the immune response could contribute to discordance between studies with respect to immune function. For example, Zhu and colleagues reported a decrease in TNFα (43) whereas Abdalla and colleagues reported an increase (23).

Although changes in glucocorticoids have been seen using all exercise modes and intensities, such considerations may be especially important when investigating the effects of high-intensity or high-volume exercise treatment doses. This is relevant because, as reviewed here, studies have tested the effects of exhaustive exercise doses (ref. 40; e.g., forced swimming for 4 hours followed by 12 hours of physical activity; ref. 54), or forced swimming of animals loaded with external weights (30, 32, 47). The latter exercise paradigms may have additional safety and ethical concerns. Indeed, one study investigating the effect of forced swimming reported four animal deaths due to drowning (30). Researchers should also be cognizant of the impact of the exercise on the animals' natural circadian rhythms. Fuss and colleagues demonstrated that voluntary wheel running occurs predominantly during the animals' dark cycle (78), therefore it would be prudent to conduct exercise training during the dark cycle. Regardless of exercise prescription, corticosterone analysis would be helpful to include in all study designs; such levels could be correlated with tumor growth endpoints. In this review, three studies analyzed systemic corticosterone levels (42, 48, 51); of these, two studies reported increases in corticosterone levels, whereas the other study reported a decrease. Interestingly, tumor growth was inhibited in all studies.

Exercise at different intensities confers remarkably different physiologic and gene expression adaptations in mammals (83); however, a key question is whether these differences translate into differential effects on tumor outcomes. In clinical trials, the efficacy of different exercise intensities varying from 50% to 100% of a patient-derived physiologic parameter (e.g., age-predicted maximum heart rate, measured exercise capacity) have been investigated. Such an approach permits personalized exercise prescriptions, which is important because exercise abilities (and therefore appropriate exercise intensity) vary considerably in patients with cancer (83). Animal-specific exercise prescriptions are challenging to implement in preclinical studies, but could be important, as findings reviewed here suggest that exercise intensity may differentially modulate tumor endpoints. For example, using a transgenic model of p53^+/− MMTV-Wnt-1, Colbert and colleagues found that exposure to forced treadmill training of different intensities accelerated tumor growth rate compared with sedentary controls, with the highest tumor multiplicity in the lowest intensity group (26). Conversely, Almeida and colleagues reported diminishing returns in the context of increasing exercise intensity using two different swimming intensities (50% or 80% of maximal workload; CT₅₀ and CT₈₀, respectively, defined using a maximum load test conducted one week prior to exercise initiation; ref. 47). CT₅₀ caused significant tumor growth inhibition, whereas CT₈₀ was ineffective. Using a model of forced treadmill running, Woods and colleagues compared the effects of “moderate” versus “exhaustive” exercise prescriptions, with no differences in mammary tumor growth or overall incidence (40). In contrast, Malicka and colleagues reported a trend towards a negative correlation between exercise intensity [varied by progressively adjusting the speed of the treadmill (low: 0.48–1.34 km/h, moderate: 0.6–1.68 km/h, high: 0.72–2.0 km/h)] and tumor incidence and multiplicity, as well as an increase in tumor cell apoptosis across all exercise prescriptions, compared with controls (45). Kato and colleagues examined duration of prescription of forced treadmill running using a nitrilotriacetate-induced renal carcinoma model. Rats were assigned to exercise exposure for either 12 weeks or 40 weeks (29). Twelve weeks of exercise increased microcarcinoma incidence and multiplicity compared with sedentary controls with no differences (compared with control) in 40 weeks of exercise.

A critical question is whether exercise exposure prior to diagnosis improves disease outcomes compared with inactivity (prior to diagnosis). Similarly, do previously sedentary patients initiating exercise after diagnosis have superior outcomes compared with those having sedentary or decreasing exercise levels after diagnosis? Exploratory findings from epidemiologic studies suggest that timing or initiation of exercise exposure could be important (84). Two studies have empirically investigated this question: Betof and colleagues and Shalamzari and colleagues found that exercise initiated after tumor transplantation (equivalent to postdiagnosis setting) inhibited tumor growth, independent of exposure to exercise prior to transplantation (65, 67). Similarly, Radak and colleagues found slower tumor growth with exercise pre- as well as post-tumor implantation in comparison with no exercise after transplant or sedentary control (61). Such findings stress the importance of maintaining exercise after diagnosis. Finally, whether the effects of exercise are different across the steps in the metastatic cascade [altered adhesion (invasion); intravasation; survival in the circulation; extravasation, and seeding at a distant site (metastatic colonization; ref. 85)] has not been investigated. Addressing this question has significant clinical implications, and further research in this area is warranted.

Several salient methodologic issues across studies were identified (see Table 5). Of these, two common issues that require particular attention regarded selection of appropriate in vivo tumor models, and lack of mechanistic studies.

Preclinical oncology studies have generally focused on subcutaneous tumor implantation models. These models permit monitoring of tumor growth kinetics but do not accurately recapitulate the tissue microenvironment of the ectopic (orthotopic) or distant organ or mimic the natural evolution of cancer. In addition, blood flow to subcutaneous tumors may not reflect that of orthotopic tumors. As the benefits/risks of using subcutaneous models are beyond the scope of this review, here we will simply caution investigators against using subcutaneous tumors. This model is not a perfect surrogate for spontaneously occurring tumors.

The majority of studies reviewed herein investigated the effects of exercise on tumor growth characteristics in the primary organ site. In contrast, studies of metastasis, the primary cause of cancer-related death, has received limited attention to date. In addition, 73% of the metastasis studies we reviewed used an intravenous (tail-vein) injection of tumor cells as a model of metastasis, which evaluates the ability of tumor cells to survive in circulation and to colonize an organ but does not enable investigation of the early steps in the metastatic cascade (86). Indeed, three studies reported on tumor cell retention in the lungs following intravenous injection (71, 72, 74), with two studies reporting a decrease in tumor cell retention in exercising animals, but no change in the final number of metastases. Interestingly, MacNeil and colleagues reported that exercise did not affect tumor cell retention in the lung. These three studies differed with respect to type of exercise and number of tumor cells injected; thus no meaningful comparisons can be made between them. The impact of the methodologic differences can only be evaluated by completing the studies-side-by-side, comparing all combinations of exercise/tumor inoculation models.

An alternative, and arguably more appropriate model of metastasis, is surgical excision of the primary tumor, which stimulates spontaneous metastasis, predominantly to the lungs; only one study to date (Yan and colleagues) has adopted this model to examine exercise effects (64) and they reported a trend towards an inverse relationship between distance run and metastatic burden. Conversely, Jones and colleagues examined the metastasis response in a prostate cancer model by quantifying the mass of “non-contiguous external masses that were grossly visible independent from the primary prostate tissue.” In this model, exercise was not associated with a significant reduction in the number or weight of metastases (55).

Emerging technology has provided researchers with a considerable number of in vivo models beyond cell line xenografts, such as patient-derived xenografts (PDX), syngeneic allografts, and GEMMs (87), as well as nonrodent models (e.g., zebrafish, Drosophila). The advantages and disadvantages of each model have been reviewed elsewhere (88–91). Ultimately, no one in vivo model will be appropriate to address all exercise–oncology questions, with model selection being contingent on the scientific question at hand as well as translational importance.

Consideration of the nature of control (nonexercising) groups should not be overlooked. To the extent possible, control animals should be exposed to the same variables as exercise counterparts including aspects related to housing, transportation to different facilities, or procedures to reinforce exercise behavior (i.e., prodding, shock). Taken even further, animals could be housed in cages with locked wheels, placed on stationary treadmills, or made to stand in very shallow pools of water, depending upon the exercise regimens used. We stress that exposing control and experimental mice to different housing or environmental conditions is a study weakness. For example, one study housed control animals in unusually small cages (5 inches in diameter and 6 inches high) to restrict activity (54), whereas exercise treatment animals were not confined. The differences in housing size and daily movement could have either induced a stress response or altered the animals' resting metabolism, thereby affecting tumor growth. We advise researchers reviewing extant publications for planning of their own exercise oncology studies to consider whether controls were properly handled before modeling their own work off of previous studies.

The majority of studies reviewed here examined the effects of exercise on tumor growth characteristics as evaluated by tumor volume or growth rates. While such endpoints are clearly important, subtle but important modulations of intratumoral physiologic or biological alterations can be masked. For instance, our group observed differences in perfusion and expression of key factors regulating metabolism and hypoxia, despite comparable primary tumor growth rates between exercised and sedentary animals (57). Elegant studies by McCollough and colleagues demonstrated that exercise improved blood flow and oxygen delivery to orthotopic prostate tumors in rats, but not to the normal prostate tissue in either tumor-bearing or control rats (92). These changes were reflected by decreased hypoxia within the tumor during exercise. While in-depth explications of the systemic or local molecular mechanisms underpinning the exercise–tumor prevention/progression relationship remains in its infancy, studies such as this one may set the precedent for future mechanistic studies in this field (Fig. 2). The current working hypothesis is that exercise modulates tumor progression via modulation of the host–tumor interaction (19). Tumor progression is regulated by complex, multifaceted interactions between the systemic milieu (host), tumor microenvironment, and cancer cells (93). The microenvironments of primary and metastatic tumors are subject to modulation by systemic and local growth/angiogenic factors, cytokines, hormones, and resident cells (94, 95). Factors such as hepatocyte growth factor (HGF), TNF, IL6, insulin, and leptin (96–98) have already been associated with higher risk of recurrence and cancer-specific mortality in a number of solid malignancies.(99) Clearly, manipulation of such factors by physical activity could alter aspects of the cancer continuum (100).

As reviewed here, multiple systemic factors are perturbed by exercise, including metabolism, inflammatory–immune, and reactive oxygen species–mediated pathways (101). The breadth of these factors likely contributes to the pleiotropic benefits of exercise in health and disease (102, 103) and likely the potential antitumor effects of exercise. (19) Notably, most cancer studies investigate single pathways in isolation, without consideration of overlap/synergism between pathways. Because the host–tumor interaction is modulated by numerous host-related factors and multiple pathways (100), an ideal study approach would be to investigate exercise effects on multiple pathways simultaneously (Fig. 2). This would fill in the missing gaps of the “multitargeted” effects of exercise. A recent analysis of preclinical exercise oncology studies by Pedersen and colleagues reported that only 30.7% evaluated systemic changes in animals (104). In addition, intratumoral signaling, and changes in tumor vascularity were examined by only 29.5% and 6.8%, respectively (104).

With a view towards future studies, we encourage the exercise–oncology field to consider certain guidelines for preclinical exercise–oncology research (see Table 5). However, we realize that it is impractical for all exercise–oncology experiments to standardize all study procedures. Nevertheless, it may behoove the field to develop a means of quantifying the exercise prescription applied, which will then permit comparisons between studies. Such an approach is readily used in the fields of radiation oncology [i.e., the biologically equivalent dose (BED), which allows comparison of different dose/fractionation schemes (105)] and hyperthermia [i.e., the cumulative equivalent minutes at 43°C (CEM43), which standardizes the thermal killing effect of hyperthermia, regardless of variations in heating efficiencies between tumors (106)]. Establishing a biological equivalent exercise dose (BEED) would facilitate comparisons across studies as well as provide an opportunity to test elements of prescriptions such as different schedules, timing, and duration.

Exercise investigations should also strive to adopt the experimental procedures and models being utilized in the general tumor biology literature. Indeed, it appears that more recent studies reviewed here have started to utilize clinically relevant tumor models, favoring transgenic mice and orthotopic tumors over carcinogen induction. The general cancer field is also starting to favor the use of patient-derived xenograft (PDX) models. PDX have certain weaknesses, including increased heterogeneity, and a requirement for immunocompromised mice, but could represent an important step towards personalized medicine. Furthermore, PDXs do not accrue additional mutations through in vitro culture and tend to be slower growing than murine-derived tumor lines. Delayed growth curves may highlight slight changes in tumor growth following manipulations of exercise dose. GEMMs should also be considered, especially in mechanistic studies. A second trend in cancer biology is use of biomarkers. The discovery of blood, imaging, and/or genomic biomarker(s) to predict or monitor exercise response is of obvious importance.

Finally, researchers must be cognizant of clinical care, and design studies that reflect the clinical scenario. For example, the vast majority of the current literature investigates the effects of exercise as monotherapy. The majority of clinical scenarios would be applying exercise as an adjuvant therapy to surgery, radiation, chemotherapy, or immunotherapies. As such, it is important for the next generation of preclinical studies aiming to study tumor progression to evaluate the interaction between exercise and the pharmacodynamic or pharmacokinetic activity of conventional and novel therapies to guide the design and interpretation of clinical studies. We advise researchers to proceed with caution and carefully include all possible controls groups, because the additional therapies could introduce new confounding factors that complicate data interpretations Conversely, studies on tumor incidence may be strengthened by eliminating additional factors such as concomitant manipulation of dietary composition.

A sound foundation of basic and translational studies will optimize the therapeutic potential of exercise on symptom control and clinical outcomes across the cancer continuum. Despite its importance, we found that the current evidence base is plagued by considerable methodologic heterogeneity in all aspects of study design, endpoints, and efficacy thereby precluding meaningful comparisons, and conclusions. To this end, we have provided an overview of methodologic and data reporting standards that we hope will set the platform for the next generation of preclinical studies required for the continued development and progression of exercise–oncology research.

No potential conflicts of interest were disclosed.

L.W. Jones is supported in part by grants from the National Cancer Institute, AKTIV Against Cancer, and the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). K.A. Ashcraft and M.W. Dewhirst are supported by NIH CA40355.